Pain and synovial pathotypes in AMP AIM

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Clinical pain phenotypes and mechanisms in inflammatory arthri3s are poorly understood. The Accelera3ng Medicines Partnership Autoimmune and Immune-Mediated Disease (AMP-AIM) Program addresses common themes across autoimmune and inflammatory-mediated diseases, and understanding the complexity and impact of pain and the dissocia3on between pa3ent and physician perceived disease burden, not necessarily related to untreated inflamma3on, is a major unmet need. Pain phenotypes such as nocicep3ve (3ssue injury), nociplas3c (central sensi3za3on), and neuropathic pain and their contribu3on to therapeu3c non-response cons3tutes a cri3cal knowledge gap. Pain is a core domain affec3ng quality of life from the perspec3ve of pa3ents with Rheumatoid Arthri3s (RA), Psoria3c Spectrum Disorder (PSD), Sjögren’s disease, and Systemic Lupus Erythematosus (SLE). This supplement will support adding comprehensive and uniform measurements of pain phenotyping to exis3ng data collec3on in RA and PSD pa3ents with prominent synovial pathology and both peripheral and central pain sensi3za3on, in parallel with the harmonized efforts in SLE and SJD. Specifically, we will 1. Iden3fy pain phenotypes associated with peripheral and central mechanisms of pain and in treatment non-responders, using both pa3ent reported outcomes (PROMIS 29, 2016 Fibromyalgia Survey) and algometer measured Quan3ta3ve Sensory Tes3ng (QST) of joint-specific hyperalgesia with a trapezius reference to assess central pain sensi3za3on, 2. Iden3fy novel mediators of pain in the RA and PsA synovium building on work that iden3fied a gene signature correla3ng with pain, where axon sprou3ng and neuron projec3on organiza3on were among the most significantly enriched pathways. Using synovial biopsies obtained in AMP-AIM, we will apply 3-dimensional staining and volume imaging to understand the interac3ons between synovial sensory nerves and synovial cell types. These studies will provide novel insights into pain sensi3za3on, non-response, and new treatment approaches.