Etanercept and uveitis: friends or foes?

Keywords: :

• Adalimumab
• Ankylosing spondylitis
• Etanercept
• Infliximab
• Uveitis

Biological agents emerged at the end of the 20th century as effective therapies for a wide spectrum of diseases. Several drugs (principally directed against cytokines or lymphocytic receptors) are currently approved by the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of various rheumatic, digestive and cutaneous diseases1. In addition, these agents have been used for a rapidly expanding number of systemic autoimmune diseases, even though they are often not licensed for this use by the FDA and the EMA2.

Although these agents have demonstrated acceptable safety and tolerability profiles, a growing number of autoimmune adverse events are reported, ranging from asymptomatic immunological alterations to life-threatening systemic autoimmune diseases. During the last 10 years, the members of the Spanish Study Group of Biological Agents in Autoimmune Diseases (BIOGEAS) of the Spanish Society of Internal Medicine have investigated the characteristics of both systemic and organ-specific autoimmune processes associated with the use of biological agents3. More than 1500 cases involving nearly 50 different systemic and organ-specific autoimmune diseases have been reported in patients with underlying autoimmune diseases treated with biological therapies2. Although almost all reports come from small case series or isolated case reports, due to the low prevalence of these induced processes (<1%), there are increasing reports from controlled trials and large postmarketing studies. Logically, these processes nearly all occur in diseases for which biological agents are licensed and extensively used, mainly in patients with rheumatoid arthritis, spondyloarthropathies, psoriatic arthritis and inflammatory bowel disease exposed anti-tumour necrosis factor (TNF) agents. But paradoxically, for many of these drug-related autoimmune processes, current treatment indications include the very biological agent producing the adverse event. As the use of biologics other than anti-TNF expands, the number and diversity of induced autoimmune disorders may be expected to increase.

Inflammatory ocular disease is one of the organ-specific autoimmune diseases reported after initiation of biological therapies. In 2007, Lim et al.4 identified 59 cases of uveitis from two large databases (excluding patients with spondyloarthropathies, psoriatic arthritis and inflammatory bowel disease), and found that 43 (73%) were related to etanercept. The BIOGEAS Registry includes 69 cases of uveitis, 16 of scleritis and 2 cases of endogenous endophthalmitis5. In 2011, Wendling et al.6 reviewed 152 cases of new onset uveitis (31 from the French Club Rhumatismes et Inflamation registry and 121 cases from the literature), of which 84% were related to etanercept, although only 28% occurred in patients diagnosed with diseases other than ankylosing spondylitis.

Uveitis is the most frequent extra-articular feature of seronegative arthritis and is part of the classification criteria for ankylosing spondylitis. In the current study, Wendling et al.7 report a higher risk of developing new-onset uveitis in patients with ankylosing spondylitis treated with etanercept in comparison with those treated with adalimumab (hazard ratio of 1.90, p = 0.0223). Some limitations to be considered are the lack of data on disease duration, the limited time frame used to evaluate the development of uveitis (only one year), the role of switching TNF agents in some patients before the development of uveitis and the possible influence of cardiovascular risk factors, as recently suggested by Berg et al.8. In spite of these limitations, Wendling et al.7 confirm the results obtained in previous studies that suggested a differentiated effect of etanercept compared with infliximab/adalimumab for the management of uveitis associated with ankylosing spondylitis.

There are two principal scenarios when anti-TNF agents are initiated in these patients: in patients without a history of uveitis, therapy should prevent (or delay) the development of the first episode of uveitis, while the target in those with a previous history of uveitis should be a reduction in the number and severity of subsequent flares. The use of anti-TNF therapies in patients with ankylosing spondylitis has been associated with a reduction in uveitis flares in comparison with placebo9. However, in 2005, Braun et al.10 reported that the reduction was greater in patients treated with infliximab compared with those treated with etanercept. Subsequent studies have compared rates of uveitis before and after anti-TNF treatment: while rates were significantly reduced after the use of infliximab (from 47–62 to 3–6 flares per 100 patient-years)11^,12 or adalimumab (from 60–68 to 0–29 flares per 100 patient-years)11^,13, rates increased after etanercept therapy (from 34–54 to 58–60 flares per 100 patient-years)11^,12. Wendling et al.7 have shown a lower frequency of a first episode of uveitis in patients with ankylosing spondylitis treated with infliximab/adalimumab. All these studies point in the same direction: that etanercept has lower efficacy than monoclonal anti-TNF, either because it causes more uveitis flares or because it is less effective in preventing new flares. Current international guidelines for inflammatory ocular disease strongly recommend the use of infliximab or adalimumab before etanercept and recommend considering switching to monoclonal anti-TNF if possible in patients treated with etanercept for other indications who present with inflammatory ocular disease (whether new onset or refractory disease)14.

In conclusion, the number of studies suggesting a differentiated therapeutic response of uveitis related to ankylosing spondylitis to etanercept with respect to monoclonal antibodies is increasing. The reasons for the lower rates of therapeutic response with etanercept are unknown, but may be related to a possible class effect, a hypothesis that should be confirmed in future studies comparing etanercept with other monoclonal agents (certolizumab, golimumab). Current evidence suggests the preferential use of monoclonal anti-TNF rather than fusion proteins in patients with ankylosing spondylitis with an active or previous history of uveitis (this is not so clear in patients without a previous history of uveitis). This specific clinical scenario has not been evaluated in international guidelines9 and should be analyzed in future consensus documents.

Transparency

Declaration of funding

This editorial was not funded.

Declaration of financial/other relationships

P.B.-Z., R.P.-A. and M.R.-C. have disclosed that they have no significant relationships with or financial interests in any commercial companies related to this study or article.

CMRO peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

P.B.-Z. is supported by the Josep Font Research Fellow Award, Hospital Clinic, Barcelona, Spain.