Response to Biologic Drugs in Patients with Rheumatoid Arthritis and Antidrug Antibodies

Importance: There are conflicting data on the association of antidrug antibodies with response to biologic disease-modifying antirheumatic drugs (bDMARDs) in rheumatoid arthritis (RA). Objective: To analyze the association of antidrug antibodies with response to treatment for RA. Design, Setting, and Participants: This cohort study analyzed data from the ABI-RA (Anti-Biopharmaceutical Immunization: Prediction and Analysis of Clinical Relevance to Minimize the Risk of Immunization in Rheumatoid Arthritis Patients) multicentric, open, prospective study of patients with RA from 27 recruiting centers in 4 European countries (France, Italy, the Netherlands, and the UK). Eligible patients were 18 years or older, had RA diagnosis, and were initiating a new bDMARD. Recruitment spanned from March 3, 2014, to June 21, 2016. The study was completed in June 2018, and data were analyzed in June 2022. Exposures: Patients were treated with a new bDMARD: adalimumab, infliximab (grouped as anti-tumor necrosis factor [TNF] monoclonal antibodies [mAbs]), etanercept, tocilizumab, and rituximab according to the choice of the treating physician. Main Outcomes and Measures: The primary outcome was the association of antidrug antibody positivity with EULAR (European Alliance of Associations for Rheumatology; formerly, European League Against Rheumatism) response to treatment at month 12 assessed through univariate logistic regression. The secondary end points were the EULAR response at month 6 and at visits from month 6 to months 15 to 18 using generalized estimating equation models. Detection of antidrug antibody serum levels was performed at months 1, 3, 6, 12, and 15 to 18 using electrochemiluminescence (Meso Scale Discovery) and drug concentration for anti-TNF mAbs, and etanercept in the serum was measured using enzyme-linked immunosorbent assay. Results: Of the 254 patients recruited, 230 (mean [SD] age, 54.3 [13.7] years; 177 females [77.0%]) were analyzed. At month 12, antidrug antibody positivity was 38.2% in patients who were treated with anti-TNF mAbs, 6.1% with etanercept, 50.0% with rituximab, and 20.0% with tocilizumab. There was an inverse association between antidrug antibody positivity (odds ratio [OR], 0.19; 95% CI, 0.09-0.38; P <.001) directed against all biologic drugs and EULAR response at month 12. Analyzing all the visits starting at month 6 using generalized estimating equation models confirmed the inverse association between antidrug antibody positivity and EULAR response (OR, 0.35; 95% CI, 0.18-0.65; P <.001). A similar association was found for tocilizumab alone (OR, 0.18; 95% CI, 0.04-0.83; P =.03). In the multivariable analysis, antidrug antibodies, body mass index, and rheumatoid factor were independently inversely associated with response to treatment. There was a significantly higher drug concentration of anti-TNF mAbs in patients with antidrug antibody-negative vs antidrug antibody-positive status (mean difference, -9.6 [95% CI, -12.4 to -6.9] mg/L; P < 001). Drug concentrations of etanercept (mean difference, 0.70 [95% CI, 0.2-1.2] mg/L; P =.005) and adalimumab (mean difference, 1.8 [95% CI, 0.4-3.2] mg/L; P =.01) were lower in nonresponders vs responders. Methotrexate comedication at baseline was inversely associated with antidrug antibodies (OR, 0.50; 95% CI, 0.25-1.00; P =.05). Conclusions and Relevance: Results of this prospective cohort study suggest an association between antidrug antibodies and nonresponse to bDMARDs in patients with RA. Monitoring antidrug antibodies could be considered in the treatment of these patients, particularly nonresponders to biologic RA drugs

Impaired executive function in male MDMA ("ecsatsy") users.

Rationale: Long-term users of ecstasy have shown impaired performance on a multitude of cognitive abilities (most notably memory, attention, executive function). Research into the pattern of MDMA effects on executive functions remains fragmented, however. Objectives: To determine more systematically what aspects of executive function are affected by a history of MDMA use, by using a model that divides executive functions into cognitive flexibility, information updating and monitoring, and inhibition of pre-potent responses. Methods: MDMA users and controls who abstained from ecstasy and other substances for at least 2 weeks were tested with a computerized cognitive test battery to assess their abilities on tasks that measure the three submodalities of executive function, and their combined contribution on two more complex executive tasks. Because of sex-differential effects of MDMA reported in the literature, data from males and females were analyzed separately. Results: Male MDMA users performed significantly worse on the tasks that tap on cognitive flexibility and on the combined executive function tasks; no differences were found on the other cognitive tasks. Female users showed no impairments on any of the tasks. Conclusions: The present data suggest that a history of MDMA use selectively impairs executive function. In male users, cognitive flexibility was impaired and increased perseverative behavior was observed. The inability to adjust behavior rapidly and flexibly may have repercussions for daily life activities

Genome-Wide Association Study and Gene Expression Analysis Identifies CD84 as a Predictor of Response to Etanercept Therapy in Rheumatoid Arthritis

Anti-tumor necrosis factor alpha (anti-TNF) biologic therapy is a widely used treatment for rheumatoid arthritis (RA). It is unknown why some RA patients fail to respond adequately to anti-TNF therapy, which limits the development of clinical biomarkers to predict response or new drugs to target refractory cases. To understand the biological basis of response to anti-TNF therapy, we conducted a genome-wide association study (GWAS) meta-analysis of more than 2 million common variants in 2,706 RA patients from 13 different collections. Patients were treated with one of three anti-TNF medications: etanercept (n = 733), infliximab (n = 894), or adalimumab (n = 1,071). We identified a SNP (rs6427528) at the 1q23 locus that was associated with change in disease activity score (ΔDAS) in the etanercept subset of patients (P = 8×10-8), but not in the infliximab or adalimumab subsets (P>0.05). The SNP is predicted to disrupt transcription factor binding site motifs in the 3′ UTR of an immune-related gene, CD84, and the allele associated with better response to etanercept was associated with higher CD84 gene expression in peripheral blood mononuclear cells (P = 1×10-11 in 228 non-RA patients and P = 0.004 in 132 RA patients). Consistent with the genetic findings, higher CD84 gene expression correlated with lower cross-sectional DAS (P = 0.02, n = 210) and showed a non-significant trend for better ΔDAS in a subset of RA patients with gene expression data (n = 31, etanercept-treated). A small, multi-ethnic replication showed a non-significant trend towards an association among etanercept-treated RA patients of Portuguese ancestry (n = 139, P = 0.4), but no association among patients of Japanese ancestry (n = 151, P = 0.8). Our study demonstrates that an allele associated with response to etanercept therapy is also associated with CD84 gene expression, and further that CD84 expression correlates with disease activity. These findings support a model in which CD84 genotypes and/or expression may serve as a useful biomarker for response to etanercept treatment in RA patients of European ancestry. © 2013 Cui et al

Off-label use of rituximab for systemic lupus erythematosus in Europe

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Off-label use of rituximab for systemic lupus erythematosus in Europe

Objectives: Rituximab (RTX) is a biological treatment used off-label in patients with systemic lupus erythematosus (SLE). This survey aimed to investigate the off-label use of RTX in Europe and compare the characteristics of patients receiving RTX with those receiving conventional therapy. Methods: Data on patients with SLE receiving RTX were taken from the International Registry for Biologics in SLE retrospective registry and complemented with data on patients with SLE treated with conventional therapy. For nationwide estimates of RTX use in patients with SLE, investigators were asked to provide data through case report forms (CRFs). Countries for which no data were submitted through CRFs, published literature and/or personal communication were used, and for European countries where no data were available, estimates were made on the assumption of similarities with neighbouring countries. Results: The estimated off-label use of RTX in Europe was 0.5%-1.5% of all patients with SLE. In comparison with patients with SLE on conventional therapy, patients treated with RTX had longer disease duration, higher disease activity and were more often treated with immunosuppressives. The most frequent organ manifestations for which either RTX or conventional therapy was initiated were lupus nephritis followed by musculoskeletal and haematological. The reason for treatment was, besides disease control, corticosteroid-sparing for patients treated with conventional therapy. Conclusions: RTX use for SLE in Europe is restrictive and appears to be used as a last resort in patients for whom other reasonable options have been exhausted

Response to biologic drugs in patients with rheumatoid arthritis and antidrug antibodies

IMPORTANCE There are conflicting data on the association of antidrug antibodies with response tobiologic disease–modifying antirheumatic drugs (bDMARDs) in rheumatoid arthritis (RA).OBJECTIVE To analyze the association of antidrug antibodies with response to treatment for RA.DESIGN, SETTING, AND PARTICIPANTS This cohort study analyzed data from the ABI-RA (Anti-Biopharmaceutical Immunization: Prediction and Analysis of Clinical Relevance to Minimize the Riskof Immunization in Rheumatoid Arthritis Patients) multicentric, open, prospective study of patientswith RA from 27 recruiting centers in 4 European countries (France, Italy, the Netherlands, and theUK). Eligible patients were 18 years or older, had RA diagnosis, and were initiating a new bDMARD.Recruitment spanned from March 3, 2014, to June 21, 2016. The study was completed in June 2018,and data were analyzed in June 2022.EXPOSURES Patients were treated with a new bDMARD: adalimumab, infliximab (grouped as anti–tumor necrosis factor [TNF] monoclonal antibodies [mAbs]), etanercept, tocilizumab, and rituximabaccording to the choice of the treating physician.MAIN OUTCOMES AND MEASURES The primary outcome was the association of antidrug antibodypositivity with EULAR (European Alliance of Associations for Rheumatology; formerly, EuropeanLeague Against Rheumatism) response to treatment at month 12 assessed through univariate logisticregression. The secondary end points were the EULAR response at month 6 and at visits from month6 to months 15 to 18 using generalized estimating equation models. Detection of antidrug antibodyserum levels was performed at months 1, 3, 6, 12, and 15 to 18 using electrochemiluminescence (MesoScale Discovery) and drug concentration for anti-TNF mAbs, and etanercept in the serum wasmeasured using enzyme-linked immunosorbent assay.RESULTS Of the 254 patients recruited, 230 (mean [SD] age, 54.3 [13.7] years; 177 females [77.0%])were analyzed. At month 12, antidrug antibody positivity was 38.2% in patients who were treatedwith anti-TNF mAbs, 6.1% with etanercept, 50.0% with rituximab, and 20.0% with tocilizumab.There was an inverse association between antidrug antibody positivity (odds ratio [OR], 0.19; 95% CI,0.09-0.38; P all the visits starting at month 6 using generalized estimating equation models confirmed the inverseassociation between antidrug antibody positivity and EULAR response (OR, 0.35; 95% CI, 0.18-0.65;P P = .03). In the multivariable analysis, antidrug antibodies, body mass index, and rheumatoid factorwere independently inversely associated with response to treatment. There was a significantly higher drug concentration of anti-TNF mAbs in patients with antidrug antibody–negative vs antidrugantibody–positive status (mean difference, −9.6 [95% CI, −12.4 to −6.9] mg/L; P concentrations of etanercept (mean difference, 0.70 [95% CI, 0.2-1.2] mg/L; P = .005) andadalimumab (mean difference, 1.8 [95% CI, 0.4-3.2] mg/L; P = .01) were lower in nonresponders vsresponders. Methotrexate comedication at baseline was inversely associated with antidrugantibodies (OR, 0.50; 95% CI, 0.25-1.00; P = .05).CONCLUSIONS AND RELEVANCE Results of this prospective cohort study suggest an associationbetween antidrug antibodies and nonresponse to bDMARDs in patients with RA. Monitoring antidrugantibodies could be considered in the treatment of these patients, particularly nonresponders tobiologic RA drugs.Pathophysiology and treatment of rheumatic disease

EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update

Objectives: To provide an update of the European League Against Rheumatism (EULAR) rheumatoid arthritis (RA) management recommendations to account for the most recent developments in the field. Methods: An international task force considered new evidence supporting or contradicting previous recommendations and novel therapies and strategic insights based on two systematic literature searches on efficacy and safety of disease-modifying antirheumatic drugs (DMARDs) since the last update (2016) until 2019. A predefined voting process was applied, current levels of evidence and strengths of recommendation were assigned and participants ultimately voted independently on their level of agreement with each of the items. Results: The task force agreed on 5 overarching principles and 12 recommendations concerning use of conventional synthetic (cs) DMARDs (methotrexate (MTX), leflunomide, sulfasalazine); glucocorticoids (GCs); biological (b) DMARDs (tumour necrosis factor inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab), abatacept, rituximab, tocilizumab, sarilumab and biosimilar (bs) DMARDs) and targeted synthetic (ts) DMARDs (the Janus kinase (JAK) inhibitors tofacitinib, baricitinib, filgotinib, upadacitinib). Guidance on monotherapy, combination therapy, treatment strategies (treat-to-target) and tapering on sustained clinical remission is provided. Cost and sequencing of b/tsDMARDs are addressed. Initially, MTX plus GCs and upon insufficient response to this therapy within 3 to 6 months, stratification according to risk factors is recommended. With poor prognostic factors (presence of autoantibodies, high disease activity, early erosions or failure of two csDMARDs), any bDMARD or JAK inhibitor should be added to the csDMARD. If this fails, any other bDMARD (from another or the same class) or tsDMARD is recommended. On sustained remission, DMARDs may be tapered, but not be stopped. Levels of evidence and levels of agreement were mostly high. Conclusions: These updated EULAR recommendations provide consensus on the management of RA with respect to benefit, safety, preferences and cost

Clinicogenomic factors of biotherapy immunogenicity in autoimmune disease: A prospective multicohort study of the ABIRISK consortium

BACKGROUND: Biopharmaceutical products (BPs) are widely used to treat autoimmune diseases, but immunogenicity limits their efficacy for an important proportion of patients. Our knowledge of patient-related factors influencing the occurrence of antidrug antibodies (ADAs) is still limited. METHODS AND FINDINGS: The European consortium ABIRISK (Anti-Biopharmaceutical Immunization: prediction and analysis of clinical relevance to minimize the RISK) conducted a clinical and genomic multicohort prospective study of 560 patients with multiple sclerosis (MS, n = 147), rheumatoid arthritis (RA, n = 229), Crohn's disease (n = 148), or ulcerative colitis (n = 36) treated with 8 different biopharmaceuticals (etanercept, n = 84; infliximab, n = 101; adalimumab, n = 153; interferon [IFN]-beta-1a intramuscularly [IM], n = 38; IFN-beta-1a subcutaneously [SC], n = 68; IFN-beta-1b SC, n = 41; rituximab, n = 31; tocilizumab, n = 44) and followed during the first 12 months of therapy for time to ADA development. From the bioclinical data collected, we explored the relationships between patient-related factors and the occurrence of ADAs. Both baseline and time-dependent factors such as concomitant medications were analyzed using Cox proportional hazard regression models. Mean age and disease duration were 35.1 and 0.85 years, respectively, for MS; 54.2 and 3.17 years for RA; and 36.9 and 3.69 years for inflammatory bowel diseases (IBDs). In a multivariate Cox regression model including each of the clinical and genetic factors mentioned hereafter, among the clinical factors, immunosuppressants (adjusted hazard ratio [aHR] = 0.408 [95% confidence interval (CI) 0.253-0.657], p < 0.001) and antibiotics (aHR = 0.121 [0.0437-0.333], p < 0.0001) were independently negatively associated with time to ADA development, whereas infections during the study (aHR = 2.757 [1.616-4.704], p < 0.001) and tobacco smoking (aHR = 2.150 [1.319-3.503], p < 0.01) were positively associated. 351,824 Single-Nucleotide Polymorphisms (SNPs) and 38 imputed Human Leukocyte Antigen (HLA) alleles were analyzed through a genome-wide association study. We found that the HLA-DQA1*05 allele significantly increased the rate of immunogenicity (aHR = 3.9 [1.923-5.976], p < 0.0001 for the homozygotes). Among the 6 genetic variants selected at a 20% false discovery rate (FDR) threshold, the minor allele of rs10508884, which is situated in an intron of the CXCL12 gene, increased the rate of immunogenicity (aHR = 3.804 [2.139-6.764], p < 1 × 10-5 for patients homozygous for the minor allele) and was chosen for validation through a CXCL12 protein enzyme-linked immunosorbent assay (ELISA) on patient serum at baseline before therapy start. CXCL12 protein levels were higher for patients homozygous for the minor allele carrying higher ADA risk (mean: 2,693 pg/ml) than for the other genotypes (mean: 2,317 pg/ml; p = 0.014), and patients with CXCL12 levels above the median in serum were more prone to develop ADAs (aHR = 2.329 [1.106-4.90], p = 0.026). A limitation of the study is the lack of replication; therefore, other studies are required to confirm our findings. CONCLUSION: In our study, we found that immunosuppressants and antibiotics were associated with decreased risk of ADA development, whereas tobacco smoking and infections during the study were associated with increased risk. We found that the HLA-DQA1*05 allele was associated with an increased rate of immunogenicity. Moreover, our results suggest a relationship between CXCL12 production and ADA development independent of the disease, which is consistent with its known function in affinity maturation of antibodies and plasma cell survival. Our findings may help physicians in the management of patients receiving biotherapies

EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update

Recent insights in rheumatoid arthritis (RA) necessitated updating the European League Against Rheumatism (EULAR) RA management recommendations. A large international Task Force based decisions on evidence from 3 systematic literature reviews, developing 4 overarching principles and 12 recommendations (vs 3 and 14, respectively, in 2013). The recommendations address conventional synthetic (cs) disease-modifying antirheumatic drugs (DMARDs) (methotrexate (MTX), leflunomide, sulfasalazine); glucocorticoids (GC); biological (b) DMARDs (tumour necrosis factor (TNF)-inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab), abatacept, rituximab, tocilizumab, clazakizumab, sarilumab and sirukumab and biosimilar (bs) DMARDs) and targeted synthetic (ts) DMARDs (Janus kinase (Jak) inhibitors tofacitinib, baricitinib). Monotherapy, combination therapy, treatment strategies (treat-to-target) and the targets of sustained clinical remission (as defined by the American College of Rheumatology-(ACR)-EULAR Boolean or index criteria) or low disease activity are discussed. Cost aspects were taken into consideration. As first strategy, the Task Force recommends MTX (rapid escalation to 25 mg/week) plus short-term GC, aiming at >50% improvement within 3 and target attainment within 6 months. If this fails stratification is recommended. Without unfavourable prognostic markers, switching to—or adding—another csDMARDs (plus short-term GC) is suggested. In the presence of unfavourable prognostic markers (autoantibodies, high disease activity, early erosions, failure of 2 csDMARDs), any bDMARD (current practice) or Jak-inhibitor should be added to the csDMARD. If this fails, any other bDMARD or tsDMARD is recommended. If a patient is in sustained remission, bDMARDs can be tapered. For each recommendation, levels of evidence and Task Force agreement are provided, both mostly very high. These recommendations intend informing rheumatologists, patients, national rheumatology societies, hospital officials, social security agencies and regulators about EULAR's most recent consensus on the management of RA, aimed at attaining best outcomes with current therapies

Integration of sequence data from a consanguineous family with genetic data from an outbred population identifies PLB1 as a candidate rheumatoid arthritis risk gene

Integrating genetic data from families with highly penetrant forms of disease together with genetic data from outbred populations represents a promising strategy to uncover the complete frequency spectrum of risk alleles for complex traits such as rheumatoid arthritis (RA). Here, we demonstrate that rare, low-frequency and common alleles at one gene locus, phospholipase B1 (PLB1), might contribute to risk of RA in a 4-generation consanguineous pedigree (Middle Eastern ancestry) and also in unrelated individuals from the general population (European ancestry). Through identity-by-descent (IBD) mapping and whole-exome sequencing, we identified a non-synonymous c.2263G>C (p.G755R) mutation at the PLB1 gene on 2q23, which significantly co-segregated with RA in family members with a dominant mode of inheritance (P = 0.009). We further evaluated PLB1 variants and risk of RA using a GWAS meta-analysis of 8,875 RA cases and 29,367 controls of European ancestry. We identified significant contributions of two independent non-coding variants near PLB1 with risk of RA (rs116018341 [MAF = 0.042] and rs116541814 [MAF = 0.021], combined P = 3.2×10-6). Finally, we performed deep exon sequencing of PLB1 in 1,088 RA cases and 1,088 controls (European ancestry), and identified suggestive dispersion of rare protein-coding variant frequencies between cases and controls (P = 0.049 for C-alpha test and P = 0.055 for SKAT). Together, these data suggest that PLB1 is a candidate risk gene for RA. Future studies to characterize the full spectrum of genetic risk in the PLB1 genetic locus are warranted. © 2014 Plenge et al