Polymyalgia rheumatica (PMR) is, as the name would suggest, a chronic inflammatory condition, which causes pain in many different muscle groups including the shoulder and pelvic girdle. It is a condition that affects the older population and is associated with serious cardiovascular and ophthalmological complications. In particular there is a strong association between PMR and giant cell arteritis (previously known as temporal arteritis) which, if left untreated, can cause blindness.

Epidemiology
PMR can occur at any time after the age of 50 years, although it is rare in those under the age of 70 years. The average age of onset of PMR is slightly over 70 years of age.1,2 The annual incidence of PMR in the UK (in those aged over 50) is 100 per 100,000 persons ie. one in 1000 over 50 year olds will develop PMR every year.3 The prevalence of this condition is continuously increasing as a result of our ageing population. As with the majority of rheumatological disorders, it is more common in women, in fact 75% of all patients with PMR are female.2,3 It is most common in Caucasians although it does occur in patients of all ethnic groups.4 Patients of Northern European/ Scandinavian background are identified to be at the highest risk of developing PMR.3

Some studies have found PMR to be more prevalent in rural compared to urban areas. However, this could possibly be attributed to different health beliefs, health awareness and behaviours amongst the different socio-economic groups as opposed to an absolute difference in the total number of cases.5 The lifetime risk of PMR is 2.4% for women and 1.7% for men.Ten to 15% of patients with PMR will at some point develop giant cell arteritis, whilst 50% of patients presenting with giant cell arteritis are found to have co-existing PMR.7.8 


Pathophysiology
The aetiology of PMR has not yet been confirmed. Links have been made to alleles HLA-DR4 and HLA-DR1, suggesting a genetic predisposition for developing the disease. This could explain how the incidence of PMR can cluster in families and geographical areas however, both of these could also be explained by similar exposure to environmental factors.3,9 Patients with PMR have been shown to have increased levels of cytokines IFN-gamma and interleukin-6 (IL-6), which also correlate well with disease activity.2,4,10,11

Ageing of the immune system, tissues and altered neurohormonal regulatory systems may be responsible for PMR. However, the exact localisation of the trigger within the immune system is not known.12  The incidence of PMR has been noted to increase after epidemics of mycoplasma pneumonia, parvovirus B19 and chlamydia pneumonia, thus suggesting an infective cause.3 It could therefore be hypothesised that PMR can occur in genetically predisposed patients following exposure to specific infections.

Clinical features
A typical history of PMR would be that of acute onset muscle pain and stiffness. The muscle groups most commonly affected are those of the shoulder, neck, pelvis, thigh and lumbar spine. The pain is typically worse in the morning and can last for several hours.

In addition to the classical symptoms, one in three patients can also develop systemic symptoms such as tiredness, fevers, weight loss and even depression if the condition is left undiagnosed.3,8 Pain in the context of PMR is usually exacerbated by movement and patients may complain of pain when attempting the simplest activities of daily living including climbing stairs and dressing. Stiffness can be exacerbated by prolonged periods of rest, causing massive disruption to a patient’s daily life. Weakness is not a symptom of PMR except in the exceptional circumstance of disuse atrophy following repeated relapses of  the condition.

Those with symptoms of temporal headache, jaw claudication or scalp tenderness, or those who develop any visual disturbances should be investigated and treated immediately due to the suspected additional diagnosis of giant cell arteritis. Occasionally (in 15–30% of patients) signs such as peripheral arthritis, oedema and carpal tunnel syndrome may also be present.8

The British Society of Rheumatology (BSR) published guidelines for the correct diagnosis of PMR in 2009.13 It centres around the presence of the following ‘inclusion criterion’:

  • Age over 50 years
  • Duration of symptoms of more than two weeks
  • Bilateral shoulder and/or pelvic girdle pain
  • Morning stiffness of more than 45 minutes duration
  • Evidence of an acute phase response (raised ESR or CRP).

 

The BSR also listed certain ‘exclusion criterion’, which is essentially a list of differential diagnoses to be considered prior to diagnosing patients with PMR.3,13 They are as follows:

  • Active cancers, in particular myeloma
  • Infection eg. osteomyelitis, tuberculosis, endocarditis
  • Giant cell arteritis
  • Other inflammatory conditions eg. rheumatoid arthritis, systemic lupus erythematosus, myopathies, connective tissue diseases
  • Osteoarthritis
  • Fibromyalgia/ pain syndromes
  • Local shoulder/ hip conditions
  • Endocrine disorders eg. hypothyroidism, osteomalacia
  • Drug induced causes eg. statins causing myositis
  • Depression 

 

Diagnosis
As stated above, the diagnosis of PMR should begin with exploring the presence of diagnostic inclusion criteria and the absence of exclusion criteria as part of a thorough history and examination. The Royal College of Physicians recommends a ‘stepped diagnostic approach’ for the evaluation of PMR that includes a trial of treatment.14 Patients fitting the aforementioned criteria should commence a course of low-dose steroids ie. prednisolone 15mg daily. The diagnosis of PMR is confirmed after 3–4 weeks when, in the absence of any alternative diagnoses, the patient reports a global improvement in their symptoms of at least 70% within a week.14 There is typically a resolution of the raised acute phase reactant in 3–4 weeks.14  The lack of ‘gold standard’ diagnostic criteria makes diagnosing PMR difficult.15,16 Despite using the ‘stepped diagnostic approach’ there may be diagnostic error as proximal pain and stiffness can occur in other conditions. 

Investigations
The following routine investigations should be performed prior to commencing therapy for PMR, the exception being in the case of PMR with symptoms of giant cell arteritis which should be treated immediately (Box 1).
PMR can be diagnosed in patients with a typical presentation and response to steroids but normal ESR/CRP, however these patients should be referred to a rheumatologist.

Temporal artery biopsy is not indicated unless there are features of giant cell arteritis. A normal temporal artery biopsy does not exclude PMR.  Analysis of synovial fluid (for patients with joint effusions) may show evidence of inflammation and poor mucin clotting. There will be predominantly CD4 positive T cells and macrophages producing interleukin 1β and 6.3 Ultrasound demonstrates synovitis in 90% of patients with PMR with proximal synovitis (90%) being more common than peripheral synovitis (41%).19 The most predictive results for the definitive diagnosis of PMR by ultrasound would be the presence of subacrominal-subdeltoid bursitis.19 Again, ultrasound is not routinely performed or required for the diagnosis of PMR.

Management


Initial management
Treatment of PMR is not an acute emergency if the patient does not display features of giant cell arteritis and therefore treatment should only be commenced after initial investigations have been performed. First line treatment is oral prednisolone 15mg OD for three weeks, with a dose reduction as follows;
12.5mg OD for three weeks
10mg OD for 4–6 weeks
Then reduce by 1mg every 4–8 weeks.13

This regime is clearly complex in nature and requires high-quality patient education in order to ensure patient safety and adequate compliance. If there is any doubt around a patient’s ability to maintain a good level of compliance, consider written weekly prompts or dossette boxes. Patients should be given a ‘steroid card’ and information leaflet on initiation of long-term glucocorticoids and educated about the risks and side effects of glucocorticoids in addition to the symptoms and urgency of giant cell arteritis. IM methylprednisolone is a suitable alternative for mild PMR, especially when symptoms are limited to the shoulder, which may reduce the risk of complications related to steroid use. In this case an initial dose of 120mg should be given every 3–4 weeks, reducing this dose by 20mg every 2–3 months.8,13 When commencing treatment with steroids it is essential to assess the risk of complications for each individual patient and simultaneously cover with appropriate bone and gastric protection as well as considering glucose and blood pressure monitoring. 


Long-term management
Consideration should be made to the psychosocial aspects of PMR, especially as it affects the older population. Consider referral to physiotherapy and occupational therapy services in the community as PMR will affect a patients’ ability to carry out activities of daily living.
Duration of treatment for PMR is usually one to three years although there is considerable variability between patients. One cohort study has found that duration of treatment was longer in those with higher initial acute phase reactants.20 The same study also found evidence that starting treatment with a prednisolone dose greater than 15mg is associated with prolonged steroid therapy.20 Possible explanations for this would be over-rapid tapering of steroid doses causing relapse and increased adrenal suppression.20 41–50% of patients who receive an initial prednisolone dose of 10–20mg per day discontinue treatment after two years, 70% after three and 91% after 11 years.21 There seems to be no difference between discontinuation rates when comparing initial doses of 10mg/day compared to 15–20mg/day.21

Steroids can be stopped once symptoms have resolved (gradually reducing dose). Raised inflammatory markers alone (without symptoms) are not an indication to restart treatment.

Atypical clinical presentations such as those listed below would require specialist referral:8,13
• Younger patients ie. younger than 60 years old
• Chronic onset
• Lack of shoulder involvement
• Lack of stiffness
• Those with red flag symptoms eg. those with prominent systemic features
• Peripheral arthritis or other features of autoimmune or muscle disease
• Those with normal or very high inflammatory markers
• Those with recurrent relapse.

Others that would benefit from referral to rheumatology services would be those who fail to respond to initial treatment, those with contraindications to corticosteroid use and those requiring a prolonged course of steroids. Alternatives to corticosteroids will depend on the severity of symptoms. Non steroidal anti inflammatory drugs (NSAIDs) may have a role in symptom control only. Alternative immunosuppressants such as methotrexate and azothiaprine can be considered in severe cases. 

Follow up
Follow up is recommended two weeks and six weeks after commencing treatment, then every three months for one year, then at yearly intervals provided there are no further relapses.8,13 Follow up can be conducted in primary care provided the patient does not fit criteria for secondary care referral. Each appointment should review the presence of any clinical symptoms or side effects from treatment, including hypertension, in addition to biochemical markers, for example, fasting glucose, renal function, lipids, CRP and an assessment of osteoporotic risk, depending upon the age and sex of the patient and ongoing treatment.14


Relapse
One systematic review found approximately 25% of patients relapsed during the follow up period (10–11 years),21 which contrasts with a previous study showing only a 10% relapse rate within 10 years.3 The rate of relapse in the first year is 33%, which may provide some evidence to support slow tapering of corticosteroid doses over a period of several months.3,21

An observational case study of 80 patients found that relapses were more common in women and as a consequence women received higher cumulative doses of corticosteroids over the disease duration and therefore were subjected to higher rates of corticosteroid related adverse effects.22 Patients with elevated ESR, CRP and IL-6 levels at initial diagnosis are at a higher risk of relapse and typically require higher initial corticosteroid doses to control symptoms.21 

As stated previously, current evidence suggests the incidence of relapse can be reduced by slow tapering of prednisolone therapy however, in the event of relapse, prednisolone should be commenced as per initial treatment dose. Clinicians should consider adjuvant immunosuppressive therapy eg. using methotrexate after two relapses.8 The evidence to support this is more scarce compared to the evidence around the initial management of PMR. Evidence taken from the treatment of rheumatoid arthritis would suggest that intramuscular or subcutaneous methotrexate have added benefits and fewer side effects compared to oral methotrexate.21 If required, methotrexate should be continued for the duration of corticosteroid treatment followed by a gradual reduction in dose after a further six months.21 In a small minority of patients it may be necessary to take long-term steroids but at the lowest possible dose due to repeated relapses.

Patient information/support
Patient education and support is an essential component in the management of any chronic disease. Basic information and advice for patients can be found from websites such as ‘Patient UK’.23 In addition to this the ‘arthritis care’ charity provide a free helpline for advice and produce factsheets which are available on their website.24 Lastly, the charity group PMRGCAUK (polymyalgia rheumatica and giant cell arteritis UK) has similar facilities.25

Further developments
Many trials have been investigating the role of tumour necrosis factor (TNF) antagonists in the management of PMR.26,27 Etanercept, a TNF-alpha inhibitor is one such drug. One particular trial has shown etanercept to improve symptoms compared to placebo, however the effects were deemed modest.26 In contrast, another small and therefore underpowered trial found that adding infliximab to prednisolone did not provide any additional benefit.27 Further studies are trying to identify a clear aetiology of PMR by mapping the production of cytokines to try and elucidate a cause.10


Conflicts of interest: none declared
References


1. Polymyalgia rheumatica. Clinical Knowledge Summaries. 2009.
2. Gonzalez-Gay MA, Vazquez-Rodriguez TR, Lopez-Diaz M J, et al. Epidemiology of giant cell arteritis and polymyalgia rheumatica. Arthritis Rheum 2009; 61(10):1454–61
3. Michet CJ, Matteson EL. Polymyalgia rheumatica. BMJ 2008; 336(7647): 765–69
4. Ghosh P, Borg F A, Dasgupta B. Current understanding and management of giant cell arteritis and polymyalgia rheumatica. Expert Rev Clin Immunol 2010; 6(6): 913–28
5. Bernatsky S, Joseph L, Pineau CA, et al. Polymyalgia rheumatica prevalence in a population-based sample. Arthritis Rheum 2009; 61(9):1264–67
6. Crowson CS, Matteson EL, Myasoedova E, et al. The lifetime risk of adult-onset rheumatoid arthritis and other inflammatory autoimmune rheumatic diseases. Arthritis Rheum 2011; 63(3): 633–39
7. Dasgupta B, Borg FA, Hassan N, Alexander L, et al. BSR and BHPR guidelines for the management of giant cell arteritis. Rheumatology (Oxford) 2010; 49(8): 1594–97
8. Bhaskar D. Concise guidance: diagnosis and management of polymyalgia rheumatica. Clin Med 2010; 10(3): 270–74
9. Haworth S, Ridgeway J, Stewart I, et al. Polymyalgia rheumatica is associated with both HLA-DRB1*0401 and DRB1*0404. Br J Rheumatol 1996; 35(7): 632–35
10. Martinez-Taboada VM, Alvarez L, RuizSoto M, et al. Giant cell arteritis and polymyalgia rheumatica: role of cytokines in the pathogenesis and implications for treatment. Cytokine 2008; 44(2): 207–20
11. Salvarani C, Cantini F, Hunder G G. Polymyalgia rheumatica and giant-cell arteritis. Lancet 2008; 372(9634): 234–45
12. Weyand CM, Goronzy JJ. Giant-cell arteritis and polymyalgia rheumatica. Ann Intern Med 2003; 139(6): 505–15
13. Management of polymyalgia rheumatica. British Society for Rheumatology. 2009. http://www.rheumatology.org.uk/includes/documents/cm_docs/2009/m/management_of_polymyalgia_rheumatica.pdf (accessed 17/11/14)
14. Royal College of Physicians. Diagnosis and management of polymyalgia rheumatica: concise guidelines. 2010. https://www.rcplondon.ac.uk/resources/concise-guidelines-diagnosis-and-management-polymyalgia-rheumatica (accessed 17/11/14)
15. Dasgupta B, Borg FA, Hassan N, Barraclough K, et al. BSR and BHPR guidelines for the management of polymyalgia rheumatica. Rheumatology (Oxford) 2010; 49(1): 186–90
16. Mackie SL, Mallen CD. Polymyalgia rheumatica. BMJ 2013; 347: f6937
17. Cantini F, Salvarani C, Olivieri I, et al. Erythrocyte sedimentation rate and C-reactive protein in the evaluation of disease activity and severity in polymyalgia rheumatica: a prospective follow-up study. Semin Arthritis Rheum 2000; 30(1): 17–24
18. Ellis ME, Ralston S. The ESR
in the diagnosis and management of the polymyalgia rheumatica/giant cell arteritis syndrome. Ann Rheum Dis 1983; 42(2):168–170
19. Falsetti P, Acciai C, Volpe A, Lenzi L. Ultrasonography in early assessment of elderly patients with polymyalgic symptoms: a role in predicting diagnostic outcome? Scand J Rheumatol 2011; 40(1): 57–63
20. Mackie SL, Hensor EM, Haugeberg G, et al. Can the prognosis of polymyalgia rheumatica be predicted at disease onset? Results from a 5-year prospective study. Rheumatology 2010; 49(4): 716–22
21. Hernandez-Rodriguez J, Cid MC, Lopez-Soto A, et al. Treatment of polymyalgia rheumatica: a systematic review. Arch Intern Med 2009; 169(20):1839–50
22. Cimmino MA, Parodi M, Caporali R, Montecucco C. Is the course of steroid-treated polymyalgia rheumatica more severe in women? Ann N Y Acad Sci 2006; 1069: 315–21
23. http://www.patient.co.uk/health/polymyalgia-rheumatica-leaflet (accessed 10/11/14)
24. http://www.arthritiscare.org.uk/AboutArthritis/Conditions/polymyalgia-rheumatica-pmr (accessed 10/11/14)
25. http://www.pmrgcauk.com/content/pmr (accessed 10/11/14)
26. Kreiner F, Galbo H. Effect of etanercept in polymyalgia rheumatica: a randomized controlled trial. Arthritis Res Ther 2010; 12(5):R176.
27. Salvarani C, Macchioni P, Manzini C, Paolazzi G, Trotta A, Manganelli P et al. Infliximab plus prednisone or placebo plus prednisone for the initial treatment of polymyalgia rheumatica: a randomized trial. Ann Intern Med 2007; 146(9): 631–39