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.

Absolute monocyte counts could predict disease activity and secondary loss of response of patients with Crohn's disease treated with anti-TNF-α drug.

BACKGROUND: Assessing Crohn's disease (CD) activity is critical for monitoring disease progression. In CD, monocytes could release TNF-α. Thus, it is extremely important to study its role in the disease activity and loss of response to anti-TNF-α biologics. METHODS: In this study, we collected CD patients treated with biologics from January 2017 to May 2022. Indicators associated with disease activity were evaluated by Spearman correlation analysis and Mann-Whitney U test. Specifically, logistic analyses were used to explore the predictors of primary nonresponse (PNR) and secondary loss of response (SLOR) within 1 year of anti-TNF-α agents. In addition, a nomogram was developed for therapeutic effect prediction. RESULTS: 283 patients with CD were identified. Disease activity group, defined as CDAI equal to or greater than 150, had significant elevated absolute monocyte counts than disease remission group based on CDAI score (p = 0.019, Z = -2.354). Logistic analyses showed that absolute monocyte counts could be an independent predictor of 1-year SLOR of anti-TNF-α agents in CD patients (p = 0.013). A nomogram established based on gender, absolute monocyte counts, and hemoglobin could predict SLOR within 1 year of anti-TNF-α agents reliably. CONCLUSION: The results of this study support the utility of absolute monocyte counts detecting disease activity and anti-TNF-α therapy effect in patients with CD.

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.

Molecular Profiling of Axial Spondyloarthritis Patients Reveals an Association between Innate and Adaptive Cell Populations and Therapeutic Response to Tumor Necrosis Factor Inhibitors.

This study aims at identifying molecular biomarkers differentiating responders and non-responders to treatment with Tumor Necrosis Factor inhibitors (TNFi) among patients with axial spondyloarthritis (axSpA). Whole blood mRNA and plasma proteins were measured in a cohort of biologic-naïve axSpA patients (n = 35), pre and post (14 weeks) TNFi treatment with adalimumab. Differential expression analysis was used to identify the most enriched pathways and in predictive models to distinguish responses to TNFi. A treatment-associated signature suggests a reduction in inflammatory activity. We found transcripts and proteins robustly differentially expressed between baseline and week 14 in responders. C-reactive protein (CRP) and Haptoglobin (HP) proteins showed strong and early decrease in the plasma of axSpA patients, while a cluster of apolipoproteins (APOD, APOA2, APOA1) showed increased expression at week 14. Responders to TNFi treatment present higher levels of markers of innate immunity at baseline, and lower levels of adaptive immunity markers, particularly B-cells. A logistic regression model incorporating ASDAS-CRP, gender, and AFF3, the top differentially expressed gene at baseline, enabled an accurate prediction of response to adalimumab in our cohort (AUC = 0.97). In conclusion, innate and adaptive immune cell type composition at baseline may be a major contributor to response to adalimumab in axSpA patients. A model including clinical and gene expression variables should also be considered.

Anti-tumor necrosis factor (aTNF) weaning strategy in juvenile idiopathic arthritis (JIA): does duration matter?

BACKGROUND: To compare outcomes of a short and long weaning strategy of anti-tumor necrosis factor (aTNF) in our prospective juvenile idiopathic arthritis (JIA) cohort. RESEARCH DESIGN AND METHODS: JIA patients on subcutaneous adalimumab with at least 6 months of follow-up were recruited (May 2010-Jan 2022). Once clinical remission on medication (CRM) was achieved, adalimumab was weaned according to two protocols-short (every 4-weekly for 6 months and stopped) and long (extending dosing interval by 2 weeks for three cycles until 12-weekly intervals and thereafter stopped) protocols. Outcomes assessed were flare rates, time to flare, and predictors. RESULTS: Of 110 JIA patients, 77 (83% male, 78% Chinese; 82% enthesitis-related arthritis) underwent aTNF weaning with 53% on short and 47% on long weaning protocol. The total flare rate during and after stopping aTNF was not different between the two groups. The time to flare after stopping aTNF was not different (p = 0.639). Positive anti-nuclear antibody increased flare risk during weaning in long weaning group (OR 7.0, 95%CI: 1.2-40.8). Positive HLA-B27 (OR 6.5, 95%CI: 1.1-30.4) increased flare risks after stopping aTNF. CONCLUSION: Duration of weaning aTNF may not minimize flare rate or delay time to flare after stopping treatment in JIA patients. Recapture rates for inactive disease at 6 months remained high for patients who flared after weaning or discontinuing medication.

Impact of filgotinib on pain control in the phase 3 FINCH studies.

OBJECTIVE: This post hoc analysis of the FINCH 1-3 (NCT02889796, NCT02873936 and NCT02886728) studies assessed specific effects of filgotinib on pain control and their relationship with other aspects of efficacy in patients with rheumatoid arthritis (RA). METHODS: Assessments included: residual pain responses of ≤10 and ≤20 mm on a 100 mm visual analogue scale (VAS); the proportion of patients who achieved VAS pain responses in addition to remission or low disease activity by Disease Activity Score-28 with C-reactive protein (DAS28-CRP) or Clinical Disease Activity Index (CDAI) criteria. RESULTS: Across studies, filgotinib reduced pain from week 2, with responses sustained throughout the studies. In FINCH 1, at week 24, 35.8%, 25.0%, 24.6% and 11.6% of patients in the filgotinib 200 mg, filgotinib 100 mg, adalimumab and placebo arms (each plus methotrexate) achieved VAS pain ≤20 mm in addition to DAS28-CRP remission; 26.3%, 17.9%, 17.2% and 7.6% achieved VAS pain ≤10 mm in addition to DAS28-CRP remission. A similar pattern was seen for CDAI remission. Time during which VAS pain was ≤10 or ≤20 mm was longest with filgotinib 200 mg and comparable between adalimumab and filgotinib 100 mg. Similar findings were reported for filgotinib in FINCH 2 and 3. CONCLUSION: In all RA populations studied, pain improvements occurred from week 2 and were sustained over time. In FINCH 1, filgotinib 100 mg provided similar pain amelioration to adalimumab, whereas filgotinib 200 mg resulted in greater pain improvement and higher proportion of patients with residual pain ≤10 or ≤20 mm and meeting DAS28-CRP remission criteria.

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.

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.

Implications of Immunogenicity Testing for Therapeutic Monoclonal Antibodies: A Quantitative Pharmacology Framework.

The interpretation of immunogenicity results for a mAb product and prediction of its clinical consequences remain difficult, despite enormous advances in methodologies and efforts toward the best practice for consistent data generation and reporting. To this end, the contribution from the clinical pharmacology discipline has been largely limited to comparing descriptively the pharmacokinetic (PK) profiles by antidrug antibodies (ADA) status or testing the significance of ADA as a covariate in a population PK setting, similar to the practice for small-molecule drugs in investigating the effect of an intrinsic/extrinsic factor on the drug disposition. There is a need for a mAb disposition framework that captures the dynamics of ADA formation and drug's interactions with the ADA and target as parts of the drug distribution and elimination. Here we describe such a framework and examine it against the PK, ADA, and clinical response data from a phase 3 trial in patients treated with adalimumab. The proposed framework offered a generalized understanding of how the dose, target affinity, and drug/ADA analyte forms affects the manifestation of ADA response with regard to its detections and alterations of drug disposition and effectiveness. Furthermore, as an example, its utility for dose considerations was demonstrated through predicting for late-stage trials of a PCSK9 inhibitor in terms of development in ADA incidence and titers, and consequences on the drug disposition, interaction with target, and downstream lowering effect on LDL-C.

Comparison between super-responders and non-super-responders in psoriasis under adalimumab treatment: a real-life cohort study on the effectiveness and drug survival over one-year.

BACKGROUND: Data on the characteristics and treatment outcomes of super-responders and non-super-responders in psoriasis under adalimumab treatment are limited. METHODS: A retrospective analysis from psoriatic patients treated with adalimumab was compared to characterize super-responders vs non-super-responders' groups, identify factors associated with super response, and assess treatment outcomes after switching. RESULTS: 15 out of 70 (21.4%) patients were categorized as super-responder. The proportion of patients achieving a PASI 100 response was significantly higher in super-responders than non-super-responders at weeks 12, 24, and 52. Female sex and Charlson Co-morbidity Index were significantly associated with super-responders. A high level of high-density lipoprotein was independently associated with PASI 90 response at weeks 24 and 52. Additionally, nearly 35%-43% of non-super-responders switching to interleukin-17A (IL-17A) inhibitors may achieve a PASI 100 response at week 12. In contrast, all super-responders switching to IL-17A inhibitors achieved a PASI 100 response at week 4. CONCLUSIONS: Super-responders treated with adalimumab have a higher rate of being female and fewer comorbidities. And super-responders have better PASI responses than non-super-responders, whether the patients were treated with adalimumab or switched to IL-17A inhibitors.

Poor prognostic factors of pharmacokinetic origin predict outcomes in inflammatory bowel disease patients treated with anti-tumor necrosis factor-α.

Introduction: We evaluated baseline Clearance of anti-tumor necrosis factors and human leukocyte antigen variant (HLA DQA1*05) in combination as poor prognostic factors (PPF) of pharmacokinetic (PK) origin impacting immune response (formation of antidrug antibodies) and disease control of inflammatory bowel disease (IBD) patients treated with infliximab or adalimumab. Methods: Baseline Clearance was estimated in IBD patients before starting treatment using weight and serum albumin concentrations. HLA DQA1*05 carrier status (rs2097432 A/G or G/G variant) was measured using real time polymerase chain reaction. The outcomes consisted of immune response, clinical and biochemical remission (C-reactive protein<3 mg/L in the absence of symptoms), and endoscopic remission (SES-CD<3). Statistical analysis consisted of logistic regression and nonlinear mixed effect models. Results and discussion: In 415 patients enrolled from 4 different cohorts (median age 27 [IQR: 15-43] years, 46% females), Clearance>0.326 L/day and HLA DQA1*05 carrier status were 2-fold more likely to have antidrug antibodies (OR=2.3, 95%CI: 1.7-3.4; p<0.001, and OR=1.9, 95%CI: 1.4-2.8; p<0.001, respectively). Overall, each incremental PPF of PK origin resulted in a 2-fold (OR=2.16, 95%CI: 1.7-2.7; p<0.11) [corrected] higher likelihood of antidrug antibody formation. The presence of both PPF of PK origin resulted in higher rates of antidrug antibodies (p<0.01) and lower clinical and biochemical remission (p<0.01). Each incremental increase in PPF of PK origin associated with lower likelihood of endoscopic remission (OR=0.4, 95%CI: 0.2-0.7; p<0.001). Prior biologic experience heightened the negative impact of PPF of PK origin on clinical and biochemical remission (p<0.01). Implementation of proactive therapeutic drug monitoring reduced it, particularly during maintenance and in the presence of higher drug concentrations (p<0.001). We conclude that PPF of PK origin, including both higher Clearance and carriage of HLA DQA1*05, impact outcomes in patients with IBD.

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.

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.

Patient self-reported experience and satisfaction with golimumab and etanercept treatments for rheumatic diseases: A cohort study.

Golimumab and etanercept both exhibit good efficacy in treating rheumatic diseases, while the patient self-reported measurement of treatment improvement and injection experience lacks sufficient evidence. Hence, this study aimed to compare the satisfaction with disease improvement and injection experience and the level of injection site reactions (ISRs) between golimumab-treated and etanercept-treated patients with rheumatic diseases. A total of 312 patients with rheumatic diseases were serially enrolled. Among them, 158 patients received golimumab (golimumab group); the other 154 patients were treated with etanercept (etanercept group) according to the actual disease status, physician advice, and patient willingness. Satisfaction with disease improvement was assessed using the 7-point Likert scale; satisfaction with injection experience and level of ISRs were both determined by the 5-point Likert scale. Satisfaction degrees with global injection experience (P = .025), injection device (P = .008), injection frequency (P = .010), and injection convenience (P = .003) were superior in the golimumab group to the etanercept group, while satisfaction degrees with global disease improvement, symptom relief, and speed of action did not vary (all P > .050) between the 2 groups. Discomfort (P = .005), swelling (P < .001), pain (P = .028), and burning (P = .035) levels were lower in the golimumab group than in the etanercept group. In addition, among 56 patients with a history of tumor necrosis factor inhibitor treatment before golimumab, 40 (71.4%) patients preferred golimumab to other tumor necrosis factor inhibitor. After switching to golimumab treatment, the level of ISRs in most patients was reduced or comparable. Golimumab achieves a satisfying injection experience and relieves the level of ISRs over etanercept in patients with rheumatic diseases.

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.