Anakinra has been approved for the treatment of rheumatoid arthritis in adults, based on previously described efficacy and safety studies.4,5,6,7
The current report confirms and extends previous safety findings by assessing prolonged treatment in a large and diverse population of adults with rheumatoid arthritis. Notably, this study included patients with varying levels of disease severity and a wide range of comorbid conditions, and allowed multimodal concomitant antirheumatic treatment; most clinical studies in rheumatoid arthritis restrict entry to patients lacking comorbid conditions and prohibit concomitant antirheumatic treatment other than methotrexate.10,12,13,14,15,16,17,18
Moreover, this design allowed for greater ability to detect the occurrence of adverse events that might, in shorter term studies, occur at rates too low to be estimated accurately. Thus the results from this study should be a close approximation of those expected in the general population of patients with rheumatoid arthritis.
The cohort for this long term safety assessment comprised 1346 patients who received up to 36 months of continuous anakinra treatment. At study entry, more than 80% of patients were using NSAIDs and more than half were using corticosteroids or methotrexate, while almost 70% of patients had comorbid conditions.9
Overall exposure to anakinra was considerable, with 510 patients completing three years of treatment. The most common adverse events leading to withdrawal were injection site reactions and rheumatoid arthritis progression, consistent with previous studies of anakinra.4,5,7
The cumulative rates for all adverse events leading to withdrawal decreased over time, and by the second year of treatment were comparable to the rate observed for placebo subjects during the six month blinded phase (33.28 v
33.90 events/100 patient‐years). Cumulative EAE rates for all adverse events, serious adverse events, and deaths among anakinra treated patients were similar during each of the three years of the study and also were similar to those observed for placebo treated patients during the randomised double blind phase of the study.
Patients with rheumatoid arthritis have an increased risk of infections, particularly those involving bones, joints, skin, soft tissues, and the respiratory tract, either because of underlying mechanisms of the disease itself, or because of treatment induced decreases in immune function, or both.19,20,21
In the current analysis, the overall cumulative EAE rate of serious infections during extended anakinra treatment was low (5.37 events/100 patient‐years), but notably was approximately threefold higher than that observed for placebo treated patients (1.6 events/100 patient‐years). However, concomitant steroid use at baseline appears to substantially increase the likelihood that an anakinra treated patient will develop an infection. These findings support the safety of anakinra over extended exposure, but also suggest that patients at high risk for infections should be carefully monitored, particularly if corticosteroid treatment is concomitant. Current labelling for anakinra contraindicates its use in patients with active infections.
The reason for increased risk of serious infections in patients with rheumatoid arthritis treated with anakinra has not been determined definitively, but may reflect immune suppression resulting from inhibition of IL1.22
Several recent studies have found increased risk of serious infections in patients with rheumatoid arthritis treated with biological agents compared with those treated with placebo or methotrexate alone.12,14,18
Other studies, however, have found no difference in frequencies of serious infections for such patient groups.15,16,17,23,24,25,26
The reasons for these disparate findings are unclear. Corticosteroid use also has been associated with an increased risk of infections,27,28,29
and a post hoc analysis of concomitant drug treatment in the six month double blind phase of the current study showed that the frequency of infections in the subset of patients who received anakinra and concomitant corticosteroids was similar to that of the overall cohort of anakinra‐treated patients.10
However, the three year safety data reported within reveal that corticosteroid use while on anakinra significantly enhances the chances of developing a serious infection.
The higher than expected incidence of melanoma observed in the current study may not be related to anakinra, as one patient had a prior history of the disease and most of the others lived in areas with high sun exposure or in close proximity to the equator. Furthermore, a higher than expected incidence of melanoma has rarely been seen in other anakinra studies.30
Only a single case of melanoma has been observed prior to the present study, and the affected patient also had a previous history of melanoma. In clinical trials of other rheumatoid arthritis biological agents such as etanercept,17,24,31
melanomas have not been found at rates higher than expected.
The increased risk for lymphoma is consistent with previous reports of increased risk of lymphoma in rheumatoid arthritis.37,38,39,40
In a case–control study, patients with rheumatoid arthritis and high disease activity were estimated to have up to a 25.8‐fold increased risk of lymphoma compared with controls without rheumatoid arthritis.41
The SIR for lymphoma (3.71 (95% CI, 0.77 to 11.0)) observed in the present study is consistent with odds ratios varying from 1.9 to 20.0 in various reports of patients with rheumatoid arthritis.37,38,42,43,44
Wolfe and Michaud44
recently reported an SIR of 2.9 (95% CI, 1.7 to 4.9) for lymphoma in patients who received biological therapies. Thus the incidence ratios for patients treated with anakinra and other biological agents appear to be within the ranges observed in rheumatoid arthritis in general, and indeed, Wolfe and Michaud concluded that the existence of a causal relation between lymphoma development and use of biological therapy in patients with rheumatoid arthritis could not be determined with the available data.44
While the current observations suggest that anakinra treatment may not be an additional risk factor for the development of lymphoma in patients with rheumatoid arthritis, continued surveillance of anakinra and other biological agents used for the treatment of this disease is warranted.
Taken together, the data presented here support the safety of extended treatment with anakinra in patients with rheumatoid arthritis. Overall, anakinra was well tolerated. Because most patients in this study used concomitant drug treatment and many had comorbid conditions, the results should be predictive of effects that would be seen in the general population of patients typically cared for in a rheumatology clinic.