Polymyalgia rheumatica and giant cell arteritis

ACRONYMS AND DEFINITIONS

ACR - American College of Rheumatology

ACPA - Anti-cyclic citrullinated peptide antibodies

CRP - C-Reactive Protein

ESR - Erythrocyte sedimentation rate

EULAR - European League Against Rheumatism

GCA - Giant cell arteritis

PMR - Polymyalgia rheumatica

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
40 - 60% of patients with GCA have PMR symptoms at diagnosis
The incidence of GCA in patients with PMR varies widely depending on the study with anywhere from 1 - 21% of PMR patients having a temporal artery biopsy positive for GCA
The two diseases share much of the same pathology including chronic inflammation, immune activation, and elevated levels of interleukin-6 [1]
GCA is sometimes referred to as "temporal arteritis," but this term should not be used since other vasculitis syndromes may involve the temporal artery [3]

Polymyalgia rheumatica

The cause of PMR is unknown
PMR is marked by inflammation of extra-articular synovial structures including bursitis of the shoulders, hips, and cervical spine
Synovial inflammation of the shoulder and hip joints may also occur
While muscle pain is common, muscle inflammation is not typically seen [1]

Giant Cell Arteritis

GCA is marked by granulomatous inflammation of the arterial wall
Lymphocytes, macrophages, and fused macrophages (giant cells) are seen on histology. Despite the name, giant cells are only seen in 50% of cases.
Arterial stenosis and occlusion may occur

Affected arteries include:

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. Can be 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]

Reference: ACR 2012 Proposed PMR Criteria
ACR 2012 PMR Diagnostic Criteria
PMR diagnosis - ALL patients MUST have the following: Age ≥ 50 years Bilateral shoulder aching Elevated ESR or C-reactive protein
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 without US - score of ≥ 4 establishes PMR diagnosis Criteria with US - score of ≥ 5 establishes PMR diagnosis
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 diagnostic criteria

GCA is diagnosed with a temporal artery biopsy
Since GCA can be segmental with skip lesions, a length of 20 mm or more is typically taken to avoid false-negatives
Elevated ESR and C-reactive protein are typically present, but an ESR of less than 50 mm/hr has been seen in up to 11% of patients with GCA
Imaging with 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% for GCA diagnosis when temporal artery biopsy was used as a reference standard. [4,5,12]
Large-vessel vasculitis occurs in up to 25% of patients with GCA. CT angiography or MR angiography may be needed to confirm a diagnosis. [9]

TREATMENT

ACR/EULAR 2015 Polymyalgia Rheumatica Treatment Recommendations
Overview Corticosteroids are the standard treatment for PMR Most patients respond to corticosteroids, but up to 45% of patients may not achieve an adequate response Methotrexate is a second-line option in nonresponders, but it has not been studied extensively The IL-6 inhibitor tocilizumab (Actemra®) has been approved to treat GCA. It's efficacy in PMR has not been proven, but trials are ongoing. Azathioprine (Imuran®) has been studied in one very small study [PMID 3511861] Tumor necrosis factor inhibitors have been studied in small trials, but no conclusive benefit has been found and they are not recommended [1,13]
Corticosteroids Prednisone Prednisone or prednisone equivalent is the recommended first-line treatment Starting: 12.5 - 25 mg once daily Initial tapering: taper to a dose of 10 mg/day within 4 - 8 weeks Tapering after remission achieved: taper daily oral prednisone by 1 mg every 4 weeks (or by 1.25 mg decrements using schedules such as 10/7.5 mg on alternate days, etc) until discontinuation as long as remission is maintained In case of relapse: increase oral prednisone to the pre-relapse dose and decrease it gradually (within 4–8 weeks) to the dose at which the relapse occurred Duration: minimum of 12 months of treatment [13] Methylprednisolone Alternative to prednisone. May be appropriate when overall lower exposure to corticosteroids is desired. Starting: 120 mg intramuscular every 3 weeks through week 9 Tapering: at week 12, give 100 mg and increase the dosing interval to every month. Reduce the dose by 20 mg every 12 weeks until week 48. Thereafter, reduce dose 20 mg every 16 weeks until discontinuation [13]
Methotrexate Methotrexate may be considered in addition to corticosteroids in the following patients: disease relapse, high risk of relapse and/or prolonged therapy, high risk of corticosteroid-related adverse events, inadequate response to corticosteroids, development of corticosteroid-related adverse events Dosing: 7.5 - 10 mg/week has been used in trials See methotrexate for drug information See Methotrexate vs Placebo in PMR below [13]
Exercise The ACR/EULAR guidelines conditionally recommend considering an individualized exercise program for PMR patients aimed at the maintenance of muscle mass and function, and reducing risk of falls [13]
Complications Side effects of chronic steroid use - see corticosteroids Increased risk of peripheral artery disease Development of GCA [1]

Giant cell arteritis treatment
Overview Up until 2017, corticosteroids were the only real treatment for GCA. In 2017, the biologic tocilizumab (Actemra®) was FDA-approved to treat GCA based on results of the study detailed below - Tocilizumab vs Placebo in GCA. Low-dose aspirin may lower the risk of stroke and vision loss, although the evidence is not conclusive Methotrexate has had mixed results in trials. Tumor necrosis factor inhibitors have not been found to be beneficial. Other disease-modifying drugs (e.g. azathioprine) have shown no conclusive benefit. [5,8]
Corticosteroid dosing In 2010, the British Society of Rheumatology published the following recommendations for corticosteroid dosing in GCA 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]
Complications Side effects of chronic steroid use - see corticosteroids Vision loss from narrowing or occlusion of the posterior ciliary arteries or retinal artery occlusion Thoracic aortic aneurysms Aortic dissections Neuropathies [1,8]

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

Tocilizumab vs Placebo in Giant Cell Arteritis, NEJM (2017) [PubMed abstract]

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

Outcome	Group 1	Group 2	Group 3	Group 4	Comparisons
Duration: 52 weeks
Primary outcome	56%	53%	14%	18%	1 or 2 vs 3: p<0.001
The incidence of adverse events was similar in all the trial groups, but fewer patients reported serious adverse events in Group 1 (15%) and Group 2 (14%) than in Group 3 (22%) and Group 4 (25%)

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.

Prednisone + Methotrexate or Placebo in PMR, Ann Intern Med (2004) [PubMed abstract]

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)

POLYMYALGIA RHEUMATICA AND GIANT CELL ARTERITIS