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Latest Research on Arthritis
     
Semin Arthritis Rheum. 2008 Mar 11 [Epub ahead of print]
Safety of Biologic Therapy in Rheumatoid Arthritis and Other Autoimmune Diseases: Focus on Rituximab.
Fleischmann RM.
University of Texas Southwestern Medical Center, and Metroplex Clinical Research Center, Dallas, TX.

OBJECTIVES: To review the safety of biologic agents used to treat rheumatoid arthritis (RA) and other autoimmune diseases, with a focus on rituximab. METHODS: Information was gathered from a search of the PubMed database and from major congress abstract listings through June 2007. RESULTS: Rituximab is approved for treating RA in patients with an inadequate response to TNF inhibitors and is under study in other indications for RA and other autoimmune disorders. The current safety profile of rituximab in RA is known from Phase II and III studies conducted preapproval, treating approximately 750 patients, as well as from long-term extension studies with repeated therapy. Clinical trials have established that the most common adverse events are infusion-associated reactions, seen in 29 to 40% of patients, most of which are mild to moderate and occur following the first rituximab infusion, with incidence and severity decreasing with subsequent infusions. Rates of infections and serious infections to date are within the range expected for RA patients treated with other biologic agents, but the longer term effects of B-cell depletion and the effects of repeated treatment on the risk of infections are uncertain. Information is limited for rituximab safety in other autoimmune disorders but current data do not suggest that there is a significant difference in adverse events from that previously reported. CONCLUSIONS: Rituximab is an important addition to the rheumatologist's armamentarium for the treatment of difficult RA and ongoing trials will determine its utility in other indications for RA and other autoimmune conditions. The true safety profile of rituximab will emerge as larger numbers of patients are treated in routine clinical practice.

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Nat Clin Pract Rheumatol. 2008 Mar 11 [Epub ahead of print]
Surgery Insight: orthopedic treatment options in rheumatoid arthritis.
Simmen BR, Bogoch ER, Goldhahn J.
BR Simmen is the Chairman and J Goldhahn is a Senior Researcher at the Upper Extremity Department of the Schulthess Klinik in Zürich, Switzerland.

Longstanding rheumatoid arthritis (RA) leads to disability, caused mainly by joint destruction. The current goals of surgical intervention are to restore function and quality of life, prevent joint deterioration, relieve pain, and correct deformity. A number of different surgical treatment options are available to patients with RA, including synovectomy, arthrodesis, joint replacement, and soft tissue and special hand surgery; nonoperative management is also important. Decision-making and timing for orthopedic intervention are complex issues because of polyarticular involvement. Functional impairment, pain, and the subsequent loss of quality of life and inability to work have become the main considerations for surgical reconstruction. Early referral for orthopedic treatment can lead to improved functional benefit for patients with RA. The decision for orthopedic intervention should be established by an interdisciplinary team that includes rheumatologists and orthopedic surgeons experienced in the surgery of RA. Priority should be given to the joint that causes the greatest disability and pain. Disease progression and pharmaceutical treatment options should be taken into consideration when establishing an orthopedic intervention protocol.

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BMC Musculoskelet Disord. 2008 Mar 7;9(1):32 [Epub ahead of print]
Long-term retention on treatment with lumiracoxib 100 mg once or twice daily compared with celecoxib 200 mg once daily: a randomised controlled trial in patients with osteoarthritis.
Fleischmann R, Tannenbaum H, Patel NP, Notter M, Sallstig P, Reginster JY.

ABSTRACT: BACKGROUND: The efficacy, safety and tolerability of lumiracoxib, a novel selective cyclooxygenase-2 (COX-2) inhibitor, has been demonstrated in previous studies of patients with osteoarthritis (OA). As it is important to establish the long-term safety and efficacy of treatments for a chronic disease such as OA, the present study compared the effects of lumiracoxib at doses of 100 mg once daily (o.d.) and 100 mg twice daily (b.i.d.) with those of celecoxib 200 mg o.d. on retention on treatment over 1 year. METHODS: In this 52-week, multicentre, randomised, double-blind, parallel-group study, male and female patients (aged at least 40 years) with symptomatic primary OA of the hip, knee, hand or spine were randomized (1:2:1) to lumiracoxib 100 mg o.d. (n = 755), lumiracoxib 100 mg b.i.d. (n = 1,519) or celecoxib 200 mg o.d. (n = 758). The primary objective of the study was to demonstrate non-inferiority of lumiracoxib at either dose compared with celecoxib 200 mg o.d. with respect to the 1-year retention on treatment rate. Secondary outcome variables included OA pain in the target joint, patient's and physician's global assessments of disease activity, Short Arthritis assessment Scale (SAS) total score, rescue medication use, and safety and tolerability. RESULTS: Retention rates at 1 year were similar for the lumiracoxib 100 mg o.d., lumiracoxib 100 mg b.i.d. and celecoxib 200 mg o.d. groups (46.9% vs 47.5% vs 45.3%, respectively). It was demonstrated that retention on treatment with lumiracoxib at either dose was non-inferior to celecoxib 200 mg o.d. Similarly, Kaplan-Meier curves for the probability of premature discontinuation from the study for any reason were similar across the treatment groups. All three treatments generally yielded comparable results for the secondary efficacy variables and all treatments were well tolerated. CONCLUSIONS: Long-term treatment with lumiracoxib 100 mg o.d., the recommended dose for OA, was as effective and well tolerated as celecoxib 200 mg o.d. in patients with OA. Trial registration: clinicaltrials.gov NCT00145301.

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Bull NYU Hosp Jt Dis. 2008;66(1):41-8.
Psoriatic arthritis and arthroplasty: a review of the literature.
[No authors listed]

Psoriatic arthritis is an inflammatory arthropathy associated with the characteristic dermatologic lesions of psoriasis. The diagnosis of psoriatic arthritis is quite difficult, due to the overlap of patients with osteoarthritis (OA) or rheumatoid arthritis (RA) with concomitant non-associated psoriasis. A nonspecific elevation in inflammatory markers (erythrocyte sedimentation rate, ESR; antinuclear antibodies, ANA; or rheumatoid factor, RF) and characteristic radiographic features are often present in these patients. The mainstay of treatment is medical management, using NSAIDs, various immuno-suppressants, and anti-TNF agents, for both pain control and possibly as disease modifying agents. Only a minority of patients require surgical intervention, leading to the limited amount of literature concerning total joint arthroplasty and psoriatic arthritis. While past literature has yielded high infection rates post-arthroplasty, newer studies have found more promising results. Alternative surgical options for treating destructive arthritis include open or arthroscopic synovectomy. While early results are promising, recurrence rates and long-term outcomes are not yet available.

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Orthopade. 2008 Mar;37(3):224-31.
[Conservative therapy of cartilage defects of the upper ankle joint.]
[Article in German]
Smolenski UC, Best N, Bocker B.
Institut für Physiotherapie, Universitätsklinikum, Erlanger Allee 101, 07740, Jena, Deutschland, ulrich.smolenski@med.uni-jena.de.

Cartilage defects of the upper ankle joint reflect the problem that great force is transmitted and balanced out over a relatively small surface area. As a pathophysiological factor, cartilage-bone contusions play a significant role in the development of cartilage defects of the upper ankle joint. Physiotherapeutic procedures belong to the standard procedures of conservative therapy. The use and selection of the type of therapy is based on empirical considerations and experience and investigations on effectiveness of particular therapies are relatively rare. At present a symptom-oriented therapy of cartilage defects of the upper ankle joint seems to be the most sensible approach. It can be assumed that it makes sense that the symptomatic treatment of cartilage defects or initial stages of arthritis also includes the subsequent symptoms of pain, irritated condition and limited function. This leads to starting points for physiotherapy with respect to pain therapy, optimisation of pressure relationships, avoidance of pressure points, improvement of diffusion and pressure release. In addition to the differential physiotherapeutic findings, the determination of a curative, preventive or rehabilitative procedure is especially important. In physical therapy special importance is placed on a scheduled serial application corresponding to the findings, employing the necessary methods, such as physiotherapy, sport therapy, medical mechanics, manual therapy, massage, electrotherapy and warmth therapy. From this the findings-related therapy is proposed as a practical therapy concept: locomotive apparatus pain therapy, optimisation of pressure relationships, improvement of diffusion and decongestion therapy. Therapy options have been selected base on the current literature and are summarised in tabular form. The art of symptomatic therapy of cartilage defects of the upper ankle joint does not lie in the multitude of sometimes speculative procedures, but in the targeted selection of a therapy regime based on the therapeutic goal, a corresponding application dose and serial design.

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J Rheumatol. 2008 Mar 1 [Epub ahead of print]
Clinical Outcome and Imaging Changes After Intraarticular (IA) Application of Etanercept or Methylprednisolone in Rheumatoid Arthritis: Magnetic Resonance Imaging and Ultrasound-Doppler Show No Effect of IA Injections in the Wrist After 4 Weeks.
Boesen M, Boesen L, Jensen KE, Cimmino MA, Torp-Pedersen S, Terslev L, Koenig M, Danneskiold-Samsøe B, Røgind H, Bliddal H.
From The Parker Institute Frederiksberg Hospital; Rigshospitalet, Department of Radiology, MRI Section, Copenhagen, Denmark; and Rheumatologic Clinic, Department of Internal Medicine, University of Genoa, Genoa, Italy.

OBJECTIVE: To assess the magnetic resonance imaging (MRI) and ultrasound (US) changes in the wrist of patients with rheumatoid arthritis (RA) 4 weeks after an US guided intraarticular (IA) injection. METHODS: Contrast enhanced MRI and US-Doppler were performed at baseline and 4 weeks after IA injection of either 40 mg methylprednisolone (n = 12) or 25 mg etanercept (n = 13) in 25 patients with RA taking disease modifying antirheumatic drugs with a therapy-resistant wrist joint. All injections were US guided. RESULTS: There was an improvement in swollen target joint score (p < 0.001), tender target joint score (p < 0.002), and physician visual analog scale score (p < 0.001) after 4 weeks. Baseline MRI synovitis score was mean 5.08 (range 3-9) and was unchanged at followup in the whole group (p = 0.52) and between treatment groups (p = 0.43). MRI edema score (mean 4.46, range 0-29) in the total group was unchanged after 4 weeks (p = 0.13), whereas MRI erosion score increased in the total group from baseline, 17.88 (range 7-40), to 4 weeks, 18.25 (range 7-40) (p < 0.001). Neither US-Doppler color fraction (0.07) nor Resistive Index (RI) (p = 0.36) changed from baseline to 4 week followup. CONCLUSION: In contrast to the clinical evaluation, imaging measures of relevance for the estimation of inflammation, US-Doppler, US RI, MRI synovitis, and bone-marrow edema did not change 4 weeks after a single IA injection of either methylprednisolone or etanercept in the wrist. Within the same period, erosive progression in some patients suggested that joints with active disease may deteriorate within as little as 1 month, and that this development is not arrested by 1 injection. Given the small sample size of our study further studies are required to confirm our results.

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J Hand Surg Eur Vol. 2008 Feb;33(1):38-44.
Two to five year follow-up of the lpm ceramic coated proximal interphalangeal joint arthroplasty.
Field J.
Consultant Orthopaedic and Hand Surgeon, Cheltenham General Hospital, Gloucestershire Hospitals NHS Foundation Trust UK, Cheltenham, UK.

This paper presents a retrospective series of 20 LPM semi-constrained ceramic coated cobalt chrome proximal interphalangeal joint arthroplasties performed consecutively in 12 patients for arthritis of the proximal interphalangeal joint by a single surgeon between 2000 and 2004. Eleven were performed for osteoarthritis, four for post-traumatic arthritis and five for rheumatoid arthritis. Although 12 joints had an improvement in pain and an increased functional arc of movement, six joints required revision surgery for implant failure at an average of 19 months, with clinical signs of increasing pain, deteriorating motion and radiological signs of implant loosening and subsidence. This rate of revision is higher than in published series for other PIP joint implants and, therefore, close surveillance of all patients with this prosthesis currently in situ is recommended. Use of the prosthesis has ceased in this unit.

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Clin Exp Rheumatol. 2008 Jan-Feb;26(1):113-6.
Glucocorticoid treatment in rheumatoid arthritis: low-dose therapy does not reduce responsiveness to higher doses.
Wolf J, Kapral T, Grisar J, Stamm T, Koeller M, Smolen JS, Aletaha D.
Second Department of Medicine, Hietzing Hospital, Vienna.

BACKGROUND: Despite low-dose gluco-corticoid (GC) treatment, many patients with rheumatoid arthritis (RA) require additional flare therapy with GC at higher doses. Since low dose GC has been suggested to confer resistance to higher doses, we aimed to assess if resistance was detectable on the clinical level in patients with active RA. METHODS: Eighty-nine patients with active RA (Disease Activity Score 28, DAS28 > 3.2; mean age 54.5 years, mean duration of RA 9.7 years) were consecutively enrolled into a one-week trial of a total of 250 mg prednisolone. We compared improvement of the DAS28 and the Simplified Disease Activity Index (SDAI) in groups of patients with (n = 41) and without (n = 48) low-dose GC at baseline (by t-test). In addition, we analyzed changes of all individual core set measures of disease activity using multivariate statistics. RESULTS: All clinical, serological and functional measures improved significantly over one week (p < 0.001). Baseline RA activity of patients with and without low-dose GC was on average +/- standard deviation similar among the two groups (DAS28: 4.8 +/- 1.2 and 4.9 +/- 1.1; mean SDAI: 26.1 +/- 14.0 and 25.9 +/- 13.0, respectively), and likewise there was no difference between the two groups in the final disease activity reached, for both the DAS28 (1.4 +/- 1.1 vs. 1.1 +/- 1.0; p = 0.14) and the SDAI (11.1 +/- 13.4 vs. 11.1 +/- 11.4; p = 0.99). Improvement in all individual measures was also not different using a multivariate model (p = 0.26). CONCLUSION:Pre-treatment with low-dose GC does not appear to portend GC resistance at least clinically, since the responsiveness to GC boosts is unaffected.

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Clin Exp Rheumatol. 2008 Jan-Feb;26(1):18-23.
Maintenance and tolerability of infliximab in a cohort of 152 patients with rheumatoid arthritis.
Figueiredo IT, Morel J, Sany J, Combe B.
Department of Immuno-Rheumatology, Teaching Hospital Lapeyronie, and University of Montpellier 1, France.

OBJECTIVE: To determine the maintenance, tolerability and safety of infliximab in an unselected cohort of patients with rheumatoid arthritis (RA). PATIENTS AND METHODS: One hundred and fifty-two RA patients receiving at least one course of infliximab between 2000 and 2003 were included in this study. Response to treatment and safety were assessed through recording adverse events, physical examinations and standard laboratory tests. The dosage of infliximab was patient specifically modified, when therapeutic response was judged inadequate by the assessment of a physician. RESULTS: The mean duration of follow-up was 401 days (85-1221). One hundred and twenty-two patients (78%) continued to receive infliximab after one year. 40 patients (26.3%) stopped infliximab therapy: 14 (9.2%) for inefficacy, 21 (13.8%) for adverse events. Fifty nine patients (38.8%) required an increase of the dosage (n = 23, 15%) or a shortening of the interval between the infusions (n = 20, 13.2%), or both (n = 16, 10.5%) for symptomatic control. Infliximab discontinuation tended to be more frequent in smokers (p = 0.055). Ninety-four patients (62%) reported at least one adverse event during the study: 64 infections (43%), 35 infusion reaction events (23%) which led to a discontinuation for 10 patients. Infusion reactions were more frequent in patients with a history of allergy. Three cases of tuberculosis and 1 breast carcinoma were reported during the study. CONCLUSIONS: Adjustments in the treatment of RA patients treated with recommended doses of infliximab were common (38.8% of the treated patients). Furthermore, the observed rate of infections (43%), including three cases of tuberculosis, should alert physicians to be vigilant in the routine care of patients treated with infliximab.

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Expert Opin Biol Ther. 2008 Jan;8(1):115-22.
Abatacept: the first T lymphocyte co-stimulation modulator, for the treatment of rheumatoid arthritis.
Chitale S, Moots R.
University of Liverpool, Academic Rheumatology Unit, School of Clinical Sciences, University Hospital Aintree, Longmoor Lane, Liverpool L9 7AL, UK.

Rheumatoid arthritis (RA) is a multisystem autoimmune disease, of unknown aetiology with high morbidity and significantly increased mortality. Over recent years, the introduction of targeted therapies with biologic agents have made major inroads to the outcomes in RA.The first such agents developed were TNF-alpha inhibitors. However, despite their high efficacy, up to 30% patients fail to respond adequately, or develop adverse reaction to TNF-alpha inhibitors. This suggests that other pathological mechanisms are involved, in addition to those mediated by TNF-alpha. Abnormal T-cell function has long been thought to play a key role in the pathogenesis of RA, stimulating both the production of pro-inflammatory cytokines and recruitment of other inflammatory cells, resulting in joint destruction and systemic disease. Abatacept, the first of a group of T-cell co-stimulation modulators, targeting T-cell activation, has recently been licensed for use in RA and shows promise as a useful drug to treat this major disabling disease.

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Prescrire Int. 2007 Dec;16(92):223-7.
Etoricoxib: new drug. Avoid using cox-2 inhibitors for pain.
[No authors listed]

(1) Paracetamol is the first-choice analgesic for joint pain. Nonsteroidal antiinflammatory drugs (NSAIDs), especially ibuprofen, are second-line options. Cox-2 inhibitors are no more effective than traditional NSAIDs and have no tangible advantages in terms of gastrointestinal tolerability. In contrast, they expose patients to an increased risk of cardiovascular adverse effects. (2) Etoricoxib is marketed in some European countries to relieve symptoms of osteoarthritis, rheumatoid arthritis, and gout attacks. (3) Many clinical trials have tested etoricoxib in these indications, as well as in ankylosing spondylitis, low back pain, and various types of acute pain. Etoricoxib was no more effective than other NSAIDs such as ibuprofen, naproxen or diclofenac in these situations. (4) Comparative trials showed a higher overall mortality rate with etoricoxib than with naproxen. A combined analysis of long-term comparative trials including 5441 patients, mainly versus naproxen, showed that etoricoxib does not reduce the risk of perforation, ulcer or severe gastrointestinal haemorrhage. Similarly, it does not reduce the risk of mild gastrointestinal events in at-risk patients: those with a history of gastrointestinal disorders, aspirin use, etc. (5) Three trials including a total of 34 701 patients (MEDAL programme) compared cardiovascular thrombotic events associated with etoricoxib and diclofenac. Overall, the cardiovascular risks appear to be similar but the thrombotic risk may be slightly higher with diclofenac than with other conventional NSAIDs. (6) Etoricoxib provoked arterial hypertension, oedema and heart failure during clinical trials. Serious skin reactions were reported both during clinical trials and after marketing, but their precise incidence is not known. Etoricoxib is partly metabolised by the cytochrome P450 isoenzyme CYP 3A4 and increases the bioavailability of ethinylestradiol. (7) When a NSAID is considered, drugs with which we have the most experience should be chosen, such as ibuprofen, and used at the lowest acceptable dose regimen (daily dose and length of treatment). Etoricoxib should be avoided.

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J Hand Surg [Am]. 2007 Dec;32(10):1496-505.
Preliminary results of nonconstrained pyrolytic carbon arthroplasty for metacarpophalangeal joint arthritis.
Parker WL, Rizzo M, Moran SL, Hormel KB, Beckenbaugh RD.
Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN.

PURPOSE: To review early outcomes of arthritic metacarpophalangeal (MCP) joints treated with nonconstrained pyrolytic carbon implants to evaluate efficacy, clinical outcomes, and durability. METHODS: One hundred forty-two consecutive arthroplasties (61 patients) were retrospectively reviewed. Diagnoses included osteoarthritis (OA), traumatic arthritis, and inflammatory arthritis. One hundred thirty were primary joint replacements, and 12 were prior-silicone revisions. The average patient age was 55 years (range, 21-77 years); 36 patients were women and 25 were men. Average follow-up period was 17 months (range, 3-42 months), and 43 patients were followed up for a minimum of 1 year. RESULTS: For OA patients, according to the analog pain scale used, pain decreased from 73.0 to 8.5 of 100, functionality increased from 20.1 to 86.6 of 100, and appearance improved from 62.7 to 93.6 of 100. The rheumatoid arthritis (RA) group showed decreased pain from 43.1 to 8.9 of 100, functional improvement from 26.7 to 83.3 of 100, and increased appearance from 25.2 to 77.1 of 100. At 1 year, satisfaction was greater than 90% for both groups. Arc of motion for OA patients improved from 44 degrees to 58 degrees . Oppositional pinch increased 126%, and grip strength improved 40%. Rheumatoid arthritis patients increased their MCP joint motion arc from 32 degrees to 45 degrees . Oppositional pinch increased 89%, but grip strength decreased. Radiographs at 1 year demonstrated stable prostheses in all of the OA joints. The RA group overall demonstrated evidence of axial subsidence (10.5% of joints) and periprosthetic erosions (16.4% of joints). In RA joints with greater than 1-year follow-up period, 55.0% had axial subsidence, 95.0% had an increased radiolucent seam, and 45.0% had periprosthetic erosions. The overall implant survivorship is 141 joints to date. The overall minor complication rate was 6%, and major complication rate was 9%. CONCLUSIONS: Preliminary results suggest that pyrolytic carbon MCP joint arthroplasty provides good pain relief, patient satisfaction, and functional improvement in managing OA and select cases of RA. Longer follow-up evaluation will help validate these promising early results. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

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Clin Rheumatol. 2007 Dec 8 [Epub ahead of print]
Statin treatment for rheumatoid arthritis: a promising novel indication.
Paraskevas KI.
Department of Clinical Biochemistry (Vascular Disease Prevention Clinic), Royal Free Hospital, Pond Street, London, NW3 2QG, UK.

The results of several cross-sectional trials suggest that patients with rheumatoid arthritis (RA) have increased vascular risk and cardiovascular mortality. It was demonstrated that inflammation plays a pivotal role in the pathogenesis of both RA and atherosclerosis. This association may explain the high incidence of cardiovascular disease in RA patients. A number of recent studies show that routine statin use in patients with RA offers considerable advantages. Statin treatment has been supported to exert a beneficial effect on disease activity, swollen joint count, endothelial dysfunction, and arterial stiffness in RA patients. These improvements are coupled with a mild to moderate improvement in plasma markers of inflammation, such as C-reactive protein and erythrocyte sedimentation rate. Statins have a satisfactory safety profile with relatively few adverse effects. In the absence of side effects and contraindications, it may be reasonable to consider statin use in selected cases, particularly in patients with a long history of active RA who are at increased cardiovascular risk.

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Rev Chir Orthop Reparatrice Appar Mot. 2007 Oct;93(6):571-81.
[Acromelic arthritis: a new entity]
[Article in French]
Welby F, Alnot JY.
Service de chirurgie orthopédique et traumatologique, Unité membre supérieur, Hôpital Bichat Claude-Bernard, 46, rue Henri-Huchard, 75018 Paris (France). france.welby@avc.aphp.fr

PURPOSE OF THE STUDY: Few patients with rheumatoid arthritis present isolated acromelic bone and joint destructions. Concerned joints are wrist, MP, PIP, DIP and forefoot. The aim of the current study is to describe and evaluate the long-term results of wrist, hand and forefoot surgery in an acromelic arthritis group. MATERIAL AND METHODS: 93 patients with acromelic arthritis were included in the study. 202 surgical procedures were performed between 1981 and 2001 in addition to medical treatment. 93 procedures concerned dorsal wrist surgery. The mean follow-up of this group was 7 years (24 months-20 years). 78 synovectomies of radio-carpal and medio-carpal joints with a Sauvé-Kapandji procedure were performed and 10 with a radio-lunate arthrodesis and 5 with other surgeries. The main indication for surgery was severe pain. RESULTS: Functional results and radiographic evolution (Larsen X-ray classification) were studied. All patients were satisfied or very satisfied and pain was significantly reduced. Radiographic lesions progressed but Larsen's stage remained unchanged in 73% of patients. All patients with forefoot surgery recovered total walk autonomy. DISCUSSION: Acromelic arthritis is a particular form of rheumatoid arthritis that progresses very slowly. Surgery should be indicated earlier, for a better joint function stabilisation.

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Clin Exp Rheumatol. 2007 Sep-Oct;25(5):709-15.
Effect of cyclosporine A on bone density in female rheumatoid arthritis patients: results from a multicenter, cross-sectional study.
Mazzantini M, Di Munno O, Sinigaglia L, Bianchi G, Rossini M, Mela Q, Del Puente A, Frediani B, Cantatore F, Adami S.
Rheumatology Units of the University of Pisa, Italy.

OBJECTIVE:To analyze the influence of cyclosporine A (CYA) on bone using data from a large multicenter, cross-sectional study on bone mineral density (BMD) in rheumatoid arthritis (RA)METHODS:We selected 558 female patients with RA and divided them into two groups on the basis of CYA use: those who had never used CYA (n = 467) and CYA users (n = 91; users for < 24 months n = 50; users for > 24 months n = 41). Demographic, disease and treatment-related variables were collected for each patient. BMD was measured at the lumbar spine and proximal femur using dual x-ray absorptiometry. Data was analyzed by means of a univariate and multivariate statistical procedure. Osteoporosis (OP) was defined as BMD < -2.5 T score.RESULTS:The frequency of OP among non-CYA users and CYA users was 28.2% and 33.3% (p=NS) for the lumbar spine, and 34.2% and 31.3% (p=NS) for the femoral neck, respectively. The prevalence of fragility fractures was not significantly different between the two groups. Mean values for the T-score at either the lumbar spine or the femoral neck were comparable in the two groups, even after adjustment for age, menopausal status, body mass index (BMI), Health Assessment Questionnaire (HAQ) score and steroid use. The generalized linear model showed that age, BMI and the HAQ score were significant independent predictors of BMD at the lumbar and femoral levels, whereas CYA use was not. Logistic analysis showed that only age, the HAQ score and BMI were significantly associated with the risk of OP. However, the duration of CYA therapy > 24 months was associated with an adjusted decreased lumbar BMD and a significantly decreased femoral neck BMD (p = 0.01). The frequency of femoral neck OP in patients on CYA for > 24 months was significantly higher than in patients on CYA for < 24 months: 46.4% vs. 19.44% (p=0.03), while the prevalence of fragility fractures did not differ significantly: 23.1% vs. 16.6%, respectively (p=NS). Logistic analysis showed that CYA use was an independent predictor of osteoporosis at the femoral site.CONCLUSION:Long-term CYA therapy may have negative effects on BMD in female RA patients.

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J Bone Joint Surg Am. 2007 Aug;89(8):1756-62.
The DUROM Cup Humeral Surface Replacement in Patients with Rheumatoid Arthritis.
Fuerst M, Fink B, Rüther W.
Department of Orthopedics, Rheumaklinik Bad Bramstedt, OskarAlexander-Strasse 26, D-24576, Bad Bramstedt, Germany. mfuerst@uke.uni-hamburg.de.

BACKGROUND: Rheumatoid arthritis often leads to severe destruction of the glenohumeral joint, including synovitis and inflammation-induced alterations of the rotator cuff. Cup arthroplasty, or surface replacement of the shoulder, was introduced in the 1980s. The aim of this study was to evaluate the midterm results of the DUROM cup surface replacement for patients with rheumatoid arthritis affecting the glenohumeral joint. METHODS: From 1997 to 2000, forty-two DUROM cup hemiprostheses were implanted in a cohort of thirty-five patients (forty-two shoulders), who were evaluated preoperatively and again at three, twelve, and more than sixty months postoperatively. Six patients (seven shoulders) were lost to follow-up. Thirty-five shoulders in twenty-nine patients (twenty-one women and eight men with an average age of 61.4 years) could be evaluated prospectively after an average follow-up period of 73.1 months. Patients were evaluated clinically with the use of the Constant score, and a detailed radiographic analysis was performed to determine the presence of endoprosthetic loosening, glenohumeral subluxation, and glenoid bone loss. RESULTS: The mean Constant score for the thirty-five shoulders increased from 20.8 points preoperatively to 64.3 points at a mean of 73.1 months postoperatively. There were three revisions: one to replace an implant that was too large, another to treat glenoid erosion, and a third due to loosening of the implant. No additional cases of loosening of the prosthesis or changes in cup position were observed radiographically. Over the five-year follow-up period, proximal migration of the cup increased in 63% of the shoulders, and the glenoid depth increased in 31%. With the numbers studied, no differences in clinical outcome were identified between patients with a massive rotator cuff tear and those with a smaller or no tear. CONCLUSIONS: The midterm results of the cemented DUROM cup surface replacement for patients with advanced rheumatoid arthritis of the shoulder are very encouraging, even for patients with a massive tear of the rotator cuff. The advantage of this cup arthroplasty is the less complex bone-sparing surgery. In the event of failure of the implant, other reliable salvage options remain. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions to Authors for a complete description of levels of evidence.

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Nat Clin Pract Rheumatol. 2007 Aug;3(8):450-8.
Combination therapy for rheumatoid arthritis: methotrexate and sulfasalazine together or with other DMARDs.
Dale J, Alcorn N, Capell H, Madhok R.
Ayr County Hospital, and Glasgow Royal Infirmary, Centre for Rheumatic Diseases, Castle Street, Glasgow, UK. dalepack@hotmail.com

Early aggressive treatment of rheumatoid arthritis is associated with improved disease control, slower radiological progression and improved functional outcomes. Tumor necrosis factor blocking therapy is effective but there remain concerns about long-term risks. Combining disease-modifying antirheumatic drugs (DMARDs) is a widely used therapeutic alternative; however, there is uncertainty surrounding the most effective regimen. A popular combination is methotrexate plus sulfasalazine, but each of these DMARDs can also be used in combination with other DMARDs and in triple therapy regimens. However, wide variations in study size, design, steroid usage and approaches to combination therapy have made it difficult to form firm conclusions regarding their efficacy. Generally, combination therapy is well tolerated and associated with no significant increase in the rate of adverse events compared with monotherapy. Methotrexate-sulfasalazine, methotrexate-chloroquine, methotrexate-cyclosporin, methotrexate-leflunomide, methotrexate-intramuscular-gold and methotrexate-doxycycline are effective combination regimens. Triple DMARD therapy is better than various DMARD monotherapy and dual therapy regimens. Methotrexate and hydroxychloroquine may have synergistic anti-inflammatory properties. Clinical trial evidence to support the use of other methotrexate and sulfasalazine combinations is often weak or lacking. Further investigation is required to determine the most effective regimen and approach to combination therapy.

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J Rheumatol Suppl. 2007 Jul;79:15-20.
What is the place of recently approved T cell-targeted and B cell-targeted therapies in the treatment of rheumatoid arthritis? Lessons from global clinical trials.
Smolen JS.
Department of Rheumatology, Medical University of Vienna, Vienna, Austria. josef.smolen@wienkav.at

The recently approved therapies abatacept and rituximab have significantly improved treatment options for patients with rheumatoid arthritis, especially for patients who have an inadequate response to tumor necrosis factor inhibitors. This article reviews the latest efficacy and safety data for both abatacept and rituximab. One-year data from abatacept and rituximab clinical trials show significantly better efficacy and reduction in radiographic damage for these therapies compared with placebo. In addition, repeated courses of rituximab confer continued efficacy for patients. The safety profile of these therapies shows that infusion reactions and infections are the most commonly reported important adverse events. Premedication with corticosteroids reduces the infusion reactions to rituximab.

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Ann Rheum Dis. 2007 Jul 31; [Epub ahead of print]
Patient-reported health outcomes in a trial of etanercept monotherapy versus combination therapy with etanercept and methotrexate for rheumatoid arthritis: the ADORE trial.
van Riel PL, Freundlich B, Macpeek D, Pedersen R, Foehl JR, Singh A.
Department of Rehumatology Radboud University, Nijmegen Medical Center, Netherlands.

OBJECTIVES: This study assessed the relative efficacy of etanercept (ETN) or etanercept and methotrexate (ETN+ MTX) for rheumatoid arthritis (RA) patients, who had an unsatisfactory response to MTX, using patient-reported outcomes (PROs) of function, pain, general health, disease activity, and morning stiffness. METHODS: The PROs were secondary assessments in a 16-week, prospective, randomised, parallel-group study conducted at 60 European centres. Patients with RA were randomly assigned either to monotherapy with ETN or combination therapy with ETN + MTX. PRO instruments administered included the Stanford Health Assessment Questionnaire (HAQ), the pain visual analog scale (VAS), the EuroQoL assessment of current health state (EQ-5D), the EQ-5D VAS, a patient global assessment of disease (PGAD) activity and an assessment of morning stiffness. Treatment groups were compared by percentage of patients within clinically meaningful categories. The primary endpoint for all PROs was comparison of mean improvement from baseline to week 16 between ETN and ETN + MTX groups. RESULTS: Three hundred fifteen patients were randomised to ETN or ETN + MTX. Both treatment arms had similar HAQ DI, EQ-5D, PGAD activity, pain or morning stiffness scores and improvement from baseline to week 16. CONCLUSIONS: For patients with active RA and intolerance or unsatisfactory response to MTX, substituting ETN for MTX and adding ETN to MTX are both effective ways to reduce disability, pain, disease activity, morning stiffness, and to improve general health.

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Arthritis Rheum. 2007 Jul 30;57(6):943-952 [Epub ahead of print]
Predictors of exercise and effects of exercise on symptoms, function, aerobic fitness, and disease outcomes of rheumatoid arthritis.
Neuberger GB, Aaronson LS, Gajewski B, Embretson SE, Cagle PE, Loudon JK, Miller PA.
University of Kansas Medical Center, Kansas City.

OBJECTIVE: To determine the effects of participation in a low-impact aerobic exercise program on fatigue, pain, and depression; to examine whether intervention groups compared with a control group differed on functional (grip strength and walk time) and disease activity (total joint count, erythrocyte sedimentation rate, and C-reactive protein) measures and aerobic fitness at the end of the intervention; and to test which factors predicted exercise participation. METHODS: A convenience sample of 220 adults with rheumatoid arthritis (RA), ages 40-70, was randomized to 1 of 3 groups: class exercise, home exercise using a videotape, and control group. Measures were obtained at baseline (T1), after 6 weeks of exercise (T2), and after 12 weeks of exercise (T3). RESULTS: Using structural equation modeling, overall symptoms (latent variable for pain, fatigue, and depression) decreased significantly at T3 (P < 0.04) for the class exercise group compared with the control group. There were significant interaction effects of time and group for the functional measures of walk time and grip strength: the treatment groups improved more than the control group (P </= 0.005). There were no significant increases in measures of disease activity. Fatigue and perceptions of benefits and barriers to exercise affected participants' amount of exercise, supporting previous research. CONCLUSION: This study supported the positive effects of exercise on walk time and grip strength, and demonstrated that fatigue and perceived benefits/barriers to exercise influenced exercise participation. Furthermore, overall symptoms of fatigue, pain, and depression were positively influenced in this selective group of patients with RA ages 40-70 years.

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Arthritis Rheum. 2007 Jul 30;57(6):935-942 [Epub ahead of print]
Minimal disease activity, remission, and the long-term outcomes of rheumatoid arthritis.
Wolfe F, Rasker JJ, Boers M, Wells GA, Michaud K.
National Data Bank for Rheumatic Diseases, Wichita, Kansas.

OBJECTIVE: To determine the prevalence of minimal disease activity (MDA) and remission in patients with rheumatoid arthritis (RA), to assess the effect of anti-tumor necrosis factor (anti-TNF) therapy on MDA, and to determine the extent to which MDA status improves long-term outcomes. METHODS: Using the Patient Activity Scale (PAS) as a surrogate, we assessed the prevalence of MDA and remission in 18,062 patients with RA using the newly developed Outcome Measures in Rheumatology Clinical Trials (OMERACT) criteria for MDA. RESULTS: MDA was noted in 20.2% of 18,062 patients and persistent MDA, operationally defined as having MDA during >/=2 consecutive 6-month observation periods, occurred in 13.5% of 7,433 patients followed longitudinally. Disease activity at remission levels was noted in 7%. Among patients with MDA, 82% received disease-modifying antirheumatic drugs or biologic agents. Following anti-TNF initiation, the cumulative probability of achieving MDA at 2 and 6 years was 4.1% and 7.6%, respectively, and persistent MDA probabilities were 2.7% and 4.5%, respectively. Regardless of RA duration, patients with MDA had substantially better outcomes, including a 10-fold reduction in work disability and an approximately 2-fold reduction in total joint replacement and mortality. CONCLUSION: Remission remains uncommon in RA, and the prevalence of new remission in community practice is substantially lower than noted in published trials of biologic therapy. On average, persons with MDA appear to have persistently mild RA. This might be the effect of milder RA and/or more effective treatment in early RA. The PAS had satisfactory levels of agreement with the full MDA criteria and appears suitable for use in clinical and epidemiologic research.

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Ann Rheum Dis. 2007 Jul 27; [Epub ahead of print]
The magnitude of early response to methotrexate therapy predicts long-term outcome of patients with juvenile idiopathic arthritis.
Bartoli M, Tarò M, Magni-Manzoni S, Pistorio A, Traverso F, Viola S, Magnani A, Gasparini C, Martini A, Ravelli A.
IRCCS Policlinico S. Matteo, Pavia, Italy.

OBJECTIVE: To investigate the relationship between the magnitude of clinical response in the first 6 months of methotrexate (MTX) therapy and the long-term outcome in children with juvenile idiopathic arthritis (JIA). METHODS: The clinical charts of 125 JIA patients who were started with MTX and were then followed for at least 5 years were reviewed. Based on the level of American College of Rheumatology (ACR) Pediatric response at 6 months, patients were divided in 4 mutually exclusive groups: 1) nonresponders; 2) responders at 30%; 3) responders at 50%; 4) responders at 70%. The long-term outcome in each response group was evaluated by calculating the percentage change in active and restricted joint counts from baseline to 1, 2 and 5 years and the frequency of inactive disease at 5 years. RESULTS: At 6 months, 42 patients were classified as nonresponders, 24 as 30% responders, 26 as 50% responders, and 33 as 70% responders. Patients who had achieved a 70% response showed a significantly greater percentage improvement in active joint count between baseline to 5 years compared with nonresponders and 30% responders, and a significantly greater percentage improvement in restricted joint count between baseline to 5 years compared with 30% responders. The 70% responders also had a greater frequency of inactive disease at 5 years compared with 30% responders. CONCLUSIONS: Our results show that the achievement of an ACR Pediatric 70 response at 6 months after start of MTX therapy predicts a more favorable long-term outcome of patients with JIA.

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Drugs Aging. 2007;24(7):573-80.
Glucosamine and chondroitin sulfate as therapeutic agents for knee and hip osteoarthritis.
Bruyere O, Reginster JY.
WHO Collaborating Center for Public Health Aspect of Osteoarticular Disorders, University of Liège, Liege, Belgium.

Osteoarthritis (OA), the most common form of arthritis, is a public health problem throughout the world. Several entities have been carefully investigated for the symptomatic and structural management of OA. This review evaluates published studies of the effect of glucosamine salts and chondroitin sulfate preparations on the progression of knee or hip OA.Despite multiple double-blind, controlled clinical trials of the use of glucosamine and chondroitin sulfate in OA, controversy regarding the efficacy of these agents with respect to symptomatic improvement remains. Several potential confounders, including placebo response, use of prescription medicines versus over-the-counter pills or food supplements, or use of glucosamine sulfate versus glucosamine hydrochloride, may have relevance when attempting to interpret the seemingly contradictory results of different clinical trials. The National Institutes of Health-sponsored GAIT (Glucosamine/chondroitin Arthritis Intervention Trial) compared placebo, glucosamine hydrochloride, chondroitin sulfate, a combination of glucosamine and chondroitin sulfate and celecoxib in a parallel, blinded 6-month multicentre study of patients with knee OA. This trial showed that glucosamine hydrochloride and chondroitin sulfate alone or in combination did not reduce pain effectively in the overall group of patients with OA of the knee. However, exploratory analyses suggest that the combination of glucosamine hydrochloride and chondroitin sulfate may be effective in the subgroup of patients with moderate-to-severe knee pain.For decades, the traditional pharmacological management of OA has been mainly symptomatic. However, in recent years, several randomised controlled studies have assessed the structure-modifying effect of glucosamine sulfate and chondroitin sulfate using plain radiography to measure joint space narrowing over years. There is some evidence to suggest a structure-modifying effect of glucosamine sulfate and chondroitin sulfate.On the basis of the results of recent randomised controlled trials and meta-analyses, we can conclude that glucosamine sulfate (but not glucosamine hydrochloride) and chondroitin sulfate have small-to-moderate symptomatic efficacy in OA, although this is still debated. With respect to the structure-modifying effect, there is compelling evidence that glucosamine sulfate and chondroitin sulfate may interfere with progression of OA.

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Curr Opin Rheumatol. 2007 May;19(3):278-83.
Early rheumatoid arthritis.
Mitchell KL, Pisetsky DS.
aDivision of Rheumatology and Immunology, Duke University Medical Center, Durham, NC, USA bVeterans Administration Hospital, Durham, NC, USA.

PURPOSE OF REVIEW: Rheumatoid arthritis is a chronic inflammatory disease in which early aggressive therapy with disease-modifying antirheumatic drugs can improve outcome and prevent joint damage. While such therapy is effective, its application can be limited by diagnostic uncertainty in patients with early inflammatory arthritis and concerns about treatment of patients whose disease would remit spontaneously. The purpose of current research is therefore to identify prognostic markers of early disease and to determine the role of aggressive treatment strategies in inducing remission in such patients. RECENT FINDINGS: Recent research has provided new information on genetic markers predicting rapid progression of joint destruction; the role of serology, in particularly, antibodies to citrullinated peptides in diagnosing rheumatoid arthritis; the utility of radiographic techniques in detecting both early synovitis and bone erosion; and the value of combination therapy in controlling signs, symptoms and radiographic progression. Recent clinical studies support the efficacy of a combination of methotrexate with a biological agent, especially a tumor-necrosis-factor blocker, in reducing disease activity. SUMMARY: While current treatment approaches can produce significant benefits in patients with early arthritis, future investigation is needed to target therapy more selectively and to determine which patients respond best to various agents or combinations.

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Curr Opin Rheumatol. 2007 May;19(3):259-64.
New therapeutic approaches for spondyloarthritis.
Manadan AM, James N, Block JA.
aJohn H. Stroger Hospital of Cook County and Rush University Medical Center, Chicago, Illinois, USA bRush University Medical Center, Chicago, Illinois, USA cSection of Rheumatology, Rush University Medical Center, Chicago, Illinois, USA.

PURPOSE OF REVIEW: Tumor necrosis factor alpha antagonists are effective for signs and symptoms of ankylosing spondylitis. Recent studies have evaluated the efficacy of these agents for structural disease modification. We critically review recent radiographic data suggesting that tumor necrosis factor alpha inhibition may have structure-modifying effects in ankylosing spondylitis, and may thereby alter the disease course. RECENT FINDINGS: Recent studies employing MRI suggest that therapy with tumor necrosis factor alpha antagonists significantly reduces spinal inflammation in active ankylosing spondylitis when compared to placebo; there was no comparable improvement in the severity of chronic stigmata, such as syndesmyophytes and vertebral bridging. These studies were of relatively short duration and small size. SUMMARY: Despite insufficient evidence to conclude definitively that tumor necrosis factor alpha-antagonist therapy provides durable and effective structure modification in ankylosing spondylitis, the data strongly suggest a benefit, at least in the short term. In the future, MRI data coupled with clinical outcomes in larger cohorts followed for longer durations may result in a paradigm shift for ankylosing spondylitis treatment similar to that undergone for rheumatoid arthritis, where patients with ankylosing spondylitis are offered therapy early in the disease course to arrest and prevent structural disease progression.

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Curr Opin Rheumatol. 2007 May;19(3):233-7.
Glucocorticoids: action and new therapeutic insights in rheumatoid arthritis.
Kirwan J, Power L.
University of Bristol Academic Rheumatology Unit, Bristol Royal Infirmary, Bristol, UK.

PURPOSE OF REVIEW: To summarize the mechanism of action of glucocorticoids, the direction that current research is taking and what this might mean for clinicians. RECENT FINDINGS: New cellular actions of glucocorticoids have been identified, and offer new drug targets. There is increasing competition to find a glucocorticoid formulation or analogue that enhances therapeutic effects while reducing adverse effects. Clinically, there is increasing evidence for the disease-modifying effects of glucocorticoids, which makes these developments topical and relevant. Better understanding of the pathology of rheumatoid arthritis and the circadian variation in symptoms that is a hallmark of the disease may also affect the way that we use these drugs. SUMMARY: Glucocorticoids are about to enter a renaissance based on better understanding of how they work and novel approaches to new therapeutic targets.

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Ann Rheum Dis. 2007 Apr 5; [Epub ahead of print]
Cardiovascular outcomes in high-risk patients with osteoarthritis treated with Ibuprofen, Naproxen, or Lumiracoxib.
Farkouh ME, Greenberg JD, Jeger RV, Ramanathan K, Verheugt FW, Cheseboro JH, Kirshner H, Hochman JS, Lay CL, Ruland S, Mellein B, Matchaba PT, Fuster V, Abramson SB.
Mount Sinai School of Medicine, United States.

BACKGROUND: Evidence suggests that both selective cyclooxygenase (COX)-2 inhibitors and non-selective NSAIDs increase the risk of cardiovascular (CV) events. However, evidence from prospective studies of currently available COX-2 inhibitors and non-selective NSAIDs is lacking in high CV risk patients taking aspirin. METHODS: The Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET) of 18,325 osteoarthritis patients comprised 2 parallel sub- studies, comparing lumiracoxib (COX-2 inhibitor) to either ibuprofen or naproxen. We performed a post hoc analysis stratified by baseline cardiovascular risk, treatment assignment, and low-dose aspirin use. The primary composite endpoint was cardiovascular mortality, nonfatal myocardial infarction, and stroke at 1 year; a secondary endpoint was the development of congestive heart failure (CHF). RESULTS: In high risk patients among aspirin users, patients in the ibuprofen sub-study had more primary events with ibuprofen than lumiracoxib (2.14% vs. 0.25%, p=0.038), whereas in the naproxen sub-study rates were similar for naproxen and lumiracoxib (1.58% vs. 1.48%, p=0.899). High risk patients not taking aspirin had fewer primary events with naproxen versus lumiracoxib (0% vs. 1.57%, p=0.027), but not ibuprofen versus lumiracoxib (0.92% vs. 0.80%, p=0.920). Overall, CHF developed more often with ibuprofen than lumiracoxib (1.28% vs. 0.14%; p=0.031), whereas no difference existed between naproxen and lumiracoxib. CONCLUSIONS: These data suggest that ibuprofen may confer an increased risk of thrombotic and CHF events relative to lumiracoxib among aspirin users at high cardiovascular risk. Our study indicates that naproxen may be associated with lower risk relative to lumiracoxib among non-aspirin users. Our data should be interpreted as hypothesis-generating.

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Ann Rheum Dis. 2007 Apr 5; [Epub ahead of print]
Open-label, pilot protocol of patients with rheumatoid arthritis who switch to infliximab after an incomplete response to etanercept: The OPPOSITE study.
Furst DE, Gaylis N, Bray V, Olech E, Yocum D, Ritter J, Weisman M, Wallace D, Crues J, Khanna D, Eckel G, Yeilding N, Callegari P, Visvanathan S, Rojas J, Hegedus R, George L, Mamun K, Gilmer K, Troum O.
University of California Los Angeles, United States.

OBJECTIVES: To incorporate a novel trial design to examine clinical response, cytokine expression, and joint imaging in rheumatoid arthritis patients switching from etanercept to infliximab. METHODS: A randomized, open-label, clinical trial of 28 patients with an inadequate response to etanercept. Eligible patients remained on background methotrexate and were randomized 1:1 to discontinue etanercept and receive infliximab 3 mg/kg at weeks 0, 2, 6, 14, and 22 or continue etanercept 25 mg twice weekly. Data were analyzed for clinical response, serum biomarker levels, radiographic progression, MRI, and adverse events. RESULTS: At week 16, 62% of infliximab-treated patients achieved ACR20 responses compared with 29% of etanercept-treated patients. A 30.8% decrease from baseline in disease activity score 28 was observed in patients receiving infliximab compared with a 16.0% decrease observed in patients receiving etanercept. ACR20 and ACR50 responses correlated at least minimally with intracellular adhesion molecule-1 and IL-8 in patients receiving infliximab. Thirty-eight percent of patients who were switched to infliximab showed reductions in health assessment questionnaire scores (>0.4) compared with 0% of etanercept patients. MRI analyses were inconclusive. Both drugs were well tolerated; 54% of infliximab-treated patients and 50% of etanercept-treated patients reported adverse events. CONCLUSIONS: In this exploratory, open-label trial (with single-blind evaluator), patients were randomized to continue etanercept or switch to infliximab. The small sample size of this hypothesis- generating study was underpowered to show statistical differences between groups. There was a numerical trend favoring patients switched to infliximab, therefore warranting further study with a more rigorous design.

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Ann Rheum Dis. 2007 Apr 3; [Epub ahead of print]
Patient preferences for treatment: Report from a randomized comparison of treatment strategies in early rheumatoid arthritis (BeSt trial).
Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, Kerstens PJ, Grillet BA, de Jager MH, Han KH, Speyer I, van der Lubbe PA, Seys PE, Breedveld FC, Dijkmans BA.
Leiden University Medical Center, Netherlands.

OBJECTIVES: To determine treatment preferences among patients with recent onset rheumatoid arthritis participating in a randomized controlled trial comparing four therapeutic strategies. METHODS: A questionnaire was sent to all 508 participants of the BeSt study, treated for an average of 2.2 years with either sequential monotherapy (group 1), step-up combination therapy (group 2), initial combination therapy with tapered high-dose prednisone (group 3), or initial combination therapy with infliximab (group 4). Treatment adjustments were made every 3 months to achieve low disease activity (DAS </= 2.4). The questionnaire explored patients' preferences or dislikes for the initial therapy. RESULTS: In total, 440 patients (87%) completed the questionnaire. Despite virtually equal study outcomes at 2 years, more patients in group 4 reported much or very much improvement of general health: 50%, 56%, 46% and 74% in groups 1-4, respectively (overall, P<0.001). Almost half of the patients expressed no preference or aversion for a particular treatment group, 33% had hoped for assignment to group 4 and 38% had hoped against assignment to group 3. This negative perception was much less prominent in patients actually in group 3. Nevertheless, 50% of patients in group 3 disliked having to take prednisone, while only 8% in group 4 disliked going to the hospital for intravenous treatment. CONCLUSIONS: Within the limitations of our retrospective study, patients clearly preferred initial combination therapy with infliximab and disliked taking prednisone. After actual exposure, this preference remained, but the perception of prednisone improved. Patient perceptions need to be addressed when administering treatment.

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Clin Exp Rheumatol. 2007 Jan-Feb;25(1):85-7.
Switching to etanercept in patients with rheumatoid arthritis with no response to infliximab.
Di Poi E, Perin A, Morassi MP, Del Frate M, Ferraccioli GF, De Vita S.
Division of Rheumatology, DPMSC,School of Medicine, University of Udine, Udine, Italy. edipoi@conecta.it

TNF-alpha is thought to play a pivotal role in the initiation and perpetuation of the chronic inflammatory process in rheumatoid arthritis. TNF-alpha blockers such as infliximab and etanercept are currently used in the treatment of active rheumatoid arthritis (RA) when traditional DMARDs have failed and are effective in a significant proportion of patients. However, about one third are non-responders to anti-TNF-alpha.The aim of this study was to verify whether rheumatoid patients, after failing infliximab, can benefit from etanercept.We analysed 18 patients with active RA with no response to at least 3 DMARDs and where infliximab therapy had failed. The patients had received infliximab associated with methotrexate: eleven of them did not show any significant response, while seven patients, after a good response, relapsed. Etanercept was then started. EULAR criteria of response were used with calculation of activity index DAS28 at baseline, after 2 weeks, 3 months and every third month until last follow-up. A moderate or good response was achieved with etanercept in 13 out of 18 patients. From our experience, etanercept can be considered as a good alternative choice when infliximab has failed.

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Clin Exp Rheumatol. 2007 Jan-Feb;25(1):40-6.
The immunogenicity, safety, and efficacy of etanercept liquid administered once weekly in patients with rheumatoid arthritis.
Dore RK, Mathews S, Schechtman J, Surbeck W, Mandel D, Patel A, Zhou L, Peloso P.
Robin K. Dore, MD, Inc, Anaheim, CA 92801, USA. rkdmail@sbcglobal.net

OBJECTIVE: To evaluate the immunogenicity, safety, and efficacy of 50 mg/mL liquid etanercept. METHODS: In a multicenter, open-label study, adults with active rheumatoid arthritis (RA) received 50 mg/mL liquid etanercept subcutaneously once weekly for 24 weeks. Immunogenicity was assessed at baseline and weeks 24 and 28, safety at all study visits, and efficacy at baseline and weeks 12 and 24. RESULTS: Of 222 treated patients, 88% completed the study; 81% were women; 84% were white; mean age was 53 years; mean RA duration was 10 years. Antibodies to etanercept, all non-neutralizing, were detected in 12 of 214 patients; 7 of the 12 were borderline positive (antibody titers <1:50). The presence of non-neutralizing anti-etanercept antibodies did not appear to affect clinical safety or efficacy. Few patients reported serious adverse events (6.3%), serious infections (2.3%), or withdrew because of adverse events (4.5%). Most adverse events were mild or moderate. The most common event, injection site reaction, occurred in 29.3% patients. At week 24, 63% of patients achieved an ACR20 response, 36% an ACR50 response, and 14% an ACR70 response. Similar responses were apparent by week 12. Week 24 mean improvement in the Health Assessment Questionnaire disability index scores was 0.6 points; improvement in the Short Form-36 Physical Component Score was 10.0 points. CONCLUSION: The 50 mg/mL liquid etanercept formulation administered once weekly was well tolerated. The incidence of anti-etanercept antibodies, the nature and frequency of adverse events, and improvements in signs and symptoms of RA and patient physical function were similar to those in previous etanercept studies.

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Tunis Med. 2007 Jan;85(1):1-8.
[Rheumatoid arthritis: current status of therapy]
[Article in French]
El Bahri DM, Meddeb N, Sellami S.
Service de Rhumatologie, Hopital La Rabta, Tunis, Tunisie.

Rheumatoid Arthritis (RA) is a frequent chronic inflammatory disease characterized by distal, bilateral and symmetrical lesions, leading to joint distortions and articular destructions. RA can also cause severe extra-articular manifestations associated with a poor prognosis. Recent advances in the field of immunopathology of RA have oriented treatment targeting the pro-inflammatory cytokines like tumor necrosis factor-alpha (TNF alpha), interleukin (IL) and IL6. These biotherapies are considered as an important therapeutic progress in the treatment of RA acting at the level of cellular processes responsible for rheumatoid disease. These new therapies are active not only in controlling the disease inflammatory processes but also to stop the radiological course of RA. These new therapies are however efficient as long as prescribed, their interruption being rapidly followed by a flare-up of RA. Multiple adverse events attributed to anti-TNF-alpha have been described especially severe opportunistic infections and tuberculosis. B cells playing a critical role in sustaining the chronic inflammatory process in RA, targeted depleting B cells therapies have been developed in refractory forms of RA giving promising results. However, before any biotherapy prescription especially of anti-TNF-alpha, an initial screening should be achieved to exclude patients with history of untreated tuberculosis, solid cancers, malignant hemopathies or demyelinating disorders. It is also essential to assure a strict follow-up in patients under biotherapy to detect adverse events that can be sometimes severe. Thus, the ratio benefit/risk must be evaluated before any biotherapy prescription.

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Ann Rheum Dis. 2007 Jan 9; [Epub ahead of print]
The comparative effectiveness of anti-TNF therapy and methotrexate in patients with psoriatic arthritis: 6- month results from a longitudinal, observational, multicenter study.
Heiberg MS, Kaufmann C, Rodevand E, Mikkelsen K, Koldingsnes W, Mowinckel P, Kvien TK.
Diakonhjemmet Hospital, Norway.

OBJECTIVES: To compare the response to treatment with tumor necrosis factor (TNF) inhibitors and methotrexate (MTX) monotherapy in patients with psoriatic arthritis (PsA) within a real life clinical setting. METHODS: We analyzed data from an ongoing longitudinal, observational multicenter study in Norway. Our data comprised 526 cases of patients with PsA who received either anti-TNF treatment (n = 146) or MTX monotherapy (n = 380) and were followed for at least 6 months with measures of disease activity, health status and utility scores. A propensity score was computed to adjust for channeling bias. The changes in measures of disease activity and health-related quality of life from baseline to 3- and 6-month follow-up were compared between the groups with adjustments for the baseline value of the dependent variable and the propensity score (analyses of covariance (ANCOVA)). RESULTS: The groups were significantly different at baseline with respect to demographic and disease activity measures. The variables included in the propensity score were age, sex, number of previous disease modifying anti-rheumatic drugs (DMARDs), presence of erosive disease, treatment center and investigator's global assessment. The adjusted changes at 6 months were significantly larger in the anti-TNF group for ESR, DAS-28, M-HAQ, patient's assessments of pain, fatigue and global disease activity on a visual analogue scale (VAS) and 4 out of 8 SF-36 dimensions. CONCLUSIONS: Clinical improvement was superior with TNF inhibitors compared to MTX monotherapy in patients with PsA, when assessed in this setting of daily clinical practice.

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Semin Arthritis Rheum. 2007 Jan 2; [Epub ahead of print]
Patients with Rheumatoid Arthritis Undergoing Surgery: How Should We Deal with Antirheumatic Treatment?
Pieringer H, Stuby U, Biesenbach G.
Section of Rheumatology, 2nd Department of Medicine, General Hospital Linz, Linz, Austria.

OBJECTIVES: To review published data on the perioperative management of antirheumatic treatment and perioperative outcome in patients with rheumatoid arthritis (RA). METHODS: The review is based on a MEDLINE (PubMed) search of the English-language literature from 1965 to 2005, using the index keywords "rheumatoid arthritis" and "surgery". As co-indexing terms the different disease-modifying antirheumatic drugs (DMARDs) as well as nonsteroidal anti-inflammatory drugs (NSAIDs) and "glucocorticoids" were used. In addition, citations from retrieved articles were scanned for additional references. Furthermore, because the number of published articles is so limited, relevant abstracts presented at congresses were included in the analysis. RESULTS: Continuation of methotrexate (MTX) appears to be safe in the perioperative period. Only a limited number of studies address the use of leflunomide and the results are conflicting. Because of the very long drug half-life, its discontinuation would need to be of long duration and is probably not necessary. Data on hydroxychloroquine do not show increased risks of infection. Regarding sulfasalazine, there are no studies from which definite answers could be drawn on whether it should be withheld perioperatively. Preliminary data show that the risk of infections during treatment with TNF-blocking agents may be lower than initially expected. The only available recommendation (Club Rhumatismes et Inflammation, CRI) suggests discontinuing the drugs before surgery for several weeks, depending on the risk of infection and the drug used. They should not be restarted until wound healing is complete. To avoid the antiplatelet effect during surgery, NSAIDs other than aspirin should be withheld for a duration of 4 to 5 times the drug half-life. Patients with chronic glucocorticoid therapy and suppressed hypothalamic-pituitary-adrenal (HPA) axis need perioperative supplementation. CONCLUSIONS: While continuation of MTX likely is safe, data on other DMARDs are sparse. In particular, more data on the perioperative use of the biologic agents are needed.

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Rheumatol Int. 2007 Jan 4; [Epub ahead of print]
Long-term benefit of radon spa therapy in the rehabilitation of rheumatoid arthritis: a randomised, double-blinded trial.
Franke A, Reiner L, Resch KL.
FBK Spa Medicine Research Institute, Lindenstr.5, 08645, Bad Elster, Germany, annegret.franke@medizinische-statistik.de.

This study investigates the effects of radon (plus CO(2)) baths on RA in contrast to artificial CO(2 )baths in RA rehabilitation using a double-blinded trial enrolling 134 randomised patients of an in-patient rehabilitative programme (further 73 consecutive non-randomised patients are not reported here). The outcomes were limitations in occupational context/daily living (main outcome), pain, medication and further quantities. These were measured before the start, after the end of treatment and quarterly in the year thereafter. Repeated-measures analysis of covariance (RM-ANCOVA) of the intent-to-treat population was performed with group main effects (GME) and group x course interactions (G x C) reported. Hierarchically ordered hypotheses ensured the adherence of the nominal significance level. The superiority of the radon treatment was found regarding the main outcome (RM-ANCOVA until 12 months: p (GME) = 0.15, p (GxC) = 0.033). Consumption of steroids (p (GME) = 0.064, p (G x C) = 0.025) and NSAIDs (p (GME) = 0.035, p (G x C) = 0.008) were significantly reduced. The results suggest beneficial long-term effects of radon baths as adjunct to a multimodal rehabilitative treatment of RA.

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Foot Ankle Int. 2006 Dec;27(12):1079-85.
Arthroscopic ankle arthrodesis: factors influencing union in 39 consecutive patients.
Collman DR, Kaas MH, Schuberth JM.
Department of Orthopaedic Surgery, Kaiser Permanente Medical Group, Modesto, CA, USA.

BACKGROUND: Arthroscopic ankle arthrodesis is an effective alternative to open techniques with established advantages in select patient populations. The purpose of this study was to evaluate patients who had arthroscopic ankle arthrodesis for end-stage arthritis with minimal to no deformity of the ankle and to report factors influencing union. METHODS: Thirty-nine consecutive patients had arthroscopic ankle arthrodesis between 1994 and 2003. Clinical records and radiographs were retrospectively reviewed to evaluate variables that could predispose patients to nonunion. Union outcomes were correlated with etiology of arthritis, ankle deformity, medical co-morbidities, and the use of demineralized bone matrix or platelet-rich plasma. Arthroscopic ankle arthrodesis was accomplished with a consistent technique using crossed transmalleolar cannulated screw fixation. RESULTS: Thirty-four of 39 patients (87.2%) achieved radiographic and clinical union. The average time to fusion was 47 (range 37 to 70) days. Poor bone quality and inherent positional ankle deformity were identified as risk factors for nonunion. Patients who smoked, had diabetes mellitus, peripheral neuropathy, or other medical co-morbidities attained ankle union in nearly all cases. In obese patients, there was an observed trend towards ankle nonunion (relative risk 5.81, p = 0.049, Fisher's Exact test). The addition of demineralized bone matrix or platelet-rich plasma did not improve the rate of ankle union. Aside from nonunion, 10 patients developed minor complications. CONCLUSION: Arthroscopic ankle arthrodesis achieves high union rates, facilitates short time to union, and permits rapid patient mobility. Careful patient selection is important for the procedure. Synthetic allograft or platelet-rich plasma did not enhance the fusion rate. Obese patients showed a trend towards nonunion in this series.

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Clin Ther. 2006 Nov;28(11):1764-78.
Role of abatacept in the management of rheumatoid arthritis.
Nogid A, Pham DQ.
Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, New York 11201-5497, USA. anna.nogid@liu.edu

BACKGROUND: Rheumatoid arthritis (RA) has been associated with significant morbidity and economic burden. Traditional pharmacotherapy (eg, NSAIDs, corticosteroids, disease-modifying antirheumatic drugs [DMARDs]) can be inadequate in controlling symptoms and disease progression. Abatacept is the first selective co-stimulation modulator approved by the US Food and Drug Administration for the management of RA. It is a fusion protein developed to modulate the T-cell co-stimulatory signal that is mediated through the CD28-CD80/86 pathway. OBJECTIVE: The objective of this manuscript was to review the clinical pharmacology, pharmacokinetic and pharmacodynamic properties, tolerability, and clinical efficacy of abatacept. METHODS: MEDLINE and International Pharmaceutical Abstracts were searched through June and May, respectively, of 2006 using the term abatacept or CTLA4-Ig. All prospective, randomized, Phase II and III trials, and their extension phases, were included. RESULTS: Phase II and III clinical trials found that abatacept, at a dose of 10 mg/kg administered as a short i.v. infusion in combination with DMARDs, was associated with significant clinical benefit in patients with active RA. After 6 months of treatment, the American College of Rheumatology (ACR) criteria for 20% clinical improvement (ACR20 response) was attained in 41.9% to 67.9% of patients who received abatacept compared with 19.5% to 39.7% of patients who received placebo (P < 0.001). The percentages of patients achieving the ACR criteria for 50% and 70% clinical improvement (ACR50 and ACR70) were 20.3% to 39.9% and 10.2% to 19.8%, respectively, in the groups that received abatacept compared with 3.8% to 16.8% and 1.5% to 6.5%, respectively, in the patients who received placebo (P = 0.03 and P < 0.001). Additionally, abatacept was found to improve disease activity, physical function, pain, and health-related quality of life (HRQOL). The most commonly reported adverse effects associated with abatacept treatment were headache (18.2%), upper respiratory tract infection (12.7%), nasopharyngitis (11.5%), and nausea (11.5%). The incidences of infections and serious infections were higher in the group that received abatacept compared with patients who received placebo (53.8% vs 48.3% and 3.0% vs 1.9%, respectively; P not reported). No significant between-group differences in mortality were found. CONCLUSIONS: Available evidence suggests that abatacept was effective in controlling symptoms and improving HRQOL in patients with active RA and an inadequate response to DMARD therapy. The most commonly reported adverse effects associated with abatacept treatment were headache, upper respiratory infection, nausea, and nasopharyngitis. Additional trials are needed to determine the long-term safety profile of this agent and whether the clinical benefits of abatacept found in the current clinical trials will be sustained over time.

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Reumatismo. 2006 Oct-Dec;58(4):261-7.
[Safety of methotrexate in rheumatoid arthritis: a retrospective cohort study in clinical practice.]
[Article in Italian]
La Montagna G, Tirri R, Vitello R, Malesci D, Buono R, Mennillo G, Valentini G.
Unita di Reumatologia, Seconda Universita degli Studi di Napoli, Italia. giovanni.lamontagna@unina2.it.

OBJECTIVE: To evaluate the treatment duration with MTX monotherapy or in association with DMARDs or TNFalpha inhibitors and the incidence and typology of adverse events (AE) occurred in rheumatoid arthritis (RA) patients. METHODS: A retrospective large cohort study of RA outpatients, consecutively seen from January 2000 to June 2005 was performed. Study group were RA patients classified according to the 1984 ACR criteria for the classification of rheumatoid arthritis. The patients were divided in 3 groups according to the treatment regimen: MTX monotherapy, MTX in combination with DMARD or with anti TNFalpha agents. We analyzed 348 therapeutic cycles, 177 of whom using MTX monotherapy. RESULTS: The 224 RA patients accumulated 800 person-years of follow up. Follow up for each of the groups was: MTX monotherapy 479.4 person-years, MTX in combination with DMARDs 244.5, or with TNFalpha inhibitors, 75.7 person-years. From the Kaplan-Meier analysis, the probability of patients remaining on treatment 5 years was 58.5 after starting MTX. The incidence of any AE was 8.87 per 100 person-years. From all, 69 (97.2%) AE were no severe. Among those, more frequently were observed at gastrointestinal tract (31%), liver (19.7%), skin (15.5%). Incidence of severe AE (lung adenocarcinoma, 1 case; pancreatitis, 1 case) was 0.25 per 100 person-years, occurring in patients taking MTX monotherapy or MTX in combination with DMARDs, respectively. CONCLUSIONS: These data confirm that methotrexate is well tolerated in clinical practice in the medium-long term. Nevertheless, the occurrence of severe AE require an accurate vigilance for methotrexate toxicity.
 

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