Systemic Sclerosis

1
Systemic Sclerosis

• Dan Mandel, MD
• UCI School of Medicine

2
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

3
Epidemiology

• Peak age range 35-64
• Younger age in women and with diffuse disease.
• FemaleMale 31
• 81 in child bearing years
• Incidence 20/million per year in US
• Prevalence 240/million in US.

4
Etiology

• Unknown
• Environmental Exposures
• 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

5
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

6
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.

7
Pathogenesis
8
Pathogenesis of Scleroderma
Up to Date
9
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.

10
2013 ACR Diagnostic Criteria
11
Limited Scleroderma

• More gradual process
• Can have Raynauds 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

12
Limited Scleroderma

• CREST Syndrome
• Calcinosis
• Raynauds
• Esophageal Dysmotility
• Sclerodactyly
• Telangiectasisa

A.D.A.M. Images
13
CREST Syndrome
ACR and Mayo Foundation
14
Calcinosis on x-ray
Gupta E., et al. Malaysian Family Physician.
20083(3)xx-xx
ACR
15
Nailfold Capillaroscopy
16
Diffuse Scleroderma

• More Rapid Process
• Often with onset of skin thickening within a year
  of Raynauds 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.

17
Diffuse Scleroderma
ACR
Netter
American Osteopathic College of Dermatology,
Grand Rounds
18
Organs Involved

• Skin
• Musculoskeletal
• Pulmonary
• Renal
• Gastrointestinal
• Cardiac

19
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.

20
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 PIPs and elbows may
  become secondarily infected.
• Digital ischemia
• with pits in the distal aspect of the digits
  related to prolonged Raynauds.
• Thinning of the lips, beak-like nose.

21
Skin Manifestations
ACR
Sclero.org International Scleroderma Network
Kahaleh B. Rheum Dis Clin N Amer 200857-71
22
Musculoskeletal

• Arthritis
• in gt 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.

23
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.

24
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

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Interstitial Lung Disease
Up to Date 2005
Up to Date 2005
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Primary Pulmonary Hypertension

• Symptoms
• exertional dyspnea.
• Frequency
• 10-15 of patients with systemic sclerosis
• Definition
• Mean PA blood pressure gt25mmHg at rest or gt30mmHg
  with exercise on right heart catheterization.
• Estimated systolic pulmonary artery pressure of
  gt35mmHg on Echocardiogram
• Pathogenesis
• Intimal fibrosis and medial hypertrophy of the
  pulmonary arterioles and arteries.

27
Pulmonary Hypertension
Doppler Echocardiogram to estimate pulmonary
artery pressure. Roberts JD. Pulm Circ
20111160-181.
Up to Date 2005
28
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.

29
Renal Manifestations of Systemic Sclerosis

• Scleroderma Renal Crisis
• Abruptly developing severe hypertension
• Rise in SBP by gt 30 mmHg, DBP by gt 20 mm Hg
• One of the following
• Increase in serum creatinine by 50 over baseline
  or creatinine gt 120 of upper limit.
• Proteinuria gt 2 by dipstick.
• Hematuria gt 2 by dipstick or gt 10 RBC/HPF
• Thrombocytopenia lt 100
• Hemolysis (schisctocytes, low platelets,
  increased reticulocyte count).
• Can cause headache, encephalopathy, seizures, LV
  failure.
• 90 with blood pressure gt 150/90.
• Can occur also with lower blood pressures lt
  140/90 and this confers worse prognosis.

Steen et al., ClinExp. Rheumatol. 2003
30
Scleroderma Renal Crisis
Up to Date 2012
31
Risk Factors for Renal Crisis

• Rapidly progressive skin thickening within the
  first 2-3 years.
• Steroid use (prednisone gt 15 mg)
• Anti-polymerase III Ab.
• Pericardial Effusion.

32
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.

33
Treatment of Scleroderma Renal Crisis
Without
Steen, Clinics in Dermatology, 1994
34
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.

35
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
• Barrets Esophagus.

36
Gastrointestinal Manifestations

• Gastric Involvement
• 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
37
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.

38
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 gt
  systolic dysfunction.
• Myocarditis
• Inflammation which leads to fibrosis
• Arrhythmias and conduction abnormalities
• Fibrosis of cardiac conduction system.
• AV conduction defects and arrhythmias.

39
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 gt 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 23545-554
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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
Anti-Ku 1-3 Overlap Ssc Muscle, Joint, SLE overlap
Adapted from Nihtyanova SI, Denton CP. Nat Rev
Rheumatol 2010 6112
41
Scleroderma Treatment

• Depends on clinical manifestations
• Aggressive disease versus stable disease
• Reversible inflammation vs Vasoconstriction.
• Organ Involvement
• Treatment is directed at organ involved.

42
Raynauds

• Calcium Channel Blockers nifedipine
• Nitroglycerin patches
• Sildenafil (Viagra) (but not in combination with
  nitroglycerine) usually for refractory
  Raynauds.
• Parental vasodilators (iloprost) for severe
  disease with impending digital ischemia.

43
Gastrointestinal Involvement

• GERD
• Proton pump inhibitor.
• Delayed Gastric Emptying and peristalis disorders
• Supportive
• Promotilants are sometimes used.

44
Pulmonary Involvement

• Interstitial Lung Disease with active
  inflammation
• 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

45
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.

46
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.

47
Skin Disease

• Stable disease no treatment
• Advancing diffuse skin involvement
• Methotrexate
• Mycophenolate
• Current trial with Tocilizumab (Actemra)
• D-penicillamine 125 mg/day.
• Research on various anti-fibrosis therapies is
  being performed (imatinib, Gleevac).

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Differential Diagnosis

• Scleredema
• No Raynauds, negative antibodies, seen in IDDM
• Proximal skin thickening (trunk, shoulders, back)
• Scleromyxedema
• Skin thickening/induration on head, neck, arms,
  trunk
• Monoclonal gammopathy (multiple myeloma/AL
  amyloid)
• Skin biopsy differentiates.
• Endocrinologic diabetes and hypothyroid myxedema
• 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
• Chronic kidney disease and gadolinium MRI
  contrast
• Can involve hands and feet.
• Eosinophilic fasciitis
• Hands and feet are spared, peripheral blood
  eosinophilia, peau de orange appearance
• Diagnosis is via skin biopsy.
• Graft versus Host disease
• History of bone marrow transplant, no Raynauds
  symptoms.

49
Cases
50
Case 1

• 50 year old female who has CREST syndrome with
  anti-centromere antibody
• Raynauds 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 PFTs 1 month ago
• Echo normal with normal estimated PA pressures.
• PFTs normal lung volumes, normal DLCO.
• What is next step

51
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 PFTs.
• General exam

52
Case 2

• 60 year old male with Raynauds 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
• Vitals T 98.9, BP 124/73, pulse 80, resp rate 18
• Raynauds 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?

53
Case 2
Strek, ME. Amer Col Chest Physicians 2012
Learningradiology.com
Oikonomou A, Prassopoulos P - Insights Imaging
(2012)

• PFTs 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?

54
Case 2

• Interstitial lung disease associated with
  scleroderma with active inflammation.
• Mycophenolate, Cytoxan, or Azathioprine
• Prednisone (low dose) 10 mg daily gradual taper

55
Case 3

• 50 year old female presents with
• onset of Raynauds 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
• 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?

56
Case 3
EMG, Nerve Conduction Studies
Seidman, RJ. Medscape
Olsen NJ, et al. Rheum Dis Clin N. Amer
199622(4)783-796

• MRI of the thigh
• Biopsy of thigh musculature
• What is the diagnosis? What is the treatment?

57
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
  patients strength improves.

58
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.
• Raynauds 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

59
Case 4
Sclero.org International Scleroderma Network

• Labs
• 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?

60
Case 4

• Digital Ischemia due to Raynauds
• 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).

61
Case 5

• 58 year old male with
• Rapid onset scleroderma with Raynauds 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.

62
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.

63
Case 5

• Scleroderma Renal Crisis
• Treatment
• Hospitalization
• Start ACE-inhibitor captopril with dose
  escalation.

64
References

• Medscape
• Up To Date
• Desai, et al Curr Opin Rheumatol 2011
  23545-554
• Curr Opin Rheumatol 23505-510
• Fischer A CHEST 2006 130976 981
• Rheum Dis Clin N Am200329293313
• Arthritis Rheum 2006543962-3970
• Rheumatology 200948iii32iii35
• Steen VD Rheum Dis Clin N Am 200329315333
• Hudson M, et al Medicine 201089976-981
• Bon LV Curr Opin Rheumatol 201123505510
• Barnes J Curr Opin Rheumatol 2012, 24165170

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Definition of Criteria
66
Skin Scoring