A Pauci-Immune Synovial Pathotype Predicts Inadequate Response to TNFα-Blockade in Rheumatoid Arthritis Patients

Abstract

Objectives: To assess whether the histopathological features of the synovium before starting treatment with the TNFi certolizumab-pegol could predict clinical outcome and examine the modulation of histopathology by treatment.Methods: Thirty-seven RA patients fulfilling UK NICE guidelines for biologic therapy were enrolled at Barts Health NHS trust and underwent synovial sampling of an actively inflamed joint using ultrasound-guided needle biopsy before commencing certolizumab-pegol and after 12-weeks. At 12-weeks, patients were categorized as responders if they had a DAS28 fall >1.2. A minimum of 6 samples was collected for histological analysis. Based on H&E and immunohistochemistry (IHC) staining for CD3 (T cells), CD20 (B cells), CD138 (plasma cells), and CD68 (macrophages) patients were categorized into three distinct synovial pathotypes (lympho-myeloid, diffuse-myeloid, and pauci-immune).Results: At baseline, as per inclusion criteria, DAS28 mean was 6.4 ± 0.9. 94.6% of the synovial tissue was retrieved from the wrist or a metacarpophalangeal joint. Histological pathotypes were distributed as follows: 58% lympho-myeloid, 19.4% diffuse-myeloid, and 22.6% pauci-immune. Patients with a pauci-immune pathotype had lower levels of CRP but higher VAS fatigue compared to lympho-and diffuse-myeloid. Based on DAS28 fall >1.2, 67.6% of patients were deemed as responders and 32.4% as non-responders. However, by categorizing patients according to the baseline synovial pathotype, we demonstrated that a significantly higher number of patients with a lympho-myeloid and diffuse-myeloid pathotype in comparison with pauci-immune pathotype [83.3% (15/18), 83.3 % (5/6) vs. 28.6% (2/7), p = 0.022) achieved clinical response to certolizumab-pegol. Furthermore, we observed a significantly higher level of post-treatment tender joint count and VAS scores for pain, fatigue and global health in pauci-immune in comparison with lympho-and diffuse-myeloid patients but no differences in the number of swollen joints, ESR and CRP. Finally, we confirmed a significant fall in the number of CD68+ sublining macrophages post-treatment in Nerviani et al.RA Pathotypes Predict Anti-TNF Response responders and a correlation between the reduction in the CD20+ B-cells score and the improvement in the DAS28 at 12-weeks.Conclusions: The analysis of the synovial histopathology may be a helpful tool to identify among clinically indistinguishable patients those with lower probability of response to TNFα-blockade.

GM-CSF Expression and Macrophage Polarization in Joints of Undifferentiated Arthritis Patients Evolving to Rheumatoid Arthritis or Psoriatic Arthritis

“…Based on H&E and immunohistochemistry staining for CD3 (T cells), CD20 (B cells), CD138 (plasma cells), and CD68 (macrophages), synovial tissue from each UA and definite arthritis group was categorized into three distinct synovial pathotypes: lympho-myeloid, diffuse-myeloid, and pauci-immune ( 37 ). Results show that, in all the groups studied, the most frequent pathotypes were lympho-myeloid and diffuse-myeloid, ranging from 40-50% each, with the pauci-imune found in around 8% of the patients ( Supplementary Table 1 ) These results are in line with those from previous studies ( 9 , 37 – 40 ). The relative prevalence of the lympho-myeloid pathotypes in our established RA cohort, with more longstanding disease, was higher than in its undifferentiated phase (75% vs. 50%) ( Supplementary Table 1 ), but the low number of cases preclude to extract further conclusion.…”

Insights Into Leukocyte Trafficking in Inflammatory Arthritis – Imaging the Joint

“…Moreover, anti-TNFα therapy reduced the numbers of CD3 + T-cells, CD22 + B-cells, and CD68 + macrophages in the joints of patients with RA over a 2 weeks period ( Taylor et al, 2000 ). Indeed, the combination of CD20, CD138 (marking plasma cells), CD3, and CD68 revealed 3 distinct leukocyte profiles (pathotypes) in the synovium of patients with early and established RA based on the absence of leukocytes (pauci-immune), diffuse myeloid infiltrate or the formation of lympho-myeloid aggregates ( Humby et al, 2019 ; Nerviani et al, 2020 ). Agreeing with earlier studies that described pauci-immune; diffuse and follicular infiltrates ( Wagner et al, 1998 ; Pitzalis et al, 2013 ).…”

“…Agreeing with earlier studies that described pauci-immune; diffuse and follicular infiltrates ( Wagner et al, 1998 ; Pitzalis et al, 2013 ). Crucially these different leukocyte synovial pathotypes impact on a patient’s response to therapy – where over 80% of patients with a lympho-myeloid or diffuse myeloid pathotype showed a decrease in their disease activity (DAS28 score) following treatment with the anti-TNFα drug, certolizumab-pegol, whilst less than 30% of patients with the pauci-immune pathotype responded ( Nerviani et al, 2020 ). Such studies reveal two important insights – firstly leukocyte pathotypes highlight the existence of different leukocyte recruitment and retention signatures in subgroups of RA patients.…”

Synovial biopsies in clinical practice and research: current developments and perspectives

“…Their presence in the synovial tissue has been inconsistently reported as associated with disease activity and an erosive RA phenotype [21,[37][38][39][40]. The pauci-immune phenotype is associated with lower levels of CRP [21,41].…”