A 41 Year-old woman with proximal muscle weakness in the setting of rheumatoid arthritis and an abnormal chest x-ray

1. A 41 Year-old woman with proximal muscle weakness in the setting of �rheumatoid arthritis� and an abnormal chest x-ray Rheumatology Rounds December 15, 2006 Lisa Christopher-Stine, MD, MPH Assistant Professor of Medicine Co-Director, The Johns Hopkins Myositis Center

2. No Relevant Financial Relationships with Commercial Interests

3. Objectives To review the historical, physical examination, and pathological findings of a patient who presents with upper extremity proximal weakness � To explore the differential diagnosis of this case To gain insight into the meaning of the associated autoantibodies noted � To review the current literature related to this clinical entity � To explore therapeutic treatment options

4. Case Presentation Referral: Proximal myopathy in the setting of a diagnosis of rheumatoid arthritis 41 year-old woman w/ complicated medical history 1984: unrestrained passenger in MVA; leg weakness; ? Upper arm soreness Circa 1988: Wheezing and SOB, attributed to smoking 1988: c/o arm weakness, soreness; neuro eval

5. History 1988: CXR shows hilar adenopathy noted on pre-employment physical examination 1989: Knee and ankle swelling; rheum eval reveals high RF ? Dx with RA and Rx w/ naproxen 1989: Dx with �asthma�; Rx nebs, inhalers 1988-1994: Notes �slow and steady decline of muscle strength� in the shoulder girdle 1989: Left quad muscle bx nondiagnostic 1994: Left neck lymph node biopsy

6. History 1994-2006 Rapid deterioration in strength; arthritis and arthralgias; enlarging goiter; jaw weakness 1995: Second muscle bx of deltoid 2000: ? Right foot drop noted 2005: Consultation in JHU Arthritis Center 2006: Referral for myopathy evaluation

7. Family History Sister: occular sarcoid, facial palsy, arthritis Maternal cousin with sarcoid Maternal grandfather: RA

8. Medications Prednisone (1994- present) MTX and CSA � short duration Etanercept 2000-2002; restarted 2 wks ago Cyclophosphamide 2002-2004 Mycophenolate mofetil 2 g/day 12/04 & 12/05: IVIG x 1 course

9. Physical Examination: General HEENT: Can open mouth only 2 fingerbreadths in diameter Neck: Enlarged goiter with palpable nodules Heart: RRR, no m/r/g Lungs: CTA b/l without wheeze, rhonchi, crackles Skin: Minimal scaly rash on MCPs bilaterally

10. Physical exam- musculoskeletal When stands, swings arms from side to side in order to move them, as there is markedly reduced upper arm strength Severe deltoid, biceps, triceps, interosseous muscle atrophy Minimal atrophy of hamstrings, quadriceps, and calf muscles B/L wrist drop Jaccoud�s arthropathy No active synovitis

11. Physical exam- musculoskeletal Strength: 0/5 deltoids 2/5 biceps and triceps 5-/5 hip flexors and extensors 5/5 knee flexion and extension 3/5 dorsiflexion

12. Outside labs 1991: NL TSH with increased T3 and T4 RF 10,240 ? 950 IU/ml Anti-CCP antibodies detected CK 394 in March �04 ANA 1:640? 1:80, homogeneous Anti-DNA negative ACE 31 (7-46) U/L

13. Ancillary studies EMG (1997): L arm � decreased action potential duration, decreased amplitude of APs, increased insertional activity of biceps and first dorsal interosseous muscles L leg: increased insertional activity w/ fibrillations in the anterior tibialis muscle. All other muscles normal

14. Ancillary studies (cont�d) EMG (2004): severe, long-standing generalized myopathy with electropysiologic features suggestive of a pathologic substrate of fiber splitting, necrosis or vacuolar change.

15. Muscle biopsy 2004 Left Triceps (June 2004): Involvement of the walls of perimysial arterioles by the inflammatory process No convincing findings of sarcoidosis in the available specimen Mild to moderate increase in internal nuclei Necrosis and regeneration A few vacuoles Heavy inflammatory exudate In one nodular exudate, the cells in the center of the nodule have epithelioid appearance

16. Ancillary Studies: Pathology (JHU Interpretation) LEFT THIGH BX (OUTSIDE SLIDES, 3/9/89),): FRAGMENTS OF SKIN AND SKELETAL MUSCLE, NEGATIVE FOR TUMOR. LYMPH NODE, LEFT NECK BX (OUTSIDE SLIDES, 3/23/94): GRANULOMATOUS INFLAMMATION CONSISTENT WITH SARCIDOSIS. MUSCLE AND LYMPH NODE (BX, OUTSIDE SLIDES, 2/16/95), A. MUSCLE: SKELETAL MUSCLE WITH GRANULOMATOUS INFLAMMATION. (outside read: neurogenic atrophy with extensive fiber type grouping into fascicles with focal inflammation) B. LYMPH NODE: NON-CASEATING GRANULOMATOUS INFLAMMATION. SPECIAL STAINS FOR ACID FAST BACILLI AND FUNGI ARE NEGATIVE. LEFT KNEE BX, (OUTSIDE SLIDES): CHRONIC SYNOVITIS WITH FEATURES SUGGESTIVE OF IMMUNE COMPLEX- MEDIATED SYNOVITIS.

17. Johns Hopkins Workup Labs: ACE WNL; 25-OH vitamin D 5 ng/mL; aldolase 8 U/L; CPK 271 IU/L Imaging: R and L shoulder x rays: anterior glenohumoral dislocation with moderate hypertrophic DJD Hand x rays: no erosions; no significant findings Ankle x rays: mild degenerative changes Thigh MRI: fatty replacement on T1 and enhancement of muscles on STIR

18. Working Diagnoses Sarcoid arthropathy vs. RA Sarcoid myopathy

19. Recommendations: Rituximab trial � no benefit Thalidomide (50 mg/day) � short duration; possible increased neuropathic symptoms Referral to Ed McFarland for glenohumeral or scapular fusions Ortho referred her to Plastic surgery (Dr. Deune)for potential latissimus tendon transfer to helpher improve her elbow flexion so that she could achieve more independence (eating, etc.)

20. A Brief History of Sarcoidosis The English physician Robert Willan in 1808 described erythema nodosum, (1946 was proved to be related also to sarcoidosis.) The skin lesions were described first by Sir Jonathan Hutchinson in 1877 and later by Ernest Henri Besnier in 1889: multiple, raised, purplish cutaneous patches on the hands and feet..." thought initially to be attributed to gout, and later to represent " a form of skin disease," �

21. Caesar Boeck in 1899 described the first case of sarcoidosis with skin changes and general destruction of lymph nodes. He first used the term �sarkoid� (�flesh-like�) in a report describing skin lesions that resembled benign sarcoma. Involvement of other parts of the body reported by J�rgen Nilsen Schaumann in 1914.

22. Lupus pernio with presence of epithelioid cells and giant cells first described in 1892 by Tenneson and Quinquaud. Bittorf and Kusnitzky in 1915 drew attention to the pulmonary manifestation of sarcoidosis. Morten Ansgar Kveim in 1941 published a test to differentiate sarcoidosis from tuberculosis. Longcope and Frieman�s descriptive monograph summarizes clinical findings over the first half of the 20th century

23. The Kveim-Siltzbach skin test� Conducted by Dr. Morten Ansgar Kveim, a Norwegian dermatologist/pathologist Popularized by Dr. Louis Siltzbach at the Mt. Sinai Medical Center in New York City The only test that, if positive, is considered to be diagnostic of sarcoidosis The test material, a suspension of granuloma-containing spleen, lymph node, or other tissue� from a confirmed case of sarcoidosis, is injected intradermally. Positive test characterized by formation of a papule at the site of injection within 4-6 weeks� which, on microscopic examination, exhibits non-necrotizing granulomas and the absence of foreign material.

24. Sarcoidosis: Background Multisystem disorder Unknown etiology Prevalence: 10-20/100,000 3-4 x more common in AA Most patients are between 10 and 40 yrs of age 50% of cases detected incidentally by CXR Histology: noncaseating granulomas in affected organs

25. Definition Of Granuloma: �� a compact (organized) collection of mature mononuclear phagocytes (macrophages and/or epithelioid cells) which may or may not be accompanied by accessory features such as necrosis or the infiltration of other inflammatory leukocytes"

26. Granulomas and the Immune System A non-specific type of inflammatory response which may be triggered by diverse antigenic agents or by inert foreign materials. The antigenic triggering agents cause activation of the cellular immune system (T lymphocytes and macrophages) Granulomas are formed as the� result of the complex interaction of cytokines produced by these cells. The antigenic triggering agents include: Infectious agents (mycobacteria, fungi, etc.) Beryllium, The unknown antigen(s) responsible for sarcoidosis

27. Sarcoid Arthropathy Seen in 25% of sarcoid patients Acute arthritis: involves knees and ankles Lofgren�s Syndrome: hilar adenopathy, acute polyarthritis, and E. Nodosum Occasionaly isolated involvement of the small joints of the hands may mimic RA

28. Sarcoid Arthropathy Chronic arthritis: several forms: Nondeforming w/ granulomatous synovitis Jaccoud�s like deformity Joint swelling adjacent to a sarcoid bony lesion Dactylitis Knees, ankles, and hands; rarely SI and TM joints involved

29. Sarcoid Arthropathy DDx Mycobaterial infections Fungal infection- histo, sporotrichosis, etc Foreign body Tophi � urate, CPPD Other granulomatous d/o: Chron�s Wegener�s, lymphomatois graulomatosis

30. Sarcoidosis: Skeletal Involvement Cystic or lacelike appearance (bilateral) Usually at the ends in small bones (hands and feet). Articular spaces are usually intact, unless extensive lesions (punched-out lesions) develop. Calcification is absent. Subcutaneous soft-tissue mass or tenosynovitis may also be present.

31. Skeletal Sarcoid DDx Tuberculosis Histoplasmosis Coccidiomycosis Leprosy Brucellosis Syphilis Wegener�s granulomatosis Eosinophilic granuloma Multiple myeloma Lymphoma Metastasis

32. Granulomatous Myopathy DDx Wegener�s granulomatosis Polymyositis Dermatomyositis Crohn�s Disease **Associated signs and symptoms of sarcoidosis should be present before a definitive dx of sarcoid myopathy can be made**

33. Sarcoid Myopathy: Background First described in 1908; remains underdiagnosed Skeletal muscle involved in 50-80% of individuals with sarcoidosis Rarely symptomatic (0.5-2.5%) Rarely the initial presentation Three clinical patterns: Insidious onset of proximal muscle weakness with normal or elevated CK/aldolase (chronic myopathy) Acute myopathy with elevated muscle enzymes Nodular myopathy (single or multiple, painful)

34. Sarcoid Myopathy: Histology H&E, 400x Non-necrotizing granuloma obliterating normal muscle architecture.

35. Muscle Involvement in Sarcoidosis: Retrospective and Follow-up Studies Retrospective chart review 1985-2001 in 2 French academic centers 5/45 sarcoidosis patients had muscle involvement Initial feature in 2 patients Chronic myopathy not observed Corticosteroids helpful Frequent relapses reported

36. Sarcoid Myopathy- The Hopkins Experience

38. Granulomatous Myositis: A clinical study of thirteen cases 13 cases of GM: 8 with sarcoidosis All patients had symmetrical proximal lower- limb weakness 3 subsequently developed distal or proximal limb involvement 3/5 with isolated GM had distal involvement and 2 had dysphagia

39. Granulomatous Myositis: A clinical study of thirteen cases One patient with acute sarcoid myopathy had good response to MTX; other immunosuppressants and etanercept proved ineffective for chronic sarcoid myopathy 3 of 5 with isolated GM responded to steroids At follow-up 3 sarcoid patients had severe disability; those with isolated GM had milder weakness

43. Anti-CCP Antibodies

45. Successful treatment of muscle sarcoidosis with thalidomide Case report: first report on the efficacy of thalidomide in muscle sarcoidosis. 36-year-old male patient suffered from therapy- resistant sarcoidosis with long-standing contractures, myopathy, skin lesions and pulmonary changes. Low-dose therapy with thalidomide (50 mg/day) was well tolerated, and the patient rapidly improved. Thalidomide was effective for muscular, cutaneous, and pulmonary involvement

46. Remaining questions What is the nature of her arthropathy? Is sarcoid myopathy a plausible diagnosis? What is the most appropriate treatment course at this time? Should we consider latissimus tendon transfer to help her improve her elbow flexion ?

47. Objectives: Review To review the historical, physical examination findings, and pathologic findings of sarcoidosis To explore the differential diagnosis of granulomatous myopathy � To review the current literature on sarcoidosis focusing on the extrapulmonary manifestations in the joints, bone, and muscle To gain a better understanding of RF and CCP positivity in this patient To review current therapeutic options with regard to sarcoid joint disease and sarcoid myopathy