Rheumatoid Arthritis: Saleem B

Saleem B, Nizam S, Emery P. · Academic Unit Section of Musculoskeletal Disease, Chapel Allerton Hospital, Leeds, West Yorkshire, UK. · Clin Exp Rheumatol. · Pubmed #17083760 No free full text.

Abstract: Remission is now the accepted goal of management in rheumatoid arthritis (RA). This article highlights the controversies surrounding the definition of remission and reviews the potential of current treatment options to achieve remission. Defining "true" remission can be difficult based on current criteria, which do not consider structural and physical function. Nonetheless, considerable advances in recent years have made the concept of remission a realistic goal.In early RA, substantial and largely irreversible radiographic damage is seen in 60% of patients within the first 2 years of diagnosis. Early therapeutic intervention would ideally lead to reduction in long-term disability in RA and likelihood of inducing and maintaining remission.Long-term maintenance therapy with disease-modifying antirheumatic drugs (DMARDs) has been shown to be effective in preventing flares of disease. Stopping therapy for short periods does not necessarily lead to flares, but the effect on long-term radiographic damage and potential to achieve similar levels of disease control following reinstatement of therapy is not established.Early use of tumour necrosis factor (TNF)-antagonist therapy (e.g. infliximab) has been shown to lead to significant improvement in disease activity measures (clinical and radiologic outcomes) when compared to monotherapy or combination DMARD and corticosteroid therapies. Response was shown to be sustained in 70% of patients receiving TNF-blocking therapy 1 year after stopping treatment. This suggests the significant role of TNF-blocking therapy in enabling sustainable remission without need for long-term administrations, which has important implications for favourable health economics. At present, little published evidence exists on the effects of withdrawal of TNF-blocking therapy in patients with established RA in remission. In conclusion, evidence indicates that remission is a realistic goal, but more evidence is required to establish optimal treatment strategies and define criteria for remission that include imaging and immunological as well as clinical assessment of the disease state.

Saleem B, Brown AK, Keen H, Nizam S, Freeston J, Karim Z, Quinn M, Wakefield R, Hensor E, Conaghan PG, Emery P. · University of Leeds, Chapel Allerton Hospital, Leeds, UK. · Arthritis Rheum. · Pubmed #19565512 No free full text.

Abstract: OBJECTIVE: For patients with rheumatoid arthritis (RA) in remission who are receiving disease-modifying antirheumatic drugs (DMARDs), radiographic progression correlates with imaging-detected synovitis as measured by power Doppler activity. In contrast, patients with disease in remission who are receiving the combination of tumor necrosis factor (TNF) blockade with methotrexate (MTX) (combination treatment) have reduced radiographic damage for the equivalent clinical state. We undertook this study to determine whether the difference in radiographic outcome is a result of more complete suppression of imaging-detected synovitis. METHODS: One hundred patients with RA in remission (Disease Activity Score in 28 joints [DAS28] <2.6) for at least 6 months while receiving either combination treatment (n = 50) or DMARDs (n = 50) were matched for clinical variables. Ultrasound of metacarpophalangeal joints 1-5 and the wrist joints was performed. Remission according to imaging results was defined as a score of 0 for both grey scale synovitis and power Doppler activity. RESULTS: In patients receiving combination treatment or DMARDs (median DAS28 1.65 versus 1.78, median disease duration 120 months versus 90 months, and median duration of remission 13 months versus 18 months), the proportion with remission according to imaging results was not significantly different (10% versus 16%, respectively). The combination treatment group had more grey scale synovitis (P < 0.001) but similar power Doppler activity (48% versus 60%, respectively; P = 0.229) in any joint as compared with the DMARD group. Results were not affected by stratification for duration of disease or remission. CONCLUSION: In RA patients with disease in remission, imaging-detected synovitis persists, with power Doppler activity seen in >/=48% of the patients regardless of therapy. These results suggest that superior radiographic outcomes in patients treated with the combination of TNF blockade and MTX may not be due to complete suppression of imaging-detected synovitis.

Buch MH, Boyle DL, Rosengren S, Saleem B, Reece RJ, Rhodes LA, Radjenovic A, English A, Tang H, Vratsanos G, O'Connor P, Firestein GS, Emery P. · Academic Unit of Musculoskeletal Disease, University of Leeds, Leeds, UK. · Ann Rheum Dis. · Pubmed #18772191 links to  free full text

Abstract: OBJECTIVES: Abatacept is the only agent currently approved to treat rheumatoid arthritis (RA) that targets the co-stimulatory signal required for full T-cell activation. No studies have been conducted on its effect on the synovium, the primary site of pathology. The aim of this study was to determine the synovial effect of abatacept in patients with RA and an inadequate response to tumour necrosis factor alpha (TNFalpha) blocking therapy. METHODS: This first mechanistic study incorporated both dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) and arthroscopy-acquired synovial biopsies before and 16 weeks after therapy, providing tissue for immunohistochemistry and quantitative real-time PCR analyses. RESULTS: Sixteen patients (13 women) were studied; all had previously failed TNFalpha-blocking therapy. Fifteen patients completed the study. Synovial biopsies showed a small reduction in cellular content, which was significant only for B cells. The quantitative PCR showed a reduction in expression for most inflammatory genes (Wald statistic of p<0.01 indicating a significant treatment effect), with particular reduction in IFNgamma of -52% (95% CI -73 to -15, p<0.05); this correlated well with MRI improvements. In addition, favourable changes in the osteoprotegerin and receptor activator of nuclear factor kappa B levels were noted. DCE-MRI showed a reduction of 15-40% in MRI parameters. CONCLUSION: These results indicate that abatacept reduces the inflammatory status of the synovium without disrupting cellular homeostasis. The reductions in gene expression influence bone positively and suggest a basis for the recently demonstrated radiological improvements that have been seen with abatacept treatment in patients with RA.

Saleem B, Mackie S, Quinn M, Nizam S, Hensor E, Jarrett S, Conaghan PG, Emery P. · Academic Section of Musculoskeletal Disease, University of Leeds, Leeds, UK. · Ann Rheum Dis. · Pubmed #18234715 No free full text.

Abstract: OBJECTIVES: To evaluate the ability of tumour necrosis factor (TNF) antagonist therapy to produce remission and prevent progression to rheumatoid arthritis (RA) in patients with poor prognosis undifferentiated inflammatory arthritis (UA). METHODS: Patients with UA of <12 months' duration and having relapsed after a single parenteral corticosteroid injection were recruited into a double-blind, placebo-controlled trial of infliximab or placebo monotherapy administered at weeks 0, 2, 6 and 14. Methotrexate was added at week 14 if no clinical response (raised C-reactive protein (CRP) and clinical synovitis) was achieved. Standard outcomes were collected at baseline, infusion visits and weeks 26 and 52. The primary outcome was clinical remission at week 26. RESULTS: 17 patients were randomised (10 infliximab, 7 placebo) all with poor prognostic features. At week 14, the infliximab group had greater improvements in CRP and Health Assessment Questionnaire (HAQ) but by week 26 there was just a trend favouring infliximab for early morning stiffness, tender joint score, swollen joint score and HAQ; there was no significant difference in 28 joint count Disease Activity Score between the two groups. Furthermore, only three patients were in clinical remission (two infliximab, one placebo). By week 52, 100% patients in the infliximab group and 71% (5/7) patients in the placebo group had developed RA. CONCLUSIONS: In poor prognosis UA, a short course of TNF antagonist therapy provided modest short-term relief but did not prevent the development of RA. Patients with UA with a poor prognosis relapsing after corticosteroid have a high risk of evolving to RA and are suitable candidates for interventional treatment.