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What Goes Wrong with the Immune System in PMR?

Polymyalgia rheumatica (PMR) is a common inflammatory rheumatic disease. Imaging studies have revealed that PMR should not be viewed as a mysterious source of pain and stiffness. Instead, PMR symptoms are linked to inflammation around joints (bursitis, tenosynovitis, tendinitis), which can be accompanied by mild joint synovitis. The exact trigger for PMR onset remains unknown. However, immunology studies and clinical trials with biological DMARDs now shed light on the immune pathways involved in PMR.

What goes wrong in the blood?

Most of our insights into the immune pathology of PMR stem from investigations of blood samples. A consistent finding in PMR is elevated serum levels of interleukin-6. Two studies have shown an increase in T helper 17 cells (i.e. IL-17 producing CD4+ T cells) in the blood of patients with PMR. During active disease, circulating B cells appear to shift from the bloodstream into the tissues, while returning into the circulating during remission. Many of these returning B cells appear to produce IL-6, fitting with their enhanced potential to differentiate into IL-6 producing B cells during active disease. There have also been reports suggesting expansions of pro-inflammatory T helper 1 cells (i.e. IFN-gamma producing CD4+ T cells) and senescent T cells (i.e. CD28 negative T cells) in the bloodstream, though these findings need further validation.

Lundberg I, et al. JIM 2022
Lundberg I, et al. J Int Med 2022; 292:717

What goes wrong in the tissues?

Until recently, limited access to inflamed tissues of patients with PMR has hindered our understanding of what goes wrong in the tissues. Early case reports from the 1960-1980s showed immune cell infiltrates in structures nowadays identified as key sites of inflammation on imaging studies. In the 1990s, an Italian research group began investigating glenohumeral biopsies obtained via arthroscopy of patients with PMR. These synovial biopsies contained high numbers of infiltrating macrophages, and to a lesser extent also T cells. This was associated with enhanced vascularity, which promotes the entry of additional immune cells into the tissue. More recently, the PMR Research On disease Mechanisms in Synovium (PROMIS) study reported its first results. Ultrasound-guided synovial biopsies were obtained from the inflamed subacromial bursa of patient with PMR. These biopsies revealed prominent infiltrates of immune cells, mostly macrophages. T helper 1 cells were also present, albeit to a lesser extent. Widespread expression of interleukin-6 was observed in the bursa tissue, with macrophages and fibroblasts identified as its sources. GM-CSF was another pro-inflammatory cytokine widely expressed in the bursa tissue. 

What can we learn from the clinical trials?

Although glucocorticoid treatment remains the cornerstone of treatment in PMR, recent studies have highlighted the therapeutic potential of biological DMARDs for this condition. Notably, three clinical trials have provided evidence for the effectiveness of anti-interleukin-6 receptor therapy in PMR (PMR-SPARE, SEMAPHORE, SAPHYR). Furthermore, a phase II study has demonstrated efficacy of B cell depletion therapy in this condition (BRIDGE-PMR). Encouraging results have also emerged from proof-of-concept studies with giant cell arteritis patients, many of whom also have PMR. This includes trials with treatments targeting the GM-CSF receptor or IL-17. These findings underscore the relevancy of the immunological perturbations that have been identified by the translational immunology studies. 

Taken together, our understanding of the immune pathology of PMR has grown in recent years. Further exploring the immune system in greater detail has the potential to reveal novel, important targets for therapy in PMR. 


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Disclosures: The author reports a speaker fee from Roche and research support from AbbVie paid to his institution.


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Kornelis van der Geest is a rheumatologist at the Department of Rheumatology and Clinical Immunology of the University Medical Center Groningen (The Netherlands). His research is focussed on the immune pathology and imaging of PMR and giant cell arteritis. For his work on the PROMIS study, Dr. van der Geest received a career research grant from FOREUM Foundation for Research in Rheumatology. He currently coordinates trials with immune cell-specific radiotracers for positron emission tomography imaging in giant cell arteritis, as part of the EU-funded Immune Image consortium. He recently became co-chair of the EULAR study group for giant cell arteritis and polymyalgia rheumatica.