PSS pdf - وهاب رزاق

Systemic Sclerosis

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

• 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 1

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

• 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

American Osteopathic College of Dermatology, Grand
Rounds

Netter

Organs Involved

• 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.

Skin Manifestations

Kahaleh B. Rheum Dis Clin N Amer 2008:57-71

Sclero.org
International
Scleroderma Network

ACR

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

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

Up to Date 2005

Doppler Echocardiogram to estimate
pulmonary artery pressure.
Roberts JD. Pulm Circ 2011;1:160-181.

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

Steen, Clinics in Dermatology, 1994

Without

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:

• 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

Adapted from Desai, et al; Curr Opin Rheumatol 2011m 23:545-554

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

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

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; 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

• 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:

• 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

• 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.

• Diagnosis is via skin biopsy.

Cases

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:

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:

• 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

•

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?

Learningradiology.com

Oikonomou A, Prassopoulos P - Insights Imaging (2012)

Strek, ME. Amer Col Chest
Physicians 2012

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:

• 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?

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

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:

• 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

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

• 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