Methotrexate and BAFF interaction prevents immunization against TNF inhibitors

Bitoun, Samuel; Nocturne, Gaëtane; Ly, Bineta; Krzysiek, Roman; Roques, Pierre; Pruvost, Alain; Paoletti, Audrey; Pascaud, Juliette; Dönnes, Pierre; Florence, Kimberly; Gleizes, Aude; Hincelin-Méry, Agnès; Allez, Matthieu; Hacein‐Bey‐Abina, Salima; Mackay, Fabienne; Pallardy, Marc; Grand, Roger Le; Mariette, Xavier

doi:10.1136/annrheumdis-2018-213403

Cited by 22 publications

(21 citation statements)

References 27 publications

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“…MTX in the presence of higher (and not lower) BAFF levels negatively impacted vaccine response to seasonal influenza vaccination, further supporting the counter-intuitive, paradoxical immune suppressive effect of BAFF in the presence of MTX. This hypothesis-driven study is a first proof of concept to confirm the recent basic-translational finding by Bitoun et al that provides a biological explanation of MTX–BAFF interaction that induces a tolerance to biological disease modifying antirheumatic drugs (ie, TNF inhibitor) and new antigens such as vaccination by generating immune suppressive adenosine and regulatory B cells 5. This study supports that BAFF–MTX interaction at the time of antigen challenge is critical and that immune modulation by DMARDs depends on host immune factors.…”

supporting

confidence: 73%

“…A possible candidate is B-cell activating factor (BAFF), which promotes B-cell activation and differentiation for antibody production 4. When patients with RA received anti-TNF treatment, a high BAFF serum level prevented formation of antidrug antibody in patients taking MTX but not those who did not 5. Thus, in the presence of MTX, BAFF may exert a paradoxical anti-inflammatory effect.…”

mentioning

confidence: 99%

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Interaction between B-cell activation factor and methotrexate impacts immunogenicity of seasonal influenza vaccination in patients with rheumatoid arthritis

et al. 2018

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supporting

confidence: 73%

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confidence: 99%

Interaction between B-cell activation factor and methotrexate impacts immunogenicity of seasonal influenza vaccination in patients with rheumatoid arthritis

et al. 2018

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“…The main immunosuppressants prescribed in the cohort were methotrexate (MTX), azathioprine, and leflunomide. A mechanism of MTX-induced tolerization was recently proposed by ABIRISK collaborators, who demonstrated in BAFF (B-cell activated factor) transgenic mice that high levels of BAFF were necessary for MTX-induced tolerization and confirmed it in the anti-TNF-treated patients of the ABIRISK prospective study [ 21 ]. BAFF induced an increase in the CD73 enzyme on the B cell surface, which catalyzes conversion of extracellular AMP (Adenosine MonoPhosphate) into the immunosuppressant adenosine.…”

Section: Discussionmentioning

confidence: 89%

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

Hässler¹,

Bachelet²,

Duhazé³

et al. 2020

PLoS Med

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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 w...

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“…Rituximab is a chimeric monoclonal antibody that has been approved for multiple types of malignancy and autoimmune diseases. Methotrexate, an inhibitor of dihydrofolate reductase, impacts rapidly dividing T and B cells (28,29). Experience from rheumatologic disorders has shown that the addition of methotrexate with other biological therapy has prevented the development of ADA against therapeutic proteins (30).…”

Section: Introductionmentioning

confidence: 99%

Benefits of Prophylactic Short-Course Immune Tolerance Induction in Patients With Infantile Pompe Disease: Demonstration of Long-Term Safety and Efficacy in an Expanded Cohort

et al. 2020

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Immune tolerance induction (ITI) with a short-course of rituximab, methotrexate, and/or IVIG in the enzyme replacement therapy (ERT)-naïve setting has prolonged survival and improved clinical outcomes in patients with infantile Pompe disease (IPD) lacking endogenous acid-alpha glucosidase (GAA), known as cross-reactive immunologic material (CRIM)-negative. In the context of cancer therapy, rituximab administration results in sustained B-cell depletion in 83% of patients for up to 26-39 weeks with B-cell reconstitution beginning at approximately 26 weeks post-treatment. The impact of rituximab on serum immunoglobulin levels is not well studied, available data suggest that rituximab can cause persistently low immunoglobulin levels and adversely impact vaccine responses. Data on a cohort of IPD patients who received a short-course of ITI with rituximab, methotrexate, and IVIG in the ERT-naïve setting and had ≥6 months of follow-up were retrospectively studied. B-cell quantitation, ANC, AST, ALT, immunization history, and vaccine titers after B-cell reconstitution were reviewed. Data were collected for 34 IPD patients (25 CRIM-negative and 9 CRIM-positive) with a median age at ERT initiation of 3.5 months (0.1-11.0 months). B-cell reconstitution, as measured by normalization of CD19%, was seen in all patients (n = 33) at a median time of 17 weeks range (11-55 weeks) post-rituximab. All maintained normal CD19% with the longest follow-up being 248 weeks post-rituximab. 30/34 (88%) maintained negative/low anti-rhGAA antibody titers, even with complete B-cell reconstitution. Infections during immunosuppression were reported in five CRIM-negative IPD patients, all resolved satisfactorily on antibiotics. There were no serious sequelae or deaths. Of the 31 evaluable patients, 27 were up to date on age-appropriate immunizations. Vaccine titers were available for 12 patients after B-cell reconstitution and adequate humoral response was observed in all except an Desai et al. Long-Term Safety of ITI in IPD Patients inadequate response to the Pneumococcal vaccine (n = 2). These data show the benefits of short-course prophylactic ITI in IPD both in terms of safety and efficacy. Data presented here are from the youngest cohort of patients treated with rituximab and expands the evidence of its safety in the pediatric population.

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Methotrexate and BAFF interaction prevents immunization against TNF inhibitors

Cited by 22 publications

References 27 publications

Interaction between B-cell activation factor and methotrexate impacts immunogenicity of seasonal influenza vaccination in patients with rheumatoid arthritis

Interaction between B-cell activation factor and methotrexate impacts immunogenicity of seasonal influenza vaccination in patients with rheumatoid arthritis

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

Benefits of Prophylactic Short-Course Immune Tolerance Induction in Patients With Infantile Pompe Disease: Demonstration of Long-Term Safety and Efficacy in an Expanded Cohort

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