Transcript Chest Pain, SOB, Tachycardia

Scleroderma
and
Inflammatory Myositis
Kathryn Dao, MD
Arthritis Consultation Center
January 22, 2010
Objectives
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
why?
Scleroderma
“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)

Scleroderma
A disorder of Collagen, Vessels
Etiology: unknown? acquired?
 Autoimmune disorder suggested by the
presence of characteristic autoantibodies
such as ANA, anti-centromere and antiSCL-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
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
Scleroderma?
Scleroderma 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 Classification
Three 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
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 - 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

Normal
SSc
Cold
Cold
Skin Scores
Extent of skin involvment
predictive of survival:
% Survival at
5 yr
Sclerodactyly 79-84
Truncal
J Rheumatol 1988;15:276-83.
10 yr
47-75
48-50 22-26
What are the typical colors of Raynaud’s?
In what order do they occur?
Why?
White, Blue, Red
pallor cyanosis  reperfusion erythema
BONUS: What country’s flag is this?
Flag of the Russian Federation
Scleroderma
A 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
Cold
Normal
PSS
??? TRUE OR FALSE ???
INFLAMMATORY
ARTHRITIS IS THE
MOST COMMON
MUSCULOSKELETAL
MANIFESTATION OF
SYSTEMIC SCLEROSIS
FALSE
Systemic 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
Systemic Sclerosis: GI






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: 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
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: 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
**** 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

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
Calcinosis
Arthralgias
Pulmonary fibrosis
Pulmonary HTN
Tend friction rubs
Renal crisis
Centromere Ab
Anti-Scl 70 Ab
Raynaud’s
Limited CREST
++
++
++
++
0
0
+++
+
+++++
Diffuse SSc
+
++++
+++
+
+++
+
+/0
++
+++++
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, antiadrenergics, 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
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




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:
Polymyositis/Dermatomyositis
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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.
2.
3.
4.
5.


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
Myositis Classification
Bohan & Peter
1.
2.
3.
4.
Primary idiopathic dermatomyositis
Primary idiopathic polymyositis
Adult PM/DM associated with
neoplasia
Childhood Dermatomyositis (or PM)
*often associated with vasculitis and calcinosis
5.
Myositis associated with collagen
vascular disease
HISTORICAL CONSIDERATIONS

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Age/Sex/Race
Acute vs. Insidious Onset
Distribution: Proximal vs. Distal
Pain?
Drugs/Pre-existing Conditions
Neuropathy
Systemic Features
DDX: Myopathies

Toxic/Drugs


Infectious




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EtOH, Cocaine, Hydroxychloroquine, Penicillamine,
Clofibrate, Taxol Colchicine, AZT, Statins, Steroids,
Hydralazine, Gemfibrozil, CYA, L-dopa, Phenytoin,
Cimetidine, Sulfonamides, PCN
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:
pathogenesis



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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

2.
3.
4.
5.
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
Why is it called a
heliotropic rash?
Calcinosis
Diagnostic Testing


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Physical Examiniation: Motor Strength (Gowers
sign), Neurologic Exam
Acute phase reactants unreliable
Muscle Enzymes




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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
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
Histopathology
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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;
perifascicular/perivascular
infiltration
Autoantibodies in PM/DM
Ab
ANA
U1-RNP
Ku
Mi2
PM1
Jo-1
SS-B (La)
PL-12,7
Freq (%)
50
15
<5
30
15
25
<5
<5
Clinical Syndrome
Myositis
SLE + myositis (MCTD)
SSc + myositis
Dermatomyositis
SSc + PM overlap
Arthritis+ ILD+ Raynaud
SLE,Sjogrens, ILD, PM
ILD + PM
What is an anti-synthetase
syndrome?
•It is a subcategory of the inflammatory
myositis
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



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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.
Dermatomyositis and Malignancy

All adults with DM should have ageappropriate 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
 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
Treatment


Early Dx, physical therapy, respiratory Rx
High dose steroids (e.g., prednisone 1-2
mg/kg/day)

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80% respond within 12 weeks
Steroid resistant
Methotrexate
 Azathioprine
 Rituximab
 CYP



IVIG, Cyclosporin, Chlorambucil, TNFi:
unproven
No response to apheresis
Prognosis

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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
Inclusion Body Myositis

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
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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
Conclusion
Scleroderma and the inflammatory
myopathies are diseases that require
prompt recognition
 Early intervention may decrease
morbidity/mortality
