- ACRONYMS AND DEFINITIONS
- ACR - American College of Rheumatology
- ACPA - Anti-cyclic citrullinated peptide antibodies
- BSR - British Society of Rheumatology
- CRP - C-Reactive Protein
- ESR - Erythrocyte sedimentation rate
- EULAR - European League Against Rheumatism
- GCA - Giant cell arteritis
- PMR - Polymyalgia rheumatica
- RCT - Randomized controlled trial
- US - Ultrasound
- EPIDEMIOLOGY
- PMR and GCA share many similarities and may be different manifestations of the same disease
- The incidence of PMR is 2 - 10 times that of GCA, but the diseases overlap with 40 - 60% of patients with GCA having symptoms of PMR and 1 - 21% of patients with PMR having temporal arteritis on biopsy
- The estimated lifetime risk of PMR in the USA is 2.43% for women and 1.66% for men. PMR is most commonly seen in whites of Northern European descent (up to 112 cases per 100,000) and is uncommon in Asians and African-Americans (1 case per 100,000). [1,2,4]
- RISK FACTORS
- Overview
- PMR and GCA are similar diseases that share common risk factors
- 1 - 21% of patients with PMR will also have GCA, and 40 - 60% of patients with GCA will have symptoms of PMR
- Known risk factors (PMR and GCA)
- Age - occurs almost exclusively in people ≥ 50 years old (mean age of onset 73 years); risk increases with advancing age
- Female sex
- Northern European descent - up to 112 cases per 100,000
- Increasing latitude - more common at higher latitudes [1,2]
- Possible risk factors (PMR and GCA)
- Seasonal - may be more common in summer months
- Rural areas - more common in rural vs urban areas
- Genetics - HLA-DRB1
- Parainfluenza virus type 1 infection
- Varicella-zoster virus - highly prevalent in GCA-positive arteries
- Infections - peaks in incidence seem to coincide with epidemics of Mycoplasma pneumoniae, parvovirus B19, and Chlamydia pneumoniae infections [1,2,10,11]
- SYMPTOMS
- Polymyalgia Rheumatica
- Pain and stiffness - primarily affects the shoulder, hip, and neck muscles; stiffness is worse in AM and after sitting; stiffness in AM lasts for ≥ 1 hour; symptoms are typically bilateral
- Low-grade fever - 40 - 50% of patients
- Distal musculoskeletal symptoms - seen in 50% of patients; non-erosive arthritis
- Swelling of the hands and feet - 8 - 12% of patients
- Malaise
- Fatigue
- Weight loss [1,2,4]
- Giant Cell Arteritis
- Headache - 75% of patients; temporal or occipital, bilateral, constant, not relieved with analgesics
- Scalp tenderness - 50% of patients; commonly seen with headache
- Jaw claudication (pain with chewing) - 50% of patients
- Vision loss - ≤ 20% of patients; ischemia of optic nerve
- Neuropathies - around 20% of patients
- Aortic arch syndrome - 10 - 15% of patients; marked by claudication of the arms and bruits over the carotid, subclavian, axillary, and brachial arteries
- Fever - up to 15% of patients; usually low-grade [1,3,4]
- PATHOPHYSIOLOGY
- Overview
- PMR and GCA share many similarities and may be different manifestations of the same disease. Both conditions are marked by chronic inflammation, immune activation, and elevated levels of interleukin-6. In studies, up to 21% of PMR patients have GCA on temporal artery biopsies. PMR symptoms are present in 40 - 60% of GCA patients at diagnosis.
- GCA is sometimes referred to as "temporal arteritis," but this term is no longer favored since other vasculitis syndromes may involve the temporal artery [1,3]
- Polymyalgia rheumatica
- PMR is marked by inflammation of extra-articular synovial structures, including bursae of the shoulders, hips, and cervical spine. Muscle pain is common, but markers of muscle inflammation are not typically elevated. The underlying cause of PMR is unknown. [1]
- Giant Cell Arteritis
- GCA is marked by granulomatous inflammation of the arterial wall. Lymphocytes, macrophages, and fused macrophages (giant cells) may be seen on histology; despite the name, giant cells are only present in 50% of cases. Sequelae of GCA include the following: (1) vision loss from retinal artery and/or posterior ciliary artery occlusion or narrowing, (2) thoracic aortic aneurysms, (3) aortic dissection, (4) neuropathies. [1,8]
- Arteries affected in GCA include the following:
- Cranial arteries - branches of the internal and external carotid. Intracranial vessels are rarely affected.
- Aortic arch and thoracic aorta - large-vessel vasculitis occurs in up to 25% of patients. It is diagnosed with CT angiography or MR angiography.
- Primary branches of the aorta - subclavian, left common carotid, brachiocephalic artery [3,4,5,9]
- DIAGNOSIS
- ESR and CRP
- Two laboratory markers of inflammation (ESR and CRP) play an important role in the diagnosis of PMR and GCA
- Most patients with GCA will have an elevated ESR, but in some studies, up to 11% of patients with GCA had an ESR of < 50 mm/hr
- For PMR, an elevated ESR or CRP is part of the diagnostic criteria, but in some studies, a normal ESR has been seen in up to 20% of patients diagnosed with PMR
- ESR and CRP can be elevated in a number of common conditions. See ESR and CRP for more. [1,4]
- Rheumatoid factor and ACPA
- The ACR lists a negative rheumatoid factor or ACPA as part of its diagnostic criteria for PMR
- Rheumatoid factor and ACPA are markers for rheumatoid arthritis, a condition that can mimic PMR, so their absence makes PMR more likely
- See rheumatoid factor and ACPA for more
- Ultrasound
- Ultrasound of the hips and shoulder has been utilized to help diagnose PMR
- Findings that are consistent with PMR include bicipital tenosynovitis, subacromial bursitis, subdeltoid bursitis, and trochanteric bursitis
- Shoulder and hip joint effusions may also be seen
- The addition of US to other findings can increase the specificity of the diagnosis
- The ACR 2012 PMR classification guidelines include US findings as part of the diagnostic criteria [1,6]
ACR 2012 PMR Diagnostic Criteria | |
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PMR diagnosis - ALL patients MUST have the following:
|
|
If the above criteria are met, then the diagnosis is based on a scoring system with the criteria below. The score required for diagnosis differs
on whether ultrasound (US) results are available.
|
|
Criteria | Score |
Morning stiffness for > 45 minutes | 2 |
Hip pain or limited range of motion | 1 |
Negative Rheumatoid factor or ACPA | 2 |
Absence of other joint pain | 1 |
When US results are available | |
At least 1 shoulder with subdeltoid bursitis and/or biceps tenosynovitis and/or glenohumeral synovitis (either posterior or axillary) and at least 1 hip with synovitis and/or trochanteric bursitis | 1 |
Both shoulders with subdeltoid bursitis, biceps tenosynovitis, or glenohumeral synovitis | 1 |
- GCA diagnosis
- GCA is diagnosed with a temporal artery biopsy. Since GCA can be segmental with skip lesions, a length ≥ 1 cm is recommended to avoid false negatives. If the initial biopsy is negative and suspicion for GCA is high, a contralateral biopsy should be performed. In studies, up to 5% of patients with a negative biopsy will have a positive biopsy on the opposite artery.
- ESR and C-reactive protein are typically elevated, but up to 11% of patients will have an ESR < 50 mm/hr
- Imaging studies, including ultrasound, arteriography, and MRA/MRI, are being used more frequently to diagnose GCA. In one study, MRI had a sensitivity of 94% and a specificity of 78% when temporal artery biopsy was used as a reference standard. [PMID 27483045]
- Large-vessel vasculitis is present in up to 25% of patients with GCA; therefore, imaging of the aorta and its branches is recommended [9]
- Recommendations for diagnosing GCA from the ACR are presented below. In 2022, the ACR and EULAR published classification criteria to help identify GCA in patients with established medium- or large-vessel vasculitis. Those criteria are available here - GCA classification criteria.
- 2021 ACR/Vasculitis Foundation recommendations for diagnosing GCA
- Patients with suspected GCA should initially have a unilateral temporal biopsy more than 1 cm in length. The biopsy should be obtained within 2 weeks of starting oral steroids. Biopsy is preferred over US and MRI for making an initial diagnosis.
- Large vessel vascular imaging that includes the aorta and its branches should be performed in patients with a negative biopsy and all newly-diagnosed cases. [15]
ACR/EULAR 2022 Classification Criteria for Giant Cell Arteritis | |
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These criteria should only be applied to patients who meet all of the following:
Sum the score from the 10 criteria below. A score ≥ 6 classifies the vasculitis as giant cell arteritis. |
|
Clinical criteria | |
Finding / symptom | Score |
Morning stiffness in shoulders/neck | 2 |
Sudden visual loss | 3 |
Jaw or tongue claudication | 2 |
New temporal headache | 2 |
Scalp tenderness | 2 |
Abnormal examination of the temporal artery (absent or diminished pulse, tenderness, or hardness) | 2 |
Laboratory, imaging, and biopsy criteria | |
Maximum ESR ≥ 50 mm/hour or maximum CRP ≥ 10 mg/liter (prior to treatment initiation) | 3 |
Positive temporal artery biopsy or halo sign on ultrasound | 5 |
Bilateral axillary involvement defined as luminal damage (stenosis, occlusion, or aneurysm) on imaging | 2 |
FDG-PET activity throughout the aorta | 2 |
- TREATMENT
ACR/EULAR 2015 Polymyalgia Rheumatica Treatment Recommendations |
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Corticosteroids
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Methotrexate
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Exercise
|
- Sarilumab (Kevzara®)
- In 2023, the FDA approved sarilumab (Kevzara®), an antibody to IL-6 receptors, for the treatment of PMR. It is the first and only biologic to receive a PMR indication. Approval was based on results of a 52-week study (N=118) that compared sarilumab 200 mg every 2 weeks to placebo. At the end of the study, 28.3% of sarilumab-treated patients achieved sustained remission compared to 10.3% of placebo-treated patients. [ClinicalTrials.gov]
- Other
- Other therapies that have been evaluated in PMR include the following:
- Tocilizumab (Actemra®) - a study found tocilizumab to be effective in treating glucocorticoid-dependent PMR (see tocilizumab PMR study below)
- Azathioprine (Imuran®) - azathioprine (Imuran®) was found to be beneficial in one small study (N=31). [PMID 3511861]
- Tumor necrosis factor inhibitors - tumor necrosis factor inhibitors have not shown a conclusive benefit in trials and are not recommended
2021 ACR/Vasculitis Foundation GCA treatment recommendations |
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Initial therapy |
Patients with visual symptoms, vision loss, or critical cranial ischemia
Patients without visual symptoms, vision loss, or critical cranial ischemia
|
Clinical response |
Remission achieved
Remission not achieved
|
- 2010 British Society of Rheumatology glucocorticoid dosing and tapering recommendations
- GCA without jaw or tongue claudication or visual symptoms:
- Prednisolone or prednisone 40 - 60 mg (not < 0.75 mg/kg) daily for 4 weeks (may need longer course if symptoms and laboratory abnormalities have not resolved)
- Then dose is reduced by 10 mg every 2 weeks to 20 mg
- Then by 2.5 mg every 2 - 4 weeks to 10 mg
- Then by 1 mg every 1 - 2 months provided there is no relapse
- GCA with visual symptoms:
- Evolving visual loss or history of amaurosis fugax: IV methylprednisolone 500 mg to 1 gram daily for 3 days
- Established vision loss: at least 60 mg prednisolone or prednisone daily
- Continue for 4 weeks (may need longer course if symptoms and laboratory abnormalities have not resolved)
- Then dose is reduced by 10 mg every 2 weeks to 20 mg
- Then by 2.5 mg every 2 - 4 weeks to 10 mg
- Then by 1 mg every 1 - 2 months provided there is no relapse [8]
- Tocilizumab
- In 2017, tocilizumab became the first drug FDA-approved for the treatment of giant cell arteritis. Approval was based on the results of a 52-week trial detailed below (see tocilizumab for GCA).
- DISEASE RELAPSE
- PMR
- Relapse is common, occurring in up to 50% of patients [1]
- GCA
- Relapse is common, occurring in up to 77% of patients who discontinue corticosteroids [5]
- STUDIES
- The trial enrolled 101 patients with active PMR who were receiving glucocorticoids
Main inclusion criteria
- PMR diagnosis by Chuang's criteria
- CRP ≥ 10 mg/L or ESR ≥ 20 mm/hr
- Glucocorticoid dependency
Main exclusion criteria
- Possible GCA
- Prednisone > 25 mg/day
- Uncontrolled dyslipidemia
- Uncontrolled hypertension
- Immunosuppressant other than methotrexate
Baseline characteristics
- Median age 68 years
- Female sex - 66%
- Median duration of PMR - 18 months
- Median CRP - 0.9 mg/dl
- Median ESR - 26 mm/hr
- Median prednisone dose - 10 mg
- Taking methotrexate - 31%
Randomized treatment groups
- Group 1 (49 patients): Tocilizumab (8 mg/kg) IV every 4 weeks for 24 weeks
- Group 2 (51 patients): Placebo
- At each study visit after week 8 (weeks 12, 16, and 20), prednisone dosages greater than 10 mg per day were tapered by 5 mg. For dosages less than or equal to 10 mg per day, if the CRP PMR-AS was less than 10, the prednisone dosage was decreased by 2 mg every 2 weeks according to the investigator's evaluation of disease activity.
Primary outcome: Composite of low disease activity, defined as CRP PMR-AS (range, 0-100; higher scores indicate
greater disease activity) less than 10, and either prednisone dosage less than or equal to 5 mg per day or prednisone dosage decrease by greater than or equal to 10 mg vs baseline at 24-week follow-up.
Results
Duration: 24 weeks | |||
Outcome | Tocilizumab | Primary | Comparisons |
---|---|---|---|
Primary outcome | 67.3% | 31.4% | p<0.001 |
CRP PMR-AS score | 7.5 | 14.9 | p<0.001 |
Stopped prednisone | 49% | 19.6% | p<0.001 |
Infection | 47% | 39% | N/A |
Headache | 14% | 2% | N/A |
Hyperlipidemia | 12% | 4% | N/A |
Cytopenia | 8% | 4% | N/A |
|
Findings: Among patients with active polymyalgia rheumatica despite prednisone therapy, tocilizumab, compared with placebo, resulted in a significantly greater percentage of patients with a CRP PMR-AS less than 10 with reduced prednisone requirements at week 24. Further research is needed to confirm efficacy and to determine the balance of potential benefits and harms.
- The trial enrolled 251 patients with active giant cell arteritis
Main inclusion criteria
- ≥ 50 years of age
- Active giant-cell arteritis within 6 weeks before baseline
- ESR > 30 mm/hour or CRP ≥ 1 mg/dL (including a presenting history of ESR> 50 mm/hour)
- Cranial symptoms of GCA or symptoms of polymyalgia rheumatica
- Evidence of GCA on imaging or temporal artery biopsy
Main exclusion criteria
- Major ischemic event, related or unrelated to GCA, within 12 weeks of screening
- History of GI disease (e.g. diverticulitis, Crohn's, ulcerative colitis) that might predispose a patient to perforations
- Serum creatinine > 1.4 mg/dL
- Total bilirubin > ULN
- ALT or AST> 1.5 X ULN
Baseline characteristics
- Average age - 69 years
- Newly-diagnosed GCA - 48%, Relapsing GCA - 52%
- Average duration of disease - 296 days
- Symptoms of PR - 61%
- Average ESR - 24 mm/hr
Randomized treatment groups
- Group 1 (100 patients): Tocilizumab 162 mg SQ once weekly + 26-week prednisone taper
- Group 2 (50 patients): Tocilizumab 162 mg SQ every other week + 26-week prednisone taper
- Group 3 (50 patients): Placebo + 26-week prednisone taper
- Group 4 (51 patients): Placebo + 52-week prednisone taper
- Prednisone was initiated at a previously used dose or continued at current dose and then tapered weekly
Primary outcome: Rate of sustained glucocorticoid-free remission at week 52 in each tocilizumab group as compared with the rate in the placebo group that
underwent the 26-week prednisone taper
Results
Duration: 52 weeks | |||||
Outcome | Toc weekly | Toc biweekly | Placebo 26 | Placebo 52 | Comparisons |
---|---|---|---|---|---|
Primary outcome | 56% | 53% | 14% | 18% | 1 or 2 vs 3: p<0.001 |
|
Findings: Tocilizumab, received weekly or every other week, combined with a 26-week prednisone taper was superior to either 26-week or 52-week prednisone
tapering plus placebo with regard to sustained glucocorticoid-free remission in patients with giant-cell arteritis. Longer follow-up is necessary to determine the durability of remission
and safety of tocilizumab.
- STUDY
- Design: Randomized, placebo-controlled trial (N=72 | length = 76 weeks) in patients with newly diagnosed PMR
- Treatment: Methotrexate 10 mg/week vs Placebo for 48 weeks. All patients received prednisone at a starting dose of 25 mg/day with a goal to taper off within 24 weeks.
- Primary outcomes: The proportion of patients no longer taking prednisone, the number of flare-ups, and the cumulative prednisone dose after 76 weeks
- Results:
- Stopped prednisone: Methotrexate - 88%, Placebo - 53% (p=0.003)
- Experienced ≥ 1 flare-up: Methotrexate - 47%, Placebo - 73% (p=0.04)
- Median cumulative prednisone dose: Methotrexate - 2.1g, Placebo - 2.97g (p=0.03)
- Findings: Prednisone plus methotrexate is associated with shorter prednisone treatment and steroid sparing. It may be useful in patients at high risk for steroid-related toxicity.
- BIBLIOGRAPHY
- 1 - PMID 23051717 Lancet review
- 2 - PMID 12140303 NEJM review
- 3 - PMID 23795218 GCA review
- 4 - PMID 18640460 - Lancet review 2008
- 5 - PMID 21460132 - Clev Clinic review
- 6 - ACR 2012 PMR classification criteria
- 7 - PMID 19919443 - BSR PMR tx recs
- 8 - PMID 20371504 BSR GSA tx recs
- 9 - PMID 24988557 NEJM review
- 10 - PMID 25695965 VZV study
- 11 - PMID 27037084 VZV study II
- 12 - PMID 27483045 High-Resolution Magnetic Resonance Imaging of Scalp Arteries for the Diagnosis of Giant Cell Arteritis: Results of a Prospective Cohort Study, Arthritis Rheumatol, (2017)
- 13 - PMID 26359488 2015 Recommendations for the management of polymyalgia rheumatica: a European League Against Rheumatism/American College of Rheumatology collaborative initiative Arthritis & Rheumatology, (2015)
- 14 - PMID 30888397 Evaluating the Erythrocyte Sedimentation Rate, JAMA (2019)
- 15 - PMID 34235884 - 2021 American College of Rheumatology/Vasculitis Foundation Guideline for the Management of Giant Cell Arteritis and Takayasu Arteritis, Arthritis & Rheumatology (2021)
- 16 - PMID 36351706 - 2022 American College of Rheumatology/EULAR classification criteria for giant cell arteritis, Ann Rheum Dis (2022)