Adalimumab safety and mortality rates from global clinical trials of six immune-mediated inflammatory diseases.

OBJECTIVES: Clinical trials of tumour necrosis factor antagonists have raised questions about the potential risk of certain serious adverse events (SAE). To assess the safety of adalimumab in rheumatoid arthritis (RA) over time and across five other immune-mediated inflammatory diseases and to compare adalimumab malignancy and mortality rates with data on the general population. METHODS: This analysis included 19,041 patients exposed to adalimumab in 36 global clinical trials in RA, psoriatic arthritis (PsA), ankylosing spondylitis (AS), Crohn's disease (CD), psoriasis and juvenile idiopathic arthritis (JIA) to 15 April 2007. Events per 100 patient-years were calculated using SAE reported after the first dose to 70 days after the last dose. Standardised incidence rates were calculated for malignancies using national and state-specific databases. Standardised mortality rates (SMR) were calculated for each disease using data from the World Health Organization. RESULTS: Cumulative rates of SAE of interest in RA have remained stable over time. Rates of SAE of interest for PsA, AS, CD, psoriasis and JIA were similar to or lower than rates for RA. Overall malignancy rates for adalimumab-treated patients were as expected for the general population. SMR across all six diseases indicated that no more deaths occurred with adalimumab than expected in the general population. CONCLUSIONS: Based on 10 years of clinical trial experience across six diseases, this safety report and the established efficacy of adalimumab in these diseases provide the foundation for a better understanding of its benefit-risk profile.

Adalimumab effectively reduces the signs and symptoms of active ankylosing spondylitis in patients with total spinal ankylosis.

OBJECTIVE: To evaluate the long-term safety and efficacy of adalimumab in patients with ankylosing spondylitis (AS) and total spinal ankylosis (TSA). DESIGN: Patients (n = 315) with active AS were randomised in a 2:1 ratio to receive adalimumab 40 mg every other week or placebo for 24 weeks followed by open-label adalimumab for up to 5 years. Two-year efficacy and safety data for 11 patients with investigator-defined TSA were evaluated. The primary end point was the ASsessment in AS International Working Group criteria for 20% improvement (ASAS20) at Week 12. On or after Week 12, ASAS20 non-responders could switch to open-label adalimumab. Other efficacy measurements included ASAS40, ASAS 5/6, ASAS partial remission, and 50% improvement in the Bath AS Disease Activity Index (BASDAI 50). RESULTS: 6 of 11 TSA patients were randomised to adalimumab and 5 to placebo. At Week 12, 50% of the adalimumab-treated patients achieved an ASAS20 response and 33% achieved an ASAS40, ASAS 5/6 and BASDAI 50. No placebo-treated patients achieved any response criteria at Week 12. 4 placebo- and 2 adalimumab-treated patients switched to open-label adalimumab before Week 24. After 1 year of adalimumab treatment, 8 of 11 patients achieved an ASAS20 response. After 2 years, 6 of the remaining 8 patients with TSA reported an ASAS20 response. There were no serious adverse events or adverse event-related study discontinuations. CONCLUSION: In patients with TSA, adalimumab treatment resulted in rapid and clinically significant improvement in the signs and symptoms of active disease. Adalimumab effectiveness and safety were sustained for at least 2 years. TRIAL REGISTRATION NUMBER: NCT00085644.

Safety analyses of adalimumab (HUMIRA) in global clinical trials and US postmarketing surveillance of patients with rheumatoid arthritis.

OBJECTIVE: To assess the safety of adalimumab in global clinical trials and postmarketing surveillance among patients with rheumatoid arthritis (RA). METHODS: Safety data for adalimumab treated patients from randomised controlled trials, open label extensions, and two phase IIIb open label trials were analysed. In addition, postmarketing spontaneous reports of adverse events in the United States were collected following Food and Drug Administration approval of adalimumab on 31 December 2002. RESULTS: As of 15 April 2005, the RA clinical trial safety database analysed covered 10,050 patients, representing 12,506 patient-years (PYs) of adalimumab exposure. The rate of serious infections, 5.1/100 PYs, was comparable to that reported on 31 August 2002 (4.9/100 PYs), and to published reports of RA populations naive to anti-tumour necrosis factor (TNF) therapy. Following implementation of tuberculosis (TB) screening in clinical trials, the rate of TB decreased. There were 34 cases of TB as of this analysis (0.27/100 PYs). The standardised incidence ratio for lymphoma was 3.19 (95% CI 1.78 to 5.26), consistent with the observed increased incidence in the general RA population. As of 30 June 2005, there were an estimated 78 522 PYs of exposure to adalimumab in the US postmarketing period. Seventeen TB cases were spontaneously reported (0.02/100 PYs) from the US. Rates of other postmarketing events of interest, such as congestive heart failure, systemic lupus erythematosus, opportunistic infections, blood dyscrasias, lymphomas, and demyelinating disease, support observations from clinical trials. CONCLUSION: Analyses of these data demonstrate that long term adalimumab treatment is generally safe and well tolerated in patients with RA.

Hemarthrosis as initial presentation of scurvy.

Vitamin C deficiency or scurvy is a disease now rarely seen except for certain populations at risk. When it occurs, diagnosis can be difficult as it can mimic other disorders. Its manifestations are primarily due to an abnormality in collagen formation causing bleeding in the skin, joints, muscles, or gastrointestinal tract and dystrophic hair deformities. We describe a case of scurvy in a 43-year-old man who presented with new onset hemarthrosis with no history of bleeding disorder. He was found to have perifollicular hyperpigmentation and corkscrew hairs, highly suggestive of scurvy. He admitted to completely eliminating fruits and vegetables from his diet and his serum vitamin C level was markedly decreased. Treatment with daily vitamin C supplement led to relief of symptoms and resolution of skin changes.