Title: BURDEN of POLYMYALGIA RHEUMATICA

Title: BURDEN OF POLYMYALGIA RHEUMATICA

Authors:

Bhaskar Dasgupta

Hilal Maradit-Kremers

Eric Mattesson

Corresponding author: Bhaskar Dasgupta, MD, FRCP Department of Rheumatology Southend University Hospital, Prittlewell Chase Westcliff, Essex SSO-ORY, UK tel: 44 1702 221048 Fax: 44 1702 221990 Email: [email protected]

Hilal Maradit-Kremers, MD MSc Department of Health Sciences Research Mayo Clinic, 200 First St. SW Rochester, MN 55905 tel: 1 507 266 3169 fax: 1 507 284 1516 e-mail: [email protected]

Eric Mattesson, MD Department of Internal Medicine, Division of Rheumatology Mayo Clinic, 200 First St. SW Rochester, MN 55905 tel: 1 507 284 3522 fax: 1 507 284 0564 e-mail: [email protected]

1 ABBREVIATIONS

APR Acute phase reactants

CRP C-reactive protein

CS Corticosteroids

ESR Erythrocyte sedimentation rate

GCA giant cell arteritis

HAQ Health Assessment Questionnaire

NICE National Institute for Clinical Excellence (UK)

OR odds ratio

PMR Polymyalgia rheumatica

QOL quality of life

SF-36 Short Form Health Questionnaire 36

VAS Visual analog scale

2 ABSTRACT

Polymyalgia rheumatica (PMR) is the most common inflammatory rheumatic disease occurring principally in elderly Caucasians and a common indication for long-term glucocorticosteroid therapy in community-based patients.

Although PMR has very characteristic symptoms, there are number of other autoimmune, infectious, endocrine and malignant disorders which may present with polymyalgia like symptoms. It is important to make the diagnosis in a safe step-wise manner based on ‘essential’ symptoms such as bilateral shoulder/hip pain and stiffness in people above 50 years age; ’essential’ exclusions such as active infection or cancer ; clinical evaluation and minimum laboratory investigations to exclude other mimics and careful evaluation of clinical and laboratory response to low-dose steroids.

The most commonly associated inflammatory condition is giant cell arteritis, which can occur in a minority of patients. The course of disease is heterogeneous and unpredictable. Glucocorticosteroid treatment results in a rapid improvement in disease symptoms in most patients but may be associated with significant side effects. Quality of life of patients with PMR is influenced early in the disease course by the initial pain, stiffness and functional limitations caused by joint involvement and systemic symptoms, and later especially by treatment related adverse effects. Life expectancy in patients with polymyalgia rheumatica is equivalent to that of the general population.

In view of the uncertainty associated with diagnosis, flexibility of treatment required depending on course and treatment side effects – we recommend that patients should be managed in a ‘seamless’ manner across primary and secondary care with early rheumatology evaluation recommended in all atypical cases. There is a large unmet need for improvement in management and research on PMR.

3 INTRODUCTION

Polymyalgia rheumatica (PMR), a common inflammatory condition of the elderly, is characterised by bilateral proximal pain and morning stiffness, an acute phase response involving elevated erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP), and a rapid response to corticosteroids (CS). This widely prevalent condition is subject to variations of practice in primary and secondary care and is a common indication for long-term steroid use in the community1. Patients are therefore vulnerable to the manifold adverse events associated with prolonged CS therapy. Accurate assessment of patient-based outcomes, disease activity and course of disease are critical to balance the benefits of CS against increased risk of adverse outcomes such as diabetic complications and fractures.

There is also considerable uncertainty regarding diagnosis and outcomes in PMR. Initial features may be variable, e.g. PMR without an elevated ESR is reported in up to 22% of patients and common mimicking conditions can present with the polymyalgic syndrome. There is no gold standard test and several diagnostic criteria have been used. This may explain the lack of agreement in PMR diagnoses between primary care physicians and rheumatologists and revision of diagnoses in 5-23% of patients on long term follow up. An international initiative to address this diagnostic conundrum is now underway to define classification criteria for the polymyalgic syndrome.

Most clinicians consider a rapid resolution of symptoms with CS therapy a diagnostic hallmark of PMR, though some studies report slower responses in many patients and lack of response may indicate an incorrect diagnosis. However there is little evidence on what constitutes a typical response and how it relates to longer term outcomes or revisions of the initial diagnosis. It is accepted that around half of patients have relapses and median duration of CS treatment around 2-3 years. PMR appears to be a heterogeneous condition. The prognostic factors at presentation that affect this heterogeneity of disease course, clinical outcomes and duration of treatment are ill understood. ESR at presentation, but not at one month, has been reported as a prognostic factor for treatment duration and relapses in PMR. A study of 27 patients proposed three categories of disease course: a rapid response without significant relapse; a rapid response requiring extended treatment; and incomplete resolution of symptoms requiring increased doses of steroids and extended treatment2.

4 This chapter will discuss: (1) the epidemiology of PMR, (2) burden of disease including the economic burden, (3) the impact of PMR, particularly the initial response to CS therapy, on clinical and patient-based outcomes (early and long term) and examine the relationship between laboratory measures and clinical outcomes, functional status and changes in QOL (4) potential medical errors in the diagnosis and management of PMR and occurrence of preventable complications, (5) guidelines and audit standards for diagnosis and management, (6) implications of these guidelines for re-design to achieve an optimal service.

1. EPIDEMIOLOGY OF PMR

The epidemiology and population burden of PMR is documented in a limited number of studies. The incidence of PMR varies markedly according to geographical region, with much higher rates in countries in the northern latitudes. In Northern United States, the average annual age- and sex-adjusted incidence of PMR per 100,000 population  50 years of age is estimated at 58.7 (95% CI: 52.8-64.7) with a significantly higher incidence in females (69.8; 95% CI: 61.2-78.4), than in males (44.8; 95% CI: 37.0-52.6)3. The incidence in Northern United States is similar to the incidence estimates from Denmark (68.3 per 100,000)4 and Norway (112 per 100,000)5, but is substantially higher than those reported in Göteborg, Sweden (28.6/100,000)6, Reggio Emilia, Italy (12.7/100,000)7 and Lugo, Spain (18.7/100,000)8. A recent large primary care database study from the United Kingdom reported an incidence of 84 per 100,000 with a female to male ratio of 2.09. This is the only study that also reported a marked increase in the incidence of PMR throughout the 1990s, from 69 per 100,000 person-years in 1990 to 93 per 100,000 person-years in 2001. However, a similar temporal increase in incidence was not observed in other studies. It is unclear whether there is a true increase in incidence of PMR, over-diagnosis or increased recognition of PMR over time. The prevalence of PMR among persons > 50 years of age in the year 2000 is estimated at 739 per 100,000, with a higher prevalence in females than in males10. The prevalence increases dramatically with age from 21 per 100,000 for ages 50 - 54 years to 4,213 per 100,000 for ages 90 - 95 years. With these prevalence estimates, 711,000 Americans are estimated to have PMR10. Survival was also examined in various studies and they all indicate that survival in PMR patients is similar to those in the general population3, 4, 11. This has been in part attributed to increased medical surveillance during the disease course.

5 2. HEALTH CARE UTILIZATION AND ECONOMIC BURDEN

Despite the relatively low incidence of PMR, in particular in countries in the southern latitudes, the medical, economic and quality-of-life burden of PMR can be significant. In a large community-based study with an average 4 years of follow-up, 364 PMR patients utilized a total of 5108 physician office visits and 2015 telephone calls12. More than two thirds of all physician visits (70%) and 61% of rheumatologist visits occurred during the first year of the disease. Mean number of generalist visits per person-years of follow-up was 7.0 during the 1st year, 3.8 during the 2nd year and  3 visits after the 2nd year. The decline in the number of rheumatologist visits was much more pronounced, from 2.2 visits per person-years during the 1st year to 0.8 visits during the 2nd year and  0.6 thereafter12. In this population, generalists provided the large majority of care and rheumatologist involvement was generally limited to diagnostic confirmation and management of complications. Interestingly, indicators of PMR disease severity such as, occurrence of GCA, PMR relapses or CS complications, were not associated with rheumatologist visits. However, the presence of these conditions was associated with an increased number of rheumatologist visits. As addressed in the following sections, the health care utilization patterns in this study is a consequence of diagnostic dilemmas in PMR and can significantly increase the burden of the disease on the health care system. Indeed, a retrospective chart review of 123 PMR patients referred to a tertiary care rheumatology clinic in Canada demonstrated that the accuracy of PMR diagnosis by non-rheumatologists was very low (24%), and that a large number of inappropriate tests were performed by non-rheumatologists in an effort to reach diagnosis13.

High utilization of health care services and diagnostic tests in PMR may result in increased cost of care, especially during the first year following diagnosis14. PMR patients have a substantially higher number of outpatient services and laboratory tests compared to matched individuals of the same age and sex. The total yearly direct medical cost of care appears to be highest during the first year of the disease ($2,814) and then stayed relatively constant at about $1,500/year in subsequent years. However, for non-PMR subjects, the total yearly cost of medical care was relatively stable at about $1,000/year. PMR was associated with a significant incremental cost of $2,233 at the 10th percentile of costs and $27,712 at the 90th percentile of costs and interestingly, the increased incremental costs were mainly accounted for comorbid cardiovascular conditions, hospital stays and imaging. Indeed, previous analyses indicate that PMR patients are significantly more likely to have a history of myocardial infarction (odds ratio [OR]: 1.78, 95%

6 CI: 1.13, 2.82), peripheral vascular diseases (OR: 2.21, 95% CI: 1.37, 3.60) and cerebrovascular diseases (OR: 1.60, 95% CI: 1.08, 2.39) compared to the matched non-PMR subjects14.

These findings emphasize the importance of careful diagnostic investigations in diagnosis of PMR as well as the economic burden associated with the management of comorbid cardiovascular conditions in these elderly PMR patients.

3. QUALITY OF LIFE AND CLINICAL OUTCOMES IN PMR

Quality of life (QOL) and functional status in PMR have been the focus of a limited number of studies15, 16. Kalke and colleagues reported on functional status in 18 newly diagnosed PMR patients15. The Health Assessment Questionnaire (HAQ) correlated with measures of disease activity and showed greater sensitivity to change than these other parameters. Sections of the HAQ dependent on morning stiffness i.e. dressing, grooming, rising and also reaching were more responsive to change and reflected disease activity better. Short-term QOL was more extensively addressed in a larger study from the UK16 and long-term QOL was examined in an unpublished study in the USA.

The UK cohort study recruited 129 patients with new-onset PMR subsequently treated with standard doses of oral prednisolone. QOL was assessed at baseline, 3 and 12 months using the Modified Health Assessment Questionnaire (HAQ) and the UK version 2 of the Short Form Health Questionnaire 36 (SF-36). Data on PMR symptoms, laboratory parameters (full blood count, ESR, CRP) and adverse events were collected at all follow-up visits. The initial CS response was assessed using proximal pain, morning stiffness, and acute phase response at the week 3 visit. Complete response was defined as: no pain or at least 70% improvement in VAS pain in the shoulders and pelvic girdle; morning stiffness of less than 30 minutes, ESR no higher than 30mm/h and CRP no higher than 10mg/dl. A lack of response was a defined as a failure to meet any of the three components, and a partial response was defined as patients meeting one or two of the components. A relapse was defined as a return of PMR symptoms requiring an increase in CS dose or maintenance of the CS dose beyond a scheduled reduction, either at or between planned assessments.

Impact of PMR and the initial CS response on clinical outcomes and QOL: QOL at presentation, as measured by mean SF-36 physical and mental scores (physical=31.4,

7 mental=39.3), was substantially lower than general population norms (physical=44.7, mental=53.2). By 12 months of follow-up, physical and mental QOL scores improved, on average, by 13.0 (95% confidence interval 11.2 to 14.8) and 11.8 (9.2 to 14.5) points, respectively. The mean change in QOL, as measured by the HAQ, was -0.88 (-0.99 to -0.76) and the percentage of patients with a score of less than 1 increased from 30% at baseline to 88% at month 12.

The initial steroid response: Only 49 (38%) patients were categorised as having a complete response to steroids at week 3 and 16 (12.4%) patients showed a lack of response, of whom one was still categorised as non-responder at week 6. There was evidence for a difference in the PCS at 3 months between complete responders and non-responders but there was little difference in QOL at either 3 or 12 months between partial and complete responders.

Relapses: High incidence of relapses (46 relapses in 40 patients) and adverse events (81%) was seen during the first year of follow up in the UK study. This observation is consistent with a US study17 where up to 70% of patients relapsed if CS were tapered too quickly (Figure 2). Compared to slow CS tapering (reference group), the risk of a relapse was 2.4 times higher when tapering was medium and 5.3 times higher when tapering was fast17. A relapse as medical error and complication of sub-optimal treatment is dealt with in the next section.

Impact of laboratory measures and clinical outcomes on changes in QOL: Higher levels of disease activity in all markers were associated with lower physical and mental composite scores. If all markers were considered separately for inclusion then only morning stiffness and proximal pain were independently associated with physical composite score only; similar results were found for the HAQ. Higher levels of ESR, CRP and morning stiffness were all independently associated with lower mental composite score.

Long-term quality of life in PMR

The long-term quality of life in PMR patients was examined in 105 PMR patients in the USA, after an average of almost 10 years (range: 1.6 - 27.3 years) following initial PMR diagnosis (Gabriel et al., unpublished communication). In this study, the physical and mental scores were standardized using the general population norms. The results indicated that, PMR patients were functioning physically worse (physical composite score 48.45, SD:10.69) but mentally better

8 (mental composite score 52.85, SD:7.27) than their peers of the same age and sex. There was no correlation between the 2 scores. The distributions of both physical and mental scores were slightly skewed and the physical composite score seemed to have a bimodal distribution. These findings are in line with the hypothesis that physical functioning declines with advancing age but mental health remains stable regardless of advancing age. The study also examined the predictors of the physical and mental scores. Age, sex, ESR, marital status and time since diagnosis (time from incidence date to survey date) were not associated with physical and mental scores. Especially lack of any trend with time since diagnosis indicates that PMR, although devastating during the course of the disease, has no long-term impact on physical and mental functioning of patients shortly after full remission of symptoms.

In conclusion, there is considerable heterogeneity in PMR. Initial presentation and steroid response does not predict the subsequent course. It is also a condition with major short term impact on QOL, as well as high incidence of relapses and adverse events within the first twelve months. These observations indicate an unmet need for improvement of therapy. Physical QOL associates with inflammatory symptomatology such as pain and stiffness and functional status indicating that the disease is best monitored based on symptoms. Similar to other rheumatic diseases, such as RA, PMR too is perhaps best assessed through patient questionnaires18. The association of mental QOL with acute phase markers is intriguing and needs further research. There may not be a long term impact on QOL if there is full remission,especially if no serious CS related side effects occur..

4. POTENTIAL MEDICAL ERRORS IN THE DIAGNOSIS AND MANAGEMENT OF PMR

The foremost factor that has hampered development of rational therapeutic approaches to management of PMR is the lack of standardized diagnostic criteria and reliable, valid and sensitive outcome measures. These deficiencies have led to an inability to accurately distinguish this clinical disease entity from other conditions presenting with the polymyalgic syndrome, and difficulty with evaluation and comparison of the efficacy of different therapeutic approaches, including novel drug therapies.

Because PMR is the most common inflammatory rheumatic disease of the elderly and the most common indication for long-term CS therapy in the community, it is not surprising that it is the

9 rheumatic disease subject to the widest variations of clinical practice. Most patients are managed in primary care settings by generalist physicians including family and general practitioners and to a variable extent by rheumatologists19-21. Very often, specialist referral is made after a prolonged disease course, for management of CS related complications12.

This heterogeneity in the clinical manifestations and the considerable heterogeneity in the clinical course of PMR make the assessment and management of the disease particularly difficult (figure 1). Treatment is with CS, but the variability of CS doses and duration required for management of the condition are a source of clinical uncertainty and doubtless contribute to the excess morbidity suffered by these patients. Better diagnostic strategies and identification of predictors of treatment response, symptom relapse, and duration of therapy combined with better treatments will shorten the disease course and reduce the need for CS therapy with its attendant side effects.

There is a lack of recognition of PMR, particularly in primary care. The accuracy of PMR diagnosis among family practitioners is low, while diagnostic investigations are generally over- utilized19. Among the various rheumatologic diseases, the lowest agreement between primary care physicians and rheumatologists is on the subject of diagnosis of PMR22, 23. In another study in the north-eastern USA, 128 physicians were presented with videos of patients presenting with symptoms of PMR and depression24. The study was designed to assess whether patient or physician attributes influenced clinical decision-making. Only 9 of the 128 physicians identified PMR as the most likely diagnosis whereas 84 considered depression most likely24.

Many features of PMR predispose the unwary clinician to diagnostic error25. The proximal pain and stiffness syndrome, which constitute the main symptoms of PMR, can occur in many other illnesses. A third of the patients have systemic symptoms such as fever, anorexia and weight loss. Half the patients may have distal musculoskeletal manifestations such as peripheral arthritis, distal hand swelling with pitting edema and carpal tunnel syndrome. Distal lower extremity swelling is rarely due to the polymyalgic syndrome. PMR is also associated with giant cell arteritis in 10% to 30% of cases26, 27.

The most treacherous error made in the diagnosis of PMR is the failure to consider that the presenting symptoms are nonspecific and may reflect a number of other serious medical conditions26-28. Clinicians should think of PMR as “polymyalgia syndrome” at first evaluation and carefully assess whether another possible life threatening illness could be underlying the

10 symptom complex. These include bacterial endocarditis, systemic vasculitis or malignancy. Many other medical conditions in the elderly may present with complaints of “stiffness” including Parkinsonism, hypothyroidism or a flare of pre-existing fibromyalgia. Rheumatoid arthritis or a late onset undifferentiated spondyloarthropathy may be the eventual diagnosis in some cases of polymyalgia syndrome.

Laboratory tests, particularly acute phase reactants such as the ESR and CRP aid in the diagnosis of PMR but are also a source of both diagnostic and therapeutic confusion (table 1). Although an ESR of at least 40 mm/hour is considered an important finding for the diagnosis of PMR, an acute phase response and elevated ESR values can occur in other settings such as neoplasia, rheumatoid arthritis and infection. Furthermore, some studies have reported that a normal ESR at diagnosis accounted for 7–20% of the patients with PMR29-31.

Treatment with a moderate dose of prednisone, 15-20 mg daily as a single AM dose helps to confirm the diagnosis of PMR (Table 2)26, 27, 32, 33. Under no circumstances should patients be given a larger dose of prednisone. Higher doses are unnecessary and will only contribute to delays in diagnosis of another condition and lead to more CS morbidity. Frequently within 24 to 48 hours patients will spontaneously report dramatic improvement, even “a miracle”. At least a 70% patient reported global improvement with normalization of the ESR and CRP should be expected within three to four weeks (table 3)32. If the initial response to treatment is not dramatic, do not continue treatment without considering other possible diagnoses. The CS dose should not be increased in an attempt to lower persistent elevation of acute phase reactants without consideration of alternative diagnoses.

The high doses (often in excess of 40 mg/day of prednisone equivalent) often employed as initial treatment for PMR are themselves a source of diagnostic confusion as well as a rocky disease course33, 34. They may serve to obscure systemic manifestations of potentially life-threatening diseases. Suppression of fever, malaise and weight loss in patients treated with high doses of CS can delay the diagnosis for example of malignancies or subacute bacterial endocarditis, with potentially life threatening or life limiting consequences.

The true outcome of standard CS therapy, which may only partially control disease and symptoms, is not known. Prednisone, 15 to 25 mg, usually suppresses inflammation dramatically26, 27, 35. The median reported starting dose of prednisone was 20 mg/d, however, up

11 to 60% of patients experience disease relapse during CS8, 26, 32, 35, 36. Recent studies indicate that oral CS should be administered for about 18 to 36 months26, 27, 33.

The uncertainty about the duration of treatment is a common cause of over-treatment. Reports from the Mayo Clinic originally described a short duration of disease both for PMR (11 months median duration of treatment with 75% of patients off CS at 2 years) and giant cell arteritis37. However, reports from Europe describe a more prolonged illness requiring several years of CS therapy marked by frequent relapses32, 38-40. The fact that the majority of patients with PMR remain on long-term CS treatment suggests persistent symptoms, and indeed, only 24% of patients may have discontinued CS completely 2 years after initiation of treatment32. There is a high incidence of relapses, largely irrespective of original CS responsiveness and up to a third complained of proximal pain at 12 months in the absence of raised inflammatory indices23, 26.

Complete, partial and non-responders to initial standard CS therapy with partial and non- responders appear to have earlier relapses leading to greater cumulative dose of CS16. Observational studies indicate that higher doses of CS about 15 mg of prednisone per day are not more effective, in reducing the incidence of relapses, and are in fact associated with an increased risk of relapse17.

The risks for side effects of this long-term treatment, particularly osteoporosis, hypertension, hyperglycemia, and cataracts, support the need for improved therapeutic options, particularly in patients at high risk for CS-related toxicity17, 41. Unfortunately there are to date no studies which adequately support the role for other therapeutic agents or approaches. In one small clinical trial, intramuscularly methylprednisolone acetate on a monthly basis was shown to have benefit in reducing cumulative CS dose and toxicity while maintaining control of disease40. Nonsteroidal anti-inflammatory agents are virtually of no value for management of polymyalgia rheumatica and are associated with considerable drug related morbidity42.

A number of studies examined the efficacy of methotrexate with conflicting findings43-45. There is some evidence to suggest that methotrexate use can reduce the duration of CS therapy and disease flares. Other alternative and adjuvant CS sparing therapies which have been suggested especially in refractory cases include anti-tumor necrosis factor-α agents are of uncertain benefit in the management of PMR46, 47.

Fortunately, there are some clinical tools which have value in predicting the likelihood of relapse in PMR. The frequently high dose of CS often employed at imitation of treatment for PMR,

12 faster tapering rate, and lack of specialist care are all factors related to a higher risk of relapse17. Awareness of CS related side effects, which can be particularly problematic in elderly patients include osteoporosis, insufficiency fractures and avascular necrosis, cataracts, CS induced myopathy, diabetes and infections motivate a strong desire by physician and patient alike to rapidly reduce the dose in the hope of a shortened disease course and less CS exposure. Unfortunately, the opposite effect is often the reality: every 5mg/day increase in initial CS dose is associated with a 7% increase in the risk of relapse at initial doses of >10 mg prednisone/day17.

The hazard of having a relapse has been found to be 4-fold higher when the CS tapering rate was rapid (from 20 mg to 3 mg over 8 weeks), than when it is slow (from 20 mg to 13 mg over the first 8 weeks of therapy)17. Management of comorbidities including prophylaxis for cardiovascular disease and osteoporosis is imperative. Potentially avoidable CS related complications due to over treatment with is frequently related to misinterpretation of underlying degenerative symptoms as persistent PMR, or attributing a persistently elevated ESR to underlying active disease.

5. GUIDELINES AND AUDIT STANDARDS FOR DIAGNOSIS AND MANAGEMENT OF PMR

Guidelines and audit standards for diagnosis and management of PMR were recently published, and will be briefly summarized here33. These guidelines incorporated evidence from the medical literature and expert opinions solicited primarily through the International PMR Classification Criteria Work Group and summary proposals of the British Society for Rheumatology48.

These guidelines emphasize (a) an approach to ensure more accurate diagnosis of patients presenting with polymyalgic symptoms, (b) encourage timely specialist referral of appropriate cases, (c) promote more cautious treatment, usually using lower doses of steroids and gradual steroid taper, and (d) ensure early bone protection to reduce the common morbidity of osteoporotic fractures.

Key Recommendations are the following:

 Use core inclusion criteria as the first step in a staged process to diagnose PMR  Initiation of low-dose CS with gradual steroid taper

13  Introduce standardized evaluation of initial steroid response  Early referral to a specialist for atypical cases and treatment dilemmas  Vigilant monitoring of proximal pain, morning stiffness, disability, osteoporotic risk factors and for any other symptoms that may suggest an alternative diagnosis  Prevention of osteoporotic complications

The guidelines are summarized in Tables 1-4 and the approach to the polymyalgic syndrome is illustrated in the Figure. A step-wise diagnostic approach is advocated with essential inclusion and exclusion criteria, careful evaluation of the steroid response and diagnostic confirmation on follow up. Although PMR has been diagnosed with normal acute phase response, the general consensus is that this requires further study and such patients should be referred for further rheumatological evaluation. Clinical assessment should note presence/absence of co-existing conditions (as a cause of persistent pain) such as osteoarthritis, degenerative and other periarticular conditions involving the shoulder, neck and hips.

Early referral to a specialist from a primary care provider is recommended for:

Patients with atypical features or features that increase likelihood of a non-PMR diagnosis such as:

 Younger patient < 60 years  Protracted (chronic) onset  Lack of shoulder involvement  Lack of inflammatory stiffness  Prominent systemic features, other ‘red flag’ features such as high grade fever, rashes, lymphadenopathy  Peripheral arthritis or other features of connective tissue disease/ muscle disease  Normal acute phase reactants (APR) , or very markedly elevated APR or treatment dilemmas such as:  Incomplete or non-response to corticosteroids  Ill-sustained response to corticosteroids  Unable to reduce corticosteroids

14  Contra-indications to corticosteroid therapy

Patients who do not have atypical features, have a complete sustained response to low dose CS and have no adverse events can be managed by the primary care provider.

Measures of process and adherence to guidelines

The following constitute the minimum dataset recorded prior to CS therapy:

 Clinical features e.g. symmetrical proximal pain and stiffness/ important exclusions

 Investigations ; as specified in guidelines

Initial steroid dose and taper

Monitoring frequency

Bone protection:

 Co-prescription of calcium and vitamin D

 Bisphosphonates with additional risk factors

 Bone mineral density measurements

7. RE-DESIGN REQUIRED TO ACHIEVE AN OPTIMAL SERVICE FOR PMR

Unlike the popular perception, it appears that the diagnosis and management of PMR often presents a ‘challenge’. This is because of the lack of universally accepted and definitive criteria for diagnosis and disease activity assessment, the large differential diagnoses for the polymyalgic syndrome, heterogeneity of presentation, steroid responsiveness, clinical course and atypical clinical features. All of these factors make it difficult to recommend a single approach and therapeutic regimen for all cases of PMR. In many ways this is no different from our approach to other inflammatory rheumatic diseases which have significant heterogeneity in clinical presentation, severity and clinical course.

Currently PMR is mainly diagnosed and managed in primary care. It presents a considerable workload for the primary care physician. There are wide variations in practice in its management. It is often referred to the rheumatologist but this is usually late - for steroid

15 complications, inability to reduce dose or due to an alternate diagnosis. These errors of over- diagnosis and under-diagnosis, over and under-treatment may occur due to failure to appreciate the complexities of PMR.

The ultimate objective of any clinical management strategy is to improve patient care. The management of PMR lends itself ideally to a ‘building bridges' approach, by developing a partnership between health care providers across the primary and secondary care divide49. Such an approach is based on the implementation of common management guidelines with uniform standards of clinical governance and audit. It needs to be underpinned by a consensus opinion on the diagnostic and remission criteria of PMR and an international prospective study to validate classification criteria for the polymyalgic syndrome is underway.

The general consensus is that most cases of PMR would merit early referral to the rheumatologist for advice on diagnosis and management. Referrals should be especially considered for treatment dilemmas, atypical features or features that increase likelihood of a non- PMR diagnosis. This will improve patient safety as well as reduce cost of investigations and visits to the family practitioner. An individualised care plan should be agreed which includes the patient and emphasises education and self-assessment. Disease should be monitored through appropriate patient questionnaires. Formation of patient support groups which disseminate factually correct and positive information giving advice on treatment guidelines, counselling, exercises, steroid effects and prevention of complications would aid this care plan. Integrated shared care guidelines should be promoted which implement seamless care pathways for disease monitoring, dose adjustment and treatment of complications. Regulatory agencies (such as NICE in the United Kingdom) for development and implementation of national guidelines need to be approached to take interest in the correct management of this prevalent and long term condition of the elderly which exacts a large toll on the quality of life with its treatment and complications.

16 TABLE 1 Polymyalgia Rheumatica: Diagnosis

Establish the diagnosis in a stepwise fashion in patients greater than 50 years, and almost always greater than 60 of age and symptoms of greater than one to two weeks’ duration.

Symptoms: Bilateral shoulder and/or pelvic girdle aching (essential)

Morning stiffness duration of greater than 45 minutes (essential)

Elevated inflammatory response parameters (erythrocyte sedimentation rate and/or C-reactive protein) (essential)

Exclude active infections, active cancer (essential)

Exclude rheumatoid arthritis and other inflammatory conditions, thyroid disorders, drugs including statins

Note coexisting relevant symptoms: osteoarthritis, soft tissue /periarticular lesions, fibromyalgia Acute phase reactants (erythrocyte sedimentation rate and/or Investigations: C-reactive protein Creatinine and urinalysis Cholesterol Triglycerides Thyroid function test Creatine phosphokinase Alkaline phosphatase Blood glucose Complete blood cell count with differential Bone mineral density study according to regional guidelines and availability Tuberculosis testing (purified protein derivative, PPD) and/or QuanteFERON gold with or without chest x-ray) according to regional guidelines and availability Ultrasonography of the hip and shoulders, where available (optional)

Legent to Table 1: This table outlines initial assessment of a potential PMR patient.

17 Table 2: Polymyalgia Rheumatica: Treatment

Treatment: Initiate corticosteroids at 15 mg of prednisone per day.

The dose of prednisone can be increased up to 20 mg per day in patients who have a response of less than 50 to 70 percent. In patients who have less than 50 percent response, an alternative diagnosis should be considered.

Steroid response: Patients should be followed within the first week to establish the clinical response (at least >70% patient global improvement) and laboratory markers of inflammation should resolve in 3-4 weeks.

In the first three months of treatment, followup visits should be every two to four weeks, and, thereafter, every three to six months, depending upon the disease course. A complete blood count and erythrocyte sedimentation rate and/or C-reactive protein with periodic glucose should be performed at patient visit. Bone mineral density should be performed every one to two years according to regional/country guidelines.

Prevention of Monitoring for diabetes Corticosteroid Prescription of calcium and vitamin D supplements Related Bisphosphonates, where appropriate Complications:

Typical Weeks 0-4: 15 mg per day Corticosteroid Weeks 5-6: 12.5 mg per day Schedule: Weeks 6-11: 10 mg per day Weeks 12-15: 10 mg every-other-day, alternating with 7.5 mg every- other-day Weeks 16-25: 7.5 mg per day Weeks 26 and thereafter: 5 mg per day and according to treatment response

Alternatively, initial prednisone dose may be 15 mg per day, and then the daily dose decreased by 1 mg every 2 to 4 weeks, with a goal of 5 mg per day at week 26, and then according to treatment response.

Intramuscular depot methylprednisolone which gives lower cumulative doses (initial dose 120 mg every 3 weeks for 4 injections, thereafter at monthly intervals at reducing doses) may also be considered but is less well studied.

Legend to Table 2. This table describes basic principles of management of steroid therapy in patients with polymyalgia rheumatica.

18 Table 3: Polymyalgia Rheumatica: Symptoms to Monitor

 Morning stiffness  Proximal shoulder and hip girdle pain  Disability related to the polymyalgia rheumatica i.e. rising, dressing, grooming, reaching  Fatigue  Adverse events including osteoporotic stress fractures  Symptoms and signs suggesting an alternative diagnosis  Laboratory monitoring (erythrocyte sedimentation rate and CBC with periodic glucose)  Bone density every one to two years  It is important to treat the patient’s symptoms, not relying exclusively on the acute-phase reactant to guide treatment.

Legend to Table 3. Continuous monitoring of response to treatment can be monitored with symptoms and lab assessments listed in this table.

19 Table 4. Guidelines for PMR: QUICK REFERENCE GUIDE

1. Establish diagnosis of PMR in a step-wise manner Include: Patients presenting age >50 years, duration >2 weeks, bilateral shoulder and/or pelvic girdle aching, morning stiffness duration of >45 minutes, raised erythrocyte sedimentation rate, C-reactive protein e.g. evidence of an acute phase response. Exclude: active cancer, infection, RA & other inflammatory diseases, thyroid, local shoulder & hip conditions, statins 2. Investigate: Full blood count, urea and electrolytes, liver function tests, C reactive protein, erythrocyte sedimentation rate, rheumatoid factor (RF), creatinine kinase, thyroid stimulating hormone, protein electrophoresis and urinalysis. May need CXR, ANA 3. Commence low dose steroids – 15mg prednisolone daily or I.M. depomedrone 120 mg 4. Evaluate steroid response ≥70% patient global response in 1 week: likely to be PMR 50- 70% response: consider increased dose up to 20 mg < 50% response: reconsider diagnosis 5. Follow up evaluation – to ensure steroid response is complete and sustained with no other features of alternative diagnosis 6. Early referral to a specialist for patients with atypical features or features that increase likelihood of a non-PMR diagnosis or treatment dilemmas 7. Prevention of osteoporotic complications Co-prescribe calcium and vitamin D supplements 8. On-going monitoring of: Symptoms Lab monitoring Bone density  Proximal pain  Full blood count  BMD every one to two  Morning stiffness  ESR/CRP years  Disability related to the PMR  Urea  Adverse events &electrolytes  Osteoporotic risk factors  Glucose  Other symptoms that may suggest an alternative diagnosis 9. Relapses . Increase steroids to previous higher dosage 1st & 2nd relapse . Single injection i.m. depomedrone 120 mg may also be considered . Consider additional immunosuppression e.g. methotrexate at 3rd relapse . GCA relapse: treat with high dose steroids 40- 60 mg prednisolone . Consider alternative diagnosis with steroid non- or partial-response

Legend to Table 4. This is a quick reference guide when evaluating patients with polymyagia rheumatica, including tests to be performed, examination of symptoms and management of steroid treatment.

20 Figure 1. How should proximal pain and stiffness be evaluated?

Presenting complaint Articular/periarticular/ Clinical features Diagnosis nonarticular Age >50 years, Polymyalgia rheumatica predominant shoulder and thigh symptoms Symmetrical

Predominant peripheral joint symptoms, RA, Other radiographs inflammatory arthritis INFLAMMATORY Morning stiffness Joint swelling Peripheral hand/foot RS3PE syndrome oedema

Multisystem disease autoantibodies SLE Vasculitis Other Collagen vascular diseases PROXIMAL PAIN Weakness of muscles, Inflammatory OR high creatine kinase myopathy STIFFNESS ARTICULAR Shoulder, Osteoarthritis Acromioclavicular joints, Septic arthritis cervical spine, hips, radiographs

PERIARTICULAR Capsular restriction etc. Adhesive capsulitis Ultrasonography Rotator cuff lesions Elevated sedimentation rate, c-reactive protein, Concomitant sepsis relevant history and tests e.g. Urinary infection e.g. urinalysis

NON- Microscopic haematuria, INFLAMMATORY fever, murmur Occult and deep sepsis, (hip, muscle and body cavity abcesses, osteomyelitis etc.), Bacterial endocarditis Weight loss, associated Neoplasia features e.g. myeloma Tender spots, long standing history Fibromyalgia, Chronic pain syndromes, Depression NONARTICULAR TSH, Bone profile Endocrinopathy, (PTH, Vitamin D) Metabolic bone disease

Rigidity, shuffle, stare, Parkinsonism gradual onset

21 Legend to Figure 1. This figure outlines evaluation of a patient presenting with proximal pain and stiffness

22 Figure 2. Risk of relapse by corticosteroid tapering rates (adopted with permission from17)

Legend to Figure 2. This figure illustrates time to disease relapse among subjects with polymyalgia rheumatica. Patients have a higher risk of relapse if their steroid treatment is tapered fast (i.e. dose reduced fast).

23 REFERENCES

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24 16. Dasgupta B, Hutchings A, Hollywood J, al e. Clinical outcomes, quality of life and diagnostic uncertainty in the first year in polymyalgia rheumatica: a prospective cohort study. Rheumatology. 2006;45(suppl 1):i170. 17. Maradit Kremers HM, Reinalda MS, Crowson CS, Zinsmeister AR, Hunder GG, Gabriel SE. Relapse in a population based cohort of patients with polymyalgia rheumatica. J Rheumatol. Jan 2005;32(1):65-73. 18. Pincus T, Maclean R, Yazici Y, Harrington JT. Quantitative measurement of patient status in the regular care of patients with rheumatic diseases over 25 years as a continuous quality improvement activity, rather than traditional research. Clin Exp Rheumatol. Nov-Dec 2007;25(6 Suppl 47):69-81. 19. Bahlas S, Ramos-Remus C, Davis P. Utilisation and costs of investigations, and accuracy of diagnosis of polymyalgia rheumatica by family physicians. Clin Rheumatol. 2000;19:278-280. 20. Chakravarty K, Elgabani SH, Scott DG, Merry P. A district audit on the management of polymyalgia rheumatica and giant cell arteritis.[comment]. Br J Rheumatol. 1994;33(2):152-156. 21. Frearson R, Cassidy T, Newton J. Polymyalgia rheumatica and temporal arteritis: evidence and guidelines for diagnosis and management in older people. Age Ageing. Jul 2003;32(4):370-374. 22. Gamez-Nava JI, Gonzalez-Lopez L, Davis P, Suarez-Almazor ME. Referral and diagnosis of common rheumatic diseases by primary care physicians. Br J Rheumatol. 1998;37(11):1215-1219. 23. Matteson EL, Salvarani C, Schirmer M, et al. Differences Among Rheumatologists and Generalists in Selection of Classification Criteria for Polymyalgia Rheumatica (PMR): Results of a Delphi survey. In press. 24. McKinlay JB, Lin T, Freund K, Moskowitz M. The unexpected influence of physician attributes on clinical decisions: results of an experiment. J Health Soc Behav. Mar 2002;43(1):92-106. 25. Jones JG, Hazleman BL. Prognosis and management of polymyalgia rheumatica. Ann Rheum Dis. 1981;40:1-5. 26. Salvarani C, Cantini F, Boiardi L, Hunder GG. Polymyalgia rheumatica and giant-cell arteritis. N Engl J Med. 2002;347(4):261-271. 27. Weyand CM, Goronzy JJ. Giant-cell arteritis and polymyalgia rheumatica. Ann Intern Med. Sep 16 2003;139(6):505-515. 28. Gonzalez-Gay MA, Garcia-Porrua C, Salvarani C, Oliveieri I, Hunder GG. The spectrum of conditions mimicking polymyalgia rheumatica in Northwestern Spain. J Rheumatol. 2000;27:2179-2184. 29. Gonzalez-Gay MA, Rodriguez-Valverde V, Blanco R, et al. Polymyalgia rheumatica without significantly increased erythrocyte sedimentation rate. Arch Intern Med. 1997;157:317-320. 30. 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. 31. Proven A, Gabriel SE, O'Fallon WM, Hunder GG. Polymyalgia rheumatica with low erythrocyte sedimentation rate at diagnosis. J Rheumatol. 1999;26(6):1333-1337. 32. Kyle V, Hazleman BL. The clinical and laboratory course of polymyalgia rheumatica/giant cell arteritis after the first two months of treatment. Ann Rheum Dis. Dec 1993;52(12):847-850.

25 33. Dasgupta B, Matteson EL, Maradit-Kremers H. Management guidelines and outcome measures in polymyalgia rheumatica (PMR). Clin Exp Rheumatol. 2007;25(suppl 47):S130-136. 34. Dasgupta B, Hutchings A, Matteson EL. Polymyalgia rheumatica: the mess we are now in and what we need to do about it. Arthritis Rheum. Aug 15 2006;55(4):518-520. 35. Gran JT. Current therapy of polymyalgia rheumatica. Scand J Rheumatol. 1999;28(5):269-272. 36. Delecoeuillerie G, Joly P, Cohen de Lara A, Paolaggi JB. Polymyalgia rheumatica and temporal arteritis: A retrospective analysis of prognostic features and different corticosteroid regimens (11 year survey of 210 patients). Ann Rheum Dis. 1988;47:733- 739. 37. Chuang TY, Hunder GG, Ilstrup DM, Kurland LT. Polymyalgia rheumatica. A 10-year epidemiologic and clinical study. Ann Intern Med. 1982;97(5):672-680. 38. Soelberg-Sorensen P, Lorenzen I. Giant cell arteritis, temporal arteritis and polymyalgia rheumatica. Acta Med Scand. 1977;201:207-213. 39. Behn AR, Perera T, Myles AB. Polymyalgia rheumatica and corticosteroids: how much for how long? Ann Rheum Dis. 1983;42(4):374-378. 40. Dasgupta B, Dolan AL, Panayi GS, Fernandes L. An initially double-blind controlled 96 week trial of depot methylprednisolone against oral prednisolone in the treatment of polymyalgia rheumaica. Br J Rheumatol. 1998;37:189-195. 41. Ferraccioli GF, Di Poi E, Damato R. Steroid sparing therapeutic approaches to polymyalgia rheumatica-giant cell arteritis. State of the art and perspectives. Clin Exp Rheumatol. Jul-Aug 2000;18(4 Suppl 20):S58-60. 42. Gabriel SE, Sunku J, Salvarani C, O'Fallon WM, Hunder GG. Adverse outcomes of anti- inflammatory therapy among patients with polymyalgia rheumatica. Arthritis Rheum. 1997;40(10):1873-1878. 43. Caporali R, Cimmino MA, Ferraccioli G, et al. Prednisone plus methotrexate for polymyalgia rheumatica: a randomized, double-blind, placebo-controlled trial. Ann Intern Med. Oct 5 2004;141(7):493-500. 44. Krall PL, Mazanec DJ, Wilke WS. Methotrexate for corticosteroid-resistant polymyalgia rheumatica and giant cell arteritis. Cleve Clin J Med. May 1989;56(3):253-257. 45. Ferraccioli G, Salaffi F, De Vita S, Casatta L, Bartoli E. Methotrexate in polymyalgia rheumatica: preliminary results of an open, randomized study. J Rheumatol. Apr 1996;23(4):624-628. 46. Cantanoso CM, Macchioni P, Boiardi L, Pipitone N, Salvarani C. Treatment of refractory polymyalgia rheumatice with etanercept: an open pilot study. Arthritis Care Res. 2007;57:1514-1519. 47. Salvarani C, Macchioni P, Manzini C, et al. Infliximab plus prednisone or placebo plus prednisone for the initial treatment of polymyalgia rheumatica: a randomized trial. Ann Intern Med. 2007;146:631-639. 48. British Society for Rheumatology (BSR) & British Health Professionals in Rheumatology (BHPR) Draft Guidelines for the Management of Polymyalgia Rheumatica (PMR). Rheumatology. 2007;in press. 49. Samanta A, Kendall J. A fresh look at polymyalgia rheumatica. Rheumatology (Oxford). Dec 2002;41(12):1455-1456.

26 DEFINITIONS, ACRONYMS, AND SYNONYMS OF KEYWORDS AND PHRASES

Polymyalgia rheumatica A common inflammatory rheumatic condition of elderly people characterised by aching and stiffness in shoulder and hip areas, elevation of markers of inflammation such as ESR and CRP and a good response to steroids.

Giant cell arteritis An inflammation of the blood vessels which is occasionally seen in association with polymyalgia rheumatica; can cause strokes and acute loss of vision

Arthritis can be due to wear and tear or due to inflammation; inflammatory arthritis such as rheumatoid arthritis in the older person can mimic and get misdiagnosed as polymyalgia rheumatica

Steroid therapy Anti-inflammatory treatment used in the treatment of many rheumatic and non-rheumatic inflammatory diseases; they form the main line of treatment for both polymyalgia rheumatica and giant cell arteritis

Osteoporosis A process of thinning of the bones and deterioration of bone quality and strength; leading to increased incidence of fractures (commonly of the wrist, spine and hip); long duration of steroid intake frequently leads to osteoporosis

Outcomes Measures by which the long term effects of treatment and course of a disease condition can be judged; these can be either clinical measure such as remission, relapses, treatment side effects or patient-reported such measures of disability and quality of life

Remission The state where there are no clinical or patient perceived signs or symptoms of the disease condition

Relapse Recurrence of clinical or patient perceived signs or symptoms of the disease condition

Adverse events Medical events that occur during or after the treatment of a disease condition; these may relate to complications of the disease itself or its treatment

Health Assessment Questionnaire is a form that is used to assess the level of disability. It documents the degree of difficulty a person may have in carrying out the common activities of daily living

Acute phase reactant A protein whose plasma concentration increases or decreases by 25% or more during inflammatory diseases; C-reactive protein (CRP), is a commonly used acute phase reactant.

27 Erythrocyte sedimentation rate is also used as a marker of inflammatory disorders. It is the rate at which red blood cells in a test tube separate from blood serum and become sediment over time, most commonly reported after one hour.

Creatinine: a test that measures kidney function

Urinalysis: examination the urine for sugar, protein and signs of infection

Cholesterol, Triglycerides: Measure of fat content of the blood

Creatine phosphokinase: a test for muscle inflammation

Alkaline phosphatase : A test which can show abnormalities of the bone, liver or inflammation

Complete blood cell count with differential: A test of the formed elements of the blood –red cells, haemoglobin, white cells and platelets

Bone mineral density: A measure of osteoporosis

Tuberculosis testing (purified protein derivative, PPD) and/or QuanteFERON gold: tests for occult or hidden TB infection within the body

Ultrasonography : A technique that uses ultrasound (high frequency sound waves to study inflammation within joints, ligaments, tendons and sacs of fluid called bursae

Bisphosphonates: Drugs used to treat osteoporosis; examples alendronate, risedronate etc

Immunosuppressives: Drugs which modulate the immune system; used to treat many rheumatic inflammatory disorders including polymyalgia rheumatica and giant cell arteritis; Methotrexate is one example