Comparative efficacy and safety of different drugs in patients with systemic juvenile idiopathic arthritis: A systematic review and network meta-analysis.

BACKGROUND: The goal of this study was to estimate the relative efficacy and safety of different biological agents (infliximab, canakinumab, baricitinib, anakinra, adalimumab, tofacitinib, tocilizumab, and rilonacept) compared with placebo for systemic juvenile idiopathic arthritis (JIA) patients, through a network meta-analysis. METHODS: Pubmed, Embase, and Cochrane Library were searched from database inception to July 2023 for randomized controlled trials comparing different biological agents (infliximab, canakinumab, baricitinib, anakinra, adalimumab, tofacitinib, tocilizumab, and rilonacept) or placebo directly or indirectly in JIA. Bayesian network meta-analyses were conducted. Data was extracted and analyzed by R with gemtc package. The treatment options were ranked using the surface under the cumulative ranking curve (SUCRA) value. RESULTS: We identified 10 randomized controlled trials and analyzed 898 participants. Canakinumab (odds ratio 55.0, 95% credible intervals 2.4-67.0) was more effective than the placebo, and the difference was statistically significant. However, there was no statistical significance between other drugs versus placebo in terms of the modified ACRpedi30 (P > .05). The SUCRA shows that canakinumab ranked first (SUCRA, 86.9%), anakinra ranked second (SUCRA, 77.7%), adalimumab ranked third (SUCRA, 61.9%), and placebo ranked the last (SUCRA, 6.3%). Nevertheless, there were no notable discrepancies in the occurrence of adverse events, hepatic-related adverse events, infectious adverse event, serious adverse events, and serious infection following treatment with canakinumab, anakinra, tocilizumab, rilonacept, or the placebo. Based on the clustergram of modified ACRpedi30 and adverse events, canakinumab is suggested for JIA according to the surface under SUCRAs considering the symptom and adverse events simultaneously. CONCLUSIONS: Among patients with JIA, canakinumab exhibited the highest likelihood of being the optimal treatment for achieving the modified ACRpedi30 response rate, and neither of the tested biological agents carried a significant risk of serious adverse events.

Vitiligo in a Patient Receiving Adalimumab for Idiopathic Uveitis.

In recent years, adalimumab has been increasingly used in the chronic treatment of non-infectious uveitis. This case report aimed to describe a drug-induced adverse event in a 34-year-old man who presented with blurred vision and floaters in the right eye and was being treated for intermediate uveitis. The patient had started topical treatment with a diagnosis of uveitis at another center. Best corrected visual acuity at presentation was 0.8 (decimal) in the right eye and 1.0 in the left eye. On examination, the anterior chamber in the right eye was clear, with anterior vitreous cells and mild haze, and snow banking and vitreous opacities in the inferior periphery. Fluorescein angiography (FA) showed hyperfluorescence in the right disc and leakage in the inferior periphery. As the inflammation did not resolve with local treatment, systemic cyclosporine was administered, after which the patient exhibited vomiting and weakness. Cyclosporine was discontinued and adalimumab treatment was started. On examination 5 months later, bilateral vitreous cells and mild vitreous opacity were noted, and FA showed mild leakage in the inferior periphery bilaterally. In addition, a depigmented patchy vitiligo lesion was observed on the chin. Due to the persistence of intraocular inflammation and on the recommendation of the dermatology clinic, adalimumab treatment was continued and topical tacrolimus was started for the lesion. On examination 3 months later, the inflammatory findings had resolved and there was no progression of the vitiligo lesion. The patient's treatment was continued. Taken together with the previous literature findings, no pathology was found in the patient's systemic examination, suggesting that this lesion was a side effect of the treatment. Ophthalmologists should be alert for this side effect in patients receiving adalimumab.

Effectiveness and safety of biological and target synthetic drugs treatment for psoriatic arthritis: a systematic review with network meta-analysis.

BACKGROUND: Psoriatic arthritis (PA) is a chronic inflammatory systemic arthritis that can result in loss of functional capacity and joint deformation. This systematic review assessed the effectiveness and safety of biological and target synthetic drugs for treating PA. METHODS: We searched for randomized clinical trials (RCTs) that evaluated the use of Adalimumab, Etanercept, Infliximab, Golimumab, Secukinumab, Certolizumab Pegol and Tofacitinib in the main general databases and clinical trial registers databases. The primary outcomes were ACR 50, PsARC, and serious adverse events. Two independent reviewers performed study selection and data extraction. Network meta-analyses were conducted using a random effects model and frequentist approach. The CINeMA software was used to assess the certainty of evidence. RESULTS: We included 33 RCTs (n = 11,034). The results from the network meta-analysis for the ACR 50 at 6-months follow-up showed that all drugs were superior to placebo, with Secukinumab (high certainty of evidence), Infliximab (very low certainty of evidence) and Adalimumab (high certainty of evidence) ranking the highest. Regarding the PsARC (at 6-months follow-up), all drugs, except for Golimumab (very low certainty of evidence), were superior to placebo, with Etanercept (low certainty of evidence), Infliximab (low certainty of evidence) and Certolizumab Pegol (low certainty of evidence) being the most effective drugs. There were no significant differences in the risk of serious adverse events between the drugs and placebo. Golimumab (very low certainty of evidence), Secukinumab (low certainty of evidence), and Adalimumab (very low certainty of evidence) ranked the highest for safety. CONCLUSIONS: In conclusion, based on the balance between efficacy and safety, Secukinumab and Adalimumab may be the preferred options among the evaluated drugs for treating patients with PsA. However, caution is necessary when interpreting the safety findings, as they are supported by evidence of low to very low certainty. Consequently, the balance between benefits and potential risks may change as new safety evaluation studies become available. PROTOCOL REGISTRATION: PROSPERO: CRD42022315577.

Risk of serious infection associated with different classes of targeted therapies used in psoriatic arthritis: a nationwide cohort study from the French Health Insurance Database (SNDS).

OBJECTIVE: To assess the risk of serious infection associated with different targeted therapies for psoriatic arthritis (PsA) in real-world settings. METHODS: This nationwide cohort study used the administrative healthcare database of the French health insurance scheme linked to the hospital discharge database to identify all adults with PsA who were new users of targeted therapies (adalimumab, etanercept, golimumab, certolizumab pegol, infliximab, secukinumab, ixekizumab, ustekinumab, and tofacitinib) from 1 January 2015 to 30 June 2021. The primary outcome was a serious infection (ie, requiring hospitalisation), in a time-to-event analysis using propensity score-weighted Cox models, with adalimumab as the comparator, estimating weighted HRs (wHRs) and their 95% CIs. RESULTS: A total of 12 071 patients were included (mean age 48.7±12.7 years; 6965 (57.7%) women). We identified 367 serious infections (3.0% of patients), with a crude incidence rate of 17.0 per 1000 person-years (95% CI, 15.2 to 18.7). After inverse propensity score weighting and adjustment for time-dependent covariates and calendar year, risk of serious infection was significantly lower for new users of etanercept (wHR 0.72; 95% CI, 0.53 to 0.97) or ustekinumab (wHR, 0.57; 95% CI, 0.35 to 0.93) than adalimumab new users. This risk was not statistically modified with the other targeted therapies. CONCLUSIONS: The incidence of serious infection was low for PsA patients who were new users of targeted therapies in real-world settings. Relative to adalimumab new users, this risk was lower among new users of etanercept and ustekinumab and unmodified for the other molecules.

Persistence and safety of anti-TNF biosimilars versus originators in immune-mediated inflammatory diseases: an observational study on the French National Health Data System.

OBJECTIVES: Biosimilar-originator equivalence has been demonstrated in phase 3 trials in a few indications of infliximab, etanercept and adalimumab. The objective of our study was to compare the persistence and safety of biosimilars versus originators in all the licensed indications of these molecules. METHODS: We used data from the French National Health Data System (SNDS), covering 99% of the French population, to identify infliximab, etanercept and adalimumab initiators from biosimilar launch (January 2015, May 2016 and October 2018, respectively) to 30 June 2021. Patients were then followed for 1 year. Treatment persistence (duration without treatment discontinuation or modification) and safety (including severe infections, all-cause hospitalisation and death) were compared between originator and biosimilar users by Cox regressions weighting the populations on the inverse probability of treatment. Analyses were performed by molecule, by disease and by biosimilar product. RESULTS: From January 2015 to June 2021, 86 776 patients were included in the study: 22 670, 24 442 and 39 664 patients had initiated infliximab, etanercept and adalimumab, respectively; 49 752 (53%) were biosimilar initiators. We did not find any risk of discontinuation (HRs were below or around 1, here all pathologies and products together: infliximab 0.88 (0.80-0.97), etanercept 0.85 (0.81-0.90) and adalimumab 0.96 (0.91-1.00)) or safety event (infection: infliximab 0.97 (0.78-1.21), etanercept 1.04 (0.81-1.33) and adalimumab 0.98 (0.83-1.16); hospitalisation: infliximab 1.08 (0.96-1.23), etanercept 0.99 (0.87-1.11) and adalimumab 0.91 (0.83-0.99)) associated with biosimilar versus originator use. CONCLUSIONS: Our study shows reassuring results regarding the persistence and safety of biosimilar tumour necrosis factor-alpha inhibitors compared with originators in all licensed indications.

Effectiveness and safety of adalimumab compared with leflunomide in patients with Takayasu arteritis: a retrospective cohort study.

OBJECTIVE: This study aims to evaluate the effectiveness and safety of adalimumab (ADA) compared with leflunomide (LEF) in patients with Takayasu arteritis (TAK). METHOD: A retrospective cohort study was performed with the following inclusion criteria: the fulfilment of the 2022 American College Classification/European Alliance of Associations for Rheumatology criteria for TAK, age ≥18 years, and written informed consent. Forty-four patients were treated with LEF (n=28) or ADA (n=16) therapy due to relapsing/refractory disease or toxicity from previous therapy. Patients were evaluated at baseline (T0), at a median of 7.0 months (T1) and at 15.0 months of follow-up (T2). Data regarding disease activity, daily dose of prednisone, side effects and angiographic progression were analysed. RESULTS: LEF and ADA groups had similar features on the baseline visit. However, intravenous methylprednisolone was more frequently prescribed for the ADA group (p=0.019). On T1 and T2 visits, complete response rates were similar for ADA and LEF groups (75.0% and 88.5%; p=0.397 and 62.5% vs 78.3%; p=0.307), respectively. The differences remained non-significant after adjusting for baseline variables by propensity score matching. Although the ADA group had a higher median daily prednisone on visit T1 (p=0.004), it was similar on visit T2 (p=0.595). Similar rates of angiographic progression were observed in ADA and LEF groups (40% vs 25%; p=0.467). Mild-to-moderate adverse events were observed only in the LEF group (17.9%). CONCLUSION: LEF and ADA had comparable outcomes after a median of 15.0 months of follow-up. However, withdrawal from therapy and mild-to-moderate adverse events were only observed in the LEF group.

Selection strategy of second-line biologic therapies in adult patients with ulcerative colitis following prior biologic treatment failure: Systematic review and meta-analysis.

BACKGROUND: Optimizing second-line biologic therapies for adult ulcerative colitis (UC) post first-line failure is essential. OBJECTIVE: Compare second-line biologic therapy efficacy in adult UC patients with prior treatment failure. METHODS: A comprehensive search of electronic databases up to May 2023 was conducted to assess second-line biologic therapy efficacy using a random effects model. Parameters analyzed included clinical remission rate, clinical response rate, mucosal healing rate, annual discontinuation rate, and colectomy rates. RESULTS: Forty-three research papers were analyzed. Clinical remission rates for second-line biologics were ranked at 6-14 weeks: Infliximab (30%) was followed by Vedolizumab (29%), Ustekinumab (27%), and Adalimumab (19%). At 52-54 weeks, the order shifted, with Vedolizumab (35%) followed by Infliximab (32%), Ustekinumab (31%), and Adalimumab (26%). The mucosal healing rate was 21%, ranked as: Infliximab (31%), Vedolizumab (21%), Adalimumab (21%), and Ustekinumab (14%). The annual discontinuation rate stood at 20%, with Adalimumab (25%), Vedolizumab (18%), Infliximab (17%), and Ustekinumab (16%). Discontinuation rates due to primary failure (PF), secondary failure (SF), and adverse events (AE) were 6%, 12%, and 3%, respectively. The annual colectomy rate was 9%, with Adalimumab (15%) followed by Vedolizumab (10%), Ustekinumab (9%), and Infliximab (5%), and colectomy rates of 10% due to PF, 12% due to SF, and 4% due to AE. CONCLUSION: For UC patients with first-line treatment failure, it is recommended to prioritize infliximab or vedolizumab as second-line biologic therapies, while avoiding adalimumab as the primary choice. Further clinical trials are necessary to assess ustekinumab efficacy accurately.

Clinical use of biologics for Crohn's disease in adults: lessons learned from real-world studies.

INTRODUCTION: The therapeutic armamentarium for managing Crohn's disease (CD) has expanded significantly in recent decades. Several biologics with three different mechanisms of action [anti-tumor necrosis factor (TNF)-α, anti-integrin α4ß7, and anti-IL 12/23] are currently available to manage CD. AREA COVERED: This narrative review aims to summarize the most significant efficacy and safety data on the use of infliximab (IFX), adalimumab (ADA), vedolizumab (VDZ) and ustekinumab (UST) for the treatment of CD obtained from studies conducted in the real world (RW), compared to the results of randomized clinical trials (RCTs). EXPERT OPINION: RW studies reported that biologic agents included in this analysis have higher remission rates and lower adverse event rates than findings from RCTs for treating patients with CD. All biological agents have proven effective and safe in RW studies, even when using biosimilars or switching to subcutaneous administration of the molecules for which they are available. Finally, anti-TNF-α agents, particularly IFX, have a higher rate of adverse events (AEs) than VDZ and UST. Therefore, patients at higher risk of AEs may benefit from other biologics than anti-TNF-α. However, further long-term RW studies are needed to confirm these findings.

Adalimumab exhibits superiority over etanercept in terms of a numerically higher response rate and equivalent adverse events: A real-world finding.

INTRODUCTION: Adalimumab (ADA) and etanercept (ETN) are the most commonly applied biologics for rheumatoid arthritis (RA) management in China; however, the evidence regarding their superiority is controversial. In addition, in real-world clinical settings, many factors may affect the application of these agents, such as dosage and administration period. Therefore, the present real-world study aimed to compare the efficacy and safety of ADA and ETN treatment in RA patients via the propensity score matching method. METHODS: In total, 105 RA patients receiving ADA (n = 66) or ETN (n = 39) were reviewed in this retrospective study. The propensity score matching method was used to eliminate discrepancies in baseline features. Clinical response, low disease activity (LDA), and remission were evaluated based on the DAS28. RESULTS: Before propensity score matching, compared with ETN, ADA yielded higher rates of clinical response at W24 (97.0% vs. 84.6%, p = .021), LDA at W12 (78.8% vs. 51.3%, p = .003), and remission at W24 (75.8% vs. 46.2%, p = .002). After propensity score matching, compared with ETN, ADA only achieved a higher rate of clinical response at W24 (96.3% vs. 77.8%, p = .043), whereas the rates of LDA and remission were not different between ADA and ETN treatments at any time point (all p > .05). In addition, the incidence of adverse events was not significantly different between the ADA and ETN treatments (all p > .05). CONCLUSION: ADA shows superiority over ETN in terms of a numerically greater response rate and equivalent adverse events.

A Systematic Review Evaluating the Efficacy, Immunogenicity and Safety of the Biosimilar FKB327 in Treating Rheumatoid Arthritis.

Biosimilars are known to be pharmaceutical products which are very similar to a biologic drug. FKB327 is one such biosimilar of the drug Adalimumab which is prescribed in treating autoimmune diseases like Rheumatoid Arthritis. The aim of this review is to evaluate the efficacy, immunogenicity and safety of the drug FKB327 in treating patients with mild to moderate Rheumatoid Arthritis and compare the same with that of the drug Adalimumab. Two databases (PubMed and Cochrane Library) were used to screen relevant publications using pre-determined inclusion and exclusion criteria. Of the 12 studies found to be relevant, 3 were found to be eligible for the review. The data were extracted for the study characteristics, outcome measures, complications, and safety. The quality of the papers was assessed through Jadad scoring. Three (3) papers were reviewed in the study although there were limitations in reviewing efficacy as one of the papers lacked required data for efficacy. Efficacy was observed through ACR20 response and DAS28 score in the 24th week of all the three studies and immunogenicity was reviewed through the presence of Anti-drug antibody in patients after administration of both the drugs in same dosage. Safety was assessed through the development of complications after the administration of the drugs. The review concludes that there are similarities in efficacy, immunogenicity and safety between FKB327 but could not adequately prove the superiority of FKB327 over Adalimumab.

Prospective study to characterize adalimumab exposure in pediatric patients with rheumatic diseases.

BACKGROUND: In pediatric rheumatic diseases (PRD), adalimumab is dosed using fixed weight-based bands irrespective of methotrexate co-treatment, disease activity (DA) or other factors that might influence adalimumab pharmacokinetics (PK). In rheumatoid arthritis (RA) adalimumab exposure between 2-8 mg/L is associated with clinical response. PRD data on adalimumab is scarce. Therefore, this study aimed to analyze adalimumab PK and its variability in PRD treated with/without methotrexate. METHODS: A two-center prospective study in PRD patients aged 2-18 years treated with adalimumab and methotrexate (GA-M) or adalimumab alone (GA) for ≥ 12 weeks was performed. Adalimumab concentrations were collected 1-9 (maximum concentration; Cmax), and 10-14 days (minimum concentration; Cmin) during ≥ 12 weeks following adalimumab start. Concentrations were analyzed with enzyme-linked immunosorbent assay (lower limit of quantification: 0.5 mg/L). Log-normalized Cmin were compared between GA-M and GA using a standard t-test. RESULTS: Twenty-eight patients (14 per group), diagnosed with juvenile idiopathic arthritis (71.4%), non-infectious uveitis (25%) or chronic recurrent multifocal osteomyelitis (3.6%) completed the study. GA-M included more females (71.4%; GA 35.7%, p = 0.13). At first study visit, children in GA-M had a slightly longer exposure to adalimumab (17.8 months [IQR 9.6, 21.6]) compared to GA (15.8 months [IQR 8.5, 30.8], p = 0.8). Adalimumab dosing was similar between both groups (median dose 40 mg every 14 days) and observed DA was low. Children in GA-M had a 27% higher median overall exposure compared to GA, although median Cmin adalimumab values were statistically not different (p = 0.3). Cmin values ≥ 8 mg/L (upper limit RA) were more frequently observed in GA-M versus GA (79% versus 64%). Overall, a wide range of Cmin values was observed in PRD (0.5 to 26 mg/L). CONCLUSION: This study revealed a high heterogeneity in adalimumab exposure in PRD. Adalimumab exposure tended to be higher with methotrexate co-treatment compared to adalimumab monotherapy although differences were not statistically significant. Most children showed adalimumab exposure exceeding those reported for RA with clinical response, particularly with methotrexate co-treatment. This highlights the need of further investigations to establish model-based personalized treatment strategies in PRD to avoid under- and overexposure. TRIAL REGISTRATION: NCT04042792 , registered 02.08.2019.

Adalimumab induced exacerbation of psoriasis in patients with combined pemphigus: A case report.

RATIONALE: Psoriasis is an immune-related disease caused by genetic factors, abnormalities in the immune system and environmental factors, while pemphigus is an autoimmune disease caused by the autoimmune system attacking the skin and mucosal tissues. Herein, we aimed to report a rare case of adalimumab induced exacerbation of psoriasis patients with pemphigus. The rare disease causes considerable challenges for clinical diagnosis and treatment. PATIENT CONCERNS: The patient was a 43-year-old man with intermittent erythema and scaling all over the body for more than 20 years, and blisters and vesicles on the trunk and limbs for 1 month. Half a year ago, the patient had blisters on the limbs, and was diagnosed with deciduous pemphigus in a hospital, and the blisters subsided after being given traditional Chinese medicine orally. Half a month ago, the erythema area was enlarged, and adalimumab 80 mg intramuscular injection was given for 1 time after consultation in the hospital. On the following day, the area of erythema and scales was suddenly enlarged obviously compared with the previous 1, and obvious blisters and vesicles appeared on the limbs, neck, and trunk, which were aggravated progressively and accompanied by obvious itching and pain. DIAGNOSES: The patient was diagnosed with psoriasis in patients with combined pemphigus. INTERVENTION: After combined treatment with methylprednisolone and cyclosporine, the skin lesions have basically recovered. OUTCOMES: The skin lesions have basically healed. Follow up for 6 months without recurrence. LESSONS: Methylprednisolone combined with cyclosporine may be an option in treating patients with psoriasis patients with pemphigus.

Efficacy of adalimumab combined with Tripterygium wilfordii Hook F in the treatment of patient with rheumatoid arthritis: A multicenter, open-label, randomized-controlled trial.

OBJECTIVES: To evaluate the efficacy and safety of adalimumab (ADA) combined with Tripterygium wilfordii Hook F (TwHF) in the treatment of methotrexate (MTX)-inadequate response patients with rheumatoid arthritis (RA). METHODS: In this multicenter, open-label, randomized controlled clinical trial, 64 RA patients with inadequate response to MTX were 1:1 randomly assigned into treatment or control groups. The treatment group was treated with ADA in combination with TwHF, and the control group was treated with ADA in combination with MTX for 24 weeks. The primary endpoint was the percentage of patients having low disease activity (2.6 ≤ DAS28-ESR < 3.2) and remission rates (DAS28-ESR < 2.6) at week 24. RESULTS: In total, 53 of the 64 patients (82.8%) completed this 24-week clinical trial. By intent-to-treat (ITT) analysis, a comparable outcome was observed between the two groups. The percentage of patients achieving low disease activity in the treatment group and control group were 43.8% and 46.9% (95% CI, 21.28 to 27.48, p = .802). Percentage of patients achieving low disease activity rates were respectively 28.1% and 31.3% in the treatment group and control group (95% CI, 19.18 to 25.58, p = .784). In per-protocol (PP) analysis, the results were consistent with the ITT model. The incidence of adverse events was comparable between the two groups. CONCLUSIONS: There were no significant differences in efficacy and safety between ADA combined with TwHF versus ADA combined with MTX in the treatment of RA. TwHF might be an alternative treatment for RA patients who are intolerant to MTX.

Tumor necrosis factor-α inhibitor for successful treatment of toxic epidermal necrolysis with severe infection: a case series.

Toxic epidermal necrolysis (TEN) is a rare severe cutaneous adverse reaction that involves more than 30% of the body surface area. TEN can be accompanied by a series of systemic symptoms and has a high risk of death. Tumor necrosis factor (TNF)-α inhibitors such as adalimumab and etanercept have been shown to be safe and effective for the treatment of TEN in some cases. However, clinical data on the use of TNF-α inhibitors to treat TEN with severe systemic infection are scarce. In the present study, three adult patients who developed TEN with serious active infection were successfully treated with etanercept. One of the three patients had active open pulmonary tuberculosis, and the other two had septicemia and/or fungal sepsis. All patients' skin lesions significantly improved after several days, and none of the patients developed emerging or re-emerging infectious diseases, adverse reactions, or a similar rash during follow-up. TNF-α inhibitors may be an effective treatment choice for TEN with severe systemic infection. However, further studies with large samples are still required for validation because clinical experience is limited.