Scleroderma and Inflammatory Myositis Kathryn Dao, MD Arthritis Consultation Center January 22,...
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Transcript of Scleroderma and Inflammatory Myositis Kathryn Dao, MD Arthritis Consultation Center January 22,...
SclerodermaSclerodermaand and
Inflammatory MyositisInflammatory Myositis
SclerodermaSclerodermaand and
Inflammatory MyositisInflammatory Myositis
Kathryn Dao, MD
Arthritis Consultation Center
January 22, 2010
ObjectivesObjectivesObjectivesObjectives
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 What 1996 movie put scleroderma on the map and scleroderma on the map and
why?why?
What 1996 movie put What 1996 movie put scleroderma on the map and scleroderma on the map and
why?why?
SclerodermaSclerodermaSclerodermaScleroderma
“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 twins)
SclerodermaSclerodermaA disorder of Collagen, VesselsA disorder of Collagen, Vessels
SclerodermaSclerodermaA disorder of Collagen, VesselsA 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 PathogenesisScleroderma PathogenesisScleroderma PathogenesisScleroderma PathogenesisHallmarks: Vasculopathy (not vasculitis) and fibrosis
Early dermal changes lymphocytic infiltrates primarily of T cells Hypersensitive 2 receptors resulting in heightened
vasoconstriction Tissue ischemia/ reperfusion
Susceptible Host
Exogenous event
Immune System Activation
Endothelial Cell Activation/Damage
Fibroblast Activation
Obliterative Vasculopathy & Fibrosis
Klippel JH, ed. Primer on the Rheumatic Disease. 2001
How do you categorize How do you categorize Scleroderma?Scleroderma?
How do you categorize How do you categorize Scleroderma?Scleroderma?
Scleroderma ClassificationScleroderma ClassificationScleroderma ClassificationScleroderma Classification
Three major disease subsets: based on extent of skin involvement:
Localized Scleroderma Systemic Sclerosis (SSc)
Diffuse SSc Limited SSc AKA "CREST" syndrome
Scleroderma sine scleroderma
Localized Scleroderma: Morphea
Linear scleroderma
What is this condition called?
“En Coup de Sabre”
Scleroderma ClassificationScleroderma ClassificationScleroderma ClassificationScleroderma ClassificationThree major disease subsets: based on extent of skin
involvement: 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 ACR Systemic Sclerosis Preliminary Classification Criteria*Preliminary Classification Criteria*
ACR Systemic Sclerosis ACR Systemic Sclerosis Preliminary Classification Criteria*Preliminary Classification Criteria*
Major Criterion Scleroderma proximal to the MCP or MTP
Minor Criteria Sclerodactyly Digital pitting or scars or loss of finger pad Bibasilar pulmonary fibrosis
* One major and two minor required for diagnosis
Diffuse SSc - ClinicalDiffuse SSc - ClinicalDiffuse SSc - ClinicalDiffuse 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
Cold
Cold
Normal
SSc
Skin ScoresExtent 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?
Why?
White, Blue, Red pallor cyanosis reperfusion erythema
Flag of the Russian Federation
BONUS: What country’s flag is this?
SclerodermaSclerodermaA disorder of Collagen, VesselsA disorder of Collagen, Vessels
SclerodermaSclerodermaA disorder of Collagen, VesselsA 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 Normal
PSS
Cold
Cold
??? TRUE OR FALSE ???
INFLAMMATORY ARTHRITIS IS THE MOST COMMON
MUSCULOSKELETAL MANIFESTATION OF
SYSTEMIC SCLEROSIS
FALSE
Systemic SclerosisSystemic SclerosisSystemic SclerosisSystemic Sclerosis
Musculoskeletal: Arthralgias >>> Arthritis Palpable tendon
friction rubs associated with an increased incidence of organ involvement.
Muscle weakness or frank myositis can be seen—can be associated with medications.
Where in the GI tract does SSc affect?
Anywhere from the mouth to the anus
Small oral aperture, dry mucosal membranes with periodontal disease
Esophageal dysmotility, reflux, esophagitis, stricture, dysphagia
Delayed stomach emptying, Pseudoobstruction of the small intestines, bacterial
overgrowth, malabsorption Wide mouth diverticuli Fecal incontinence due rectal sphincter fibrosis
Systemic Sclerosis: GISystemic Sclerosis: GISystemic Sclerosis: GISystemic Sclerosis: GI
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.
Systemic Sclerosis: RenalSystemic Sclerosis: Renal
Scleroderma Renal CrisisScleroderma Renal CrisisScleroderma Renal CrisisScleroderma 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 CrisisScleroderma Renal CrisisScleroderma Renal CrisisScleroderma 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
vasodilators: 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
TRUE
Systemic Sclerosis: RenalSystemic Sclerosis: RenalSystemic Sclerosis: RenalSystemic 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
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: PulmonarySystemic Sclerosis: PulmonarySystemic Sclerosis: PulmonarySystemic Sclerosis: Pulmonary
**** LEADING CAUSE OF MORTALITY ***
Interstitial fibrosis +/- pulmonary hypertension Dyspnea, cough, chest pain Other manifestations:
Pulmonary embolism Pulmonary vasculitis Pulmonary hemorrhage Lung cancer Aspiration Respiratory distress from muscle disease
Decreased DLCO is the earliest marker (especially with normal lung volumes)
Increased A-a Gradient with Exercise Restrictive Pattern
VC, FEV1/FVC
PFT’s in Systemic SclerosisPFT’s in Systemic SclerosisPFT’s in Systemic SclerosisPFT’s in Systemic Sclerosis
Systemic Sclerosis: CardiacSystemic Sclerosis: CardiacSystemic Sclerosis: CardiacSystemic 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 SScComparison CREST v. Diffuse SScComparison CREST v. Diffuse SScComparison 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 + ++
+ Relative percentages: +++++ 81-100%; ++++ 61-80%; +++ 41-60%; ++ 21-40%; + 1-20%
Raynaud’s +++++ +++++
Telangiectasia +++++ ++++
Esophageal dysmotility
+++++ +++++
5 yr Survival +++++ ++++
Treatment of SScTreatment of SScTreatment of SScTreatment 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 SkinDDX of Tight SkinDDX of Tight SkinDDX of Tight Skin
Pseudosclerodactyly IDDM, Hypothyroidism
Drugs: Tryptophan, bleomycin, pentazocine, vinyl chloride, solvents
Eosinophilic fasciitis Overlap syndromes Scleredema Scleromyxedema
(papular mucinosis)
DDX of Tight SkinDDX of Tight SkinDDX of Tight SkinDDX of Tight Skin Scleroderma-like conditions
Porphyria cutanea tarda Nephrogenic fibrosing dermopathy
Inflammatory Myositis:Inflammatory Myositis: Polymyositis/DermatomyositisPolymyositis/Dermatomyositis
Inflammatory Myositis:Inflammatory Myositis: Polymyositis/DermatomyositisPolymyositis/Dermatomyositis
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 What percentage of patient with DM/PM will have pain?with DM/PM will have pain?What percentage of patient What percentage of patient with DM/PM will have pain?with DM/PM will have pain?
Less than 50%
Proposed Criteria for MyositisProposed Criteria for MyositisProposed Criteria for MyositisProposed Criteria for Myositis1. Symmetric proximal muscle weakness2. Elevated Muscle Enzymes (CPK, aldolase,
AST, ALT, LDH)3. Myopathic EMG abnormalities4. Typical changes on muscle biopsy5. 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 ClassificationMyositis ClassificationBohan & PeterBohan & Peter
Myositis ClassificationMyositis ClassificationBohan & PeterBohan & Peter
1. Primary idiopathic dermatomyositis2. Primary idiopathic polymyositis3. Adult PM/DM associated with
neoplasia4. 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
HISTORICAL CONSIDERATIONS
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
DDX: MyopathiesDDX: MyopathiesDDX: MyopathiesDDX: Myopathies
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
Nonmyopathic DDxNonmyopathic DDxNonmyopathic DDxNonmyopathic DDx
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
Inflammatory myositis: Inflammatory myositis: pathogenesispathogenesis
Inflammatory myositis: Inflammatory myositis: pathogenesispathogenesis
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
Dermatomyositis: Skin featuresDermatomyositis: Skin featuresDermatomyositis: Skin featuresDermatomyositis: Skin features
Why is it called a heliotropic rash?
CalcinosisCalcinosisCalcinosisCalcinosis
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 TestingDiagnostic TestingDiagnostic TestingDiagnostic 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
Diagnostic TestingDiagnostic TestingDiagnostic TestingDiagnostic Testing
Inflammatory cells Edema and/or fibrosis Atrophy/ necrosis/ degeneration Centralization of nuclei Variation in muscle fiber size hydroxyapatite crystals (rare)
HistopathologyHistopathologyHistopathologyHistopathology
Polymyositis: CD8+Tcells, endomysial infiltration
Dermatomyositis: Humoral response B cells, CD4+ T cells; perifascicular/perivascular infiltration
Autoantibodies in PM/DMAutoantibodies in PM/DMAutoantibodies in PM/DMAutoantibodies 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 What is an anti-synthetase syndrome?syndrome?
What is an anti-synthetase What is an anti-synthetase syndrome?syndrome?
•It is a subcategory of the inflammatory myositisdefined 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
Higher association with DM, less common with polymyositis
Studies found 20-32% with DM developed CA
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.
Malignancy and myositisMalignancy and myositisMalignancy and myositisMalignancy and myositis
Dermatomyositis and MalignancyDermatomyositis and MalignancyDermatomyositis and MalignancyDermatomyositis 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 ComplicationsPM/DM ComplicationsPM/DM ComplicationsPM/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
Early Dx, physical therapy, respiratory Rx High dose steroids (e.g., prednisone 1-2 mg/kg/day)
80% respond within 12 weeks Steroid resistant
Methotrexate Azathioprine Rituximab CYP
IVIG, Cyclosporin, Chlorambucil, TNFi: unproven No response to apheresis
TreatmentTreatmentTreatmentTreatment
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
disease 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
PrognosisPrognosisPrognosisPrognosis
Bimodal age distribution, maybe hereditary 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
Inclusion Body MyositisInclusion Body MyositisInclusion Body MyositisInclusion Body Myositis
ConclusionConclusionConclusionConclusion
Scleroderma and the inflammatory myopathies are diseases that require prompt recognition
Early intervention may decrease morbidity/mortality