Systemic and
Localized Scleroderma
Julie Schwartzman, MD
Assistant Professor
Medicine and Rheumatology
Director, Jacobi and NCB Arthritis Clinics
Scleroderma: Systemic Sclerosis
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Chronic disease that causes skin thickening and
tightening, and can involve fibrosis and other
types of damage to internal body organs.
Thought to be an autoimmune disease, affects
both adults and children, most commonly adult
women.
While effective treatments are available for some
manifestations of the disease, scleroderma is not
yet curable.
SSc
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Uncommon problem affecting only 200 to
300/million in the U.S.
Traditional DMARDs have limited effect
Increasingly, different aspects of scleroderma
are becoming treatable.
Research is shedding new light on the
relationship between the immune system and
scleroderma.
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CHARACTERIZED BY VASCULAR
CHANGES, INTIMAL PROLIFERATION
LEADING TO DEPOSITION OF
COLLAGEN AND FIBROSIS.
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PRESENTATION AND PROGRESSION IS
VARIABLE
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NO EFFECTIVE TREATMENT
“Scleroderma” = more than one syndrome
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Localized scleroderma or morphea: confined
to the skin and subcutaneous structures
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Systemic sclerosis: more uniform skin
involvement and the potential for involvment of
multiple visceral organs
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Multiple clinical variants
Limited, Diffuse, Overlap Syndrome
CREST: variant of Limited SSc
Localized Scleroderma
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Each of the several forms of localized scleroderma is a
disorder of skin and sometimes the deeper tissues.
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The most visible effects of the disease are skin lesions
referred to as morphea.
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Morphea can be differentiated from SSc by the
distribution of lesions (no sclerodactyly or perioral
involvement), absence of Raynaud’s and/or periungual
telangiectasia, and rarity of severe systemic disease
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Age of diagnosis usually 20-40, linear disease <18yrs, deep
morphea mean age 46
Morphea
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The typical morphea lesion begins as a patch of
erythema or edema that may have an associated
violaceous border (inflammatory stage).
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Primary lesions=hyperpigmented patches.
Become progressively indurated, porcelain white
or yellow hue.
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Upon resolution, atrophy, depigmentation, or
hyperpigmentation may occur.
Plaque morphea
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Involves dermis and, occasionally,
the superficial panniculus.
Trunk is generally more
commonly involved than the
extremities, although the face,
neck, or scalp can be involved.
Plaque morphea comprises more
than 50% of cases.
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Guttate morphea: This subset usually occurs on the
upper trunk. Typically, it presents as multiple oval
lesions between 2-10 mm in diameter.
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The lesions often manifest as faint erythema, followed by
mild induration and hypopigmentation or
hyperpigmentation.
Keloid morphea: This presents as nodules that
resemble keloids in the presence of typical morphea.
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Lichen sclerosus et atrophicus: shiny, white
plaques often preceded by violaceous discoloration
of the skin; predilection for the anogenital area.
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There is higher incidence of autoimmune-related diseases
(eg, vitiligo, alopecia areata).
Atrophoderma of Pasini and Pierini:
asymptomatic, hyperpigmented atrophic patches
with well demarcated "cliff drop borders" on the
trunk.
There are no pronounced inflammatory or sclerotic
changes.
 The course is chronic, with spontaneous resolution usually
after 10 years.
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Localized scleroderma including deep and
extensive lesions can prevent normal motion of
joints and interfere with daily activities.
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However, localized scleroderma does not affect
internal organs of the body.
Generalized morphea
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Generalized morphea or linear scleroderma:
widespread lesions; thickness and scarring spreads down
to the underlying structures including fat, muscle and, on
rare occasion, bone.
Disease can be more serious.
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Individual plaques of morphea become confluent lesions.
It can affect more than 2 anatomic sites, including the upper
trunk, breasts, abdomen, and upper thighs.
Arms, legs, face, neck, and scalp also may be involved.
Bullae may develop in localized areas, particularly around the
abdomen.
Keratoses and calcinosis may occur.
Contractures may occur in limbs, and mobility may be
restricted.
Linear scleroderma
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One or more linear streaks and induration that can involve dermis,
subcutaneous tissue, muscle, and bone.
It occurs on the extremities, face, or scalp of children and adolescents.
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Linear scleroderma: discrete linear induration that primarily affects the
extremities.
 In more than 90% involvement is unilateral.
 Complicated by deformities, joint contractures, and severe limb atrophy.
 Can affect the growth of bony structures.
Linear Scleroderma
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Lesions en coup de sabre: If the face or scalp is
affected with linear scleroderma, the involvement
is often compared to a stroke from a sword
(sabre).
 Lesions start with contractions and firmness
of the skin over the affected area.
 Then, an ivory, irregular, sclerotic plaque with
hyperpigmentation at the edge will develop.
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Progressive hemifacial atrophy (ParryRomberg syndrome): results in hemiatrophy of
the face.
 The primary lesions occur in the subcutaneous
tissue, muscle, and bone.
 The disease usually begins in the first 2
decades of life.
Deep morphea: deep dermis, subcutaneous tissue, fascia, or
superficial muscle.
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Lesions more diffuse than in linear scleroderma
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Subcutaneous morphea: panniculus or
subcutaneous tissue. The onset is rapid, occurring
during a period of several months.
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More inflammatory condition than other types.
Morphea profunda: entire skin feels thickened,
bound down, and taut. Patients develop deep
sclerosis of the skin.
Patients younger than 14 years.
 The extensor aspect of the extremities and trunk develops
sclerotic plaques that extend deep into the subcutaneous
tissue, fascia, muscle, and bone..
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Deep morphea: deep dermis, subcutaneous tissue, fascia, or
superficial muscle
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Disabling pansclerotic morphea of childhood:
aggressive and mutilating generalized, full-thickness
involvement of the trunk, extremities, face, and
scalp.
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Fingertips and toes usually are spared.
Eosinophilic fasciitis: painful peau d'orange
appearance involving the extremities, proximal to the
hands and feet.
The fascia is the predominant level of involvement.
 Patients seem to spontaneously regress or remain
unchanged for years.
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The diagnosis of morphea is based on clinical
findings, although histopathologic confirmation
is often needed to exclude other disorders
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Eosinophilia can be seen in generalized and linear
scleroderma and often correlates with extent of
disease.
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Polyclonal hypergammaglobulinemia can occur in
50% of patients with linear scleroderma
Autoantibodies?
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Most titers correlate with the burden of skin
disease
antinuclear antibodies (46%-80%)
 anti–single-stranded DNA antibodies (50%)
 antihistone antibodies (47%).
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The presence of rheumatoid factor (60% of
cases) may predict articular involvment
Although anticentromere antibodies have been
detected in up to 12% of patients with morphea,
anti-topoisomerase I antibodies have only been
reported in a handful of cases.
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Progression to SSc is rare (0.9%-5.7% of cohorts)
Despite this, certain extra-cutaneous manifestations can
occur.
Arthralgias commonly occur, then resolve with
progression of skin disease.
Other findings: synovitis, uveitis, congenital vertebral
abnormalities (especially spina bifida),
cardiomyopathies, fever, and lymphadenopathy.
Raynaud’s and carpal tunnel syndrome can develop as a
secondary result of extensive extremity fibrosis.
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Morphea rarely coexists with other systemic
autoimmune disorders, including dermatomyositis,
polymyositis, systemic lupus erythematosus, primary
biliary cirrhosis, rheumatoid arthritis, and MCTD
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Lesions typically regress spontaneously over 3 to 5
years, usually with residual pigmentary and atrophic
changes.
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Although the few controlled trials did not show efficacy
compared with placebo several therapeutic options are
available particularly for patients with evidence of
inflammatory changes and/or progressive lesions
Systemic Sclerosis
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Diffuse systemic sclerosis: can affect the skin
over almost any body area. Fibrosis proximal to
elbows, knees.
Rapid onset of disease following appearance of
Raynauds
 More likely to have pulm fibrosis, GI, renal, cardiac
 ANA, Scl-70
 Variable but overall poor prognosis, survival 40-60%
at 10 years
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Systemic Sclerosis
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Limited systemic sclerosis: skin involvement is
limited to forearms, hands, legs, feet, and face.
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Pts usually have Raynauds for years.
Late visceral disease w/ prominent HTN and digital
amputation
CREST subgroup
Anti-centromere Ab
Relatively good prognosis, >70% survival at 10 years
Overlap Syndromes
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Diffuse or limited SSc with one or more features of another
CTD
MCTD: features of SLE, SSc, PM, RA and presence of antiU1 RNP
SSc
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Pathologic remodeling of connective tissues
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Cardinal features: excessive collagen production and
deposition, vascular damage, and
inflammation/autoimmunity.
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Widespread small-vessel vasculopathy and fibrosis
in the setting of immune system activation
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Vascular injury affects small arteries, arterioles,
capillaries
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The pathogenesis is initiated by microvascular injury (i). This induces
inflammation and autoimmunity (ii), which have direct and indirect roles in
inducing fibroblast activation (iii), a key event in the development of fibrosis.
The number of fibroblasts and their precursors in affected tissues is increased
by trafficking as well as by the differentiation of mesenchymal cells (iv).
Activated myofibroblasts in the lesional tissue perform a series of functions
culminating in fibrosis (v). MSC, mesenchymal stem cell.
Transforming growth factor–b
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Stimulates cell growth, apoptosis, and differentiation
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Promotes collagen and matrix protein production
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Decreases the synthesis of collagen-degrading
metalloproteinases
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Stimulates fibroblasts to maintain an activated state.
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Stimulates CTGF synthesis in fibroblasts, vascular smooth
muscles,and endothelial cells.
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CTGF can trigger angiogenesis, apoptosis, chemotaxis, extracellular
matrix formation, and the structural organization of connective tissues.
Non–TGFb–related pathways that involve the activities of p38
kinase,C-delta kinase, and phosphatidylcholine phospholipase C
kinase may also play a role
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Genetics likely predisposes patients to the disease, but
whether scleroderma is the result of some combination
of genetic factors and other exposures is unknown.
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Some data suggests that exposure to industrial solvents
or an environmental agent may play a role in
predisposing to scleroderma.
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Scleroderma-like syndromes also have been clearly
linked to agents as varied as contaminated rapeseed oil,
polyvinylchloride, and a contaminant in one preparation
of L-tryptophan.
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Majority of patients with scleroderma do not have a
history of exposure to any suspicious toxins.
Who gets scleroderma
Relatively rare, affecting only 75,000 – 100,000 people in
the United States.
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75% percent are women usually diagnosed between the
ages of 30 and 50 years.
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Twins and family members of patients with
scleroderma or other autoimmune CTD appear to be at
a slightly increased risk.
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Children can get scleroderma, although the pattern and
extent of disease may be different in children.
Who gets scleroderma
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Ethnicity influences severity and survival

Progressive IPF less frequent and w/ better survival
rates in Caucasians
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Caucasians: inc rate of anti-centromere Ab
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African Americans: inc rate Scl 70
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Inc presence of parvovirus B19 in BM
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Occupational exposure to silica: RR 25, silicosis RR 110
Clinical Features: Cutaneous
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Thickened skin: abnl production of type 1
collagen by fibroblasts, accumulation of GAG
and fibronectin in ECM. Begins in fingers and
hands
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Calcinosis: deposits of basic CaPhos
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Telangiectasias: dilated sm v.
More common in LSSc
 Can bleed when in GI mucosa
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SYSTEMIC SCLEROSIS
CREST VARIANT
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CALCINOSIS
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RAYNAUD’S
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ESOPHOGEAL DYSFUNCTION
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SCLERODACTALY
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TELANGECTASIA
Clinical Features – Raynaud’s
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Almost all (more than 90%) of people with
scleroderma also have Raynaud's phenomenon.
Raynauds
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Triphase event affecting the hands and feet, the nose, the ears, and
the tongue
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Characterized by abrupt pallor (white), followed by cyanosis
(blue), and sometimes, painful erythema secondary to restoration
of blood flow.
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The succession of phases is linked to 3 pathogenic mechanisms—
vasoconstriction, ischemia, and reperfusion.
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Small areas of fingertip ischemic necrosis are frequent, often
leaving pitted scars or ulcerations.
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On microscopic examination in Raynaud’s of some
duration, the capillary circulation is altered by the
appearance of tortuous and dilated or giant loops
and, in dcSSc, by a paucity of nailfold vessels or
dropout
Primary Raynauds
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FEMALE PREDOMINENCE
ONSET AT MENARCHE
ALL DIGITS INVOLVED
MULTIPLE ATTACKS DAILY
EMOTIONAL AND COLD
NO ISCHEMIC ULCERS
NORMAL NAIL BED CAPILLARIES
NO SYSTEMIC SYMPTOMS
NORMAL SEROLOGY
Secondary Raynauds
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LATER ONSET
MAY INVOLVE ONLY A FEW DIGITS
EMOTION IS LESS OF A TRIGGER
ISCHEMIC ULCERS MAY BE PRESENT
EDEMA MAY BE PRESENT
PERIUNGUAL CAPILLARIES MAY BE
ABNORMAL
SYSTEMIC FEATURES
ANA
Pt with Raynauds may progress to
SSc if:
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+ANA, anti-centromere, anti-Scl-70
Nailfold capillary abnl, dropout or dilatation
Tendon friction rubs
Puffy swollen fingers
Associated GERD
If Raynauds preceeds skin changes by >1 yr, likely
Limited SSc
If Raynauds and skin changes occur at same time,
likely dSSc
TREATMENT OF RAYNAUD’S
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NON-PHARMACOLOGIC – LIFESTYLE ASJUSTMENTS
TO PRECIPITANTS: STOP SMOKING, AVOIDANCE OF
b-BLOCKERS, EXERCISE, KEEP WARM
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ORAL VASODILATOR DRUGS: CALCIUM CHANNEL
BLOCKERS, ACE INHIBITORS/ANGIOTENSION
RECEPTOR ANTAGONISTS, TOPICAL
NITROGLYCERINE, PROSTACYCIN (IV) IF AVAILABLE
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DIGITAL SYMPATHECTOMY
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PROMPT TREATMENT OF FINGERTIP ULCERATIONSANTIBIOTICS AND DEBRIDEMENT
GI- 2nd most commonly affected organ system
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75-90% patients
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Lower Esoph Dysmotility: smooth muscle fibrosis,
esophageal dysfunction in 80% pts- GERD, fibrosis
and stricture formation, aspiration PNA
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Gastroparesis, telangiectases, watermelon stomach
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SI: malabsorption and diarrhea secondary to bacterial
overgrowth, functional ileus from musclar fibrosis w/
hypomotility and dilatation
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Colorectal: severe constipation, megacolon, wide mouth
diverticula
GI MANAFESTATIONS
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© 2005 Elsevier
Treatment - GI
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Elevation of the head of the bed at night and
appropriate diet plus the use of H2 blockers and/or
proton pump inhibitors.
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Metoclopramide and erythromycin are prokinetic drugs
that can be used to promote GI motility, particularly of
the upper GI. Esophageal stricture requires periodic
endoscopic dilatation.
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The bleeding telangiectasias and ecstatic superficial
vessels of watermelon stomach can be treated with
sclerotherapy and laser coagulation, respectively.
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In the lower GI tract, symptoms related to
bacterial overgrowth may improve with 2- to 4week courses of broad-spectrum antibiotics
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Octreotide, given subcutaneously, is moderately
effective as a prokinetic agent for lower GI
symptoms.
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Rarely, TPN will be needed in patients whose
small intestine is essentially nonfunctional.
SYSTEMIC SCLEROSIS
PULMONARY DISEASE
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INTERSTIAL FIBROSIS
PULMONARY HYPERTENSION
ASPIRATION PNEUMONIA
PLEURAL DISEASE
NEOPLASM
Most common initial respiratory sx is DOE,
w/o cough or chest pain
Pulmonary
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Pulmonary manifestations of SSc occur in more
than 70% of patients.
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Most common SSc-related cause of death.
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Pulmonary fibrosis is a common cause of severe
restrictive lung disease
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CXR shows interstitial thickening in a reticular
pattern of linear, nodular densities most easily
seen in the lower lung fields.
Pulmonary
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High-resolution CT more sensitive for detecting
interstitial lung disease
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Abnormal findings: ground-glass appearance
possibly associated with
inflammation/alveolitis, bronchiectasis and/or
honeycombing (associated with fibrosis).
Alveolitis can be documented by either
broncho-alveolar lavage or open lung biopsy
Pulmonary
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Restrictive lung disease on PFTs used as a marker for pulmonary
fibrosis.
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In a somewhat later disease, the presence of bibasilar rales on
physical examination is found.
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Some patients with interstitial lung disease develop slowly
progressive respiratory failure over the course of 2 to 10 years,
especially those with anti-topoisomerase I antibody.
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In Diffuse SSc, ILD more common
In Limited SSc P HTN more common
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PAH
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Pulmonary hypertension is more common than
previously thought (up to 30% of patients) and can
occur early.
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Signs of pulmonary arterial hypertension (PAH) occur
in approximately 10% to 15% patients with SSc but
may be found on echocardiogram or right heart
catheterization in 20% to 40% of patients.
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There are 3 patterns of PAH:
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severe isolated PAH without significant interstitial fibrosis,
which occurs predominantly in patients with lcSSc after 10 to
30 years;
PAH complicating interstitial pulmonary fibrosis, which
occurs predominantly in dcSSc patients
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Third type of pulmonary vascular disease reflects
the combined vascular and fibrotic pathologic
processes of the disease and results in a more
indolent pulmonary process.
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Found in those patients who have very slow progressive PAH
and who have a secondary pulmonary vascular component in
the context of relatively mild fibrosis, distinct from the severe
interstitial process seen in true secondary PAH.
Symptomatically, patients will present with
progressive dyspnea but, in late PAH, may present
with syncopy.
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The pulmonic component of the second heart
sound is accentuated, and ultimately, right-sided
cardiac failure develops.
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The diffusing capacity for carbon monoxide is
very low relative to the forced vital capacity,
consistent with impaired gas exchange across
thickened small pulmonary blood vessels.

Diagnosis is confirmed by echocardiogram or by
right heart catheterization.
Treatment
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Prophylactic influenza and Streptococcus pneumoniae vaccinations
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In persons with alveolitis, immunosuppressive drugs,
cyclophosphamide and azathioprine, may be effective.
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In intrinsic PAH intermittent and continuous intravenous
prostacyclin analogs; the endothelin-1 antagonist, bosentan; and the
phosphodiesterase type 5 inhibitor, sildenafil have been approved.
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Anticoagulation is often prescribed.
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Heart-lung or single lung transplantation is an option for end-stage
lung disease
Renal
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Kidney involvement in SSc may be manifested
by scleroderma renal crisis (SRC).
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Scleroderma renal crisis used to be the most
severe complication in scleroderma and the
most frequent cause of the death in these
patients.
Renal
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Over the last 20 to 25 years, ACE-I have dramatically
improved SRC outcome.
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Although death and dialysis within 6 weeks were
common before the advent of aggressive ACE
inhibitor use, 60% of patients with SRC no longer
require dialysis or require only temporary dialysis.
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Clinically evident renal involvement is almost exclusive
to persons with dcSSc, especially those with rapidly
progressive skin thickening than 5 years in duration.
Renal Crisis
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Scleroderma renal crisis develops in about 18%
of pts with dcSSC
Abrupt onset of accelerated hypertension, followed
by oliguric renal failure.
 Sx: headache and visual blurring from hypertensive
retinopathy, seizures, and acute dyspnea due to
sudden left ventricular failure.
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Renal Crisis
Microscopic hematuria and low-grade proteinuria
within several days or weeks along with rapidly
increasing serum Cr, oliguria or anuria.
 Risks: diffuse skin disease, new unexplained anemia,
use of steroids, pregnancy, and anti-RNA
polymerase III Ab
 Poorer outcome in males, older, Cr >3 mg/dl
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Microangiopathic hemolytic anemia with
thrombocytopenia frequently occurs
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Non renal crisis abnormalities:
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Mild proteinuria, mild elevation in the plasma creatinine
concentration, and/or hypertension are observed in as many
as 50% of patients.
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Impaired renal reserve may be present in patients in the
absence of clinical renal disease.
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Clinically evident disease is less common, but autopsy studies
suggest that 60% to 80% of patients with dcSSc have
pathologic evidence of renal involvement
Treatment
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Prompt detection is the most important aspect of therapy for
renal crisis.
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Patients with early dcSSc are advised to take their blood pressure
every several days to weekly and to report a rise of systolic
pressure of 30 mm Hg or greater.
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ACE inhibitors are the drugs of choice, but early aggressive
therapy with other potent antihypertensive agents can also be
successful.
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Some patients may require dialysis, but most can be maintained
on ACE inhibitors, and dialysis can be discontinued after 3 to 24
months.
Successful renal transplants have been reported.
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Cardiac
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Primary cardiac involvement: myocardial fibrosis, LV
or biventricular CHF, myocarditis, pericarditis with
or without effusion, valvular abnormalities, or
supraventricular or ventricular arrhythmias.
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Acute symptomatic pericarditis is unusual.
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Left sided congestive heart failure secondary to
myocardial fibrosis occurs in fewer than 5% of
dcSSc patients.
Cardiac
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Cardiac arrhythmias include complete heart block
and other EKG abnormalities.
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Valvular disease usually minor, not hemodynamically
significant.
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Secondary cardiac disease occurs in association with
SSc pulmonary or renal disease or in overlap with
other illnesses such as systemic lupus erythematosus
or polymyositis.
Treatment
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Nonsteroidal anti-inflammatory drugs or low-dose
corticosteroids can be used for symptomatic pericarditis.
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If myocarditis is identified clinically or by endomyocardial
biopsy, high-dose glucocorticoid therapy should be tried.
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Digitalis and diuretics are the mainstay of therapy.
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The typical progressive left ventricular failure caused
bymyocardial fibrosis is unaffected by any therapy and may lead
to cardiac transplantation.
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Serious arrhythmias are treated in the standard way
MSK
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Manifestations may include muscle weakness and
rheumaticcomplaints ranging from simple arthralgias to
frank arhtritis.
In dcSSc, symptoms often start with symmetric
polyarthralgia and joint stiffness (with or without gross
synovitis), myalgia, and puffiness of the skin.
Joint pain, immobility, and contractures are the result
of fibrosis around tendons and other periarticular
structures.
Contractures of the hands from this process are most
common, but large joint contractures involving the
wrists, elbows, hips and ankles may also occur.
MSK
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Some patients may have palpable and/or audible deep
periarticular tendon friction rubs during motion; this may be due
to fibrinous tenosynovitis.
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Severe arthritis or destructive joint disease should make one
suspect an overlap syndrome with rheumatoid arthritis.
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2 principal patterns of muscle involvement
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Scleroderma myopathy, frequently mild and relatively nonprogressive,
p/w minor proximal weakness and slight to moderate elevations of CPK
Sclerodermatomyositis, a true overlap between scleroderma and
polymyositis
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Far less common.
Weakness is often more profound, with significantly elevated CPK and
EMG/muscle biopsy abnormalities typical for inflammatory myopathy.
Neuro
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Neurologic involvement occurs in up to 40% of
patients with SSc.
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Manifestations include cranial nerve abnormalities,
peripheral nerve involvement, and autonomic
neuropathy.
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Central nervous system involvement is usually
secondary to SSc renal or cardiopulmonary
involvement.
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Neuropathy can be asymptomatic or can be lifethreatening if autonomic nervous system is involved.
Disease Modifying Treatments
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While some treatments have proven effective in treating
the disorder, scleroderma is not yet curable.
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Much research has gone into addressing the various
manifestations of the disease, but no drug has been
found that can arrest or reverse the skin thickening that
is the hallmark of disease.
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Treatments are disease modifying vs. symptomatic (by
organ system affected) as presented
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DMARDs can be selected on basis of other coexisting
conditions if there is disease overlap
Suppression of autoimmunity and inflammation
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Cyclophosphamide: data NIH randomized, double-blind,
placebo-controlled trial (The Scleroderma Lung Study) showed
beneficial effects of cyclophosphamide over placebo in SSc
patients with active alveolitis.
 Treatment had a modest effect on pulmonary function, a
larger effect on pulmonary symptoms and a clear, and a
statistically significant effect on skin in patients with diffuse
skin involvement.
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MTX
Chlorambucil
5-FU
Stem cell transplant
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Since 1996, autologous peripheral blood stem cell
(PBSC) transplantation used worldwide with a low early
mortality of 5%
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Based on these data, intensive myelo- and immuno
suppression followed by autologous hematopoietic
stem cell transplantation (HSCT) has been used to treat
severe SSC
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Since 1996, approx 1000 PBSC transplants for
autoimmune diseases have been reported
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140 SSc patients in the EBMT (European Group for Blood
and Marrow Transplantation) and EULAR (European League
Against Rheumatism) database as to March 2007.
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The early results from the phase I/II clinical trials
showed that HSCT is feasible in carefully selected
patients with diffuse SSc

2004 follow up report from the EBMT-EULAR
database, consisting of different centers and treatment
schemes, showed positive responses at 3 years in
two thirds of 57 patients with an early treatment
related mortality of 8.7%

The specific aims of this study: evaluate the
survival and the durability of responses up to 7
years of follow-up in SSc patients treated by
autologous HSCT.

Long-term follow up results of all the Dutch and
French patients included in two similar phase I/II
trials, using uniform eligibility criteria and a single
transplantation protocol
Patients and Methods




All patients-ACR preliminary criteria for SSc and
had the diffuse cutaneous form.
Patients eligible if : (a) age < 66 years
(b) rapidly progressive disease (2 years
duration with a modified Rodnan skin score
(mRSS) above 20,
ESR > 25 mm/first h and/or Hb < 11 g/dL,
not explained by other causes than active SSc
Patients and Methods
 OR

(c) a disease duration >2 years plus a progression of
the mRSS (20%) plus major organ involvement related
to SSc as defined by either:



(1) lung involvement: with a vital capacity (VC) or DLCO
below 70% predicted, or a mean pulmonary artery pressure
(PAP) above 40 mmHg (measured by echocardiography);
(2) digestive tract involvement: with serum albumin <25 g/L
or weight loss exceeding 10% body weight in the preceding
year;
(3) kidney involvement: with 24-h urinary protein above 0.5 g
or serum creatinine above 120 mmol/L.
Exclusion Criteria



Uncontrolled arrhythmia, left ventricular
ejection fraction (LVEF) <50% or mean PAP
>50 mmHg measured by ECHO
DLCO <45% of predicted, creatinine clearance
<20 ml/min
Platelets <80 000/mm3, hemorrhagic cystitis,
HIV or HTLV1 seropositivity, malignancy,
pregnancy, a cardiac or vascular prosthesis, and
no vascular access

After a median follow-up of 5.2 (1–7.5) years, death from disease
progression occurred in 2 patients (8%): both from relapse at 18
months after transplantation, one after initial PR and the other
after initial MR.

A third patient, a heavy smoker, died from small cell lung cancer 64
months after HSCT.

Among the others showed 35% (n=9) sustained MR, 50%
(n=13) sustained PR, and 3% (n=1) progressed after PR.

Event-free survival (EFS) for the patients with at least 6 months
of follow-up after autologous HSCT was 64.3% (95% CI 47.9–
86.3%) at 5 years and 57.1% (95% CI 39.3–83.1%) at 7 years

Results
The WHO performance status improved throughout
the follow up, from baseline values at median 2.12
(0–4, n=26) to 0.60 (0– 2, n=15 p,0.05) after 5 years
of follow-up (fig 2).
 A significant fall in mRSS was observed up to 7
years after HSCT with faster regression within the
first year and sustained fall thereafter.
 In comparison with baseline values for all patients,
there was no significant change in FEV1 or DLCO
during follow-up. Cardiac and renal function
remained stable during follow-up

Benefits and Survival

After a median follow-up of 5.3 (1–7.5) years 81% (n=21/26) of
the patients demonstrated a clinically beneficial response.

The Kaplan–Meier estimated survival at 5 years was 96.2% (95%
CI 89–100%) and at 7 years 84.8% (95% CI 70.2–100%) and
event-free survival, defined as survival without mortality, relapse
or progression of SSc, resulting in major organ dysfunction was
64.3% (95% CI 47.9–86%) at 5 years and 57.1% (95% CI 39.3–
83%) at 7 years.

The positive effect of HSCT on survival rate needs to be
interpreted with care, due to a wide range in the duration of
patients’ follow-up and the uncontrolled nature of this study, but
the results are encouraging.
Agents to inhibit fibrosis




Gamma interferons
Interferon alpha
D-penicillamine
Relaxin
Prevention of vascular damage

Prostacyclin analoge: poprostenol and treprostinil,
benefit exercise capacity, dyspnea score,
cardiopulmonary hemodynamics, and survival.



The inhaled form of Iloprost, another prostacyclin derivative, is
also available in the United States.
Data supporting the use of Iloprost in SSc PAH are mostly
symptomatic
Bosentan: oral mixed endothelin A/B antagonist, which
improves PAH because it antagonizes endothelin-1, a
potent vasoconstrictor and smooth muscle mitogen.

Two randomized, placebo-controlled studies have shown that
bosentan improves exercise capacity, cardiopulmonary
hemodynamics, decreased pulmonary vascular resistance, and
decrease pulmonary artery pressure.
Prevention of vascular damage

Sildenafil: phosphodiesterase-5 inhibitor causes
preferential pulmonary vasodilation, decreases
pulmonary vascular resistance index, and improves gas
exchange in patients with severe lung fibrosis and
secondary pulmonary hypertension

ACE-I: despite rising serum creatinine concentrations
while taking an ACE inhibitor, the drug should be
continued as part of the antihypertensive therapy.


These treatments, and those being tested in
current research trials, may provide significant
benefit to patients with lung disease in
scleroderma.
The basic process of fibrosis awaits proven
effective therapy.
Case Report

65-yr-old Korean female visited the Rheumatology
Clinic due to the thickening of hand and facial skin
with digital pallor and cyanosis on cold exposure x 2
mo.

On the first visit, BP 130/80 mmHg
PE: skin thickening on the fingers of both hands, and
on the right hand dorsum and right forearm.


She was diagnosed with systemic sclerosis of the
limited cutaneous subset
J Korean Med Sci. 2006 Dec;21(6):1121-1123.
A Case of Renal Crisis in a Korean Scleroderma Patient with Anti-RNA polymerase I and III Antibodies

WBC 8.39×109/L, Hgb 12.1 g/dL, platelets 240×109/L
ESR 8 mm/hr, ALT 21U/L, AST 18 U/L, total bilirubin 0.6
mg/dL, albumin 3.7 g/dL, BUN 11 mg/dL, and creatinine
0.7 mg/dL.

ANA+, but anti-centromere and anti-SCL-7- negative.

PFTs: FVC 73%; forced expiratory volume in 1 sec, 79%; and
DLCO 121%.

High resolution CT of the lungs revealed old TB in the right
lower lobe with pleural thickening and calcifications without
evidence of interstitial lung disease.

Prazosin 1 mg/day was administered for Raynaud's phenomenon
and intermittent antihistamines for skin pruritus.


Twenty- two months after the diagnosis of limited SSc, her skin
thickening began to rapidly progress above elbows and knees,
and finally involved the trunk.

Blood pressure was in the normal range.

The diagnosis was converted to SSc of the diffuse cutaneous
subset and she was started on D-penicillamine 250 mg/day.

A month later, she visited the emergency room due to the
sudden onset of facial edema and severe dyspnea.
 Her blood pressure was 220/134 mmHg, heart rate 120
beats/ min, respiration rate 48/min, and body temperature
35℃.
 She reported that the dyspnea had begun 10 days previously
and that her urine output had decreased markedly.

A physical examination revealed facial and pre-tibial edema, and
pulmonary rales in the whole lung field.

Laboratory data showed hemoglobin at 9.9 g/dL, LDH 703 IU/L,
total bilirubin 2.9 mg/dL, indirect bilirubin 1.8 mg/dL, and
schistocytes with polychromasia on peripheral blood
smear, suggesting intravascular hemolysis.

Antineutrophil cytoplasmic antibody was negative.

Urinalysis and microscopic examination showed mild proteinura
(1+), hematuria (≥100 RBC per high power field with dysmorphic
RBC >90%), and pyuria (20-29 white blood cells per high power
field).

Urine culture grew no organisms.

Azotemia was also detected with a BUN of 31 mg/dL
and a creatinine of 2.2 mg/dL.

CXR: cardiomegaly and bilateral hilar infiltrates
consistent with pulmonary edema.

She was transferred to intensive care unit, intubated,
and assisted with a mechanical ventilator.

Under a diagnosis of scleroderma renal crisis, captopril
was begun, but failed to reverse a deteriorating renal
function despite successful blood pressure control
within 2 days.

Renal biopsy showed severe fibrinoid necrosis with
luminal obliteration in interlobar arteries and arterioles,
strongly suggesting scleroderma renal crisis

Immunofluorescence staining showed no evidence of
immune complex or autoantibody deposition.

Because scleroderma renal crisis has been reported to
be associated with anti-RNAP I or III antibodies, pt was
tested and, anti-RNAP I/III antibodies were detected

Hemodialysis was started and has been continued for 3
yr without renal recovery.