1. Dan Mandel, MD UCI School of Medicine
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 Female:Male = 3:1
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.

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: % 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 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%

12. Limited Scleroderma CREST Syndrome Calcinosis Raynaud’s
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. 2008;3(3):xx-xx
ACR

15. Nailfold Capillaroscopy

16. 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.

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: Late 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 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.

21. Skin Manifestations ACR Sclero.org International Scleroderma Network
Kahaleh B. Rheum Dis Clin N Amer 2008:57-71

22. Musculoskeletal Arthritis Carpal Tunnel Syndrome. Contractures
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.

23. Pulmonary leading cause of death Symptoms: Types of lung Involvement:
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

25. Interstitial Lung Disease
Up to Date 2005
Up to Date 2005

26. 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.

27. Pulmonary Hypertension
Doppler Echocardiogram to estimate pulmonary artery pressure.
Roberts JD. Pulm Circ 2011;1:
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 > 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

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 > 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:
Barret’s 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 > 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
> 60%
MRI/nuclear medicine
Calcium channel blockers
Macrovascular CAD
25%
Coronary Angiogram
Stenting/medical tx
Bradyarrhythmias
EKG/Holter
Pacemaker
Tachyarrhythmias
15%
Diltiazem, ablation, defibrillator
Adapted from Desai, et al; Curr Opin Rheumatol 2011m 23:

40. 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
Renal, Pulmonary HTN
Centromere
15-40
lcSSc, CREST
Pulmonary HTN
Esophageal
U1-RNP
5-35
lcSSC, MCTD
Muscle
U3 RNP (fibrillarin)
Nucleolar
1-5
dcSSC, poor prognosis
PM-SCL
3-6
Overlap, mixed
Th/To
1-7
lcSSc
Pulmonary HTN,
Lung fibrosis,
Small bowel
Anti U11/U12
lcSSc & dcSSC
Lung Fibrosis
Anti-Ku
1-3
Overlap Ssc
Muscle, Joint, SLE overlap
Adapted from: Nihtyanova SI, Denton CP. Nat Rev Rheumatol 2010; 6:112

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. 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.

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).

48. 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 Raynaud’s symptoms.

49. Cases

50. Case 1
50 year old female who has CREST syndrome with anti-centromere antibody:
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:

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 PFT’s.
General exam

52. 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:
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?

53. Case 2
Strek, ME. Amer Col Chest Physicians 2012
Learningradiology.com
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?

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 Exam: Labs:
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:
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 MRI of the thigh Biopsy of thigh musculature
EMG, Nerve Conduction Studies
Seidman, RJ. Medscape
Olsen NJ, et al. Rheum Dis Clin N. Amer 1996;22(4):
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 patient’s strength improves.

58. Case 4 35 year old female with Exam
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

59. Case 4 Labs: What is the diagnosis? What is next step?
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 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).

61. Case 5 58 year old male with: Exam:
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.

62. Case 5 Labs What is the diagnosis? What is the next step.
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; 23:
Curr Opin Rheumatol 23;
Fischer A; CHEST 2006; 130:976 –981
Rheum Dis Clin N Am;2003;29:293–313
Arthritis Rheum 2006;54:
Rheumatology 2009;48:iii32–iii35
Steen VD; Rheum Dis Clin N Am 2003;29:315–333
Hudson M, et al; Medicine 2010;89:
Bon LV; Curr Opin Rheumatol 2011;23:505–510
Barnes J; Curr Opin Rheumatol 2012, 24:165–170

65. Definition of Criteria

66. Skin Scoring