Long term efficacy and safety of adalimumab plus methotrexate in patients with rheumatoid arthritis: ARMADA 4 year extended study.

OBJECTIVE: To evaluate the efficacy and safety of adalimumab plus methotrexate (MTX) given for up to 4 years in patients with active, longstanding rheumatoid arthritis. METHODS: Patients responding inadequately to MTX were entered into a 24 week, controlled study (ARMADA) with adalimumab plus MTX or placebo plus MTX, and some were enrolled in a subsequent open label extension. The efficacy and safety of treatment were evaluated. Additional analyses were made for those patients whose corticosteroid and/or MTX dosages were adjusted during the extension. RESULTS: Of 271 patients in the original ARMADA trial, 262 received at least one dose of adalimumab and were evaluated. At the time of analysis, 162/262 (62%) patients had remained in the study and received treatment for a mean of 3.4 years. Withdrawals were for lack of efficacy (8%), adverse events (12%), and other reasons (18%). In 147 patients who completed 4 years' treatment, efficacy achieved at 6 months was maintained. At 4 years, 78%, 57%, and 31% had achieved ACR20/50/70; 43% achieved clinical remission (DAS28 <2.6); and 22% had no physical function abnormalities (HAQ = 0). Results were similar for 196 patients who received treatment for 2-4 years. Efficacy was maintained in many patients when dosages were decreased (corticosteroids (51/81 (63%) patients), MTX (92/217 (42%)), or both (25/217 (12%))). Serious adverse events were comparable during open label treatment and the controlled phase. Serious infections occurring during open label treatment and the blinded period were similar (2.03 v 2.30 events per 100 patient-years, respectively). CONCLUSIONS: Adalimumab plus MTX sustained clinical response and remission in patients with RA during 4 years. The safety profile during the first 6 months was similar to that after 4 years' follow up. Reduction of corticosteroid and/or MTX dosages did not adversely affect long term efficacy.

Association between baseline radiographic damage and improvement in physical function after treatment of patients with rheumatoid arthritis.

OBJECTIVES: To identify factors associated with poor physical function in rheumatoid arthritis and to assess whether baseline joint damage has an impact on improvement in physical function during infliximab treatment. METHODS: 428 patients with active rheumatoid arthritis despite methotrexate treatment received methotrexate alone or with infliximab (3 mg/kg or 10 mg/kg every four or eight weeks) for 54 weeks (the ATTRACT trial). Data on clinical outcomes and physical function (assessed by the health assessment questionnaire (HAQ)) were collected. Structural damage was assessed using the van der Heijde modification of the Sharp score. Odds ratios (OR) for factors associated with severe functional disability (HAQ > or =2.0) at baseline were estimated using multiple logistic regression analyses, and baseline factors related to the change in physical function after treatment at week 54 were determined. RESULTS: Baseline radiographic scores were correlated with baseline HAQ scores. After adjustment for demographic characteristics in the logistic regression model, baseline disease activity scores, radiological joint damage, fatigue, and morning stiffness were found to be associated with severe functional disability (HAQ >2.0), with OR values of 2.00 (1.53 to 2.63), 1.82 (1.15 to 2.87), 1.19 (1.05 to 1.34), and 1.07 (1.01 to 1.13), respectively. In multiple linear regression analysis, physical disability, joint damage, and fatigue at baseline were correlated with less improvement in physical function after treatment. Infliximab treatment was associated with greater improvement in physical function. CONCLUSIONS: Greater joint damage at baseline was associated with poorer physical function at baseline and less improvement in physical function after treatment, underlining the importance of early intervention to slow the progression of joint destruction.

The role of interleukin-1 in bone resorption in rheumatoid arthritis.

Bone loss in RA includes juxta-articular osteopenia, erosions and systemic osteoporosis. In each case, synthesis of new bone matrix is unable to balance osteoclast-mediated bone resorption, resulting in net bone loss. IL-1, TNF and other proinflammatory cytokines stimulate osteoclast differentiation and activation, resulting in bone loss. In addition, these proinflammatory cytokines stimulate synovial fibroblasts and chondrocytes to produce proteinases that degrade cartilage. In animal arthritis models, blocking IL-1 significantly reduces bone erosions and cartilage degradation, whereas blocking TNF decreases synovitis. In patients with active RA, treatment with the TNF blockers etanercept and infliximab, as well as with anakinra, a recombinant human IL-1 receptor antagonist, significantly reduced erosions and joint space narrowing. It remains to be determined, however, whether slowing radiographic progression with these biological therapies will significantly improve long-term outcomes in RA.

Anti-tumor necrosis factor-alpha monoclonal antibody therapy for rheumatoid arthritis.

Because it plays a central role in the immunopathogenesis of rheumatoid arthritis (RA), TNF-alpha is an attractive target for immunomodulatory therapy. In a number of rigorous studies, monoclonal antibodies (mAb) specific for TNF-alpha have proved efficacious in patients with active RA. Data from these studies and issues related to mechanisms of action, potential toxicity, and future directions for this novel therapeutic approach are considered in this review.

Repeat treatment of rheumatoid arthritis patients with a murine anti-intercellular adhesion molecule 1 monoclonal antibody.

OBJECTIVE: To assess the safety and efficacy of a second course of treatment with a murine monoclonal antibody (MAb) to intercellular adhesion molecule 1 (ICAM-1; CD54) in active rheumatoid arthritis (RA). METHODS: In an open-label study, 8 patients who had previously received a course of anti-ICAM-1 MAb received a second course. RESULTS: The second course of therapy was associated with adverse effects suggestive of immune complex formation. Such adverse effects were not seen during the initial course of therapy. Clinical efficacy associated with the second course of therapy was less than that observed in the first course. CONCLUSION: Repeated courses of therapy with a murine MAb to ICAM-1 would probably not be a useful therapeutic strategy in patients with RA, probably because of its immunogenicity.

Elevated cytokine messenger RNA levels in the peripheral blood of patients with rheumatoid arthritis suggest different degrees of myeloid cell activation.

OBJECTIVE: To determine whether monocytes in rheumatoid arthritis (RA) are activated to produce proinflammatory cytokines in the peripheral circulation before entering the synovium and whether the pattern of cytokines that is expressed correlates with disease activity. METHODS: Cytokine messenger RNA (mRNA) levels were assessed in peripheral blood mononuclear cells (PBMC) from 14 RA patients and 14 healthy controls by semiquantitative reverse transcription-polymerase chain reaction technology. The method employed was sufficiently sensitive to assess cytokine mRNA levels in freshly isolated cells without the necessity of in vitro stimulation. Thus, an estimate of the in vivo state of activation could be obtained. RESULTS: Interleukin-8 (IL-8) mRNA levels were elevated in all 14 RA patients compared with normal controls, whereas 7 of 14 RA patients had elevated levels of mRNA for IL-6 or IL-10. IL-1beta mRNA levels were below the normal range in 3 of 14 patients, within normal limits in 4 of 14, and elevated in 7 of 14. Tumor necrosis factor alpha mRNA levels were within the normal range in 9 of 14 patients and below normal in 5 of 14. There was a statistically significant difference between the mean IL-10 (P < 0.05) and IL-8 (P < 0.001) mRNA levels in RA patients and normal controls. Of note, the 7 patients with elevated IL-1beta mRNA levels also expressed the highest levels of IL-8 mRNA. Whereas a strong correlation between the expression of IL-1beta and IL-8 mRNA (P < 0.001) was found, expression of all other mRNA occurred independently of each other. Levels of cyclooxygenase 2 (COX-2) mRNA were also determined to evaluate the status of myeloid cell activation more completely. COX-2 mRNA levels were within the normal range in 4 of 11 patients and below normal in 7 of 11, but did not correlate with the expression of any of the cytokine mRNA. CONCLUSION: Elevated levels of mRNA for selected cytokines that are predominantly produced by monocytes can be found in the PBMC of many RA patients. The data indicate that myeloid precursor cells become activated to produce cytokines before they enter the synovium, a finding which emphasizes the systemic nature of RA.

The relationship of socioeconomic status, race, and modifiable risk factors to outcomes in patients with systemic lupus erythematosus.

OBJECTIVE: To study the relationship of race, socioeconomic status (SES), clinical factors, and psychosocial factors to outcomes in patients with systemic lupus erythematosus (SLE). METHODS: A retrospective cohort was assembled, comprising 200 patients with SLE from 5 centers. This cohort was balanced in terms of race and SES. Patients provided information on socioeconomic factors, access to health care, nutrition, self-efficacy for disease management, health locus of control, social support, compliance, knowledge about SLE, and satisfaction with medical care. Outcome measures included disease activity (measured by the Systemic Lupus Activity Measure), damage (measured by the SLICC/ACR damage index), and health status (measured by the SF-36). RESULTS: In multivariate models that were controlled for race, SES, center, psychosocial factors, and clinical factors, lower self-efficacy for disease management (P < or = 0.0001), less social support (P < 0.005), and younger age at diagnosis (P < 0.007) were associated with greater disease activity. Older age at diagnosis (P < or = 0.0001), longer duration of SLE (P < or = 0.0001), poor nutrition (P < 0.002), and higher disease activity at diagnosis (P < 0.007) were associated with more damage. Lower self-efficacy for disease management was associated with worse physical function (P < or = 0.0001) and worse mental health status (P < or = 0.0001). CONCLUSION: Disease activity and health status were most strongly associated with potentially modifiable psychosocial factors such as self-efficacy for disease management. Cumulative organ damage was most highly associated with clinical factors such as age and duration of disease. None of the outcomes measured were associated with race. These results suggest that education and counseling, coordinated with medical care, might improve outcomes in patients with SLE.

Risk factors for early work disability in systemic lupus erythematosus: results from a multicenter study.

OBJECTIVE: To study the risk factors for early work disability in systemic lupus erythematosus (SLE). METHODS: A sample of 159 SLE patients who had been employed at some time since diagnosis was drawn from a multicenter study of outcome in SLE. Disease activity, organ damage, education, income, source of health insurance, and work-related factors were measured in a standardized interview. Work disability was defined by patient self-report of not working because of SLE. The outcome measure was current work status. Seven patients were excluded from the analysis because their choice not to work was unrelated to SLE. RESULTS: An average of 3.4 years after diagnosis, 40% had quit work completely, and job modification was substantial. Univariate analysis (chi-square and t-test) showed that significant predictors of early work disability included having a high school education or less, receiving Medicaid or having no health insurance, having a job which required more physical strength, having an income below poverty level, and having greater disease activity at diagnosis. In multivariate models, significant predictors were education level (P = 0.0004), higher physical demands of the job (P = 0.0028), and higher disease activity at diagnosis (P = 0.0078). Race, sex, cumulative organ damage at diagnosis, and disease duration were not significant. CONCLUSION: Early work disability in SLE is strongly associated with some sociodemographic factors that might be amenable to intervention.