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					Morning Report
 November 2, 2011

     Dr Keating
   Rowan Karaman
MKSAP
   A 45-year-old woman is evaluated for a 2-week history of pleuritic
    chest pain. She has a 6-month history of arthralgia and a 2-month
    history of myalgia and mild proximal muscle weakness. She has
    difficulty climbing stairs, rising from a chair, and removing dishes from
    a high cabinet. She also has a 10-year history of Raynaud phenomenon.

   On physical examination, temperature is 36.4 °C (97.6 °F), blood
    pressure is 125/78 mm Hg, pulse rate is 90/min, and respiration rate is
    18/min. Cardiopulmonary examination is normal. Abdominal
    examination is unremarkable. There are healed ulcerations on the
    second and third fingers of the right hand. There is no synovitis.
    Proximal upper- and lower-extremity muscle strength is 4/5 and is
    associated with mild muscle tenderness.
MKSAP
   Laboratory studies:
      Hemoglobin: 12 g/dL (120 g/L)
      Erythrocyte sedimentation rate: 63 mm/h
      Serum creatinine: 0.9 mg/dL (68.7 µmol/L)
      Creatine kinase 896 U/L
   Alanine aminotransferase 98 U/L
   Aspartate aminotransferase 67 U/L
   Alkaline phosphatase 80 U/L
   Antinuclear antibodies Titer of 1:2560
   Urinalysis
   Normal

   A chest radiograph shows blunting of the costophrenic angles.
MKSAP
   Which of the following antibody assays will confirm the most likely diagnosis?
   A. Antimitochondrial
   B. Antiribonucleoprotein
   C. Anti-Ro/SSA
   D. Anti-Smith
   E. Antitopoisomerase I (anti–Scl-70)
MKSAP
   This patient most likely has mixed connective tissue disease, which is a specific disorder that combines clinical
    findings of systemic lupus erythematosus, systemic sclerosis, and polymyositis and is characterized by high
    titers of anti-ribonucleoprotein antibodies. This patient’s long-standing Raynaud phenomenon with associated
    digital ulcerations, arthralgia, myositis (characterized by proximal muscle weakness and elevated muscle enzyme
    levels, including alanine and aspartate aminotransferase and creatine kinase levels), and pleuritic chest pain
    compatible with serositis is consistent with mixed connective tissue disease.

   Antiribonucleoprotein antibodies may be present in patients with systemic lupus erythematosus (SLE),
    particularly those whose manifestations include Raynaud phenomenon and mild myositis. Furthermore, SLE
    may be associated with pleuritis and antinuclear antibodies. However, this patient does not have additional
    features associated with SLE, including malar or discoid rash, oral ulcers, or renal or neurologic involvement.
    This patient’s prominent muscle weakness and Raynaud phenomenon also are more consistent with mixed
    connective tissue disease than SLE. Anti-Smith antibodies are highly specific for SLE but are associated with
    glomerulonephritis and central nervous system disease, which also are absent in this patient.

   Antimitochondrial antibodies are present in approximately 95% of patients with primary biliary cirrhosis..

   Patients with Sjögren syndrome often have anti-Ro/SSA antibodies, but this patient does not have the
    symptoms of keratoconjunctivitis sicca (dryness of the eyes and mouth) that characterize this condition. Anti-
    Ro/SSA antibodies also may be associated with SLE, particularly subacute cutaneous disease. Subacute
    cutaneous SLE manifests as a papulosquamous or annular rash that typically involves the neck, trunk, and
    extensor surfaces of the arms, which this patient does not have.
   This patient most likely has mixed connective tissue disease, which is a specific disorder that combines clinical
    findings of systemic lupus erythematosus, systemic sclerosis, and polymyositis and is characterized by high
    titers of anti-ribonucleoprotein antibodies. This patient’s long-standing Raynaud phenomenon with associated
    digital ulcerations, arthralgia, myositis (characterized by proximal muscle weakness and elevated muscle enzyme
    levels, including alanine and aspartate aminotransferase and creatine kinase levels), and pleuritic chest pain
    compatible with serositis is consistent with mixed connective tissue disease.

   Antiribonucleoprotein antibodies may be present in patients with systemic lupus erythematosus (SLE),
    particularly those whose manifestations include Raynaud phenomenon and mild myositis. Furthermore, SLE
    may be associated with pleuritis and antinuclear antibodies. However, this patient does not have additional
    features associated with SLE, including malar or discoid rash, oral ulcers, or renal or neurologic involvement.
    This patient’s prominent muscle weakness and Raynaud phenomenon also are more consistent with mixed
    connective tissue disease than SLE. Anti-Smith antibodies are highly specific for SLE but are associated with
    glomerulonephritis and central nervous system disease, which also are absent in this patient.

   Antimitochondrial antibodies are present in approximately 95% of patients with primary biliary cirrhosis..

   Patients with Sjögren syndrome often have anti-Ro/SSA antibodies, but this patient does not have the
    symptoms of keratoconjunctivitis sicca (dryness of the eyes and mouth) that characterize this condition. Anti-
    Ro/SSA antibodies also may be associated with SLE, particularly subacute cutaneous disease. Subacute
    cutaneous SLE manifests as a papulosquamous or annular rash that typically involves the neck, trunk, and
    extensor surfaces of the arms, which this patient does not have.

   Systemic sclerosis may manifest as Raynaud phenomenon associated with digital ulcerations.
    Antitopoisomerase I (anti–Scl-70) antibodies are present in approximately 30% of patients with systemic
    sclerosis and are particularly associated with diffuse skin disease. However, this patient has no additional signs
    of skin thickening characteristic of this condition or additional manifestations of systemic sclerosis, such as
    gastroesophageal involvement or basilar fibrosis visible on chest radiography. Furthermore, this patient’s
    arthritis, serositis, and myositis are more suggestive of mixed connective tissue disease than systemic sclerosis.
Case Presentation
   47-year-old male presents to ED because he can no
    longer walk without assistance.
HPI
 Started ~2 months ago
 Bilateral calf and knee pain
 Weak when getting out of bed and climbing stairs
 Pain so severe that he could not work this week
 Now senses weakness in his upper extremities
 +20 lb weight loss, +morning stiffness
   PMH                                  Allergies: NKDA
       Diabetes mellitus 2              Family Hx: none
       HTN                              Social Hx
       Asthma                               No EtOH, tobacco, or illicits
   PSH                                      No children
       Umbilical hernia repair              Lives alone in Chicago
                                             Machinist for Pepsi
   Home Meds                                No foreign travel
       Olmesartan 20mg daily
       Glimepiride 1mg daily
       Triamcinolone inhaled daily
Physical Examination
   Temp 37.5, pulse 115, BP 116/64, RR 20, sat 99% RA, 184 lb (down from 215 lb),
    5’6”
   General: alert, oriented, no acute distress. Breathing comfortably.
   HEENT: no mouth or nasal septal ulcerations, dry mucous membranes.
   Neck: no thyromegaly, carotid bruits, or LAD.
   Lungs: CTA bilaterally, no wheezes/crackles/rhonchi.
   Cardiac: tachycardic, regular rhythm, no murmurs/rubs/gallops, normal S1 and S2.
   Abd: soft, nontender, nondistended. No HSM.
   MSK: normal muscle bulk. Strength in bilateral deltoids 4/5, proximal upper
    extremities 3/5, distal upper extremities 5/5, distal lower extremities 5/5, proximal
    lower extremities 3/5. Boggy R 2nd MCP, tenderness over L wrist, bilateral olecranon
    bursal swelling. Bilateral bursal inflammation below the patella. Thighs tender to
    palpation. No calf tenderness.
   Neuro: Decreased DTRs in the lower extremities. Left eyelid ptosis, diplopia on L
    lateral gaze. Normal Babinski. Antalgic gait. Normal cerebellar exam.
   Skin: unremarkable
Labs
                                    8.1    3.3                    Hgb A1c 8.7%
140     100     15                                                TSH 1.68
                            277
4.0     29      0.7                 0.2


                                     28        41
               8.1
 22.1                         575         92

                                     Urinalysis: 3+ gluc, neg blood, neg
                                     pro
 N 88 L 6 M 3 E 2
 Retic 0.26%                         ESR 106
 Iron 9
                                     CRP 133
 TIBC 226
 % iron sat 4                        CK 1019
 Ferritin 1458
                                     Aldolase 34
 B12, folate, epo: normal
                                     Trop: negative
    Muscle Weakness Differential
Medications                                              Rheumatologic
-   Amiodarone, Anti-thyroid agens (PTU,                 -   Dermatomyositis, polymyositis, inclusion
    methimazole), antiretroviral (zidovudine),               body myositis, anti-synthetase syndrome,
    cimetidine, cocaine, corticosteroids, gemfibrozil,       RA, SLE, PMR, Systemic
    lupron, nsaids, PCN, sulfonamides, statins               sclerosis/scleroderma
Infectious                                               Genetic
-   EBV, HIV, Influenza, Lyme disease, Meningitis,       -   Becker Muscular dystrophy, limb-girdle
    Polio, Rabies, Syphilis, Toxoplasmosis                   muscle dystrophy, myotonic dystrophy
Neurologic                                               Metabolic
-   ALS, CVA, Demyelinating disorders (GBS, MS),         -   Glycogen and lipid storage disease,
    Neoplasm, NM disorders (Botulism, Lambert-               mitochondrial disease, hypokalemia, kalemia
    Eaton, MG), radiculopathies                              periodic paralysis, hypercalcemia
Endocrine                                                Misc
-   Adrenal insufficiency, glucocorticoid excess,            -Amyloidosis, Sarcoidosis, EtOH
    secondary hyperPTH (CKD), hyper/hypoTSH
Muscle Weakness Evaluation
   Attempt to differentiate asthenia, fatigue and primary
    weakness
       Asthenia: Sense of weariness or exhaustion in the absence of muscle
        weakness
       Fatigue: Inability to continue performing a task with repetition
   Determine Onset and progression:
       Often significant overlap b/w disorders
   Pinpoint the distribution of weakness
       Global
       Proximal/distal
       Focal
   Clues in history and physical may be subtle
Imaging?
MRI Brain




Normal (incidental arachnoid cyst)
CT chest/abd/pelvis




Scattered nonspecific micronodules in the lung.
L tibia/fibula: no fracture or malalignment
R tibia/fibula:1.5-cm focus of heterotopic
ossification within the posteromedial soft
tissues, which is of indeterminate age.
No fracture or malalignment.
Imaging not so helpful
More labs
   ANA 1:640                                IgG 1922 (1700 upper limit of
   Anti dsDNA Ab: negative                   normal)
   Rheumatoid factor: 9 (normal)            IgA, IgM: normal
   Vascular ANCA IFA: negative              Paraneoplastic panel: negative
   C3: 170 (normal)
                                             Smooth muscle Ab: negative
   C4: 27 (normal)
                                             FOBT: negative
   Jo-1 Ab: negative
                                             CSF: no organisms, 1 WBC, 1 RBC, gluc
   Anti RNP: normal
                                              117, pro 39, culture negative
   Anti Smith: normal
                                             ACE enzyme: normal
   Ss-A: 21 (20 upper limit of normal)
                                             AChR binding Ab: negative
   Ss-B: 3 (normal)
   Cryoglobulin <0.5% (normal)              HIV, hepatitis panel, RPR: negative
                                             SPEP/UPEP: negative
What would help clinch a diagnosis?
   Bone marrow biopsy: granulocytic proliferation with
    normal maturation. Decreased erythropoiesis, but
    mature. Mild plasmacytosis. Abundant iron with
    decreased sideroblasts.
       Flow cytometry, cytogenetics, FISH without abnormalities
       Reactive marrow most likely given the above.
       Anemia of chronic disease
Further workup
 Muscle biopsy?
 Deltoid biopsy: active inflammatory necrotizing
  neuromyopathy consistent with connective tissue
  disease
Working toward a diagnosis…
   Myositis (NOS) and undifferentiated connective tissue
    disease with severe leukemoid reaction
Any treatment indicated?
 Received high dose methylprednisolone and 2 doses of
  IVIG as inpatient
 Weakness improved
 Ptosis and lateral gaze palsy resolved
 Tachycardia resolved
 Discharged home on methotrexate weekly and
  prednisone 30mg
Further follow-up
 After months of treatment, muscle weakness persisted
  and was determined by outpatient rheumatologist to
  have failed IVIG, MTX, azathioprine, mycophenolate.
 Developed hyperpigmentation across shoulders and
  axillae.
       Biopsy showed superficial and deep perivascular dermatitis
        consistent with dermatomyositis
 Started Rituximab and tacrolimus
 Myositis panel at this time showed moderate positive
  PL-7
 Finally diagnosed with dermatomyositis
Inflammatory myopathies
   Dermatomyositis
       Humorally mediated microangiopathy
   Polymyositis
       T-cell mediated disorder in which a cytotoxic attack against
        single nonnecrotic muscle fibers occurs
   Inclusion body myositis
Inflammatory Myopathies
   Polymyositis and dermatomyositis usually develop over
    weeks to months
      Proximal weakness, i.e. difficulty rising from chair,
       climbing stairs, lifting
      Distal weakness (fine motor) much later in the course
   Inclusion-body myositis (won’t discuss today)
   Extraocular movements not affected (except in our case)
   Rare dysphagia and respiratory muscle weakness
   Myalgias in minority

                       Dalakas, Hohlfeld. Lancet 2003; 362: 971–82
Inflammatory myopathies
Dermatomyositis
   Skin manifestations
      Heliotrope rash on eyelids
      Rash on face, neck, chest (V sign)
      Rash on back and shoulders (shawl sign)
      Rash on MCP and IP joints (Gottron’s papules/rash)
          Not the phalanges like in SLE

      Rough, cracked lines on palms and laterally (mechanic’s hands)
      Dilated nail bed capillary loops
      Subcutaneous calcifications
   Muscle weakness
      Can be mild  severe
      Perivascular and perimysial inflammation
Polymyositis
 Usually subacute and affects proximal muscles
 Diagnosis of exclusion
       No rash, myopathy-inducing drug exposure, endocrine
        disease, neuro disease, dystrophy
       Weeks months not monthsyears
Other Findings
   Dysphagia
   AV conduction defects, tachyarrhythmias, myocarditis
   ILD
      PFT
   Malignancy (esp dermatomyositis)
      GI, lung, breast, ovaries, non-Hodgkin
      Perform standard screening with CXR
      Some prefer full-body scans
      Can appear decades later
   Scleroderma and mixed connective-tissue disease
You’ll need some tests
   Elevated CK, aldolase, AST, ALT, LDH
      CK sometimes normal in active dermatomyositis!
   MRI
      T2/STIR
      Muscle edema in inflammation is hyperintense
   EMG: fibrillations, increased spontaneous activity, complex
    repetitive discharges
Testing
   Muscle biopsy (most important)
      Dermatomyositis: inflammation is perivascular or around the
       fascicles.
          Fibers go through phagocytosis and necrosis  atrophy

          Layers of atrophic muscle fibers at the periphery of fascicles
           is diagnostic
      Polymyositis: CD8+ lymphocytes (directed against MHC-I
       antigens) surround and invade muscle fibers (primary
       inflammation)
      May need another sample since inflammation could be focal
   Dermatomyositis skin lesions have perivascular inflammation with
    CD4+ cells in the dermis
Perifascicular atrophy in dermatomyositis
                      Dalakas MC, Hohlfeld R. Polymyositis and dermatomyositis. Lancet 2003; 362: 971–82.
Autoantibodies
 Directed against nuclear and cytoplasmic antigens,
  ribonucleoproteins involved in protein synthesis (anti-
  synthetase) and translation (anti-signal-recognition
  particle)
 Keep in mind that they occur in <25% of patients with
  dermato/polymyositis and they can be positive in ILD
  without myositis
Dalakas, Hohlfeld. Lancet 2003; 362: 971–82
Immunopathology
   Dermatomyositis
      Antibodies against endothelial cells of endomysial capillaries 
       activated C3  formation of C3b, C4b, C5b-9 membranolytic attack
       complex
      These stick to capillaries, leading to necrosis, perivascular
       inflammation, ischemia, and atrophy
      Various cytokines and chemokines facilitate the entry of activated T
       cells and macrophages to the perimysium and endomysium
      Generally humoral process characterized by B cells and CD4+ T cells
   Polymyositis and inclusion-body myositis
      Very complicated
      CD8+ cells invade MHC-I-antigens on muscle fibers
Antisynthetase syndrome
   Inflammatory myopathy, arthritis/arthralgias, ILD, fever,
    Raynaud’s, mechanic’s hands
   Autoantibodies to tRNA synthetases
      Catalyze binding of amino acids to matching tRNA in
        translation
      20 synthetases, each for a specific amino acid
      Antibodies against 8 of them identified
   Somehow, tRNA synthetases are released from muscle cells
    (virus? injury?) and induce cytokines
ILD in antisynthetase syndrome
   ILD seen in as many as 86% of anti-Jo-1 + patients
      Major factor in morbidity and mortality
      Myositis may be absent in presence of ILD

   Diffuse patchy ground glass, irregular linear opacities, basal
    consolidations
        Less likely honeycombing and bronchiectasis
   Need a lung biopsy for etiology and treatment
   NSIP, UIP, COP/BOOP, DAD
   Treatment along same lines as for the myositis
Treatment for dermatomyositis and polymyositis
   Corticosteroids (first line)
      Most will respond; some will need other forms of
        immunosuppression
   Azathioprine (takes months to work)
   Methotrexate
   IVIG
   Cyclosporine
   Mycophenolate mofetil
   Cyclophosphamide
   Anti-TNF agents?
   Rituximab?
Current state of our patient
 Wants to try to go back to work (drives a truck for his
  job) but cannot do any lifting
 4/5 strength proximally
 CK usually around 1500 (peaked at 3000)
 On methotrexate 25mg weekly, prednisone 40mg daily,
  azathioprine 150mg daily
 Needs Rituximab but has difficulty obtaining it
Take-Home Points
 When evaluating muscle weakness, pinpoint exactly
  what is weak
 Full ROS absolutely necessary
 Think of ILD and malignancy in patients with
  inflammatory myopathies
 Occasionally, even if you do all the “right” things, only
  time will tell
References and Photo Credits
   Dalakas MC, Hohlfeld R. Polymyositis and dermatomyositis. Lancet 2003; 362: 971–
    82.
   Katzap E, Barilla-LaBarca M-L, Marder G. Antisynthetase syndrome. Curr Rheumatol
    Rep 2011; 13:175–181.
   Brigham and Women’s Experts’ Approach to Rheumatology by Coblyn, Bermas,
    Weinblatt, and Helfgott.
   Porphyria cutanea tarda, dermatomyositis and non-Hodgkin lymphoma in virus C
    infection. European Journal of Dermatology 2003; 13: 302-4.
   Dugan EM, Huber AM, Miller FW, Rider LG. Photoessay of the cutaneous
    manifestations of the idiopathic inflammatory myopathies. Dermatology Online
    Journal 15 (2): 1.

				
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