Background Rheumatoid Arthritis (RA) is a severe joint disease characterized by chronic inflammation of synovial tissue. The inflammatory infiltrate within the rheumatoid synovium may be differently arranged, defining three distinct histopathotypes: myeloid (prevalent macrophage infiltration), lymphoid (B/T lymphocyte aggregates), and fibroid (fibroblastic infiltration with paucity of immune cells)1. Despite enabling a remarkable improvement of the disease's outcome, biologics are not effective in around 30–40% of treated patients. To date, no reliable pre-therapy predictors of response have been identified. The histological characterization of synovitis may represent a valuable tool in predicting response to biologics prior to treatment.
Objectives To evaluate the role of synovial pathology in predicting clinical response to certolizumab-pegol combined with DMARD.
Methods 32 RA patients fulfilling UK NICE criteria for starting TNF-inhibitors were enrolled at Barts Health Trust. Patients underwent a baseline US-guided biopsy prior to commencing certolizumab-pegol and a second biopsy after 12 weeks of treatment. Synovial immune infiltrate was assessed through immunohistochemical staining for CD3/CD20/CD68/CD138 and quantified using a semi-quantitative scoring system (0–4); accordingly, patients were classified as lymphoid (B cells aggregates grade ≥2), myeloid (sub-lining macrophages >2, +/− grade 1 aggregates) and fibroid (sub-lining macrophages ≤2). Therapeutic response was evaluated at 3 months according to EULAR criteria. Logistic regression model was performed to identify factors associated with good EULAR response at 3 months; the factors included clinical and biochemical parameters (ESR, CRP) as well as histopathology. The model selection was implemented using forward processes by AIC with 5-fold cross-validation (error=0.25).
Results Out of 32 baseline biopsies, 53% were classified as lymphoid, 19% myeloid and 28% fibroid. Decrease in the number of sub-lining CD68-positive macrophages significantly correlated with clinical response (p<0.05). Baseline demographic and clinical parameters were comparable between the three histological groups; the CRP level was significantly higher in the myeloid compared to fibroid. The histological pathotype adjusted for baseline VAS pain and patient global health score, ESR, HAQ score and concomitant steroid treatment, was identified as a significant predictor of good response to certolizumab-pegol by forward selection (AUC 0.97, CI 0.92–1). The chance of achieving a good EULAR response to certolizumab-pegol was 91% lower in patients classified as a fibroid pathotype at baseline compared to myeloid/lymphoid pathotypes (OR 0.09, CI 0, 1.75).
Conclusions Our study shows that patients with a fibroid pathotype at baseline are less likely to respond to Certolizumab-pegol. Moreover, we identified a novel prediction model of response based on clinical parameters and synovial histopathological classification. Histological assessment of synovial tissue may be of critical importance for developing personalised treatment for RA.
Pitzalis C et al, New learnings on the pathophysiology of RA from synovial biopsies. Curr Opin Rheumatol. 2013
Disclosure of Interest None declared