Systemic and

Localized Scleroderma
Julie Schwartzman, MD
Assistant Professor
Medicine and Rheumatology
Director, Jacobi and NCB Arthritis Clinics
Scleroderma: Systemic Sclerosis
 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
 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.
 CHARACTERIZED BY VASCULAR
CHANGES, INTIMAL PROLIFERATION
LEADING TO DEPOSITION OF COLLAGEN
AND FIBROSIS.

 PRESENTATION AND PROGRESSION IS

VARIABLE

 NO EFFECTIVE TREATMENT
 “Scleroderma” = more than one syndrome

 Localized scleroderma or morphea:

confined to the skin and subcutaneous
structures
 Multiple clinical variants

 Systemic sclerosis: more uniform skin

involvement and the potential for involvment
of multiple visceral organs
 Limited, Diffuse, Overlap Syndrome

 CREST: variant of Limited SSc

 Localized Scleroderma
 Each of the several forms of localized scleroderma is a
disorder of skin and sometimes the deeper tissues.

 The most visible effects of the disease are skin lesions

referred to as morphea.

 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
 Age of diagnosis usually 20-40, linear disease <18yrs,
deep morphea mean age 46
 Morphea
 The typical morphea lesion begins as a patch of
erythema or edema that may have an associated
violaceous border (inflammatory stage).

 Primary lesions=hyperpigmented patches.

Become progressively indurated, porcelain
white or yellow hue.

 Upon resolution, atrophy, depigmentation, or

hyperpigmentation may occur.
 Plaque morphea
 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.
 Guttate morphea: This subset usually occurs on
the upper trunk. Typically, it presents as multiple
oval lesions between 2-10 mm in diameter.
 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.
 Lichen sclerosus et atrophicus: shiny, white
plaques often preceded by violaceous discoloration
of the skin; predilection for the anogenital area.
 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.
 Localized scleroderma including deep and
extensive lesions can prevent normal motion
of joints and interfere with daily activities.

 However, localized scleroderma does not

affect internal organs of the body.
 Generalized morphea
 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.
 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
 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.
 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
 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.

 Progressive hemifacial atrophy (Parry-Romberg

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.
 Lesions more diffuse than in linear
scleroderma
 Subcutaneous morphea: panniculus or
subcutaneous tissue. The onset is rapid, occurring
during a period of several months.
 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..
Deep morphea: deep dermis, subcutaneous tissue, fascia, or
superficial muscle

 Disabling pansclerotic morphea of childhood :

aggressive and mutilating generalized, full-
thickness involvement of the trunk, extremities,
face, and scalp.
 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.
 The diagnosis of morphea is based on clinical
findings, although histopathologic confirmation
is often needed to exclude other disorders

 Eosinophilia can be seen in generalized and

linear scleroderma and often correlates with
extent of disease.

 Polyclonal hypergammaglobulinemia can occur

in 50% of patients with linear scleroderma
 Autoantibodies?
 Most titers correlate with the burden of skin
disease
 antinuclear antibodies (46%-80%)
 anti–single-stranded DNA antibodies (50%)

 antihistone antibodies (47%).

 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.
 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.
 Morphea rarely coexists with other systemic
autoimmune disorders, including dermatomyositis,
polymyositis, systemic lupus erythematosus, primary
biliary cirrhosis, rheumatoid arthritis, and MCTD

 Lesions typically regress spontaneously over 3 to 5

years, usually with residual pigmentary and atrophic
changes.

 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
 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
 Systemic Sclerosis
 Limited systemic sclerosis: skin involvement is
limited to forearms, hands, legs, feet, and face.
 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
 Diffuse or limited SSc with one or more features of another
CTD
 MCTD: features of SLE, SSc, PM, RA and presence of
anti- U1 RNP
 SSc
 Pathologic remodeling of connective tissues

 Cardinal features: excessive collagen production and

deposition, vascular damage, and
inflammation/autoimmunity.

 Widespread small-vessel vasculopathy and fibrosis

in the setting of immune system activation

 Vascular injury affects small arteries, arterioles,

capillaries
 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
 Stimulates cell growth, apoptosis, and differentiation

 Promotes collagen and matrix protein production

 Decreases the synthesis of collagen-degrading

metalloproteinases

 Stimulates fibroblasts to maintain an activated state.

 Stimulates CTGF synthesis in fibroblasts, vascular smooth

muscles,and endothelial cells.
 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
 Genetics likely predisposes patients to the disease,
but whether scleroderma is the result of some
combination of genetic factors and other exposures is
unknown.

 Some data suggests that exposure to industrial

solvents or an environmental agent may play a role in
predisposing to scleroderma.

 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.

 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.

 75% percent are women usually diagnosed between

the ages of 30 and 50 years.

 Twins and family members of patients with

scleroderma or other autoimmune CTD appear to be
at a slightly increased risk.

 Children can get scleroderma, although the pattern

and extent of disease may be different in children.
 Who gets scleroderma
 Ethnicity influences severity and survival

 Progressive IPF less frequent and w/ better survival

rates in Caucasians

 Caucasians: inc rate of anti-centromere Ab

 African Americans: inc rate Scl 70

 Inc presence of parvovirus B19 in BM

 Occupational exposure to silica: RR 25, silicosis RR

110
 Clinical Features: Cutaneous
 Thickened skin: abnl production of type 1
collagen by fibroblasts, accumulation of GAG
and fibronectin in ECM. Begins in fingers and
hands

 Calcinosis: deposits of basic CaPhos

 Telangiectasias: dilated sm v.
 More common in LSSc
 Can bleed when in GI mucosa
 SYSTEMIC SCLEROSIS
CREST VARIANT

 CALCINOSIS

 RAYNAUD’S

 ESOPHOGEAL DYSFUNCTION

 SCLERODACTALY

 TELANGECTASIA
 Clinical Features – Raynaud’s
 Almost all (more than 90%) of people with
scleroderma also have Raynaud's
phenomenon.
 Raynauds
 Triphase event affecting the hands and feet, the nose, the ears,
and the tongue

 Characterized by abrupt pallor (white), followed by cyanosis

(blue), and sometimes, painful erythema secondary to
restoration of blood flow.

 The succession of phases is linked to 3 pathogenic mechanisms

—vasoconstriction, ischemia, and reperfusion.

 Small areas of fingertip ischemic necrosis are frequent, often

leaving pitted scars or ulcerations.

 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
 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
 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:
 +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

 NON-PHARMACOLOGIC – LIFESTYLE ASJUSTMENTS

TO PRECIPITANTS: STOP SMOKING, AVOIDANCE OF
b-BLOCKERS, EXERCISE, KEEP WARM

 ORAL VASODILATOR DRUGS: CALCIUM CHANNEL

BLOCKERS, ACE INHIBITORS/ANGIOTENSION
RECEPTOR ANTAGONISTS, TOPICAL
NITROGLYCERINE, PROSTACYCIN (IV) IF AVAILABLE

 DIGITAL SYMPATHECTOMY

 PROMPT TREATMENT OF FINGERTIP ULCERATIONS-

ANTIBIOTICS AND DEBRIDEMENT
 GI- 2nd most commonly affected organ system
 75-90% patients

 Lower Esoph Dysmotility: smooth muscle fibrosis,

esophageal dysfunction in 80% pts- GERD, fibrosis
and stricture formation, aspiration PNA

 Gastroparesis, telangiectases, watermelon stomach

 SI: malabsorption and diarrhea secondary to bacterial

overgrowth, functional ileus from musclar fibrosis w/
hypomotility and dilatation

 Colorectal: severe constipation, megacolon, wide

mouth diverticula
GI MANAFESTATIONS

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© 2005 Elsevier
 Treatment - GI
 Elevation of the head of the bed at night and
appropriate diet plus the use of H2 blockers and/or
proton pump inhibitors.

 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.

 The bleeding telangiectasias and ecstatic superficial

vessels of watermelon stomach can be treated with
sclerotherapy and laser coagulation, respectively.
 In the lower GI tract, symptoms related to
bacterial overgrowth may improve with 2- to
4-week courses of broad-spectrum antibiotics

 Octreotide, given subcutaneously, is

moderately effective as a prokinetic agent for
lower GI symptoms.

 Rarely, TPN will be needed in patients whose

small intestine is essentially nonfunctional.
 SYSTEMIC SCLEROSIS
PULMONARY DISEASE
 INTERSTIAL FIBROSIS
 PULMONARY HYPERTENSION
 ASPIRATION PNEUMONIA
 PLEURAL DISEASE
 NEOPLASM
 Most common initial respiratory sx is DOE,
w/o cough or chest pain
 Pulmonary
 Pulmonary manifestations of SSc occur in
more than 70% of patients.
 Most common SSc-related cause of death.

 Pulmonary fibrosis is a common cause of

severe restrictive lung disease

 CXR shows interstitial thickening in a reticular

pattern of linear, nodular densities most easily
seen in the lower lung fields.
 Pulmonary
 High-resolution CT more sensitive for
detecting interstitial lung disease
 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
 Restrictive lung disease on PFTs used as a marker for
pulmonary fibrosis.

 In a somewhat later disease, the presence of bibasilar rales on

physical examination is found.

 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.

 In Diffuse SSc, ILD more common

 In Limited SSc P HTN more common
 PAH
 Pulmonary hypertension is more common than
previously thought (up to 30% of patients) and can
occur early.

 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.

 There are 3 patterns of PAH:

 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
 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.
 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.
 The pulmonic component of the second heart
sound is accentuated, and ultimately, right-sided
cardiac failure develops.

 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
 Prophylactic influenza and Streptococcus pneumoniae
vaccinations

 In persons with alveolitis, immunosuppressive drugs,

cyclophosphamide and azathioprine, may be effective.

 In intrinsic PAH intermittent and continuous intravenous

prostacyclin analogs; the endothelin-1 antagonist, bosentan; and
the phosphodiesterase type 5 inhibitor, sildenafil have been
approved.

 Anticoagulation is often prescribed.

 Heart-lung or single lung transplantation is an option for end-stage

lung disease
 Renal
 Kidney involvement in SSc may be manifested
by scleroderma renal crisis (SRC).

 Scleroderma renal crisis used to be the most

severe complication in scleroderma and the
most frequent cause of the death in these
patients.
 Renal
 Over the last 20 to 25 years, ACE-I have dramatically
improved SRC outcome.

 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.

 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
 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.
 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
 Microangiopathic hemolytic anemia with
thrombocytopenia frequently occurs

 Non renal crisis abnormalities:

 Mild proteinuria, mild elevation in the plasma creatinine
concentration, and/or hypertension are observed in as many
as 50% of patients.

 Impaired renal reserve may be present in patients in the

absence of clinical renal disease.

 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
 Prompt detection is the most important aspect of therapy for
renal crisis.

 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.

 ACE inhibitors are the drugs of choice, but early aggressive

therapy with other potent antihypertensive agents can also be
successful.

 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.
 Cardiac
 Primary cardiac involvement: myocardial fibrosis,
LV or biventricular CHF, myocarditis, pericarditis
with or without effusion, valvular abnormalities, or
supraventricular or ventricular arrhythmias.

 Acute symptomatic pericarditis is unusual.

 Left sided congestive heart failure secondary to

myocardial fibrosis occurs in fewer than 5% of
dcSSc patients.
 Cardiac
 Cardiac arrhythmias include complete heart block
and other EKG abnormalities.

 Valvular disease usually minor, not

hemodynamically significant.

 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
 Nonsteroidal anti-inflammatory drugs or low-dose
corticosteroids can be used for symptomatic pericarditis.

 If myocarditis is identified clinically or by endomyocardial

biopsy, high-dose glucocorticoid therapy should be tried.

 Digitalis and diuretics are the mainstay of therapy.

 The typical progressive left ventricular failure caused

bymyocardial fibrosis is unaffected by any therapy and may
lead to cardiac transplantation.

 Serious arrhythmias are treated in the standard way

 MSK
 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
 Some patients may have palpable and/or audible deep
periarticular tendon friction rubs during motion; this may be
due to fibrinous tenosynovitis.

 Severe arthritis or destructive joint disease should make one

suspect an overlap syndrome with rheumatoid arthritis.

 2 principal patterns of muscle involvement

 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
 Far less common.
 Weakness is often more profound, with significantly elevated CPK and
EMG/muscle biopsy abnormalities typical for inflammatory myopathy.
 Neuro
 Neurologic involvement occurs in up to 40% of
patients with SSc.

 Manifestations include cranial nerve abnormalities,

peripheral nerve involvement, and autonomic
neuropathy.

 Central nervous system involvement is usually

secondary to SSc renal or cardiopulmonary
involvement.

 Neuropathy can be asymptomatic or can be life-

threatening if autonomic nervous system is involved.
 Disease Modifying Treatments
 While some treatments have proven effective in
treating the disorder, scleroderma is not yet curable.

 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.

 Treatments are disease modifying vs. symptomatic

(by organ system affected) as presented

 DMARDs can be selected on basis of other coexisting

conditions if there is disease overlap
 Suppression of autoimmunity and inflammation
 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.
 MTX
 Chlorambucil
 5-FU
 Stem cell transplant
 Since 1996, autologous peripheral blood stem cell
(PBSC) transplantation used worldwide with a low
early mortality of 5%

 Based on these data, intensive myelo- and immuno

suppression followed by autologous hematopoietic
stem cell transplantation (HSCT) has been used to
treat severe SSC

 Since 1996, approx 1000 PBSC transplants for

autoimmune diseases have been reported
 140 SSc patients in the EBMT (European Group for Blood
and Marrow Transplantation) and EULAR (European
League Against Rheumatism) database as to March 2007.
 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:
analog 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
 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.