Diagnosis of polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) is based on typical clinical, histologic, and laboratory features. Ultrasonographic imaging in PMR with assessment especially of subdeltoid bursitis can aid in diagnosis and in following response to treatment. In GCA, diagnosis and disease activity are supported with ultrasonographic, MRI, or [ 18 F]fluorodeoxyglucose PET evaluation of large vessels. Glucocorticoids are the primary therapy for PMR and GCA. Methotrexate may be used in patients at high risk for glucocorticoid adverse effects and patients with frequent relapse or needing protracted therapy. Other therapeutic approaches including interleukin 6 antagonists are under evaluation.
Key points
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Polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) are diseases of older persons most common in persons of Northern European ancestry. There is considerable clinical overlap between the diseases, and there are many disease mimics.
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Advanced imaging can be useful in support of the diagnosis of the diseases.
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In PMR, typical ultrasonographic findings include subdeltoid bursitis and bicipital tendonitis, which resolve on successful treatment.
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Prompt initiation of treatment is important to avoid complications of visual loss in GCA and severe functional impairment in PMR.
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The course of the diseases is variable. They generally require treatment with glucocorticoids for 1 to 3 years and often longer.
Introduction
Polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) are both inflammatory disorders of older people, generally older than 50 years, with a peak incidence about the age of 73 years. PMR is the second most common inflammatory rheumatic disease in the elderly after rheumatoid arthritis (RA), and GCA is the most frequent form of idiopathic vasculitis of older persons. PMR and GCA affect similar patient populations, predominately but not exclusively persons of Northern European ancestry. Women are affected 2 to 3 times more frequently than men.
Features of PMR occur in 40% to 60% of patients with GCA, and 16% to 21% of patients with PMR may also have GCA.
PMR is a disabling condition because of the severe musculoskeletal pain, stiffness, and limitations of joint mobility, especially in the shoulder and hip. GCA may lead to sudden visual loss, including blindness in 1 or both eyes, and it is associated with morbidity caused by large-vessel disease, including acute or chronic large-vessel stenosis as well as aortic aneurysms. Regular evaluation and monitoring of patients with GCA for vascular complications is essential. Besides, optimal management of risk factors for atherosclerosis is necessary given that both patients with PMR and GCA are at an increased risk for peripheral arterial disease.
Although life expectancy of patients with PMR and GCA is generally not different from the general population, patients who develop aneurysms have a markedly reduced life expectancy.
Introduction
Polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) are both inflammatory disorders of older people, generally older than 50 years, with a peak incidence about the age of 73 years. PMR is the second most common inflammatory rheumatic disease in the elderly after rheumatoid arthritis (RA), and GCA is the most frequent form of idiopathic vasculitis of older persons. PMR and GCA affect similar patient populations, predominately but not exclusively persons of Northern European ancestry. Women are affected 2 to 3 times more frequently than men.
Features of PMR occur in 40% to 60% of patients with GCA, and 16% to 21% of patients with PMR may also have GCA.
PMR is a disabling condition because of the severe musculoskeletal pain, stiffness, and limitations of joint mobility, especially in the shoulder and hip. GCA may lead to sudden visual loss, including blindness in 1 or both eyes, and it is associated with morbidity caused by large-vessel disease, including acute or chronic large-vessel stenosis as well as aortic aneurysms. Regular evaluation and monitoring of patients with GCA for vascular complications is essential. Besides, optimal management of risk factors for atherosclerosis is necessary given that both patients with PMR and GCA are at an increased risk for peripheral arterial disease.
Although life expectancy of patients with PMR and GCA is generally not different from the general population, patients who develop aneurysms have a markedly reduced life expectancy.
Clinical features
The cardinal symptoms of PMR include bilateral pain and stiffness of the shoulders and hips. Symptoms often begin acutely, over a matter of a few days to a few weeks. Bilateral shoulder and hip pain and stiffness can quickly lead to functional impairment. Even rising out of a chair or bed may become impossible because of pain and stiffness, not muscle weakness. Other symptoms may include peripheral arthritis, constitutional features such as weight loss, flulike symptoms, fatigue, and depression. Inflammatory markers including the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels are elevated at diagnosis in more than 90% of patients with PMR.
All these features have been captured by the provisional classification criteria for PMR set forth by the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) developed for the study of this disease ( Table 1 ).
| Criteria | Points Without Ultrasonography (0–6) | Points with Ultrasonography a (0–8) |
|---|---|---|
| Morning stiffness duration >45 min | 2 | 2 |
| Hip pain or limited range of movement | 1 | 1 |
| Absence of RF or ACPA | 2 | 2 |
| Absence of other joint involvement | 1 | 1 |
| ≥1 shoulder with subdeltoid bursitis and/or biceps tenosynovitis and/or glenohumeral synovitis (either posterior or axillary) and ≥1 hip with synovitis and/or trochanteric bursitis | n/a | 1 |
| Both shoulders with subdeltoid bursitis, biceps tenosynovitis, or glenohumeral synovitis | n/a | 1 |
Clinical features of GCA include scalp tenderness and jaw claudication. Headache occurs in only about 50% to 70% of patients. Occasionally, the temporal artery or other superficial cranial arteries may feel nodular and thickened to palpation. Diplopia and partial or complete loss of vision occur in up to 20% of patients; stroke and cranial nerve palsy may also be observed. Systemic features include polymyalgia symptoms, weight loss, fatigue, and fever.
Some patients with GCA, particularly those with extracranial GCA, may present with extensive systemic inflammation suffering from constitutional symptoms (eg, fever of unknown origin) or treatment-resistant PMR (referred to 60 years ago as polymyalgia arteritica) rather than ischemic complications. Another subset of patients with GCA (≤25%) develops symptoms related to extracranial large-vessel vasculitis such as arm claudication, arterial bruits, and heart murmurs.
Inflammatory markers including CRP and ESR are increased in about 95% of patients with GCA at disease onset. Biopsy of the temporal artery is the standard for definitive diagnosis of cranial disease, which can be aided or even replaced in individual cases by ultrasonographic imaging. Sonography of affected arteries may reveal a halo (ie, a hypoechoic thickening of the arterial wall), stenosis, or occlusion in the active phase of the disease. MRI and computed tomography-aided arteriography are especially useful for defining structural abnormalities including aneurysm and stenosis of extracranial large vessels, whereas for the assessment of disease activity, ultrasonography, MRI, and fluorodeoxyglucose (FDG) PET may be more useful as imaging tools.
Key features of GCA are included in the 1990 ACR Classification Criteria for this disease, developed to distinguish GCA from other forms of systemic vasculitis ( Box 1 ).
- 1.
Age at onset of disease greater than 50 years
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New headache
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Temporal artery abnormality (tenderness to palpation or decreased pulse)
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Increased ESR greater than 50 mm/h
- 5.
Abnormal findings on biopsy of the temporal artery. The histopathology of the artery shows vasculitis with predominant mononuclear cells or granulomatous inflammation usually with multinucleated giant cells
Misdiagnosis of PMR and GCA is common; up to 30% of patients initially diagnosed with PMR were found to have another condition during follow-up. The most important differential diagnosis is RA, given that 65% of patients with PMR whose diagnosis was corrected during follow-up suffered from this condition. Other important differential diagnostic considerations include osteoarthritis, spondyloarthritis, crystalline arthropathy, systemic lupus erythematosus and other connective tissue diseases, other forms of vasculitis, systemic infections, hematologic malignancy, thyroid and parathyroid disease, and Parkinson disease.
There is no specific laboratory test for PMR and GCA. The presence of abnormal results of electrophoresis or autoantibody testing (such as antinuclear antibodies [ANA], anticitrullinated protein antibodies [ACPA], or antineutrophil cytoplasmic antibodies [ANCA]) may suggest another diagnosis.
Basic laboratory tests in patients being evaluated for new-onset PMR and GCA include ESR, CRP, serum electrophoresis, ACPA (PMR only), ANCA (GCA only), full blood count, liver function tests, serum glucose, urea, creatinine, electrolytes, serum lipids, creatine kinase, urine analysis, and thyroid-stimulating hormone. Depending on the clinical scenario, other tests may be requested such as ANA or tuberculosis testing. Patients should be evaluated for the presence of comorbidities such as hypertension, diabetes, or osteoporosis.
Management
Rapid diagnosis and initiation of treatment are essential to reduce pain and stiffness in those with PMR and to prevent blindness and other ischemic complications in patients with GCA. Fast-track pathways with initial assessment and treatment of patients with suspected GCA within 1 to a few days are gaining ground as the standard of care. In Southend, UK, this strategy has led to a significant reduction of permanent sight loss compared with a historical cohort ( Fig. 1 ). Accordingly, patients with suspected GCA are immediately started on prednisone 40 to 60 mg daily and referred to the fast-track clinic, where they are seen within a working day by a rheumatologist. Patients with ischemic symptoms or jaw pain in addition receive intravenous pulse glucocorticoids (GCs) immediately. Patients then undergo full assessments, including temporal artery ultrasonography and biopsy, and are seen back within 2 weeks, during which time oral GCs are continued at 40 to 60 mg daily. In cases in which a diagnosis is confirmed, patients are followed up in the rheumatology outpatient clinic; otherwise, GCs are rapidly tapered off and patients further evaluated as dictated by symptoms and disease course.
General principles of management of PMR and GCA include (1) assurance of proper diagnosis, (2) evaluation of comorbidities, relevant medications, and risk factors for GC-related side effects, (3) assessment of risk factors for relapse/prolonged therapy, (4) an individualized disease management plan considering the patient’s perspective/preferences and shared decision making between the patient and the treating physician, (5) patient education about the disease; and (6) regular monitoring and management of disease activity, side effects, and comorbidities.
PMR is commonly treated in primary care but it is suggested to consider specialist referral, particularly in cases of atypical presentation and complex disease course and therapy. It is important to pay attention to patients’ physical function, encouraging physical fitness and mobility, to maintain long-term independence and a satisfying quality of life.
Because PMR and GCA are associated with an increased risk of peripheral arterial disease and patients with GCA are prone to cardiovascular complications over the course of the disease, management should include periodic evaluation for these conditions.
Mechanisms of glucocorticoid actions
The reasons for the successful use of GCs are their strong antiinflammatory and immunosuppressive effects. To understand their established effectiveness in PMR and GCA (and many other) diseases, a short description of their mechanisms of action may be helpful. This description seems to be especially appropriate in this context because different dosages are used in the treatment of PMR and GCA, ranging from maintenance treatment in PMR with low dosages of 5 mg/d or less prednisone equivalent to pulse therapy with grams of methylprednisolone (MP) in complicated GCA ( Fig. 2 ).
GCs exert their main antiinflammatory and immunosuppressive effects primarily on leucocytes and secondary immune cells, where their functions as well as their distribution are affected. These antiinflammatory and immunosuppressive effects are primarily produced via so-called genomic mechanisms, that is, the classic mechanism of action mediated by the cytosolic GC receptor (cGR). This genomic mechanism of GC action can be divided into the transactivation and the transrepression processes. The so-called transrepression results in a decreased expression of proinflammatory cytokines, whereas the increased synthesis of antiinflammatory (and other) proteins is termed transactivation. The current view is that transactivation could account for several adverse effects (but also mediating immunosuppressive effects), whereas transrepression is to a greater extent responsible for the main part of the therapeutic effects of GCs.
The higher the administered GC dose, the more cGR are recruited and the more intense are the genomic effects induced. It has been reported that 7.5 and 15 mg/d of prednisone would result in blood concentrations 8 hours after the dose that would bind the receptors to 42% and 63% of saturation, respectively (see Fig. 2 ). According to this calculation, higher doses (ie, ≥100 mg prednisone equivalent) result in nearly complete receptor saturation (see Fig. 2 ). With increasing GC doses, more cGR are recruited. This situation leads to more intense genomic effects, achieving about 100% at around 100 mg/d. Therefore, additional therapeutic benefits with dosages of 100 mg/d or greater are considered to be obtained via qualitatively different, nongenomic effects that come increasingly into play at dosages of 50 to 100 mg/d and higher. Dosages greater than 100 mg/d cannot produce stronger clinical effects via genomic effects. Therefore, additional therapeutic benefits produced by these higher doses are considered to be obtained via qualitatively different, nongenomic effects (see Fig. 2 ).
These nongenomic effects are mediated via (1) nonspecific interactions of GCs with cellular membranes, (2) nongenomic effects mediated by the cGR, and (3) specific interactions with a membrane-bound GR (mGR). Experimental data suggest that these differential effects come increasingly into play greater than 50 to 100 mg/d.
From these considerations, there are 3 major messages that are relevant for the treatment of PMR and GCA with GC:
- 1.
GCs form the mainstay of therapy for PMR and GCA because they exert manifold and strong antiinflammatory and immunosuppressive effects.
- 2.
Therapeutically, most important are the classic genomic mechanisms that are mediated via the cGR. These effects occur at any dosages, also at low ones, but the higher the dosage, the more receptors are activated and the stronger the GC effects reaching a maximum at a dosage of around 100 mg/d.
- 3.
At higher GC dosages (as with pulse therapy in GCA), rapid nongenomic effects also come into play that contribute to their therapeutic efficacy.
Why does clinical efficacy of glucocorticoid therapy vary among different patients?
The efficacy of certain (especially lower) GC dosages varies among different patients. The reasons for this situation are not entirely known, but this observation explains why GC dosing recommendations are for dose ranges rather than specific dosages for the treatment of diseases such as PMR and GCA.
There are several reasons for variation in efficacy of specific GC dosages, including (1) interindividual variability in pharmacokinetics, including differences in both number of cGC sites and binding affinities ; (2) mediation of (relative) glucocorticoid receptor (GCR) resistance, including polymorphic changes or overexpression of (co-)chaperones, overexpression of the GCR β isoform, the multidrug-resistance pump, and an altered membrane-bound GCR expression ; (3) variation in activation of mitogen-activated protein kinase pathways by certain cytokines; (4) excessive activation of the transcription factor activator protein 1; (5) reduced histone deacetylase-2 expression; (6) increased macrophage migration inhibitory factor; and (7) increased P-glycoprotein-mediated drug efflux.
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