TITLE: POLYMYALGIA RHEUMATICA AND GIANT CELL ARTERITIS
AUTHORS: PETER J. EMBI, MD, MS -- Assistant Professor of Medicine
University of Cincinnati
GARY S. HOFFMAN, MD, MS -- Professor of Medicine,
Harold C. Schott Chair of Rheumatic and Immunologic Diseases
Center for Vasulitis Care and Research,
Lerner College of Medicine
Cleveland Clinic Foundation
PUBLISHED: DECEMBER 7, 2004
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Polymyalgia rheumatica (PMR) and giant-cell arteritis (GCA) are closely related, immune-mediated, inflammatory conditions of the elderly. They may coexist clinically, with PMR developing in about 40% of patients with GCA and GCA developing in at least 10% of patients with PMR.

Indeed, these conditions likely represent extremes of one disease spectrum as evidenced by their preference for the same patient populations, the same HLA haplotypes, similar serum and vessel immunohistochemistry cytokine patterns, and recent findings by positron emission tomography of similar arterial involvement in patients with clinical GCA or PMR.1-3
POLYMYALGIA RHEUMATICA
DEFINITION
PMR is an inflammatory illness of the elderly that is characterized by proximal, symmetric musculoskeletal pain and stiffness as well as features of systemic inflammation. The condition was first described by Bruce in 1888 as "senile rheumatic gout," a name that highlights its propensity for the aged.4 In 1957, the term "polymyalgia rheumatica" was proposed. As it was then, PMR remains an often challenging condition to diagnose but a rewarding condition to treat, given its typical dramatic response to corticosteroids (CS).
EPIDEMIOLOGY

PMR is unusual in those younger than age 50 years. In those over age 50, the annual incidence is between 12 and 50 per 100,000, with Caucasians, especially those of northern European descent, being afflicted more commonly than those of African or Asian ancestry. For instance, among the population of Olmsted County, Minnesota, a group composed predominantly of persons of Scandinavian descent, the prevalence is 59 per 100,000 persons among adults older than age 50 years.5

The incidence of both PMR and GCA increases with age, with an average age of onset of about 70 years. Women are affected about twice as often as men.6
PATHOPHYSIOLOGY

Although much has been learned about PMR since it was first described, its cause remains unknown. Nevertheless, there is a growing body of evidence to suggest that its etiology, onset, and severity are multifactorial, resulting from the interplay of age, environmental (possibly infectious), and genetic factors (it is associated with certain HLA antigens).
SIGNS AND SYMPTOMS

Although presentations differ, the typical patient describes a subacute onset and persistence of symptoms. Most report symmetric aching and stiffness in the shoulder girdle region (70%-95%) and the neck and pelvic girdle (50%-70%). Concurrent pain in the upper arms and thighs may be noted. Pain and stiffness is usually most severe for the first hour or more after awakening from sleep. Nighttime symptoms are not unusual, with bed partners often noting restlessness or even moaning during sleep. Discomfort may lead patients to experience difficulty performing such activities as dressing, brushing hair, or rising from a seated position. In addition to musculoskeletal complaints, about one third of patients have systemic symptoms such as fever, malaise, anorexia, and weight loss. They will often describe these symptoms as "a flu that won't go away."7

Examination may reveal limited active range of motion due to pain, but barring the comorbidity of true arthritis, passive range of motion is usually normal. Although subjective symptoms of weakness may be reported, PMR does not cause objective muscle weakness. Therefore, findings of "weakness" in the context of an examination with aggressive coaching to demonstrate strength either represents another condition or is the manifestation of decreased effort due to discomfort. Up to one half of patients manifest distal extremity findings that may include modest swelling of knees, wrists, or metacarpophalangeal joints, or carpal-tunnel syndrome. Diffuse soft-tissue swelling and pitting edema of the dorsal hands, ankles, and feet may occur, but is uncommon. If frank synovitis is noted, it may indicate that the patient has rheumatoid arthritis or another inflammatory arthropathy rather than PMR (See Chapter on Rheumatoid Arthritis). Therefore, caution must be exercised.
DIAGNOSIS

PMR is a clinical diagnosis. The clinical features noted above serve as the basis for the diagnosis, with laboratory findings supportive in the right setting. In more than 90% of cases, the erythrocyte sedimentation rate (ESR) is greater than 40 mm/hr. Additional laboratory findings of systemic inflammation are often noted and include elevated C-reactive protein (CRP), normocytic normochromic anemia, elevated platelet count, and elevated alkaline phosphatase. Of note, muscle enzymes such as creatine kinase are normal, as myocyte damage is not a feature of PMR.

Over the years, several diagnostic criteria have been proposed for the diagnosis of PMR (Table 1). Each provides insight into the typical manifestations of PMR. In 1979, Bird et al proposed that any three of his proposed criteria be met or that any one plus a positive temporal artery biopsy be present, thereby emphasizing the link between GCA and PMR.8 In 1981, Jones and Hazelman proposed somewhat different criteria and added the requirement that the patient experience a rapid response to CS therapy.9 Chuang et al followed in 1982 with criteria that proposed lowering the age to 50 as well as requiring the presence of all their criteria.10 Finally, in 1984, Healey proposed criteria that further emphasized that certain clinical and steroid response features be present to be certain about the diagnosis of PMR.11

Although patients meeting these criteria likely have PMR, despite the stated requirement that most or all of these features must be present in order to diagnose PMR, most authorities agree that no single feature is absolutely necessary to diagnose PMR in all cases. Having said that, the similarity among these criteria serves to highlight the typical and most common features of PMR. Indeed, the features noted in the criteria above are so common that should patients present atypically or should response to CS therapy be suboptimal, reconsideration of the diagnosis may be. Differential diagnostic considerations include malignancies, chronic infections, and other rheumatic conditions such as rheumatoid arthritis; the latter can sometimes be difficult to differentiate from PMR at presentation.12
THERAPY
As has been the case for decades, the cornerstone of therapy for PMR is CS. Typical treatment is with prednisone, starting at 10 to 15 mg daily, with only the occasional patient requiring more than 20 mg daily. Such therapy typically leads to near-total symptom relief within a few days to 1 week. Indeed, although it can happen, lack of response to steroids is so unusual that it should prompt reconsideration of the diagnosis. In addition to symptomatic relief, a gradual decline in acute phase reactants is also expected. However, laboratory tests should not be the primary gauge of treatment adequacy.

If response is achieved, the initial dose is typically maintained for 1 month before being tapered gradually in approximately 2.5 mg decrements every 2 to 4 weeks. Disease flares with CS tapering are common and often require temporary escalations in therapy. Distinguishing a PMR flare from CS withdrawal can be challenging, and laboratory tests are variably helpful in making the distinction. Relapses may occur with normal ESRs. However, a marked increase in ESR not attributable to comorbidities is very worrisome because vague symptoms may be a feature of relapse or a soon-to-become-apparent relapse. Thus, an isolated increase in ESR should lead to more careful follow-up. Most patients require 6 months to 2 years of low-dose CS therapy, but some require treatment for many years.13

Disease-modifying antirheumatic drugs, like methotrexate, have not been proven to be effective for the treatment of PMR.14,15
OUTCOMES
With adequate treatment, most patients are able to remain symptom free. However, this may require prolonged CS therapy in a significant number of patients. It is important to maintain adequate follow-up in order to monitor for complications of the disease and of CS therapy.

Because PMR may precede the development of GCA, physicians and patients should remain vigilant for the development of GCA symptoms and signs. The development of new headache and visual disturbances should prompt immediate medical evaluation and escalation of the CS dose. In addition, physicians should check blood pressures in both arms and listen for bruits throughout the vasculature to uncover signs of large-vessel stenosis or aneurysms due to GCA.

Screening for and treatment of osteoporosis is also critical in these patients. The necessity for long-term CS therapy in these elderly patients increases their risk for losing bone mineral density and sustaining fractures. Monitoring for CS-associated complications, including the development of diabetes mellitus or glaucoma as well as complications like steroid-induced sleep and mood disturbances, is also important.
GIANT CELL ARTERITIS
DEFINITION

Giant cell (temporal) arteritis (GCA) is the most common form of vasculitis affecting adults in western countries. It is an inflammatory vasculopathy characterized by sterile granulomatous inflammation of medium and large arteries. Although widespread arterial involvement may occur, aortic arch vessels and cranial arteries are preferentially targeted.

PREVALENCE
In the United States, GCA affects about 18 of 100,000 people age 50 years or older in the population. The epidemiologic characteristics of GCA mirror those of PMR. The incidence of GCA is much higher in the northern latitudes; mean age of onset is 74 years; and women are affected more commonly than men (2-3:1). These conditions may represent ends of a disease spectrum, and some patients manifest features of both PMR and GCA. Indeed, about 40% of patients with GCA concurrently have features of PMR at some point in their disease course.
PATHOPHYSIOLOGY
Although the cause of GCA remains unknown, our knowledge of the nature of the inflammatory lesions has progressed over the past 10 years. Inflammation begins in the adventitia of affected vessels. Immune-reactive cells (dendritic cells, macrophages, and TH1-type lymphocytes) enter the vessel wall via the vasa vasorum. A small (2%-5%) but presumably significant subset of activated T lymphocytes in the temporal artery wall are clonally expanded. The same clonal expansion is not present in the systemic circulation of individuals with GCA or in controls. These data have been cited to support the notion that the putative antigen responsible for GCA is present in affected vessels, requiring only a unique immunologically predisposed host to consummate the disease. A broad range of proinflammatory cytokines and matrix-degrading mediators lead to arterial damage and contribute to the systemic inflammatory features of GCA. Activated macrophages and giant cells produce growth factors that contribute to intimal proliferation and stenosis of arteries, events that eventually lead to the ischemic effects. A better understanding of the roles of these cytokine relationships has led to ongoing clinical trials to assess the efficacy of selected cytokine blockade strategies. Preliminary, promising reports of improvement with anti-tumor necrosis factor treatment have been published.6,16,17
SIGNS AND SYMPTOMS
As with PMR, the typical patient with GCA is elderly and Caucasian. Symptom onset is usually gradual but may be sudden and severe. Manifestations resulting from systemic inflammation occur in about one half of patients and include fever, malaise, fatigue, and weight loss. Vascular symptoms relate to the consequences of arterial inflammation, namely occlusion or aneurysm formation of involved vessels.

Classic symptoms of cranial involvement include the new onset of atypical and often severe headache, scalp tenderness, visual symptoms (transient or persistent blindness or diplopia), "jaw" (masseter muscle) claudication, or stroke. If aortic branch vessels are involved, symptoms of upper extremity claudication may occur.

It is important to note, however, that as many as 40% of patients may not present with classic symptoms and may instead manifest features such as cough, throat pain, fever of unknown origin, or pain elsewhere in the head and neck (tongue, cheeks, etc). Any such symptoms in an elderly person with an elevated ESR should raise the possibility of GCA.

Examination may reveal a thickened, nodular, tender, or pulseless temporal artery, although arteries may also be normal to palpation. Asymmetry of pulses or blood pressures in the extremities, bruits over subclavian or carotid arteries, or the murmur of aortic insufficiency suggest involvement of the aorta and/or its branches. PMR features may be present in about one half of patients with GCA.
DIAGNOSIS
As with PMR, there is no precise serologic test for GCA. Diagnosis is based on a clinically compatible presentation, the presence of highly abnormal acute phase reactants, a positive temporal artery biopsy, or angiographic findings of large-vessel abnormalities that are compatible with those seen in GCA.

Laboratory findings are similar to those found in PMR. ESR is elevated in the vast majority of patients (>80%), and elevated CRP, platelet count, alkaline phosphatase, and anemia may be noted. Elevated interleukin-6 levels appear to be a sensitive indicator of active disease, but most laboratories do not yet offer measurement of this marker.18

Temporal artery biopsy before initiating therapy is ideal, but this is often not possible and delay of therapy is often not prudent. The positive yield of biopsy in those diagnosed clinically with GCA may be 50% to 80%, depending on the size, timing, and number of biopsies performed. Positive findings may be noted on biopsies obtained 2 weeks or longer into treatment, but the goal should be to biopsy as soon as possible after starting therapy. A specimen at least 2-cm long will optimize chances for a positive result. Unilateral biopsies are usually sufficient. While some have claimed that bilateral biopsies increase the yield by about another 10%, others have not endorsed this approach.19 This remains an area of ongoing controversy.
THERAPY

Once a diagnosis of GCA is made, treatment with CS should begin immediately. Although lower doses may be effective in some patients, most authorities administer 40 to 60 mg of prednisone daily. The higher dose is preferred when ophthalmic, neurologic, or other serious manifestations are present. In the setting of recent (<24-48 hours) blindness, many authorities have advocated use of intravenous pulse methylprednisolone (1,000 mg/day for 1 to 3 days), although the utility of this approach has not been evaluated in randomized controlled trials. The initial effective oral dose is usually maintained for 1 month before gradual tapering is started. As with PMR, treatment with low-dose CS is often necessary for 1 to 2 years or longer.

Current evidence does not support the use of cytotoxic agents to help reduce total CS dose or improve patient outcomes.20 Newer biologic agents are undergoing investigation and may prove to be effective, but there are currently insufficient data to recommend their use in GCA. CS remain the mainstay of treatment.
OUTCOMES
Although some studies have found overall mortality of GCA patients to be similar to that of the general age- and sex-matched population, others have noted increased risk of death, particularly related to cardiovascular events. Indeed, it is critical that patients be monitored long-term for late vascular complications. Aortic aneurysms, particularly in the thoracic region, are much more likely to occur in GCA patients than in the general population and may occur early or even years after disease onset. Moreover, patients who develop aortic aneurysms have increased mortality rates, with up to one half going on to dissection or rupture, even years after what may appear to be disease "resolution."21-24

As for PMR, screening for and treatment of osteoporosis is also critical. The necessity for long-term CS therapy in these elderly patients increases their risk of progressive diminution of bone mineral density and of fractures. Monitoring for CS-associated complications, including the development of diabetes mellitus, glaucoma, or sleep and mood disturbances, is also important.
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