Polymyalgia Rheumatica and Giant Cell Arteritis

1. Polymyalgia Rheumatica and Giant Cell Arteritis

2. History of PMR and GCA • First description: 940-1010 BC • Treatment was removal of affected artery • English literature • Bruce (1888) PMR – “senile rheumatic gout” • Hutchinson (1890) – provided description of GCA • Horton (1932) • Classic histology findings • Coined “giant cell arteritis” • Barber (1957) • Coined “polymyalgia rheumatica”

3. Pathogenesis • Genetic predisposition influenced by exposures • Increased incidence @ higher latitudes • Scandinavian background • Occasional familial cases • Initiating viral pathogen? • Parainfluenza virus type1 • Mycoplasma • Parvovirus

4. Genetics of PMR and GCA • HLA-DRB1*01 and *04 • Associated w/ susceptibility to GCA/PMR • Rheumatoid Arthritis • Mutually exclusive populations • Different part of genes involved in each condition

5. Common Pathogenesis of PMR and GCA • Activated circulating monocytes • Inflammatory cytokine production • Th1 response in vessel wall • No autoantibody component NEJM 2003;349(2): 160-169.

6. Pathogenesis of GCA • A: Activation of Dendritic cells • B: Oxidative damage by macrophages • C, D: Differential expression of VEGF and PDGF NEJM 2003;349: 160-169.

8. Relation of PMR to GCA • PMR seen in 40-50% of pts w/ GCA • About 15% of PMR pts develop GCA • Some view PMR as forme fruste GCA • Vasculitis remains subclinical

9. Epidemiology of PMR • Prevalence: 3300 per 100,000 • Incidence • Scandinavian/N. European: 50-68/100,000 • Spain, Italy: 12-18 per 100,000 • Women > Men, about 3:1 • Highly unlikely in those < age 50 • Mean age at onset is 70 Gonzalez-Gay et al. Arthritis Rheum 2009;61:1454-1461

10. Polymyalgia Rheumatica (PMR) • Clinical syndrome • Seen in “elderly” patients • Characterized by pain/stiffness (> 4 wks) • Involves neck, shoulder initially then hip region • Constitutional symptoms common • Laboratory evidence of systemic inflammation • ESR, CRP, anemia

11. Other PMR Features • Fever/chills • GCA, infection, malignancy • Arthritis / joint inflammation • Non-erosive synovitis

12. Arthritis in PMR NEJM 2002; 347, 261-278.

13. Diagnosis of PMR • Compatible clinical syndrome • Exclusion of diff dx • Elevated acute phase response • Response to corticosteroids NEJM 2002; 347:261-278.

14. Differential Diagnosis - PMR RS3PE – Remitting Symmetric Synovitis with Pitting Edema

15. PMR and Malignancy • No excess malignancy in PMR • Consider paraneoplastic PMR-like syndrome • Poor or incomplete response to steroids • Young age • Relatively low ESR • Most common malignancies • Colon, Lung, Kidney, Leukemia, Lymphoma • Without findings suggestive of cancer ensure age-appropriate screening is current

16. Treatment of PMR: Steroids • Very responsive to oral steroids: 10 – 20 mg daily • What is best initial dose? • Ann Rheum Dis 1989;48:658-661. • Average duration of steroid therapy 2 years • Prevention of bone loss • Gradually taper steroids • Some patients require low dose prednisone • ? Role of steroid sparing agents • Monitor for relapses • Clinical features > labs

17. Sample Steroid Taper for PMR • Start 20 mg daily for 4 weeks • Decrease by 2.5 mg daily every 2-4 weeks to 10 mg daily • From 10 mg daily decrease by 1 mg daily every 2-4 weeks • For relapse return to higher dose

18. Methotrexate for PMR • Limitations of trials • Few patients • Varying steroid and methotrexate doses • Short duration • Prior negative studies • Feinberg et al. J Rheum 1996;23(9):1550-1552. • Open-controlled; 12.5mg/wk not steroid sparing • Van der Veen et al. Annals Rheum Dis 1996;55:218-223. • RDBPC; 7.5 mg/week not steroid sparing

19. Methotrexate for PMR • Two positive trials • Ferraccioli et al.J Rheum 1996 ;23(4):624-628. • Open, randomized; 10 mg methotrexate IM weekly • Total steroid dose reduced at 1 year • Caporali et al. Ann Intern Med 2004;141:493-500. • RDBPC; 10 mg methotrexate po weekly; 72 patients • 25 mg prednisone both arms • Shorter prednisone treatment / lower dose in MTX arm • High starting dose prednisone (25 mg daily) • High weekly folinic acid supplement (7.5 mg weekly)

20. Other “Steroid Sparing” Drugs in PMR • Azathioprine • De Silva et al. Ann Rheum Dis 1986 Feb;45(2):136-138. • 31 patients, 100-150 mg / day azathioprine • Steroid sparing effect seen at 1 year • Anti-TNF • Enbrel: Catanoso et al.Arthritis Rheum. 2007 Dec 15;57(8):1514-9. • Open case series 6 patients, steroid dependent PMR • 24 weeks treatment, 36 weeks follow-up • Significant reduction in steroid dose • Infliximab: Salvarani et al. J Rheumatol. 2003 Apr;30(4):760-3. • 3 of 4 patients had clinical response sustained at 1 year

21. Epidemiology - GCA • Age >50 years (mean 70) • Incidence increases progressively w/ age • Most common vasculitis in northen hemisphere • Gender • Women > men about 2:1 • Population prevalence (Age 50 or older) • Scandinavian/N. European: 22-76/100K • Spain, Israel: 10 per 100K • France, Italy: 6.9-9.4 per 100K • Shelby Co, TN: 2.2 Cauc., 0.4 AA per 100K

22. Synonyms of GCA • Temporal arteritis • Cranial arteritis • Granulomatous arteritis • Horton’s headache

23. GCA: Classification Criteria NEJM 2002; 347, 261-278.

24. Presentations of GCA • Cranial Arteritis • Headaches • Ischemic Optic Neuropathy • Jaw Claudication • PMR • Fever/Wasting Syndrome • Fever and chills • Anorexia, weight loss • Night sweats • Weakness • Depression GCA PMR Syndrome • Large-vessel GCA/aortitis • Arm claudication • Pulselessness • Raynaud’s phenomenon • Aortic aneurysm • Aortic insufficiency • PMR • Isolated PMR • Pelvic girdle muscles • Pain in shoulder and • Stiffness

25. Cranial Arteritis - Symptoms • Headache – 2/3 of patients • Throbbing, sharp or dull • Usually severe, seek medical attention • Scalp tenderness • Usually over temporal artery • Wearing glasses, grooming, lying down • Jaw/tongue claudication – up to 50% of patients • Masseter/temporalis muscles • Painful dysphagia

26. Eye symptoms in GCA • Various presentations • Diplopia • Amaurosis fugax • Scotoma • Ptosis • Partial or complete blindness • Above can be transient or permanent • Permanent partial/complete blindness • 15 to 20% of patients in most literature

27. GCA – Other Symptoms • Musculoskeletal complaints are common • PMR (40%) • Peripheral arthritis • Swelling and pitting edema • Arm claudication • 10-25% patients • Bruits • Diminished neck or arm pulses

28. GCA – Other Symptoms • CNS events – 20 to 30% of patients • TIA or CVA • Carotid/vertebrobasilar • Neuropathy • Pulmonary – up to 25% • Cough, hoarseness, chest pain • Pulmonary hemorrhage (case report)

29. GCA as an FUO • Subset of patients with: • Systemic inflammatory syndrome • Malaise, anorexia, weakness • Fatigue, wasting, depression • Physical exam not consistent with: • Cranial arteritis • Large vessel occlusive disease • PMR

30. Large-vessel GCA • 10-15% of patients • Targets aortic branches • Carotid, subclavian, axillary arteries • Aortic arch syndrome • Claudication of arms • Absent/asymmetrical pulses • Parasthesias, Raynaud’s phenomenon • Occasional peripheral gangrene

31. Large-vessel GCA • Often without cranial arteritis • No headaches, other cranial symptoms • Normal temporal artery exam • 50% of temporal artery biopsies negative

32. Giant Cell Arteritis - Exam

33. Temporal Arteries • Thickened, tender and nodular • Occasionally erythematous • Pulses reduced or absent • 1/3 of patients, temporal arteries grossly normal • Other external carotid branches • Occipital/superficial scalp vessels

34. Cranial arteritis and the eye • Ophthalmologic emergency • Prompt treatment can prevent blindness • Ischemic optic neuropathy • Most common cause of visual loss

35. Causes of visual loss in GCA % of 63 Patients AION – anterior ischemic optic neuropathy BRAO – branch retinal artery occlusion PION – posterior ischemic optic neuropathy CI – choroidal infarct CRAO – central retinal artery occlusion OA – optic atrophy (unclear etiology) Liu et al. Ophthalmology 1994;101:1779-1785.

36. Other Exam Findings • Vascular bruits • Carotid, Subclavian, Axillary • Differential BP between arms • Diminished pulses

37. Laboratory Features of GCA • Elevated ESR, CRP • Up to 23% with normal ESR at diagnosis • Elevated IL-6 • Highest sensitivity for ongoing disease • Both before/after corticosteroid therapy • Anemia of chronic disease • Elevated platelet count • Elevated alkaline phosphatase

38. Differential Diagnosis – GCA • Other vasculitis or pseudovasculitis • Vascular headache/migraine • Infections (acute sinusitis) • Hypothyroidism • Neoplastic / paraneoplastic process • Multiple myeloma, leukemia, lymphoma • Joint disease (OA, RA) • PM/DM, other myositis

39. Making the Diagnosis of GCA • Compatible clinical syndrome • Exclusion of differential diagnosis • Look for physical exam clues • Majority have dramatic acute phase response • Superficial temporal artery • Easiest site to biopsy • Most useful for intermediate pre-test probability • False negative biopsies can occur: • Take a sufficient length of biopsy (5 cm) • Examine serial sections • Consider contralateral bx if 1st is negative • Limit time of treatment prior to biospy

40. Utility of Signs and Symptoms in Suspected Giant-Cell Arteritis Weyand, C. M. et. al. Ann Intern Med 2003;139:505-515.

42. Timing of Temporal Artery Biopsy • Ray-Chaudhuri et al.Br J Ophth 2002; 86: 530-532. • Prospective study of 11 patients • All met ACR criteria for GCA (before bx) • All started on steroids at time of dx • 9/11 - Positive biopsies overall • 6/7 - Biopsy (+) 4-6 wks after steroids • Narvaez et al.Semin Arthritis Rheum. 2007 Aug;37(1):13-9. • 35/45 biopsies (+) within 2 weeks • 13/20 biopsies (+) 2-4 weeks • 2/5 biopsies (+) 4 weeks or more

43. Histopathology • 50% have pan-arteritis with giant cell formation, often in close proximity to disrupted elastic lamina • Large and medium arteries • Involvement is focal and segmental

44. Giant-Cell Arteritis of the Temporal Artery Weyand C and Goronzy J. N Engl J Med 2003;349:160-169

45. Adjunctive Diagnostic Tools • Ultrasound • “Dark halo” around temporal artery • Results of 86 patients (U/S then bx) • Any halo, 40% sens and 79% spec • 1mm or >, 40% sens and 93% spec • Conclusion • Only modest predictor of positive biopsy • Did not improve dx accuracy of PE Salvarani et al. Annals 2002;137: 232-238.

46. Ultrasound - Halo

47. Other Diagnostic Tools If extracranial GCA suspected, may consider: • Angiography • Document disease of large arteries • MRA • Useful for diagnosis • Rheumatology (Oxford). 2005 Apr;44(4):479-83. • May improve finding of vasculitis in FUO • Annals Rheum Dis. 2005 Jan;64(1):105-10 .

48. Large Vessel GCA • Tapering of L maxillary artery • Aneurysm of ascending aorta • Dilation and thickening of descending aorta

49. PET Scan and GCA • Vascular FDG uptake at diagnosis • 29 of 35 patients (83%) • Most common in subclavian vessels (74%) • Aorta 51% thoracic and 54% abdominal • Not predictive of relapse Blockmans et al. Arthritis Rheum 2006;55(1):131-137.

50. GCA Treatment • Corticosteroids • Initiate promptly to avoid visual loss • Start with 40-60 mg/day of prednisone (1mg/kg) • Single or divided doses • Recent visual loss • Hospitalize for IV methylprednisolone • Pulse dose qday or divided q6h • Aspirin reduces stroke • 2 retrospective studies (341 patients total) • Arthritis Rheum. 2004 Apr;50(4):1332-7. NNT = 5. • Arthritis Rheum. 2006 Oct;54(10):3306-9. NNT = 3.