Current clinical challenges and new approaches in polymyalgia rheumatica (PMR)

17.10.2024 17:52

After rheumatoid arthritis (RA), PMR is the second most common inflammatory rheumatic disease in people over 50 years of age. [1,2] It presents clinicians with major clinical challenges, as diagnosis is challenging and treatment options with glucocorticoids, the only approved therapy, are very limited. [3,4] At the annual meeting of the German Society for Rheumatology (DGRh Congress 2024), experts chaired by Prof. Dr. Elisabeth Märker-Hermann, Wiesbaden, discussed these challenges and presented future treatment options.

Challenges in the diagnosis and treatment of PMR

PMR is a systemic disease with a multifactorial etiology. The exact cause is unclear. Various cytokines are involved in its pathogenesis, including interleukin (IL) [6,5,6].

"We know that IL-6 plays a significant role in the pathogenesis of PMR," explained Prof. Dr. Andreas Krause, Berlin. IL-6 contributes to the development of local and systemic inflammation and thus to the typical symptoms of PMR—such as pain in the shoulders, neck, and pelvic area, as well as morning stiffness. [6] The diagnosis of PMR is challenging, as only older classification criteria exist, but no specific diagnostic criteria, and possible differential diagnoses must be excluded. [3,7]

The currently recommended standard treatment for PMR is glucocorticoids (GC). PMR usually responds well to GC therapy. In stable remission, a gradual dose reduction is recommended. The goal is to discontinue therapy. However, 40–60% of patients experience a relapse or relapses during GC tapering. This delays or prevents the goal of discontinuing GC therapy from being achieved. [7–9] Many PMR patients require long-term GC treatment. The proportion of patients still receiving GC therapy after 1, 2, and 5 years is 77%, 51%, and 25%, respectively. [10,11] Furthermore, long-term GC treatment is associated with significant side effects. Approximately 50% of PMR patients develop adverse events (AEs) and complications during GC therapy, so the need for effective and safe new therapies is high. [8,9,12,13]

Currently, the current 2017 PMR guideline only recommends the use of methotrexate (MTX) in addition to GCs for difficult-to-treat PMR patients. However, the use of MTX as a GC-sparing agent in PMR is only possible off-label, and the data regarding its efficacy are inconclusive. [7,8] "We need new therapeutic options, especially to conserve GCs and prevent their long-term side effects," explained Prof. Krause. Alternative therapies are also necessary in cases of GC intolerance and/or insufficient GC efficacy. One promising approach, which has already been tested in randomized, controlled trials, is IL-6 receptor inhibition. [9]

IL-6 receptor inhibition in rheumatology – effectiveness and safety

Prof. Dr. Gerd R. Burmester, Berlin, discussed in more detail the inhibition of the IL-6 receptor signaling pathway as a potential new therapeutic approach for PMR, which has already led to positive results in phase III clinical trials. [14-16] For example, the efficacy and safety of the IL-6 receptor inhibitor sarilumab were investigated in the SAPHYR phase III study in PMR patients who experienced a relapse during tapering of GC therapy. Sarilumab is a fully human monoclonal antibody that binds to the α subunit of the IL-6 receptor, thus efficiently blocking the IL-6 signaling pathway. [14]

In the SAPHYR study, 118 patients were randomized 1:1 to receive either sarilumab 200 mg subcutaneously twice monthly with GC tapering over 14 weeks or placebo plus GC tapering over 52 weeks for 52 weeks. [14] Significantly more patients in the sarilumab arm achieved the primary endpoint of sustained remission at 52 weeks compared to the placebo group (28 vs. 10, p = 0.02). The results of a sensitivity analysis excluding the inflammatory markers C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were also consistent with the primary study results. An advantage of sarilumab was demonstrated in all individual components of the primary endpoint and other parameters (e.g., fewer PMR relapses and improved health-related quality of life). [14] At the same time, GC exposure was significantly lower in the sarilumab arm (median cumulative GC dose at week 52: 777 mg vs. 2044 mg, p < 0.001). [14] Sarilumab was well tolerated, with a known safety profile consistent with the results from long-term RA studies. The most common AEs were neutropenia, which, however, was not associated with an increased infection rate. [14-16] "IL-6 receptor inhibition is a good approach to treating PMR, especially in cases that do not respond or do not respond sufficiently to GC or require higher GC doses," concluded Prof. Burmester.

Relevance of IL-6 receptor inhibition for clinical care

According to Dr. Peer M. Aries, Hamburg, additional challenges in PMR care lie in the treatment of patients with comorbidities and risk factors for side effects of GC therapy. He sees a need for improvement in the monitoring of GC-related side effects and the early identification of patients with an increased need for new treatment options. [17,18] The "check2control" concept can provide assistance here. Disease activity and comorbidities/risk factors are determined, if possible, after the initial diagnosis, and the appropriate therapy is then selected or adapted.

Dr. Aries also highlighted the "increasing evidence for the efficacy of IL-6 receptor blockade in PMR." [14-16] He pointed out that the current PMR guideline of the French Society of Rheumatology already recommends its use in cases of severe comorbidities and recurrences in GC [19], and that the German S3 guideline for PMR treatment is currently being revised. According to Dr. Aries, "IL-6 inhibition therapy will be the preferred treatment in the future to save steroids."

New approaches to polymyalgia rheumatica, Industry Symposium at the DGRh Congress 2024, September 19, 2024

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