Anti-TNF-α agents for refractory intestinal Behçet’s disease: case series and meta-analysis

Abstract

Background: Behçet’s disease (BD) is a relapsing systemic immune disorder, and intestinal BD is a significant cause of mortality in patients with BD. Conventional therapeutic strategies for intestinal BD showed unsatisfactory outcomes, especially in those patients with refractory subtypes. In recent years, biologic agents have exhibited promising results in this field. While the sample sizes of existing studies were limited, the results were heterogeneous. Objectives: This study aimed to observe the efficacy of different biologics in clinical symptomatic improvement and intestinal mucosal healing. Design: This is a study including the report of case series and meta-analysis. Data sources and methods: This meta-analysis was conducted following the PRISMA guidelines. Free-text words and subject terms, including ‘Behcet’s Syndrome’, ‘Biologics’, ‘Tumor Necrosis Factor Antagonist’, were used to systematically research the relevant studies in the electronic databases (PubMed, Web of Science, Embase, and Cochrane Library). All retrieved articles were from inception to July 2021, and the data from our institution were also included in this meta-analysis. A double arcsine transformation was performed to stabilize the variance of the original ratio. Heterogeneity was evaluated via Q-test and I2 statistics. Random-effects or fixed-effects model was used to calculate the pooled parameters, and the results were presented as forest plots with 95% confidence intervals. Results: Twelve studies were included, but only antitumor necrosis factor alpha (anti-TNF-α) agents were prescribed as biologicals for refractory intestinal BD. The symptom improvement rates at our institution ranged from 57.1 to 81.8%, and the mucosal healing rates were from 20 to 60% in different therapeutic periods. A total of 514 patients were enrolled in the meta-analysis, and the synthesized ratios showed that 59.8% ( n = 377) and 73.7% ( n = 317) of patients who received maintenance therapy with anti-TNF-α agents could achieve clinical symptomatic improvement during short-term (10–14 weeks) and long-term (48–54 weeks) periods, respectively. Furthermore, 77.8% ( n = 229) of patients with intestinal BD maintained therapeutic efficacy for a longer time (100 weeks). In addition, 60.9% ( n = 120) of the patients achieved sustained intestinal mucosal healing during a long-term follow-up (24–52 weeks). Conclusion: Anti-TNF-α treatment is effective in treating refractory intestinal BD but more studies are required to evaluate the effects of new biologics for intestinal BD in the near future. Registration: This study has been registered on PROSPERO, the ID is CRD42022329211. Plain language summary Anti-TNF-α agents are effective and safe in patients with intestinal Behçet’s disease Behçet’s disease (BD) is a disease affecting several organs including the gastrointestinal tract. Nowadays, the efficacy of existing therapy strategies is still unsatisfactory and some patients are suffering from repeated attacks of the disease. We noticed that a new kind of medicine, called antitumor necrosis factor alpha (anti-TNF-α) agents, was applied to these patients recently. The therapeutic efficacy is not convincing enough to evaluate since the number of patients receiving this new medicine was small in every individual study. Regarding this, we conducted a research to learn about the efficacy of this medicine at our own institution. Besides, we composed the results of other studies in an appropriate way. Then, we drew a conclusion on the exact efficacy of anti-TNF-α agents after the data analysis. We unveiled that the anti-TNF-α agents appeared both effective and safe in the management of intestinal BD patients when the classical therapy failed. More than half of the patients could achieve discomfort remission when they got the therapy of the new medicine at our institution. We also found that intestinal ulcers in most patients improved after they received the treatment. All in all, it offered another foothold for getting relief in these patients who were caught in this mire.

TNFα rs1800629 Polymorphism and Response to Anti-TNFα Treatment in Behçet Syndrome: Data from an Italian Cohort Study

“…Not all patients have long-term remission, so the discontinuation of the TNFα inhibitor therapy has become an area of interest, due to obvious economic and risk-benefit concerns. These aspects underline the need to have useful biomarkers for predicting the response to therapy [ 4 , 5 , 6 , 9 , 16 , 18 , 27 , 28 ]. Due to advances in DNA genotyping and sequencing approaches, genetic variations become an interesting source of markers able to predict treatment responses and to obtain useful information within the field of personalized medicine.…”

“…Infliximab, Adalimumab, and Etanercept are more effective for the treatment of RA, PsA, and AS. This variability response could be related to differences in pharmacokinetics, tissue distribution and functional properties of each anti- TNFα agent [ 1 , 9 , 16 , 18 , 27 , 29 , 40 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 ].…”

“…The approach of targeting TNFα has considerably improved success in the treatment of BS, in particular for patients with refractory, severe BS, and in particular for ocular, central nervous system, and gastrointestinal manifestations, as well as vascular involvement [ 6 , 9 , 15 , 16 , 17 , 18 ]. Five different TNFα inhibitors are now used: infliximab, etanercept, adalimumab, golimumab, and certolizumab-pegol.…”

“…Although biological treatments with anti- TNFα agents are effective in BS, not all patients are definite responders. Non-responder patterns could be due to alternative non- TNFα -related pathways of inflammation, the presence of anti-drug antibodies or development and polymorphic alleles of the TNFα gene [ 4 , 5 , 6 , 7 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ]. TNFα (RefSeq NG_007462.1) is located quite close to the Major Histocompatibility Complex (MHC) at chromosome 6 (6p21.33), and encodes a 233-amino-acid type II transmembrane protein.…”

“…No significant association was recognized between the polymorphism and the clinical parameters, as well as between SNP and disease severity [ 2 ]. The association between the SNP and both susceptibility and clinical patterns of BS was investigated with conflicting data [ 4 , 5 , 6 , 7 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ]. Poorer data are currently available regarding the association of this polymorphism and its responsiveness to TNFα blockers in BS patients, in particular in Italian populations.…”