POS0352 GENETIC DETERMINANTS OF RESPONSE TO ABATACEPT IN PATIENTS WITH IGG4-RELATED DISEASE

Background IgG4-related disease (IgG4RD) is a fibro-inflammatory disorder of unknown etiology. Emerging evidence indicates that chronic inflammation in IgG4RD sustained by persistent mutual activation antigen-specific B and T lymphocytes. Targeting B-T cell co-stimulation represents, therefore, rationale therapeutic approach for IgG4RD. Objectives Threefold aim the present work was (i) to assess efficacy abatacept (a selective inhibitor based on replica CTLA4) treatment IgG4RD; (ii) study patients; (iii) identify functional genetic predictors response patients. Methods Three patients with active (Pt1-3) were treated monthly intravenous infusions (750mg) 6 months without concomitant glucocorticoids. All underwent 18F-FDG PET scan before after response. To we used multicolour flow-cytometry Whole Exome Sequencing (WES). Flow-cytometry using CD3, CD19, CD4, CD25, CTLA4 antibodies performed CD4+ upon exposure recombinant humanized CD3/CD28 120 hours vitro colture. Results compared 10 healthy controls rheumatoid arthritis (RA). WES screen mutations panel 452 genes related known monogenic immune mediated diseases. Pt 1 47 years old male bilateral submandibular gland involvement (Figure - A arrow ; arrows ) subcutaneous lesions (B circle ). Pt2 78 woman right orbital pseudotumor – arrow), sinonasal arrowhead ), skin asterisk Pt3 68 left lacrimal parotid glands Abatacept led marked decrease dimension 18-F FDG uptake Pt1 Pt2. showed increased pathological her minimal morphologic changes at magnetic resonance, consistent metabolic progression. In vitro, there no difference expression baseline between (p>0.05). Yet, activation, displayed premature cells donors (p<0.01), suggesting defective inhibition. Similar results observed RA. Accordingly, expansion activated CD25+ (p<0.05). three found eterozigous germline LRBA gene (p.Arg2646His (c.7937G>A)) (Pt1), (p.Gly109Glu (c.326G>A)) (Pt2), DOCK8 (p.Gln1550Leu (c.4649A>T)) (Pt3). None these has been previously reported medical literature remains uncertain significance but all had CADD score > 20, thus predicting deleterious impact protein structure. Of note, LRBA, CTLA4, are associated systemic autoimmunity, lymphoproliferation, deficiency. particular, as opposed gene, encode functionally proteins regulates reclycing membrane antigen engagement inhibit activation. Conclusion demonstrate from show aberrant reduced inhibitory molecule CTLA4. not respond additional mechanisms least proportion Patients responding display, indeed, pathway may represent ideal candidates abatacept. Reference [1]Lanzillotta M, et al. Advances diagnosis management IgG4 disease. BMJ, 2020:16;369:m1067. Figure 1. Acknowledgements: NIL. Disclosure Interests Declared.