Background/Purpose: So far no mechanism for non response to biologicals targeting TNFα  has been described  despite one third of rheumatoid arthritis patients treated are  non-responders. A link to the gut mirobiota its ability to drive an autoimmune disease. Immunity. 2010 Jun 25;32(6):815-27 can be made vie segmented filamentous bacteria (SFB) that cooperate to generate potent IgA and Th17 cell responses. Immunity. 2014 Apr 17;40(4):608-20. We investigated the differences in seroreactivity of patients responding and not responding to TNF therapies prior and after therapy and identified diagnostically applicable IgA autoantigenicity  set to identify non response 

Methods: Screening with patient sera were conducted  with 5 different roteins candidates which were identified by protein maroarray screening (Anal Biochem. 1999 May 15;270(1):103-11.9) expressed recombinantly in E. coli, purified and further stratified with a large well defined patient cohort by ELISA. Baseline sera form PREDICT  trial treated with  Enbrel)  and  patients treated with Humira in the  HIT HARD ( Ann Rheum Dis. 2013 Jun;72(6):844-509 trial and 66  baseline sera from Charite  in addition treated  with ( Cimzia ,Infiximab ) were ivestigated by Pre. mark TNF ELISA from DRDx  GmbH.

Results: Pretreatment sera from patients with diagnosis of RA based on the ACR classification criteria who were initiated on therapy with TNFalpha inhibitors were analyzed with five markers from the biomarker set of highest priority (RAB11B, PPP2R1A, KPNB1,Cog 4, FTFT1 ) using an ELISAs assay. . In total, analyses of 203 patients were carried out, of which 162 were clearly defined as Responder and 41 were clearly defined as non-Responder after 6 month treatment. 81% of Non-responder could be clearly identified with the pre.markTNF Test. The assay has currently a specificity 94%. Moreover, 80 baseline serum samples from the PREDICT study with Enbrel and 57 baseline sera from an early intervention trial Hit Hard ( Ann Rheum Dis. 2013 Jun;72(6):844-509) with Humira were analysed. In early subset, all 3 non-responder were identified and the specificity of the assay was 98 %. In the PREDICT study Enbrel non responders were identified with 68.8 % sensitivity and a specificity of 92.5 %. The amount of IgA produceing B cell in the synovia differs significantly between the patients which is not seen with IgG produceing B cells. Moreover the potent IgA response  is linked to Th17 cell response. A dual pathomechnism of local TNF produceing IgA B cells in RA synovial tissue and TNF produceing macrophages is proposed

Conclusion: These data suggest that non-response to anti-TNFα biologicals might be predicted based on frequency and magnitude of autoantibodies to specific IgA autoantigens. SFB can stimulate multiple intestinal homeostatic IgA and Th17 cell responses and specific IgA and TNF producing B cells might be important for disease persistence in TNFα non responders

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/autoantibodies-of-the-iga-type-a-link-between-the-gut-and-the-anti-tnf-therapy-response-in-rheumatoid-arthritis-patients-analysed-in-two-clinical-trials/