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What Causes PMR?

What causes polymyalgia rheumatica (PMR)? It could be said that PMR occurs when trajectories of aging take a wrong turn, but it’s still not clear exactly what it is that causes this to happen. 

The ideas that follow will doubtless seem, to immunologists, vague and oversimplified; but even a partial picture might still offer a possible framework for clinicians and patients for thinking about treatment and care. For researchers, speculative explanations might prompt the experiment or study that leads to new knowledge and improve our models of pathogenesis. 

Let’s start with where we feel confident: PMR causes widespread pain and stiffness, especially around the shoulder and hip girdles, usually accompanied by an acute phase response. The age distribution of PMR is remarkably similar to that of the related disease giant cell arteritis (GCA), peaking in the mid-70s. Like GCA, PMR is commoner in women than men; and no clear autoantibody association has yet been described. 

What sort of cause should we look for? PMR/GCA seems to happen when a trajectory of aging takes a wrong turn, culminating in a self-perpetuating inflammatory process that only glucocorticoid therapy seems to be able to shift. It’s as if some “glitch” occurs during the continual back-and-forth of adaptation and counter-adaptation to age-related change. One might imagine that, depending on what tissue happens to be affected by this “glitch” (either periarticular, or perivascular), either PMR or GCA might result.

The oddest, and most intriguing, thing about PMR is that the risk factor that seems to matter most is the number of years lived - years on the clock, as it were. Moreover, PMR doesn’t particularly seem to cluster with other “diseases of aging” like osteoarthritis, osteoporosis, cancer or dementia. Nor is PMR usually preceded by a gradual multi-system decline, of the sort that we might associate with advanced old age. Instead PMR has a subacute pattern of symptoms: some patients report the first symptoms occurring almost overnight, while others report a progressive worsening over weeks or months. PMR can affect anyone from midlife onwards, from competitive triathletes to care-home residents.

PMR is not a monogenic disease – at least, it’s not inherited in a Mendelian fashion; and the genetic links we know about seem to be associations, not causes. Unlike the HLA-B27 association of ankylosing spondylitis, the described genetic associations of GCA/PMR in studies to date (such as HLA-DRB1*04 alleles in GCA [1]) are either too common in the general population, or too rare in GCA/PMR, to be useful for clinical diagnosis. It’s indeed possible that diverse, rare genetic variants might be responsible for some cases of PMR, especially people who develop PMR at a younger age. Whether we should still group these under an umbrella-diagnosis of “PMR”, or instead recognise a collection of new conditions that might not yet even have names, is a matter for debate. 

Given the strong link of PMR/GCA with aging, it is tempting to propose somatic mutation as the mechanism; the story of VEXAS [2] illustrates that molecular mechanisms can cut across traditional diagnostic classifications. But the prognosis of VEXAS is very different to that of PMR. 

Various final triggers may precede PMR. The exact nature of this trigger appears to vary from person to person: viral or bacterial infection, physical trauma or injury, or acute psychological stress have all been anecdotally reported [3]. Recall bias is the obvious limitation to these studies. But even if we can identify for sure what pulled the trigger, that doesn’t tell us what loaded the metaphorical gun in the first place.

So we are back to ageing. The immune system is a paradigmatic complex adaptive system: an immensely complex set of multiple, interacting biological pathways, forming both sub-cellular and intracellular networks each of which is constrained by the local tissue topologies. As vividly described by Isaacs and Burmester [4], a network with this type of structure has high levels of redundancy; this provides an evolutionary advantage, conferring resilience to the effects of any random “hits” that may occur over life. 

If a component of this vastly complex network takes a “hit”, the network simply can adapt, re-routing information flow, like Google Maps sending cars on a detour if it detects a road closure. But this re-routing puts extra traffic through certain “hub” elements of the network. This extra traffic can cause further stress on the system. In response, the system might re-route itself again. The new set of available routes might become increasingly different for different individuals as they age: different “trajectories of aging”. 

This repeated “re-routing” is one way of thinking about the gradual accumulation of systemic inflammatory burden (“inflamm-aging”) that appears, even in healthy aging, at the same time as a gradual age-related decline in adaptive immunity (“immunosenescence”). Over the course of a person’s life, the immune system continually adapts to accumulating age-related changes; until, one day, adaptation becomes maladaptive, the system becomes unstable and pathological inflammation ensures. Inflammation is a metabolically hungry process, generating local oxidative stress, and this puts additional pressure on the “hubs” with downstream effects throughout the whole system. 

As Isaacs and Burmester describe [4], it is possible to selectively target over-active “hubs” with modern immunomodulatory (DMARD or biologic) treatments that may restore some degree of stability to the system. 

This view of PMR/GCA, then, has two parts: an age-related predisposition, plus some final unlucky trigger, resulting in self-perpetuating inflammation. Why then does PMR ever resolve at all? How is it that most patients with PMR do in fact manage to taper and stop steroids? There are at least two possible explanations for this. 

One possible explanation is that the predisposing factor (ageing) may still be present, but the inciting trigger has long gone; success in stopping steroids then would be determined by how easy it is for an individual to avoid future triggers. Pro-inflammatory triggers might include abrupt drops in glucocorticoid dose. Patient communities tell us that for some patients with PMR, very gradual symptom-directed tapers, involving tiny decrements in prednisone dose (reducing the dose by 0.5mg at a time, perhaps) may work where standard taper strategies have previously failed. This is hopeful news, and would be testable in clinical trials.

A second, less encouraging, explanation is that the inflammation ultimately “burns itself out”, with progressive age-related changes within the network reducing the overall traffic until a new stable state of the system emerges, which may itself have new, unpredictable dysfunctions. We know from clinical experience that PMR can evolve not just into GCA but alternatively into other chronic, immune-related inflammatory diseases, such as rheumatoid arthritis.

Either way, given a “trajectories of aging” explanation for what causes PMR, it would not be surprising if patients with PMR followed a chronic disease course over many years. Even after they have stopped prednisone treatment, we cannot assume that they have returned to their former state of health. Cessation of glucocorticoid therapy does not necessarily imply the disease has resolved, or is in “remission”; all we really know is that the prescriptions have ceased. We urgently need studies of long-term outcomes after steroid cessation in PMR. Early, as yet unpublished indications have shown concerning clues [5, 6]. 

The elephant in the room, where PMR epidemiology is concerned, is the “diagnostic overshadowing” issue. Simply put, it’s probably a lot easier to receive a PMR diagnosis if you have advantages in life like being well-educated, articulate, and with few comorbidities to complicate the evaluation or to dissuade the doctor from prescribing glucocorticoids. 

Whether these comorbidities also have a secondary effect of somehow protecting the body from developing PMR at all is doubtful, and in any case difficult to test using epidemiological methods if there is underdiagnosis. Multimorbidity is generally a pro-inflammatory state, so it’s hard to see how it would prevent or suppress PMR. More plausibly multimorbidity might mask the symptoms of PMR: patients may be assumed to be getting older and frailer as a natural consequence of their other medical conditions, and so the PMR diagnosis is missed. We call this “diagnostic overshadowing”. A common view of PMR as “diagnosis of exclusion”, and the constant worry for physicians that they have missed a “PMR mimic”, does not help. How many tests should we do in the quest for PMR mimics? What happens when one of those tests – thyroid-stimulating hormone, for example - returns a slightly out-of-range result? These are thorny questions. The lack of a specific, easily-available blood test for PMR is one of the chief barriers to resolving them. 

According to UK primary care data[7] PMR is diagnosed more often in the affluent South of England than in the north of the country. This leads to a self-perpetuating problem: clinical pathways for PMR may have become over-optimised for the more affluent, advantaged part of the population. Heuristics developed in a particular place or time, that once worked quite well for one sector of the population, may become faulty when applied elsewhere. 

Some people living with PMR have told me that, on reading the current PMR diagnosis and treatment guidelines, they have a strange, disconcerting feeling that these guidelines do not seem to represent their lived experience at all: as if the guidelines are written for someone else, not for them. The British Society for Rheumatology is currently updating its PMR treatment guideline under the leadership of Dr Max Yates; meanwhile, the fundamental mysteries of what causes PMR remain unsolved. 


  1. Mackie SL, Taylor JC, Haroon-Rashid L, Martin S, Dasgupta B, Gough A, Green M, Hordon L, Jarrett S, Pease CT, Barrett JH, Watts R, Morgan AW; UK GCA Consortium; UKRAG Consortium. Association of HLA-DRB1 amino acid residues with giant cell arteritis: genetic association study, meta-analysis and geo-epidemiological investigation. Arthritis Res Ther. 2015 Jul 30;17(1):195. doi: 10.1186/s13075-015-0692-4. 
  2. Beck DB, Ferrada MA, Sikora KA, Ombrello AK, Collins JC, Pei W, Balanda N, Ross DL, Ospina Cardona D, Wu Z, Patel B, Manthiram K, Groarke EM, Gutierrez-Rodrigues F, Hoffmann P, Rosenzweig S, Nakabo S, Dillon LW, Hourigan CS, Tsai WL, Gupta S, Carmona-Rivera C, Asmar AJ, Xu L, Oda H, Goodspeed W, Barron KS, Nehrebecky M, Jones A, Laird RS, Deuitch N, Rowczenio D, Rominger E, Wells KV, Lee CR, Wang W, Trick M, Mullikin J, Wigerblad G, Brooks S, Dell'Orso S, Deng Z, Chae JJ, Dulau-Florea A, Malicdan MCV, Novacic D, Colbert RA, Kaplan MJ, Gadina M, Savic S, Lachmann HJ, Abu-Asab M, Solomon BD, Retterer K, Gahl WA, Burgess SM, Aksentijevich I, Young NS, Calvo KR, Werner A, Kastner DL, Grayson PC. Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease. N Engl J Med. 2020 Dec 31;383(27):2628-2638. doi: 10.1056/NEJMoa2026834. 
  3. Tshimologo M, Saunders B, Muller S, Mallen CD, Hider SL. Patients' views on the causes of their polymyalgia rheumatica: a content analysis of data from the PMR Cohort Study. BMJ Open. 2017 Jan 25;7(1):e014301. doi: 10.1136/bmjopen-2016-014301. 
  4. Isaacs JD, Burmester GR. Smart battles: immunosuppression versus immunomodulation in the inflammatory RMDs. Ann Rheum Dis. 2020 Aug;79(8):991-993. doi: 10.1136/annrheumdis-2020-218019.
  5. Van Sleen Y, Arends S, Van der Geest K, et al. AB0743 The impact of giant cell arteritis and polymyalgia rheumatica on frailty, daily functioning and quality of life in a prospective longitudinal standard-of-care cohort. Annals of the Rheumatic Diseases 2023;82:1577-1578.
  6. Charikleia Chatzigeorgiou, John C. Taylor, Faye Elliott, Eoin P. O’Sullivan, UK Biobank Eye and Vision Consortium, Ann W. Morgan, Jennifer H. Barrett, Sarah L. Mackie. Common comorbidities in polymyalgia rheumatica and giant cell arteritis: cross-sectional study in UK Biobank. medRxiv 2023.05.08.23289633; doi:
  7. Partington RJ, Muller S, Helliwell T, Mallen CD, Abdul Sultan A. Incidence, prevalence and treatment burden of polymyalgia rheumatica in the UK over two decades: a population-based study. Ann Rheum Dis. 2018 Dec;77(12):1750-1756.  


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Dr Sarah Mackie is an academic rheumatologist based in Leeds, UK. Her research interests are giant cell arteritis (GCA) and polymyalgia rheumatica (PMR). She is first author of the 2020 British Society for Rheumatology guideline on giant cell arteritis. Her team won a 2022 British Society for Rheumatology Best Practice award for their GCA diagnostic pathway. She is Co-Chair of the Outcome Measures in PMR Working Group which has produced a Core Domain Set for clinical trials in PMR. She is Chief Investigator of the STERLING-PMR trial which will start recruiting soon.