CME Rheumatology Clinical Medicine 2013, Vol 13, No 4: 398–400

Polymyalgia Relationship to giant cell arteritis Diagnosis There is a well-known association between Diagnosis of PMR involves recognising the rheumatica: PMR and giant cell arteritis (GCA). Many clinical syndrome of PMR and excluding patients with GCA also have polymyalgic common differential diagnoses. This has been pathogenesis and symptoms and some patients with PMR conceptualised as a ‘stepped approach’.8 subsequently develop GCA.6 A subset of The clinical syndrome of PMR consists of management patients with PMR may have subclinical pain and stiffness that is typically worst in the GCA.7 There is some discussion as to early hours of the morning or on waking, and Sarah Louise Mackie, academic clinical whether PMR and GCA are separate tends to improve over the course of the day. lecturer in rheumatology disease entities or two conditions on a The neck, shoulder and hip areas are classi- University of Leeds, UK single pathophysiological spectrum. For cally affected first. Inflammatory markers are the practising clinician it is important to typically elevated and anaemia of inflamma- realise that PMR and GCA are treated with tion may be present. If any of these features different doses of glucocorticoids and that are missing then particular efforts should be What is polymyalgia rheumatica? treatment of GCA is a medical emergency, made to search for other diagnoses prior to Polymyalgia rheumatica (PMR) is an inflam- whereas the immediate priority with PMR considering glucocorticoid treatment. ‘PMR matory musculoskeletal disorder, with a is to exclude other conditions before with a normal ESR’ has been described; in lifetime risk of 2.4% for women and 1.7% starting treatment. The subset of PMR these cases it is may be useful to check CRP for men.1 Its cause is unknown, but ultra- patients that later develop GCA tend to levels. sound and magnetic resonance imaging have higher inflammatory markers and Other features at presentation may support (MRI) studies reveal extra-capsular inflam- particular HLA-DRB1 alleles (a subclass of alternative diagnoses. Although weight loss, mation, such as bursitis, in addition to syno- the human leukocyte antigen [HLA]) and fever and synovitis/tenosynovitis have all been vitis.2 PMR classically responds very well to so receive a higher than usual dose of glu- described in PMR, they should raise a suspi- 6 systemic glucocorticoids. cocorticoids at PMR onset. Indeed, studies cion of malignancy, of deep-seated or dis- PMR, if undiagnosed, has devastating of GCA consistently reveal an association seminated infection (such as endocarditis or effects: patients typically cannot get out with HLA-DRB1*04 alleles, whereas no osteomyelitis) or of inflammatory arthritides of, or even turn over in, bed. The cata- consistent HLA association of PMR has such as rheumatoid arthritis (RA), spondy- 9,10 strophic effects on physical functioning been found. At present PMR may be best loarthropathy or crystal arthropathy. and quality of life are reversed by treat- viewed as a clinical syndrome with hetero- Even in apparently classical PMR, it is ment.3 Rapid diagnosis is therefore geneous aetiology, overlapping with GCA advisable to perform a complete physical essential. in only a minority of cases. investigation and basic laboratory investi- Diagnosis of PMR can be challenging. gations including tests for full blood count (FBC), urea and electrolytes (U+E), liver The classical history consists of profound Relationship to ageing pain and stiffness affecting the neck, function tests (LFT), calcium, creatinine shoulder and hip areas. Symptoms are By far the strongest risk factor for PMR is kinase (CK), thyroid stimulating hormone maximal in the morning and improve increasing age. PMR is virtually unheard (TSH) and immunoglobulins to screen for 8 throughout the day. Physical examination of in those under 50 years old and inci- other medical conditions. may be unremarkable but may give clues dence of the disease becomes more to mimics of PMR (such as malignancy, common with each decade, with a peak Initial treatment deep seated infection or other inflamma- incidence around 75 years. The reason for tory illness).4 Inflammatory markers, this is unclear. Ageing of the immune Once a clinical diagnosis of PMR has been such as C-reactive protein (CRP), eryth- system (immunosenescence), ageing of made, treatment is commenced:11 15mg rocyte sedimentation rate (ESR) and the tissues and ageing of neurohumoral prednisolone daily is typically used. Clinical plasma viscosity (PV) are typically regulatory systems may all be involved. response does not confirm the diagnosis as elevated. Based on the clustering of cases in space many other inflammatory conditions also Reflecting the difficulty in diagnosis, and time, it has been proposed that PMR respond to glucocorticoids.5 However, multiple sets of diagnostic criteria for PMR may be triggered by infection in some failure to respond within a few days to have been produced, none with perfect cases. This could lead to persistent inflam- 15–20 mg prednisolone daily should raise performance. Recent provisional criteria mation on a background of chronic low- suspicions of other conditions and the incorporate optional ultrasound features;5 grade inflammation secondary to decline diagnosis should be reconsidered. Also, it should be emphasised that these are clas- in adaptive immunity and a compensatory patients with PMR may be left with some sification criteria (disease-defining) and increase in innate immune mechanisms. pain and stiffness despite glucocorticoid have not yet been validated as diagnostic Neurohumoral mechanisms may also be therapy,3,5 which may perhaps relate to criteria. involved. comorbid osteoarthritis in older patients.

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Ongoing treatment lative. A similar argument applies to the small expectation is that glucocorticoid therapy number of patients for whom biologic drugs can be gradually withdrawn and ultimately After the initial symptomatic response to have been tried, with mixed results. stopped. However, many patients relapse as glucocorticoids, the dose is gradually reduced. the glucocorticoid dose is reduced, particu- A typical regimen is reduction by 2.5 mg Comorbidity larly those with higher inflammatory prednisolone every 2–4 weeks, until reaching markers pre-treatment. Typically, half of all 10 mg daily, and then by 1 mg per month At the time of diagnosis of PMR it is impor- patients still require treatment 2 years after until cessation or until symptoms flare. Some tant to assess patients for comorbidities and diagnosis.6 Because patients with PMR patients need a slower reduction of 0.5 mg to continue to monitor patients during the almost invariably receive glucocorticoids it per month. Tapering of glucocorticoid dose course of treatment. Given the strong associa- is difficult to determine whether subse- should be guided by clinical symptoms, not tion with GCA, patients should be alerted to quent adverse events are due to the PMR, to by inflammatory markers; thus recording possible GCA symptoms (eg headache, scalp the glucocorticoids, or both. When pro- 12 relevant patient-reported outcomes repre- tenderness, jaw claudication, visual symp- spectively monitored, a high rate of adverse sents good practice. In the case of symptom toms), but there is no need for a temporal events has been noted.3 Patients should be flare, returning to the previous effective dose artery biopsy if there are no clinical features involved in decisions about their treatment, is usually sufficient. If GCA supervenes, treat- of GCA. It is also important to remember as the balance between the risk of relapse ment should be as for de novo GCA with that glucocorticoids can cause adverse effects and the risk of treatment-related complica- high-dose glucocorticoids. in elderly people.19 When committing patients tions may be different for each individual. At present there does not seem to be any to long-term glucocorticoid treatment, there alternative to glucocorticoid therapy. Oral should be an assessment of conditions that References prednisolone/prednisone is currently used may be caused, or exacerbated, by glucocorti- for almost all patients, but alternatives coids, including osteoporosis, diabetes, hyper- 1 Crowson CS, Matteson EL, Myasoedova E include periodic intramuscular methyl- tension, vascular disease, increased body et al. The lifetime risk of adult-onset rheu- prednisolone.13 weight and peripheral oedema.20 These matoid arthritis and other inflammatory There is little evidence to justify the use autoimmune rheumatic disorders. Arthritis conditions should then be monitored during Rheum 2011;63:633–9. of steroid-sparing drugs in PMR. the course of the patient’s treatment. 2 Camellino D, Cimmino MA. Imaging of 14–16 17 Methotrexate and azathioprine have Co-prescription of gastric and bone protec- polymyalgia rheumatica: indications on its been proposed, but one study15 gave negative tion (at least calcium and vitamin D supple- pathogenesis, diagnosis and prognosis. results and methotrexate does not seem to ments) is advisable throughout the period of Rheumatology (Oxford) 2012;51:77–86. 3 Hutchings A, Hollywood J, Lamping DL lead to a substantial reduction in glucocorti- treatment with steroids. 18 et al. Clinical outcomes, quality of life and coid-related adverse events. The difficulty diagnostic uncertainty in the first year of with interpreting the evidence is the clinical Prognosis polymyalgia rheumatica. Arthritis Rheum heterogeneity of PMR and ascertainment 2007;57:803–9. issues of each case. It may be that the weak It is important to keep an open mind about 4 Gonzalez-Gay MA, Garcia-Porrua C, effect of methotrexate in some studies is due diagnosis, at least for the first year of treat- Salvarani C et al. The spectrum of condi- tions mimicking polymyalgia rheumatica to patients with apparent PMR actually ment, as other conditions may take time to in Northwestern Spain. J Rheumatol having RA, which usually responds well to declare themselves. PMR itself is usually 2000;27:2179–84. methotrexate. However this theory is specu- seen as a self-limiting disorder and the 5 Dasgupta B, Cimmino MA, Kremers HM et al. 2012 provisional classification criteria for polymyalgia rheumatica: a European Key points League Against Rheumatism/American College of Rheumatology collaborative ini- Polymyalgia rheumatica (PMR) is a treatable, inflammatory musculoskeletal disease tiative. Arthritis Rheum 2012;64:943–54. mostly affecting those over 50 years of age 6 Mackie SL, Hensor EM, Haugeberg G et al. Can the prognosis of polymyalgia rheu- Diagnosis of PMR can be difficult and is primarily based on the history of the patient matica be predicted at disease onset? plus consideration of alternative diagnoses including infection, malignancy and other Results from a 5-year prospective study. musculoskeletal disorders Rheumatology 2010;49:716–22. It is important to check inflammatory markers prior to treatment. If either the 7 Schmidt WA, Gromnica-Ihle E. Incidence symptoms or inflammatory markers do not respond rapidly to 15–20 mg prednisolone of temporal arteritis in patients with poly- daily, the diagnosis of PMR should be reconsidered myalgia rheumatica: a prospective study using colour Doppler ultrasonography of Patients with PMR should be alerted to possible giant cell arteritis (GCA) symptoms, the temporal arteries. Rheumatology including what they should do if they develop any of these symptoms (Oxford) 2002;41:46–52. Patients treated for PMR should be monitored for adverse effects of long-term 8 Dasgupta B, Borg FA, Hassan N et al. BSR glucocorticoids and BHPR guidelines for the management KEY WORDS: Polymyalgia rheumatica (PMR), pathogenesis, management, giant cell of polymyalgia rheumatica. Rheumatology arteritis (GCA) (Oxford) 2010;49:186–90.

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9 Pease CT, Haugeberg G, Morgan AW et al. resolve over 2–3 weeks, but most patients Diagnosing late onset rheumatoid arthritis, Treatment of subsequently experience recurrent attacks polymyalgia rheumatica, and temporal involving other joints and can develop joint arteritis in patients presenting with poly- hyperuricaemia myalgic symptoms. A prospective longterm damage and clinically apparent subcuta- evaluation. J Rheumatol 2005;32:1043–6. neous MSU crystal concretions (tophi) 10 Falsetti P, Acciai C, Volpe A, Lenzi L. and gout (Fig 1). Treatment aims to first relieve the Ultrasonography in early assessment of severe pain and inflammation of acute gout 1 elderly patients with polymyalgic symptoms: Edward Roddy, senior lecturer and and then to reduce the SUA level sufficiently a role in predicting diagnostic outcome? honorary consultant rheumatologist; to prevent crystal formation and to dissolve Scand J Rheumatol 2011;40:57–63. Michael Doherty,2 professor of 11 Hernández-Rodríguez J, Cid MC, López- existing crystals, thereby preventing further rheumatology Soto A et al. Treatment of polymyalgia attacks and irreversible joint damage. rheumatica: a systematic review. 1Keele University, UK; 2University of Arch Intern Med 2009;169:1839–50. Nottingham, UK 12 Matteson EL, Maradit-Kremers H, Management of acute gout Cimmino MA et al. Patient-reported Treatment of acute gout aims to provide outcomes in polymyalgia rheumatica. J Rheumatol 2012;39:795–803. Introduction rapid relief of pain and inflammation. The 13 Dasgupta B, Dolan AL, Panayi GS, affected joint should be rested and the appli- Fernandes L. An initially double-blind Gout is the most prevalent inflammatory cation of local ice-packs can safely reduce controlled 96 week trial of depot methyl- arthritis, affecting 1.4% of adults in the UK.1 pain and swelling.2 Pharmacological options prednisolone against oral prednisolone in Chronic elevation of serum uric acid (SUA), are oral non-steroidal anti-inflammatory the treatment of polymyalgia rheumatica. or hyperuricaemia, is required for gout to Br J Rheumatol 1998;37:189–95. drugs (NSAIDs), oral colchicine and 14 Ferraccioli G, Salaffi F, De Vita S et al. develop. Risk factors for hyperuricaemia and corticosteroids.3,4 Although no individual Methotrexate in polymyalgia rheumatica: gout are summarised in Box 1. When the NSAID appears superior to another, any preliminary results of an open-randomized SUA level increases above the physiological quick-acting NSAID can be used at the full study. J Rheumatol 1996;23:624–8. saturation threshold, monosodium urate dose together with a proton pump inhibitor. 15 van der Veen MJ, Dinant HJ, van Booma- (MSU) crystals precipitate in and around Frankfort C et al. Can methotrexate be Indometacin is best avoided in view of used as a steroid-sparing agent in the peripheral joints. After a prolonged period of frequent gastrointestinal, central nervous treatment of polymyalgia rheumatica and asymptomatic hyperuricaemia, gout typi- system and cardiovascular adverse effects. giant cell arteritis? Ann Rheum Dis cally presents clinically as an acute attack of Until recently, oral colchicine was often used 1996;55:218–23. excruciating joint pain, swelling and tender- in high doses, which frequently led to severe 16 Caporali R, Cimmino MA, Ferraccioli G ness, commonly affecting the first metatar- 5 et al. Prednisone plus methotrexate for diarrhoea, nausea or vomiting. However, polymyalgia rheumatica: a randomized, sophalangeal joint. Attacks characteristically current advice is to use a lower dose of 500 double-blind, placebo-controlled trial. µg two to four times daily, which remains Ann Intern Med 2004;141:493–500. Box 1. Risk factors for hyperuricaemia and effective and is better tolerated.3,4,6,7 17 De Silva M, Hazleman BL. Azathioprine in gout.1 The single most effective treatment for giant cell arteritis/polymyalgia rheumatica: a double-blind study. Ann Rheum Dis • Male gender acute gout is combined joint aspiration 1986;45:136–8. • Family history and/or genetic factors (immediately reducing intra-articular pres- 18 Cimmino MA, Salvarani C, Macchioni P • Metabolic syndrome sure and severe pain) and injection of intra- et al. Long-term follow-up of polymyalgia • Hypertension articular corticosteroid. This is particularly • Insulin resistance rheumatica patients treated with appropriate when NSAIDs and colchicine are methotrexate and steroids. Clin Exp • Obesity Rheumatol 2008;26:395–400. • Dietary factors (increased risk) contra-indicated or poorly tolerated and 19 Mazzantini M, Torre C, Miccoli M et al. — alcohol (particularly beer) enables a definitive diagnosis by synovial fluid Adverse events during longterm low-dose — purine-rich foods (red meat and seafood) MSU crystal identification. Intramuscular or glucocorticoid treatment of polymyalgia — fructose and sugar-sweetened soft drinks oral corticosteroids (eg prednisolone 20 mg • Dietary factors (reduced risk) rheumatica: a retrospective study. daily) are effective alternatives when NSAIDs J Rheumatol 2012;39:552–7. — cherries 20 van der Goes MC, Jacobs JW, Boers M et al. — vitamin C and colchicine are not appropriate, when Monitoring adverse events of low-dose — dairy products attacks are oligo- and/or polyarticular or glucocorticoid therapy: EULAR recom- — coffee when monoarticular attacks occur at sites mendations for clinical trials and daily • Medication that are not amenable to aspiration (eg mid- practice. Ann Rheum Dis 2010;69:1913–9. — diuretics (loops and thiazides) — ciclosporin foot joints). Address for correspondence: — pyrazinamide — ethambutol Dr SL Mackie, Wellcome Trust Brenner Long-term management • Impaired renal function Building, St James’s University • Osteoarthritis (gout only) Once the acute attack has resolved, long- Hospital, Leeds LS9 7TF. • Chronic lead poisoning term management aims to reduce the level Email: [email protected] • Myeloproliferative disorders of SUA below the saturation point,

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