Meta-analysis of seventy trials «Kourbeti IS, Ziakas PD, Mylonakis E. Biologic ther...»1, all together data on 32,504 patients (21,916 patients on biologics and 10,588 on control).
The PubMed and EMBASE databases were searched for randomized trials (last access on June 24, 2013), for pertinent literature in English. Search terms included "(rheumatoid AND arthritis)", "randomized", "(infliximab OR etanercept OR adalimumab OR certolizumab OR golimumab OR anakinra OR abatacept OR tocilizumab OR rituximab)" for both databases.
A randomized trial on a biologic agent was considered eligible if it fulfilled all of the following conditions: (a) randomized patients with rheumatoid arthritis, (b) randomized FDA-approved biologics for treatment of RA, (c) compared the effect of a biologic agent to control drug, and, (d) provided safety data to calculate at least one outcome of interest. The control arm included either placebo or Disease Modifying Antirheumatic Drugs (DMARDs)/conventional therapy. Low dose corticosteroids (< 10 mg equivalent to prednisolone) were permitted in all arms.
The primary outcome was all OIs (opportunistic infection) that occurred during the randomized period. The spectrum of OIs included mycobacterial, herpetic and fungal infections. The secondary outcomes included mycobacterial (Mycobacterium tuberculosis and non-tuberculous mycobacteria), herpes virus-related infections including herpes simplex virus (HSV), Epstein-Barr virus (EBV), cytomegalovirus (CMV), varicella zoster virus (VZV) and fungal infections (with Pneumocystis Jirovecii pneumonia (PJP) analyzed separately). Mortality attributed to an OI was also a secondary outcome.
The following potential moderators of outcomes were modified: duration of rheumatoid arthritis, duration of study (short term < 24 weeks and long term ≥ 24 weeks), drug mode of action (anti-Tumor Necrosis Factor (TNF) inhibitor vs non- anti-TNF) and prior exposure to anti-TNF drugs (before enrollment). Based on the mean disease duration reported, RA was classified in three groups, namely disease onset < 2 years (or "early"), disease onset 2–10 years and disease onset > 10 years before enrollment.
Publication bias was assessed by inspecting funnel plots and calculating Egger's test.
Overall, patients receiving biologic agents were more likely to develop OIs compared to control (OR 1.79; 95 % CI 1.17–2.74, NNH = 582). This effect corresponds to 1.7 excess OIs per 1,000 patients treated with biologics.
More specifically, the use of biologics was associated with increased risk of mycobacterial (OR 3.73; 95 % CI 1.72–8.13; I2= 0) and all viral OIs (OR 1.91; 95 % CI 1.02–3.58; I2= 0), as opposed to all fungal infections (OR 1.31; 95 % CI 0.46–3.72), invasive fungal infections (OR 2.85; 95 % CI 0.68–11.91), PJP (OR 1.77; 95 % CI 0.42–7.47) and VZV infections (OR 1.51; 95 % CI 0.71–3.22) where differences did not reach statistical significance.
In subgroup analysis, the combined effect of anti-TNF drugs was significant for OIs (OR 2.10; 95 % CI 1.27–3.45; I2= 0), as opposed to non-anti-TNF agents (OR 1.20; 95 % CI 0.54–2.68). However, the comparison of effects was not significant (p interaction was 0.18). Interestingly, biologics were associated with increased risk of OIs across studies with median RA duration > 10 years (OR 5.20; 95 % CI 1.19–22.86) as well with median duration of 2–10 years (OR 1.93; 95 % CI 1.17–3.18). The effect was not significant in early RA (OR 0.76; 95 % CI 0.28–2.04; I2= 0). The comparison of effects across studies with median RA duration > 10 years vs early RA was significant (p interaction 0.03), as opposed to RA lasting 2–10 (p interaction 0.15). These differences suggest that the risk of OIs due to biologics amplifies for long lasting disease.
The combined effect was significantly higher across short-term studies (OR, 4.89; 95 % CI 1.78–13.40; I2= 0) compared to intermediate and long-term studies (OR, 1.45; 95 % CI 0.91–2.31, p interaction 0.03). On clinical grounds this difference may signify that OIs are early events after biologic therapy initiation. A difference that did not reach statistical significance was noted for patients without prior exposure to anti-TNF agents (OR 2.05; 95 % CI 1.23–3.42; I2= 0) compared to patients that had a previous exposure to anti-TNF agents (OR 1.33; 95 % CI 0.62–2.85, p interaction 0.36).
There was no difference in OIs-associated mortality. There were 4 OI-related deaths in biologics vs 1 on controls (OR 1.91; 95 % CI 0.29–12.64).
Among rheumatoid arthritis patients, biologic agents are associated with a small but significant risk of specific opportunistic infections.