A 41 Year-old woman with proximal muscle weakness in the setting of

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
Lisa Christopher-Stine, MD, MPH
Disclosures
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
• Jaccouds 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 1640? 180, 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 (contd)

• 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 Jörgen 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 Friemans 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"

(Adams DO. Am J Pathol 197684163-192)
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

Yale Rosen., M.D.
27
Sarcoid Arthropathy

• Seen in 25 of sarcoid patients
• Acute arthritis involves knees and ankles
• Lofgrens 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
• Jaccouds 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 Chrons Wegeners,
  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.

http//mskcases.com/index.php?modulearticleview
70
31
Skeletal Sarcoid DDx

• Tuberculosis
• Histoplasmosis
• Coccidiomycosis
• Leprosy
• Brucellosis
• Syphilis
• Wegeners granulomatosis
• Eosinophilic granuloma
• Multiple myeloma
• Lymphoma
• Metastasis

32
Granulomatous Myopathy DDx

• Wegeners granulomatosis
• Polymyositis
• Dermatomyositis
• Crohns Disease
• Associated signs and symptoms of sarcoidosis
  should be present before a definitive dx of
  sarcoid myopathy can be made

Simmonds MJ, Hoffbrand BI. J Neurosurg Psychiatry
199053998
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

• HE, 400x
• Non-necrotizing granuloma obliterating normal
  muscle architecture.

missinglink.ucsf.edu/.../sarcoid.he.2.jpg
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

J Rheumatol 2006 3398-103
36
Sarcoid Myopathy- The Hopkins Experience
Johns CJ, Michele TM. Medicine. 1999 Mar
78(2)65-111
37

Johns CJ, Michele TM. Medicine. 1999 Mar
78(2)65-111
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

Karine Le Roux, MD 1, Nathalie Streichenberger,
MD 1, Christophe Vial, MD, et al . Muscle Nerve.
2006 Oct 26 Epub ahead of print
40
Patient
Karine Le Roux, MD 1, Nathalie Streichenberger,
MD 1, Christophe Vial, MD, et al . Muscle Nerve.
2006 Oct 26 Epub ahead of print
41
(No Transcript)
42

• Rheumatoid Factor
• Autoimmune diseases (in adition to RA) that
  may have associated RF
• Sjogrens Syndrome
• Systemic lupus erythematosusSystemic lupus
  erythematosus
• Scleroderma
• Polymyositis
• Dermatomyositis
• Mixed Connective Tissue Disease
• Other infections or conditions which can be
  associated with positive RF
• Bacterial endocarditis
• Osteomyelitis
• Tuberculosiss
• Syphilis
• Hepatitis
• Mononucleosis
• Diffuse interstitial pulmonary fibrosis

43
Anti-CCP Antibodies
44
(No Transcript)
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

Acta Myol. 2003 May22(1)22-5
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