Systemic Sclerosis
Dan Mandel, MD
UCI School of Medicine
Systemic Sclerosis (definition)
• Multisystem disorder
• Unknown etiology
• Thickening of skin caused by accumulation of
connective tissue (collagen types I and III)
• Involvement of visceral organs
Epidemiology
• Peak age range: 35-64
• Younger age in women and with diffuse disease.
• Female:Male = 3:1
• 8:1 in child bearing years
• Incidence: 20/million per year in US
• Prevalence: 240/million in US.
Etiology
• Unknown
• Environmental Exposures
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Silica exposure in men conferred increased risk
Silicone breast implants: no definite risk identified
Aniline laced Contaminated rapseed oil in Spain
Vinyl chloride exposure increased risk of SSc like
disorder: Eosinophilic Fasciitis
• bleomycin
• L-tryptophan: Eosinophilia Myalgia syndrome
Etiology
• Genetic Factors
• Familial Clustering: 1.5-2.5% of those with 1st degree
relative
– Choctow Native Americans: prevalence 4720/million.
• HLA-haplotypes: there are higher risk haplotypes in
certain populations
Pathogenesis: general principles
• Endogenous or exogenous pathogen stimulates antigen
presenting cells.
• Antigen presenting cells stimulate CD4+ T cells
• Cytokines are produced by both of these cells.
• Cytokines stimulate growth factors to stimulate fibroblasts
to produce collagen
• Vascular damage occurs with thickened intima and
narrowing of the lumen.
• Narrowing of the lumen leads to ischemia.
• Ischemia leads to prostacyclin production which is a
platelet aggregant and platelets bind to endothelium and
release PDGF which is chemotactic and mitogenic for
fibroblasts.
Pathogenesis
Pathogenesis of Scleroderma
Up to Date
Forms of Systemic Sclerosis
• Limited Scleroderma
• Skin thickening is distal to elbows and knees, not involving
trunk
• Can involve perioral skin thickening (pursing of lips)
• Less organ involvement
• Seen in CREST syndrome
• Isolated pulmonary hypertension can occur
• Diffuse Scleroderma
• Skin thickening proximal to elbows and knees, involving the
trunk
• More likely to have organ involvement
• Pulmonary fibrosis and Renal Crisis are more common.
2013 ACR Diagnostic Criteria
Limited Scleroderma
• More gradual process
• Can have Raynaud’s for years (even up to decade)
• Skin involvement distal to elbows and knees
• Often with perioral involvement (pursing of lips)
• Capillaroscopy
• with dilated capillary loops but without dropout.
• Less organ involvement
• though 10-15% with isolated pulmonary hypertension.
• Renal involvement is rare.
• Anti-centromere Ab in 70-80%
Limited Scleroderma
• CREST Syndrome
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Calcinosis
Raynaud’s
Esophageal Dysmotility
Sclerodactyly
Telangiectasisa
A.D.A.M. Images
CREST Syndrome
ACR and Mayo Foundation
Calcinosis on x-ray
Gupta E., et al. Malaysian Family
Physician. 2008;3(3):xx-xx
ACR
Nailfold Capillaroscopy
Diffuse Scleroderma
• More Rapid Process
• Often with onset of skin thickening within a year of
Raynaud’s symptoms
• Skin involvement proximal to elbows and knees
• Often can involve the trunk
• Capillaroscopy reveals dropout
• With capillary dilatation and dropout.
• Early organ involvement
• Renal, interstitial lung disease, myocardial, diffuse
gastrointestinal – often within the first 3 years.
• Antibodies
• Anti-Scl-70, anti-RNA Polymerase III.
Diffuse Scleroderma
ACR
Netter
American Osteopathic College of Dermatology, Grand
Rounds
Organs Involved
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Skin
Musculoskeletal
Pulmonary
Renal
Gastrointestinal
Cardiac
Skin Involvement
• Early stages:
• Perivascular infiltrate which are primarily T cells.
• Skin swelling which eventually becomes skin thickening.
• Involves the hands and/or feet (distal).
• Late Stages:
• Finger-like projections of collagen extend from the dermis to
the subcutaneous tissue to anchor skin deeper.
• Skin becomes firm, thick and tight.
• Skin thickening moves proximally.
• Fibroblasts and collagen deposition.
• Hair and wrinkles overlying area of skin thickening
disappears.
Skin involvement in Scleroderma
• May regress on its own over years
• reverse pattern (ie, starting with regression of skin
thickening in the trunk, then proximal extremities, then
more distal).
• Digital Ulcers:
• on extensor surface of PIP’s and elbows; may become
secondarily infected.
• Digital ischemia:
• with pits in the distal aspect of the digits related to
prolonged Raynaud’s.
• Thinning of the lips, beak-like nose.
ACR
Skin Manifestations
Sclero.org
International
Scleroderma Network
Kahaleh B. Rheum Dis Clin N Amer 2008:57-71
Musculoskeletal
• Arthritis
• in > 50% with swelling, stiffness, and pain in the joints
of the hands.
• Carpal Tunnel Syndrome.
• Contractures
• related to skin thickening.
• Polymyositis
• may occur as part of mixed connective tissue disease or
overlap.
Pulmonary
• leading cause of death
• since we are better at control of renal disease.
• Symptoms:
• exertional dyspnea
• Types of lung Involvement:
• Interstitial lung disease.
• Isolated pulmonary hypertension.
Interstitial Lung Disease
• Inflammatory phase
• with ground glass opacities and linear infiltrates
• lower 2/3 of the lung fields on CT scan.
• Fibrosis:
• Late phase with honeycombing.
• Diagnosis
– Pulmonary function tests
• restrictive pattern with low FVC, low residual volume, low DLCO.
– High Resolution CT Scan
– BAL: often not required
– Lung biopsy: often not required
• ILD is most commonly associated with diffuse scleroderma.
• Anti-Scl-70
Interstitial Lung Disease
Up to Date 2005
Up to Date 2005
Primary Pulmonary Hypertension
• Symptoms:
• exertional dyspnea.
• Frequency
• 10-15% of patients with systemic sclerosis
• Definition:
• Mean PA blood pressure >25mmHg at rest or >30mmHg with
exercise on right heart catheterization.
• Estimated systolic pulmonary artery pressure of >35mmHg
on Echocardiogram
• Pathogenesis
• Intimal fibrosis and medial hypertrophy of the pulmonary
arterioles and arteries.
Pulmonary Hypertension
Doppler Echocardiogram to estimate
pulmonary artery pressure.
Roberts JD. Pulm Circ 2011;1:160-181.
Up to Date 2005
Other Pulmonary Associations
• Pneumonia:
• due to aspiration secondary to GERD; skin thickening of
chest may reduce effectiveness of cough.
• Alveolar carcinoma: increased incidence
• Bronchogenic carcinoma: increased incidence.
Renal Manifestations of Systemic
Sclerosis
• Scleroderma Renal Crisis
• Abruptly developing severe hypertension
– Rise in SBP by > 30 mmHg, DBP by > 20 mm Hg
• One of the following:
– Increase in serum creatinine by 50% over baseline or creatinine > 120%
of upper limit.
– Proteinuria > 2+ by dipstick.
– Hematuria > 2+ by dipstick or > 10 RBC/HPF
– Thrombocytopenia < 100
– Hemolysis (schisctocytes, low platelets, increased reticulocyte count).
• Can cause headache, encephalopathy, seizures, LV failure.
• 90% with blood pressure > 150/90.
• Can occur also with lower blood pressures < 140/90 and this
confers worse prognosis.
Steen et al., ClinExp. Rheumatol. 2003
Scleroderma Renal Crisis
Up to Date 2012
Risk Factors for Renal Crisis
• Rapidly progressive skin thickening within the
first 2-3 years.
• Steroid use (prednisone > 15 mg)
• Anti-polymerase III Ab.
• Pericardial Effusion.
Treatment of Scleroderma Renal Crisis
• Medical Emergency: generally with admission.
• Initiation of ACE inhibitors such as captopril;
lifelong treatment with ACE inhibitors.
• Dose escalation of captopril.
• ACE-inhibitors do not prevent SRC.
Treatment of Scleroderma Renal Crisis
Without
Steen, Clinics in Dermatology, 1994
Renal Crisis - Prognosis
• Improved overall with ACE-inhibitors.
• Even with ACE-inhibitors 20-50% will progress
to ESRD.
• Among patients who required dialysis during
the acute phase, an appreciable proportion
(40-50%) will be able to discontinue dialysis.
Gastrointestinal Manifestations
• Esophageal dysmotility: in up to 90%.
• Pathophysiology:
– reduced tone of gastroesophageal sphincter and distal dilatation of the
esophagus.
– Lamina propia and submucosal tissue with Inflammatory changes and
increased collagen on pathology.
• Symptoms
– Dysphagia, GERD; many asymptomatic.
• Diagnosis:
– Esophageal manometry, Esophagram, CT scan.
• Treatment
– Proton Pump Inhibitors
– Elevation of head of the bed.
• Complications:
– Barret’s Esophagus.
Gastrointestinal Manifestations
• Gastric Involvement:
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Symptoms: Early satiety.
Diagnosis: Nuclear Gastric Emptying Test.
Treatment: promotility agents
Watermelon Stomach: dilated vessel which can cause bleeding.
• Small Intestinal involvement
• Symptoms: distension, pain, bloating, steatorrhea
• nutritional deficiencies secondary to bacterial overgrowth.
» Vitamin B6/B12/folate/25-OH Vit D, low albumin
• Diagnosis:
– glucose hydrogen breath test
– Low D-xylose absorption test
– small bowel aspiration (only if resistance to rotating antibiotics)
• Treatment: Rotating antibiotics, Reglan, Erythromycin
Image of Watermelon Stomach: University of Michigan Rheumatology Website
Gastrointestinal Manifestations
• Colon Involvement:
• Can cause symptoms of constipation due to decreased
peristalsis.
• Fecal incontinence can occur due to alterations of
internal and external sphincter.
Cardiac Manifestations
• Forms of cardiac involvement
• Pericardial Effusion
– symptomatic pericarditis in 20%
• Microvascular CAD:
– recurrent vasospasm of coronary arteries
– Necrosis
– patchy myocardial fibrosis; leads to diastolic > systolic
dysfunction.
• Myocarditis
– Inflammation which leads to fibrosis
• Arrhythmias and conduction abnormalities
– Fibrosis of cardiac conduction system.
– AV conduction defects and arrhythmias.
Cardiac Involvement
Cardiac Manifestation
Prevalence
Diagnosis
Treatment
Myocarditis
Rare
Cardiac MRI, Biopsy
Cytoxan + steroids
Pericardial effusion
5-16%
Echocardiogram
None; NSAIDs if
symptomatic
Microvascular CAD
> 60%
MRI/nuclear medicine Calcium channel
blockers
Macrovascular CAD
25%
Coronary Angiogram
Stenting/medical tx
Bradyarrhythmias
Rare
EKG/Holter
Pacemaker
Tachyarrhythmias
15%
EKG/Holter
Diltiazem, ablation,
defibrillator
Adapted from Desai, et al; Curr Opin Rheumatol 2011m 23:545-554
Scleroderma Autoantibodies
Antigen
ANA
Pattern
Frequency
Clinical
Associations
Organs Involved
Scl-70
(topoisomerase 1)
Speckled
10-40
dcSSC
Lung fibrosis
RNA Polymerase III
Speck/Nuc
4-25
dcSSC
Renal,
Pulmonary HTN
Centromere
Centromere
15-40
lcSSc, CREST
Pulmonary HTN
Esophageal
U1-RNP
Speckled
5-35
lcSSC, MCTD
Muscle
U3 RNP (fibrillarin)
Nucleolar
1-5
dcSSC, poor prognosis
Muscle
Pulmonary HTN
PM-SCL
Nucleolar
3-6
Overlap, mixed
Muscle
Th/To
Nucleolar
1-7
lcSSc
Pulmonary HTN,
Lung fibrosis,
Small bowel
Anti U11/U12
Nucleolar
1-5
lcSSc & dcSSC
Lung Fibrosis
1-3
Overlap Ssc
Muscle, Joint,
SLE overlap
Anti-Ku
Adapted from: Nihtyanova SI, Denton CP. Nat Rev Rheumatol 2010; 6:112
Scleroderma Treatment
• Depends on clinical manifestations
• Aggressive disease versus stable disease
• Reversible inflammation vs Vasoconstriction.
• Organ Involvement
• Treatment is directed at organ involved.
Raynaud’s
• Calcium Channel Blockers: nifedipine
• Nitroglycerin patches
• Sildenafil (Viagra) (but not in combination
with nitroglycerine) –usually for refractory
Raynaud’s.
• Parental vasodilators (iloprost) – for severe
disease with impending digital ischemia.
Gastrointestinal Involvement
• GERD
• Proton pump inhibitor.
• Delayed Gastric Emptying and peristalis
disorders
• Supportive
• Promotilants are sometimes used.
Pulmonary Involvement
• Interstitial Lung Disease: with active
inflammation
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Mycophenolate
Azithioprine
Cytoxan - IV
plus lower dose of steroids if RNA Poly III neg (ie 10 mg
daily); avoid steroids if RNA Poly III positive.
• Pulmonary Hypertension
• Vasodilators: bosentan, sildenafil, epoprostenol,
treprostinil, iloprost.
• Lung Heart Transplant
Myositis
• Polymyositis overlap or MCTD
• Similarly to myositis alone with methotrexate,
azathioprine in combination of low dose steroids.
• Tend to keep prednisone dose at around 10 mg or less
to avoid risk of renal crisis.
Cardiac Involvement
• Pericarditis:
• NSAIDs
• Drainage of effusion if tamponade
• Myocarditis with elevated CK-MB & troponin
• If CAD is excluded, MRI and biopsy confirms, then
treatment would generally be with low dose
prednisone (10 mg/day) and cytoxan; nifedipine may
also be helpful.
Skin Disease
• Stable disease: no treatment
• Advancing diffuse skin involvement:
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Methotrexate
Mycophenolate
Current trial with Tocilizumab (Actemra)
D-penicillamine 125 mg/day.
Research on various anti-fibrosis therapies is being
performed (imatinib, Gleevac).
Differential Diagnosis
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Scleredema
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Scleromyxedema
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Chronic kidney disease and gadolinium MRI contrast
Can involve hands and feet.
Eosinophilic fasciitis:
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Can be associated with skin induration.
In diabetes can have sclerodactyly (Diabetic Cheiroarthropathy) - dorsal
POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin thickening).
Nephrogenic Systemic fibrosis
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Skin thickening/induration on head, neck, arms, trunk
Monoclonal gammopathy (multiple myeloma/AL amyloid)
Skin biopsy differentiates.
Endocrinologic: diabetes and hypothyroid myxedema
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No Raynauds, negative antibodies, seen in IDDM
Proximal skin thickening (trunk, shoulders, back)
Hands and feet are spared, peripheral blood eosinophilia, peau de orange appearance
Diagnosis is via skin biopsy.
Graft versus Host disease
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History of bone marrow transplant, no Raynaud’s symptoms.
Diagnosis is via skin biopsy.
Cases
Case 1
• 50 year old female who has CREST syndrome with anticentromere antibody:
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Raynaud’s controlled with nifedipine
only digital skin thickening of the hands which is unchanged
GERD on omeprazole
telangiectasia.
She currently has no complaints.
• Labs:
• CMP, CBC, ESR, CRP, total CK all normal, anti-centromere Ab positivity.
• Echocardiogram and PFT’s 1 month ago:
• Echo: normal with normal estimated PA pressures.
• PFT’s: normal lung volumes, normal DLCO.
• What is next step:
Case 1
• Renew medications
• Nifedipine and omeprazole
• This case highlights the most typical case seen
in clinics with stable disease.
• Things to watch for:
• Change in skin disease
• Periodic echocardiogram and PFT’s.
• General exam
Case 2
• 60 year old male with Raynaud’s for 4 months prior to onset of skin
involvement
• Skin thickening has ascended to involve proximal extremities, chest, and abdomen within
1 year.
• The patient reports mild shortness of breath recently.
• Exam:
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Vitals: T 98.9, BP 124/73, pulse 80, resp rate 18
Raynaud’s is noted without digital ulcer.
Cardiovascular exam normal.
Gastrointestinal exam is normal.
Dry crackles noted at both bases.
Extremities: no edema.
• Labs:
• CBC, CMP, total CK are all normal
• ESR 35, CRP 1.8 (upper limit of normal is 1.0).
• Anti-Scl-70 Ab positive, RNA Pol III negative.
• What is next step?
Case 2
Strek, ME. Amer Col Chest
Physicians 2012
Learningradiology.com
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Oikonomou A, Prassopoulos P - Insights Imaging (2012)
PFT’s: TLC decreased 80% to 55%, VC decreased 85% to 50%, RV decreased 83% to 62%, DLCO
decreased 75% to 45%.
Bronchoscopy performed: all cultures & cytology negative (neutrophils and eosinophils are
present).
Echocardiogram: no pulmonary hypertension.
Lung Biopsy shown on right.
What is the diagnosis? What is the treatment?
Case 2
• Interstitial lung disease associated with
scleroderma with active inflammation.
• Mycophenolate, Cytoxan, or Azathioprine
• Prednisone (low dose) 10 mg daily; gradual
taper
Case 3
• 50 year old female presents with
• onset of Raynaud’s for 1 year,
• developed skin thickening from the digits of the hands to just distal to the
elbows.
• She has noticed difficulty getting out of chairs and lifting objects overhead.
• Exam:
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VS: Temp 98.2, BP 124/72, pulse 78, respiratory rate 16
Cardiovascular and pulmonary exams normal.
Gastrointestinal exam is normal.
Muscle weakness of thighs and shoulder regions is noted.
No skin lesions other than skin thickening.
• Labs:
• CBC, chem-7, ESR, CRP all normal, PM-SCL Ab positivity
• Total CK 3000 (mostly CKMM), AST 158, ALT 105, GGT normal.
• What is the next step?
EMG, Nerve Conduction Studies
Case 3
Seidman, RJ. Medscape
Olsen NJ, et al. Rheum Dis Clin N. Amer 1996;22(4):783-796
• MRI of the thigh
• Biopsy of thigh musculature
• What is the diagnosis? What is the treatment?
Case 3
• Scleroderma/Myositis overlap.
• Methotrexate or Azathioprine
• Low dose prednisone: 10 mg daily
• Over the next few months, CK levels normalize
and prednisone dose is gradually tapered, and
the patient’s strength improves.
Case 4
• 35 year old female with
• limited scleroderma for 3 years, anti-centromere Ab positive.
• with stable skin disease involving the digits of the hands
only; new “rash” appeared 1 month ago, gradually
worsening, no change in last week.
• Raynaud’s have been quite severe, but not on therapy.
• Exam
• VS: Temp 97.9, BP 123/76, pulse 82, RR 16
• Cardiac, pulmonary, gastrointestinal exams normal, no
edema
• Skin: see next slide
Case 4
• Labs:
Sclero.org
International Scleroderma Network
• CBC, CMP, ESR, CRP all normal; anti-centromere Ab
positive, anti-phospholipid Ab neg, echo with bubble
study negative
• What is the diagnosis? What is next step?
Case 4
• Digital Ischemia due to Raynaud’s
• Start calcium channel blocker
• Nifedipine 30 mg PO daily.
• Close follow-up and increase dose of nifedipine as
blood pressure tolerates.
• If not responding:
• Can start nitroglycerin patch or can start sildenafil (not
both).
Case 5
• 58 year old male with:
• Rapid onset scleroderma with Raynaud’s for 6 months then
skin thickening that spread to proximal arm, proximal thigh,
chest, and abdomen within 1.5 years.
• Blood pressure generally runs 110/70
• has mild headache, and has noticed some swelling of the
legs.
• Exam:
• VS: Temp 98.4, BP 160/105, pulse 70, RR 16.
• Cardiac, pulmonary, gastrointestinal exam all normal;
neurologic exam is non-focal.
• There is only mild bilateral lower extremity edema.
Case 5
• Labs
• Creatinine 2.0 (baseline is 0.6), CBC normal, ESR and
CRP normal, urine with 1+ protein, no RBC or WBC;
known to be RNA Pol III positive.
• What is the diagnosis? What is the next step.
Case 5
• Scleroderma Renal Crisis
• Treatment:
• Hospitalization
• Start ACE-inhibitor: captopril with dose escalation.
References
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Medscape
Up To Date
Desai, et al; Curr Opin Rheumatol 2011; 23:545-554
Curr Opin Rheumatol 23;505-510
Fischer A; CHEST 2006; 130:976 –981
Rheum Dis Clin N Am;2003;29:293–313
Arthritis Rheum 2006;54:3962-3970
Rheumatology 2009;48:iii32–iii35
Steen VD; Rheum Dis Clin N Am 2003;29:315–333
Hudson M, et al; Medicine 2010;89:976-981
Bon LV; Curr Opin Rheumatol 2011;23:505–510
Barnes J; Curr Opin Rheumatol 2012, 24:165–170
Definition of Criteria
Skin Scoring