Medical management of polymyalgia rheumatica

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Review

Medical management of polymyalgia rheumatica Miguel A Gonzalez-Gay†, Mario Agudo, Cristina Martinez-Dubois, Orlando Pompei & Ricardo Blanco 1.

Introduction

2.

Management of PMR

3.

Drugs used in the treatment of

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PMR 4.

Conclusions

5.

Expert opinion

Division of Rheumatology, Hospital Universitario Marques de Valdecilla and School of Medicine of Cantabria, Santander, Spain

Importance of the field: Polymyalgia rheumatica (PMR) is a relatively frequent condition in individuals older than 50 who originate from Western countries. Corticosteroids constitute the cornerstone therapy in the management of patients with PMR. Areas covered in this review: This review summarizes the current literature on clinical clues for the diagnosis of PMR, conditions mimicking PMR, relapses in the setting of PMR and the main therapeutic strategies. What the reader will gain: With this information, the reader receives an overview on the current available data on clinical diagnosis and treatment options in PMR. Take-home messages: An initial dose of prednisone of 10 -- 20 mg/day yields clinical improvement in the majority of patients with PMR. This is generally achieved within 7 days of the onset of this therapy. Conditions different from isolated PMR should be considered in atypical cases or when a good response to 20 mg/day of prednisone is not achieved. Relapses of PMR are not uncommon when the dose of prednisone is equal to or below than 5 mg/day. Methotrexate is the most commonly used corticosteroid sparing agent. Osteoporosis prophylaxis is also recommended. Keywords: bisphosphonates, giant-cell arteritis, infliximab, methotrexate, polymyalgia rheumatica, prednisolone, relapses Expert Opin. Pharmacother. (2010) 11(7):1077-1087

1.

Introduction

Polymyalgia rheumatica (PMR) can be defined as a disease characterized by severe bilateral pain and aching involving the neck, the shoulder and the pelvic girdles, associated with morning stiffness [1]. The condition is relatively common in individuals more than 50 years of age from Western countries, in particular in those of Scandinavian origin [2]. PMR occurs more frequently in women than men. The incidence of PMR increases with age, peaking in the 70- to 80-year age group [2]. PMR is generally associated with elevation of acute phase reactants such as C-reactive protein and erythrocyte sedimentation rate (ESR). In this regard, an ESR higher than 40 -- 50 mm/1st hour has often been considered as a classification criterion for the diagnosis of this entity [3,4]. However, cases with abnormally low ESR have also been described [5]. Genetic and environmental factors have been implicated in the susceptibility to PMR [6,7]. Magnetic resonance imaging and ultrasonography have disclosed the presence of inflammation of subacromial and subdeltoid bursae in association with synovitis of the glenohumeral joints and tenosynovitis of the biceps as well as the presence of trochanteric, iliopsoas, ischiogluteal and low cervical interspace bursitis in patients with PMR [8-11]. The typical features of patients with PMR are summarized in Box 1.

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Article highlights. • Polymyalgia rheumatica (PMR) is characterized by severe bilateral pain and aching involving the neck, the shoulder and the pelvic girdles, associated with morning stiffness in individuals older than 50 years. • Corticosteroids constitute the cornerstone therapy in the management of patients with PMR. • An initial prednisone dose of 10 -- 20 mg/day yields clinical improvement in the majority of patients with PMR. • Conditions different from isolated PMR should be considered in atypical cases or when a good response to 20 mg/day of prednisone is not achieved. • Relapses of PMR are common. They present as a flareup of polymyalgia symptoms, frequently associated with an increase of erythrocyte sedimentation rate values, which are again suppressed by resumption of, or increase in, corticosteroid dose.

to these drugs are not uncommon. In addition, there is no consensus on what optimal initial corticosteroid dose should be and how it should be tapered during the long disease course in patients with isolated PMR [17]. In this regard, relapses are frequency observed when corticosteroid dose is tapered or it has been discontinued [18,19]. Diagnostic approach of PMR In the presence of typical clinical manifestations, a PMR can be diagnosed in a straightforward fashion. Rapid response to 10 -- 20 mg of prednisone/day in less than 1 week is typical in patients with isolated (‘pure’) PMR [1,20]. In this regard, PMR is remarkably predictable in its rapid and complete or nearly complete improvement after initiation of lowdose prednisone therapy. Therefore, in a typical case, extensive work-up for tumor infections, other rheumatic diseases or GCA is not needed [21]. 2.2

This box summarizes key points contained in the article.

When should the presence of GCA be suspected in a patient with PMR features? 2.2.1

Box 1. Typical features in patients with PMR. Age 50 years and older Bilateral aching and morning stiffness for at least 1 month involving two of three regions: neck, shoulder girdle and pelvic girdle ESR of at least 40 mm/1st hour Exclusion of other diseases* Rapid response to prednisone (20 mg/day or less) *PMR may be the presenting manifestation of giant cell arteritis (GCA). However, GCA requires a higher dose of prednisone (generally 40 -- 60 mg/day).

2.

Management of PMR

General considerations Although new classification criteria based on active discussion among highly experienced physicians who are familiar with PMR have emerged [12], to date, there are no gold standard tests for the diagnosis of PMR. In this regard, several conditions, including infectious, tumors or connective tissue diseases, may mimic or present polymyalgia features [13]. In addition, PMR may be an isolated disease [14] or may be the presenting feature in patients who later develop typical cranial manifestations of giant-cell arteritis (GCA), a systemic largevessel vasculitis that also involves individuals aged >50 years and may lead to permanent visual loss [1]. GCA and PMR are relatively common and often overlapping conditions in the elderly in Western countries. With respect to this, population-based studies have shown the presence of ‘silent’ biopsy-proven GCA in some patients presenting with PMR features [15]. Moreover, PMR manifestations are frequently observed in patients with biopsy-proven GCA [16]. Although, corticosteroid therapy successfully controls disease symptoms in patients with PMR, side effects related 2.1

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Regardless of the presence of PMR, elevated acutephase reactants, along with new features in elderly individuals -- such as headache or an unexplained pain located above the neck -- should prompt the physician to consider the possibility of GCA [22]. PMR and GCA share common features. Both conditions are characterized by late age at disease onset, are generally more common in women, exhibit evidence of high systemic inflammatory response, and generally respond well to corticosteroids [1,2]. As observed in isolated PMR, the incidence of GCA increases with aging and peaks in patients older than 70 years [1,2,7]. Biopsy-proven GCA patients may present clinical manifestations of PMR in up to 50% of cases [1,2,7,16,23-25]. Moreover, PMR may be the presenting feature in patients who later develop typical cranial manifestations of GCA [26,27]. In a variable proportion of cases, generally 9 -- 20%, temporal artery biopsies taken from patients with isolated PMR, without any cranial manifestation related to vascular involvement in the setting of GCA at that time, may yield inflammatory changes of GCA [3,15,28]. An epidemiologic study aimed to establish clinical differences between patients with isolated (‘pure’) PMR and those with PMR associated with GCA disclosed subtle differences between both conditions [14]. For this purpose, GCA patients with a negative temporal artery biopsy were excluded [14]. Of note, patients with isolated PMR were significantly younger than those with PMR associated with biopsyproven GCA. Isolated PMR patients had a lower frequency of asthenia, anorexia, and weight loss, and seemed to have a milder inflammatory disease, as shown by significantly less abnormality in the majority of laboratory findings [14]. In this regard, patients with PMR associated with biopsyproven GCA exhibited higher elevation of ESR and platelet counts, and lower values of hemoglobin than those with isolated PMR [14].

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Gonzalez-Gay, Agudo, Martinez-Dubois, Pompei & Blanco

Based on our experience, we recommend that a temporal artery biopsy should be performed in patients presenting with isolated PMR, that is to say, without any clinical manifestation of GCA, if they have constitutional syndrome (asthenia, anorexia and weight loss) and/or the ESR is >80 mm/1st hour [14,18]. Following this procedure, temporal artery biopsies were taken in 89 patients with PMR without any clinical manifestation of GCA. However, only eight (9%) had positive biopsy results for GCA [28]. In our experience, the potential development of cranial manifestations of GCA in those patients initially diagnosed as having isolated PMR generally occurs within the first 2 years of the onset of PMR symptoms. We observed that < 3% of patients diagnosed as having isolated PMR, who did not exhibit symptoms of GCA within the first 2 years after the diagnosis of PMR, develop features of GCA later during their extended follow-up. Moreover, a retrospective study aimed to determine the best set of predictors for a positive temporal artery in patients with PMR showed that in those patients younger than 70 years and without cranial features of GCA, the risk of GCA was so low that the temporal artery biopsy could be initially avoided and the patient treated with low-dose corticosteroids [29]. In GCA, regardless of the presence of PMR manifestations, a dose of 40 -- 60 mg/prednisone/day is initially required to prevent the development of blindness [30]. A prednisone dose of 10 -- 20 mg/day may improve polymyalgia manifestations but it does not decrease the risk of permanent visual loss in biopsy-proven GCA patients [31,32]. When should the presence of a condition different from PMR and GCA be suspected in a patient presenting with polymyalgia features?

2.2.2

In view of the lack of specific diagnostic tests, clinicians should remain alert to the possibility of another disease mimicking PMR, and assess clues to the presence of another disease when present [13,33]. This is particularly true when atypical symptoms are present or response of 20 mg/day prednisone is not observed. Several series have shown no relationship to malignancy or other diseases [34,35]. However, PMR features also may be observed in context of other well-defined diseases (Box 2) [13,33]. In this regard, several decades ago Healey described patients who had episodes of corticosteroid-responsive conditions, which, at different times, were typical of PMR and seronegative rheumatoid arthritis (RA) [36,37]. Later, Bahlas et al. also described patients with PMR who during followup satisfied four of the 1987 American College classification criteria for rheumatoid arthritis (RA) [38]. Musculoskeletal manifestations, including mono- or oligoarthritis, have been described in PMR [13,39,40]. Also, some patients with PMR present with a benign symmetrical synovitis satisfying the American College of Rheumatology classification criteria for RA, have a rapid response to corticosteroids and a clinical course similar to PMR. These patients have a clinical

condition different from ‘classic’ RA and most closely resemble PMR [41,42]. However, it is not exceptional to see patients initially fulfilling classification criteria for PMR that, during the extended follow-up, develop a well-established polyarthritis fulfilling classification criteria for RA [13,18,33,37]. This is especially true for a subset of RA beginning in the elderly that may present at disease onset with polymyalgia symptoms that sometimes are difficult to differentiate from PMR [43]. Complicating this picture is the observation that peripheral synovitis may be present in up to 25% of patients with PMR [39]. However, synovitis in patients with isolated PMR is often asymmetric and non-erosive and it frequently involves the knee and wrist. These manifestations resolve completely after corticosteroid therapy is started or the corticosteroid dose is increased [39]. Interestingly, recent results have shown that anticyclic citrullinated peptide antibodies are negative in PMR, but often positive in seronegative elderly-onset RA patients with similar initial clinical appearance to that of PMR [44]. The distal swelling and edema observed in PMR patients [40] are often similar to those found in patients with remitting seronegative symmetrical synovitis with pitting edema syndrome (RS3PE syndrome) [45]. In this regard, many similarities exist between RS3PE syndrome and PMR [39,40-46]. A percentage of PMR patients (ranging between 8 -- 12%) present distal extremity swelling with pitting edema similar to that observed in RS3PE syndrome. These distal findings are considered to be part of the PMR inflammatory process (associated with proximal PMR manifestations, age at onset >50 years, and prompt response to corticosteroids), whose clinical spectrum may be wider than what has been considered, including patients with RS3PE syndrome [46]. Although there is a predominance of men in pure RS3PE syndrome and of women in isolated (‘pure’) PMR, both conditions occur in the elderly, are negative for rheumatoid factor, have increased acute phase reactants, similar frequency of peripheral synovitis and rapid response to corticosteroids [39,40,46]. Late-onset seronegative spondyloarthropathy, which is characterized by oligoarthritis, distal pitting edema (in particular of lower limbs), minimal involvement of axial skeleton, constitutional symptoms and an elevated ESR, may also mimic PMR [47,48]. Olivieri et al. reported a series of seven patients with lateonset undifferentiated spondyloarthropathy presenting typical PMR symptoms at the onset of the disease [48]. All met welldefined classification criteria for spondyloarthropathy. Patients with late-onset undifferentiated spondyloarthropathy and PMR features had inflammatory swelling with pitting edema due to tenosynovitis of the extensor tendons of hand or foot. In these cases, the diagnosis of spondyloarthropathy became evident during follow-up when they failed to respond to corticosteroid therapy and developed typical manifestations of spondyloarthropathy [48]. A clue to distinguish late-onset spondyloarthropathy is the response to oral corticosteroids.

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Box 2. Summary of the main conditions that may present with polymyalgic syndrome. Rheumatic diseases Late-onset rheumatoid arthritis Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) Late-onset spondyloarthopathy Late-onset systemic lupus erythematosus Polymyositis Vasculitis Pseudogout (calcium pyrophosphate deposition disease) Fibromyalgia Infections: viral or bacterial infections, in particular infectious endocarditis Malignancies Hematologic Multiple myeloma Lymphoma Leukemia Myelodysplasia Lymphocytoplasmic Solid tumors Colon Gastric Pancreatic Renal-cell carcinoma Prostate Ovary Uterus Hypothyroidism Amyloidosis

In this regard, as pointed out by Olivieri et al., it is different in PMR and late-onset spondyloarthropathy. The response is always dramatic in PMR and absent or partial in most patients with undifferentiated spondyloarthropathy [48]. Also, a detailed clinical history revealing the presence of other manifestations of spondyloarthropathy, such as peripheral enthesitis and/or dactylitis, the association with HLAB27 and the radiological evidence of sacroiliitis, helps to differentiate late-onset spondyloarthropathy from PMR. Cases of shoulder involvement due to pseudogout (calcium pyrophosphate deposition disease) mimicking PMR have also been described [49]. Late-onset systemic lupus erythematosus (SLE) presenting as PMR has been previously reported [13,33,50,51]. Although a minority of patients with PMR has positive antinuclear antibodies (ANA), the presence of positive ANA in elderly persons by itself does not exclude PMR. In an effort to control medical costs, patients with PMR might not routinely have ANA or anti-DNA performed. In patients with PMR, the presence of leukopenia with lymphopenia and, in special the observation of unexplained high titers of ANA, should lead to a more complete analytical study including antinative DNA, anti-ENA, C3, and C4. In these cases a detailed clinical history may be of help in eliciting symptoms related to SLE if present. A physical examination may also disclose clinical features, such as pleuritis or pericarditis, that are 1080

common in late-onset SLE that along with the presence hematological abnormalities such as leukopenia or thrombocytopenia should raise the suspicion of this condition. Other rheumatic conditions that may present with PMR features are summarized in Box 2. With respect to the presence of an underlying infection in a patients presenting with PMR, it is important to take into account the fact that low-grade fever may be observed in patients presenting with PMR [3]. Due to this, other conditions presenting with fever and symptoms of polymyalgia should be considered when there are some clues to suspect an underlying disease. This is especially true when there is little response to corticosteroids. In this respect, it is of special interest to exclude the possibility of an underlying systemic infection, even when the fever is low grade. The presence of inappropriate malaise and low-grade fever along with musculoskeletal manifestations are good reasons to exclude infectious endocarditis [52], which may cause musculoskeletal manifestations in up to almost 30% of the patients [53]. In these cases blood cultures should be taken and transthoracic echocardiogram should be performed. Also, in some parts of the world, chronic infectious diseases should be considered. In this regard, in our experience, polymyalgia symptoms may be present in infection caused by Brucella abortus [54]. The incidence of malignancy in PMR and GCA is not more common than in the general population [55,56]. However, although uncommon, a neoplastic disease can manifest itself in symptoms resembling those of polymyalgia. This is ‘polymyalgia-like syndrome’ and is in fact a paraneoplastic syndrome presenting as PMR [57]. Hematologic malignancies, in special multiple myeloma, should be considered in elderly patients sent to the clinic because of long-standing asthenia, aches, and muscle pain, especially if there are atypical symptoms of PMR, such as lack of accentuation of symptoms with movement, minimal morning stiffness and a more diffuse continuous aching [13,58,59]. In this regard, severe anemia and diffuse aching symptoms that are not limited to shoulder and hip girdles, along with proteinuria, may indicate the presence of a multiple myeloma in elderly patients presenting with polymyalgia symptoms [33]. The development of lymphnode enlargement in a patient previously diagnosed with PMR may alert the physician to possible paraneoplastic manifestations of an evolving lymphoma [60,61]. Solid malignancies, for example of the colon, stomach, kidney and ovary, might also present with PMR-like symptoms [33,62-64]. Other conditions, such as hypothyroidism [13,33] or amyloidosis [65], may present with polymyalgia symptoms or stiffness involving the extremities and may be differentiated from a pure PMR. Work-up of diagnosis of a patient with PMR As described above, patients with isolated (‘pure’) PMR with classic features of this condition and without any suspicion of any other underlying disease should be treated with 2.3

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Gonzalez-Gay, Agudo, Martinez-Dubois, Pompei & Blanco

10 -- 20 mg prednisone/day. In these cases, the absence of improvement of symptoms after 7 days of the onset of prednisone should require the search for other conditions, especially GCA. In this case, the patients should be referred for specialist assessment and a temporal artery biopsy should be considered. In this regard, a careful physical examination is of main importance to establish a diagnosis of GCA in a patient presenting with PMR. With respect to this, the presence of headache, jaw claudication or other cranial manifestations or tender and swollen or even nodular temporal arteries with a decreased pulse should alert the clinician to the presence of a GCA and, in this case, a temporal artery biopsy should be performed. The presence of other findings on physical examination -such as synovitis involving the small joints of hands and feet, peripheral enthesitis and/or dactylitis, liver or spleen enlargement, lymphadenopathies, or unexplained fever -should lead to the consideration of the presence of a disease presenting with PMR symptoms. This would be also the case if hematologic cytopenias, severe anemia or unexplained biochemistry abnormalities, such as hematuria, elevation of muscle enzymes, or positive ANA at high titers, are present. In view of the above, we suggest the following work-up in a patient presenting with polymyalgia symptoms (Figure 1) [17,21]:

should require a search for either solid or hematologic malignancies. 3) Routine analysis should include full blood count tests and ESR or C-reactive protein, blood biochemistry including liver and function tests, protein electrophoresis, rheumatoid factor, ANA, and urinalysis. a) Presence of bicytopenia or severe anemia (150 mg, urine electrophoresis should be performed to measure the proportion of albumin and other proteins and discard light-chain myeloma.

1) Clinical history should be taken. The interview should include the following: a) Duration of symptoms (more than 4 weeks duration of polymyalgia symptoms almost exclude the majority of viral diseases). b) Clinical symptoms of GCA (GCA may be associated with PMR but this vasculitis requires a higher prednisone dose to prevent visual complications). c) Exclusion of symptoms of spondyloarthropathy, particularly of late-onset spondyloarthropathy and connective tissue diseases, mainly SLE. d) Data about possible infections, undulant fever, contacts of persons with active tuberculosis or a possible epidemiologic context related to other infectious diseases such as brucellosis.

4) If no secondary causes of PMR are obvious, treatment with prednisone at a dosage between 10 and 20 mg/ day is mandatory. If no improvement is obtained after 7 days of therapy, the possibility of GCA should be considered. In this regard, if a temporal artery biopsy is negative for GCA, a more exhaustive study to exclude solid malignancies should be considered.

What to do when relapses of PMR occur Patients with PMR frequently experience disease relapses, which make management of the disease more difficult. A relapse of PMR is considered present if after a definite objective improvement with corticosteroid treatment there is a flare-up of polymyalgia symptoms, frequently associated with an increase of ESR values, which is again suppressed by resumption of, or increase in corticosteroid dose [18,19]. Moreover, it is important to take into account that PMR relapses can also involve the onset of GCA. An isolated increase of ESR should not be considered sufficient for an increase in corticosteroid dose. Moreover, it is not exceptional to see recurrences of the disease that may occur after at least 1 year since the corticosteroids have been discontinued [18]. 2.4

2) Physical examination: a) Fever may not be related to PMR and in these cases systemic infections, including infectious endocarditis, should be excluded. b) Presence of arthritis. In general, asymmetric and nonerosive arthritis involving the knee or wrist may be found in PMR but in these cases the 1987 American College of Rheumatology classification criteria for RA are usually not fulfilled. c) The presence of a cardiac murmur may be a reason to perform an echocardiogram, especially if no previous history of murmur was recorded. Also, visceral enlargement or lymphadenopathies

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Polymyalgic syndrome

Typical features

Atypical features

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Associated with: • Cranial ischemic manifestations or other features of GCA and/or • Constitutional syndrome and/or • ESR > 80 mm/1st h Search for conditions mimicking PMR

Isolated ‘pure’ polymyalgic syndrome

Prednisone 10 – 20 mg/day

No improvement

Do TAB to exclude GCA

Consider contralateral TAB

TAB negative

TAB positive

ACG: Prednisone 40 – 60 mg/day

Good response

PMR

If relapse occurs

Increase prednisone dose to the previous effective dose

Figure 1. Management of a patient presenting with polymyalgia symptoms.

Relapses may be observed in more than 20% of the patients with isolated PMR and in some series they involve up to 55% of the cases [18,19,66]. Patients who taper corticosteroids rapidly are more likely to experience relapses [18,19]. In this regard, we observed that a tapering rate of
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