Behçet’s disease is a complex multisystem disease. A standalone positive typing for HLA-B51 is not considered diagnostic, and the diagnosis of this uveitic entity is based on a myriad of multisystem clinical signs that make up the diagnostic criteria.[1] The genetic predisposition to this disease afforded by HLA-B51 positivity (along with other non-HLA genes) has been postulated to get along with an altered microbiome in the gut of Behçet patients, with an additional possible contribution from infectious agents such as Streptococcus sanguinis, to trigger and then sustain an immune response, which disrupts a previously intact T-cell homeostatic environment. This recent understanding has expanded treatment horizons beyond standard treatment protocols, to include biologic therapy, especially tumor necrosis factor-alpha (TNF-α) antagonists, to achieve control of repeated disrupted immune response.[1] Progressive sight-threatening Behçet’s disease involving the entire uveal tract blinds up to 25% of patients within a course of 10 years, after which the disease progression tends to stabilize.[1,2] This mandates an excellent control of inflammation within this all-important “window period” to save the eye either from the direct inflammatory manifestations of Behçet’s uveitis or its potentially blinding complications.[1] The consensus in uveitis management in Behçet’s disease (according to the European Alliance of Associations of Rheumatology [EULAR] and the American Academy of Ophthalmologists’ guidelines) recommends limitation of steroid administration for control of acute inflammation and substituting steroids with conventional disease-modifying antirheumatic drugs (DMARDs) or biologic therapy. Furthermore, the American Academy of Ophthalmology goes a step further to recommend bypassing the “classic DMARDs” in favor of anti-TNF-α agents in severe, sight-threatening uveitis.[3] Thus, EULAR updated its guidelines in 2018 to recommend administering steroids in posterior segment ocular Behçet’s disease patients, but only in combination with steroid-sparing therapies such as azathioprine (AZA), cyclosporine A (CsA), interferon alpha, or monoclonal anti-TNF antibodies.[3] In the current study[4] of Behçet’s disease with ocular lesions from India, all patients have received steroids and 80% patients have been treated with immunosuppression along with steroids. Randomized controlled trials have shown that the antimetabolite AZA and T-cell inhibitor CsA are effective in the treatment of posterior uveitis in Behçet’s disease. Hence, the updated 2018 EULAR guidelines recommended the use of these two drugs (as against others) in the initial therapy of posterior uveitis.[3] Further, the combined use of AZA and CsA, whether as first- or second-line therapy, has shown efficacy in controlling ocular Behçet’s disease (with more periodic side effect monitoring).[1] In the current study from India, AZA and CsA have been combined in 24% of the patients.[4] In Behçet’s disease, TNF-α production by macrophages, CD4+ and CD8+ T cells, and natural killer cells is increased. The reduction of circulating TNF-α has been shown to result in dramatic improvement in the inflammatory activity of patients with severe pan or posterior uveitis.[1] These anti-TNF-α drugs used are recombinant monoclonal antibodies directed against TNF-α. Due to their potent and fast effects, these agents are now used alone or in combination therapy in refractory ocular Behçet’s cases, or sometimes even as first-line treatment in severe sight-threatening attacks.[3] Adalimumab (ADA) is a fully human monoclonal antibody directed against TNF-α and has been tested against a placebo in both active and quiescent, noninfectious uveitis (VISUAL I and VISUAL II studies, respectively). Ocular Behçet’s disease represented 7% of the uveitic cases enrolled in them.[1] Further, other uncontrolled studies have shown significant results regarding the efficacy of ADA in Behçet’s uveitis.[5] Early initiation of ADA in two children with Behçet’s uveitis succeeded in control of the disease activity, allowing tapering of topical and systemic steroids.[6] Comparative studies have been conducted between ADA and the other agent infliximab (IFX), notably a multicenter study on 177 patients with refractory Behçet’s disease uveitis, which found that both agents gave significantly better control in terms of disease activity as the first-line treatment, but the ADA group had higher percentage of patients with better best corrected visual acuity and fewer drug-related reactions.[7] One must remember that exclusion of tuberculosis and other infectious diseases as well as occult malignancies is mandatory before starting therapy with these agents. Also, an additional immunosuppressant (like methotrexate) may be advisable to prevent anti-chimeric, or antihuman, antibody production, which decreases the efficacy of these agents leading to secondary failure.[1] In the current study from India, biologic agents have been used in 40% of the patients; of which ADA was used in 28% and IFX in 12% of patients.[4] Finally, studies have recently reported success with Janus kinase (JAK) inhibitors in the treatment of noninfectious autoimmune uveitis refractory to conventional DMARDs and anti-TNF-α agents. Successful results have been reported with the JAK inhibitor tofacitinib in refractory Behçet’s disease uveitis,[8] and moving forward, these agents shall most likely further expand our treatment horizons for Behçet’s disease.
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May 23, 2023
Chunmei Qin + 3
Open Access
