• Information
  1. Characteristics
  2. Symptoms
  3. Laboratory
  4. Pathophysiology
  5. Differential Diagnosis
  6. Treatment

A. Characteristics

1. Abrupt onset of polyarticular ± muscular pain
2. This is a proximal arthritis, often with marked myalgia
3. Joint Arthritis
   1. Pain usually out of proportion to degree of synovitis
   2. Localization to peri-articular and muscle regions is common
   3. Pain usually localized in shoulders, upper arms, back of neck, hips
   4. Unlike rheumatoid arthritis (RA), PMR is a non-erosive arthritis
4. Usually affects >50 year old patients
   1. Incidence 40-60 per 100,000 persons >50 years old per year
   2. Prevalence ~6 per 1000 persons >50 years old [1]
   3. Common disease in patients >65 years old
   4. Majority of patients (70%) are women
5. Association with Giant Cell (Temporal) Arteritis (GCA) [3]
   1. Up to 20% of PMR patients will have temporal artery inflammation
   2. Any PMR patient with symptoms of GCA should have a temporal artery biopsy
   3. Key symptoms in PMR patients which suggest GCA are cranial and jaw symptoms
   4. PMR in persons over 70 is also more likely to be accompanied by GCA
   5. Main reason for biopsy is that GCA is treated with higher doses of glucocorticoids

B. Symptoms

1. Symmetrical joint stiffness and aching, worse in morning
   1. Usually with an acute onset and severe debilitation
   2. May awaken patient from sleep
   3. Elderly onset rheumatoid arthritis (EORA) may mimic symptoms
2. More commonly affects upper compared with lower extremities
   1. Neck and shoulder areas
   2. Upper arms, particularly triceps
   3. Distal pain about the wrists and hands is not uncommon
3. Atypical Findings [4]
   1. Peripheral distal synovitis
   2. Lower leg pain
   3. Frank muscle weakness
4. Must inquire about symptoms of GCA: PMR in patients >70 years with abrupt headache or jaw claudication is likely GCA [3]

C. Laboratory

1. No definitive diagnostic criteria
   1. Diagnosis with clinical symptoms AND
   2. Rapid response to prednisone 20mg/d or less is sometimes considered diagnostic [4]
   3. Response to prednisone particularly useful in suspected PMR with normal ESR [5]
2. Erythrocyte Sedimentation Rate (ESR)
   1. Often increased >70mm/hr
   2. ESR >40mm/hr in ~60% of persons
   3. Normal ESR found in ~20% of PMR (<30mm/hr) [5,6]
   4. About 50% of patients with normal ESR and PMR are men
   5. PMR with an ESR <40mm/hr may be clinically less severe than classic PMR [5]
   6. C-reactive protein (CRP) may be more sensitive than ESR [1,3]
   7. CRP should be ordered if ESR is normal and diagnosis is strongly suspected [3]
   8. IL-6 levels are good predictors of PMR and GCA
3. Seronegative for Autoantibodies
   1. Rheumatoid Factor (RF) and ANA negative or very weekly positive
   2. ANCA negative
   3. Negative for other nuclear and cytoplasmic autoantibodies
4. Radiography
   1. Joint damage does not appear to occur
   2. Radiography is negative for bone deformation
   3. Magnetic resonance imaging (MRI) shows subdeltoid bursitis is most common in PMR
   4. MRI also shows tenosynovitis as major finding in PMR with swelling and pitting edema
   5. Positron emission tomography (18F-glucose) can show inflammation of aorta in PMR [7]
5. Creatine Kinase (CPK), aldolase, and other muscle enzyme levels are normal
6. HLA-DR4 predisposition (similar to RA) but test is not helpful

D. Pathophysiology [2,8]

1. Systemic Inflammatory Disease
   1. Primarily affects large arteries (above the diaphragm)
   2. Typically associated with systemic symptoms and polyarthralgias
   3. Due to dendritic cell and CD4+ T lymphocyte initiation of Type 1 T helper response
   4. Activated dendritic cells produce chemokines CCL19 and CCL21, attracts other cells
   5. T cells and macrophages typically cause granulomas in vessel wall
2. CD4+ T helper lymphocytes produce inflammatory cytokines
   1. B cells and gamma-delta T cells are not present in synovitic regions
   2. Activated macrophages and IFNg positive CD4+ T cells are present in synovium
   3. This synovitis is not errosive (no pannus is present)
   4. Contrast with synovium in RA patients, where B and gd-T cells are found with a pannus
3. Cytokine Patterns From Temporal Artery Biopsies
   1. IL-1ß, IL-6 and TGF-ß1 expressed in temporal arteries of GCA and PMR patients
   2. GCA patients had both IFN gamma and IL-2 mRNA production
   3. PMR patients had only IL-2, without IFN gamma
   4. Suggests that IFN gamma is involved in development of severe vasculitis
   5. This is consistent with role of activated macrophages in vessel destruction
4. Muscle inflammation, damage, or infarction is not observed

E. Differential Diagnosis [1,4]

1. Rheumatologic Disease
   1. Seronegative RA
   2. Elderly onset RA
   3. Remitting seronegative symmetric synovitis with pitting edema (RS3PE)
   4. SLE
   5. Spondyloarthropathy - usually asymmetric
   6. Muscle Disorders: Polymyositis, dermatomyositis, others
   7. Granulomatous vasculitis
   8. Giant Cell Arteritis
2. Infections
   1. Bacterial Endocarditis
   2. Tuberculosis, disseminated
   3. HIV Infection Se Card "HIV"
   4. Other systemic infection (usually subacute)
3. Malignant Neoplasms
   1. Hematologic - leukemia, lymphoma, myeloma, myelodysplasia, Waldenstrom's Disease
   2. Solid Tumors - renal cell carcinoma, uterine, gastric, pancreatic, others
4. Other
   1. Amyloidosis
   2. Hypothyroid myopathy (Hoffman's Syndrome)
   3. Fibromyalgia

F. Treatment [2,3]

1. Should respond to low dose prednisone (<20mg/day)
   1. Initiate prednisone therapy at 12.5-15mg/day x 2-4 days
   2. Some patients will require 20-25mg/day initially for 4-7 days [9]
   3. Taper usually by 1-2.5 mg per week usually down to 5-7.5mg qd over 12-24 weeks
   4. Most ofen require maintenance dose (5-6mg) of prednisone to prevent attacks
   5. "Glucocorticoid Sparing" agents such as methotrexate (MTX) or azathioprine may be used
   6. Methotrexate 10mg weekly may allow more rapid reduction in glucocorticoids [9,10]
   7. MTX should always be given with supplemental folate (7.5mg weekly)
   8. Most patients can discontinue glucocorticoids after ~2 years
2. Health Maintenance on Glucocorticoids
   1. Vaccinations should be up to date
   2. Osteoporosis should be prevented with at least calcium + vitamin D
   3. Strongly consider additional prevention with concommitant bisphosphonate therapy
   4. MTX use in initial therapy leads to reduction in total prednisone dose over 2 years
3. ESR Monitoring
   1. ESR (or CRP) are very useful to monitor therapy
   2. Risk of GCA complications usually related to ESR
   3. Maintain ESR < ~40mm/hr to reduce symptoms and risk of GCA
   4. Glucocorticoid dose should be titrated to symptoms AND ESR
4. However, recurrence / chronic symptoms is most common
5. NSAIDs
   1. May be added with some benefit and permit reduction in glucocorticoid dose
   2. May actually be treating RF negative EORA
   3. Severe gastric distress often occurs in elderly patients with NSAIDs + steroids
   4. Strongly recommend GI prophylaxis with H-2 blocker OR
   5. Consider use of GI-sparing NSAID such as nabumetone or COX-2 selective inhibitor
6. MTX [9,10]
   1. Glucocorticoid resistant PMR may be improved with MTX
   2. Patients requiring more than 7-8mg/d prednisone may benefit from MTX
   3. MTX may act as a "glucocorticoid or steroid sparing" agent
   4. MTX may be safer than steroids when monitored properly
   5. Initiated therapy at 5-10mg po q week after baseline laboratory testing
   6. MTX 10mg weekly allowed more rapid tapering of prednisone in PMR patients [9]
   7. Hepatic function and CBC monitoring is critical to safe use of this agent
7. Azathioprine
   1. Mainly used as a "steroid sparing" agent to permit reduction in steroid doses
   2. Initial dose is 1mg/kg po qd; can escalate after 2-4 weeks to 2-4mg/kg/day po
   3. Blood counts, amylase, and liver function tests must be monitored monthly
   4. Effects seen in 6-12 weeks after initiating this agent
8. Tumor Necrosis Factor alpha (TNFa) Blockade
   1. Infliximab (Remicade®) added to glucocorticoids was of no benefit, with possible harm, in initial treatment of PMR [11]
   2. In addition, maintenance therapy with infliximab following glucocorticoid-induced remission of GCA of no benefit, and may be harmful [12]

References

1. Salvarani C, Cantini F, Hunder GG. 2008. Lancet. 372(9634):234
2. Weyand CM and Goronzy JJ. 2003. NEJM. 349(2):160
3. Weyand CM and Goronzy JJ. 2003. Ann Intern Med. 139(6):505
4. Brooks RC and McGee SR. 1997. Arch Intern Med. 157(2):162
5. Gonzalez-Gay MA, Rodriguez-Valverde V, Blanco R, et al. 1997. Arch Intern Med. 157(3):317
6. Helfgott SM and Kieval RI. 1996. Arthritis Rheum. 39(2):304
7. Blockmans D, Stroobants S, Maes A, Mortelmans L. 2000. Am J Med. 108(3):246
8. Weyand CM, Schonberger, Oppitz U, 1997. Arthritis Rheum. 40(1):40
9. Caporali R, Cimmino MA, Ferraccioli G, et al. 2004. Ann Intern Med. 141(7):493
10. Stone JH. 2004. Ann Intern Med. 141(7):569
11. Salvarani C, Macchioni P, Manzini C, et al. 2007. Ann Intern Med. 146(9):631
12. Hoffman GS, Cid MC, Rendt-Zagar KE et al. 2007. Ann Intern Med. 146(9):621