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Latest Research on Lupus
     
J Pediatr. 2008 Apr;152(4):550-6. Epub 2007 Nov 5.
Clinical and laboratory characteristics and long-term outcome of pediatric systemic lupus erythematosus: a longitudinal study.
Hiraki LT, Benseler SM, Tyrrell PN, Hebert D, Harvey E, Silverman ED.
Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, Canada.

OBJECTIVES: To determine the frequency and characteristics of clinical signs, symptoms, laboratory findings, and medication use in children with pediatric systemic lupus erythematosus (pSLE) at presentation and during the course of the disease, and to examine correlations among disease manifestations, disease activity, and damage over time. STUDY DESIGN: The study involved an analysis of medical records and the SLE database of an inception cohort of 256 patients with pSLE (female:male ratio, 4.7:1). RESULTS: The most common clinical manifestations were arthritis (67%), malar rash (66%), nephritis (55%), and central nervous system (CNS) disease (27%). At diagnosis, patients with both renal and CNS disease had the highest SLE Disease Activity Index (SLEDAI) scores (P < .0001), but these scores were similar to those of the total group at 1 year (P = .11). Patients who developed renal and CNS disease more than 1 year after diagnosis had higher SLEDAI scores at disease onset. Some 34% of patients had Systemic Lupus International Collaborative Clinics Damage Index (SLICC-DI) scores >1 at a mean follow-up of 3.5 years. A greater proportion of patients with renal and CNS disease had SLICC-DI scores of >1, and these patients had higher mean scores compared with patients without major organ involvement (70% vs 11% [P < .0001] and 1.4 vs 0.1 [P < .0001], respectively). CONCLUSIONS: Most of the patients in our cohort exhibited major organ involvement. These patients had the highest SLEDAI scores at diagnosis, which normalized at 1 year but preceded development of renal and CNS disease. The average SLICC-DI score was lower than that previously reported in patients with pSLE.

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Nat Clin Pract Rheumatol. 2008 Apr;4(4):184-91. Epub 2008 Feb 19.
Technology Insight: hematopoietic stem cell transplantation for systemic rheumatic disease.
Nikolov NP, Pavletic SZ.
Sjögren's Syndrome Clinic, Molecular Physiology and Therapeutics Branch of the National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD, USA. nikolovn@mail.nih.gov

Hematopoietic stem cells (HSCs) have the capacity for self-renewal and the potential to differentiate into all types of hematopoietic and immune system cells. These features have been successfully used to treat a multitude of hematologic malignancies and nonmalignant diseases such as aplastic anemia, hemoglobinopathies, inborn errors of metabolism and congenital immunodeficiency states. The application of HSC transplantation has been expanded over the past decade to include immune-mediated diseases such as multiple sclerosis, treatment-refractory rheumatoid arthritis, systemic lupus erythematosus and systemic sclerosis. Transplantation of HSCs for the treatment of autoimmune diseases aims to fundamentally correct the dysregulated immune system, which could result in sustained clinical remission or potential cure. The use of this approach is currently restricted to clinical research, as there is no standard conditioning regimen to attain these aims in autoimmune diseases. HSC transplantation is associated with inherent morbidity and mortality, both treatment-related and disease-related, and selecting the correct group of patients with the best risk:benefit ratio is a challenging task.

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J Rheumatol. 2008 Mar 15 [Epub ahead of print]
Fulvestrant (faslodex), an estrogen selective receptor downregulator, in therapy of women with systemic lupus erythematosus. Clinical, serologic, bone density, and T cell activation marker studies: A double-blind placebo-controlled trial.
Abdou NI, Rider V, Greenwell C, Li X, Kimler BF.
From the Center for Rheumatic Disease, Allergy-Immunology, St. Luke's Hospital, University of Missouri, Kansas City, Missouri; Department of Biology, Pittsburg State University, Pittsburg, Kansas; and Department of Radiation Oncology, University of Kansas Medical Center, Kansas City, Kansas, USA.

OBJECTIVE: Estrogen plays a role in the activation of systemic lupus erythematosus (SLE) and in upregulating intracellular signals by binding to the estrogen receptor(s). Fulvestrant (Faslodex, AstraZeneca Pharmaceuticals, Wilmington, DE, USA), an estrogen selective receptor downregulator, competes for receptor binding in vitro and inhibits estrogen action in target cells. We evaluated the efficacy, side effects, and expression of T cell activation markers, following the administration of fulvestrant or placebo to premenopausal patients with SLE. METHODS: Twenty women with moderate SLE Disease Activity Index (SLEDAI; 7.87 +/- 3.7) were enrolled. They were premenopausal with regular menstrual cycles and not taking exogenous hormones. The study was double-blind and placebo-controlled. Ten patients received 250 mg fulvestrant intramuscularly for 12 months, and 10 received the placebo. All were observed monthly and 3 months after final fulvestrant/placebo injection. Measures studied were monthly SLEDAI scores, routine and serologic markers for lupus, and serum concentrations of estrogen and fulvestrant. Expression of T cell calcineurin and CD154 mRNA in peripheral T cells was measured by polymerase chain reaction. Medications the patients were taking were recorded each visit. Bone density was obtained at baseline and at visit 12. RESULTS: Sixteen patients completed the 15-month study, 8 from each group. SLEDAI improved significantly in the fulvestrant group at both 12 months (p = 0.02) and 15 months (p = 0.002), but serologic markers, routine laboratory tests, and bone density did not. Serum estrogen levels were higher in the fulvestrant group and dropped when fulvestrant was discontinued; these differences were not statistically significant. Medications for therapy of lupus to the fulvestrant group were reduced, whereas the placebo group medications were unchanged or increased. Comparison of relative values at individual timepoints revealed significantly lower median values for the T cell activation markers CD154 (p < 0.001) and calcineurin (p = 0.013) in the fulvestrant arm. CONCLUSION: Blocking estrogen receptors in vivo by an estrogen selective receptor downregulator could be considered as a new and relatively safe therapeutic approach in the management of SLE patients with moderately active disease for the 1-year study period.

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Lupus. 2008;17(3):166-70.
Lupus: improving long-term prognosis.
Doria A, Briani C.
Division of Rheumatology, Department of Clinical and Experimental Medicine, University of Padova, Padova, Italy;

AbstractOver recent decades short- and medium-term survival has greatly improved in patients affected with systemic lupus erythematosus, but long-term prognosis still remains poor mainly due to complications of the disease and/or its treatment. To improve long-term prognosis in systemic lupus erythematosus, we should try to adopt, early in the disease course, strategies that can contribute to reducing long-term complications, including screening for and prophylaxis against infections, control of risk factors for atherosclerosis, and cancer surveillance. However, in patients with systemic lupus erythematosus all these preventive strategies are often not sufficient. Indeed, two important systemic lupus erythematosus-related factors play a relevant role in all these complications: severe disease manifestations, such as glomerulonephritis and central nervous system involvement, and corticosteroid and cyclophosphamide use. Therefore, to prevent long-term complications, we should try to control disease activity and severity using the lowest effective dosage of these drugs. Moreover, strategies directed at preventing clinical manifestations in asymptomatic antinuclear antibody-positive individuals or in antiphospholipid antibody-positive systemic lupus erythematosus patients, as well as at preventing severe manifestations in patients with mild systemic lupus erythematosus at the time of the diagnosis should be considered.

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Nat Clin Pract Rheumatol. 2008 Mar 18 [Epub ahead of print]
Therapy Insight: cardiovascular disease in pediatric systemic lupus erythematosus.
Sandborg C, Ardoin SP, Schanberg L.
C Sandborg is Professor of Pediatrics and Chief of the Division of Pediatric Rheumatology at Stanford University School of Medicine, CA, USA.

In 15-20% of cases, systemic lupus erythematosus (SLE) presents before the age of 18 years, and such early-onset SLE seems to be particularly severe. SLE is an independent risk factor for premature atherosclerosis and death in young, premenopausal women with SLE, even after controlling for traditional cardiovascular risk factors. Children and adolescents with SLE are particularly susceptible to this long-term threat to their cardiovascular health because they have an increased disease severity and a lengthy disease burden. Factors that contribute to premature atherosclerosis include the inflammatory and immune abnormalities that are intrinsic to SLE, primary dyslipidemias, and the secondary effects of treatments such as corticosteroids. However, few rheumatologists provide appropriate preventive or management strategies for the increased atherosclerosis risk in this age-group. Screening should be performed on a regular basis, including evaluation of, and counseling for, traditional risk factors. Studies of treatment in pediatric patients are limited, and treatment strategies are often extrapolated from adult studies. Statins hold promise because they have both lipid-lowering and anti-inflammatory effects. There have been few studies of the use of statins in adults or adolescents with SLE; however, trials are currently underway to address the safety and efficacy of statin use in pediatric SLE.

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Rheumatology (Oxford). 2008 Mar 17 [Epub ahead of print]
Intravenous immunoglobulin therapy in pregnant patients affected with systemic lupus erythematosus and recurrent spontaneous abortion.
Perricone R, De Carolis C, Kröegler B, Greco E, Giacomelli R, Cipriani P, Fontana L, Perricone C.
Department of Rheumatology, University of Rome Tor Vergata, S. Giacomo Hospital, ASL RMA, Gynaecology and Obstetrics, Department of Rheumatology, University of L’Aquila, L’Aquila and Department of Internal Medicine, University of Rome Tor Vergata, Rome, Italy.

Objectives. We aimed to test the maternal and fetal outcome of SLE patients who suffered from recurrent spontaneous abortion (RSA) treated with intravenous immunoglobulin (IVIg) alone during pregnancy and whether the clinical response to IVIg treatment is accompanied by modifications of SLE-associated antibodies and of complement levels. Methods. Twelve SLE-RSA pregnant patients were treated with high-dose IVIg and compared with 12 SLE-RSA pregnant patients treated with prednisolone and NSAIDs. They were evaluated for the clinical response [lupus activity index-pregnancy (LAI-P) scale] and for ANA, anti-dsDNA, anti Ro/SS-A or La/SS-B, aCL, LAC, C4, C3 before and during pregnancy, and before and after each treatment course. Pregnancy outcome in the two groups was also evaluated. Results. The groups characteristics were homogeneous at the beginning of pregnancy. A beneficial clinical response following IVIg treatment was noted in all patients and mean LAI-P decreased from 0.72 +/- 0.43 at the beginning of pregnancy to 0.13 +/- 0.19 at the end of pregnancy (P < 0.0001). Antibodies and complement levels tended to normalize in most of the patients. These clinical and laboratory improvements were significant with respect to the control group. Pregnancy was successfully carried out in 12/12 (100%) SLE-RSA patients with a mean Apgar score of 8.92. Three patients in the control group got aborted (25%). Conclusions. IVIg has a high response rate among SLE-RSA pregnant patients and may be considered safe and effective.

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Pediatr Nephrol. 2008 Mar 7 [Epub ahead of print]
Slowing chronic kidney disease progression: results of prospective clinical trials in adults.
Nguyen T, Toto RD.
Internal Medicine – Nephrology, The University of Texas Southwestern Medical Center Dallas, 5323 Harry Hines Blvd, Dallas, TX, 75390-8856, USA.

Chronic kidney disease is generally thought to be a progressive disorder regardless of etiology. Over the past 15 years, investigations into the mechanisms of disease progression and treatment designed to slow or halt disease progression have been conducted, largely in the adult kidney disease population. Intervention trials have demonstrated that lowering blood pressure in hypertensive patients and administration of drugs that block the renin-angiotensin aldosterone system are effective at slowing kidney disease progression, including diabetes, hypertension, and various glomerular diseases. In addition, novel strategies including anemia therapy with erythropoietin-stimulating agents have been conducted to determine whether treatment of this common complication of kidney disease can stabilize kidney function. Whereas substantial success has been achieved in more common forms of adult kidney disease such as diabetes and hypertension, slowing progression of some immune-mediated
glomerular disease such as lupus nephritis and immunoglobulin A (IgA) nephropathy remain a great challenge. Moreover, there is no proven strategy, including multifactorial interventions, that clearly halts progressive chronic kidney disease that has been studied prospectively in a large-scale, long-term trial. The purpose of this review is to discuss these trials, as they form the underpinnings for current clinical practice guidelines in adults with chronic kidney disease.

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Isr Med Assoc J. 2008 Jan;10(1):55-7.
Low dose intravenous immunoglobulin in systemic lupus erythematosus: analysis of 62 cases.
Sherer Y, Kuechler S, Jose Scali J, Rovensky J, Levy Y, Zandman-Goddard G, Shoenfeld Y.
Department of Medicine B and Center for Autoimmune Diseases, Sheba Medical Center, Tel Hashomer, Israel.

BACKGROUND: Systemic lupus erythematosus is an autoimmune disease with diverse clinical manifestations that cannot always be regulated by steroids and immunosuppressive therapy. Intravenous immunoglobulin is an optional immunomodulatory agent for the treatment of SLE, but the appropriate indications for its use, duration of therapy and recommended dosage are yet to be established. In SLE patients, most publications report the utilization of a high dose (2 g/kg body weight) protocol. OBJECTIVES: To investigate whether lower doses of IVIg are beneficial for SLE patients. METHODS: We retrospectively analyzed the medical records of 62 patients who received low dose IVIg (approximately 0.5 g/kg body weight). RESULTS: The treatment was associated with clinical improvement in many specific disease manifestations, along with a continuous decrease in SLEDAI scores (SLE Disease Activity Index). However, thrombocytopenia, alopecia and vasculitis did not improve following IVIg therapy. CONCLUSIONS: Low dose IVIg is a possible therapeutic option in SLE and is associated with lower cost than the high dose regimen and possibly fewer adverse effects.

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Expert Opin Investig Drugs. 2008 Jan;17(1):31-41.
Systemic lupus erythematosus: pharmacological developments and recommendations for a therapeutic strategy.
Pego-Reigosa JM, Isenberg DA.
1Hospital do Meixoeiro (Complexo Hospitalario Universitario de Vigo), Rheumatology Section, Alto do Meixoeiro s/n, 36200 Vigo (Pontevedra), Spain +1 34 98 622 9912 ; +1 34 98 681 1169 ; jose.maria.pego.reigosa@sergas.es , 2University College of London, Centre for Rheumatology Research, Division of Medicine, Room 331, 3rd Floor, The Windeyer Building, 46 Cleveland Street, London, W1T 4JF, UK.

The management of systemic lupus erythematosus (SLE) has improved thanks to a better understanding of the immunopathogenesis of the disease and important advances in drug development. In contrast to the worrying paucity of new therapies for SLE at the end of the last century, several agents have emerged as useful treatments for this condition in the last decade. The efficacy of mycophenolate mofetil in the treatment of patients with lupus nephritis has been recently established in several clinical trials. There are increasing data from open-label studies to support the belief that B-cell depletion using the chimeric antibody rituximab is useful in the treatment of SLE. However, larger double-blind clinical trials to confirm this belief are awaited. Other specific targeted therapeutic agents that act by inducing B-cell depletion, inhibiting co-stimulatory molecules necessary for T-cell activation, tolerising B and T cells, blocking pro-inflammatory cytokines or complement and immunoablation are exciting advances in the race towards improving the outcome for patients with SLE.

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Lupus. 2008;17(1):40-5.
Mycophenolate mofetil as the primary treatment of membranous lupus nephritis with and without concurrent proliferative disease: a retrospective study of 29 cases.
Kasitanon N, Petri M, Haas M, Magder LS, Fine DM.
Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Studies of immunosuppressive therapy, particularly mycophenolate mofetil (MMF), in membranous lupus nephritis (MLN) are limited. We report on our experience with primary (first-line) MMF therapy to induce and sustain renal remission in MLN with and without a concurrent proliferative lesion. Systemic lupus erythematosus (SLE) patients were studied, retrospectively, if treated with MMF for newly diagnosed MLN. Complete remission was defined as proteinuria less than 0.5 g/24h, inactive urine sediment and normal estimated glomerular filtration rate. Response in pure MLN (Group I, n = 10) was compared with mixed MLN and proliferative lupus nephritis (Group II, n = 19). By 12 months, 4 (40%) patients in Group I and 7 (36.8%) in Group II achieved complete remission (P = 0.87). One (10%) patient in Group I and 2 (10.5%) in Group II had worsening renal disease (P = 0.97). Mean time to remission was more than seven months in both groups. The remaining patients had stable disease without improvement or worsening. Only 2 of 11 achieving initial remission had a relapse with an average of 28 months of follow-up after remission. Self-limited gastrointestinal symptoms occurred in 12 patients, none requiring withdrawal of the drug. Mycophenolate mofetil as a primary therapy in MLN was successful in inducing complete remission in about 40% of MLN, particularly in patients with mild proteinuria. However, 12 months of therapy was necessary for best outcomes. Response rate was not different in the presence or absence of a proliferative lesion.

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Eur J Clin Pharmacol. 2007 Dec 20 [Epub ahead of print]
Topical tacrolimus and pimecrolimus in the treatment of cutaneous lupus erythematosus: an evidence-based evaluation.
Tzellos TG, Kouvelas D.
Department of Pharmacology, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece, kouvelas@auth.gr.

BACKGROUND: Lesions of cutaneous lupus erythematosus (CLE) are refractory to a wide range of topical or systemic therapies. The pathogenesis of CLE is multifactorial and polygenic, and many of its details remain unclear. However, immunologic evidence suggests the possible therapeutic use of tacrolimus and pimecrolimus. CLE is one of the most common dermatological autoimmune disorders worldwide, which includes systemic lupus erythematosus (SLE) with malar rash, subacute cutaneous lupus erythematosus (SCLE) and discoid lupus erythematosus (DLE). OBJECTIVE: Our aim was to determine the efficacy of topical pimecrolimus and tacrolimus in the treatment of cutaneous lupus erythematosus. METHODS: The literature was systematically reviewed. Medline, Embase, and the Cochrane Database were searched for systemic reviews, randomised controlled trials and nonrandomised clinical trials using the search terms "pimecrolimus", "Elidel", "SDZ ASM 981", "tacrolimus", "Protopic", "FK506" and "cutaneous lupus erythematosus". Studies were assessed independently by two authors. RESULTS: Five studies were eligible for inclusion in this review. Only one of them was a randomised controlled trial (RCT). There was no significant difference between tacrolimus and clobetasol; however, evidence indicates the highest tolerability of tacrolimus compared with corticosteroids. This review indicates the efficacy of tacrolimus and pimecrolimus in, at least initial, cutaneous lesions of SLE. However, in SCLE and DLE lesions, the efficacy appears to be lower, perhaps due to the chronicity of those lesions. CONCLUSION: The lack of RCTs is characteristic. Future studies should focus on efficacy, short- and long-term effects and cost-effectiveness. However, tacrolimus and pimecrolimus show efficacy, and such effort is worthwhile.

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Pediatr Nephrol. 2007 Dec 19 [Epub ahead of print]
Rituximab therapy for juvenile-onset systemic lupus erythematosus.
Nwobi O, Abitbol CL, Chandar J, Seeherunvong W, Zilleruelo G.
Division of Pediatric Nephrology, Department of Pediatrics, University of Miami/Holtz Children’s Hospital, 1611 NW 12th Avenue, Annex 5, Miami, FL, 33126, USA, cabitbol@med.miami.edu.

Rituximab (RTX), an anti-CD20 monoclonal antibody, has been proposed for use in the therapy of systemic lupus erythematosus (SLE). We present the initial long-term experience of the safety and efficacy of rituximab for treatment of SLE in children. Eighteen patients (mean age 14 +/- 3 years) with severe SLE were treated with rituximab after demonstrating resistance or toxicity to conventional regimens. There was a predominance of female (16/18) and ethnic African (13/18) patients. All had lupus nephritis [World Health Organization (WHO) classes 3-5] and systemic manifestations of vasculitis. Clinical disease activity of the SLE was scored with the SLE-disease activity index 2K (SLEDAI-2K). Patients were followed-up for an average of 3.0 +/- 1.3 years (range 0.5 to 4.8 years). B-cell depletion occurred within 2 weeks in all patients and persisted for up to 1 year in some. Clinical activity scores, double-stranded DNA (dsDNA) antibodies, renal function and proteinuria [urine protein to creatinine ratio (Upr/cr)] improved in 93% of the patients. Five patients required multiple courses of RTX for relapse, with B-cell repopulation. One died of infectious endocarditis related to severe immunosuppression. In conclusion, our data support the efficacy of rituximab as adjunctive treatment for SLE in children. Although rituximab was well tolerated by the majority of patients, randomized controlled trials are required to establish its long-term safety and efficacy.

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Lupus. 2007;16(12):972-80.
Mycophenolate mofetil as induction and maintenance therapy for lupus nephritis: rationale and protocol for the randomized, controlled Aspreva Lupus Management Study (ALMS).
Sinclair A, Appel G, Dooley MA, Ginzler E, Isenberg D, Jayne D, Wofsy D, Solomons N.
Aspreva Pharmaceuticals Corp, Victoria, BC, Canada.

The Phase III Aspreva Lupus Management Study (ALMS) will investigate mycophenolate mofetil (MMF) therapy for lupus nephritis (LN). Eligibility criteria include: 12-75 years of age; diagnosis of systemic lupus erythematosus according to revised American College of Rheumatology criteria; and biopsy-demonstrated LN (Class III-V). Randomized patients will receive open-label induction therapy with MMF or cyclophosphamide in combination with corticosteroids for 24 weeks. The primary efficacy endpoint is treatment response [decreased proteinuria and stabilized (within 25% of baseline) or improved serum creatinine level]. Patients achieving response or complete remission (normalization of all parameters) will be rerandomized to double-blind, placebo-controlled maintenance treatment with MMF or azathioprine, both plus corticosteroids. The maintenance phase primary endpoint is time to treatment failure. To detect a 15% rate improvement in the MMF group compared with cyclophosphamide, and to provide 90% power, a total of 358 patients will be required for the induction phase. On the basis of a projected 278 rerandomized patients, the maintenance phase will have 90% power to detect a difference between treatment groups assuming azathioprine and MMF three-year failure rates of 59.5% and 40.7%, respectively. Aspreva Lupus Management Study may provide invaluable comparative data on the efficacy and safety of MMF as LN induction and maintenance therapy.

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J Eur Acad Dermatol Venereol. 2007 Nov 12 [Epub ahead of print]
The use of topical calcineurin inhibitors in lupus erythematosus: an overview.
Wollina U, Hansel G.
Department of Dermatology and Allergology, Academic Teaching Hospital Dresden-Friedrichstadt, Dresden, Germany.

Lupus erythematosus (LE) shows a broad range of cutaneous symptoms, including acute, subacute and chronic lesions. The gold standard of established topical treatment consists of medium- to high-potency corticosteroids. Because face and neck are often involved, adverse effects of prolonged corticosteroid use are not uncommon. There is a need of steroid-free topical treatment in LE. With the development of topical calcineurin inhibitors, tacrolimus and pimecrolimus, there is an alternative available. The present study reviews the literature data on topical tacrolimus and pimecrolimus for malar rash, subacute lesions and discoid chronic lesions among others. The present data argue for an efficacy of these compounds in acute and subacute cutaneous LE manifestations with a rapid response and only minor side-effects when used as an adjunct to systemic treatment. In chronic discoid LE, hypertrophic plaques do not well respond because of limited penetration. The primary target seems to be the decrease or blocking of cytokine production by activated T lymphocytes.

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Ann Rheum Dis. 2007 Sep 7; [Epub ahead of print]
Treatment of refractory SLE with rituximab plus cyclophosphamide: clinical effects, serological changes, and predictors of response.
Jónsdóttir T, Gunnarsson I, Risselada A, Welin Henriksson E, Klareskog L, van Vollenhoven RF.
Department of Medicine, Rheumatology Unit, Karolinska University Hospital, Sweden.

OBJECTIVE: To evaluate efficacy, serological responses, and predictors of response in patients with severe and refractory systemic lupus erythematosus (SLE) treated with rituximab (RTX) plus cyclophosphamide (CYC). METHODS: Sixteen patients entered a treatment protocol using RTX plus CYC. Disease activity was assessed by Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and by British Isles Lupus Assessment Group (BILAG) index. RESULTS: At 6 months follow-up, mean SLEDAI values decreased significantly from 12.1(+/-2.2) to 4.7(+/-1.1). Clinical improvement (50% reduction in SLEDAI) occurred in all but 3 patients. All but 1 patient responded according to BILAG. Remission defined as SLEDAI<3 was achieved in 9/16 patients. Isotype analysis of anti-dsDNA antibodies revealed preferential decreases of IgG and IgA, but not IgM. Higher absolute numbers of CD19+ cells at baseline were correlated with shorter depletion time (r=-0.6). CONCLUSION: The majority of patients improved following RTX plus CYC. The differential downregulation of anti-DNA of the IgG and IgA but not the IgM isotypes supports the hypothesis that cells producing pathogenic autoantibodies are preferentially targeted by the treatment. The fact that higher absolute numbers of CD19+ cells at baseline predict a less impressive clinical and serological response suggests that more flexible dosing could be advantageous.

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Transfus Apher Sci. 2007 Aug 30; [Epub ahead of print]
Intravenous immunoglobulin in autoimmune and inflammatory diseases: More than mere transfer of antibodies.
Sibéril S, Elluru S, Negi VS, Ephrem A, Misra N, Delignat S, Bayary J, Lacroix-Desmazes S, Kazatchkine MD, Kaveri SV.
Centre de Recherche des Cordeliers, Equipe 16- Immunopathology and therapeutic immunointervention, Université Pierre et Marie Curie – Paris 6, UMR S 872, 15 rue de l’Ecole de Médicine, Paris, F-75006, France; Université Paris Descartes, UMR S 872 Paris, F-75006, France; INSERM, U872, Paris, F-75006, France.

Initially used for the treatment of immunodeficiencies, intravenous immunoglobulin (IVIg) has increasingly been used as an immunomodulatory agent in immune thrombocytopenic purpura, autoimmune neuropathies, systemic lupus erythematosus, myasthenia gravis, Guillain-Barré syndrome, and Kawasaki disease. Although IVIg benefits have been reported in many autoimmune and systemic inflammatory diseases, its mechanisms of immunomodulation are not fully understood and probably involve Fc-dependent and/or F(ab')(2)-dependent mutually non-exclusive effects. These mechanisms of action of IVIg reflect the importance of natural antibodies in the maintenance of immune homeostasis. We discuss here the recent advances in the understanding of immunoregulatory effects of IVIg.

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Lupus. 2007;16(9):724-30.
Hypertension and Afro-descendant ethnicity: a bad interaction for lupus nephritis treated with cyclophosphamide?
de Castro WP, Morales JV, Wagner MB, Graudenz M, Edelweiss MI, Gonçalves LF.
Post-Graduation Program in Medical Sciences: Nephrology, Faculdade de Medicina da Universidade Federal do Rio Grande do Sul, Brazil. wcastro@portoweb.com.br.

Hypertension and ethnicity are important prognostic factors in evolution of lupus nephritis. A cohort of 75 patients with lupus nephritis treated with cyclophosphamide was conducted to investigate the evolution of creatinine levels between Caucasians and Afro-descendants. A multiple linear model was used to evaluate the combined effects of ethnicity and hypertension over delta creatinine controlling confounders. Sample characteristics were: 85% females; mean (+/-SD) age of 33.6 +/- 12.0 years; 77% Caucasians; 40% hypertensive at renal biopsy; 91% WHO class IV; mean basal creatinine: 1.5 +/- 1.3 mg/dL; mean final creatinine: 2.1 +/- 2.5 mg/dL; 40% anaemia; proteinuria: 5.4 +/- 4.8 g/day. Comparing Caucasians and Afro-descendants, it was found: 28.1% versus 72.2% for hypertension (P = 0.002); 31.6% versus 66.7% for anaemia (P = 0.018); 5.9 +/- 5.0 versus 3.8 +/- 4.0. g/day (P = 0.02) for proteinuria. Other comparisons including basal creatinine did not reach statistical significance. Comparing outcomes between Caucasians and Afro-descendants, it was found: 10.5% versus 22.2% for doubling of creatinine (P = 0.24); 0.41 +/- 2.03 versus 1.05 +/- 2.41 for delta creatinine ( P = 0.29); 8.8% versus 22.2% for haemodialysis (P = 0.21) and 3.5% versus 5.6% for death (P = 0.99). Analysing delta creatinine with multiple linear regression showed that hypertension had a significant overall effect (b = 0.80; SE = 0.32; P = 0.015), ethnicity alone was not significant (b = 0.35; SE = 0.29; P = 0.228); however, the effect of hypertension on delta creatinine was more intense among Afro-descendants than among Caucasians (interaction term b = - 0.83; SE = 0.37; P = 0.027). Afro-descendants lupus patients experience worst prognosis of renal function probably due to the effect of hypertension and not ethnicity per se.

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Drugs Aging. 2007;24(9):701-15.
Elderly-onset systemic lupus erythematosus : prevalence, clinical course and treatment.
Lazaro D.
Department of Medicine, Division of Rheumatology, SUNY Downstate Medical Center, Brooklyn, New York, USADepartment of Medicine, Section of Rheumatology, VA-New York Harbor Healthcare System, Brooklyn, New York, USA.

Systemic lupus erythematosus is an autoimmune multi-system disease of uncertain aetiology with highly variable clinical manifestations. Women of child-bearing age are most often affected; however, approximately 10-20% of cases occur in older patients. Elderly-onset lupus has been defined in various studies as onset of lupus after age 50-65 years. Menopause and changes in cellular immunity with aging may contribute to development of lupus in older adults. Many studies suggest that the clinical and serological features of elderly-onset lupus differ from those of lupus in younger patients. Arthritis, fever, serositis, sicca symptoms, Raynaud's syndrome, lung disease and neuropsychiatric symptoms are more common in patients with elderly-onset lupus, while malar rash, discoid lupus and glomerulonephritis are less common in elderly-onset patients compared with younger lupus patients. Most elderly-onset lupus patients have a positive anti-nuclear antibody test, but the prevalence of anti-double-stranded DNA and hypocomplementaemia is lower in elderly-onset patients than in younger patients. Rheumatoid factor, anti-Ro/Sjögren's syndrome (SS) A and anti-La/SSB are more often positive in elderly-onset patients. The diagnosis of elderly-onset lupus may be delayed for many months: insidious onset, low prevalence and similarity to other more common disorders make the diagnosis of lupus challenging in this population. Treatment of lupus in the elderly may be complicated by co-morbidities and increased risk of toxicities from usual treatments. Optimal management of elderly-onset lupus is empiric because of a lack of randomised controlled studies. However, the approach to treatment is similar regardless of the age of the patient. This article discusses the prevalence, clinical course, serological features, prognosis and treatment of elderly-onset systemic lupus erythematosus.

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Lupus. 2007;16(8):684-91.
Review: New treatment strategies for proliferative lupus nephritis: keep children in mind!
Ranchin B, Fargue S.
Paediatric Nephrology Unit, Centre de Référence des Maladies Rénales Héréditaires, Hospices Civils de Lyon and Université Lyon 1, Lyon, France. bruno.ranchin@chu-lyon.fr.

Renal involvement is frequent in children with systemic lupus erythematosus (SLE) and carries significant short and long-term morbidity. Treatment strategy in proliferative glomerulonephritis relies mainly on studies in adult patients where conventional treatment regimens including high doses of cyclophosphamide (CYC) and steroids may cause severe side effects. New strategies including sequential therapies of various combinations of low dose CYC, calcineurine inhibitors (cyclosporine or tacrolimus), mycophenolate mofetil, azathioprine, rituximab are now under investigation in adult patients with very few data in children. Organization of international registries and controlled trials in children with lupus nephritis is mandatory to determine long term prognosis and to validate less toxic therapy regimens in childhood.

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Lupus. 2007;16(8):677-83.
Review: Systemic lupus erythematosus in children: current and emerging therapies.
Macdermott E, Adams A, Lehman T.
Division of Pediatric Rheumatology, Hospital for Special Surgery, New York, USA.

Treatment of children with systemic lupus erythematosus (SLE) is challenging. The therapeutic issues and risks and balances faced by adult patients are further complicated by an unpredictable disease course and long requirement for therapy in children with SLE. Further, non-compliance is a major obstacle to satisfactory outcome which must be recognized and dealt with in every adolescent in our efforts to attain optimal outcome. Treatment with combinations of cytotoxic agents and biologics which result in significant B-cell depletion often provide improved disease control. As our knowledge of the pathogenesis of SLE delineates more specific targets for immunotherapy the incidence of long-term remission rises. Our current emphasis is on therapeutic regimens which will induce remission followed by maintenance therapy in the oncologic model. SLE like neoplastic disease is no longer simply ;treatable'. With appropriate therapy many children with SLE attain sustained remissions. In the foreseeable future childhood SLE may be curable.

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Lupus. 2007;16(8):606-12.
Review: Lupus in adolescence.
Kone-Paut I, Piram M, Guillaume S, Tran TA.
Department of Pediatrics and Pediatric Rheumatology, Hôpital de Bicêtre, Le Kremlin-Bicêtre, France. isabelle.kone-paut@bct.aphp.fr.

Juvenile systemic lupus erythematosus (JSLE) represents 15-20% of all SLE cases. The leading presenting symptoms of JSLE are constitutional and not specific such as fatigue, headache, weight loss or mood swings. They are also encountered in healthy adolescents, which explains frequent diagnosis delay. The frequency of irreversible damage is high in JSLE and involves especially the renal, musculoskeletal and neuropsychiatric systems. Although the overall prognosis has markedly improved, thanks to earlier diagnosis and new therapeutic approaches, cardiovascular, hematological events and chronic renal failure remain severe, and constitute the main disease-related causes of death. Treatment is based on hydroxycloroquine and corticosteroids. Immunosuppressive agents must be discussed to decrease the duration of corticosteroids use. New drugs and monoclonal antibodies targeting B-cells and B-cell related cytokines are being evaluated with encouraging results. Management of JSLE has to challenge three objectives: controlling disease progression, obtaining patient's adherence to treatment, and preventing consequences of medication side effects on growth, puberty, development and fertility. Patients' quality of life and psychosocial development have also to be taken into account, as well as the organization of a successful transition from paediatric to adult care.

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Lupus. 2007;16(8):600-5.
Review: Contraception in adolescents with systemic lupus erythematosus.
Tincani A, Nuzzo M, Lojacono A, Cattalini M, Meini A.
Department of Rheumatology and Clinical Immunology, Brescia Hospital and University of Brescia, Brescia, Italy. tincani@bresciareumatologia.it.

In the management of adolescents with systemic lupus erythematosus (SLE), sexual activity and prevention of unwanted pregnancies are important topics. Many contraceptive methods are available nowadays. Oral contraceptives (OCs) are the preferred choice among adolescents in general. However, the use of these medications in adolescents with SLE raises serious concerns, particularly the risk of thrombotic events from estrogen exposure and the impact of these medications on lupus activity. In this article, different contraceptive methods available are reviewed and their application in adolescents with SLE is discussed. In conclusion, OCs are the methods of choice in adolescents with stable disease and no antiphospholipid antibodies (aPL) detected. In patients with aPL, fewer options are available, and the selection of the preferred form of contraception should be made on an individual basis.

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Lupus. 2007;16(8):564-71.
Review: Neuropsychiatric involvement in pediatric systemic lupus erythematosus.
Benseler SM, Silverman ED.
Divisions of Rheumatology, Department of Paediatrics and Immunology, The Hospital for Sick Children, University of Toronto, Toronto, Canada.

Neuropsychiatric (NP) manifestations are found in approximately 25% of children and adolescents with pediatric SLE (pSLE). In 70% of those, NP involvement will occur within the first year from the time of diagnosis. Headaches (66%), psychosis (36%), cognitive dysfunction (27%) and cerebrovascular disease (24%) are the most common presentations. The support of a psychiatrist is often required. Anti-phospholipid antibodies are associated with distinct NP disease entities and may be implicated in the pathogenesis of several manifestations of NP-pSLE including chorea, cerebrovascular disease and seizures. The role of novel auto-antibodies and imaging modalities is currently explored. The treatment of NP-pSLE is not based on prospective studies; however, an immunosuppressive combination therapy consisting of high doses of prednisone and a second line agent such as cyclophosphamide or azathioprine is commonly suggested for children with NP-pSLE. The role of novel therapies is currently studied. The outcome of children with NP-pSLE is relatively good. The overall survival is 95-97%, 20% of children experience a disease flare during childhood and 25% have evidence of permanent neuropsychiatric damage.

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Bone Marrow Transplant. 2007 May 7; [Epub ahead of print]
Autologous hematopoietic stem cell transplantation in systemic lupus erythematosus patients with cardiac dysfunction: feasibility and reversibility of ventricular and valvular dysfunction with transplant-induced remission.
Loh Y, Oyama Y, Statkute L, Traynor A, Satkus J, Quigley K, Yaung K, Barr W, Bucha J, Gheorghiade M, Burt RK.
1Division of Immunotherapy, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.

Patients with cardiac dysfunction may be at increased risk of cardiac toxicity when undergoing hematopoietic stem cell transplantation (HSCT), which may preclude them from receiving this therapy. Cardiac dysfunction is, however, common in systemic lupus erythematosus (SLE) patients. While autologous HSCT (auto-HSCT) has been performed increasingly for SLE, its impact on cardiac function has not previously been evaluated. We, therefore, performed a retrospective analysis of SLE patients who had undergone auto-HSCT in our center to determine the prevalence of significant cardiac involvement, and the impact of transplantation on this. The records of 55 patients were reviewed, of which 13 were found to have abnormal cardiac findings on pre-transplant two-dimensional echocardiography or multi-gated acquisition scan: impaired left ventricular ejection fraction (LVEF) (n=6), pulmonary hypertension (n=5), mitral valve dysfunction (n=3) and large pericardial effusion (n=1). At a median follow-up of 24 months (8-105 months), there were no transplant-related or cardiac deaths. With transplant-induced disease remission, all patients with impaired LVEF remained stable or improved; while three with symptomatic mitral valve disease similarly improved. Elevated pulmonary pressures paralleled activity of underlying lupus. These data suggest that auto-HSCT is feasible in selected patients with lupus-related cardiac dysfunction, and with control of disease activity, may improve.Bone Marrow Transplantation advance online publication, 7 May 2007; doi:10.1038/sj.bmt.1705698.

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Nat Clin Pract Rheumatol. 2007 May;3(5):273-81; quiz 305-6.
Therapy insight: guidelines for selection of contraception in women with rheumatic diseases.
Sammaritano LR.
Weill Medical College of Cornell University, Hospital for Special Surgery, Department of Medicine, New York, NY, USA. sammaritan@hss.edu

Use of contraceptives by women with rheumatic diseases, especially those with systemic lupus erythematosus, has long been thought to carry risks, such as disease exacerbation, thrombosis and other adverse effects. The use of effective contraception has, therefore, been avoided, despite many affected women being of reproductive age. Knowledge of risks and benefits of contraceptive methods in the general population has improved, as have the safety and effectiveness of hormonal contraceptives. Methods of administration have evolved and now include transdermal and intravaginal routes, a progesterone-releasing intrauterine device, and an extended-cycle oral contraceptive. Birth control pills are not all alike; the risk of adverse effects varies depending on the amount of estrogen and type of progestin used. Data show that patients with stable systemic lupus erythematosus are not at increased risk of disease flare while taking standard oral contraceptives. Despite a lack of randomized studies, evidence strongly suggests that the elevated risk of thrombosis makes estrogen-containing contraceptives unsuitable for patients with antiphospholipid antibody. Other important issues include potential interactions between hormonal contraceptives and other medications and possible risk of infection if an intrauterine device is used. Rheumatologists are increasingly working with gynecologists and patients to make choices about which contraceptive methods to use. Decisions should be individualized according to the patient's medical status, personal preference, and stage of reproductive life.

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Acta Dermatovenerol Croat. 2007;15(1):39-44.
Thalidomide and its dermatologic uses.
Paghdal KV, Schwartz R.
Kapila V. Paghdal, PharmD Department of Dermatology New Jersey Medical School 185 South Orange Avenue Newark, New Jersey 07103 USA roschwar@cal.berkeley.edu.

Thalidomide is a beneficial agent for treating a variety of refractory dermatologic disorders including erythema nodosom leprosum, lupus erythematosus, prurigo nodularis, actinic prurigo, pyoderma gangrenosum and aphthous stomatitis. Two thalidomide analogues, lenalidomide and CC-4047, are considerably more potent with decreased side effects when compared to thalidomide. They are currently undergoing trials and show promise, as they have increased immunomodulatory and anti-angiogenic activity. This category of medication and its use will be reviewed.

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Nat Clin Pract Rheumatol. 2007 May;3(5):262-72.
Monoclonal antibody and intravenous immunoglobulin therapy for rheumatic diseases: rationale and mechanisms of action.
Bayry J, Lacroix-Desmazes S, Kazatchkine MD, Kaveri SV.
Institut National de la Sante et de la Recherche Medicale (INSERM), Universite Rene Descartes, Centre de Recherche des Cordeliers, Paris, France. srini.kaveri@umrs681@jussieu.fr

Advances in our understanding of the pathogenesis of rheumatic diseases such as rheumatoid arthritis and systemic lupus erythematosus have led to the emergence of immunoglobulin-based therapy as a major therapeutic force. Numerous monoclonal antibodies that target proinflammatory cytokines or their receptors (e.g. infliximab, adalimumab, tocilizumab, belimumab, HuMax-IL-15), and cell-surface or co-stimulatory molecules (e.g. rituximab) are either in clinical development or have been approved for clinical use. These antibodies are safe and effective in the long-term therapy of many rheumatic diseases. In addition, polyclonal immunoglobulins (intravenous immunoglobulin) obtained from pooled plasma from healthy blood donors are an effective therapeutic approach in certain rheumatic diseases. The mechanisms of action of monoclonal antibodies and intravenous immunoglobulin include cytolysis of target cells through complement or antibody-dependent cell-mediated cytotoxicity, induction of apoptosis of target cells, blockade of co-stimulatory molecules, and neutralization of pathogenic antibodies and soluble factors such as cytokines and their receptors, which ultimately lead to amelioration of the inflammatory process. The success of currently available therapeutic immunoglobulins has led to considerable interest in the identification of novel molecular therapeutic targets in rheumatic diseases.

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Lupus. 2007;16(3):227-31.
Exploring new territory: the move towards individualised treatment.
Haubitz M.
Department of Nephrology, Medical School Hannover, Hannover, Germany. Haubitz.Marion@MH-Hannover.de

The main goal of therapy for lupus nephritis is to achieve remission, as this has a major impact on patient and renal survival. Furthermore, early treatment success has been shown to improve long-term prognosis. This has traditionally been achieved with intravenous cyclophosphamide, but recent data show that mycophenolate mofetil is equally effective and causes fewer adverse effects. Research is ongoing to find new treatment targets. Possible future therapies include monoclonal antibodies against CD20 (rituximab), CD22 (epratuzumab) and CD40, and therapies targeted at cytokine secretion, immunoglobulin secretion, B-cell maturation and T-cell proliferation and differentiation. Rituximab has shown promise in patients with active proliferative lupus nephritis, which suggests that B-cell depletion may be successful. Anti-double-stranded DNA antibodies correlate with flares of lupus nephritis and may represent another therapeutic target. Therapy with LIP 394, which crosslinks anti-double-stranded DNA antibodies in solution or on the B-cell surface, has been shown to reduce flares. Cardiovascular disease is a major cause of mortality in systemic lupus erythematosus, and this must also be addressed if long-term outcomes are to be improved. Many patients with systemic lupus erythematosus have subclinical atherosclerosis quite early in the disease course, and the risk of coronary artery disease at any level of traditional cardiovascular risk factors is higher than in the general population. Specific lupus-associated risk factors include the inflammatory process itself and anticardiolipin antibodies. Possible strategies to reduce the risk include reduction of disease activity to improve endothelial function and reduction of steroid dose whenever possible. Therapy with aspirin or statins may be another possibility. Thus treatment of lupus nephritis is evolving from standardised therapy to individualised therapy based on analysis of organ involvement, risk factors and cytokine, antibody or cell profiles.

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Lupus. 2007;16(3):221-6.
Exploring new territory: considering the future.
Schneider M.
Clinic for Endocrinology, Diabetology and Rheumatology, Heinrich-Heine-University, Dusseldorf, Germany. schneider@rheumanet.org

The European League Against Rheumatism (EULAR)'s guidelines for lupus state that mycophenolate mofetil has at least equivalent efficacy to and less toxicity than cyclophosphamide for the short-and medium-term treatment of lupus nephritis but that long-term data are available only for cyclophosphamide. New therapies are needed to reduce toxicity and the need for steroids and to offer the possibility of cure. Therapies under investigation include other immunosuppressive agents, anti-cellular therapies, drugs that modify cell-cell interactions, (anti-)cytokine therapy, hormone therapy and lupus-specific immunomodulation. Rituximab has shown promise in patients refractory to conventional immunosuppression, which suggests that targeting B cells may be successful. Other anti-cell therapies include epratuzumab, belimumab and alemtuzumab. Anti-cytokine approaches include tumour necrosis factor alpha blockade with infliximab, anti-interleukin 6-receptor therapy with tocilizumab and interferon-alpha blockade. As antidouble-stranded DNA antibodies correlate with flares of lupus nephritis, they may represent another therapeutic target--as do monocyte chemoattractant protein-1 and protein kinase CK2. Therapeutic options to prevent damage in lupus nephritis include non-immunosuppressive treatments aimed at reducing cardiovascular risk (such as statins, angiotensin-converting enzyme inhibitors and aspirin). As was the case with rheumatoid arthritis, a change in therapeutic aims--from survival through prevention of renal failure to induction of remission--may modify outcomes. EULAR's guidelines state that renal biopsy is the best monitor of clinical outcome in lupus nephritis, as immunological tests have limited predictive value. Measurement of urinary mRNA for cytokine and growth factor genes may provide a more sensitive, non-invasive method of monitoring therapeutic response.

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Lupus. 2007;16(3):217-20.
Current management of lupus nephritis: popular misconceptions.
Jayne D.
Adenbrooke's Hospital, Cambridge, UK. dj106@cam.ac.uk

The management of lupus nephritis is typified by popular misconceptions: that there is a 'standard of care', that treatment has well-defined aims and that the optimum length of treatment is established. In reality, however, uncertainties still exist and the evidence base remains weak. Until recently, initial therapy for class IV lupus nephritis typically involved intravenous cyclophosphamide, yet although cyclophosphamide is superior to azathioprine in improving renal function, it is not superior in terms of mortality. In fact, recent studies show mycophenolate mofetil to be superior to cyclophosphamide in terms of response rate and safety profile and at least as effective as other immunosuppressants. The role of steroids is unclear. Clearly, no standard of care exists in lupus nephritis. The Euro-Lupus Nephritis Trial found that treatment response at six months, in terms of reduced serum creatinine and proteinuria, was the best predictor of long-term renal outcome. Proteinuria, however, can take a long time to reach baseline levels, and normalization of urine is not the same as loss of histological disease activity. Response to treatment thus is not the same as disease remission. Although treatment should aim to reduce the risk of end-stage renal disease and death, control of proteinuria and prevention of flares are also important. Patients who have nephritic flares are almost seven times as likely to progress to end-stage renal disease compared with those who do not. Regimens involving maintenance phases have been developed, but uncertainty remains about the risk of flares and how they can be predicted. The optimum duration of treatment has yet to be determined.

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Lupus. 2007;16(3):212-6.
Thirty years of cyclophosphamide: assessing the evidence.
Houssiau F.
Department of Rheumatology, Cliniques Universitaires Saint-Luc, Universite catholique de Louvain, Brussels, Belgium. houssiau@ruma.ucl.ac.be

The ideal therapy for lupus nephritis should reduce mortality and end-stage renal disease in the long term, induce early response and remission, prevent flares, have minimal side-effects and not compromise fertility. It should also be active in all ethnic groups, widely available and cost effective. Despite 30 years' clinical experience, the ability of cyclophosphamide to meet these needs is not supported by robust evidence. The first National Institutes for Health (NIH) trial in 1986 led to a shift from oral to intravenous cyclophosphamide. The three NIH trials together then led to the dogma that high-dose intravenous cyclophosphamide is the only cytotoxic agent superior to steroids alone in lupus nephritis and to its general acceptance as the 'standard of care'. Since then, high-dose intravenous cyclophosphamide has been shown to have no impact on survival, to be less effective in black patients and to have many side-effects, particularly an unacceptable risk of premature menopause. The Euro-Lupus Nephritis Trial found that low-dose intravenous cyclophosphamide could be used as an alternative to a high-dose regimen and was associated with half as many severe infections. Other advantages include no hospitalisation and virtually no risk of premature gonadal failure. Other studies have looked at regimens in which cyclophosphamide is entirely replaced--for example, with mycophenolate mofetil--and have found fewer side-effects and better induction of remission. Intravenous cyclophosphamide is the only therapy with long-term data for reduction of end-stage renal disease. As data on other therapies accumulate, however, intravenous cyclophosphamide might no longer be considered the standard treatment for lupus nephritis.

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Clin Med Res. 2006 Dec;4(4):310-21.
Lupus and pregnancy: complex yet manageable.
Dhar JP, Sokol RJ.
Harper University Hospital, 6 Hudson, Mailbox in Gastroenterology Area, 3990 John R, Detroit, MI 48201 USA. PDhar@med.wayne.edu.
Full free text at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=17210979

Systemic lupus erythematosus is a chronic multi-system autoimmune disease that occurs predominantly in women of childbearing age. The risk of complications and adverse fetal outcomes in pregnant women with lupus is high. Moreover, pregnancy can cause flares of lupus disease activity necessitating maternal immunosuppressive intervention. Interestingly, many potential complications of pregnancy present as symptoms of lupus making diagnosis and treatment a challenge.Advancing technology and better understanding of the maternal-fetal dyad in lupus have improved outcomes in lupus pregnancies over the last 40 years. This article will briefly review the important issues in pregnancies complicated by lupus and provide a general guideline to physicians for monitoring and treatment.

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Arthritis Res Ther. 2006 Dec 12;8(6):R182 [Epub ahead of print]
Systematic review and meta-analysis of randomised trials and cohort studies of mycophenolate mofetil in lupus nephritis.
Moore RA, Derry S.
Pain Research and Nuffield Department of Anaesthetics, University of Oxford, The Churchill, Headington, Oxford OX3 7LJ, UK. andrew.moore@pru.ox.ac.uk.

ABSTRACT: Mycophenolate mofetil (MMF) is an immunosuppressant drug being used for induction and maintenance of remission of lupus nephritis in systemic lupus erythematosus. Evidence about its use was sought from full publications and abstracts of randomised trials and cohort studies by using a variety of search strategies. Efficacy and adverse event outcomes were sought. Five randomised trials enrolled patients with World Health Organization (WHO) class III, IV, or V (mostly IV) lupus nephritis, predominantly comparing MMF (1 to 3 g daily) with cyclophosphamide and steroid. Complete response and complete or partial response was significantly more frequent with MMF than with cyclophosphamide, with numbers needed to treat of 8 (95% confidence interval 4.3 to 60) to induce one additional complete or partial response, with wide confidence intervals. Death was reported less frequently with MMF (0.7%, 1 death in 152 patients) than with cyclophosphamide (7.8%, 12 deaths in 154 patients), with a number needed to treat to prevent (NNTp) one death of 14 (8 to 48). Hospital admission was also lower with MMF (1.7% versus 15%; NNTp 7.4 [4.8 to 16]). Serious infections, leucopaenia, amenorrhoea, and hair loss were all significantly less frequent with MMF than with cyclophosphamide, but diarrhoea was significantly more common with MMF. Ten of 18 cohort studies enrolled only patients with lupus nephritis (author-defined or WHO class III to V). Seven of these 10 reported that complete or partial response with MMF (mostly 1 or 2 g daily) with steroid occurred in 121/151 (80%) and that treatment failure or no response occurred in 30/151 (20%). Adverse events were generally similar in cohort studies with and without only patients with lupus nephritis. In all 18 cohorts, gastrointestinal adverse events (diarrhoea, nausea, vomiting) occurred in 30%, infection in 23%, and serious infection in 4.3%. Adverse event discontinuations occurred in 14% and lack of efficacy occurred in 10%. There was a single death with MMF, a mortality rate over the course of 1 year of approximately 0.2%. The results form a basis on which to plan future studies and provide a guide for the use of MMF in lupus nephritis until results of larger studies are available. At least one such study is under way.

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Lupus. 2006;15(11):778-83.
Immunizing patients with systemic lupus erythematosus: a review of effectiveness and safety.
O'Neill SG, Isenberg DA.
Centre for Rheumatology, University College London, London, UK. sean.oneill@uclh.nhs.uk

Concerns regarding the safety and efficacy of immunization in patients with SLE have persisted for over 60 years, despite the increased risk of infection in these patients. There are many anecdotal case reports of SLE induction or exacerbation following immunization, but overall, these events seem to be very rare. Evidence from prospective trials suggests that inactivated and component vaccines are probably safe in patients with SLE. Live vaccines are contraindicated in patients on immunosuppressive agents or high dose steroids (prednisone 20 mg/day or greater). There is limited evidence regarding efficacy of vaccination in patients with SLE. Studies assessing serological response to vaccination have generally shown that the majority of patients have an appropriate response, but a significant minority do not. Response to hepatitis B vaccination may be impaired and serological responses should be assessed post vaccination. It is not clear if disease activity or immunosuppressive medications are risk factors for a poor response, rather than intrinsic abnormalities of immune function in patients with SLE. The majority of patients appear to have a reasonable serological response to vaccination.

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J Adv Nurs. 2006 Dec;56(6):617-35.
Effectiveness of non-pharmacological interventions for fatigue in adults with multiple sclerosis, rheumatoid arthritis, or systemic lupus erythematosus: a systematic review.
Neill J, Belan I, Ried K.
School of Nursing and Midwifery, Flinders University, Adelaide, Australia. jane.neill@flinders.edu.au

AIM: This paper reports a systematic review of non-pharmacological interventions for fatigue in adults with three common autoimmune conditions. BACKGROUND: A considerable proportion of people with multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus experience compromised quality of life due to fatigue. Recent reviews of pharmacotherapies for fatigue in these conditions remain inconclusive, and systematic evidence for effectiveness of non-pharmacological interventions was unavailable. Our paper addresses this gap. METHODS: The literature search used the key words fatigue, energy, multiple sclerosis, rheumatoid arthritis and systemic lupus. It included 19 electronic databases and libraries, three evidence-based journals, two internet search engines, was dated 1987-2006, and limited to English. Non-pharmacological experimental studies about fatigue comprising more than five adults were included. Meta-analysis was not possible due to diverse interventions and outcome measures, therefore studies were analysed by types of interventions used to reduce fatigue. RESULTS: Of 653 hits, 162 papers were reviewed, and 36 met the inclusion criteria. Thirty-three primary studies reported 14 randomized controlled trials and 19 quasi-experimental designs. Most interventions were tested with people with multiple sclerosis. Exercise, behavioural, nutritional and physiological interventions were associated with statistically significant reductions in fatigue. Aerobic exercise was effective, appropriate and feasible for reducing fatigue among adults with chronic autoimmune conditions. Electromagnetic field devices showed promise. The diversity of interventions, designs, and using 24 different instruments to measure fatigue, limited comparisons. CONCLUSION: Low impact aerobic exercise gradually increasing in intensity, duration and frequency may be an effective strategy in reducing fatigue in some adults with chronic auto-immune conditions. However, fatigue is a variable and personal experience and a range of behavioural interventions may be required. Well-designed studies testing these promising strategies and consensus on outcome fatigue measures are needed.

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Joint Bone Spine. 2006 Dec;73(6):591-8. Epub 2006 Oct 11.
Treatment of systemic lupus erythematosus in 2006.
Sibilia J.
Rheumatology Department, Strasbourg Teaching Hospital-Hautepierre Hospital, 1, avenue Moliere, 67098 Strasbourg cedex, France. jean.sibilia@wanadoo.fr

After many barren years, conceptual advances and the introduction of new biotherapies are yielding improvements in the management of systemic lupus erythematosus (SLE). The result is a radical change in the management strategy. The main therapeutic advances rest on new discoveries (or rediscoveries), some of which are original. They can be summarized under 12 headlines. Smoking is inadvisable, as it promotes not only atheroma but also lupus flares. Hydroxychloroquine and conventional drugs (cyclophosphamide) are helpful provided they are used appropriately. Combined oral contraception and hormone replacement therapy may be less hazardous than previously thought, although caution remains in order. Drugs used in transplant recipients, such as mycophenolic acid, are generating optimism as treatments for SLE. Rituximab and new anti-B-cell drugs hold promise for the treatment of severe SLE. Efforts to develop an "etiologic" treatment for SLE based on type 1 (alpha/beta) interferon blockade still face a number of obstacles. Peptide vaccines, whose main effect is stimulation of regulator T cells, hold promise-but confirmation is needed. Whether TNF antagonists can be used in lupus with skin and joint manifestations or in SLE is generating debate. Complement blockade for treating SLE and antiphospholipid syndrome is an attractive avenue of research. Numerous new immunotherapy modalities based on modulating intracellular signaling are being evaluated. In the most severe forms of SLE, autologous peripheral stem cell transplantation deserves consideration. A key component of the treatment of SLE is control of atheroma, which is among the most severe complications. This rich harvest of new treatment possibilities can be expected to radically modify the prognosis of SLE, whose more aggressive forms remain severe.

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Semin Arthritis Rheum. 2006 Oct 24; [Epub ahead of print]
Treatment of Proliferative Lupus Nephritis-A Critical Approach.
Buhaescu I, Covic A, Deray G.
Saint Vincent Hospital, Department of Internal Medicine, Worcester, Massachusetts.

OBJECTIVES: To discuss the current management of proliferative lupus nephritis (PLN), with a focus on strategies to improve long-term outcome and reduce treatment toxicity while minimizing the risk of relapse. METHODS: The literature on treatment strategies used in systemic lupus erythematosus (SLE) and PLN from 1975 to 2006, using PubMed from the National Library of Medicine, was reviewed. RESULTS: The high efficacy of the standard therapeutic regimen of PLN, traditionally associating cyclophosphamide (CYC) with corticosteroids (CS), has markedly ameliorated the prognosis of the disease, with more than 80% of patients achieving complete or partial remission. The ameliorated renal prognosis has positively influenced the general survival rates. Ten-year survival rates now surpass 75% and continue to improve. In view of the improved survival, the major aims of treatment now include preventing long-term organ damage and minimizing treatment toxicity, which can contribute significantly to the chronic morbidity and mortality of lupus. A number of high-quality trials have been reported, making us more confident of the value of different immunosuppressive protocols, and several novel immunosuppressive drugs are still under investigation. CONCLUSION: Recent basic and clinical research has enormously improved our understanding of the pathogenesis of SLE and has suggested new, targeted approaches to therapy. These targeted novel therapies are expected to help the patients with PLN in the next decade.
 

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