Background: Polymyalgia rheumatica (PMR) is a common, rheumatic inflammatory disease. Inflammation of bursae and tendon sheaths is a characteristic finding in patients with PMR. Glucocorticoid treatment remains the mainstay treatment for PMR. A study published in 1996 reported that macrophages dominate the inflammatory infiltrates in the glenohumeral synovium of PMR patients ¹ , suggesting the importance of these cells in the immunopathology of PMR. However, the functional and phenotypical heterogeneity of the tissue-infiltrating macrophages in PMR remains obscure. Although treatment with anti-IL-6 receptor (tocilizumab) has shown promising results ² , it is unclear whether macrophages contribute to IL-6 production in PMR. Additionally, anti-GM-CSF receptor therapy (mavrilimumab), recently shown to be efficacious in the closely related disease giant cell arteritis ³ , may also be useful for the treatment of PMR. Knowledge on the functional heterogeneity of monocytes/macrophages in PMR may aid in identifying novel therapeutic targets for this condition.

Objectives: To determine the phenotype of monocyte/macrophages in peripheral blood, bursal/tenosynovial fluid and bursal tissue of patients with PMR.

Methods: Paired peripheral blood (PB), bursal/tenosynovial fluid (SF) and bursal tissue biopsy samples from 11 PMR patients were included in our study. Bursal and tenosynovial samples were obtained from the shoulder. Distribution of the monocyte subsets (classical, intermediate and non-classical monocytes) was determined based on the level of CD14 and CD16 expression by flow cytometry. To study monocyte activation status, markers of ‘M1’ like (CD80 and CD64) and ‘M2’ like (CD206 and FRβ) macrophage polarization were included in the flow cytometry analysis. Immunohistochemistry of bursal tissue biopsies was focused on macrophage markers (CD68, CD86, CD64, CD206 and FRβ) andproinflammatory cytokines (IL-6 and GM-CSF), which were scored semi-quantitatively. Double immunofluorescence stainings were performed to determine the expression of IL-6 and GM-CSF by tissue-infiltrating macrophages in bursal tissue.

Results: Monocytes were detected in the SF of PMR patients. The proportion of classical monocytes was significantly lowered ( p =0.001) in SF versus PB, while the proportion of intermediate monocytes was significantly elevated ( p =0.001). The expression of CD206 was significantly elevated ( p =0.001) but not FRβ in SF monocytes, suggesting GM-CSF skewed phenotype. In bursal tissue, macrophages displayed mixed ‘M1’/’M2’ traits with high expression of all macrophage polarization markers. Proinflammatory cytokines IL-6 and GM-CSF were highly expressed throughout the bursal tissue biopsies. Double immunofluorescence staining confirmed the expression of IL-6 and GM-CSF by the infiltrating macrophages.

Conclusion: SF monocytes and bursal tissue macrophages show a pro-inflammatory phenotype in PMR. Moreover, tissue-infiltrating macrophages show a prominent IL-6 and GM-CSF response in PMR. Our data add to the rationale of targeting IL-6 and GM-CSF as treatment options in PMR.

REFERENCES:

[1]Meliconi R, Pulsatelli L, Uguccioni M, et al. Leukocyte infiltration in synovial tissue from the shoulder of patients with polymyalgia rheumatica. Quantitative analysis and influence of corticosteroid treatment. Arthritis Rheum . 1996;39(7):1199-1207.

[2]Devauchelle-Pensec V, Berthelot JM, Cornec D, et al. Efficacy of first-line tocilizumab therapy in early polymyalgia rheumatica: a prospective longitudinal study. Ann Rheum Dis . 2016;75(8):1506-1510.

[3]Cid MC, Unizoni S, Pupim L, et al. Mavrilimumab (anti GM-CSF Receptor α Monoclonal Antibody) Reduces Time to Flare and Increases Sustained Remission in a Phase 2 Trial of Patients with Giant Cell Arteritis [Abstract]. Arthritis Rheumatol. 2020; 72 (suppl 10).

Acknowledgements: This work was supported by a research grant from FOREUM Foundation for Research in Rheumatology. The PMR Research On disease Mechanisms In Synovium (PROMIS) study was also funded by the Rheumatology Grant (Dutch Society for Rheumatology) and Mandema Stipend (University Medical Center Groningen).

Disclosure of Interests: William Febry Jiemy: None declared, Rosanne Reitsema: None declared, Anqi Zhang: None declared, Maria Sandovici: None declared, Annemieke Boots: None declared, Peter Heeringa: None declared, Elisabeth Brouwer Speakers bureau: E. Brouwer reports speaker and consulting fees from Roche in 2017-2018, outside the submitted work, Consultant of: E. Brouwer reports speaker and consulting fees from Roche in 2017-2018, outside the submitted work, Kornelis van der Geest Consultant of: K. van der Geest reports personal fees from Roche, outside the submitted work.