POLYMYALGIA RHEUMATICA AND GIANT CELL ARTERITIS
























  • 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




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]






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

Duration: 52 weeks
Outcome Group 1 Group 2 Group 3 Group 4 Comparisons
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.