Scleroderma and Inflammatory Myositis

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Scleroderma and Inflammatory Myositis

• Kathryn Dao, MD
• Arthritis Center
• February 16, 2006

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Scleroderma

• Skleros- hard -derma skin
• Incidence 1-2/100,000 in USA
• Peak age of onset 30-50 y.o.
• Femalemale 7-12 1
• Disease manifestation is a result of host factors
  environment (concordance is similar in
  monozygotic and dizygotic twins)

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Scleroderma

• Three major disease subsets based on extent of
  skin dz
• Localized Scleroderma
• Morphea manifests as focal patches
• Linear scleroderma band-like (linear) areas of
  thickening. (Coup de Sabre)
• Limited disease AKA "CREST" syndrome
• Calcinosis, Raynauds, Esophageal dysmotility
  Sclerodactyly, Telangiectasias
• Diffuse disease - skin abnormalities extending to
  the proximal extremities (AKA - PSS)
• (Scleroderma sine scleroderma)

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DDX of Tight Skin

• Pseudosclerodactyly
• IDDM, Hypothyroidism
• Drugs Tryptophan, bleomycin, pentazocine, vinyl
  chloride, solvents
• Eosinophilic fasciitis
• Overlap syndromes
• Scleredema

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DDX of Tight Skin

• Scleromyxedema (popular mucinosis)
• Scleroderma-like conditions
• Eosinophil myalgia syndrome (tryptophan)
• Porphyria cutanea tarda
• Toxic oil syndrome
• Nephrogenic fibrosing dermopathy

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ACR Systemic Sclerosis Preliminary Classification
Criteria

• Major Criterion
• Proximal Scleroderma
• Minor Criteria
• Sclerodactyly
• Digital pitting or scars or loss of finger pad
• Bibasilar pulmonary fibrosis

One major and two minor required for diagnosis
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Scleroderma Onset

• Raynauds
• Swollen or puffy digits
• Loss of skin folds, no hair growth
• Digital pulp sores/scars
• Arthralgias gtgt Arthritis

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SclerodermaA disorder of Collagen, Vessels

• Etiology unknown?
• Autoimmune disorder suggested by the presence of
  characteristic autoantibodies such as ANA,
  anti-centromere and anti-SCL-70 antibodies.
• Pathology
• Early dermal changes lymphocytic infiltrates
  primarily of T cells
• Major abnormality is collagen accumulation with
  fibrosis.

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SclerodermaA disorder of Collagen, Vessels

• Small to medium-sized blood vessels, which show
  bland fibrotic change Vasculopathy, NOT
  vasculitis!
• Small thrombi may form on the altered intimal
  surfaces.
• Microvascular disease

Cold
Normal
Cold
PSS
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PSS - Clinical

• Skin
• Skin thickening is most noticeable in the hands,
  looking swollen, puffy, waxy.
• Thickening extends to proximal extremity, truncal
  and facial skin thickening is seen.
• Raynaud's phenomenon is present.
• Digital pits or scarring of the distal digital
  pulp
• Musculoskeletal Arthralgias and joint stiffness
  are common.
• Palpable tendon friction rubs associated with an
  increased incidence of organ involvement.
• Muscle weakness or frank myositis can be seen.

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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 198815276-83.
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PSS - Clinical

• Gastrointestinal Esophageal dysmotility,
  dysphagia, malabsorptive or blind loop syndrome,
  constipation.

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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.
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Scleroderma Renal Crisis

• Risk Factors
• diffuse skin involvement
• rapid progression of skin thickening
• disease course lt 4 years
• anti-RNA-polymerase III-antibodies
• newly manifested anemia
• newly manifested cardiac involvement
• pericardial effusion
• heart insufficiency
• preceded high-dose corticoid therapy
• pregnancy

Am J Med 198476779-786.
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Scleroderma Renal Crisis

• Microangiopathic hemolytic anemia Microscopic
  hematuria
• Fatal before the introduction of ACE-I, CCB
• Survival without ACE-I 16 _at_ 1 year, with ACE-I
  45 at 5 years
• Continue use of ACE-I even if dialysis appears
  imminent

Ann Int Med 1990113352-357.
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Pulmonary Manifestations of PSS

• Dyspnea
• Pulmonary HTN primarily in CREST
• Ground glass (alveolitis)
• Interstitial fibrosis (bibasilar)
• High resolution CT vs Gallium Scan
• Major cause of death
• RARE
• Pulmonary embolism
• Pulmonary vasculitis

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PFTs in Systemic Sclerosis

• Decreased DLCO is the Earliest Marker
• Increased A-a Gradient with Exercise
• Restrictive Pattern
• ? VC, ? FEV1/FVC
• Pulmonary Vascular Disease
• ? DLCO with Normal Volumes

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Cardiac Findings in PSS

• Myocardial fibrosis
• Dilated cardiomyopathy
• Cor pulmonale
• Arrhythmias
• Pericarditis
• Myocarditis
• Congestive heart failure
• Myocardial infarction (Raynauds)

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Comparison CREST v. PSS
Raynauds
Telangiectasia
Esophageal dysmotility
5 yr Survival
Relative percentages 81-100
61-80 41-60 21-40 1-20
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Treatment of Scleroderma

• Localized none
• Raynauds warmth, skin protection, vasodilator
  therapy
• CREST same as Raynauds
• PSS none proven
• No Value Steroids, Penicillamine, MTX
• Cytoxan for lung disease?
• Experimental stem cell transplant, TNF-I
• Epoprostenol (Flolan) Prostacyclin
• Bosentan (Tracleer) Endothelin receptor
  antagonist
• Finger ulcers difficult vasodilators, Abx

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Inflammatory Myositis Polymyositis/Dermatomyositi
s

• FM 21
• Acute onset
• Weakness ( myalgia) Proximal gt Distal
• Skeletal muscle dysphagia, dysphonia
• Sx Rash, Raynauds, dyspnea
• 65 elevated CPK, aldolase
• 50 ANA ()
• 90 EMG
• 85 muscle biopsy

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Proposed Criteria for Myositis

• Symmetric proximal muscle weakness
• Elevated Muscle Enzymes (CPK, aldolase, AST, ALT,
  LDH)
• Myopathic EMG abnormalities
• Typical changes on muscle biopsy
• 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

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Polymyositis ClassificationBohan Peter

• Primary idiopathic dermatomyositis
• Primary idiopathic polymyositis
• Adult PM/DM associated with neoplasia
• Childhood Dermatomyositis (or PM)
• often associated with vasculitis and calcinosis
• Myositis associated with collagen vascular disease

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MYOPATHY HISTORICAL CONSIDERATIONS

• Age/Sex/Race
• Acute vs. Insidious Onset
• Distribution Proximal vs. Distal
• Pain?
• Drugs/Pre-existing Conditions
• Neuropathy
• Systemic Features

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DDX MYOPATHIIES

• Toxic/Drugs
• Etoh, Cocaine, Steroids, Plaquenil,
  Penicillamine, Colchicine, AZT, Statins,
  Clofibrate, Tryptophan, Taxol, Emetine
• Infectious
• Coxsackie, HBV, HIV, Stept, Staph, Clostridium,
  Toxoplasma, Trichinella
• Inflammatory Myopathies
• Congenital/metabolic myopathies
• Neuropathic/Motor Neuron Disorders-MG, MD
• Endocrine/Metabolic-hypothyroidism
• Inclusion body myositis

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NONMYOPATHIC CONSIDERATIONS

• Fibromyalgia/Fibrositis/Myofascial Pain disorder
• Polymyalgia Rheumatica
• Caucasians, gt 55 yrs, MF
• ESR gt 100, normal strength, no synovitis
• CTD (SLE, RA, SSc)
• Vasculitis
• Adult Still's Disease

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INFLAMMATORY MYOSITISImmunopathogenesis

• Infiltrates - T cells (HLA-DR) monocytes
• Muscle fibers express class I II MHC Ags
• T cells are cytotoxic to muscle fibers
• t-RNA antibodies role? FOUND IN lt50 OF PTS
• Infectious etiology? Viral implicated
• HLA-B8/DR3 in childhood DM
• DR3 and DRW52 with t-RNA synthetase Ab

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DERMATOMYOSITIS5 Skin Features

• Heliotrope Rash over eyelids
• Seldom seen in adults
• Gottrons Sign/Papules (pathognomonic) MCPs,
  PIPs, MTPs, knees, elbows
• V-Neck Rash violaceous/erythema anterior chest
  w/ telangiectasias
• Periungual erythema, digital ulcerations
• Calcinosis

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Why is it called a heliotropic rash?
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Calcinosis
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DIAGNOSTIC TESTING

• Physical Examiniation Motor Strength (Gowers
  sign), Neurologic Exam
• Acute phase reactants unreliable
• Muscle Enzymes
• CPK elevated gt65 gt10 MB fraction is possible
• Muscle specific- Aldolase, Troponin, Carb.
  anhydraseIII
• AST gt LDH gt ALT
• Beware of incr. creatinine (ATN) and
  myoglobinuria
• EMG increased insertional activity, amplitude,
  polyphasics, neuropathic changes,
  incremental/decremental MU changes

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DIAGNOSTIC TESTING

• Muscle Biopsy (an URGENT not elective procedure)
• 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 Scans
• Serologic Tests ANA () 60, Abs against
  t-RNA synthetases

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INFLAMMATORY MYOSITISBiopsy Findings

• Inflammatory cells
• Edema and/or fibrosis
• Atrophy/ necrosis/ degeneration
• Centralization of nuclei
• Variation in muscle fiber size
• Rarely, calcification

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Polymyositis CD8Tcells, endomysial infiltration
Dermatomyositis Humoral response B cells, CD4 T
cells perifascicular/perivascular infiltration
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Anti-synthetase syndrome ILD, fever, arthritis,
Raynauds, Mechanics hands
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Autoantibodies in PM/DM
Ab Freq () Clinical Syndrome
ANA 50 Myositis
U1-RNP 15 SLE myositis
Ku lt5 PSS myositis
Mi2 30 Dermatomyositis
PM1 15 PSS PM overlap
Jo-1 25 Arthritis ILD Raynaud
SS-B (La) lt5 SLE,Sjogrens, ILD, PM
PL-12,7 lt5 ILD PM
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Anti-synthetase syndrome ILD, fever, arthritis,
Raynauds, Mechanics hands association with Jo-1
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INFLAMMATORY MYOSITIS

• NORMAL/NOT INVOLVED
• Face Uncommon
• Renal
• RES LN, spleen, liver (enzymes from muscle)
• NOT UNCOMMON
• RA-like arthritis
• Fever/chills/night sweats
• Myalgias

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MALIGNANCY MYOSITIS

• Higher association with DM, less common with
  polymyositis
• Common tumors Breast, lung, ovary, stomach,
  uterus, colon, NHL
• 60 the myositis appears 1st, 30 neoplasm 1st,
  and 10 contemporaneously
• Studies found 20-32 with DM developed CA

Lancet 2001 Ann Int Med 2001.
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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

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PM/DM Complications

• PULMONARY
• Aspiration pneumonitis
• Infectious pneumonitis
• Drug induced pneumonitis
• Intercostal, diaphragm involvement
• Fibrosing alveolitis
• RARE
• Pulmonary vasculitis
• Pulmonary neoplasia

• CARDIAC
• Elev. CPK-MB
• Mitral Valve prolapse
• AV conduction disturbances
• Cardiomyopathy
• Myocarditis

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Recap PM/DM Diagnosis

• Symmetric progressive proximal weakness
• Elevated muscle enzymes (CPK, LFTs)
• Muscle biopsy evidence of myositis
• EMG inflammatory myositis
• Characteristic dermatologic findings

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INFLAMMATORY MYOSITISTreatment

• Early Dx, physical therapy, respiratory Rx
• Corticosteroids 60-80 mg/day
• 80 respond within 12 weeks
• Steroid resistant
• Methotrexate
• Azathioprine
• IVIG, Cyclosporin, Chlorambucil unproven
• No response to apheresis

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PROGNOSIS

• Poor in pts. with delayed Dx, low CPK, early
  lung or cardiac findings, malignancy
• PT for muscle atrophy, contractures, disability
• Kids50 remission, 35 chronic active disease
• Adult lt 20 yrs. do better than gt55 yrs.
• Adults Mortality rates between 28-47 _at_ 7
  yrs.
• Relapses functional disability are common
• Death due to malignancy, sepsis, pulm. or
  cardiac failure, and complications of therapy

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RHABDOMYOLYSIS

• Injury to the sarcolemma of skeletal muscle with
  systemic release of muscle macromolecules such as
  CPK, aldolase, actin, myoglobin, etc
• Maybe LIFE-THREATENING from hyperkalemia, met.
  acidosis, ATN from myoglobinuria
• Common causes EtOH, Cocaine, K deficiency,
  infection, PM/DM, infection (clostridial, staph,
  strept), medications, exertion/exercise, cytokines

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INCLUSION BODY MYOSITIS

• Bimodal age distribution, maybe hereditary
• Males gt females
• Slow onset, progressive weakness
• Painless, distal and proximal weakness
• Normal or mildly elevated CPK
• Poor response to corticosteroids
• Dx light microscopy may be normal or show CD8
  lymphs and vacuoles with amyloid.
  Tubulofilamentous inclusion bodies on electron
  microscopy

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Inflammatory Myositis

• Polymyositis (PM) and dermatomyositis (DM) are
  types of idiopathic inflammatory myopathy (IIM).
  IIM are characterized clinically by proximal
  muscle weakness
• Etiology There is now known etiology.
• Demographics PM is more common than DM in
  adults. Peak incidence occurs between 40 and 60
  yrs. FM 21
• Muscles Proximal muscle weakness, dysphagia,
  aspiration. respiratory failure or death.
• Skin Gottron's papules, heliotrope rash, "V"
  neck rash, periungual erythema, "Mechanic's
  hands", calcinosis
• Dx Muscle enzymes (CPK, aldolase), EMG, Biopsy
• Rx Steroids, MTX, Azathioprine, IVIG