scleroderma myositis 012210 by qingyunliuliu

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Inflammatory Myositis

         Kathryn Dao, MD
   Arthritis Consultation Center
         January 22, 2010

 Define scleroderma
 Identify the inflammatory myopathies
 Describe the subsets of these diseases
 Recognize their clinical features and
  disease that may mimic them
 Understand possible complications that
  may occur in these diseases
    What 1996 movie put
scleroderma on the map and

 “Skleros-” = hard    “-derma” = skin
 Incidence 1-2/100,000 in USA
 Peak age of onset 30-50 y.o.
 Female:male 3: 1
 Disease manifestation is a result of host
  factors + environment (concordance is
  similar in monozygotic and dizygotic
    A disorder of Collagen, Vessels

 Etiology: unknown? acquired?
 Autoimmune disorder suggested by the
  presence of characteristic autoantibodies
  such as ANA, anti-centromere and anti-
  SCL-70 antibodies.
         Scleroderma Pathogenesis
Hallmarks: Vasculopathy (not vasculitis) and fibrosis
     Early dermal changes lymphocytic infiltrates primarily of T cells
     Hypersensitive a2 receptors resulting in heightened
     Tissue ischemia/ reperfusion

                          Susceptible Host
                                   Exogenous event

      Immune System                          Endothelial Cell
      Activation                             Activation/Damage

                   Obliterative Vasculopathy &
                                              Klippel JH, ed. Primer on the Rheumatic Disease. 2001
How do you categorize
        Scleroderma Classification
Three major disease subsets: based on extent of skin
   Localized Scleroderma
   Systemic Sclerosis (SSc)
     Diffuse SSc
     Limited SSc AKA "CREST" syndrome

   Scleroderma sine scleroderma
Localized Scleroderma:
Linear scleroderma
What is this condition called?

  “En Coup de Sabre”
        Scleroderma Classification
Three major disease subsets: based on extent of skin
   Localized Scleroderma
   Systemic Sclerosis (SSc)
     Diffuse SSc - skin abnormalities extending to the
      elbows/knees, often include the face, neck, & trunk
     Limited SSc AKA "CREST" syndrome
     Calcinosis, Raynauds, Esophageal dysmotility
      Sclerodactyly, Telangiectasias
   Scleroderma sine scleroderma
      ACR Systemic Sclerosis
 Preliminary Classification Criteria*
    Major Criterion
      Scleroderma     proximal to the MCP or MTP
    Minor Criteria
      Sclerodactyly
      Digitalpitting or scars or loss of finger pad
      Bibasilar pulmonary fibrosis

* One major and two minor required for diagnosis
     Diffuse SSc - Clinical
   Skin:
     Skin thickening: most noticeable in the hands --
      swollen, puffy, waxy.
     Thickening extends to proximal extremity, truncal
      and facial skin thickening is seen.
     Loss of skin folds, no hair growth
     Digital pits or scarring of the distal digital pulp
     Calcinosis, telangiectasias
     Raynaud's phenomenon

                              Skin Scores
                              Extent of skin involvment
                              predictive of survival:
                              % Survival at   5 yr    10 yr
                              Sclerodactyly 79-84     47-75
                              Truncal         48-50   22-26

J Rheumatol 1988;15:276-83.
What are the typical colors of Raynaud’s?
     In what order do they occur?
                  White, Blue, Red
       pallor cyanosis  reperfusion erythema

                 BONUS: What country’s flag is this?

                   Flag of the Russian Federation
     A disorder of Collagen, Vessels
       Small to medium-sized
        blood vessels, which
        show bland fibrotic
        Vasculopathy, NOT
       Small thrombi may
        form on the altered
        intimal surfaces.

   Microvascular disease       Cold   Normal
                                Cold   PSS
          Systemic Sclerosis
 Arthralgias >>> Arthritis
   Palpable tendon
    friction rubs associated
    with an increased
    incidence of organ
   Muscle weakness or
    frank myositis can be
    seen—can be
    associated with
  Where in the GI tract does
        SSc affect?

Anywhere from the mouth to
        the anus
                Systemic Sclerosis: GI
   Small oral aperture, dry mucosal
    membranes with periodontal
   Esophageal dysmotility, reflux,
    esophagitis, stricture,
   Delayed stomach emptying,
   Pseudoobstruction of the small
    intestines, bacterial overgrowth,
   Wide mouth diverticuli
   Fecal incontinence due rectal
    sphincter fibrosis
      Systemic Sclerosis: Renal
Kidney involvement is an ominous finding and
important cause of death in diffuse scleroderma. A
hypertensive crisis (AKA renal crisis) may herald
the onset of rapidly progressive renal failure.
        Scleroderma Renal Crisis
   Risk Factors
      diffuse skin involvement
      rapid progression of skin thickening
      disease course < 4 years
      anti-RNA-polymerase III-antibodies
      newly manifested anemia
      newly manifested cardiac involvement

     high-dose corticoid therapy
     pregnancy

                                         Am J Med 1984;76:779-786.
        Scleroderma Renal Crisis

   Microangiopathic hemolytic anemia
    +Microscopic hematuria
   Fatal before the introduction of ACE-I
      Survival without ACE-I 16% @ 1 year, with
       ACE-I 45% at 5 years
      ACE-I increases levels of two potent renal
               bradykinin and angiotensin 1-7

                                     Ann Int Med 1990;113:352-357.
       ???TRUE or FALSE???
ACE inhibitors should be continued in
patients with renal crisis despite rising
       creatinine and potassium

       Systemic Sclerosis: Renal

   Some patients will require dialysis despite
    ACE-I and good blood pressure control
   As long as the ACE-I are continued during
    dialysis, approximately 50% will have enough
    improvement to stop dialysis in 6-18 months.
   Inconsistent data with ARBs

                               Rheum Dis Clin North Am. 1996 Nov;22(4):861-78
    Systemic Sclerosis: Pulmonary


   Interstitial fibrosis +/- pulmonary hypertension
   Dyspnea, cough, chest pain
   Other manifestations:
     Pulmonary embolism
     Pulmonary vasculitis
     Pulmonary hemorrhage
     Lung cancer
     Aspiration
     Respiratory distress from muscle disease
     PFT’s in Systemic Sclerosis

 Decreased DLCO is the earliest marker
  (especially with normal lung volumes)
 Increased A-a Gradient with Exercise
 Restrictive Pattern
       VC,  FEV1/FVC
     Systemic Sclerosis: Cardiac
   Symptoms are subtle
   Myocardium, myocardial blood vessels,
    pericardium can all be involved:
     Myocardial fibrosis
     Dilated cardiomyopathy
     Cor pulmonale
     Arrhythmias
     Pericarditis (30-40%)
     Myocarditis
     Congestive heart failure (diastolic dysfunction)
     Myocardial infarction (Raynaud’s)
        Comparison CREST v. Diffuse SSc
              Feature                   Limited CREST                   Diffuse SSc
              Calcinosis                      ++                             +
             Arthralgias                      ++                           ++++
          Pulmonary fibrosis                  ++                            +++
           Pulmonary HTN                      ++                             +
          Tend friction rubs                   0                            +++
             Renal crisis                      0                             +
           Centromere Ab                     +++                            +/0
            Anti-Scl 70 Ab                     +                            ++
             Raynaud’s                     +++++                          +++++
            Telangiectasia                   +++++                          ++++
        Esophageal dysmotility               +++++                         +++++
             5 yr Survival                   +++++                          ++++

+ Relative percentages: +++++ 81-100%; ++++ 61-80%; +++ 41-60%; ++ 21-40%; + 1-20%
               Treatment of SSc
   Morphea: none
   Treat the manifestations of the disease:
   Raynauds: warmth, skin protection, vasodilator
    therapy (e.g., NTG, CCB, ARB, Niacin, anti-
    adrenergics, prostacyclin, endothelin antagonists,
    nerve blocks)
   Systemic therapy:
      Unproven benefits--Steroids, Penicillamine, MTX
      CYP: for alveolitis
      Experimental: stem cell transplant
      Finger ulcers: difficult; vasodilators, Abx
         DDX of Tight Skin
   Pseudosclerodactyly
      IDDM, Hypothyroidism
   Drugs: Tryptophan,
    bleomycin, pentazocine,
    vinyl chloride, solvents
   Eosinophilic fasciitis
   Overlap syndromes
   Scleredema
   Scleromyxedema
    (papular mucinosis)
               DDX of Tight Skin
   Scleroderma-like conditions
     Porphyria cutanea tarda
     Nephrogenic fibrosing dermopathy
           Inflammatory Myositis:
   F:M = 2:1
   Acute onset
   Weakness: Proximal > Distal
   Skeletal muscle: dysphagia, dysphonia
   Sx: Rash, Raynauds, dyspnea
   65% elevated CPK, aldolase
   50% ANA (+)
   90% +EMG
   85% + muscle biopsy
What percentage of patient
with DM/PM will have pain?

      Less than 50%
     Proposed Criteria for Myositis
1.   Symmetric proximal muscle weakness
2.   Elevated Muscle Enzymes (CPK, aldolase,
     AST, ALT, LDH)
3.   Myopathic EMG abnormalities
4.   Typical changes on muscle biopsy
5.   Typical rash of dermatomyositis

    PM Dx is Definite with 4/5 criteria and
     Probable with 3/5 criteria
    DM Dx Definite with rash and 3/4 criteria and
     Probable w/ rash and 2/4 criteria
         Myositis Classification
                    Bohan & Peter

1.   Primary idiopathic dermatomyositis
2.   Primary idiopathic polymyositis
3.   Adult PM/DM associated with
4.   Childhood Dermatomyositis (or PM)
      *often associated with vasculitis and calcinosis
5.   Myositis associated with collagen
     vascular disease

   Age/Sex/Race
   Acute vs. Insidious Onset
   Distribution: Proximal vs. Distal
   Pain?
   Drugs/Pre-existing Conditions
   Neuropathy
   Systemic Features
                  DDX: Myopathies
   Toxic/Drugs
       EtOH, Cocaine, Hydroxychloroquine, Penicillamine,
        Clofibrate, Taxol Colchicine, AZT, Statins, Steroids,
        Hydralazine, Gemfibrozil, CYA, L-dopa, Phenytoin,
        Cimetidine, Sulfonamides, PCN
   Infectious
       Coxsackie, HBV, HIV, Strep, Staph, Clostridium,
        Toxoplasma, Trichinella
   Congenital/metabolic myopathies
   Neuropathic/Motor Neuron Disorders (MG, MD)
   Endocrine/Metabolic-hypothyroidism
   Inclusion body myositis
 Nonmyopathic DDx
 Fibromyalgia
   Polymyalgia Rheumatica
     Caucasians, > 55 yrs, M=F
     Elevated ESR/CRP, normal strength,
      no synovitis
   CTD (SLE, RA, SSc)
   Vasculitis
   Adult Onset Still's Disease
        Inflammatory myositis:
   Infiltrates - T cells (HLA-DR+) & monocytes
   Muscle fibers express MHC class I & II Ags
   T cells are cytotoxic to muscle fibers
   Infectious etiology? Viral implicated
   HLA-B8/DR3 in childhood DM
   DR3 and DRW52 with t-RNA synthetase Ab
Dermatomyositis: Skin features

1.   Heliotrope Rash: over eyelids
         Seldom seen in adults
2.   Gottrons Sign/Papules
     (pathognomonic): MCPs, PIPs, MTPs,
     knees, elbows
3.   V-Neck Rash: violaceous/erythema
     anterior chest w/ telangiectasias
4.   Periungual erythema, digital ulcerations
5.   Calcinosis
Why is it called a
heliotropic rash?
                Diagnostic Testing
    Physical Examiniation: Motor Strength (Gowers
    sign), Neurologic Exam
    Acute phase reactants unreliable
    Muscle Enzymes
       CPK: elevated >65%; >10% MB fraction is possible
       Muscle specific- Aldolase, Troponin, Carb. anhydraseIII
       AST > LDH > ALT
       Beware of rising creatinine (ATN) and myoglobinuria
    EMG: increased insertional activity, amplitude,
    polyphasics, neuropathic changes,
    incremental/decremental MU changes
           Diagnostic Testing
   Muscle Biopsy (an URGENT not elective
     Call the neuropathologist! 85% Sensitive.
     Biopsy involved muscle (MRI guided)
     Avoid EMG/injection sites or sites of trauma
    Magnetic Resonance Imaging - detects
    incr. water signal, fibrous tissue,
    infiltration, calcification
    Investigational: Tc-99m Scans, PET
    Serologic Tests: ANA (+) 60%, Abs
    against t-RNA synthetases

   Inflammatory cells
   Edema and/or fibrosis
   Atrophy/ necrosis/ degeneration
   Centralization of nuclei
   Variation in muscle fiber size
   hydroxyapatite crystals (rare)
                             Polymyositis: CD8+Tcells,
                             endomysial infiltration

Dermatomyositis: Humoral
response B cells, CD4+ T cells;
     Autoantibodies in PM/DM
Ab          Freq (%)   Clinical Syndrome
ANA            50      Myositis
U1-RNP         15      SLE + myositis (MCTD)
Ku             <5      SSc + myositis
Mi2            30      Dermatomyositis
PM1            15      SSc + PM overlap
Jo-1           25      Arthritis+ ILD+ Raynaud
SS-B (La)      <5      SLE,Sjogrens, ILD, PM
PL-12,7        <5      ILD + PM
   What is an anti-synthetase
•It is a subcategory of the inflammatory
defined by the presence of autoantibodies to
aminoacyl-tRNA synthetases.
•Specific clinical manifestations :ILD,
arthritis, Raynaud's phenomenon, fever, and
mechanics hands.
•Examples: Antibodies to Jo-1, PL-12, OJ,
EJ, PL-7, KS, and Zo are some that have
been reported.
Mechanics hands– association with Jo-1
       Malignancy and myositis
   Higher association with DM, less common
    with polymyositis
   Studies found 20-32% with DM developed
   Common tumors: Breast, lung, ovary,
    stomach, uterus, colon, NHL
    60% the myositis appears 1st, 30%
    neoplasm 1st, and 10% simultaneously

                                   Lancet 2001
                                   Ann Int Med 2001.
Dermatomyositis and Malignancy

   All adults with DM should have age-
    appropriate screening annually during
    first several years after presentation:
     CXR
     Colonoscopy   or sigmoidoscopy
     PSA/prostate exam in men
     Mammogram, CA-125, pelvic exam,
      transvaginal ultrasonography in women
            PM/DM Complications

PULMONARY                     CARDIAC
 Aspiration pneumonitis
                               Elev. CPK-MB
 Infectious pneumonitis
                               Mitral Valve prolapse
 Drug induced
  pneumonitis                  AV conduction
 Intercostal, diaphragm        disturbances
  involvement                  Cardiomyopathy
 Fibrosing alveolitis
                               Myocarditis
      Pulmonary vasculitis
      Pulmonary neoplasia
   Early Dx, physical therapy, respiratory Rx
   High dose steroids (e.g., prednisone 1-2
       80% respond within 12 weeks
   Steroid resistant
     Methotrexate
     Azathioprine
     Rituximab
     CYP

   IVIG, Cyclosporin, Chlorambucil, TNFi:
   No response to apheresis
    Poor in pts. with delayed Dx, low CPK, early
    lung or cardiac findings, malignancy
    PT for muscle atrophy, contractures, disability
    Kids:50% remission, 35% chronic active
    Adult < 20 yrs. do better than >55 yrs.
    Adults: Mortality rates between 28-47% @
    7 yrs.
    Relapses & functional disability are common
    Death: due to malignancy, sepsis, pulm. or
    cardiac failure, and complications of therapy
       Inclusion Body Myositis
    Bimodal age distribution, maybe
   Males > females
    Slow onset, progressive weakness
    Painless, distal and proximal weakness
    Normal or mildly elevated CPK
    Poor response to therapy
    Dx: light microscopy may be normal or
    show CD8+ lymphs and vacuoles with
    amyloid. Tubulofilamentous inclusion
    bodies on electron microscopy

 Scleroderma and the inflammatory
  myopathies are diseases that require
  prompt recognition
 Early intervention may decrease

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