What evidence is out there for the use of adalimumab for Behcet's disease?

Comment by InpharmD Researcher

Evidence for adalimumab in Behcet's disease is well-established, particularly for severe, refractory manifestations. Systematic reviews and meta-analyses demonstrate its effectiveness in achieving clinical and endoscopic remission in intestinal Behcet's and in controlling inflammation and improving vision in Behcet's uveitis. The drug also shows a significant corticosteroid-sparing effect and a generally acceptable safety profile.

Background

The 2015 review provides an in-depth analysis of the use of adalimumab in the management of Behçet’s disease (BD), a complex, systemic inflammatory disorder. BD is noted for its relapsing nature and the diverse array of symptoms it presents, affecting multiple organ systems. The study emphasizes that while many manifestations of BD are self-limiting, those involving the eyes, gastrointestinal tract, central nervous system, and cardiovascular system can be life-threatening due to their resistance to conventional immunosuppressive treatments. The review highlights the increased use of tumor necrosis factor alpha antagonists, particularly adalimumab, to manage patients whose BD does not respond adequately to standard immunosuppressive regimens. Ueda et al. provide a comprehensive overview of clinical experiences using adalimumab for severe BD manifestations, noting the therapeutic promise of this humanized monoclonal antibody. The advantages of adalimumab over infliximab, such as the convenience of self-administration and improved patient compliance, are underscored, along with its favorable side effect profile. The review collates data from prospective open-label studies, retrospective analyses, and case reports that document the positive responses to adalimumab in refractory cases of BD, including those previously treated with infliximab. The authors argue for further randomized, prospective studies to definitively establish the efficacy of adalimumab in treating refractory BD and to explore its long-term safety profile. [1]

A 2019 publication reported on the use of adalimumab for treating pediatric Behçet’s disease (BD), characterized by systemic vasculitis and prominent manifestations affecting mucosal surfaces, skin, and occasionally other systems. The paper highlights a challenging case involving a 9-year-old patient with persistent symptoms including recurrent aphthous stomatitis, genital ulcers, erythema nodosum, and papulo-pustules, alongside systemic features like high fever and systemic inflammation. This clinical presentation was unresponsive to standard therapies involving corticosteroids and colchicine, prompting the introduction of adalimumab, an anti-TNF therapy. After initiating adalimumab at a dose of 20 mg biweekly, in conjunction with colchicine, the patient experienced a significant clinical response within 2 weeks, marked by the resolution of symptoms and sustained remission over six months without adverse effects. The analysis involved a systematic review of relevant literature using databases such as MEDLINE/PubMed and Scopus, focusing on pediatric cases receiving adalimumab for BD. This review identified four case reports and two case series alongside three additional studies, predominantly indicating adalimumab’s positive therapeutic impact, often leading to complete remission of symptoms. The cases predominantly involved severe manifestations of BD, including ocular and neurological complications, with adalimumab demonstrating rapid and effective interventions. Importantly, no significant adverse effects were reported across these cases, emphasizing the potential of adalimumab as a safe and effective treatment option in the pediatric population, though it underscores the necessity for further research to consolidate this therapeutic role. [2]

A 2024 systematic review and meta-analysis explored the long-term efficacy and safety of adalimumab (ADA) in patients with Behçet uveitis, drawing on data sourced from ten observational studies. This comprehensive analysis assessed multiple parameters, including visual acuity, intraocular inflammation, central macular thickness, corticosteroid sparing effects, and the incidence of adverse events. The meta-analysis revealed that ADA treatment resulted in a significant improvement of 0.124 logMAR in visual acuity, alongside a noteworthy reduction in intraocular inflammation grades, with a standardized mean difference of -1.187. Furthermore, central macular thickness showed a reduction with a standardized mean difference of -0.564, and there was a considerable decrease in corticosteroid dosage, with a standardized mean difference of -1.809. The adverse event rate associated with ADA was identified as 8.5% among the 301 patients evaluated. Additional results highlighted the VA improvement was less pronounced with increased disease duration before ADA treatment, suggesting the crucial need for early intervention. The analysis identified ADA as an effective controlling agent for intraocular inflammation, macular edema, and retinal vasculitis in Behçet uveitis. Despite the heterogeneity of the data sources, which included studies conducted across Asia and Europe, the findings underscore ADA's potential as a first-line treatment for Behçet uveitis, especially where traditional therapies might fail. The evident corticosteroid-sparing effect also highlights ADA's benefit in reducing steroid-related adverse effects, thereby supporting its favorable safety profile. [3]

A 2022 meta-analysis and systematic review synthesized data from 13 single-arm cohort studies involving 739 patients with intestinal Behcet’s disease to evaluate the efficacy and safety of anti-tumor necrosis factor (TNF) agents, including infliximab and adalimumab. Study participants, predominantly from East Asia, had moderate to severe disease or were refractory to conventional therapies such as corticosteroids and immunomodulators. Pooled efficacy outcomes demonstrated clinical remission rates of 61% (95% CI: 48–78%), 51% (95% CI: 40–66%), 57% (95% CI: 48–67%), and 38% (95% CI: 16–88%) at 3, 6, 12, and 24 months following treatment initiation, respectively. Endoscopic remission, a critical outcome indicating mucosal healing, was achieved in 66% (95% CI: 50–86%), 82% (95% CI: 48–98%), 65% (95% CI: 51–81%), and 69% (95% CI: 39–100%) of patients at the same time points. Subgroup analysis showed comparable efficacy between infliximab and adalimumab, although moderate heterogeneity was noted across studies. Adverse drug reactions (ADRs) related to infliximab were reported in 22% (95% CI: 7–69%) of patients, with infusion reactions and infections being the most common events, occurring in 12% (95% CI: 5–29%) and 21% (95% CI: 6–80%) of cases, respectively. Adalimumab-associated ADRs were reported at rates of 30.7 and 28.7 events per 100 patient-years. Severe adverse events, including two cases of severe infection leading to hospitalization, were infrequent, and no deaths related to therapy were reported. These findings emphasize the promising role of anti-TNF agents as an effective therapeutic strategy for achieving remission and mucosal healing in patients with intestinal Behcet’s disease, especially in those refractory to conventional treatments. However, limitations such as reliance on observational studies and heterogeneous follow-up protocols warrant further randomized controlled trials to establish definitive guidance. [4]

A 2020 systematic review and meta-analysis aimed to evaluate the effectiveness and safety of anti-tumor necrosis factor-alpha (TNF-a) agents in the treatment of Behcet's disease-associated uveitis. The study comprehensively searched three major electronic databases—Embase, MEDLINE, and the Cochrane Library—for relevant publications from January 2010 to September 2019. Eligible studies included those with a follow-up period of at least six months and a minimum of ten patients, focusing on anti-TNF-a therapies such as infliximab and adalimumab. The meta-analysis incorporated data from 18 studies comprising 968 patients, with a mix of retrospective and prospective designs. The primary outcome measures included inflammation remission, visual acuity improvement, central macular thickness decrease, and corticosteroid-sparing effects. Safety was assessed based on reported adverse events, both minor and severe. The findings of the 2020 review indicated a pooled inflammation remission rate of 68% and a visual acuity improvement rate of 60%. Central macular thickness decreased by an average of 112.70 mm following treatment. Notably, anti-TNF-a therapy demonstrated significant corticosteroid-sparing effects, with 38% of patients able to suspend corticosteroid use and 34% able to taper the dose. Despite some reports of severe adverse events, the overall incidence was deemed acceptable. Severe adverse events included infusion reactions, infections such as tuberculosis and pneumonia, and rare occurrences of melanoma and lymphoma. The meta-analysis concluded that anti-TNF-a agents represent a promising therapeutic approach for managing Behcet's disease-associated uveitis, delivering substantial efficacy in reducing inflammation and preserving visual function while maintaining an acceptable safety profile. [5]

References:

[1] Ueda A, Takeno M, Ishigatsubo Y. Adalimumab in the management of Behçet's disease. Ther Clin Risk Manag. 2015;11:611-619. Published 2015 Apr 13. doi:10.2147/TCRM.S56163
[2] Poddighe D, Mukusheva Z, Dauyey K, Assylbekova M. Adalimumab in the treatment of pediatric Behçet's disease: case-based review. Rheumatol Int. 2019;39(6):1107-1112. doi:10.1007/s00296-019-04300-0
[3] Sener H, Evereklioglu C, Horozoglu F, Gunay Sener AB. Efficacy and Safety of Adalimumab in Patients with Behçet Uveitis: A Systematic Review and Meta-Analysis. Ocul Immunol Inflamm. 2024;32(1):89-97. doi:10.1080/09273948.2022.2157288
[4] Zhang M, Liu J, Liu T, et al. The efficacy and safety of anti-tumor necrosis factor agents in the treatment of intestinal Behcet's disease, a systematic review and meta-analysis. J Gastroenterol Hepatol. 2022;37(4):608-619. doi:10.1111/jgh.15754
[5] Hu Y, Huang Z, Yang S, Chen X, Su W, Liang D. Effectiveness and Safety of Anti-Tumor Necrosis Factor-Alpha Agents Treatment in Behcets' Disease-Associated Uveitis: A Systematic Review and Meta-Analysis. Front Pharmacol. 2020;11:941. Published 2020 Jun 24. doi:10.3389/fphar.2020.00941

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

What evidence is out there for the use of adalimumab for Behcet's disease?

Level of evidence

B - One high-quality study or multiple studies with limitations  Read more→



Please see Tables 1-2 for your response.


Long-term safety and efficacy of adalimumab for intestinal Behçet’s disease in the open label study following a phase 3 clinical trial
Design Open-label study following a phase 3 clinical trial N= 20
Objective To evaluate the long-term safety and effectiveness of adalimumab for the treatment of intestinal Behçet’s disease over 100 weeks
Study Groups All patients (n= 20)
Inclusion Criteria Patients aged ≥15 years with intestinal BD, an ileocecal ulcer of ≥1 cm in diameter, and a global gastrointestinal symptom score of ≥3
Exclusion Criteria Patients who did not respond to infliximab (IFX)
Methods Patients initiated adalimumab therapy at 160 mg at week 0, followed by 80 mg at week 2, then 40 mg every other week. Dose escalation to 80 mg every other week was allowed for inadequate response or disease flare. Efficacy was assessed using a composite efficacy index combining global gastrointestinal symptoms and endoscopic assessments
Duration November 2010 to June 2013
Outcome Measures Primary: Long-term safety and incidence of adverse events Secondary: Marked improvement (MI) and complete remission (CR) rates using a composite efficacy index
Baseline Characteristics   All patients (n= 20)
Mean duration of adalimumab treatment, days (SD) 637.5 (±237.98)
Patients dose-escalated to 80 mg every other week 7
Patients receiving concomitant corticosteroids at baseline 12
Patients tapered corticosteroids by week 100 8
Patients discontinued corticosteroids by week 100 6
Results   Week 52 Week 100
Marked Improvement (MI) 60.0% (12/20) 40.0% (8/20)
Complete Remission (CR) 20.0% (4/20) 15.0% (3/20)
GI symptoms improvement ≥1 category 90.0% (18/20) 60.0% (12/20)
GI symptoms score ≤1 80.0% (16/20) 45.0% (9/20)
Endoscopic improvement score ≤1 65.0% (13/20) 60.0% (12/20)
Endoscopic improvement score 0 55.0% (11/20) 50.0% (10/20)
Adverse Events The incidence of adverse events was 544.4 events/100 person-years. Common adverse events included nasopharyngitis, headache, and Behçet’s syndrome. Serious adverse events included intestinal abscess, appendicitis, and autoimmune thyroiditis. No unexpected trends were observed
Study Author Conclusions Long-term treatment with adalimumab was well tolerated and led to sustained reduction of clinical and endoscopic disease activity in patients with intestinal BD refractory to conventional treatment
Critique The study provides valuable long-term safety and efficacy data for adalimumab in a rare condition. However, the small sample size and open-label design may limit the generalizability of the findings. The study's reliance on a composite efficacy index may also introduce subjectivity in outcome assessment

 

References:

Inoue N, Kobayashi K, Naganuma M, et al. Long-term safety and efficacy of adalimumab for intestinal Behçet's disease in the open label study following a phase 3 clinical trial. Intest Res. 2017;15(3):395-401. doi:10.5217/ir.2017.15.3.395

Successful Optimization of Adalimumab Therapy in Refractory Uveitis Due to Behçet’s Disease
Design Open-label multicenter study N= 65
Objective To assess efficacy, safety, and cost-effectiveness of adalimumab (ADA) therapy optimization in patients with uveitis due to Behçet disease who achieved remission after ADA use
Study Groups Optimized group (n= 23) Nonoptimized group (n= 42)
Inclusion Criteria Patients with uveitis due to BD who achieved remission after ADA therapy, refractory to corticosteroids and at least one conventional synthetic immunosuppressive drug
Exclusion Criteria Malignancy or systemic infectious diseases, including hepatitis B or C infection
Methods ADA was optimized by prolonging the dosing interval progressively after remission was achieved. Comparison between optimized and nonoptimized patients was performed. Efficacy was assessed by intraocular inflammation, macular thickness, visual acuity, and glucocorticoid sparing effect.
Duration Follow-up: 34.7 ± 13.3 months (optimized group), 26 ± 21.3 months (nonoptimized group)
Outcome Measures Primary: Efficacy, safety, and cost-effectiveness Secondary: Intraocular inflammation, macular thickness, visual acuity, glucocorticoid sparing effect
Baseline Characteristics Characteristic Patients with Optimized Dose (n= 23) Patients without Optimized Dose (n= 42)
Age, mean (SD) years 37.2 (13.4) 39.1 (9.3)
Sex, men/women, n/n 15/8 19/23
HLA-B51 positive, n (%) 14 (60.8) 29 (74)
Duration of uveitis before ADA, median [IQR] months 43 [23-74.5] 24 [6-36]
Results Outcome Optimized group (n= 23) Nonoptimized group (n= 42) p-value
Relapses, n (per 100 patients/year) 2 (3.0) 4 (4.4) 0.66
Severe side-effects, n (per 100 patients/year) 0 (0) 4 (4.4) 0.19
Cost (mean), euros per year 6101.25 12 339.48 <0.01
Adverse Events Relevant adverse effects were only seen in the nonoptimized group: lymphoma, pneumonia, severe local reaction at the injection site, and bacteremia by Escherichia coli
Study Author Conclusions ADA optimization in BD uveitis refractory to conventional therapy is effective, safe, and cost-effective.
Critique The study provides valuable insights into ADA optimization in BD uveitis, demonstrating cost-effectiveness and safety. However, the open-label design and lack of randomization may introduce bias. The study's findings may not be generalizable to all populations due to the specific inclusion criteria and the focus on a Spanish cohort.

 

References:

Martín-Varillas JL, Calvo-Río V, Beltrán E, et al. Successful Optimization of Adalimumab Therapy in Refractory Uveitis Due to Behçet's Disease. Ophthalmology. 2018;125(9):1444-1451. doi:10.1016/j.ophtha.2018.02.020