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Systemic sclerosis
1. 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
2. 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.
3. 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
4. Etiology
⢠Genetic Factors
⢠Familial Clustering: 1.5-2.5% of those with 1st
degree
relative
â Choctow Native Americans: prevalence 4720/million.
⢠HLA-haplotypes: there are higher risk haplotypes in
certain populations
5. 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.
8. 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. Limited Scleroderma
⢠More gradual process
⢠Can have Raynaudâs 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%
15. Diffuse Scleroderma
⢠More Rapid Process
⢠Often with onset of skin thickening within a year of
Raynaudâs 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 â often within the first 3 years.
⢠Antibodies
⢠Anti-Scl-70, anti-RNA Polymerase III.
18. 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.
19. 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 PIPâs and elbows; may become
secondarily infected.
⢠Digital ischemia:
⢠with pits in the distal aspect of the digits related to
prolonged Raynaudâs.
⢠Thinning of the lips, beak-like nose.
21. 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.
22. 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.
23. 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
â Pulmonary function tests
⢠restrictive pattern with low FVC, low residual volume, low DLCO.
â High Resolution CT Scan
â BAL: often not required
â Lung biopsy: often not required
⢠ILD is most commonly associated with diffuse scleroderma.
⢠Anti-Scl-70
25. 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.
26. Pulmonary Hypertension
Up to Date 2005
Doppler Echocardiogram to estimate
pulmonary artery pressure.
Roberts JD. Pulm Circ 2011;1:160-181.
27. 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.
28. Renal Manifestations of Systemic
Sclerosis
⢠Scleroderma Renal Crisis
⢠Abruptly developing severe hypertension
â Rise in SBP by > 30 mmHg, DBP by > 20 mm Hg
⢠One of the following:
â Increase in serum creatinine by 50% over baseline or creatinine > 120%
of upper limit.
â Proteinuria > 2+ by dipstick.
â Hematuria > 2+ by dipstick or > 10 RBC/HPF
â Thrombocytopenia < 100
â 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. 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.
31. 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. 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.
34. Gastrointestinal Manifestations
⢠Esophageal dysmotility: in up to 90%.
⢠Pathophysiology:
â reduced tone of gastroesophageal sphincter and distal dilatation of the
esophagus.
â Lamina propia and submucosal tissue with Inflammatory changes and
increased collagen on pathology.
⢠Symptoms
â Dysphagia, GERD; many asymptomatic.
⢠Diagnosis:
â Esophageal manometry, Esophagram, CT scan.
⢠Treatment
â Proton Pump Inhibitors
â Elevation of head of the bed.
⢠Complications:
â Barretâs Esophagus.
35. 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.
Âť Vitamin B6/B12/folate/25-OH Vit D, low albumin
⢠Diagnosis:
â glucose hydrogen breath test
â Low D-xylose absorption test
â small bowel aspiration (only if resistance to rotating antibiotics)
⢠Treatment: Rotating antibiotics, Reglan, Erythromycin
Image of Watermelon Stomach: University of Michigan Rheumatology Website
36. 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.
37. Cardiac Manifestations
⢠Forms of cardiac involvement
⢠Pericardial Effusion
â symptomatic pericarditis in 20%
⢠Microvascular CAD:
â recurrent vasospasm of coronary arteries
â Necrosis
â patchy myocardial fibrosis; leads to diastolic > systolic
dysfunction.
⢠Myocarditis
â Inflammation which leads to fibrosis
⢠Arrhythmias and conduction abnormalities
â Fibrosis of cardiac conduction system.
â AV conduction defects and arrhythmias.
40. Scleroderma Treatment
⢠Depends on clinical manifestations
⢠Aggressive disease versus stable disease
⢠Reversible inflammation vs Vasoconstriction.
⢠Organ Involvement
⢠Treatment is directed at organ involved.
41. Raynaudâs
⢠Calcium Channel Blockers: nifedipine
⢠Nitroglycerin patches
⢠Sildenafil (Viagra) (but not in combination
with nitroglycerine) âusually for refractory
Raynaudâs.
⢠Parental vasodilators (iloprost) â for severe
disease with impending digital ischemia.
42. Gastrointestinal Involvement
⢠GERD
⢠Proton pump inhibitor.
⢠Delayed Gastric Emptying and peristalis
disorders
⢠Supportive
⢠Promotilants are sometimes used.
43. 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
44. 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.
45. 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.
46. 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).
47. 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 Raynaudâs symptoms.
⢠Diagnosis is via skin biopsy.
49. Case 1
⢠50 year old female who has CREST syndrome with anti-
centromere antibody:
⢠Raynaudâs 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 PFTâs 1 month ago:
⢠Echo: normal with normal estimated PA pressures.
⢠PFTâs: normal lung volumes, normal DLCO.
⢠What is next step:
50. 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 PFTâs.
⢠General exam
51. Case 2
⢠60 year old male with Raynaudâs 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
⢠Raynaudâs 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?
52. Case 2
⢠PFTâs: 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?
Learningradiology.com Oikonomou A, Prassopoulos P - Insights Imaging (2012)
Strek, ME. Amer Col Chest
Physicians 2012
53. Case 2
⢠Interstitial lung disease associated with
scleroderma with active inflammation.
⢠Mycophenolate, Cytoxan, or Azathioprine
⢠Prednisone (low dose) 10 mg daily; gradual
taper
54. Case 3
⢠50 year old female presents with
⢠onset of Raynaudâs 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?
55. Case 3
⢠MRI of the thigh
⢠Biopsy of thigh musculature
⢠What is the diagnosis? What is the treatment?
EMG, Nerve Conduction Studies
Olsen NJ, et al. Rheum Dis Clin N. Amer 1996;22(4):783-796
Seidman, RJ. Medscape
56. 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 patientâs strength improves.
57. 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 ârashâ appeared 1 month ago, gradually
worsening, no change in last week.
⢠Raynaudâs 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
58. Case 4
⢠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?
Sclero.org
International Scleroderma Network
59. Case 4
⢠Digital Ischemia due to Raynaudâs
⢠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).
60. Case 5
⢠58 year old male with:
⢠Rapid onset scleroderma with Raynaudâs 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.
61. 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.
62. Case 5
⢠Scleroderma Renal Crisis
⢠Treatment:
⢠Hospitalization
⢠Start ACE-inhibitor: captopril with dose escalation.
63. References
⢠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 â981
⢠Rheum Dis Clin N Am;2003;29:293â313
⢠Arthritis Rheum 2006;54:3962-3970
⢠Rheumatology 2009;48:iii32âiii35
⢠Steen VD; Rheum Dis Clin N Am 2003;29:315â333
⢠Hudson M, et al; Medicine 2010;89:976-981
⢠Bon LV; Curr Opin Rheumatol 2011;23:505â510
⢠Barnes J; Curr Opin Rheumatol 2012, 24:165â170