Relationship between early bone mineral density changes and long-term function and radiographic progression in rheumatoid arthritis.

OBJECTIVE: To ascertain whether bone mineral density loss during the first year of treatment for early rheumatoid arthritis (RA) as assessed by dual x-ray absorptiometry (DXA) is associated with long-term function, quality of life, and radiographic progression. METHODS: Early RA patients, prior to commencing disease-modifying antirheumatic drug therapy, underwent evaluation with DXA scans of both hands, femoral neck, and lumbar spine at the time of diagnosis, then at 1 year and final followup at >6 years. Clinical and laboratory data and hands and feet radiographs were obtained at baseline and final followup. RESULTS: Sixty-four patients were assessed. At baseline, median disease duration was 6 months, mean 28-joint Disease Activity Score was 5.85, and median Health Assessment Questionnaire score was 1.38. Median followup was 6.4 years (range 5.1-7.2 years). For erosion scores, 86% of patients with hand bone density loss above the smallest detectable change after 1 year progressed versus 55% of those with no hand bone density loss (P = 0.006). However, baseline radiographs showed a similar strength of association. Eighty-four percent of patients with erosions at baseline had erosion progression versus 57% of those with no baseline erosions (P = 0.021). Additionally, first-year bone density loss was not associated with function and quality of life status at followup. CONCLUSION: Hand bone loss during the first year of treatment in early RA, as assessed with DXA, was associated with a high likelihood of radiographic progression; however, in the current study this was not superior to baseline radiographs. Furthermore, it was not associated with patient-reported outcomes.

Ischaemic manifestations in giant cell arteritis are associated with area level socio-economic deprivation, but not cardiovascular risk factors.

OBJECTIVES: To determine whether ischaemic manifestations of GCA are associated with pre-existing hypertension, atherosclerosis or area-level socio-economic deprivation. METHODS: We conducted an observational study of rheumatologist/ophthalmologist-diagnosed GCA in eight UK centres. The main outcome measure was ischaemic manifestations observed during active GCA: visual loss/blurring, aura, diplopia, jaw/tongue/limb claudication, cerebral/myocardial ischaemia or scalp necrosis. RESULTS: Out of 271 patients, 222 had ischaemic manifestations. Adjusted odds ratios (ORs) for the influence of hypertension and atherosclerosis were 1.6 (95% CI 0.8, 3.1) and 1.5 (0.6, 3.5). The most striking finding was an association of ischaemic manifestations with increasing Index of Deprivation 2007 score: OR 4.2 (95% CI 1.3, 13.6) for the most-deprived quartile compared with the least-deprived quartile. Similar effect sizes were seen within each recruitment centre. Deprivation was associated with smoking and negatively associated with previous polymyalgia. However, neither of these variables, nor hypertension or atherosclerosis, appeared responsible for mediating the effect of deprivation on ischaemic complications. Smoking was not associated with ischaemic manifestations. Median symptom duration before treatment was 30 days; after adjusting for symptom duration, the OR for ischaemic complications was 3.2 (95% CI 1.0, 10.8) for the most-deprived quartile compared with the least-deprived quartile. CONCLUSIONS: In GCA, area-level socio-economic deprivation was associated with ischaemic manifestations: this was not mediated by traditional cardiovascular risk factors. These findings are novel and require replication. Delay between first symptoms and treatment may play a role. Public awareness campaigns about GCA should aim especially to engage individuals living in more deprived areas to encourage early presentation and prompt treatment.

Benefits 8 years after a remission induction regime with an infliximab and methotrexate combination in early rheumatoid arthritis.

OBJECTIVE: To ascertain whether a 1-year remission induction therapy with an infliximab-MTX (INF-MTX) combination in patients with early RA provided sustained benefit after INF cessation compared with conventional treatment. METHODS: Twenty patients with poor prognosis RA of < 1 year of disease duration were randomized to receive either INF and MTX or placebo infusions and MTX for 1 year. They then stepped down to MTX monotherapy and were treated according to standard clinical care. After 8 years, disease activity, function and quality of life (QoL) data were collected. RESULTS: At follow-up, data were available for 18 patients (1 in each group had died). Median 28-joint DAS was significantly lower in the INF-MTX group compared with placebo-MTX group (2.7 vs 4.3, P = 0.02). Four patients in the INF-MTX group were in remission vs none in the placebo-MTX group. One patient in the INF-MTX group achieved drug-free remission. Both RAQoL and HAQ median scores were lower in the INF-MTX group; however, this did not reach statistical significance (median RAQoL 3 vs 8, P = 0.18; median HAQ 1.0 vs 1.5, P = 0.12). CONCLUSION: A remission induction regime with an INF-MTX combination for 1 year in early RA can improve long-term clinical outcomes. Larger studies will be required to confirm the implications of these findings.

Effect of the early use of the anti-tumor necrosis factor adalimumab on the prevention of job loss in patients with early rheumatoid arthritis.

OBJECTIVE: To compare work disability and job loss in early rheumatoid arthritis (RA) patients receiving adalimumab plus methotrexate (adalimumab + MTX) versus MTX alone. METHODS: In this multicenter, randomized, controlled trial, patients with RA for <2 years who had never taken MTX and who self-reported work impairment were randomized to adalimumab + MTX or placebo + MTX for 56 weeks. Primary outcome was job loss of any cause and/or imminent job loss at or after week 16. Secondary outcomes included disease activity, function (Health Assessment Questionnaire [HAQ] score), and RA quality of life (RAQoL) questionnaire score. Work was evaluated with work diaries and the RA Work Instability Scale. RESULTS: Although job loss during the 56-week study was significantly lower with adalimumab + MTX (14 of 75 patients) compared with MTX alone (29 of 73 patients; P=0.005), the primary end point was not met (12 of 75 versus 20 of 73 patients; P=0.092), likely owing to early drop out in the MTX group. There were significant improvements in American College of Rheumatology 20% response criteria, 28-joint Disease Activity Score, DeltaHAQ, DeltaRAQoL, and working time lost in the adalimumab + MTX group. Twenty-four serious adverse events were reported in 17 participants, with no differences between groups. CONCLUSION: Adalimumab + MTX reduced job loss and improved productivity in early RA when compared with MTX alone, which supports the early use of anti-tumor necrosis factor therapy and suggests its cost efficacy.

Therapy of patients with rheumatoid arthritis: outcome of infliximab failures switched to etanercept.

OBJECTIVE: The role of alternative tumor necrosis factor (TNF) antagonist therapies in the context of failure of initial TNF antagonist therapy in patients with rheumatoid arthritis (RA) has yet to be clearly defined. The goal of this study was to determine the efficacy of etanercept in patients who failed to respond to infliximab. METHODS: Ninety-five patients with RA who failed to respond to infliximab and methotrexate were treated with etanercept (with continuation of concomitant methotrexate). Thirty-four patients never achieved a response to infliximab (primary nonresponse), 38 had an initial response to infliximab but relapsed (secondary nonresponse), and 23 demonstrated toxicity. Disease Activity Score in 28 joints (DAS28), European League Against Rheumatism (EULAR) response, and American College of Rheumatology (ACR) response were determined after 12 weeks of etanercept. RESULTS: After 12 weeks of etanercept, 38% of patients achieved an ACR 20% response (ACR20) on etanercept. Of these, 24% and 15% achieved ACR50 and ACR70 responses, respectively. In the primary infliximab nonresponse group, 42%, 30%, and 15% achieved ACR20, ACR50, and ACR70 responses, respectively; the percentages for the secondary nonresponse group were 34%, 21%, and 14%, respectively. Significant DAS28 reductions were observed in the entire cohort and nonresponse subtype groups. Sixty-one percent of the cohort achieved either a moderate or good EULAR score (67% of primary and 56% of secondary infliximab failures). No toxicity was observed in patients who stopped infliximab due to intolerance; 19 of 23 continued etanercept after week 12. CONCLUSION: This study confirms that etanercept is effective in patients who fail to respond to infliximab and suggests a higher response in patients who have never had a response to infliximab.

C-reactive protein as a predictor of infliximab treatment outcome in patients with rheumatoid arthritis: defining subtypes of nonresponse and subsequent response to etanercept.

OBJECTIVE: Nonresponse to anti-tumor necrosis factor alpha in patients with rheumatoid arthritis (RA) is poorly understood. The aims of this study were to define nonresponse patterns using infliximab and C-reactive protein (CRP) profiles, to assess the predictive power of a CRP response for outcome, and to correlate these findings with subsequent response to etanercept. METHODS: We studied 207 patients with resistant RA who were started on treatment with infliximab. After 12 weeks, the American College of Rheumatology 20% improvement criteria (ACR20) were used to classify patients as responders (ACR20 response or greater) or nonresponders (NRs). The NRs were further subdivided into 3 groups according to the CRP response at weeks 2, 6, and 12. Within the NR group, those with a suppressed CRP at week 12 continued taking infliximab for a further 12 weeks; those without a CRP response were switched to etanercept, and the ACR response at 12 weeks was calculated. RESULTS: At week 12, 54% of patients achieved an ACR20 response, and 46% failed to achieve a response. Of the NRs, 63% demonstrated a significant reduction in the CRP level at week 12, 59% of whom achieved an ACR20 response at week 24 on continuation of infliximab. Of the patients who did not demonstrate a significant reduction in the CRP level after the first infusion, 86% failed to show a biochemical or ACR20 response by week 12. Twenty-four percent of the NRs had a temporary reduction in the CRP level, and 13% of the NRs showed no CRP reduction. Seventy-five percent of these NRs switched to etanercept, and 68% of this group achieved an ACR20 response at week 12 (51% achieved an ACR50 response), with a CRP response in 63%. CONCLUSION: Infliximab NRs comprise subtypes with distinct CRP patterns. Failure to suppress the CRP at week 2 identified the majority of patients who were NRs at week 12. CRP suppression at week 12 in the NRs was associated with a late clinical improvement with infliximab treatment (24 weeks), whereas failure to suppress the CRP at week 12 was associated with a good response on switching to etanercept.

Lack of response to anakinra in rheumatoid arthritis following failure of tumor necrosis factor alpha blockade.

OBJECTIVE: In patients with rheumatoid arthritis (RA) treated with tumor necrosis factor alpha (TNF alpha)- blocking therapy, there is heterogeneity of response. This raises the possibility that in certain circumstances, cytokines such as interleukin-1 (IL-1) may dominate the drive toward joint inflammation. This study was undertaken to investigate whether blocking the action of IL-1 with an IL-1 receptor antagonist (IL-1Ra) is efficacious in patients with disease that did not respond to TNF alpha blockade. METHODS: We identified 26 RA patients whose disease had failed to respond to TNF alpha-blocking therapy, defined as failure to achieve or sustain a 20% improvement in disease activity according to the criteria of the American College of Rheumatology (ACR20 response). These patients were then treated with anakinra (100 mg/day subcutaneously) for 12 weeks, and their levels of response were assessed. RESULTS: After 3 months of anakinra therapy, only 2 of 26 patients (8%) achieved an ACR20 response; none achieved an ACR50 or ACR70 response. A rise in the mean C-reactive protein level and an increase in the mean swollen joint count were noted during the study period. CONCLUSION: This study demonstrates that patients with disease that fails to respond to TNF alpha blockade also do not respond to IL-1Ra. These data do not provide evidence of a dominant role for IL-1 in patients who do not respond to TNF alpha blockade, but they do not exclude a role for other proinflammatory mediators.