RESUMEN
INTRODUCTION: Tumor necrosis factor alpha (TNF alpha) blockers such as infliximab (IFX) and adalimumab (ADA) had significantly changed the course of inflammatory diseases such as rheumatoid arthritis (RA), spondyloarthritis (SpA) and Crohn's disease (CD). However, about 30% of patients do not respond to these treatments. This lack of response may be due to the formation of antibodies against these drugs (anti-drug antibodies: ADAbs). The aim of this study was to determine the prevalence of ADAbs against IFX and ADA, and the trough serum concentration of IFX and ADA in RA, SpA or CD patients and to assess their impact on the therapeutic response. METHODS: A cross sectional, multi-centric study was conducted, including patients with RA, SpA or CD treated with IFX or ADA as a first biotherapy for at least 6 months. ADAbs and trough levels were measured by an Enzyme Linked Immunosorbent assay (ELISA). RESULTS: 197 patients were included (57 RA, 73 SpA and 67 CD). ADAbs were positive in 40% of cases for IFX and 25% for ADA. They were positive in 40% of SpA, 35% of RA, and 21% of CD. The presence of ADAbs was inversely correlated to the trough levels of IFX and ADA during RA (p = 0.01 and p < 0.0001), SpA (p < 0.01 and p < 0.0001) and CD (p = 0.001 and p = 0.04). For all pathologies, the presence of ADAbs was not correlated with disease activity. Concomitant methotrexate significantly reduced immunogenicity. CONCLUSION: In our study, the presence of ADAb and low trough levels seem to not affect the therapeutic response in patients on TNF alpha antagonists. Other tracks more than immunogenicity should be investigated to explain the loss of response to these biotherapies.
Asunto(s)
Adalimumab , Antirreumáticos , Infliximab , Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Estudios Transversales , Infliximab/uso terapéutico , Infliximab/inmunología , Adalimumab/uso terapéutico , Adalimumab/inmunología , Adalimumab/sangre , Túnez/epidemiología , Antirreumáticos/uso terapéutico , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/inmunología , Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/inmunología , Artritis Reumatoide/sangre , Anticuerpos/sangre , Resultado del Tratamiento , Anciano , Enfermedad de Crohn/tratamiento farmacológico , Enfermedad de Crohn/inmunología , Enfermedad de Crohn/sangre , Espondiloartritis/tratamiento farmacológico , Espondiloartritis/inmunología , Espondiloartritis/sangreRESUMEN
BACKGROUND: Desmoglein 1 (Dsg1), the pemphigus foliaceus (PF) antigen, is produced as a precursor (preDsg1) and is transported to the cell surface as the mature form (matDsg1). Recent studies show that B cells from North American individuals without pemphigus can potentially produce anti-preDsg1 IgG antibodies, but ELISA screening of large numbers of normal people in North America and Japan hardly ever shows circulating antibodies against preDsg1 or matDsg1. In contrast, in Tunisia, where PF is endemic, anti-Dsg1 IgGs are frequently detected in healthy individuals. OBJECTIVE: To characterize these anti-Dsg1 antibodies from normal individuals in Tunisia. METHODS: Sera from 16 healthy individuals and 9 PF patients in the endemic PF area in Tunisia, and sera from Japanese non-endemic PF patients were analyzed by immunoprecipitation-immunoblotting using recombinant proteins of preDsg1, matDsg1, and domain-swapped Dsg1/Dsg2 molecules. RESULTS: Sera from normal Tunisian individuals reacted to preDsg1 alone (8/16) or more strongly to preDsg1 than to matDsg1 (7/16), while those from all Tunisian PF patients and Japanese non-endemic PF patients reacted similarly to preDsg1 and matDsg1, or preferentially to matDsg1. The epitopes recognized by anti-Dsg1 IgGs from normal Tunisian individuals were more frequently found in the C-terminal extracellular domains (EC3 to EC5), while those in Tunisian endemic PF patients were more widely distributed throughout the extracellular domains, suggesting IgGs against EC1 and EC2 developed during disease progression. CONCLUSIONS: These findings indicate that IgG autoantibodies against Dsg1 are mostly raised against preDsg1 and/or C-terminal domains of Dsg1 in healthy Tunisians in the endemic area of PF.