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Important Note: The following information
is provided for your education. It should not be relied upon for
personal diagnosis or treatment. If you believe that a
particular therapy applies to you or someone you care about, be
sure to consult a doctor before trying it.
Lupus
Research: 2002-2006
Expert Opin Biol Ther. 2006 Sep;6(9):943-9.
Epratuzumab (humanised anti-CD22 antibody) in autoimmune
diseases.
Steinfeld SD, Youinou P.
Erasme University Hospital, Department of Rheumatology, Route de Lennik 808,
Brussels 1070, Belgium. ssteinfe@ulb.ac.be
B cells play an important role in the pathogenesis of many autoimmune diseases.
Different approaches targeting the B cell compartment are under investigation.
Selective modulation of B cells has been recently achieved using a humanised
monoclonal antibody against the B cell surface marker CD22. This antibody (epratuzumab)
was originally developed for the treatment of non-Hodgkin's lymphoma and was
found to be effective, with a very good safety profile. Recent studies have
demonstrated the efficacy and safety of epratuzumab in several autoimmune
diseases, including systemic lupus erythematosus and primary Sjogren's syndrome.
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Curr Opin Rheumatol. 2006 Sep;18(5):468-75.
Pathogenesis and treatment of systemic lupus erythematosus
nephritis.
Davidson A, Aranow C.
aDepartments of Medicine, Columbia University Medical Center, USA bDepartments
of Microbiology, Columbia University Medical Center, New York, New York, USA.
PURPOSE OF REVIEW: Glomerulonephritis is a challenging complication of systemic
lupus erythematosus that still results in kidney loss in up to 30% of patients.
In this review we highlight the development of integrated efforts to link
pathogenesis with disease definition and new therapeutics. RECENT FINDINGS:
Immune complex deposition in the kidney initiates an inflammatory cascade that
causes glomerular disease but there are many modulating factors including
genetic predisposition, products of the innate immune system, cytokines,
complement and activated cells (both renal and immune). Animal models can help
dissect potential disease mechanisms but the study of multiple models will be
required since there are multiple subsets of human disease. Recent therapeutic
studies in humans address the distinction between therapies for remission
induction and remission maintenance. Multiple studies confirm the therapeutic
equivalence of mycophenolate mofetil and cyclophosphamide in induction of
remission but results are still far from ideal. The next few years should see
the testing of new biologic reagents in humans. Another area of interest is the
search for noninvasive measures of disease and disease response. SUMMARY:
Although there has been remarkable progress in our understanding of the
immunology and phenotype of lupus nephritis current therapies have insufficient
efficacy. As new therapies emerge, improved clinical design coupled with
mechanistic studies will be needed to identify agents that may be effective only
in some patient subpopulations.
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Arthritis Rheum. 2006 Aug 31;54(9):2970-2982 [Epub ahead of print]
Long-term comparison of rituximab treatment for refractory
systemic lupus erythematosus and vasculitis: Remission, relapse, and
re-treatment.
Smith KG, Jones RB, Burns SM, Jayne DR.
University of Cambridge School of Clinical Medicine, and Addenbrooke's Hospital,
Cambridge, UK.
OBJECTIVE: Current treatments for systemic lupus erythematosus (SLE) and
vasculitis contribute to mortality and incapacity and are only partially
effective; thus, newer therapies are clearly needed. Depletion of B cells has
led to disease control in patients with autoimmune disorders. We sought to
assess the long-term efficacy and safety of a B cell-depleting therapy in
patients with SLE and patients with vasculitis. METHODS: In a prospective study
with a median followup of 24 months, 11 patients with active or refractory SLE
and 11 patients with active or refractory antineutrophil cytoplasmic
antibody-associated vasculitis (AAV) received a course of therapy with rituximab
(an anti-CD20 monoclonal antibody) along with a single dose of intravenous
cyclophosphamide. RESULTS: Remission followed rapid B cell depletion, with
response rates of 100% among the 11 patients with SLE (6 patients had a complete
response, and 5 patients had a partial response) and 91% among the 11 patients
with AAV (9 patients had a complete response, and 1 patient had partial
remission). A renal response occurred in all 6 patients with lupus nephritis.
Clinical improvement was accompanied by significant reductions in the daily dose
of prednisolone. Relapse occurred in 64% of the patients with SLE and in 60% of
those with AAV. B cell return preceded relapse in the majority of patients, and
further treatment with rituximab proved effective. IgG and IgM levels were
maintained in the normal range. The incidence of infective complications was
low; however, infusion reactions were common, and human antichimeric antibodies
developed in 5 of 14 patients. CONCLUSION: B cell depletion offers the prospect
of sustained disease remission and improved disease control combined with low
toxicity in patients with active or refractory SLE or AAV. Relapse following
treatment is common, but re-treatment is rapidly effective.
-----
Kidney Int. 2006 Aug 23; [Epub ahead of print]
Update on the treatment of lupus nephritis.
Waldman M, Appel GB.
1Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney
Disease, Bethesda, Maryland, USA.
Lupus nephritis (LN) is a major cause of morbidity and mortality in patients
with systemic lupus erythematosus. Although the use of aggressive
immunosuppression has improved both patient and renal survival over the past
several decades, the optimal treatment of LN remains challenging. Improved
outcomes have come at the expense of significant adverse effects owing to
therapy. Moreover with long-term survival, the chronic adverse effects of
effective therapies including risk of malignancy, atherosclerosis, infertility,
and bone disease all become more important. Finally, some patients fail to
achieve remission with standard cytotoxic therapy and others relapse when
therapy is reduced. For these reasons, recent clinical trials have attempted to
define alternate treatment protocols that appear to be efficacious in achieving
and maintaining remission, but with less toxicity than standard regimens. This
paper discusses established and newer treatment options for patients with
proliferative and membranous LN, with an emphasis on the results of these recent
clinical trials. We also review the experimental and human data regarding some
of the novel targeted forms of therapy that are under investigation and in
different phases of clinical trials.Kidney International advance online
publication, 23 August 2006; doi:10.1038/sj.ki.5001777.
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Kidney Int. 2006 Aug;70(4):732-42. Epub 2006 Jul 5.
Azathioprine/methylprednisolone versus cyclophosphamide in
proliferative lupus nephritis. A randomized controlled trial.
Grootscholten C, Ligtenberg G, Hagen EC, van den Wall Bake AW, de Glas-Vos JW,
Bijl M, Assmann KJ, Bruijn JA, Weening JJ, van Houwelingen HC, Derksen RH,
Berden JH; Dutch Working Party on Systemic Lupus Erythematosus.
Division of Nephrology, Radboud University Nijmegen Medical Center, Nijmegen,
The Netherlands. m.grootscholten@aig.umcn.nl
Until recently, intravenous cyclophosphamide pulses with oral corticosteroids
were regarded standard therapy for proliferative lupus nephritis (LN).
Azathioprine, a less toxic alternative, was never proven to be inferior. In the
first Dutch lupus nephritis study (enrollment between 1995 and 2001), we
randomized 87 proliferative LN patients to either cyclophosphamide pulses (750
mg/m(2), 13 pulses in 2 years) combined with oral prednisone (CY) or to
azathioprine (2 mg/kg/day in 2 years) combined with intravenous pulses of
methylprednisolone (3 x 3 pulses of 1000 mg) and oral prednisone (AZA). After a
median follow-up of 5.7 years (interquartile range 4.1-7.2 years), doubling of
serum creatinine was more frequent in the AZA group, although not statistically
significant (relative risk (RR): 4.1, with 95% confidence interval (95% CI):
0.8-20.4). Relapses occurred more often in the AZA group (RR: 8.8, 95% CI:
1.5-31.8). Creatinine and proteinuria at last visit did not differ between the
two treatment arms. Moreover, 88.4% of the patients in the AZA arm were still
free of cyclophosphamide treatment. During the first 2 years, the frequency of
remission was not different, but infections, especially herpes zoster virus
infections (HZV) were more frequent in the AZA group. Parameters for ovarian
function did not differ between the two groups. In conclusion, in this
open-label randomized controlled trial, cyclophosphamide was superior to
azathioprine with regard to renal relapses and HZV. At last follow-up, there
were no differences in serum creatinine or proteinuria between the two groups.
However, since our study lacked sufficient power, longer follow-up is needed to
reveal putative differences.
-----
Presse Med. 2006 Jul-Aug;35(7-8):1138-42.
[Treatment of chronic lupus erythematosus with sulfasalazine in
18 patients: reappraisal]
[Article in French]
Duparc A, Staumont-Salle D, Broly F, Piette F, Delaporte E.
Clinique dermatologique, Hopital Claude-Huriez, Cedex, France.
OBJECTIVE: To evaluate the efficacy and the tolerance of sulfasalazine in the
treatment of chronic lupus erythematosus (CLE). PATIENTS AND METHODS: We
prescribed sulfasalazine (2 g/d) for 18 patients with severe CLE, all of whom
had contraindications for or treatment failure with antimalarial drugs and
thalidomide. This study analyses their response to treatment, duration of
therapy, reasons for stopping, adverse effects, and the influence of the N-acetyltransferase
2 (NAT2) phenotype. RESULTS: We observed 10 complete and 3 partial responses,
and 4 patients maintained complete response for at least 7 years. Eight patients
experienced adverse effects, and 2 needed to stop treatment (because of
photosensitization and development of antinuclear antibodies). All side effects
occurred in the first 3 months of treatment. None of the 18 patients developed
systemic lupus erythematosus. Of the 10 complete responders, 9 were rapid
acetylators (RA), while 4 of the 5 who failed to respond were slow acetylators
(SA). Leukopenia and photosensitization were observed in SA patients, while
different side effects occurred in RA patients (headaches, diarrhea, moderate
increase in liver enzymes and antinuclear antibodies). CONCLUSION: These
findings confirm our earlier reports and demonstrate that sulfasalazine can be
used successfully to treat severe CLE. NAT2 genotyping before initiating
treatment helps to identify potential responders and avoid side effects. In RA
patients, sulfasalazine can be an alternative to thalidomide after antimalarial
drugs, whereas in SA patients, it should remain a third-line treatment, to be
used only after antimalarials and thalidomide.
-----
Harefuah. 2006 Jul;145(7):489-92, 551.
[Thalidomide therapy for discoid lupus erythematosus]
[Article in Hebrew]
Lyakhovisky A, Baum S, Shpiro D, Salomon M, Trau H.
Dermatology Department, Sheba Medical Center, Tel Hashomer, Israel. annaly@bezeqint.net
INTRODUCTION: Discoid lupus erythematosus (DLE) is a chronic form of cutaneous
lupus. Thalidomide has been reported as an effective treatment in at least 200
cases of severe DLE. In this article we studied the efficacy and adverse effects
of thalidomide in 10 patients with disseminated DLE. METHODS: This report
presents the retrospective evaluation of 10 patients treated with thalidomide in
our department during the period 1996-2005. RESULTS: All patients treated with
thalidomide had been unresponsive to at least two other systemic treatments. The
patients were treated with low-dose thalidomide of 50-200 mg per day. The dose
was tapered after a clinical remission. All patients had a favorable response
within 6 weeks. Of 10 patients 9 had complete regression of lesions. Four
patients remain free of disease without maintenance treatment and 5 patients
relapsed after cessation of thalidomide. All relapses responded after the
reinstitution of the drug. The side effects of thalidomide treatment were mostly
transient. The most common adverse effects were sedation and weight gain. Two
patients developed peripheral sensory neuropathy resolved with discontinuation
of thalidomide. Two patients of premenopausal age reported amenorrhea.
CONCLUSION: Low-dose thalidomide treatment is an effective treatment option for
discoid lupus erythematosus in cases resistant to other treatments. It is
essential to be conversant with all the precautions in order to minimize the
risks of side effects.
-----
Drugs. 2006;66(9):1191-207.
Pharmacotherapy of lupus nephritis in children: a recommended
treatment approach.
Adams A, MacDermott EJ, Lehman TJ.
Division of Pediatric Rheumatology, Hospital for Special Surgery, New York, NY
10021, USA.
Systemic lupus erythematosus (SLE) is a multisystem inflammatory disease of
unknown aetiology, which is characterised by recurrent disease flares that may
affect any organ system. Renal involvement remains one of the chief causes of
morbidity and mortality in children with lupus. Nephritis occurs in
approximately two-thirds of patients, ranging from mild glomerulitis to
life-threatening occurrences of diffuse proliferative glomerulonephritis. As
lupus nephritis is a condition of no single aetiology, there is no single cure.
Corticosteroids, although still the first line of treatment, are increasingly
being superseded by cytotoxic drugs, in particular cyclophosphamide and
corticosteroid-sparing agents. Newer agents such as mycophenolate mofetil,
although effective in the treatment of lupus in adults, are less effective in
children. Standard of care for highly active lupus nephritis in children remains
intravenous cyclophosphamide, although preliminary experience suggests that the
addition of rituximab may allow for remission induction with a reduction in
cumulative cyclophosphamide dose. Combination therapies and newer agents appear
promising for the future as our understanding of the immune system and its
dysregulation in SLE improves. In this review, we discuss the current standards
of care, newer therapies currently in use, and emerging treatments still
undergoing development and investigation. We conclude by discussing our
guidelines for treatment at the present time and suggestions for the
comprehensive care of children with lupus nephritis.
-----
Rheumatology (Oxford). 2006 Jun 15; [Epub ahead of print]
Adult stem cells in the treatment of autoimmune diseases.
Van Laar JM, Tyndall A.
Department of Rheumatology, Leiden University Medical Center, The Netherlands.
During the past 10 yrs, over 700 patients suffering from severe autoimmune
disease (AD) have received an autologous haematopoietic stem cell transplant as
treatment of their disorder with durable remission being obtained in around
one-third. The most commonly transplanted ADs have been systemic sclerosis
(scleroderma), multiple sclerosis, rheumatoid arthritis, juvenile idiopathic
arthritis and systemic lupus erythematosus. A fewer number of patients have
received an allogeneic transplant. The initially reported overall
treatment-related mortality of 7% has since fallen, with no further cases being
reported in systemic sclerosis or multiple sclerosis in the past 3 yrs. This is
thought to be due to more careful patient selection.The phase I/II data has led
to currently running prospective randomised trials in systemic sclerosis,
multiple sclerosis and systemic lupus erythematosus in Europe and North America.
Immune reconstitution data suggests a 'resetting' of autoimmunity in those
patients achieving stable remission, rather than simply prolonged
immunosuppression. Recent results from in vitro experiments, animal models and
early human experience in severe acute graft vs host disease suggest that
multipotent mesenchymal stromal cells obtained from the bone marrow and expanded
ex vivo, may exert a clinically useful immunomodulatory effect. Such cells are
immune privileged and apparently of low toxicity. Further characterization of
these cells and consideration of their possible clinical application in AD is
underway.
-----
Am J Med. 2006 Apr;119(4):355.e25-33.
Long-term outcome of diffuse proliferative lupus
glomerulonephritis treated with cyclophosphamide.
Mok CC, Ying KY, Ng WL, Lee KW, To CH, Lau CS, Wong RW, Au TC.
Department of Medicine, Tuen Mun Hospital, New Territories, Hong Kong, China.
ccmok2005@yahoo.com
PURPOSE: To report the long-term outcome of diffuse proliferative lupus
nephritis (DPLN) treated with cyclophosphamide (CYC) in Chinese patients.
METHODS: Patients with biopsy-proven DPLN treated with prednisolone and CYC were
identified. The long-term renal outcome and treatment-related toxicities were
reported. RESULTS: A total of 212 patients were studied (89% women; mean age
30.9 +/- 10.9 years; mean system lupus erythematosus [SLE] duration 36.7 +/-
55.1 months). At renal biopsy, 148 (70%) patients were nephrotic, and 78 (37%)
had impaired serum creatinine. One hundred and three (49%) patients received
daily oral CYC, whereas 109 (51%) received intravenous bolus CYC. At last dose
of CYC, 126 (59%) patients responded completely, and 56 (26%) responded
partially. In a logistic regression model, the cumulative CYC dose and
histologic chronicity score predicted complete response. One hundred fifty-five
(73%) patients received maintenance immunosuppression for at least 3 years (88%
azathioprine). After a follow-up of 1873 patient-years, 66 patients experienced
renal flares, 30 had doubling of serum creatinine, 18 developed end-stage renal
failure, and 14 died. The renal survival rates were 88.7%, 82.8% and 70.7% at 5,
10 and 15 years, respectively. Failure to respond completely to CYC and the
absence of maintenance immunosuppression were independent predictors of a poor
renal outcome. Ovarian toxicity was more frequent with the oral CYC regimen.
Increasing age and higher cumulative doses of CYC were independent risk factors.
CONCLUSIONS: In Chinese patients with DPLN, the cumulative dose, rather than the
route of CYC administration, determines the initial treatment response and
ovarian toxicity. Maintenance immunosuppression is associated with a better
long-term prognosis. The oral CYC regimen is more toxic and should be reserved
for high-risk patients.
-----
Hautarzt. 2006 Apr;57(4):345-360.
[Cutaneous lupus erythematosus : Part 2: Diagnostics and
therapy.]
[Article in German]
Kuhn A, Gensch K, Stander S, Bonsmann G.
Hautklinik, Heinrich-Heine-Universitat Dusseldorf, Moorenstrasse 5, 40225 ,
Dusseldorf, kuhnan@uni-duesseldorf.de.
The diagnosis of cutaneous lupus erythematosus (CLE) requires a specific
diagnostic approach to identify subtypes, to address differential diagnostic
considerations, and to rule out systemic organ involvement. In addition to a
detailed patient's history and clinical evaluation of the skin, histopathologic
and immunofluorescent examination of a skin biopsy as well as laboratory
screening are recommended. Photoprovocation tests can be performed to confirm
the diagnosis of CLE and to assess photosensitivity in these patients. Recently,
a scoring system for the activity of the cutaneous manifestations in CLE has
been developed and validated which involves anatomical areas and morphologic
signs of the skin lesions. In all subtypes of CLE, antimalarials are still the
treatment of choice. Advances in biotechnology have led to the development of
several novel agents for the treatment of autoimmune diseases; however,
controlled trials have not been performed in patients with CLE. Furthermore,
there is need for specific immunointervention, especially for patients who fail
to respond to standard therapies. The second part of this review will enable the
reader to differentiate CLE from other diseases and to suggest specific
diagnostic procedures and treatment approaches.
-----
Semin Nephrol. 2006 Mar;26(2):95-104.
Lupus nephritis.
Agrawal N, Chiang LK, Rifkin IR.
Department of Medicine, Boston University School of Medicine, Boston, MA 02118,
USA.
Lupus nephritis is one of the more serious manifestations of the systemic
autoimmune disease, systemic lupus erythematosus, and is associated with
considerable morbidity and even mortality. Treatment remains problematic,
particularly in terms of controlling the underlying disease process while at the
same time preventing unacceptable side effects of therapy. In recent years,
clinical trials have started to define optimum regimens of the immunosuppressive
agents presently in use. The etiology and pathogenesis of systemic lupus
erythematosus and lupus nephritis still are understood incompletely.
Nevertheless, insights gained from basic science research in both animals and
human beings now are being translated into newer therapies that have the
potential to be safer and more specific than those currently available.
-----
J Am Acad Dermatol. 2006 Mar;54(3):479-86.
UV hardening therapy: a novel intervention in patients with
photosensitive cutaneous lupus erythematosus.
Sanders CJ, Lam HY, Bruijnzeel-Koomen CA, Sigurdsson V, van Weelden H.
Department of Dermatology/Allergology, University Medical Centre, Utrecht, The
Netherlands. c.sanders@umcutrecht.nl
BACKGROUND: Patients with cutaneous lupus erythematosus (LE) and a history of
disease- related photoaggravation, confirmed by phototesting, may not respond to
photoprotection and/or medical intervention. Ultraviolet B-hardening therapy may
improve tolerance for environmental ultraviolet radiation (UVR) in
photosensitive disorders. OBJECTIVE: We studied the effect of UVB hardening on
the cutaneous manifestations of patients with LE and their tolerance for UVR.
PATIENTS AND METHODS: A retrospective study of continuous, home-based, UVB-hardening
therapy in 44 patients with cutaneous LE (systemic LE: 9 patients; chronic LE:
21 patients; subacute cutaneous LE: 10 patients; cutaneous LE not specified: 4
patients) who had confirmed photosensitivity. Exposure to the UVB source was
performed year-round, 3 times weekly, with increasing doses to a maximum of 10
minutes per session. Tolerance for environmental UVR was established through
questionnaires, phototesting, and assessment of disease activity by physician
and patient. RESULTS: Of 44 patients, 35 were able to gradually increase their
monthly UVB doses. Nine patients dropped out because of insufficient efficacy or
skin irritation, or were unable to adhere to the hardening regimen. Of the 35
patients who succeeded in hardening their skin with UVB, 28 patients reported an
improved tolerance for environmental UVR. This outcome was confirmed by repeat
phototesting in a subgroup. In only 5 patients, an improvement of cutaneous LE
symptoms was noted by either physician or patient. No serious adverse events
were encountered. LIMITATIONS: This was a retrospective study and no control
group was used. CONCLUSION: This is the first report that describes UVB
hardening as a potential therapy in patients with cutaneous LE and confirmed
photosensitivity. This intervention may lead to improved tolerance for
environmental UVR and, in a minority of patients, even to decreased cutaneous
activity of LE.
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Nephrol Dial Transplant. 2006 Feb 2; [Epub ahead of print]
Withdrawal of therapy in patients with proliferative lupus
nephritis: long-term follow-up.
Moroni G, Gallelli B, Quaglini S, Banfi G, Rivolta E, Messa P, Ponticelli C.
Divisione di Nefrologia, Ospedale Maggiore IRCCS, Milan, Italy.
BACKGROUND: Whether corticosteroid and immunosuppressive therapy may be safely
withdrawn in patients with proliferative lupus nephritis is still unclear.
METHODS: In 32 patients with biopsy-proven proliferative lupus nephritis
previously put into remission, therapy was gradually tapered off. RESULTS: When
immunosuppressive therapy was stopped (median: 38 months; 25th-75th percentile:
24-81 months, after biopsy), 24 patients were in complete remission and eight
had a median proteinuria of 1.05 g/24 h (25th-75th percentile: 0.91-1.1 g/24 h)
with normal renal function. After stopping therapy, patients were followed for a
median of 203 months (25th-75th percentile: 116-230 months). Fifteen patients
(Group 1) never developed lupus activity. The other 17 patients (Group 2)
developed lupus exacerbations in a median of 34 months (25th-75th percentile:
29-52 months) after stopping therapy and were re-treated. The only significant
differences between the two groups were the longer median durations of
treatment, 57 months (25th-75th percentile: 41.5-113.5 months) vs 30 months
(25th-75th percentile: 18-41 months; P<0.009), and remission, 24 months
(25th-75th percentile: 18-41) vs 12 months (25th-75th percentile: 7-20 months;
P<0.02), before stopping therapy in Group 1 than in Group 2. At last follow-up,
12 patients of Group 1 were in complete remission, two had mild proteinuria and
one had died. In Group 2, one patient died, 14 were in complete remission, one
had mild proteinuria and in another patient serum creatinine doubled.
CONCLUSIONS: Some patients with severe lupus nephritis who enter stable
remission can be maintained without any specific treatment for many years. Those
patients who have new flares can again go into remission with an appropriate
treatment. The longer the treatment and remission before withdrawal, the lower
the risk of relapse.
-----
Rheum Dis Clin North Am. 2006 Feb;32(1):149-56, x.
Abetimus sodium (riquent) for the prevention of nephritic flares
in patients with systemic lupus erythematosus.
Furie R.
New York University School of Medicine, New York, NY, USA. furie@nshs.edu
Abetimus sodium has been under development for the treatment of systemic lupus
erythematosus since the early 1990s. Because its administration results in the
selective reduction of circulating double-stranded DNA antibodies, La Jolla
Pharmaceutical Company has focused on the agent's ability to prolong time to
nephritic flare. Fourteen trials have been initiated since 1994, but the two
pivotal registration trials failed to meet primary end points. The US Food and
Drug Administration issued a letter in October 2004 that stated abetimus sodium
was "approvable" pending the successful completion of a trial demonstrating
clinical benefit. The fate of this agent lies in the ability of the company to
successfully complete a phase III study.
-----
Australas J Dermatol. 2006 Feb;47(1):13-27.
Cutaneous lupus erythematosus: A personal approach to management.
Callen JP.
Division of Dermatology, University of Louisville, Louisville, Kentucky, USA.
SUMMARY Skin disease in patients with lupus erythematosus may be subdivided into
two broad categories - those lesions that when biopsied demonstrate interface
dermatitis and those that do not demonstrate interface dermatitis. The skin
lesions that are represented by the interface dermatitis include discoid lupus
erythematosus, subacute cutaneous lupus erythematosus and acute cutaneous lupus
erythematosus. Patients with these 'specific' manifestations have varying
degrees of systemic involvement from rare systemic disease in patients with
localized discoid lupus erythematosus to common and often severe involvement in
patients with acute cutaneous lupus erythematosus. Patients who do not
demonstrate interface dermatitis also may have systemic disease and in some
instances the skin manifestations are linked to some of the more severe systemic
manifestations. Many patients with cutaneous lesions characterized by the
interface dermatitis can be controlled with 'standard' therapies including
sunscreens, protective clothing and behavioural alteration, and topical
corticosteroids with or without an oral antimalarial agent. This review presents
a brief summary of each common cutaneous manifestation of lupus erythematosus,
its relationship to systemic involvement and treatment issues to effectively
deal with the lupus erythematosus patient who has skin disease.
-----
Indian J Dermatol Venereol Leprol. 2005 Jan-Feb;71(1):9-13.
Dexamethasone-cyclophosphamide pulse therapy in systemic lupus
erythematosus.
Dhabhai R, Kalla G, Singhi MK, Ghiya BC, Kachhawa D.
Departments of Skin and V. D., Dr. S. N. Medical College, Jodhpur, Rajasthan,
India. mks_2_in@yahoo.com.
BACKGROUND AND AIMS: Therapy systemic lupus erythematosus (SLE) has been
generally discouraging. Methyl-prednisolone pulse therapy has been used for
various connective tissue disorders. We used intravenous dexamethasone
cyclophosphamide pulse therapy to treat SLE. METHODS: Fourteen patients (10
females and 4 males) between the age of 15-48 years with definite or classical
clinical criteria laid by American Rheumatism Association criteria were treated
by Dexamethasone-Cyclophosphamide pulse (DCP) therapy at our center. RESULTS: It
was possible to induce a complete clinical remission with DCP therapy in most of
the patients thereby offering them life free from disease and drugs. The side
effects commonly observed with conventional daily dose regimen of
corticosteroids were not present or were mild. CONCLUSIONS: Almost all patients
had good response after 3-4 pulses to allow them a normal life style. Fever,
malar rash and oral ulceration responded early but photosensitivity, discoid
rash, alopecia and joint pains took some more time.
-----
J Rheumatol. 2006 Jan;33(1):57-60.
Flares in lupus: Outcome Assessment Trial (FLOAT), a comparison
between oral methylprednisolone and intramuscular triamcinolone.
Danowski A, Magder L, Petri M.
Division of Rheumatology, Department of Medicine, Johns Hopkins University
School of Medicine, MD 21205, USA.
OBJECTIVE: Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune
disease characterized by a relapsing-remitting course. When a mild/moderate
flare occurs, treatment with corticosteroids is often instituted. There are 2
methods of acutely giving a boost of steroids: triamcinolone injection or a
short-term boost of oral prednisone or methylprednisolone. We investigated
whether triamcinolone is superior to oral corticosteroids for mild/moderate
flare in patients with lupus. METHODS: In a clinical trial, 50 patients with SLE
presenting with a mild or moderate flare [defined using the Safety of Estrogens
in Lupus Erythematosus: National Assessment-SLE Disease Activity Index (SELENA-SLEDAI)
flare instrument] were randomized to receive oral methylprednisolone with rapid
tapering (medrol dose-pack) or triamcinolone 100 mg, given intramuscularly. The
patients completed a Likert scale of activity and the Medical Outcomes Study
Short Form-36 health status questionnaire on the randomization day, and repeated
them the next day, 2 days, one week, 2 weeks, 3 weeks, and one month later.
RESULTS: Complete improvement occurred in 0% at one day, 0% at 2 days, 8.3% at
one week, 20.8% at 2 weeks, 20.8% at 3 weeks, and 25% at 4 weeks in the
methylprednisolone group versus 4.3% at one day, 4.3% at 2 days, 8.6% at one
week, 12.5% at 2 weeks, 30.4% at 3 weeks, and 34.7% at 4 weeks in the
triamcinolone group. Improvement in health status by Week 4 occurred in 66.6% of
the patients in the methylprednisolone group versus 73.9% in the triamcinolone
group. CONCLUSION: The triamcinolone and oral methylprednisolone groups did
equally well. Triamcinolone may lead to a more rapid response than the oral
methylprednisolone (69.5% vs 41.6% with some improvement at day one).
-----
Clin Rev Allergy Immunol. 2005 Dec;29(3):219-28.
Intravenous immunoglobulin therapy and systemic lupus
erythematosus.
Zandman-Goddard G, Levy Y, Shoenfeld Y.
Center for Autoimmune Diseases and Department of Medicine B; Lupus Clinic, Sheba
Medical Center, Tel Aviv, Israel.
Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease with
diverse manifestations. We suggest that intravenous immunoglobulin (IVIg)
therapy may be beneficial and safe for various manifestations in SLE. A
structured literature search of articles published on the efficacy of IVIg in
the treatment of SLE between 1983 and 2005 was conducted. We searched the terms
"IVIg," "intravenous immunoglobulin," "lupus," "SLE," and "systemic lupus
erythematosus." The various clinical manifestations of SLE that were reported to
be successfully treated by IVIg in case reports include autoimmune hemolytic
anemia, acquired factor VIII inhibitors, acquired von Willebrand disease, pure
red cell aplasia, thrombocytopenia, pancytopenia, myelofibrosis, pneumonitis,
pleural effusion, pericarditis, myocarditis, cardiogenic shock, nephritis,
end-stage renal disease, encephalitis, neuropsychiatric lupus, psychosis,
peripheral neuropathy, polyradiculoneuropathy, and vasculitis. The most
extensive experience is with lupus nephritis. There are only a few case series
of IVIg use in patients with SLE with various manifestations, in which the
response rate to IVIg therapy ranged from 33 to 100%. We suggest that IVIg
devoid of sucrose, at a dose of 2 g/kg over a 5-d period given uniformly and at
a slow infusion rate in patients without an increased risk for thromboembolic
events or renal failure, is a safe and beneficial adjunct therapy for cases of
SLE that are resistant to or refuse conventional treatment. The duration of
therapy is yet to be established. Controlled trials are warranted.
-----
Arthritis Rheum. 2005 Dec 15;53(6):838-44.
Effects of supervised cardiovascular training program on exercise
tolerance, aerobic capacity, and quality of life in patients with systemic lupus
erythematosus.
Carvalho MR, Sato EI, Tebexreni AS, Heidecher RT, Schenkman S, Neto TL.
Universidade Federal de Sao Paulo, Sao Paulo, Brazil.
OBJECTIVE: To determine if supervised cardiovascular training improves exercise
tolerance, aerobic capacity, depression, functional capacity, and quality of
life in patients with systemic lupus erythematosus (SLE). METHODS: Sixty women
with SLE (ages 18-55 years) were evaluated using Short Form 36, visual analog
scale for pain, scale for fatigue, Beck Depression Inventory, and Health
Assessment Questionnaire (HAQ), and participated in a training protocol of
incremental load on a treadmill with computed gas metabolic analysis. Maximum
oxygen consumption (VO(2max)) and anaerobic threshold VO(2) were calculated with
a SensorMedics Vmax29C analyzer (Sensor Medics, Yorba Linda, CA), and heart rate
was measured by electrocardiogram. Patients were divided into 2 groups: a
training group (41 patients) that participated in the supervised cardiovascular
training program and a control group (19 patients) that did not participate in
the program. All variables were analyzed at baseline and after 12 weeks for both
groups. The training program occurred in the morning for 60 minutes, 3 times a
week for 12 weeks. Statistical analysis included Wilcoxon's rank sum test,
Mann-Whitney U test, chi-square test, and Fisher's exact test. P values <0.05
were considered to be statistically significant. RESULTS: The 2 groups were
homogeneous and comparable at baseline. The training group showed a significant
improvement of aerobic capacity measured by anaerobic threshold VO(2) (14.67 +/-
3.03 versus 17.08 +/- 3.35 ml/kg/minute, P < 0.001). Comparison of the training
group and control group after 12 weeks showed a significant difference relating
to VO(2max) (24.31 +/- 4.61 versus 21.21 +/- 3.88 ml/kg/minute, P = 0.01) and
anaerobic threshold VO(2) (17.08 +/- 3.35 versus 13.66 +/- 2.82 ml/kg/minute, P
< 0.0001). After cardiovascular training, we found a significant improvement of
Beck inventory score (8.37 +/- 12.79 versus 2.90 +/- 3.00, P < 0.001) and HAQ
score (0.14 +/- 0.21 versus 0.06 +/- 0.19, P < 0.01) in the training group.
CONCLUSION: This study showed significant improvement in exercise tolerance,
aerobic capacity, quality of life, and depression after a supervised
cardiovascular training program in patients with SLE.
-----
G Ital Nefrol. 2005 Nov-Dec;22 Suppl 33:S27-33.
[Treatment of lupus nephritis]
[Article in Italian]
Ferrantelli A, Bono L, Tortorici C, Termini R, Giammarresi C, Rotolo U.
U.O. Nefrologia, Dialisi e Trapianti ARNAS Civico, Palermo. angelonef@libero.it
SLE begins with renal symptoms in about 30-50% of the patients and after 10
years over 70% of them has complications. In the last years the medical therapy
improved the outcome of SLE and its complications. Presently, the survival for
lupus nephritis is 80% after five years. The nephritis treatment is divided into
remission-inducing treatment that is followed by remission-maintaining
treatment. Moreover, it is considered the therapy for preventing or reducing
toxic and side-effects from drugs and the therapy for flare-ups. To initiate the
specific therapy is important to consider the histological class (WHO). In the
remission-inducing treatment steroids are used alone for 3-6 months in class IIB
or in association with cyclophosphamide in classes III-IV and V and for
flare-ups. For remission-maintaining treatment steroids are used in association
with azathioprine. The drugs improved the outcome of nephritis but produced
side-effects that determined the suspension of the drug and/or reduction of
dosage and/or the use of other drugs like mycophenolate mofetil or rituximab.
-----
Autoimmunity. 2005 Nov;38(7):549-55.
Positive and negative effects of thalidomide on refractory
cutaneous lupus erythematosus.
Briani C, Zara G, Rondinone R, Iaccarino L, Ruggero S, Toffanin E, Ermani M,
Ghirardello A, Zampieri S, Sarzi-Puttini P, Doria A.
University of Padova, Department of Neurosciences, Via Giustiniani, 5, 35128,
Padova, Italy. chiara.briani@unipd.it
BACKGROUND: Thalidomide is used in cutaneous lupus erythematosus (CLE)
refractory to conventional therapies. Peripheral neuropathy (PN) is the most
severe side effect, but the incidence of PN and its relation to thalidomide dose
are still unclear.OBJECTIVE: To prospectively evaluate the efficacy as well as
the occurrence of PN in CLE patients treated with thalidomide, and to assess
whether PN, when occurs, correlates with thalidomide dose and/or length of
treatment.METHODS: Fourteen female patients with CLE in low-dose thalidomide
therapy were followed for up to 24 months. Prior to, and regularly during
treatment patients underwent rheumatological, dermatological, neurological and
electrophysiological evaluations. A decline in sural SNAP of 50% or more from
baseline value was considered as criterion of sensory axonal PN.RESULTS: All
patients showed a dramatic improvement of skin manifestations. Ten patients
(71.4%) developed a sensory axonal PN. The median time free from this
complication was 14 months. No correlations were found between age of the
patients nor thalidomide cumulative dose and occurrence of PN (Mann-Whitney U
Test; p>0.16). Other adverse effects were: tremor, paresthesias, somnolence,
amenhorrea, constipation and thoracic pain.CONCLUSIONS: Low does thalidomide is
efficacious in treating CLE, but PN is a common complication whose occurrence
does not seem to correlate with total thalidomide dose, whereas with the
duration of therapy. A closer electrophysiological follow-up is therefore
recommended in the long-term treatment.
-----
Autoimmunity. 2005 Nov;38(7):531-40.
Effects of dehydroepiandrosterone supplement on health-related
quality of life in glucocorticoid treated female patients with systemic lupus
erythematosus.
Nordmark G, Bengtsson C, Larsson A, Karlsson FA, Sturfelt G, Ronnblom L.
Department of Medical Sciences, Section of Rheumatology, University Hospital,
Uppsala, Sweden. gunnel.nordmark@medsci.uu.se
The objective of this study was to evaluate the efficacy of low dose
dehydroepiandrosterone (DHEA) on health-related quality of life (HRQOL) in
glucocorticoid treated female patients with systemic lupus erythematosus (SLE).
Forty one women ( >or= 5 mg prednisolone/day) were included in a double-blind,
randomized, placebo-controlled study for 6 months where DHEA was given at 30
mg/20 mg ( <or= 45/ >or= 46 years) daily, or placebo, followed by 6 months open
DHEA treatment to all patients. HRQOL was assessed at baseline, 6 and 12 months,
using four validated questionnaires and the patients' partners completed a
questionnaire assessing mood and behaviour at 6 months. DHEA treatment increased
serum levels of sulphated DHEA from subnormal to normal. The DHEA group improved
in SF-36 "role emotional" and HSCL-56 total score (both p<0.05). During open
DHEA treatment, the former placebo group improved in SF-36 "mental health"
(p<0.05) with a tendency for improvement in HSCL-56 total score (p=0.10). Both
groups improved in McCoy's Sex Scale during active treatment (p<0.05). DHEA
replacement decreased high-density lipoprotein (HDL) cholesterol and increased
insulin-like growth factor I (IGF-I) and haematocrit. There were no effects on
bone density or disease activity and no serious adverse events. Side effects
were mild. We conclude that low dose DHEA treatment improves HRQOL with regard
to mental well-being and sexuality and can be offered to women with SLE where
mental distress and/or impaired sexuality constitutes a problem.
-----
Autoimmunity. 2005 Nov;38(7):507-18.
Drug-induced lupus erythematosus.
Sarzi-Puttini P, Atzeni F, Capsoni F, Lubrano E, Doria A.
Department of Rheumatology, Rheumatology Unit, L Sacco University Hospital, via
GB Grassi 74, Milan 20157, Italy. sarzi@hotmail.com
Drug-induced lupus is a syndrome which share symptoms and laboratory
characteristics with idiopathic systemic lupus erythematosus (SLE). The terms
drug-induced lupus (DIL) and drug-induced lupus erythematosus (DILE) are
preferred, but other ones are also used-drug-related lupus, lupus-like syndrome
and lupus erythematosus medicamentosus. The first case of DILE was reported in
1945 and associated with sulfadiazine. In 1953, it was reported that DILE was
related to the use of hydralazine. More than 80 drugs have been associated with
DILE. The average age of patients with DILE is nearly twice that of patients
with idiopathic SLE. Approximately half the patients with drug-induced SLE are
women, compared with 90% of patients with idiopathic SLE. Similarly to
idiopathic lupus, DILE can be divided into systemic, sub-acute cutaneous and
chronic cutaneous lupus. The syndrome is characterised by arthralgia, myalgia,
pleurisy, rash and fever in association with antinuclear antibodies in the
serum. The clinical and laboratory manifestations of drug-induced SLE are
similar to those of idiopathic SLE, but central nervous system and renal
involvement are rare in DILE. Recognition of DILE is important because it
usually reverts within a few weeks after stopping the drug. This review
discusses the general issues in DILE, such as pathogenic mechanisms, clinical
forms and diagnostic criteria, and provides more detailed information for some
of the most recent implicated drugs: minocycline, statins, anti-TNF-alpha
agents.
-----
Ann Dermatol Venereol. 2005 Nov;132(11 Pt 1):853-6.
[Thalidomide in the treatment of chronic discoid lupus
erythematosus]
[Article in French]
Brocard A, Barbarot S, Milpied B, Stalder JF.
Clinique Dermatologique, CHU Hotel-Dieu, Nantes.
INTRODUCTION: Thalidomide is the second line treatment of chronic lupus
erythematosus. The efficacy of this treatment, the minimal effective doses and
tolerance are poorly documented in the literature. PATIENTS AND METHODS: We
present the data of a single-center retrospective studied among 18 patients with
chronic lupus erythematosus, treated with thalidomide from 1998 to 2003.
Inclusion criteria were: the presence of clinical lesions evoking the disease,
confirmed by histological examination and direct immunofluorescence and
treatment with thalidomide for more than 2 months. RESULTS: Mean age on
diagnosis was of 35.8 years. Thalidomide had been initiated a mean of 10.6 years
after diagnosis of chronic lupus erythematosus. In 13 out of 18 patients,
thalidomide had been prescribed because of failure with prior treatments.
Fifteen patients were improved by thalidomide (83.3 p. 100), with 11 (61 p. 100)
complete and 4 (22 p. 100) partial remissions. Two (11 p. 100) patients were
stabilized and treatment failed in one. The mean initial dose was of 100 mg/d
(50-150), and maintenance dose was of around 50 mg/d (56 mg/d). The mean
follow-up with thalidomide was of 19.4 months. Only one withdrawal due to side
effects was reported. The most frequent side effects were: asthenia (33 p. 100),
paresthesia (22 p. 100) and weight gain (16.6 p. 100). No side effects were
reported in 10 out of 18 patients. DISCUSSION: This study confirms the efficacy
of low dose thalidomide in the treatment of chronic lupus erythematosus. In our
experience, tolerance to this treatment is good, the most frequent side effect
was asthenia, but usually mild. No significant peripheral neuropathy was noted.
The fear of side effects, notably neurological, should not delay initiation of
thalidomide in the case of failure with current treatments.
-----
Transplantation. 2005 Oct 15;80(2 Suppl):S265-71.
Use of mycophenolate mofetil in autoimmune and renal diseases.
Appel GB, Radhakrishnan J, Ginzler EM.
1 Department of Nephrology, Columbia University, College of Physicians and
Surgeons, New York, NY. 2 Department of Medicine, Rheumatology Division, State
University of New York Downstate Medical Center, Brooklyn, NY.
Progress in understanding the pathogenesis and treatment of rheumatologic and
glomerular diseases such as systemic lupus erythematosus and particularly lupus
nephritis has been closely linked with the development of newer
immunosuppressive agents. With improved patient survival following the
institution of cyclophosphamide and corticosteroid therapy, longer-term
management issues came to the forefront, especially how to decrease adverse
effects of the immunosuppressive regimen. Many of the immunosuppressive regimens
used in lupus patients were first established as efficacious and safe through
their use in solid organ transplantation. Mycophenolate mofetil (MMF) is now
widely used in the field of transplantation. Following anecdotal reports
describing benefits of MMF in lupus and lupus nephritis patients, small studies
and finally large randomized, controlled trials have established the use of MMF
in these patients, particularly those with lupus nephritis. MMF use in other
rheumatologic and renal diseases has been evaluated in only smaller studies and
very few randomized controlled trials. Nevertheless, many studies currently are
ongoing with this immunosuppressive agent. This article will review the
published data and the experience of two major New York medical centers with the
use of MMF in autoimmune and renal diseases.
-----
Nephrology (Carlton). 2005 Oct;10(5):504-10.
Randomized controlled trial of pulse intravenous cyclophosphamide
versus mycophenolate mofetil in the induction therapy of proliferative lupus
nephritis.
Ong LM, Hooi LS, Lim TO, Goh BL, Ahmad G, Ghazalli R, Teo SM, Wong HS, Tan SY,
Shaariah W, Tan CC, Morad Z.
Department of Medicine, Penang Hospital, Malaysia.
Background: The aim of the present study was to evaluate the efficacy of
mycophenolate mofetil in the induction therapy of proliferative lupus nephritis.
Methods: Forty-four patients from eight centres with newly diagnosed lupus
nephritis World Health Organization class III or IV were randomly assigned to
either mycophenolate mofetil (MMF) 2 g/day for 6 months or intravenous
cyclophosphamide (IVC) 0.75-1 g/m(2) monthly for 6 months in addition to
corticosteroids. Results: Remission occurred in 13 out of 25 patients (52%) in
the IVC group and 11 out of 19 patients (58%) in the MMF group (P = 0.70). There
were 12% in the IVC group and 26% in the MMF group that achieved complete
remission (P = 0.22). Improvements in haemoglobin, the erythrocyte sedimentation
rate, serum albumin, serum complement, proteinuria, urinary activity, renal
function and the Systemic Lupus Erythematosus Disease Activity Index score were
similar in both groups. Twenty-four follow-up renal biopsies at the end of
therapy showed a significant reduction in the activity score in both groups. The
chronicity index increased in both groups but was only significant in the IVC
group. Adverse events were similar. Major infections occurred in three patients
in each group. There was no difference in gastrointestinal side-effects.
Conclusions: MMF in combination with corticosteroids is an effective induction
therapy for moderately severe proliferative lupus nephritis.
-----
An Pediatr (Barc). 2005 Oct;63(4):321-9.
[Systemic lupus erythematosus in children.]
[Article in Spanish]
Stichweh D, Pascual V.
Baylor Institute for Immunology Research. Dallas. Texas. United States.
Pediatric systemic lupus erythematosus (pSLE) is a chronic mutisystemic
autoimmune disease with complex clinical manifestations. Although the
presentation, clinical manifestations, immunological findings and treatment
issues of pSLE are similar to those of adult SLE patients, there are special
issues which need to be considered when dealing with SLE in children. During the
last decade survival has improved remarkably as a result of earlier diagnosis,
recognition of milder disease and better approaches to therapy. However, pSLE
remains a potentially serious condition. Although the pathogenesis of SLE
remains poorly understood, susceptibility involves a combination of
environmental, hormonal and genetic factors.Better understanding of SLE
pathogenesis will hopefully lead to more specific and less toxic therapies for
this disease.
-----
Am J Obstet Gynecol. 2005 Oct;193(4):1444-55.
Pregnancy outcomes before and after a diagnosis of systemic lupus
erythematosus.
Dhar JP, Essenmacher LM, Ager JW, Sokol RJ.
Department of Internal Medicine, Wayne State University School of Medicine,
Detroit, MI, USA. pdhar@med.wayne.edu
OBJECTIVE: The purpose of this study was to evaluate pregnancy outcomes before
and after diagnosis of lupus. STUDY DESIGN: Successive selection criterion
applied to 148 lupus and 78,905 non-lupus pregnancies, generated 3 groups: lupus
group, 84 pregnancies (not-yet-diagnosed group, 15 women; already-diagnosed
group, 69 women), and control group, 51,000 pregnancies. Three-way analysis of
variance and the chi-squared test were used for analyses. RESULTS: Stillbirth
outcome was increased in the lupus group compared with the control group (odds
ratio, 4.84 [95% CI, 1.72,11.08]); the not-yet-diagnosed group (odds ratio, 9.89
[95% CI, 1.09,42.63]), and the already-diagnosed group (odds ratio, 3.85 [95%
CI, 1.02,10.31]). Considering >1 pregnancy per patient would have overestimated
the stillbirth rate. Stillbirth risk was increased significantly in severe
maternal disease that was marked by central nervous system involvement. The
already-diagnosed group had more hypertensive complications (P = .001 and
.0001). Both lupus groups showed a significantly greater proportion of preterm
births (P = .03), growth restriction (P = .019), and infants in the very low
birth weight category (P = .021) compared with the control group. CONCLUSION:
Poor fetal outcomes are seen in pregnancies that are complicated by lupus, even
before clinical appearance of disease, which supports a predisease state.
-----
Arthritis Rheum. 2005 Oct;52(10):3073-8.
Double-blind, randomized, controlled clinical trial of
clofazimine compared with chloroquine in patients with systemic lupus
erythematosus.
Bezerra EL, Vilar MJ, da Trindade Neto PB, Sato EI.
Universidade Federal do Rio Grande do Norte, Natal, Brazil. elaine@ufrnet.br
OBJECTIVE: To evaluate the efficacy of clofazimine (CFZ) compared with
chloroquine diphosphate (CDP) for the treatment of cutaneous involvement in
systemic lupus erythematosus (SLE). METHODS: A prospective, randomized,
controlled, double-blind clinical trial was carried out in SLE patients with
active cutaneous lesions, of whom 16 were randomized to receive CFZ at 100
mg/day and 17 received CDP at 250 mg/day for 6 months. All drugs had a similar
appearance to avoid identification. Both groups received broad-spectrum
sunscreens twice a day and the prednisone dose was kept stable during the study.
Cutaneous lesions were evaluated by 2 blinded observers at baseline and at
months 1, 2, 4, and 6. RESULTS: Thirty-three patients were randomized to a
treatment group, of whom 27 completed 6 months of treatment. The groups were
homogeneous and comparable in terms of demographic and clinical characteristics.
Five CFZ-treated patients and 1 CDP-treated patient (P = 0.15) dropped out due
to development of severe lupus flare. At the end of the study, 12 CFZ-treated
patients (75%) and 14 CDP-treated patients (82.4%) had complete or near-complete
remission of skin lesions; intention-to-treat analysis showed no significant
difference in the response rates between groups. Side effects, mainly skin and
gastrointestinal events, were frequent in both groups, but no patients had to
discontinue their treatment. CONCLUSION: These findings suggest that CFZ is
equally as effective as CDP in controlling cutaneous lesions in SLE patients.
However, we cannot exclude the possibility that the CFZ itself could be the
cause of systemic lupus flare.
-----
Lupus. 2005;14(9):683-6.
Cardiac involvement in systemic lupus erythematosus.
Doria A, Iaccarino L, Sarzi-Puttini P, Atzeni F, Turriel M, Petri M.
Division of Rheumatology, University of Padua, Padua, Italy. adoria@unipd.it
Pericarditis is the most common cardiac abnormality in systemic lupus
erythematosus (SLE) patients, but lesions of the valves, myocardium and coronary
vessels may all occur. In the past, cardiac manifestations were severe and life
threatening, often leading to death. Therefore, they were frequently found in
post-mortem examinations. Nowadays cardiac manifestations are often mild and
asymptomatic. However, they can be frequently recognized by echocardiography and
other noninvasive tests. Echocardiography is a sensitive and specific technique
in detecting cardiac abnormalities, particularly mild pericarditis, valvular
lesions and myocardial dysfunction. Therefore, echocardiography should be
performed periodically in SLE patients. Vascular occlusion, including coronary
arteries, may develop due to vasculitis, premature atherosclerosis or
antiphospholipid antibodies associated with SLE. Premature atherosclerosis is
the most frequent cause of coronary artery disease (CAD) in SLE patients.
Efforts should be made to control traditional risk factors as well as all other
factors which could contribute to atherosclerotic plaque development.
-----
Rheumatol Int. 2005 Sep 28;:1-7 [Epub ahead of print]
Pilot clinical study of Adacolumn cytapheresis in patients with
systemic lupus erythematosus.
Soerensen H, Schneidewind-Mueller JM, Lange D, Kashiwagi N, Franz M, Yokoyama T,
Ramlow W.
Hospital Waldfriede, Berlin, Germany.
The aim of this study is to investigate the clinical effects of cytapheresis
using the Adacolumn system (selective removal of circulating monocytes and
granulocytes by means of an extracorporeal type column) in patients with active
systemic lupus erythematosus (SLE). An open uncontrolled multicenter pilot study
was conducted in 18 SLE patients who were showing a SLEDAI score of 8 or more
under conventional medication. Patients with lupus nephritis (>class 1, WHO
classification) were excluded. Extracorporeal cytapheresis with the Adacolumn
system was administered once a week for five consecutive weeks. The efficacy of
the treatment was evaluated using the SLEDAI for 10 weeks after the first
cytapheresis session. The median SLEDAI decreased from 16 at baseline to six at
week 11 (10 weeks after the first apheresis) (p<0.001). Significant improvements
in musculoskeletal and dermal systems were observed. Arthritis and alopecia were
present in 14 and nine patients at baseline and this number decreased to five
and one patients, respectively by week 11.Three mild and one moderate adverse
events out of the 42 reported events were judged 'probably related' to the
treatment; no serious adverse events were reported. Selective removal of
monocytes and granulocytes from the blood in an extracorporeal circulation
system was associated with clinical improvement in this small series of patients
with SLE. Since this approach seems not to have the disadvantages of
pharmacological immunosuppression, further controlled studies of Adacolumn
cytapheresis are warranted in SLE.
-----
Rheumatology (Oxford). 2005 Sep 27; [Epub ahead of print]
B-cell depletion in the treatment of patients with systemic lupus
erythematosus: a longitudinal analysis of 24 patients.
Leandro MJ, Cambridge G, Edwards JC, Ehrenstein MR, Isenberg DA.
Centre for Rheumatology, University College London, London, UK.
Objectives. To assess the clinical and basic serological consequences of B-cell
depletion with rituximab in the treatment of patients with systemic lupus
erythematosus (SLE) who have failed conventional immunosuppression. Methods. An
open study of 24 patients with severe SLE followed for a minimum of 3 months is
reported. In the majority of patients (19 out of 24), 6 months follow-up data
are described. Disease activity in these patients was assessed every 1-2 months
using the British Isles Lupus Assessment Group (BILAG) system and estimates of
anti-double-stranded DNA antibodies and serum C3 levels. During the follow-up
period, significant side-effects were sought and the reduction in oral
prednisolone was recorded. It was our general practice to stop concomitant
immunosuppression (e.g. azathioprine, mycophenolate) when B-cell depletion was
given (in most cases in the form of two 1 g intravenous infusions of rituximab 2
weeks apart accompanied by two 750 mg intravenous cyclophosphamide infusions and
two methylprednisolone infusions of 250 mg each). Results. Twenty-two patients
were female and two male. At the time of B-cell depletion, the mean age was 28.9
yr (range 17-49) and the mean disease duration was 7.9 yr (range 1-18). The
global BILAG score (P < 0.00001), serum C3 (P < 0.0005) and double-stranded DNA
binding (P < 0.002) all improved from the time of B-cell depletion to 6 months
after this treatment. Only one patient failed to achieve B-lymphocyte depletion
in the peripheral blood. The period of B-lymphocyte depletion ranged from 3 to 8
months except for one patient who remains depleted at more than 4 yr. Analysis
of the regular BILAG assessments showed that improvements occurred in each of
the eight organs or systems. The mean daily prednisolone dose fell from 13.8 mg
(s.d. 11.3) to 10 mg (s.d. 3.1). Conclusion. In this open study of patients who
had failed conventional immunosuppressive therapy, considerable utility in the
use of B-cell depletion has been demonstrated. Our data provide strong support
for the performance of a full double-blind control trial.
-----
Lupus. 2005;14(8):593-7.
Cyclophosphamide for lupus during pregnancy.
Clowse ME, Magder L, Petri M.
Department of Medicine, Division of Rheumatology, Johns Hopkins University
School of Medicine, Baltimore, MD, USA. meganclowse@hotmail.com
Severe systemic lupus erythematosus often requires the use of cyclophosphamide
in women of reproductive age. As cyclophosphamide is generally avoided during
pregnancy because of its teratogenic risk, its impact on fetal survival is
poorly understood. This is a case series of lupus patients exposed to
cyclophosphamide during pregnancy. We reviewed pregnancies in patients with
lupus seen at a large university hospital between October 1986 and September
2003. The pregnancies were evaluated prospectively for cyclophosphamide
exposure, lupus activity, and fetal outcome. Comparison was made between
pregnancies with severe lupus requiring cyclophosphamide and those that did not.
We identified four pregnancies with cyclophosphamide exposure. Two pregnancies
were inadvertently exposed to cyclophosphamide early in the first trimester;
both resulted in first trimester miscarriages. Two patients were administered
cyclophosphamide for severe lupus nephritis and thrombocytopenia during the
second trimester. Soon after the administration of cyclophosphamide, both
pregnancies ended with fetal demise. Pregnancies exposed to cyclophosphamide for
severe lupus flare resulted in a higher rate of fetal losses than pregnancies
with severe lupus but not requiring the drug (100% versus 31.25%). In conclusion
we present four pregnancies exposed to cyclphosphamide, each ending with
pregnancy loss. Based on our experience, the survival of the fetus is strongly
in doubt when cyclophosphamide is required to treat lupus in the mother.
------
Rheumatology (Oxford). 2005 Sep 13; [Epub ahead of print]
Pimecrolimus 1% cream for the treatment of discoid lupus
erythematosus.
Tlacuilo-Parra A, Guevara-Gutierrez E, Gutierrez-Murillo F, Soto-Ortiz A, Barba-Gomez
F, Hernandez-Torres M, Salazar-Paramo M.
Medical Research Division, UMAE, Hospital de Pediatria, Centro Medico Nacional
de Occidente, Instituto Mexicano del Seguro Social, Guadalajara, Jalisco and
Universidad de Colima, Mexico.
Objectives. To determine the safety and efficacy of pimecrolimus cream on
lesions of discoid lupus erythematosus. Methods. In an open-label phase II
trial, patients with discoid lupus were treated with pimecrolimus 1% cream twice
daily for 8 weeks. We assessed skin involvement with a clinical severity score,
quality of life, patient improvement and toxicity. The changes were documented
by skin biopsy at baseline and at the end of treatment. Results. Ten patients
with a mean age of 34 +/- 17 yr and disease duration of 3 yr (range 1-8) were
studied; 90% were female and 40% had received prior topical or systemic therapy
without response. In all patients, improvement of skin damage was observed after
therapy. A significant decrease of 52% was observed in the mean +/- s.d.
clinical severity score, from 6.1 +/- 1.4 before treatment to 2.9 +/- 1.5 after
treatment (P = 0.005). Quality of life score (0 = no effect, 100 = maximum
effect on quality of life) showed a mean improvement of 46%, from 42.8 +/- 23.1
before to 23 +/- 16.5 after treatment (P = 0.008). According to the patients'
assessment of the response to treatment, 50% qualified as marked improvement,
40% moderate and 10% slight improvement. The treatment was well tolerated;
adverse reactions consisted of minimal erythema and pruritus, which resolved
without any further action. Conclusions. Our data suggest that pimecrolimus
cream for discoid lupus erythematosus seems to be a safe and clinically
effective option. However, this was an open and uncontrolled study, and
double-blind, placebo-controlled studies are needed.
-----
Clin Exp Immunol. 2005 Jul;141(1):1-9.
Haematopoietic stem cell transplantation in the treatment of
severe autoimmune disease: results from phase I/II studies, prospective
randomized trials and future directions.
Tyndall A, Saccardi R.
Department of Rheumatology, University Hospital Basle, Basle, Switzerland.
alan.tyndall@fps-basel.ch
Around 700 patients have received an autologous haematopoietic stem cell
transplant (HSCT) as treatment for a severe autoimmune disease (AD). The
majority of these have been within the context of phase I/II clinical trials and
following international guidelines proposed 7 years ago. In general, a positive
benefit/risk ratio has led to phase III prospective randomized controlled trials
in multiple sclerosis (MS), systemic sclerosis (SSc) and rheumatoid arthritis
(RA) in Europe. In the US, similar trials are being planned for SSc, MS and
systemic lupus erythematosus (SLE). Transplant related mortality (TRM) has
fallen in all disease subgroups since the inception due to more appropriate
patient selection, and so far a clear advantage of the more intense
myeloablative regimens in terms of remission induction and relapse rate has not
emerged. Although each AD has a different profile, over a third of patients have
sustained a durable remission, often with no further need for immunosuppressive
drugs. In those who relapsed, many responded to agents which pre transplant had
been ineffective. The study of immune reconstitution and gene expression pre and
post HSCT is being undertaken to further understand the mechanism of
autoimmunity.
-----
J Rheumatol. 2005 Jun;32(6):1047-52.
Mycophenolate mofetil in systemic lupus erythematosus: efficacy
and tolerability in 86 patients.
Pisoni CN, Sanchez FJ, Karim Y, Cuadrado MJ, D'Cruz DP, Abbs IC, Khamasta MA,
Hughes GR.
Lupus Research Unit, The Rayne Institute, St. Thomas' Hospital, London, UK.
ceciliapisoni@yahoo.com.ar
OBJECTIVE: To assess the indications, efficacy, and tolerability of
mycophenolate mofetil (MMF) in patients with systemic lupus erythematosus (SLE)
resistant to other immunosuppressive therapy. METHODS: Records of 93 patients
with SLE were retrospectively reviewed. Seven patients were excluded. The
remaining 86 patients received other immunosuppressive drugs before MMF.
Efficacy was measured by changes in daily oral prednisolone dose, European
Consensus Lupus Activity Measurement Index (ECLAM), erythrocyte sedimentation
rate (ESR), C-reactive protein, and dsDNA antibody titer. In renal patients,
changes in serum creatinine, creatinine clearance, chromium-51 EDTA glomerular
filtration rate (EDTA-GFR), and 24 hour urine protein excretion were also
evaluated. RESULTS: Indications for MMF were mainly renal involvement (59% of
patients), uncontrolled disease activity (14%), and other SLE related
manifestations (13%). Overall, we found a significant reduction in the steroid
dosage, ECLAM, ESR, and anti-dsDNA antibody titer. Renal patients (n = 35)
showed a significant reduction in urinary 24 hour protein excretion. Levels of
serum creatinine, creatinine clearance, and EDTA-GFR showed no significant
change during treatment. Thirty-seven patients (42.8%) developed adverse events.
Gastrointestinal intolerance in 25 (29%) and infections in 20 (23.2%) were the
most frequent. The drug was discontinued in 14 (16.3%) patients due to side
effects and 6 patients discontinued MMF because they achieved disease remission
and were trying to conceive. MMF was stopped due to lack of efficacy in 12
patients. CONCLUSION: Our data suggest that MMF is a good therapeutic
alternative for patients with SLE and renal involvement or refractory disease
activity.
-----
Ann Intern Med. 2005 Jun 21;142(12 Pt 1):953-62.
The effect of combined estrogen and progesterone hormone
replacement therapy on disease activity in systemic lupus erythematosus: a
randomized trial.
Buyon JP, Petri MA, Kim MY, Kalunian KC, Grossman J, Hahn BH, Merrill JT,
Sammaritano L, Lockshin M, Alarcon GS, Manzi S, Belmont HM, Askanase AD, Sigler
L, Dooley MA, Von Feldt J, McCune WJ, Friedman A, Wachs J, Cronin M,
Hearth-Holmes M, Tan M, Licciardi F.
Hospital for Joint Diseases, New York University School of Medicine, New York,
New York, USA. jill.buyon@nyumc.org
BACKGROUND: There is concern that exogenous female hormones may worsen disease
activity in women with systemic lupus erythematosus (SLE). OBJECTIVE: To
evaluate the effect of hormone replacement therapy (HRT) on disease activity in
postmenopausal women with SLE. DESIGN: Randomized, double-blind,
placebo-controlled noninferiority trial conducted from March 1996 to June 2002.
SETTING: 16 university-affiliated rheumatology clinics or practices in 11 U.S.
states. PATIENTS: 351 menopausal patients (mean age, 50 years) with inactive
(81.5%) or stable-active (18.5%) SLE. Interventions: 12 months of treatment with
active drug (0.625 mg of conjugated estrogen daily, plus 5 mg of
medroxyprogesterone for 12 days per month) or placebo. The 12-month follow-up
rate was 82% for the HRT group and 87% for the placebo group. MEASUREMENTS: The
primary end point was occurrence of a severe flare as defined by Safety of
Estrogens in Lupus Erythematosus, National Assessment-Systemic Lupus
Erythematosus Disease Activity Index composite. RESULTS: Severe flare was rare
in both treatment groups: The 12-month severe flare rate was 0.081 for the HRT
group and 0.049 for the placebo group, yielding an estimated difference of 0.033
(P = 0.23). The upper limit of the 1-sided 95% CI for the treatment difference
was 0.078, within the prespecified margin of 9% for noninferiority. Mild to
moderate flares were significantly increased in the HRT group: 1.14
flares/person-year for HRT and 0.86 flare/person-year for placebo (relative
risk, 1.34; P = 0.01). The probability of any type of flare by 12 months was
0.64 for the HRT group and 0.51 for the placebo group (P = 0.01). In the HRT
group, there were 1 death, 1 stroke, 2 cases of deep venous thrombosis, and 1
case of thrombosis in an arteriovenous graft; in the placebo group, 1 patient
developed deep venous thrombosis. LIMITATIONS: Findings are not generalizable to
women with high-titer anticardiolipin antibodies, lupus anticoagulant, or
previous thrombosis. CONCLUSIONS: Adding a short course of HRT is associated
with a small risk for increasing the natural flare rate of lupus. Most of these
flares are mild to moderate. The benefits of HRT can be balanced against the
risk for flare because HRT did not significantly increase the risk for severe
flare compared with placebo.
-----
Lupus. 2005;14(6):434-9.
Long-term thalidomide use in refractory cutaneous lesions of
lupus erythematosus: a 65 series of Brazilian patients.
Coelho A, Souto MI, Cardoso CR, Salgado DR, Schmal TR, Waddington Cruz M, de
Souza Papi JA.
Department of Internal Medicine, Clementino Fraga Filho University Hospital,
Medical School, Federal University of Rio de Janeiro. alycia@email.iis.com.br
Thalidomide has been reported as efficacious in refractory cutaneous lupus
erythematosus (LE). The most fearful side-effects are teratogenicity and
neuropathy. We reported clinical efficacy of long-term low-dose use of
thalidomide in 65 patients with LE, emphasizing the prevalence of adverse
effects, especially of neuropathy and its related factors. Data obtained from
medical records included age, sex, disease duration, and the presence of
diagnostic criteria for systemic lupus erythematosus (SLE), the extent and
activity of cutaneous lesions and previous treatments. Sixty-three patients
(98.9%) presented complete or partial improvement with thalidomide therapy.
Drowsiness occurred in 50 patients (77%). Twenty-eight patients (43.2%)
presented neuropathy symptoms. Nerve conduction studies were done in 21 (75%) of
them and were abnormal in 12 (57%). With the interruption of thalidomide, 24
(82.5%) had complete or partial improvement of neuropathy symptoms and 23 (82%)
of them had cutaneous relapse. There were no significant differences between
those who developed or not neuropathy in treatment duration, age, total dose and
systemic versus cutaneous LE. In conclusion, thalidomide can be used in
refractory cutaneous LE with great efficacy and relative security. Controlled
studies with schemes with lower doses or intermittent usage or alternative drugs
are wanted to reduce the burden of cutaneous morbidity of lupus erythematosus.
-----
Clin Exp Rheumatol. 2005 May-Jun;23(3):393-6.
Skin manifestations of systemic lupus erythematosus refractory to
multiple treatment modalities: poor results with mycophenolate mofetil.
Pisoni CN, Obermoser G, Cuadrado MJ, Sanchez FJ, Karim Y, Sepp NT, Khamashta MA,
Hughes GR.
Lupus Research Unit, The Rayne Institute, St Thomas' Hospital, Lambeth Palace
Road, London, United Kingdom. ceciliapisoni@yahoo.com.ar
OBJECTIVE: Skin disease can be one of the most refractory clinical
manifestations of systemic lupus erythematosus (SLE). The standard therapy
consists of sunscreens, topical corticosteroids and antimalarials. However in
difficult cases a variety of other drugs have been tried. Here we describe our
clinical experience with mycophenolate mofetil (MMF) in patients with cutaneous
manifestations of SLE. METHODS: Seven patients with SLE and skin involvement
(including acute cutaneous lupus, subacute cutaneous lupus, discoid lupus
erythematosus, vasculitis, urticarial rash and chilblain lupus) who had received
treatment with MMF were included. The clinical characteristics,
serologicalfindings and response to treatment were recalledfrom retrospective
review of the files. RESULTS: Our results showed no response in 5 patients,
partial response in 1 patient and initial response but skin flare whilst on MMF
in 1 patient. The median dose of MMF was 2 g (range 2-3 g). Adverse events on
MMF were mild, mainly gastrointestinal and occurred in 5 patients. No patients
discontinued MMF due to adverse events. CONCLUSIONS: MMF appears not to be
particularly effective in the treatment of skin disease in SLE. It should be
noted that our group of patients had previously failed to respond to a median of
4 (range 2-10) different drugs used to treat SLE skin disease. Thus, the
patients in the study could be considered at the severe end of skin disease
spectrum.
-----
Clin Exp Immunol. 2005 May;140(2):205-12.
New therapies for systemic lupus erythematosus.
Goldblatt F, Isenberg DA.
Centre for Rheumatology, The Middlesex Hospital, University College London,
Arthur Stanley House, 40-50 Tottenham Street, London W1T 4NJ, UK. fgoldblatt@aol.com
In the past 40 years, prognosis for patients with systemic lupus erythematosus (SLE)
has improved, with 10-year survival now approximately 90%. This is due probably
to a combination of earlier disease diagnosis and diagnosis of milder disease,
due in part to availability of multiple serological tests for SLE, use of
steroids and other immunosuppressive agents, and availability of renal dialysis
and transplantation. Despite this, however, the potential for significant
morbidity and mortality remains in the group of patients with partially
responsive or treatment resistant disease. More recently, advancements in the
understanding of molecular mechanisms involved in the pathogenesis of SLE have
translated to the development of novel therapies, offering possible alternatives
to this patient cohort. Discussion of these pharmacological options and ongoing
research forms the basis of this review.
-----
Am J Kidney Dis. 2005 May;45(5):903-11.
The long-term prognosis of renal transplantation in patients with lupus
nephritis.
Moroni G, Tantardini F, Gallelli B, Quaglini S, Banfi G, Poli F, Montagnino
G, Meroni P, Messa P, Ponticelli C.
BACKGROUND: Few data are available about the long-term outcome of renal
transplantation in patients with systemic lupus erythematosus (SLE). Methods:
Between June 1982 and 2004, a total of 33 adults with lupus nephritis received
35 kidney allografts. Outcomes of these grafts and those of 70 controls matched
for age, sex, and donor source who underwent transplantation during the same
period were compared. Results: Mean follow-up after renal transplantation was 91
+/- 59 months for patients with lupus and 90 +/- 64 months for controls.
Actuarial 15-year patient (80% versus 83%) and death-censored graft survival
rates (69% versus 67%) were not significantly different between patients with
lupus and controls. Risks for acute and chronic rejection, arterial
hypertension, and infection were not different between the 2 groups. Mean serum
creatinine levels also were similar in the 2 groups at the last follow-up visit.
Intravascular thrombotic events occurred in 9 patients with SLE (26%) and 6
controls (8.6%; P = 0.038). In the SLE group, 6 of 7 antiphospholipid (aPL)
antibody-positive versus 3 of 17 aPL antibody-negative patients experienced
thrombotic events ( P = 0.015). Recurrence of lupus nephritis was documented in
3 renal grafts (8.6%), but no graft was lost because of recurrent lupus
nephritis. Conclusion: Long-term patient and graft survival probabilities were
similar in patients with SLE and matched controls. The risk for thrombotic
complications was greater in patients with SLE, particularly aPL-positive
patients. Nephritis recurred in less than 10% of patients with SLE and did not
influence graft survival.
-----
Rheumatology (Oxford). 2005 Apr 12; [Epub ahead of print]
Ultraviolet-A1 phototherapy modulates Th1/Th2 and Tc1/Tc2 balance in patients
with systemic lupus erythematosus.
Szegedi A, Simics E, Aleksza M, Horkay I, Gaal K, Sipka S, Hunyadi J, Kiss E.
Department of Dermatology, Medical and Health Science Centre, University of
Debrecen, Debrecen, Hungary.
Objective. Ultraviolet-A1 (UVA1) phototherapy is effective for a variety of
dermatological diseases. We examined the effectiveness and reliability of
low-dose UVA1 phototherapy (60 kJ/m(2)/treatment) in patients suffering from
systemic lupus erythematosus (SLE). We studied the changes in immunological
parameters. Methods. The patients received a 9-week course of phototherapy
according to the following regimen: five times a week during the first 3 weeks,
three times a week during the second 3 weeks and twice during the last 3 weeks.
Among other things, we analysed the proportions of T helper 1 (Th1), Th2, T
cytotoxic (Tc1) and Tc2 cell populations in the peripheral blood of patients by
flow cytometric detection of intracytoplasmic interferon gamma (IFN-gamma) and
interleukin 4 (IL-4). Results. Our study showed the improvement of clinical
symptoms determined by the subjective clinical disease activity scoring and the
SLE Disease Activity Index (SLEDAI). By the end of UVA1 phototherapy, the mean
value of SLEDAI had decreased from 7.2+/-5.6 to 0.9+/-1.8, which was significant
(P = 0.005). Immunological investigations detected a decrease in the frequency
of IFN-gamma-producing Th1 and Tc1 cells and a decrease in the Th1/Th2 and
Tc1/Tc2 ratios after UVA1 therapy. Conclusion. According to the literature, IFN-gamma
has a pathogenic role in the development of SLE. We observed a decreased
proportion of IFN-gamma-secreting cells, which we think is presumably one of the
beneficial effects of UVA1 therapy. On the basis of our study, UVA1 phototherapy
does seem to be an effective adjuvant in the treatment of SLE patients.
-----
Nephron Clin Pract. 2005 Apr 11;100(3):c92-c100 [Epub ahead of print]
Mycophenolate Mofetil for Remission Induction in Severe Lupus Nephritis.
Cross J, Dwomoa A, Andrews P, Burns A, Gordon C, Main J, Mathieson P,
O'donoghue D, Jayne D.
Renal Unit, Addenbrooke's Hospital, Cambridge, UK.
Background: Mycophenolate mofetil (MMF) is a potential alternative
immunosuppressive to cyclophosphamide or azathioprine for the treatment of lupus
nephritis. It has a superior toxicity profile to cyclophosphamide and is more
effective than azathioprine when used in combination with cyclosporin for renal
transplantation. Methods: This open label study assessed the safety and efficacy
of an induction regimen of MMF and prednisolone in 24 patients, with active WHO
Class III, IV or V lupus nephritis, without previous exposure to
cyclophosphamide or MMF. Patients received MMF 2 g/day and a tapering dose of
oral prednisolone and were followed for 12 months. Renal response was defined
using the validated BILAG (British Isles Lupus Assessment Group) Index. Results:
20 patients achieved complete renal remission, 2 partial renal remission and 2
had renal disease refractory to MMF. Five patients were withdrawn, 2 for
progressive renal disease, 2 for extra-renal flares and 1 following a severe
infection. No patient was withdrawn for drug intolerance. There were 18 adverse
events of which 10 were infections. Clinical improvement was mirrored by
normalisation of complement levels and marked falls in circulating
anti-double-stranded DNA antibodies. Follow-up for a mean period of 35 months
documented only one episode of renal relapse which subsequently remitted with
re-introduction of MMF. One patient died after 18 months' follow-up with uterine
malignancy. Conclusions: MMF with prednisolone was effective for remission
induction in severe lupus nephritis and was well tolerated. Copyright (c) 2005
S. Karger AG, Basel.
-----
Lupus. 2005;14(3):210-4.
Anti-B cell therapy (rituximab) in the treatment of autoimmune diseases.
Chambers SA, Isenberg D.
Centre for Rheumatology, The Middlesex Hospital, University College, London, UK.
The use of B cell depletion as a mode of treatment for non-Hodgkin's lymphoma
was first utilized in 1997 when Rituximab, a chimeric human-mouse monoclonal
antibody which has a high affinity to the CD20 antigen expressed on B cells,
became available. Over 500000 lymphoma patients have been treated worldwide with
this drug and it has a good safety record. The notion that B cells might be
critical to the development of rheumatoid arthritis led to the extension of the
use of B cell depletion to this condition and a recent double blind controlled
trial has shown very encouraging results. In addition, B cell depletion either
using Rituximab alone, or in combination with cyclophosphamide and
corticosteroids has also been reported to have been of great benefit in some
patients with severe systemic lupus erythematosus albeit in open label studies.
This review considers the mechanism of action of the drug, the clinical trials
that have been reported, and tries to place its current use in patients with
autoimmune rheumatic disease in context.
-----
Lupus. 2005;14(3):181-8.
Theory, targets and therapy in systemic lupus erythematosus.
Vasoo S, Hughes GR.
The Lupus Research Unit, The Rayne Institute, St Thomas' Hospital London, UK.
The treatment of systemic lupus erythematosus (SLE) has been refined over the
years, with the recognition that a fine balance lies between aggressive and
prompt therapy and attendant complications brought upon by immunosuppressive
therapy itself. However, there has been limited change to the repertoire of
drugs available to treat this challenging disease. The current standard therapy
for severe manifestations of SLE includes the use of high-dose corticosteroids
and cytotoxic agents such as cyclophosphamide (CYC), which have been associated
with an increased risk of serious and opportunistic infections. The need for
safer, more targeted therapies has been recognized and now, with the exponential
increase in the understanding of immunopathogenic mechanisms in SLE, the way has
been paved for the development of biologic or targeted therapies in SLE.
Although the potential immunosuppression, long-term safety issues and
cost-effectiveness remain unclear. These targeted therapies may range from small
molecules that specifically inhibit inflammatory processes at an intracellular,
cell-cell or cell-matrix level to monoclonal antibodies, soluble receptors or
natural antagonists that interfere with cytokine function, cellular activation
and inflammatory gene transcription.
-----
Lupus. 2005;14 Suppl 1:s33-8.
Maintenance therapies for proliferative lupus nephritis: mycophenolate mofetil,
azathioprine and intravenous cyclophosphamide.
Contreras G, Tozman E, Nahar N, Metz D.
Division of Nephrology, Miller School of Medicine, University of Miami, Florida
33136, USA. gcontrer@med.miami.edu
For the treatment of proliferative lupus nephritis, long-term cyclophosphamide
(CY) regimens are efficacious, however, at the expense of substantial toxicity.
In the last decade, sequential regimens of short-term CY induction followed by
either mycophenolate mofetil (MMF) or azathioprine (AZA) maintenance have shown
to be efficacious and safe reducing the long-term exposure to CY. In a
maintenance study including predominantly Hispanics and African-Americans, the
patients who received MMF and AZA maintenance had a higher cumulative
probability of remaining free of the composite of death or chronic renal failure
(CRF) compared to quarterly intravenous CY (IVCY) maintenance (89% in MMF, 80%,
in AZA and 45% in IVCY). Likewise, MMF and AZA maintenance were associated with
significantly lower incidence of severe infections (2% in each MMF or AZA, and
25% in IVCY), sustained amenorrhea (6% in MMF, 8% in AZA, and 32% in IVCY), and
hospitalizations (one hospital-days per patient-year in each MMF or AZA, and 10
in IVCY). In a European induction study including predominantly Caucasians,
patients who received any of two sequential regimens, low dose versus high dose
IVCY induction both followed by AZA maintenance, had a high cumulative
probability of remaining free of treatment failure (84% in low dose IVCY and 80%
in high dose IVCY; treatment failure defined as a composite of free of
corticosteroid resistant flare, nephrotic syndrome, doubling creatinine, and
persistent elevated creatinine). Low dose IVCY and high dose IVCY induction were
associated with low incidence of sustained amenorrhea (4% in each group) and
severe infections (11% in low dose and 22% in high dose IVCY induction). Of
interest, most of the severe infection episodes occurred while patients were
receiving IVCY induction. Finally an Asian study demonstrated that patients with
proliferative lupus nephritis could be effectively treated with short-term oral
CY induction followed by AZA maintenance. The cumulative probability of complete
remission was 76%. The relapse rate was only 11%. The incidence of permanent
amenorrhea and infection were 8% and 33%, respectively. None of the Asian
patients had an increase in serum creatinine level to double the baseline value.
Maintenance therapies with MMF or AZA following short-term CY induction in a
sequential regimen are efficacious and safe for the treatment of high-risk
patients with proliferative lupus nephritis.
-----
Lupus. 2005;14 Suppl 1:s27-32.
Lupus nephritis: induction therapy.
Chan TM.
Department of Medicine, University of Hong Kong, Queen Many Hospital, Hong Kong.
dtmchan@hku.hk
Effective induction therapy is of pivotal importance in minimizing renal
parenchymal damage by the active immune-mediated inflammatory processes in
severe proliferative lupus nephritis. Preservation of nephron mass is
prerequisite to long-term renal survival. Data from US-based studies have shown
improved efficacy with induction treatment comprising corticosteroid and
cyclophosphamide, compared with corticosteroid treatment alone. Data from
European studies have shown similar efficacy with a modified treatment regimen,
in which smaller doses of cyclophosphamide were given at weekly or fortnightly
intervals over a shortened treatment duration, and the treatment related adverse
effects appeared less frequent with the reduced-dose regimen. We have also
reported that sequential immunosuppression with prednisolone and oral
cyclophosphamide as induction followed by azathioprine maintenance was
associated with a high incidence of remission and relatively favourable
long-term renal outcome in Chinese patients. However, cyclophosphamide treatment
is associated with considerable adverse effects, which could be potentially
fatal. Mycophenolate mofetil selectively inhibits lymphocyte proliferation, and
thus targets an instrumental step in the pathogenesis of systemic lupus
erythematosus. There is accumulating evidence that the combined use of
mycophenolate mofetil and corticosteroid presents an effective treatment for
severe proliferative lupus nephritis in different ethnic groups, and is
associated with much fewer adverse effects compared with cyclophosphamide-based
regimens. Recent data from our group also demonstrate the long-term efficacy of
mycophenolate mofetil in preserving renal survival, when used continuously as
both induction and maintenance therapy.
-----
Clin Pharmacokinet. 2005;44(1):61-98.
Pharmacokinetics and pharmacodynamics of systemically
administered glucocorticoids.
Czock D, Keller F, Rasche FM, Haussler U.
Division of Nephrology, University Hospital Ulm, Ulm, Germany.
Glucocorticoids have pleiotropic effects that are used to treat diverse diseases
such as asthma, rheumatoid arthritis, systemic lupus erythematosus and acute
kidney transplant rejection. The most commonly used systemic glucocorticoids are
hydrocortisone, prednisolone, methylprednisolone and dexamethasone. These
glucocorticoids have good oral bioavailability and are eliminated mainly by
hepatic metabolism and renal excretion of the metabolites. Plasma concentrations
follow a biexponential pattern. Two-compartment models are used after
intravenous administration, but one-compartment models are sufficient after oral
administration.The effects of glucocorticoids are mediated by genomic and
possibly nongenomic mechanisms. Genomic mechanisms include activation of the
cytosolic glucocorticoid receptor that leads to activation or repression of
protein synthesis, including cytokines, chemokines, inflammatory enzymes and
adhesion molecules. Thus, inflammation and immune response mechanisms may be
modified. Nongenomic mechanisms might play an additional role in glucocorticoid
pulse therapy.Clinical efficacy depends on glucocorticoid pharmacokinetics and
pharmacodynamics. Pharmacokinetic parameters such as the elimination half-life,
and pharmacodynamic parameters such as the concentration producing the
half-maximal effect, determine the duration and intensity of glucocorticoid
effects. The special contribution of either of these can be distinguished with
pharmacokinetic/pharmacodynamic analysis. We performed simulations with a
pharmacokinetic/pharmacodynamic model using T helper cell counts and endogenous
cortisol as biomarkers for the effects of methylprednisolone. These simulations
suggest that the clinical efficacy of low-dose glucocorticoid regimens might be
increased with twice-daily glucocorticoid administration.
-----
Arthritis Rheum. 2004 Dec;50(12):3934-40.
Early response to immunosuppressive therapy predicts good renal
outcome in lupus nephritis: lessons from long-term followup of patients in the
Euro-Lupus Nephritis Trial.
Houssiau FA, Vasconcelos C, D'Cruz D, Sebastiani GD, de Ramon Garrido E, Danieli
MG, Abramovicz D, Blockmans D, Mathieu A, Direskeneli H, Galeazzi M, Gul A, Levy
Y, Petera P, Popovic R, Petrovic R, Sinico RA, Cattaneo R, Font J, Depresseux G,
Cosyns JP, Cervera R.
Universite Catholique de Louvain, Brussels, Belgium. houssiau@ruma.ucl.ac.be
OBJECTIVE: In the Euro-Lupus Nephritis Trial (ELNT), 90 patients with lupus
nephritis were randomly assigned to a high-dose intravenous cyclophosphamide (IV
CYC) regimen (6 monthly pulses and 2 quarterly pulses with escalating doses) or
a low-dose IV CYC regimen (6 pulses of 500 mg given at intervals of 2 weeks),
each of which was followed by azathioprine (AZA). After a median followup of 41
months, a difference in efficacy between the 2 regimens was not observed. The
present analysis was undertaken to extend the followup and to identify
prognostic factors. METHODS: Renal function was prospectively assessed quarterly
in all 90 patients except 5 who were lost to followup. Survival curves were
derived using the Kaplan-Meier method. RESULTS: After a median followup of 73
months, there was no significant difference in the cumulative probability of
end-stage renal disease or doubling of the serum creatinine level in patients
who received the low-dose IV CYC regimen versus those who received the high-dose
regimen. At long-term followup, 18 patients (8 receiving low-dose and 10
receiving high-dose treatment) had developed permanent renal impairment and were
classified as having poor long-term renal outcome. We demonstrated by
multivariate analysis that early response to therapy at 6 months (defined as a
decrease in serum creatinine level and proteinuria <1 g/24 hours) was the best
predictor of good long-term renal outcome. CONCLUSION: Long-term followup of
patients from the ELNT confirms that, in lupus nephritis, a remission-inducing
regimen of low-dose IV CYC followed by AZA achieves clinical results comparable
with those obtained with a high-dose regimen. Early response to therapy is
predictive of good long-term renal outcome.
-----
Ann Rheum Dis. 2004 Dec;63(12):1623-6.
Dehydroepiandrosterone suppresses interleukin 10 synthesis in
women with systemic lupus erythematosus.
Chang DM, Chu SJ, Chen HC, Kuo SY, Lai JH.
Tri-Service General Hospital, National Defense Medical Center, 325, Cheng-Kung
Road, Sec. 2, Neihu, 114, Taipei, Taiwan, China. ming0503@ms3.hinet.net.
OBJECTIVE: To study the effects of dehydroepiandrosterone (prasterone, DHEA) 200
mg/day on cytokine profiles in adult women with active systemic lupus
erythematosus (SLE). METHODS: In a double blind, randomised, placebo controlled
study conducted as part of a larger multicentre study, 30 adult women with
active SLE received oral DHEA 200 mg/day or placebo for 24 weeks. Baseline
prednisone (<10 mg/day) and other concomitant SLE medications were to remain
constant. The levels of cytokines including interleukin (IL) 1, IL2, interferon
gamma, IL4, and IL10 were determined by ELISA. The mean change from baseline to
24 weeks of therapy was analysed. RESULTS: The two groups (DHEA n = 15; placebo
n = 15) were well balanced for baseline characteristics. Only IL1beta and IL10
could be detected in the serum of lupus patients; however, there was no
significant mean (SD) difference in serum IL1beta before and after treatment
(9.94 (8.92) v 9.20 (6.49) pg/ml). IL10 demonstrated a greater and significant
reduction from baseline (9.21 (9.66) to 1.89 (1.47) pg/ml in the DHEA treatment
group). CONCLUSIONS: In a 24 week study of adult Chinese women with mild to
moderate SLE, treatment with DHEA 200 mg once daily resulted in significant
reduction of serum levels of IL10. This finding may suggest why DHEA could
significantly reduce lupus flares.
-----
Kidney Int. 2004 Dec;66(6):2411-5.
Mycophenolate therapy of SLE membranous nephropathy.
Spetie DN, Tang Y, Rovin BH, Nadasdy T, Nadasdy G, Pesavento TE, Hebert LA.
Department of Internal Medicine, Dorothy M. Davis Heart and Lung Research
Institute, The Ohio State University Medical Center, Columbus, Ohio, USA.
BACKGROUND: The immunosuppressant mycophenolic acid (MMF) has been used
successfully to manage proliferative forms of systemic lupus erythematosus (SLE)
glomerulonephritis (GN) World Health Organization (WHO) Classes III and IV. Less
is known about MMF treatment of membranous SLE GN (WHO Class V, SLE MN).
METHODS: We report our experience with MMF therapy in 13 consecutive SLE MN
patients participating in a prospective study of risk factors for SLE flare.
RESULTS: Baseline characteristics were: mean age 33 +/- 14 SD years, female/male
ratio 11/2, Caucasians 7, African Americans 5, Oriental 1, serum creatinine 1.02
+/- 0.41, and mean 24-hour urine protein (P)/creatinine (C), ratio 5.1 +/- 4.1.
Initial therapy was prednisone mean dose 31 +/- 17 mg/day, and MMF mean dose
1173 +/- 746 mg/day. Therapy also featured interventions to achieve
renoprotection and proteinuria reduction. At 6 months of therapy, complete or
partial remission was achieved in 10 of 13 patients. At most recent follow-up
visit (mean follow-up 16 +/- 8 months), 9 of 13 patients were in complete
remission, and in 11 of 13 patients, urine P/C ratio was < 0.8. During
follow-up, serum creatinine either stabilized or was improved. The only serious
complication during 208 patient months of follow-up was histoplasma pneumonia in
1 patient. CONCLUSION: These promising results suggest that moderate dose MMF in
combination with renoprotective/antiproteinuria therapy warrants further study
in the management of SLE MN.
-----
Ann Rheum Dis. 2004 Dec 15; [Epub ahead of print]
Tolerance and short-term efficacy of rituximab in 43 patients
with systemic autoimmune diseases.
Gottenberg J, Guillevin L, Lambotte O, Combe B, Allanore Y, Cantagrel A,
Larroche C, Soubrier M, Bouillet L, Dougados M, Fain O, Farge D, Kyndt X,
Lortholary O, Masson C, Moura B, Remy P, Thomas T, Wendling D, Anaya J, Sibilia
J, Mariette X.
Hopital de Bicetre, (AP-HP), Le Kremlin-Bicetre.
OBJECTIVE: To assess the tolerance and efficacy of rituximab in patients with
various autoimmune diseases seen in daily rheumatological practice. Patients and
METHODS: Eight hundred and sixty-six rheumatology and internal medicine
practitioners were contacted by E-mail to obtain the files of patients treated
with rituximab for systemic autoimmune diseases. Patients with lymphoma were
analysed if the evolution of the autoimmune disease could be evaluated. RESULTS:
A total of 43 of 49 cases could be analysed in this retrospective
study,including 14 patients with rheumatoid arthritis (RA), 13 with systemic
lupus erythematosus (SLE), 6 with primary Sjogren's syndrome (pSS), 5 with
systemic vasculitis and 5 with other autoimmune diseases. Rituximab was
prescribed for lymphoma in 2 patients with RA and 2 with pSS. In the 39 other
cases, rituximab was given because of the refractory character of the autoimmune
disease. The mean follow-up period was 8.3 months (2-26 months). Eleven adverse
events were observed in 10 patients and treatment had to be discontinued in 6
patients. The efficacy of rituximab was observed in 30 patients (70%): 11 RA, 9
SLE, 5 pSS, 2 vasculitis, 2 antisynthetase syndromes and 1 sarcoidosis. The mean
decrease in daily corticosteroid intake was 9.5 mg/day (0-50) in responders.
Seven patients experienced relapse after 8.1 months (5-15), on average. Three
patients died because of refractory autoimmune disease. CONCLUSION: Despite the
absence of marketing authorization, rituximab is used to treat various
refractory autoimmune diseases in daily rheumatological practice. The present
study shows good tolerance, short-term clinical efficacy and marked
corticosteroid reduction with rituximab therapy in patients with RA, SLE, pSS,
vasculitis or polymyositis.
-----
Semin Reprod Med. 2004 Nov;22(4):379-88.
Dehydroepiandrosterone replacement therapy.
Arlt W.
Division of Medical Sciences, Institute of Biomedical Research, University of
Birmingham, Birmingham, United Kingdom. w.arlt@bham.ac.uk
Dehydroepiandrosterone (DHEA) replacement therapy has attracted considerable
attention over recent years. Significant beneficial effects of DHEA replacement
have been reported in patients representing the pathophysiological model of
complete DHEA deficiency, in other words, adrenal insufficiency (AI). This
includes effects on well-being, energy levels, mood, and libido, which is
usually impaired in AI, particularly in female patients. DHEA exerts its action
mainly indirectly via downstream metabolism to sex steroids, and conversion to
active androgens is likely to play a major role. In addition, DHEA has
well-described neurosteroidal properties, and by exerting anti-gamma
aminobutyric acid(GABA)ergic action it may have antidepressive potential. Other
patient groups that may benefit from DHEA replacement are patients receiving
chronic exogenous glucocorticoid treatment, which invariably leads to persistent
suppression of DHEA production. In patients with systemic lupus erythematosus,
DHEA has been shown to reduce disease activity and has a glucocorticoid-sparing
effect. However, caution is required regarding DHEA treatment in individuals
with only a relative decline in circulating DHEA levels. This particularly
includes the physiological decline of DHEA and its sulfate ester observed with
aging. Even the elderly maintain circulating levels of DHEA that are orders of
magnitude higher than what is observed in AI. Even physiological menopause does
not necessarily lead to a decrease in circulating androgens while estrogen
production invariably ceases. Current evidence from randomized, controlled
trials in healthy elderly persons including several cohorts of postmenopausal
women does not justify the use of DHEA. However, DHEA may be a suitable option
for androgen replacement in women with established androgen deficiency, for
example, bilateral oophorectomy and premature menopause.
-----
Arthritis Rheum. 2004 Nov;50(11):3591-5.
The effect of dehydroepiandrosterone on lumbar spine bone mineral
density in patients with quiescent systemic lupus erythematosus.
Hartkamp A, Geenen R, Godaert GL, Bijl M, Bijlsma JW, Derksen RH.
Department of Rheumatology and Clinical Immunology, University Medical Center,
3508 GA Utrecht, The Netherlands.
OBJECTIVE: Because dehydroepiandrosterone (DHEA) is an adrenal steroid hormone
with weak intrinsic androgenic properties that can be converted in peripheral
tissues into more potent sex hormones, one might expect a positive effect of
DHEA on bone mineral density (BMD). We evaluated the effects on lumbar BMD of
oral DHEA, 200 mg/day, for 1 year in female patients with quiescent systemic
lupus erythematosus (SLE). METHODS: The study subjects were 60 women with SLE.
All participants gave informed consent to participate in a double-blind,
placebo-controlled study on the effects of DHEA on fatigue and general
well-being. BMD was measured with dual-energy x-ray absorptiometry (DEXA) at
baseline and after 12 months. RESULTS: Fifty-eight patients (mean age 42.6
years) could be evaluated; 2 patients (both in the DHEA group) refused to
undergo DEXA a second time. In premenopausal women, DHEA did not influence BMD
significantly. There was a significant increase in BMD with use of DHEA in
postmenopausal women who were not receiving bisphosphonates or
estrogen-containing medications. This increase was not observed in the group
receiving placebo. CONCLUSION: In premenopausal women with quiescent SLE, use of
DHEA does not have a significant effect on BMD. DHEA may increase BMD in
postmenopausal SLE patients if they are not already protected from bone loss by
use of estrogens or bisphosphonates. Small numbers, due to the absence of
stratification for menopausal status, and the use of antiresorptive agents at
randomization preclude firmer conclusions based on the results of this study.
-----
Arthritis Rheum. 2004 Oct;50(10):3161-9.
Safety and efficacy of tumor necrosis factor alpha blockade in
systemic lupus erythematosus: an open-label study.
Aringer M, Graninger WB, Steiner G, Smolen JS.
Internal Medicine III, Medical University of Vienna, Vienna, Austria.
OBJECTIVE: To investigate the safety of therapeutic tumor necrosis factor alpha
(TNFalpha) blockade in patients with systemic lupus erythematosus (SLE), in whom
this proinflammatory cytokine is significantly increased and may be involved in
the disease pathogenesis. METHODS: In an open-label study, 6 patients with
moderately active SLE (4 with nephritis and 3 with arthritis refractory to other
therapies) were given 4 300-mg doses of infliximab, a chimeric anti-TNFalpha
antibody, in addition to immunosuppression with azathioprine or methotrexate.
RESULTS: The only significant adverse events observed were urinary tract
infection in 3 patients, 1 of which was accompanied by Escherichia coli
bacteremia, and a prolonged febrile episode of putatively viral origin in 1 of
them. These patients had similar infectious conditions in the past. In none of
the patients was it necessary to terminate the treatment prematurely. Levels of
antibodies to double-stranded DNA and cardiolipin increased in 4 patients each,
but this was not associated with a decrease in serum complement levels, with
vascular events, or with flares. In contrast, disease activity declined during
therapy. All 3 patients with joint involvement experienced remission of
arthritis, which relapsed 8-11 weeks after the last infliximab infusion. In the
4 patients with lupus nephritis, proteinuria decreased significantly within 1
week after initiation of therapy and was diminished by > or = 60% within 8
weeks, remaining at low levels until the end of the observation period (at least
several months). CONCLUSION: Infliximab did not lead to adverse events related
to an increase in SLE activity, although autoantibodies to double-stranded DNA
and cardiolipin increased, as expected. This finding, coupled with the clinical
improvement in the inflammatory manifestations of the disease, indicates that
further study in larger controlled trials is warranted. Copyright 2004 American
College of Rheumatology
-----
Arch Immunol Ther Exp (Warsz). 2004 Sep-Oct;52(5):356-65.
Treatment options for severe lupus nephritis.
Lenz O, Contreras G.
Division of Nephrology and Hypertension, University of Miami, Miami, FL, USA.
Renal involvement in systemic lupus erythematosus is a common complication that
significantly worsens morbidity and mortality. Landmark trials conducted by the
National Institutes of Health established cyclophosphamide as the mainstay of
therapy. Since then, the prognosis of patients with lupus nephritis has markedly
improved, and 10-year survival rates now surpass 75%.These superior outcomes
have come at the expense of adverse events such as serious infections and
gonadal failure in a significant number of patients,and the relapsing nature of
the disease continues to pose a problem. For thesereasons, new treatment
protocols, such as mycophenolate mofetil induction or sequential therapies using
azathioprine or mycophenolate mofetil in the maintenance phase, have been
developed in recent years with the goal to maintain remission and reduce adverse
events. In addition, ongoing research into the pathogenesis of lupus nephritis
has confirmed the importance of B and T cell activation, leading to the
identification of potential new therapeutic targets. This article discusses
established and novel treatment options for patients with severe lupus nephritis
corresponding to WHO classes III, IV, and V withIII or V with IV.
-----
Arthritis Rheum. 2004 Sep;50(9):2858-68.
Effects of prasterone on disease activity and symptoms in women
with active systemic lupus erythematosus.
Petri MA, Mease PJ, Merrill JT, Lahita RG, Iannini MJ, Yocum DE, Ginzler EM,
Katz RS, Gluck OS, Genovese MC, Van Vollenhoven R, Kalunian KC, Manzi S,
Greenwald MW, Buyon JP, Olsen NJ, Schiff MH, Kavanaugh AF, Caldwell JR,
Ramsey-Goldman R, St Clair EW, Goldman AL, Egan RM, Polisson RP, Moder KG,
Rothfield NF, Spencer RT, Hobbs K, Fessler BJ, Calabrese LH, Moreland LW, Cohen
SB, Quarles BJ, Strand V, Gurwith M, Schwartz KE.
Johns Hopkins University Medical Center, Baltimore, Maryland 21205, USA. mpetri@welch.jhu.edu
OBJECTIVE: To determine whether prasterone administration results in improvement
or stabilization of systemic lupus erythematosus (SLE) disease activity and its
symptoms. METHODS: Women with active SLE were treated with prasterone 200 mg/day
plus standard SLE treatments or with placebo plus standard SLE treatments for up
to 12 months in this randomized, double-blind investigation conducted at 27
centers. Standard SLE treatments included prednisone (</=10 mg/day),
antimalarials, and immunosuppressive agents; dosages were required to be stable
for >/=6 weeks prior to enrollment and remain unchanged during protocol
treatment. Responders were patients who experienced no clinical deterioration
and had improvement or stabilization over the duration of the study in 2 disease
activity measures (the SLE Disease Activity Index [SLEDAI] and the Systemic
Lupus Activity Measure) and 2 quality of life measures (patient's global
assessment and the Krupp Fatigue Severity Scale). RESULTS: A total of 381 women
with SLE were enrolled. Among patients with clinically active disease at
baseline (SLEDAI score >2), 86 of 147 in the prasterone group (58.5%)
demonstrated improvement or stabilization without clinical deterioration, as
compared with 65 of 146 in the placebo group (44.5%) (P = 0.017). Acne and
hirsutism were reported in 33% and 16%, respectively, of the prasterone group
and in 14% and 2%, respectively, of the placebo group (P < 0.05 for both
comparisons). However, most cases of acne and hirsutism were mild and did not
require withdrawal from therapy. Myalgias and oral stomatitis were reported less
frequently in the prasterone group (22% and 15%, respectively) than in the
placebo group (36% and 23%, respectively) (P < 0.05 for both comparisons). Serum
levels of high-density lipoprotein cholesterol, triglycerides, and C3 complement
significantly decreased, while levels of testosterone and, to a lesser extent,
estradiol increased in the prasterone group. CONCLUSION: In adult women with
active SLE, administration of prasterone at a dosage of 200 mg/day improved or
stabilized signs and symptoms of disease and was generally well tolerated.
-----
Ann Rheum Dis. 2004 Sep 2 [Epub ahead of print]
Preliminary results of safety and efficacy of the interleukin-1
receptor antagonist anakinra in patients with severe lupus arthritis.
Ostendorf B, Iking-Konert C, Kurz K, Jung G, Sander O, Schneider M.
Center for Rheumatology, Department of Endocrinology, Diabetology and
Rheumatology, Germany.
BACKGROUND: Joint involvement occurs in most patients with systemic lupus
erythematosus (SLE) and severe lupus arthritis, including Jaccoud's arthropathy,
is often refractory to conventional therapies. Anakinra is a recombinant version
of human IL-1Ra admitted for the therapy of rheumatoid arthritis (RA). Its
therapeutic potential has not been proven in patients with SLE. OBJECTIVE: To
determine the safety/tolerability and efficacy of anakinra in SLE patients with
leading joint involvement. METHODS: In SLE patients with active polyarthritis
and no other uncontrolled systemic/organ manifestations, 100 mg/day anakinra was
self- administrated s.c. over three months. Disease activity was assessed by
VAS, number of swollen / tender joints and ECLAM score as well as by serological
and immunological parameters. RESULTS: Four SLE patients were included to the
study protocol. Anakinra was apparently safe in all four patients. In
particular, no safety parameters were out of normal range and no drug-related
serious adverse events occurred. Our data showed a subjective benefit in all
patients and a trend to better activity parameters after four weeks (e.g. ECLAM,
total joint count, CRP). After an initial response, one patient dropped out of
the study because of an arthritic flare after six weeks. CONCLUSION: Experiences
relating to anakinra in SLE patients with arthritis have not yet been published.
In our study anakinra was apparently safe and well tolerated and gave rise to a
certain clinical and serological improvement. Based on our preliminary results,
anakinra might be an interesting alternative in individual patients with lupus
arthritis not responding to conventional therapies.
-----
Zhonghua Nei Ke Za Zhi. 2004 Aug;43(8):568-71.
[A pilot study of T cell vaccination in systemic lupus
erythematosus]
[Article in Chinese]
Mu R, Dai ZP, Li ZG, Gao XM.
Department of Rheumatology and Immunology, People's Hospital, Peking University
Medical School, Beijing 100044, China. Email: zgli98@yahoo.com
OBJECTIVE: Autoreactive T cells play a critical role in pathogenesis of systemic
lupus erythematosus (SLE). Immunization with inactivated autoreactive T cells (T
cell vaccination) may activate the idiotype anti-idiotypic network to deplete
specific subsets of autoreactive T cells involved in SLE. We conducted a pilot
clinical trial of T cell vaccination to investigate the efficiency and safety of
T cell vaccination in treatment of SLE. METHODS: Autoreactive T cell clones were
derived from peripheral blood mononuclear cells of 6 SLE patients. After
irradiated with 80 Gy gamma radiation, 1 x 10(7) T cells were inoculated
subcutaneously at 0, 2, 6, 8 week respectively. The patients were followed up
for 20 - 27 months, and monitored for clinical characteristics and side effects
from the vaccination. RESULTS: The clinical manifestations and laboratory
abnormalities were improved after inoculation without increasing the dose of
corticosteroids and immunosuppressants in most patients. SLEDAI score were
decreased remarkably. Proliferative responses against the T cell vaccine were
observed in 4/6 patients. No side effect was noticed and CD(3)(+), CD(4)(+) and
CD(8)(+) T cell were all in normal ranges after the vaccination and during the
follow-up period. CONCLUSION: The results of this pilot study indicate that T
cell vaccination is a safe and effective treatment in SLE patients.
------
Presse Med. 2004 Aug 28;33(14 Pt 1):944-52.
[The significance and treatment of antiphospholipid antibodies]
[Article in French]
Godeau B, Piette JC.
Service de medecine interne 1, CHU Henri Mondor, Creteil. bertrand.godeau@hmn.ap-hop-paris.fr
ANTIBODIES: The term antiphospholipid antibodies (APLA) regroups a family
antibodies that recognise anionic and neutral phospholipids, which are the
components of plasmatic cell membranes. These antibodies expose the patients to
risk of venous and/or arterials thromboembolic accidents and obstetrical
complications such as repeated early miscarriage or, more rarely foetal loss. A
SYNDROME: The presence of such antibodies associated with this type of clinical
events defines the antiphospholipid antibody syndrome (APS) that can be isolated
and defined as primary or associated with systemic lupus erythematosus. The APS
represents one of the most frequent thrombophilic states. The two APLA used in
the diagnosis of APS are the circulating lupus anticoagulant and anticardiolipid
antibodies. Indeed, these are the only APS for which research techniques have
been standardised. PERSONALISED TREATMENT: Treatment relies on anticoagulants.
Steroids are unnecessary except when APS is associated with lupus during the
catastrophic syndrome of APS, characterised by multiorgan failure related to
thrombotic microangiopathy lesions. The modalities of use of anticoagulants
(indications, dose and duration) remain debated and underline the great risk of
recurrent thrombosis on withdrawal of treatment.
-----
Lupus. 2004;13(9):673-8.
Ovarian failure in systemic lupus erythematosus patients treated
with pulsed intravenous cyclophosphamide.
Katsifis GE, Tzioufas AG.
Department of Pathophysiology, School of Medicine, University of Athens, Greece.
Pulsed intravenous cyclophosphamide is considered as standard therapy for lupus
nephritis and several other severe manifestations of systemic lupus
erythematosus (SLE). While the response rate to intravenous cyclophosphamide is
substantial, concern has arisen about its toxicity. In addition to increased
susceptibility to infection, bone marrow suppression, alopecia, hemorrhagic
cystitis and malignancy, ovarian failure is an important side effect associated
with the use of cyclophosphamide. Prior research on cyclophosphamide-treated
women has consistently demonstrated that the risk of sustained amenorrhea
depends on the age of the patient and the cumulative dose received. Sustained
amenorrhea is difficult to avoid in women 32 years or older, even with very
short intravenous cyclophosphamide courses. Younger women seem to have a
substantially lower incidence of ovarian failure, but this side effect may be
far more problematic for these patients. In these young women the risk may be
modulated by the prior SLE disease duration, the presence of anti-U1RNP
antibodies and anti-Ro antibodies. Co-treatment with gonadotropin-releasing
hormone agonists may preseserve the future fertility and ovarian function in
young women. Ovarian banking before administration of cyclophosphamide should be
considered in selected patients.
-----
Arthritis Rheum. 2004 Aug;50(8):2580-9.
B cell depletion as a novel treatment for systemic lupus
erythematosus: a phase I/II dose-escalation trial of rituximab.
Looney RJ, Anolik JH, Campbell D, Felgar RE, Young F, Arend LJ, Sloand JA,
Rosenblatt J, Sanz I.
University of Rochester School of Medicine and Dentistry, Rochester, New York
14642, USA. John_Looney@URMC.Rochester.edu
OBJECTIVE: Safer and more effective therapies are needed for the treatment of
systemic lupus erythematosus (SLE). B lymphocytes have been shown to play
fundamental pathogenic roles in SLE, and therefore, elimination of B cells with
the use of rituximab may represent a new therapy for SLE. METHODS: A phase I/II
dose-escalation trial of rituximab added to ongoing therapy in SLE was
conducted. Rituximab was administered as a single infusion of 100 mg/m2 (low
dose), a single infusion of 375 mg/m2 (intermediate dose), or as 4 infusions (1
week apart) of 375 mg/m2 (high dose). CD19+ lymphocytes were measured to
determine the effectiveness of B cell depletion. The Systemic Lupus Activity
Measure (SLAM) score was used as the primary outcome for clinical efficacy.
RESULTS: Rituximab was well tolerated in this patient population, with most
experiencing no significant adverse effects. Only 3 serious adverse events,
which were thought to be unrelated to rituximab administration, were noted. A
majority of patients (11 of 17) had profound B cell depletion (to <5 CD19+ B
cells/microl). In these patients, the SLAM score was significantly improved at 2
and 3 months compared with baseline (P = 0.0016 and P = 0.0022, respectively, by
paired t-test). This improvement persisted for 12 months, despite the absence of
a significant change in anti-double-stranded DNA antibody and complement levels.
Six patients developed human antichimeric antibodies (HACAs) at a level > or
=100 ng/ml. These HACA titers were associated with African American ancestry,
higher baseline SLAM scores, reduced B cell depletion, and lower levels of
rituximab at 2 months after initial infusion. CONCLUSION: Rituximab therapy
appears to be safe for the treatment of SLE and holds significant therapeutic
promise, at least for the majority of patients experiencing profound B cell
depletion. Based on these results, controlled trials of rituximab appear to be
warranted.
-----
Arthritis Rheum. 2004 Aug 15;51(4):625-34.
Effects of a stress-reduction program on psychological function,
pain, and physical function of systemic lupus erythematosus patients: a
randomized controlled trial.
Greco CM, Rudy TE, Manzi S.
University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15232,
USA. grecocm@upmc.edu
OBJECTIVE: To assess the effects of a stress-reduction program on pain,
psychological function, and physical function in persons with systemic lupus
erythematosus (SLE) who experience pain. METHODS: Ninety-two SLE patients were
assigned randomly to receive either biofeedback-assisted cognitive-behavioral
treatment (BF/CBT), a symptom-monitoring support (SMS) intervention, or usual
medical care (UC) alone. RESULTS: BF/CBT participants had significantly greater
reductions in pain and psychological dysfunction compared with the SMS group
(pain, P = 0.044; psychological functioning, P < 0.001) and the UC group (pain,
P = 0.028; psychological functioning, P < 0.001). BF/CBT had significantly
greater improvement in perceived physical function compared with UC (P = 0.035),
and improvement relative to SMS was marginally significant (P = 0.097). At a
9-month followup evaluation, BF/CBT continued to exhibit relative benefit
compared with UC in psychological functioning (P = 0.023). CONCLUSION: This
study supports the utility of a brief stress management program for short-term
improvement in pain, psychological function, and perceived physical function
among persons with SLE who experience pain.
-----
Curr Opin Pharmacol. 2004 Aug;4(4):398-402.
Anti B cell therapy (rituximab) in the treatment of autoimmune
diseases.
Kazkaz H, Isenberg D.
Centre for Rheumatology, The Middlesex Hospital, Arthur Stanley House, 40-50
Tottenham Street, London W1T 4NJ, UK.
B cells play an important role in the pathogenesis of many autoimmune diseases.
Selective targeting of these cells has been recently achieved using a chimeric
monoclonal antibody against the pan B cell surface marker CD20 (rituximab). This
antibody was originally developed for the treatment of non-Hodgkin's lymphoma.
It was found to be effective, well tolerated and had a very good safety profile.
Recent studies have demonstrated the efficacy of rituximab in several refractory
autoimmune disorders including rheumatoid arthritis, systemic lupus
erythematosus, immune thrombocytopenic purpura, chronic cold agglutinin disease,
IgM-mediated neuropathies and mixed cryoglobulinemia.
-----
Arthritis Rheum. 2004 Jun;50(6):1832-41.
A randomized clinical trial of a psychoeducational intervention
to improve outcomes in systemic lupus erythematosus.
Karlson EW, Liang MH, Eaton H, Huang J, Fitzgerald L, Rogers MP, Daltroy
LH.
Brigham and Women's Hospital, and Robert B. Brigham Arthritis and
Musculoskeletal Diseases Clinical Research Center, Boston, Massachusetts 02115,
USA. ekarlson@partners.org
OBJECTIVE: In a cross-sectional study, we previously identified 2 potentially
modifiable risk factors for adverse outcomes in systemic lupus erythematosus (SLE):
self-efficacy and social support. The goal of this study was to evaluate in a
randomized controlled trial a theory-based intervention to improve patient
self-efficacy and partner support to manage SLE. METHODS: Patients with SLE ages
18 years and older who met the American College of Rheumatology criteria and
were able to identify a partner (spouse or family member) were recruited from 2
academic medical centers and randomized into an experimental group or a control
group. Patients in the experimental group and their partners received an
intervention designed to enhance self-efficacy, couples communication about
lupus, social support, and problem solving, in the form of a 1-hour session with
a nurse educator followed by monthly telephone counseling for 6 months. Patients
in the control group and their partners received an attention placebo, including
a 45-minute video presentation about lupus, and monthly telephone calls.
Measures of physical and mental health status, disease activity, and
psychosocial factors were collected at baseline, 6 months, and 12 months. The
effect of the intervention on physical and mental health and disease activity at
6 and at 12 months was modeled with linear regression and adjusted for baseline
health status, disease activity, sociodemographic factors, treatment change, and
psychosocial factors. RESULTS: One hundred twenty-two patients (plus their
partners) were enrolled and randomized as follows: 64 to the experimental
intervention and 58 to the attention control group. The participants were
predominantly white, approximately half were college educated, and the groups
were balanced for sociodemographic factors. At 6 months, significantly higher
scores for couples communication (P = 0.01) and problem-focused coping (P =
0.03) were seen in the experimental group compared with the control group. At 12
months (6 months after the intervention ended), social support was higher (4.4
versus 4.1; P = 0.03), self-efficacy was higher (7.2 versus 6.2; P = 0.02),
couples communication was higher (3.5 versus 3.1; P = 0.03), and fatigue was
lower (5.1 versus 6.3; P = 0.02) in the experimental group compared with the
control group. Global mental health status at 12 months, as measured by the
Short Form 36 survey, was 69 points in the experimental group compared with 58
points in the control group (P = 0.04). In multivariate models, adjusting for
baseline covariates, scores for couple communication (P = 0.01) were
significantly higher at 6 months, and scores for self-efficacy (P = 0.004) and
global mental health status (P = 0.03) were significantly higher at 12 months in
the experimental group compared with the control group, and the mean score for
global physical function was higher by 7 points, which was a clinically
meaningful change (P = 0.2). The mean score for fatigue was also significantly
lower in the experimental group than in the control group (P = 0.05). SLE
disease activity was unchanged by this intervention. CONCLUSION: This
randomized, controlled trial of a theory-based educational intervention in SLE
demonstrated significantly higher scores for couple communication,
self-efficacy, and mental health status, and lower fatigue scores in the
experimental group compared with the control group. Because couple communication
and self-efficacy appear to be modifiable risk factors, they may also be
potential targets in more disadvantaged populations.
-----
Ann Rheum Dis. 2004 May;63(5):525-9.
EULAR randomised controlled trial of pulse cyclophosphamide and
methylprednisolone versus continuous cyclophosphamide and prednisolone followed
by azathioprine and prednisolone in lupus nephritis.
Yee CS, Gordon C, Dostal C, Petera P, Dadoniene J, Griffiths B, Rozman B,
Isenberg DA, Sturfelt G, Nived O, Turney JH, Venalis A, Adu D, Smolen JS, Emery
P.
Rheumatology, University of Birmingham, UK.
OBJECTIVE: To compare the efficacy and side effects of intermittent pulse
cyclophosphamide plus methylprednisolone with continuous oral cyclophosphamide
plus prednisolone, followed by azathioprine, in patients with proliferative
glomerulonephritis caused by systemic lupus erythematosus (SLE). METHODS: A
multicentre randomised controlled trial was conducted between June 1992 and May
1996 involving eight European centres. All patients satisfied the American
College of Rheumatology criteria for SLE and had biopsy proven proliferative
lupus nephritis. All received corticosteroids in addition to cytotoxic drugs, as
defined in the protocol, for two years. The trial was terminated after four
years as recruitment was disappointing. RESULTS: 32 SLE patients with lupus
nephritis were recruited: 16 were randomised to intermittent pulse
cyclophosphamide and 16 to continuous cyclophosphamide plus azathioprine. Mean
duration of follow up was 3.7 years in the continuous group (range 0 to 5.6) and
3.3 years in the pulse group (range 0.25 to 6). Three patients were excluded
from the pulse therapy group as they were later found to have pure mesangial
glomerulonephritis. Two patients in the continuous therapy group developed end
stage renal failure requiring dialysis, but none in the intermittent pulse
therapy (p = 0.488; NS). There were similar numbers of side effects and
withdrawals from treatment in both groups. There were three deaths: two in the
intermittent pulse therapy group and one in the continuous therapy group.
CONCLUSIONS: There was no statistically significant difference in efficacy and
side effects between the two regimens. Infectious complications occurred
commonly, so careful monitoring is required during treatment.
-----
J Fr Ophtalmol. 2004 Apr;27(4):367-73.
[Analysis of 925 patients on long-term hydroxychloroquine or
chloroquine treatment: results of ophthalmological screening]
[Article in French]
Ingster-Moati I, Crochet M, Manchon E, Anquetil D, Lestrade C, Jacob A, Le Brun
D, Albuisson E.
Service de Biophysique, Hopital Lariboisiere, Universite Paris 7, INSERM-U483,
Paris. isabelle.ingster-moati@lrb.ap-hop-paris.fr
PURPOSE: The aim of this 4-Year study was to analyze the population referred to
our laboratory for the visual follow-up of hydroxychloroquine or chloroquine
treatment. MATERIAL AND METHODS: We received 925 patients: 78% female, 22% male.
For each patient, a 13-item criteria was filled out and regular exams were
performed. The pathologies were divided in to 4 groups: rheumatoid polyarthritis
(P), lupus (L), sarcoidosis (S), others (O). RESULTS: The pathologies were
distributed as follows: 48% "P", 29% "L", 3% "S", 1% "P + L", 19% "O". Of these
patients, 19% had less than 1 Year of treatment, 73% 1-10 Years and 8% more than
10 Years. The screening exposed no retinal intoxications but 3% presented
pre-clinical intoxication (PCI) and 80% were allowed to continue their
treatment. The most important statistical results were: 1) a significant
relation between the PCI and the duration of the treatment (p<0.001); 2) a
non-significant relation between the PCI and the daily dose (p=0.417); and 3) a
significant relation between PCI and the cumulative dose (p=0.003). CONCLUSION:
The results shows the advantage of the ERG in screening to prevent anti-malarial
retinal toxicity. This study confirms that the cumulative dose seems to be more
important than the daily dose, but we agree with the international consensus to
respect a daily dose under 6.5 mg/kg/d. The results also demonstrated that, with
this large and diversified population, there is a need for prospective and
multi-centric studies. With the above results, international standards should be
established in order to obtain the most efficient screening for each category of
patient.
-----
Acta Med Croatica. 2004;58(1):13-7.
[Intermittent intravenous administration of cyclophosphamide in
patients with lupus nephritis]
[Article in Croatian]
Morovic-Vergles J, Galesic K, Dancuo I, Vergles D.
Zavod za klinicki imunologiju i reumatologiju Klinika za unutarnje bolesti
Klinicka bolnica Dubrava Av. G. Suska 6 10000 Zagreb, Hrvatska.
PATIENTS AND METHODS: Patients with systemic lupus erythematosus (SLE) and lupus
nephritis submitted to renal biopsy were retrospectively analyzed. All patients
were admitted to Dubrava University Hospital, Department of Clinical Immunology
and Rheumatology and Department of Nephrology. The diagnosis of SLE based on the
criteria proposed by the American Rheumatology Association was made in 46
patients treated during the last 4 years. There were 39 female and seven male
patients, mean age 39.5 years. Renal biopsy was performed in 16 patients (three
male and 13 female, mean age 34 years). RESULTS: Diffuse proliferative
glomerulonephritis (type IV) was diagnosed in ten, focal segmental
glomerulonephritis (type III) in three, and mesangioproliferative
glomerulonephritis (type II) in two patients. The type of lupus nephritis was
classified according to the World Health Organisation (WHO) criteria. In one
patient, the tissue obtained proved inadequate for histologic analysis. Pulsed
cyclophosphamide therapy was indicated in patients with lupus nephritis type III
and IV (WHO). Cyclophosphamide was administered at a dose of 500-1000 mg i.v..
All patients received corticosteroids. One patient was administered intravenous
immunoglobulin 400 mg/kg body weight. In ten out 13 patients with lupus
nephritis types III and IV, the therapeutic protocol was completed, while the
treatment is still under way in the remaining three patients. In nine and four
of 13 patients, complete and incomplete remission was achieved after 6-month
treatment, respectively. Two of 15 patients with type II mesangioproliferative
glomerulonephritis were treated only with corticosteroids alone. CONCLUSION: We
believe that intermittent pulsed cyclophosphamide therapy produces favorable
effects in the management of lupus nephritis type III and IV.
-----
Rev Alerg Mex. 2004 Mar-Apr;51(2):61-5.
[Hematopoietic steam cell transplantation in the management of
systemic lupus erythematosus resistant to treatment]
[Article in Spanish]
Rojas Ramos E, Martinez Jimenez NE, Reyes Salina A.
Departamento de inmunologia clinica, alergia y reumatologia, Hospital 1 de
Octubre, ISSSTE, Mexico, DF. drenriquerojas@correo.unam.mx
Recently stem cell transplantation has been suggested like novel treatment in
some severe auto-immune diseases, specifically in severe and refractory to
conventional treatment in systemic lupus erythematosus patients. Autologus
hematopoietic steam cell transplantation has been used in systemic lupus
erythematosus, because it does not represent risk of development in graft versus
host disease, which is the most common and severe complication in alogenic
transplant. This type of transplant is poorly used because of the difficulty to
get donors and laboratory background. Patients under this type of treatment
received high dosage of chemotherapy, followed by alogenic hematopoietic steam
cell transplantation with or without T cell depletion. Most of cases have
successes in treatment and some patients get clinical and serological remission
even for 34 months. However, a longer following is necessary to obtain
concluding results. This paper reviews those treatments in clinical cases
reported in the literature.
-----
Lupus. 2004;13(5):359-65.
Autologous stem cell transplantation for systemic lupus
erythematosus.
Jayne D, Tyndall A.
Department of Medicine, Addenbrooke's Hospital, Cambridge, UK.
Some patients with severe systemic lupus erythematosus do not respond to
conventional immunosuppression or suffer severe side effects from such
treatment. In order to explore the concept of immunoablation followed by
haematopoietic stem cell transplantation (HSCT) or 'rescue', an international
collaboration has occurred over the past seven years. The European Group for
Blood and Marrow Transplantation (EBMT) and The European League Against
Rheumatism (EULAR) have analysed their collective phase I and II studies and
found a remission rate (based on a reduction of the SLEDAI to < 3) in 66%,
one-third of whom later relapsed to some degree. The most often used protocol
was cyclophosphamide (CY) and G-CSF for mobilization and CY plus anti thymocyte
globulin as conditioning. Procedure related mortality was 12% in this sick group
of patients with major organ involvement. The North American, mostly single
centre experience showed higher rates of remission and one procedure related
death. Some relapse was also observed. Phase II studies designed to assess the
role of post-HSCT maintenance therapy are being considered by the EBMT/EULAR
group.
-----
Lupus. 2004;13(5):366-71.
Cyclophosphamide: new approaches for systemic lupus erythematosus.
Petri M.
Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. mpetri@jhmi.edu
Cyclophosphamide remains the 'gold standard' treatment for severe organ
threatening systemic lupus erythematosus (SLE), especially renal and central
nervous system lupus. Intravenous and oral cyclophosphamide have been compared,
retrospectively, with similar two year remission rates of 73% and 90%. In a
meta-analysis, intravenous cyclophosphamide with oral prednisone is more
effective than oral prednisone alone. The efficacy of cyclophosphamide in lupus
nephritis has been proven in multiple clinical trials, but efficacy has to be
balanced with toxicity, including infection, gonadal failure, and malignancy.
Although the continued use ofcyclophosphamide for renal lupus has been
challenged by a recent trial of mycophenolate mofetil, and may be challenged in
the future by planned trials of biologics, it continues to be widely used. This
review will touch on the traditional intravenous 'pulse' cyclophosphamide
regimen, consider its toxicity, and contrast it with newer approaches to
cyclophosphamide.
-----
N Engl J Med. 2004 Mar 4;350(10):971-80.
Sequential therapies for proliferative lupus nephritis.
Contreras G, Pardo V, Leclercq B, Lenz O, Tozman E, O'Nan P, Roth D.
Dialysis Unit, Veterans Affairs Medical Center and University of Miami, Miami,
USA. gcontrer@med.miami.edu.
BACKGROUND: Long-term therapy with cyclophosphamide enhances renal survival in
patients with proliferative lupus nephritis; however, the beneficial effect of
cyclophosphamide must be weighed against its considerable toxic effects.
METHODS: Fifty-nine patients with lupus nephritis (12 in World Health
Organization class III, 46 in class IV, and 1 in class Vb) received induction
therapy consisting of a maximum of seven monthly boluses of intravenous
cyclophosphamide (0.5 to 1.0 g per square meter of body-surface area) plus
corticosteroids. Subsequently, the patients were randomly assigned to one of
three maintenance therapies: quarterly intravenous injections of
cyclophosphamide, oral azathioprine (1 to 3 mg per kilogram of body weight per
day), or oral mycophenolate mofetil (500 to 3000 mg per day) for one to three
years. The base-line characteristics of the three groups were similar, with the
exception that the chronicity index was 1.9 points lower in the cyclophosphamide
group than in the mycophenolate mofetil group (P=0.009). RESULTS: During
maintenance therapy, five patients died (four in the cyclophosphamide group and
one in the mycophenolate mofetil group), and chronic renal failure developed in
five (three in the cyclophosphamide group and one each in the azathioprine and
mycophenolate mofetil groups). The 72-month event-free survival rate for the
composite end point of death or chronic renal failure was higher in the
mycophenolate mofetil and azathioprine groups than in the cyclophosphamide group
(P=0.05 and P=0.009, respectively). The rate of relapse-free survival was higher
in the mycophenolate mofetil group than in the cyclophosphamide group (P=0.02).
The incidence of hospitalization, amenorrhea, infections, nausea, and vomiting
was significantly lower in the mycophenolate mofetil and azathioprine groups
than in the cyclophosphamide group. CONCLUSIONS: For patients with proliferative
lupus nephritis, short-term therapy with intravenous cyclophosphamide followed
by maintenance therapy with mycophenolate mofetil or azathioprine appears to be
more efficacious and safer than long-term therapy with intravenous
cyclophosphamide. Copyright 2004 Massachusetts Medical Society
-----
Cochrane Database Syst Rev. 2004;(1):CD002922.
Treatment for lupus nephritis.
Flanc RS, Roberts MA, Strippoli GF, Chadban SJ, Kerr PG, Atkins RC.
Nephrology, Monash Medical Centre, Clayton Rd, Clayton, VIC, Australia.
BACKGROUND: Lupus nephritis is the renal manifestation of systemic lupus
erythematosus (SLE) - a disease mainly affecting young women with substantial
morbidity and mortality. It is classified by the World Health Organization (WHO)
criteria I - VI based on histology. WHO Class IV is a diffuse proliferative
glomerulonephritis which has the worst prognosis without treatment, with a
reported 17% five year survival in the era 1953-1969. This survival was 82% in
the early 1990's and continues to improve. An important factor behind this has
been the use of cytotoxics such as cyclophosphamide in addition to steroids.
OBJECTIVES: To assess the benefits and harms of different treatments in
biopsy-proven proliferative lupus nephritis (LN). SEARCH STRATEGY: We searched
the Cochrane Renal Group's specialised register (January 2003), the Cochrane
Central Register of Randomised Controlled Trials (CENTRAL - The Cochrane Library
issue 1, 2003), MEDLINE (1966 - 31 January 2003), EMBASE (1980 - 31 January
2003) and handsearched reference lists of retrieved articles. SELECTION
CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs comparing
treatments for PLN in both adult and paediatric patients with Class III, IV, Vc,
Vd lupus nephritis were included. All treatments were considered. DATA
COLLECTION AND ANALYSIS: Data was extracted and quality assessed independently
by two reviewers, with differences resolved by discussion. Dichotomous outcomes
are reported as relative risk (RR) and measurements on continuous scales are
reported as weighted mean differences (WMD) with 95% confidence intervals.
Subgroup analysis by study quality, drug type and drug route have been performed
where possible to explore reasons for heterogeneity. MAIN RESULTS: Of 920
articles identified, 25 were RCTs suitable for inclusion, which enrolled 915
patients. The majority compared cyclophosphamide or azathioprine plus steroids
versus steroids alone. Cyclophosphamide plus steroids reduced the risk of
doubling of serum creatinine (RR 0.59, 95% CI 0.40 to 0.88) compared to steroids
alone but had no impact on mortality (RR 0.98, 95% CI 0.53 to 1.82). The risk of
ovarian failure was significantly increased (RR 2.18, 95% CI 1.10 to 4.34).
Azathioprine plus steroids reduced the risk of all cause mortality compared to
steroids alone (RR 0.60, 95% CI 0.36 to 0.99), but did not alter renal outcomes.
Neither therapy was associated with increased risk of major infection.No benefit
was found with addition of plasma exchange to cyclophosphamide or azathioprine
plus steroids for mortality ( RR 0.71, 95% CI 0.50 to 1.02), doubling of serum
creatinine (RR 0.17, 95% CI 0.02 to 1.26) or end-stage renal failure (RR 1.24,
95% CI 0.60 to 2.57). There was also no increased risk of major infection (RR
0.69, 95% CI 0.35 to 1.37). REVIEWER'S CONCLUSIONS: Until future RCTs of newer
agents are completed, the current use of cyclophosphamide combined with steroids
remains the best option to preserve renal function in proliferative LN. The
smallest effective dose and shortest duration of treatment should be used to
minimise gonadal toxicity, without compromising efficacy.
-----
Rheumatology (Oxford). 2004 Mar;43(3):377-80. Epub 2004 Jan 06.
Lupus nephritis: treatment with mycophenolate mofetil.
Kapitsinou PP, Boletis JN, Skopouli FN, Boki KA, Moutsopoulos HM.
Department of Pathophysiology, Medical School, National University of Athens, 75
Mikras Asias Street, 11527 Athens, Greece.
OBJECTIVE: To evaluate the safety and efficacy of mycophenolate mofetil (MMF)
treatment in patients with lupus nephritis. METHODS: Eighteen patients with
biopsy-proven lupus nephritis (17 females, one male; mean age 31.6 yr; mean
lupus duration 92 months; mean duration of nephritis 57 months; nine with focal
proliferative glomerulonephritis, three with diffuse proliferative
glomerulonephritis, six with membranous nephropathy) were included. With five
exceptions, all patients had been treated previously with cyclophosphamide and
were selected because of either toxicity or inadequate clinical response to
treatment. MMF was given at 2 g daily in combination with steroids for up to 31
months (mean 15.3 months). The side-effects of MMF were recorded and efficacy
was assessed as the renal function profile. RESULTS: Complete remission was
observed in 10/18 patients and another 4/18 went into partial remission. Both
creatinine clearance and proteinuria were significantly improved during MMF
treatment in patients with the proliferative forms of nephritis. MMF
demonstrated a steroid-sparing effect in the whole population. Treatment failure
was recorded in 4/18 patients, all with membranous nephropathy. Two patients
developed gastrointestinal complaints and infectious meningitis occurred in one
patient. CONCLUSION: MMF appears to be an efficacious and safe treatment in
patients with proliferative forms of lupus nephritis who do not respond to or
cannot tolerate conventional treatment. The efficacy of MMF in lupus membranous
nephropathy remains unclear.
-----
Ann Rheum Dis. 2004 Mar;63(3):321-3.
Combined intravenous methotrexate and cyclophosphamide for
refractory childhood lupus nephritis.
Lehman TJ, Edelheit BS, Onel KB.
Division of Paediatric Rheumatology, Hospital for Special Surgery, and
Department of Paediatrics, Sanford Weill Medical College of Cornell University,
New York, NY 10021, USA. goldscout@aol.com
OBJECTIVE: To evaluate the efficacy and safety of combining monthly intravenous
methotrexate (IV MTX) with monthly IV cyclophosphamide (CYTX; given on the same
day) for the treatment of children who develop recurrent diffuse proliferative
glomerulonephritis secondary to systemic lupus erythematosus during or after the
standard 3 year course of IV CYTX. METHODS: Five children were treated with nine
monthly doses of IV CYTX (750-1000 mg/m(2)/month) and IV MTX (50-300
mg/m(2)/month) given on the same day. Their clinical and laboratory measurements
were collected every other week throughout the nine months. RESULTS: All
children improved dramatically. SLEDAI scores decreased from an average of 13.8
to 4.4, mean (SD) serum creatinine level fell from 100 (60) to 80 (40) micro
mol/l, and serum albumin rose from 28 (11) g/l to 41 (6) g/l, while the mean
(SD) C3 level increased from 0.5 (0.1) g/l to 0.9 (0.4) g/l. Clinical
improvement persisted after 4 years' follow up despite discontinuing MTX and
CYTX after 9 months. The average daily dose of corticosteroids has been reduced
from 27.6 mg/day at the start of treatment to 12.5 mg/day at follow up.
CONCLUSION: Combined IV MTX and IV CYTX treatment effectively controls recurrent
or refractory lupus nephritis in children with significant disease activity
after treatment with IV CYTX alone.
-----
Am J Kidney Dis. 2004 Feb;43(2):269-76.
Treatment of pure membranous lupus nephropathy with prednisone
and azathioprine: an open-label trial.
Mok CC, Ying KY, Lau CS, Yim CW, Ng WL, Wong WS, Au TC.
Department of Medicine, Tuen Mun Hospital, New Territories, Hong Kong, SAR,
People,s Republic of China. ccmok@netvigator.com
BACKGROUND: The aim of this study was to report the outcome of pure membranous
lupus nephropathy treated with prednisone and azathioprine (AZA). METHODS:
Consecutive patients with pure membranous lupus glomerulonephritis (World Health
Organization [WHO] Va and Vb) from 4 regional hospitals were recruited for an
open-label treatment trial consisting of prednisone and AZA. Remission status
was evaluated at 12 months. Maintenance treatment with low-dose prednisone and
AZA was continued indefinitely for those who achieved remission. Factors
predictive of initial renal remission and subsequent relapse were studied by
statistical analyses. RESULTS: Thirty-eight patients (31 women and 7 men) were
studied. The mean age was 35.0 +/- 9.2 years, and the duration of systemic lupus
erythematosus was 48.5 +/- 59 months. Seventeen (45%) patients had WHO class Va
lupus nephritis, whereas 21 (55%) had class Vb disease. Two patients withdrew
from the protocol because of idiosyncratic reactions to AZA. At 12 months, 24
(67%) patients achieved complete remission (CR), 8 (22%) achieved partial
remission (PR), and 4 (11%) were treatment resistant. Patients who achieved CR
or PR were maintained on low-dose prednisone and AZA. Over a mean follow-up
period of 90.4 +/- 59 months, 6 (19%) patients had relapse of nephritis (proteinuric
flare in 4 and nephritic flare in 2). The cumulative risk of renal relapse was
12% at 36 months and 16% at 60 months. No particular clinical variables were
found to predict renal remission or relapses. Over a mean follow-up of 90
months, 13% of patients had decline of creatinine clearance by 20%, but none had
doubling of serum creatinine. Renal outcome was not significantly worse in
patients presenting with nephrotic syndrome. Treatment generally was well
tolerated. CONCLUSION: A combination of prednisone and AZA is reasonably
effective for the initial treatment of pure membranous lupus nephritis. Severe
adverse effects are uncommon. The additional efficacy of AZA in comparison with
prednisone alone has to be confirmed with randomized, controlled trials.
-----
Am J Kidney Dis. 2004 Feb;43(2):197-208.
Treatment of diffuse proliferative lupus nephritis: a
meta-analysis of randomized controlled trials.
Flanc RS, Roberts MA, Strippoli GF, Chadban SJ, Kerr PG, Atkins RC.
Department of Nephrology, Monash Medical Centre, Clayton, Victoria, Australia.
robert.flanc@med.monash.edu.au
BACKGROUND: In this systematic review of randomized controlled trials (RCTs), we
assess the benefits and harm of current treatments for diffuse proliferative
lupus nephritis (DPLN). METHODS: The Cochrane Controlled Trial Registry,
MEDLINE, and EMBASE were searched for RCTs of treatment for DPLN. All available
RCTs of patients with biopsy-proven DPLN were included, and data were extracted
for overall mortality, end-stage renal disease, doubling of serum creatinine
level, relapse, major infection, herpes zoster infection, ovarian failure,
malignancy, and bladder toxicity. Treatment effects on these outcomes were
summarized as relative risk (RR) with 95% confidence interval (CI) and pooled by
using a random-effects model. RESULTS: Twenty-five of 920 articles identified
were eligible RCTs and were included. The majority compared cyclophosphamide or
azathioprine plus steroids versus steroids alone. Cyclophosphamide plus steroids
reduced the risk for doubling of serum creatinine level (4 RCTs, 228 patients;
RR, 0.59; 95% CI, 0.40 to 0.88) compared with steroids alone, but had no impact
on overall mortality (5 RCTs, 226 patients; RR, 0.98; 95% CI, 0.53 to 1.82).
However, risk for ovarian failure was increased significantly (3 RCTs, 147
patients; RR, 2.18; 95% CI, 1.10 to 4.34). In studies from the 1970s,
azathioprine plus steroids reduced the risk for all-cause mortality compared
with steroids alone (3 RCTs, 78 patients; RR, 0.60; 95% CI, 0.36 to 0.99), but
had no effect on renal outcomes. Neither therapy was associated with increased
risk for major infection. The addition of plasma exchange to these treatments
offered no benefit, and information on other agents, including mycophenolate
mofetil, was insufficient for analysis. CONCLUSION: Until future RCTs of newer
agents are completed, the current use of cyclophosphamide combined with steroids
remains the best option to preserve renal function in patients with DPLN. The
smallest effective dose and shortest duration of treatment should be used to
minimize gonadal toxicity without compromising efficacy.
-----
N Engl J Med. 2004 Mar 4;350(10):971-80.
Sequential therapies for proliferative lupus nephritis.
Contreras G, Pardo V, Leclercq B, Lenz O, Tozman E, O'Nan
P, Roth D.
Dialysis Unit, Veterans Affairs Medical Center and University
of Miami, Miami, USA. gcontrer@med.miami.edu.
BACKGROUND: Long-term therapy with cyclophosphamide enhances
renal survival in patients with proliferative lupus nephritis;
however, the beneficial effect of cyclophosphamide must be weighed
against its considerable toxic effects. METHODS: Fifty-nine patients
with lupus nephritis (12 in World Health Organization class III,
46 in class IV, and 1 in class Vb) received induction therapy
consisting of a maximum of seven monthly boluses of intravenous
cyclophosphamide (0.5 to 1.0 g per square meter of body-surface
area) plus corticosteroids. Subsequently, the patients were randomly
assigned to one of three maintenance therapies: quarterly intravenous
injections of cyclophosphamide, oral azathioprine (1 to 3 mg per
kilogram of body weight per day), or oral mycophenolate mofetil
(500 to 3000 mg per day) for one to three years. The base-line
characteristics of the three groups were similar, with the exception
that the chronicity index was 1.9 points lower in the cyclophosphamide
group than in the mycophenolate mofetil group (P=0.009). RESULTS:
During maintenance therapy, five patients died (four in the cyclophosphamide
group and one in the mycophenolate mofetil group), and chronic
renal failure developed in five (three in the cyclophosphamide
group and one each in the azathioprine and mycophenolate mofetil
groups). The 72-month event-free survival rate for the composite
end point of death or chronic renal failure was higher in the
mycophenolate mofetil and azathioprine groups than in the cyclophosphamide
group (P=0.05 and P=0.009, respectively). The rate of relapse-free
survival was higher in the mycophenolate mofetil group than in
the cyclophosphamide group (P=0.02). The incidence of hospitalization,
amenorrhea, infections, nausea, and vomiting was significantly
lower in the mycophenolate mofetil and azathioprine groups than
in the cyclophosphamide group. CONCLUSIONS: For patients with
proliferative lupus nephritis, short-term therapy with intravenous
cyclophosphamide followed by maintenance therapy with mycophenolate
mofetil or azathioprine appears to be more efficacious and safer
than long-term therapy with intravenous cyclophosphamide. Copyright
2004 Massachusetts Medical Society
-----
Lupus. 2004;13(2):89-94.
High-dose immunosuppression with autologous stem
cell transplantation in severe refractory systemic lupus erythematosus.
Lisukov IA, Sizikova SA, Kulagin AD, Kruchkova IV, Gilevich
AV, Konenkova LP, Zonova EV, Chernykh ER, Leplina OY, Sentyakova
TN, Demin AA, Kozlov VA.
Novosibirsk State Medical Academy, Novosibirsk, Russia. depsct@online.nsk.su
Systemic lupus erythematosus (SLE) is an immune-mediated disease
that is responsive to suppression or modulation of the immune
system. Patients with SLE who experience persistent multiorgan
dysfunction, despite standard doses of intravenous cyclophosphamide
(Cy), represent a subset of patients at high risk of early death.
We investigated the efficacy and toxicity of high-dose immunosuppression
and autologous hematopoietic stem cell transplantation (SCT) to
treat such patients. Six patients (all female, age 15-29 years)
with severe refractory SLE were enrolled in the clinic of our
institution from 1998 to 2003. All patients were seriously ill,
with SLE disease activity indices (SLEDAI) of 6-30, including
two cases with central nervous system lupus, one case with lung
vasculitis, and three cases with nephritis and nephrotic syndrome.
All patients were registered in the European Group for Blood and
Marrow Transplantation (EBMT)/European League Against Rheumatism
(EULAR) database. Previous immunosuppression included pulse Cy
intravenous, prednisolone (standard doses and pulse therapy),
oral Cy and azathioprine, with little or no effect on disease
progression. Autologous hemopoietic stem cells were collected
from bone marrow (n = 4) or mobilized from peripheral blood with
Cy and granulocyte colony-stimulating factor (G-CSF) (n = 2).
Pre-transplant conditioning regimens included BEAM +/- ATG (n
= 2), melphalan 140 mg/m2 + etoposid 1600 mg/m2 (n = 2) and Cy
200 mg/kg +/- ATG (n = 2). Median time to an absolute neutrophil
count (ANC) greater than 0.5 x 10(9)/L and platelet count greater
than 50 x 10(9)/L was 13 and 15 days, respectively. Three patients
died on days 11, 22 and 63 due to transplant-related complications.
The follow-up is now 60 and six months for two patients (complete
remission), and 42 months for one other patient (partial response).
All patients had experienced multiple and severe episodes of infections
pre-SCT and long-term history of corticosteroid therapy (3-14
years). We conclude that achievement of prolonged, corticosteroid-free
remissions is a reality. Judicious selection of patients earlier
in disease or in remission, but with a high risk of relapse or
further progression, will diminish transplantation-related mortality.
-----
Am J Clin Dermatol 2003;4(6):379-87
Thalidomide in cutaneous lupus erythematosus.
Pelle M, Werth V.
Department of Dermatology, School of Medicine, University of Pennsylvania,
Philadelphia, Pennsylvania, USA.
For nearly 50 years, thalidomide has struggled between success
and controversy. After causing an epidemic of phocomelia and other
birth defects during the 1960s, affecting thousands of neonates,
thalidomide was used as a sedative in selective disorders including
leprosy. The potent anti-inflammatory properties of thalidomide
were serendipitously discovered while treating patients with erythema
nodosum leprosum, and the drug is now approved by the US FDA for
the treatment of this disease. Subsequently, the immunosuppressant
effects of thalidomide, including the complex modulation of many
cytokines, have been recognized. One promising application of
thalidomide has been the treatment of cutaneous lupus erythematosus.
Among the largest series reviewed, the drug has been found to
ameliorate cutaneous lupus erythematosus in 90% of patients, on
average. Remission is achieved in approximately 15-20% of patients
with cutaneous lupus erythematosus at doses between 50-400mg daily.
Contraceptive concerns and the recognized neuropathic effects
of thalidomide limit the use of the drug in patients with cutaneous
lupus. Physicians who prescribe thalidomide in the US must be
registered with the drug manufacturer. With appropriate control
of drug access and close physician monitoring, thalidomide provides
a needed therapeutic option for the treatment of refractory cases
of cutaneous lupus erythematosus.
-----
Ann Rheum Dis 2003 Jun;62(6):534-539
Mycophenolate mofetil prevents a clinical relapse
in patients with systemic lupus erythematosus at risk.
Bijl M, Horst G, Bootsma H, Limburg PC, Kallenberg CG.
Department of Clinical Immunology, University Hospital, Groningen,
The Netherlands. Department of Rheumatology, University Hospital,
Groningen, The Netherlands. Department of Pathology and Laboratory
Medicine, University Hospital, Groningen, The Netherlands.
BACKGROUND: Systemic lupus erythematosus (SLE) is characterised
by the presence of antibodies to double stranded DNA (dsDNA),
which are involved in the pathogenesis of SLE. Previous studies
showed that at least two thirds of patients develop a clinical
relapse within six months after a significant rise in the anti-dsDNA
level, and most relapses were prevented by the administration
of corticosteroids at the time of the rise. OBJECTIVE: To determine
whether mofetil mycophenolate (MMF) can prevent a clinical relapse
without the side effects associated with corticosteroids. METHODS:
36 patients with SLE were examined monthly to determine whether
a rise in anti-dsDNA level had occurred. A rise was defined as
an increase of 25% of the level of the previous sample of at least
15 IU/ml within a four month period. After a rise patients were
treated with MMF 2000 mg daily for six months. Patients were monitored
monthly for the occurrence of a clinical relapse and to assess
the serological activity and state of activation of CD4+, CD8+,
and CD19+ lymphocyte subsets. RESULTS: Anti-dsDNA rose in 10 patients.
Treatment with MMF was started in all these patients, and after
six months no clinical relapse had occurred. Side effects were
minimal. Antibodies to dsDNA decreased during the treatment (p<0.001),
associated with a decrease in the state of activation of CD19+
lymphocytes. No changes were found in the state of activation
of CD4+ or CD8+ lymphocyte subsets. CONCLUSION: Administration
of MMF after a rise in antibodies to dsDNA is well tolerated,
decreases anti-dsDNA and B cell activation, and seems to prevent
the occurrence of a clinical relapse in patients with SLE.
-----
BioDrugs 2003;17(3):212-215
Abetimus: Abetimus sodium, LJP 394.
Abetimus [Abetimus sodium, LJP 394, Rentol trade mark, Riquent
trade mark ] is a synthetic Toleragen((R)) molecule consisting
of four double-stranded oligodeoxyribonucleotides attached to
nonimmunogenic polyethylene glycol, a proprietary carrier platform.This
profile has been selected from R&D Insight trade mark, a pharmaceutical
intelligence database produced by Adis International Ltd. It was
originated by La Jolla Pharmaceuticals.Abetimus is an immunomodulating
agent that induces tolerance in B cells directed against double-stranded
DNA (dsDNA). It does this by cross-linking surface antibodies.
These antibodies are thought to be responsible for lupus nephritis,
a chronic kidney disease that develops in patients with systemic
lupus erythematosus. A phase III trial of abetimus was completed
in December 2002. La Jolla Pharmaceuticals previously established
two licensing agreements for abetimus, which have since been terminated.
One of the agreements was with Leo Pharmaceutical Products of
Denmark. The company was licensed rights to abetimus covering
Europe and the Middle East. The other agreement was with Abbott
Laboratories. Abbott returned all rights to abetimus to La Jolla
Pharmaceuticals in September 1999 based on the results of an analysis
of the phase II/III trial of abetimus in lupus patients with a
history of renal disease.A phase III trial, named 'PEARL' (Program
Enabling Antibody Reduction in Lupus), has been conducted in the
US in patients with lupus nephritis. It enrolled 317 patients
with a history of lupus who were treated with a weekly dose of
abetimus 100mg or placebo. The trial was completed in December
2002 and preliminary results were reported in February 2003.PEARL
was designed to determine whether abetimus can significantly delay
renal flares and delay the need for treatment with high-dose corticosteroids
and/or cyclophosphamide in patients with high affinity IgG antibodies
to the double-stranded oligonucleotide epitope in abetimus. Patients
with high-affinity antibodies, were selected using a surface plasmon
resonance (SPR)-based pharmacoproteonomics assay provided by Biacor
International.Following the completion of PEARL in December 2002,
La Jolla Pharmaceuticals initiated an on-going, open-label, follow-on
trial. All patients who had completed PEARL were eligible to enrol
and receive weekly treatment with abetimus. However, in April
2003, La Jolla Pharmaceuticals announced that it was closing this
trial, which was designed to collect additional long-term safety
data, to conserve resources for the continued development of the
drug.Previously, La Jolla Pharmaceuticals and Abbott initiated
a phase II/III trial of abetimus in more than 200 patients with
lupus nephritis. However, this trial was discontinued in May 1999
because the primary end-point (time to renal flare) was much shorter
than expected. After the trial was halted, further analysis of
trial data using a new blood test to measure the strength of the
binding between abetimus and a patient's antibodies to dsDNA was
conducted. The additional analysis showed that the number of renal
flares in the high-affinity patients (responders) treated with
abetimus was less than half of the number of renal flares in high-affinity
patients treated with placebo. Responders also showed a significant
reduction in the use of high-dose corticosteroids and cyclophosphamide.
Being able to screen patients to identify those likely to respond
to therapy lead La Jolla Pharmaceuticals to initiate PEARL after
Abbott's withdrawal from the drug. It is believed that screening
patients will help increase the cost-effectiveness of clinical
development.In September 2000, the US FDA granted orphan drug
status for abetimus in the treatment of lupus nephritis. The European
Commission followed suit in November 2001, granting orphan drug
status for abetimus in the EU.
-----
Clin Ther 2003 Feb;25(2):342-95
Thalidomide: a review of approved and investigational
uses.
Matthews SJ, McCoy C.
Department of Pharmacy Practice, School of Pharmacy, Bouve College
of Health Sciences, Northeastern University, Boston, Massachusetts
02115, USA. s.matthews@neu.edu
BACKGROUND: Thalidomide is best known as a major teratogen
that caused birth defects in up to 12,000 children in the 1960s.
More recently, this agent has been approved by the US Food and
Drug Administration for the treatment of erythema nodosum leprosum
(ENL) through a restricted-use program. Its immunomodulatory,
anti-inflammatory, and antiangiogenic properties are currently
under study in a number of clinical conditions. OBJECTIVE: This
article reviews the pharmacology of thalidomide; its approved
and off-label uses in dermatologic, oncologic, and gastrointestinal
conditions; and adverse events associated with its use. METHODS:
Relevant articles were identified through searches of MEDLINE
(1966-June 2002), International Pharmaceutical Abstracts (1970-June
2002), and EMBASE (1990-June 2002). Search terms included but
were not limited to thalidomide, pharmacokinetics, pharmacology,
therapeutic use, and teratogenicity, as well as terms for specific
disease states and adverse events. Further publications were identified
from the reference lists of the reviewed articles. Abstracts of
recent symposia were obtained from the American Society of Clinical
Oncology Web site. RESULTS: Thalidomide is thought to exert its
therapeutic effect through the modulation of cytokines, particularly
tumor necrosis factor-alpha. In addition to its approved indication
for ENL, thalidomide has been studied in various other conditions,
including graft-versus-host disease, discoid lupus erythematosus,
sarcoidosis, relapsed/refractory multiple myeloma, Waldenstrom's
macroglobulinemia, myelodysplastic syndromes, acute myeloid leukemia,
myelofibrosis with myeloid metaplasia, renal cell carcinoma, malignant
gliomas, prostate cancer, Kaposi's sarcoma, colorectal carcinoma,
oral aphthous ulcers, Behcet's disease, Crohn's disease, and HIV/AIDS-associated
wasting. Adverse events most frequently associated with its use
include somnolence, constipation, rash, peripheral neuropathy,
and thromboembolism. CONCLUSIONS: Use of thalidomide is limited
by toxicity, limited efficacy data, and restricted access. Evidence
of its efficacy in conditions other than ENL awaits the results
of controlled clinical trials.
-----
Arthritis Rheum 2003 Apr;48(4):1067-70
Treatment of systemic lupus erythematosus-associated
type B insulin resistance syndrome with cyclophosphamide and mycophenolate
mofetil.
Gehi A, Webb A, Nolte M, Davis J Jr.
University of California, San Francisco, 94143, USA.
Systemic lupus erythematosus (SLE) is an autoimmune disease
characterized by loss of immunologic self-tolerance and the subsequent
development of autoantibodies. These antibodies are thought to
be important in relation to the clinical manifestations of the
disease. One example is the development of multiple cytopenias
secondary to cytolytic or cytotoxic antibodies directed toward
red blood cells, platelets, and white blood cells. Other antibodies
may mediate abnormal cellular mechanisms such as those seen with
neuropsychiatric manifestations of SLE. We report the occurrence
of autoantibodies directed toward insulin receptors and the subsequent
development of type B insulin resistance syndrome in a woman with
SLE. This syndrome was treated successfully with cyclophosphamide
and mycophenolate mofetil.
-----
Arthritis Rheum 2003 Mar;48(3):719-27
A short course of BG9588 (anti-CD40 ligand antibody)
improves serologic activity and decreases hematuria in patients
with proliferative lupus glomerulonephritis.
Boumpas DT, Furie R, Manzi S, Illei GG, Wallace DJ, Balow JE,
Vaishnaw A; BG9588 Lupus Nephritis Trial Group.
National Institute of Arthritis and Musculoskeletal and Skin Diseases,
National institutes of Health, Department of Health and Human
Services, Bethesda, Maryland, USA. boumpasd@med.uoc.gr
OBJECTIVE: CD40-CD40 ligand (CD40L) interactions play a significant
role in the production of autoantibodies and tissue injury in
lupus nephritis. We performed an open-label, multiple-dose study
to evaluate the safety, efficacy, and pharmacokinetics of BG9588,
a humanized anti-CD40L antibody, in patients with proliferative
lupus nephritis. The primary outcome measure was 50% reduction
in proteinuria without worsening of renal function. METHODS: Twenty-eight
patients with active proliferative lupus nephritis were scheduled
to receive 20 mg/kg of BG9588 at biweekly intervals for the first
3 doses and at monthly intervals for 4 additional doses. Safety
evaluations were performed on all patients. Eighteen patients
receiving at least 3 doses were evaluated for efficacy. RESULTS:
The study was terminated prematurely because of thromboembolic
events occurring in patients in this and other BG9588 protocols
(2 myocardial infarctions in this study). Of the 18 patients for
whom efficacy could be evaluated, 2 had a 50% reduction in proteinuria
without worsening of renal function. Mean reductions of 38.9%
(P < 0.005), 50.1% (P < 0.005), and 25.3% (P < 0.05)
in anti-double-stranded DNA (anti-dsDNA) antibody titers were
observed at 1, 2, and 3 months, respectively, after the last treatment.
There was a significant increase in serum C3 concentrations at
1 month after the last dose (P < 0.005), and hematuria disappeared
in all 5 patients with significant hematuria at baseline. There
were no statistically significant reductions in lymphocyte count
or serum immunoglobulin, anticardiolipin antibody, or rubella
IgG antibody concentrations after therapy. CONCLUSION: A short
course of BG9588 treatment in patients with proliferative lupus
nephritis reduces anti-dsDNA antibodies, increases C3 concentrations,
and decreases hematuria, suggesting that the drug has immunomodulatory
action. Additional studies will be needed to evaluate its long-term
effects.
-----
Med Klin 2003 Feb 15;98(2):79-90
[Neuropsychiatric involvement in systemic lupus
erythematosus. Part 2: diagnostic and therapy]
[Article in German]
Weiner SM, Otte A, Uhl M, Brink I, Schumacher M, Peter HH.
Abteilung fur Rheumatologie und Klinische Immunologie, Medizinische
Klinik der Albert-Ludwigs-Universitat Freiburg. stefan.weiner@ruhr-uni-bochum.de
Background: The diagnosis of neuropsychiatric lupus erythematosus
(NPSLE) can be difficult and has to be differentiated from neurologic
complications that result from hypertension, drugs, infection,
uremia, and metabolic changes. Diagnostics: There is no single
test which is diagnostic. Therefore, the clinical presentation,
serologic tests and neuroimaging techniques have to be combined
to support the diagnosis of cerebral lupus. Magnetic resonance
imaging (MRI) is routinely used with a sensitivity of 50-87%.
However, the abnormalities such as white matter lesions or brain
atrophy are nonspecific and were also found in asymptomatic patients
(16-52%). A negative MRI result does not exclude a diagnosis of
cerebral lupus. Antibodies against phospholipids are an important
immunoserologic marker due to the close association with thromboembolic
events. Echocardiography and cerebrospinal fluid examination should
be added to rule out cardiac embolic disease and CNS infection.
Functional brain imaging techniques such as single-photon emission
computed tomography, positron emission tomography, magnetization
transfer imaging or magnetic resonance spectroscopy may be helpful
especially in patients with unconspicuous MRI, but the findings
are not SLE-specific. Therapy: The treatment of cerebral lupus
is empiric, due to a lack of randomized studies. Inflammatory
brain lesions are treated with corticosteroids and immunosuppressive
drugs (e. g., cyclophosphamide). Anticoagulant therapy with coumarins
(at a target INR of 3.0-3.5) is recommended in cases of thrombotic
events associated with antiphospholipid antibodies. However, no
studies exist on patients with arterial thrombosis, including
strokes, supporting this target INR.
-----
Cancer Control 2003 Jan-Feb;10(1):57-65
Intense immunosuppression and stem-cell transplantation
for patients with severe rheumatic autoimmune disease: a review.
Van Laar JM, Tyndall A.
Department of Rheumatology, Leiden University Medical Center,
2300 RC Leiden, The Netherlands. j.m.van_laar@lumc.nl
BACKGROUND: Intense immunosuppression plus stem-cell transplantation
(SCT) has emerged as a new treatment modality for patients with
refractory, severe rheumatic autoimmune disease. Its rationale
is based on eliminating autoaggressive lymphocytes by lympho-
or myeloablative conditioning followed by stem-cell rescue. Preclinical
studies in animal models of autoimmune disease and observations
in patients with rheumatoid arthritis (RA) who were cured after
allogeneic bone marrow transplantation for concomitant hematologic
malignancy have provided support for the concept. METHODS: The
authors reviewed the results of recent phase I/II studies and
data from the EBMT/EULAR Registry on more than 400 patients with
autoimmune diseases including RA, systemic lupus erythematosus
(SLE), systemic sclerosis (SSc), and juvenile idiopathic arthritis
(JIA). RESULTS: Toxicity resulting from stem-cell grafting depended
on underlying disease and the intensity of the conditioning regimen.
Treatment-related mortality was low in RA (1.4%) but relatively
high (>10%) in patients with JIA, SLE, and SSc, possibly related
to visceral involvement in these patients. With the application
of uniform and strict criteria, safety has improved. Long-term
remissions up to 4 years have been observed in SSc and JIA, while
relatively more relapses have occurred in patients with SLE and
RA. Sensitivity to antirheumatic drugs was restored in RA and
SLE patients, however, resulting in improved disease control.
CONCLUSIONS: Intense immunosuppression and SCT may be an effective
therapy for selected patients with severe rheumatic autoimmune
disease. Its merits need to be proven via multicenter phase III
studies by comparing efficacy and safety with conventional therapy.
-----
Br J Dermatol 2003 Feb;148(2):353-6
Efficacy of topical tacrolimus for treating the
malar rash of systemic lupus erythematosus.
Kanekura T, Yoshii N, Terasaki K, Miyoshi H, Kanzaki T.
Department of Dermatology, Kagoshima University Faculty of Medicine,
8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan. takurok@m2.kufm.kagoshima-u.ac.jp
The rash of systemic lupus erythematosus (SLE) is usually treated
with topical corticosteroids, but prolonged use causes adverse
cutaneous side-effects. We assessed the efficacy of topical tacrolimus
for treating the skin lesions of SLE. Three patients with SLE
affecting their facial skin applied 0.1% tacrolimus ointment on
one side of their face twice daily for 3 weeks, in conjunction
with a sunscreen cream. After 3 weeks, erythema on the treated
side was ameliorated in all three patients compared with the untreated
side. Although the study is preliminary, the results demonstrate
that topical tacrolimus may be useful for treating the malar rash
of SLE.
-----
Arthritis Rheum 2002 Dec;46(12):3251-8
Treatment of systemic lupus erythematosus by inhibition
of T cell costimulation with anti-CD154: a randomized, double-blind,
placebo-controlled trial.
Kalunian KC, Davis JC Jr, Merrill JT, Totoritis MC, Wofsy D; IDEC-131
Lupus Study Group.
University of California, Los Angeles School of Medicine, USA.
kkalunian@mednet.ucla.edu
OBJECTIVE: To evaluate the safety and efficacy of a humanized
monoclonal antibody against CD154 (IDEC-131) in patients with
active systemic lupus erythematosus (SLE). METHODS: In this phase
II, double-blind, placebo-controlled, multiple-center, multiple-dose
study, 85 patients with mild-to-moderately active SLE were randomized
to receive 6 infusions of IDEC-131, ranging from 2.5 mg/kg to
10.0 mg/kg, or placebo over 16 weeks. Efficacy was assessed at
week 20, primarily by the Systemic Lupus Erythematosus Disease
Activity Index (SLEDAI) and secondarily, by multiple measures
of disease activity. Safety was assessed through week 28 by clinical
and laboratory evaluation. Immunogenicity studies were also performed.
RESULTS: SLEDAI scores improved from the baseline levels of disease
activity in all groups, including the placebo group. However,
these scores were not statistically different among the IDEC-131
treatment and placebo groups at week 20. Evaluations of secondary
variables did not indicate significant differences between the
IDEC-131 treatment and placebo groups. The type and frequency
of adverse events were similar between the IDEC-131 and placebo
groups. CONCLUSION: IDEC-131 administered at doses ranging 2.5-10.0
mg/kg over 16 weeks was safe and well tolerated in patients with
SLE. Efficacy of the drug compared with placebo was not demonstrated.
There were statistically significant improvements from baseline
in all groups, including the placebo group.
-----
Drugs 2003;63(2):167-80
Newer drugs for the treatment of lupus nephritis.
Kuiper-Geertsma DG, Derksen RH.
Department of Rheumatology, Isalaklinieken, Zwolle, and Ijsselmeerziekenhuizen,
Emmeloord, The Netherlands.
This article first reviews the current treatment of lupus nephritis,
with a focus on the most serious forms, that is, the proliferative
subtypes. Current standards for treatment have been developed
empirically. Corticosteroids form the basis of all regimens. Cyclophosphamide
given intravenously for prolonged periods is the current gold
standard. Azathioprine can be regarded as an effective drug for
maintenance treatment of lupus nephritis. Studies on its efficacy
in schedules for remission induction are in progress. It has been
learned from studies on 'conventional' immunosuppression that
randomised, clinical trials should comprise large numbers of patients
and a follow-up of many years to elucidate differences between
effective strategies. These requirements are not met by any of
the 'new' treatments we discuss in this review. There is only
limited experience in patients with lupus nephritis with drugs
that are currently used for immunosuppression in other autoimmune
diseases, such as methotrexate, cyclosporin and high-dose intravenous
gammaglobulins, nor with new immunosuppressive drugs that have
been developed for immunosuppression in organ transplantation
(mycophenolate mofetil, tacrolimus, fludarabine and cladribine).
Hormonal therapy with the weak androgen prasterone (dehydroepiandrosterone;
DHEA) has no role in treatment of active lupus nephritis. There
are interesting experiences with agents that have evolved from
progress in immunobiology and in our understanding of immunological
processes. These modalities enable more specific immunosuppression
and include monoclonal antibodies directed at immune cells, cytokines
and components of the complement system, constructs developed
to induce tolerance in pathogenic B cells, and gene therapy. Finally,
we review data on autologous bone marrow transplantation in patients
with systemic lupus erythematosus. We conclude that some strategies
(like mycophenolate mofetil) are good candidates for further investigation
in large-scale, prospective, randomised trials with prolonged
follow-up (which are almost by definition hard to perform). Most
new biological agents still are in a pre-clinical phase.
-----
Drugs 2003;63(3):257-74
Treatment of lupus nephritis.
Hejaili FF, Moist LM, Clark WF.
Division of Nephrology, London Health Sciences Centre, Westminster
Campus, The University of Western Ontario, Canada.
Renal involvement in systemic lupus erythematosus (SLE) is
a serious complication of the disease. However, the prognosis
of patients with lupus nephritis is continually improving with
10-year survival rates now greater than 75%. This improvement
reflects earlier diagnosis due to more sensitive and specific
diagnostic tests, better clinical appreciation of the natural
history, and improved treatment of SLE and its manifestations.
This review of the treatment of lupus nephritis has graded the
level of evidence of specific treatment using the guidelines of
the US Preventive Service Task Force. Although many new treatments
have been advocated, the best evidence for treating proliferative
lupus nephritis relies on a strategy combining specific treatment
of the SLE as well as generalised treatment of the associated
comorbidities. This strategy involves a combination of corticosteroids
and cytotoxic agents plus or minus the adjunctive use of antimalarials,
coordinated aggressive management of hypertension, proteinuria,
infections, dyslipidaemia, thrombotic coagulopathy and potential
renal replacement therapies.
-----
Arch Dermatol 2003 Jan;139(1):50-4
Low-dose thalidomide therapy for refractory cutaneous
lesions of lupus erythematosus.
Housman TS, Jorizzo JL, McCarty MA, Grummer SE, Fleischer AB Jr,
Sutej PG.
Department of Dermatology, Wake Forest University School of Medicine,
Winston-Salem, NC 27157-1071, USA.
BACKGROUND: Thalidomide is an anti-inflammatory agent and an
immunomodulator that inhibits the production of tumor necrosis
factor alpha. It has shown promise as a treatment option for the
cutaneous manifestations of lupus erythematosus (LE). OBJECTIVE:
To assess the degree of clinical response per subtype of cutaneous
lupus, the duration of therapy before documented clinical improvement,
and the incidence of adverse effects, including peripheral neuropathy,
with low-dose thalidomide therapy at 100 mg daily in the treatment
of refractory cutaneous lesions of LE. METHODS: This retrospective
medical record review of patients with refractory cutaneous manifestations
of LE is one of the largest modern series in the literature. There
were 29 patients seen at the Department of Dermatology, Wake Forest
University School of Medicine (Winston-Salem, NC), who were unresponsive
to conventional agents including antimalarial agents, and who
started treatment between 1998 and 2000. Twenty-three patients
who took the drug for 1 month or more were included in the analysis.
Clinical responses were assessed by the investigators based on
statements of improvement listed in the clinic notes and were
categorized as "no response," "partial response,"
and "complete response." Partial response was classified
as either 75% or greater or less than 75% improvement. The incidence
of adverse effects including peripheral neuropathy was determined.
RESULTS: Of the 23 patients, 17 (74%) demonstrated complete resolution
of the cutaneous manifestations of LE, whereas 3 patients (13%)
demonstrated 75% or greater partial improvement; 3 patients (13%)
had less than 75% partial clinical improvement; and 21 patients
(91%) who demonstrated a complete or partial response did so within
8 weeks of initiating thalidomide therapy. CONCLUSIONS: Based
on the results of this case series, we believe that thalidomide
should be given prime consideration as a treatment for antimalarial
drug-resistant interface lesions of LE. The design of prospective,
randomized, double-blind, placebo-controlled trials for this indication
is warranted.
-----
Arthritis Rheum 2003 Jan;48(1):166-73
High-dose cyclophosphamide without stem cell transplantation
in systemic lupus erythematosus.
Petri M, Jones RJ, Brodsky RA.
Johns Hopkins University School of Medicine, Baltimore, Maryland
21205, USA.
OBJECTIVE: High-dose chemotherapy followed by hematopoietic
stem cell transplantation is increasingly being studied as a treatment
for severe autoimmune disorders, such as systemic lupus erythematosus
(SLE). High-dose cyclophosphamide, the foundation of virtually
all conditioning regimens for stem cell transplantation, is not
myeloablative; therefore, when high-dose cyclophosphamide is used
alone, autografting, with its potential for reinfusing autoreactive
effector cells, is not required. We undertook this study to investigate
the safety and efficacy of high-dose cyclophosphamide without
stem cell transplantation in refractory SLE. METHODS: We treated
14 patients with moderate-to-severe SLE that had been refractory
to corticosteroids and one or more additional immunosuppressive
drugs. All patients received 50 mg/kg of cyclophosphamide for
4 consecutive days followed by 5 microg/kg granulocyte colony-stimulating
factor until the neutrophil count was 1 x 10(9)/liter for 2 consecutive
days. Patients were followed up monthly for disease activity using
the physician's global assessment, SLE Disease Activity Index,
and assessment of functioning of involved organs. The Responder
Index for Lupus Erythematosus was used to define partial or complete
response. RESULTS: The median time to achieve a neutrophil count
of 0.5 x 10(9)/liter was 14 days (range 11-22 days) after the
last dose of cyclophosphamide. Patients required a median of 2
units (range 2-5) of packed red blood cells, and a median of 16
days (range 0-23 days) elapsed from the last dose of cyclophosphamide
to the last platelet transfusion. There were no deaths or fungal
infections. Significant improvements in physician's global assessment
(mean difference 1.4; P < 0.0001), SLE Disease Activity Index
(mean difference 4.1; P = 0.0039), and prednisone dosage (mean
difference 14.9 mg/day; P = 0.002) were observed. Responses, including
5 durable complete responses, were observed in all organ systems
(renal, central nervous system, and skin) with involvement that
had led to patient enrollment. CONCLUSION: High-dose cyclophosphamide
without stem cell transplantation leads to rapid hematopoietic
reconstitution and has significant clinical benefit in patients
with refractory SLE. Therefore, this approach deserves further
study.
-----
Arthritis Rheum 2003 Feb;48(2):455-9
The relationship of FcgammaRIIIa genotype to degree
of B cell depletion by rituximab in the treatment of systemic
lupus erythematosus.
Anolik JH, Campbell D, Felgar RE, Young F, Sanz I, Rosenblatt
J, Looney RJ.
University of Rochester School of Medicine and Dentistry, Rochester,
New York 14642, USA.
OBJECTIVE: Despite wide use of the anti-CD20 monoclonal antibody
rituximab in the treatment of B cell lymphomas, the mechanism
by which it causes B cell depletion remains a subject of controversy.
As part of an ongoing phase I/II trial of rituximab in the treatment
of systemic lupus erythematosus (SLE), we sought to determine
whether the effectiveness of B cell depletion was influenced by
polymorphisms of Fc receptors (FcR) on effector cells. METHODS:
During rituximab treatment of 12 SLE patients, B cell depletion
was monitored as a function of the serum rituximab level and FcgammaRIIa
and FcgammaRIIIa genotypes at baseline and at 1 month and 2 months
after treatment. FcR genotypes were determined by polymerase chain
reaction. Serum levels of rituximab were measured by enzyme-linked
immunosorbent assay (ELISA). B lymphocyte percentages were assessed
by flow cytometry. RESULTS: B cell depletion was highly variable
in this patient cohort, with B cell percentages at the 1-2-month
posttreatment nadir ranging from undetectable (<0.1 cell/microl)
to 16% ( approximately 30 cells/microl) of the total peripheral
blood lymphocytes. At 2 months posttreatment, B cell percentages
were highly correlated with both the serum rituximab level and
the FcgammaRIIIa genotype (R(2) = 0.75, P = 0.002). The FcgammaRIIIa
genotype was a significant independent predictor of the efficacy
of B cell depletion (P = 0.019). CONCLUSION: These results highlight
the potential variability of B cell depletion by rituximab in
the treatment of autoimmune disease and indicate that Fc receptors
are an important determinant of that variability. The findings
further suggest the importance of antibody-dependent cell-mediated
cytotoxicity and/or apoptosis induction via FcgammaRIIIa-expressing
effector cells in the mechanism of B cell depletion by this widely
used monoclonal antibody.
-----
Ann Dermatol Venereol 2002 Aug-Sep;129(8-9):1023-6
[Extracorporeal photochemotherapy in therapy-refractory
subacute lupus]
[Article in French]
Richard MA, Saadallah S, Lefevre P, Poullin P, Buscaylet S, Grob
JJ.
Service de Dermatologie, Hopital Sainte Marguerite, Marseille,
France. mrichard@mail.ap-hm.fr
BACKGROUND: Extracorporeal photopheresis is a leukapheresis
therapy that uses psoralen and ultraviolet A irradiation. We report
the case of a woman with a refractory sub acute lupus which dramatically
but transitionally responded to extracorporeal photopheresis.
CASE REPORT: This women, born in 1960, developed erythematous
and squamous patches located on face and neckline, associated
with hyperpigmented and atrophic lesions on the arms and shoulders.
Investigations confirmed the diagnosis of subacute lupus without
systemic disease. All lesions progressed, despite all conventional
therapies leading to major aesthetic prejudice. Extracorporeal
photopheresis was initiated, and after two months, all lesions,
including atrophic and healing lesions had regressed, but laboratory
abnormalities did not change. Extracorporeal photopheresis was
well tolerated. However, treatment was discontinued nine months
later, since the cutaneous lesions relapsed. COMMENTS: Extracorporeal
photopheresis could be efficient in the treatment of cutaneous
autoimmune diseases through several immunomodulatory mechanisms.
Extracorporeal photopheresis is a potent alternative agent in
the therapy of refractory dermatological diseases
-----
Arthritis Rheum 2002 Nov;46(11):2917-23
Hematopoietic stem cell transplantation for severe
and refractory lupus. Analysis after five years and fifteen patients.
Traynor AE, Barr WG, Rosa RM, Rodriguez J, Oyama Y, Baker S, Brush
M, Burt RK.
Northwestern Memorial Hospital and Northwestern University School
of Medicine, Chicago, Illinois, USA.
OBJECTIVE: To determine the safety and long-term efficacy of
immune ablation and autologous hematopoietic stem cell transplantation
(HSCT) in severe systemic lupus erythematosus (SLE). METHODS:
Fifteen patients with persistently active SLE after intravenous
(IV) cyclophosphamide (CYC) therapy underwent HSCT. Stem cells
were mobilized with CYC (2.0 gm/m(2)) and granulocyte colony-stimulating
factor (5 microg/kg/day). Lymphocytes were depleted from the graft
by selection of CD34-positive cells. The conditioning regimen
used was CYC (200 mg/kg), antithymocyte globulin (90 mg/kg), and
methylprednisolone (3 mg/kg). Outcome was evaluated by the SLE
Disease Activity Index (SLEDAI), serum complement levels, serologic
features, function of diseased organs, and immunosuppressive medication
requirements. RESULTS: Fifteen patients with persistent, severe
SLE, 7 of whom were critically ill, were treated. No deaths occurred
following treatment. The median followup after HSCT has been 36
months (range 12-66 months). All patients demonstrated a gradual,
but marked, improvement. The SLEDAI score has declined to <or=5
in 12 patients. Complement and anti-double-stranded DNA levels
have normalized and marked improvements in end organ function
have occurred in all subjects. Of the 12 patients followed up
for >1 year after HSCT, 10 have discontinued immunosuppressive
medications, and the prednisone dosage has been tapered to 15
mg/day in 1. Only 2 patients have demonstrated clinical evidence
of recurrence of active lupus. One of these patients currently
requires no immunosuppressive medication and has a normal performance
status. The other patient is currently receiving IV CYC. CONCLUSION:
In patients experiencing the persistence of organ-threatening
lupus following standard, aggressive therapy, HSCT may be performed
safely, with marked improvement and sustained withdrawal of all
immunosuppressive medication for most patients. A phase III randomized
trial is warranted to determine the relative efficacy and durability
of remission of HSCT compared with standard therapies.
-----
Postgrad Med J 2002 Oct;78(924):599-606
Current concepts for the management of systemic
lupus erythematosus in adults: a therapeutic challenge.
Ioannou Y, Isenberg DA.
Centre for Rheumatology, Department of Medicine, University College
London, London, UK.
Systemic lupus erythematosus (SLE) is a chronic, autoimmune
rheumatic disease with many clinical presentations typically affecting
women of childbearing age. The successful therapy of SLE depends
upon treating both symptoms and the underlying inflammation. Both
non-pharmacological as well as pharmacological therapies are invariably
required. Non-pharmacological therapy includes avoiding over-exposure
to sunlight with the use of adequate sunscreen protection, avoiding
"live" vaccination if on immunosuppressive agents, adherence
to a diet low in saturated fat and high in fish oil, stress avoidance,
and smoking cessation. Pharmacological measures revolve around
four main classes of drugs: non-steroidal anti-inflammatory drugs,
antimalarials, corticosteroids, and cytotoxic agents. Cyclophosphamide
and azathioprine are the two most commonly used cytotoxic agents
and these in combination with corticosteroids need to be employed
early if there is major organ involvement to prevent or minimise
irreversible damage. The potential side effects of corticosteroids
and cytotoxic agents need constant consideration. The rapid developments
in biotechnology of recent years may soon lead to new and more
specific therapies for patients with SLE.
-----
Postepy Hig Med Dosw 2002;56(2):169-84
[Chloroquine--miscellaneous properties of the
antimalarial drug]
[Article in Polish]
Jarzyna R.
Zaklad Regulacji Metabolizmu Instytutu Biochemii Uniwersytetu
Warszawskiego. rjarzyna@biol.uw.edu.pl
Chloroquine is a drug with over 60 years of safe clinical use
in the treatment of malaria. The multiple mechanisms of chloroquine
action have appeared to be useful in the therapy of many miscellaneous
disorders well beyond its original antimalarial purposes. This
paper is focused on the application of chloroquine for the treatment
of malaria, porphyria cutanea tarda, rheumatoid arthritis, palindromic
rheumatism and lupus. The possibility of the use of chloroquine
in the therapy of other disorders such as diabetes mellitus, AIDS,
hyperlipidemia, sarcoidosis, hypercalcemia, and melanoma is reviewed.
Mechanisms of action of the drug as well as side effects on metabolism
are discussed in view of recent discoveries.
-----
Rev Alerg Mex 2002 Nov-Dec;49(6):176-80
[New prospects for the treatment of systemic lupus
erythematosus]
[Article in Spanish]
Iniestra Flores F, Orea Solano M.
Alergologo e inmunologo clinico, adscrito al departamento de medicina
interna del Hospital de Especialidades del Centro Medico Nacional
La Raza, IMSS, Mexico, DF.
The systemic lupus erythematosus is a significant therapeutic
challenge: Multiorgan involvement and a variable disease course,
characterized by clinical exacerbations and remissions, make difficult
to predict the outcome. Few products have been specifically developed
for this affection, and most accepted therapies have not been
tested in randomized controlled trials of systemic lupus erythematosus.
A variety of biological agents under investigation as potential
treatments for systemic lupus erythematosus are designed to interfere
with specific immunologic responses, hopefully avoiding generalized
immunosuppression. Agents, which interfere with T cell-B cell
collaboration, such as CTLA-4-Ig and anti-CD154 ligand monoclonal
antibodies, may result in long-term therapeutic benefit. Products
designed to decrease production of anti-dsDNA antibodies or inhibit
complement activation, may prevent immune complex deposition and
ameliorate organ-specific manifestations, such as renal disease.
More aggressive interventions include gene therapy and stem cell
transplantation.
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Ann Acad Med Singapore 2002 Nov;31(6):702-6
Immunotherapy in autoimmune diseases.
Fong KY.
Rheumatology Division, Department of Medicine, National University
Hospital, 5 Lower Kent Ridge Road, Singapore 119074.
Immunotherapy has the potential to modify or re-balance the
immune system and hence useful in the management of autoimmune
conditions. This article aims to review clinically useful immunotherapies
available for treatment of autoimmune conditions, with particular
emphasis on Type I diabetes mellitus, multiple sclerosis, rheumatoid
arthritis and systemic lupus erythematosus. A Medline search for
the period 1992 to 2002 (10 years) using the unrestricted keywords
"immunotherapy AND autoimmune" was done. Full-length
articles were selected for reviews based on the contents of their
published abstracts. Additional Medline searches were focussed
on the keywords "immunotherapy AND diabetes mellitus",
"immunotherapy AND multiple sclerosis", "immunotherapy
AND rheumatoid arthritis", and "immunotherapy AND systemic
lupus erythematosus". Relevant publications referenced in
the reviewed literature were further included for review, if not
present in the original Medline search. Immunotherapy in Type
I diabetes mellitus has focussed on the induction of tolerance
to beta cell antigens, and in multiple sclerosis trials of anti-alpha
4 integrins and altered peptide ligand of myelin basic protein
(MBP 83-99) showed initial promising results. The use of anti-cytokine
therapy (anti-TNF alpha and IL-1Ra) in rheumatoid arthritis has
improved the quality of life of patients with refractory disease.
The use of anti-CD20 monoclonal antibody for in vivo B cells depletion
and early trials of autologous peripheral stem cell transplants
represent additional immunomodulatory treatment modalities for
systemic lupus erythematosus patients. Better understanding of
autoimmune conditions and advances in the production of humanized
monoclonal antibodies, promises better immunotherapy in the near
future.
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Clin Exp Rheumatol 2002 Sep-Oct;20(5):709-18
Thalidomide: focus on its employment in rheumatologic
diseases.
Ossandon A, Cassara EA, Priori R, Valesini G.
Dipartimento di Terapia Medica, Cattedra di Reumatologia, Universita
degli Studi di Roma La Sapienza, Rome, Italy.
Thalidomide is an immunomodulatory agent; although its mechanisms
of action are not fully understood, many authors have described
its anti-inflammatory and immunosuppressive properties. More interestingly,
thalidomide has shown the ability to suppress tumor necrosis factor
alpha (TNF alpha) production and to modify the expression of TNF
alpha induced adhesion molecules on endothelial cells and on human
leukocytes. Thalidomide has been used in several diseases (i.e.
dermatological, autoimmune, gastrointestinal). In this review
we focus specifically on the use of this drug in disorders with
rheumatological features such as lupus erythematosus, rheumatoid
arthritis and Still's disease, ankylosing spondylitis, and Behcet's
disease. Despite its well known side effects, first of all peripheral
nerve involvement and teratogenesis, which can be avoided by following
strict guidelines, thalidomide could represent an alternative
drug in some rheumatological conditions, particularly in patients
who show resistance, contraindication or toxicity with other conventional
treatments.
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Arthritis Rheum 2002 Oct;46(10):2673-7
An open study of B lymphocyte depletion in systemic
lupus erythematosus.
Leandro MJ, Edwards JC, Cambridge G, Ehrenstein MR, Isenberg DA.
Rheumatology, Middlesex Hospital, University College, 4th Floor
Arthur Stanley House, 40-50 Tottenham Street, London W1T 4NJ,
UK. maria.leandro@ucl.ac.uk
OBJECTIVE: To gain preliminary evidence for the safety and
efficacy of B lymphocyte depletion therapy in refractory systemic
lupus erythematosus (SLE). METHODS: Six female patients with active
SLE, resistant to standard immunosuppressive therapy, were treated
on an open-label basis. During a 2-week period, each patient received
two 500-mg infusions of rituximab, two 750-mg infusions of cyclophosphamide,
and high-dose oral corticosteroids. RESULTS: No significant adverse
events were observed during followup. Patient 1 had not improved
at 3 months but was then lost to followup. At 6 months, all 5
remaining patients had improved, as evidenced by improvement in
British Isles Lupus Assessment Group global scores, from a median
of 14 (range 9-27) at baseline to a median of 6 (range 3-8) at
6 months. Manifestations of SLE such as fatigue, arthralgia/arthritis,
and serositis responded particularly well to this protocol. Hemoglobulin
levels increased in patients 2, 3, 5, and 6. The erythrocyte sedimentation
rate decreased in patients 2, 3, 4, and 5 and was stable in patient
1. In patients 4 and 5, the urinary protein-to-creatinine ratio
decreased significantly. C3 serum levels increased in all 5 patients
who had low levels at baseline; in two of these patients, patients
2 and 5, C3 values were normal at 6 months. The variation in the
level of anti-double-stranded DNA antibody was different in individual
patients. CONCLUSION: This study provides sufficient evidence
for the safety and possible efficacy of B lymphocyte depletion
therapy in SLE to justify a formal controlled trial.
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Scand J Rheumatol 2002;31(4):187-91
Biological treatments for systemic lupus erythematosus.
Isenberg D, Leckie MJ.
d.isenberg@ucl.ac.uk
There have been many recent advances in therapeutic approaches
to systemic lupus erythematosus (SLE). The roles of cyclophosphamide,
hydroxychloroquine, methotrexate and hormonal treatments in the
management of SLE have been investigated in recent randomised
controlled trials (1). However, although these pharmacological
agents have a role to play in some patients with lupus, broad
based effects have led to problems with side effects and adverse
reactions. For this reason, more specific therapies are urgently
required. Such strategies currently under evaluation include altering
the cytokine balance, reducing T cell activation and inducing
tolerance, blocking T cell costimulatory molecules, reducing auto-antibody
production from B cells, targetting specific genes and stem cell
transplantation. These are known as "biological" treatments
as their aim is to alter patho-physiological processes occurring
in the diseased state. This review will focus on the biological
therapies currently under investigation-with particular attention
on the cytokine-directed therapies.
-----
Intern Med 2002 Aug;41(8):608-12
High-dose immunoablative therapy with hematopoietic
stem cell support in the treatment of severe autoimmune disease:
current status and future direction.
Tyndall A, Koike T.
Department of Rheumatology, University of Basel, Switzerland.
In the past 5 years approximately 500 patients worldwide suffering
from severe autoimmune disease (AD) have received an autologous
hematopoietic stem cell transplantation (HSCT) as treatment following
high-dose chemotherapy. The EBMT and EULAR data base contains
370 registrations, the most frequently transplanted ADs being
multiple sclerosis (MS), systemic sclerosis (SSc), rheumatoid
arthritis (RA), juvenile idiopathic arthritis (JIA), systemic
lupus erythematosus (SLE) and idiopathic thrombocytopenic purpura
(ITP). Around 70% responded initially well, with durable remission/stabilization
seen more frequently in MS and SSc than in RA and SLE, the latter
having around 2/3 relapses, the majority of which respond to simple
agents. Overall 8% transplant-related mortality was seen with
large inter AD differences (12.5% in SSc and only one patient
in RA) probably reflecting the degree of vital organ involvement
at the time of transplant. This phase I/II data has led to a running
phase III randomized trial in SSc called the Autologous Stem cell
Transplantation International Scleroderma (ASTIS) trial, and it
will soon begin in MS (ASTIMS) and RA (ASTIRA). The concept of
immunological "re-setting" has evolved, and needs to
be confirmed by longer follow-up and the multicentre, international
phase III randomized studies.
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Lupus 2002;11(7):405-10
High-dose cyclophosphamide for severe systemic
lupus erythematosus.
Gladstone DE, Prestrud AA, Pradhan A, Styler MJ, Topolsky DL,
Crilley PA, Hoch S, Huppert A, Brodsky I.
Drexel University, College of Medicine, Department of Medicine,
Philadelphia, PA, USA. deg25@drexel.edu
Cytotoxic therapy is a cornerstone for patients with severe
systemic lupus erythematosus (SLE). High-dose cyclophosphamide,
200 mg/kg, can induce a complete remission without the need for
stem cell rescue in patients with autoimmune illnesses. Here we
report on our first four patients treated for severe SLE with
this treatment approach. Patients received cyclophosphamide, 200
mg/kg, divided over 4 days. Starting day 10, patients received
filgrastim, 5 micrograms/kg/day, until their absolute neutrophil
count (ANC) rose to 10.0 x 10(9)/l for two consecutive days. Disease
activity as evaluated by scores from the Systemic Lupus Activity
Measure-2, the SLE Disease Activity Index and the Responder Index
for Lupus Erythematosus were completed before and after high-dose
therapy. Before high-dose cyclophosphamide, SLE disease duration
ranged from 8 to 21 (mean 12.5) years. Their average disease activity
measured by SLAM-2 and SLEDAI was 15.5 (range 11-19) and 23.25
(range 20-26), respectively. At a median of 22 (range 12-39) months
of follow-up, mean disease activity measured by SLAM-2 and SLEDAI
decreased to 6.25 and 7.75, respectively. All patients experienced
febrile neutropenia. No long-term morbidities or mortalities were
observed. High dose cyclophosphamide is a therapy capable of decreasing
disease severity in poor prognosis SLE patients. Future study
is warranted for both refractory patients as well as primary therapy
for patients with moderate to severe disease presentations.
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Lupus 2002;11(6):340-7
Celecoxib for systemic lupus erythematosus: case
series and literature review of the use of
NSAIDs in SLE.
Lander SA, Wallace DJ, Weisman MH.
Department of Medicine, Cedars-Sinai Medical Center, Los Angeles,
California 90048, USA.
The primary objectives of this study were to evaluate the safety
and efficacy of the cyclooxygenase-2 inhibitor celecoxib in systemic
lupus erythematosus (SLE) patients both with and without a self-reported
sulfa drug allergy and to review the literature on the use of
nonsteroidal agents in SLE subjects. A retrospective review of
medical records was performed for 50 SLE patients seen by a community-based
rheumatologist and treated with open label celecoxib in doses
of 200-400 mg/day for a period of 1-9 months. A MEDLINE search
of all articles pertaining to the use of NSAIDs in patients with
SLE since 1966 was undertaken. We noted that, in this cohort of
celecoxib-treated SLE patients from an office rheumatology practice,
the majority demonstrated some improvement, and little toxicity
was observed. SLE patients with self-reported sulfa allergies
were not more likely to have adverse reactions to celecoxib than
non-sulfa allergic patients. The literature review performed herein
reveals that, although NSAID toxicity should be a continuing concern
in an SLE population, structural dissimilarities between celecoxib
and the sulfonamide antimicrobials may make true cross-allergenicity
less likely to be a clinical problem. These results suggest that
patients with SLE can be safely and effectively treated with celecoxib;
however, further studies are needed to assess the effectiveness
and safety of all NSAIDs in SLE.
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