Indian Journal of Rheumatology 2010 June

Review Article
Volume 5, Number 2; pp. 69–75

Diagnosis and management of systemic sclerosis

Dinesh Khanna

ABSTRACT

Systemic sclerosis (Scleroderma, SSc) is associated with major mortality and morbidity that arises from the devel-
opment of specific complications of the disease, including organ-based complications. The frequency and diverse
nature of these complications makes systematic assessment and long-term follow-up essential to good manage-
ment of SSc. This review will discuss the natural history of SSc, the predictors of progressive skin and internal organ
involvement and current therapeutic management of these complications.
Keywords: Systemic scleroderma, systemic sclerosis, treatment, rapidly progressing systemic sclerosis, review,
clinical trials, treatment.

INTRODUCTION The majority of cases of rapidly progressive SSc can be

Systemic sclerosis (Scleroderma, SSc) is an autoimmune dis-
ease that affects skin and internal organ system. The major
mortality and much of the morbidity of SSc arises from the
development of specific complications of the disease, includ-
ing organ-based complications such as cardiopulmonary, renal
or gastrointestinal manifestations. The frequency and diverse
nature of these complications makes systematic assessment
and long-term follow-up essential for the good management
of SSc. This review details the natural history of SSc, dis-
cusses the predictors of progressive skin and internal organ
involvement and current therapeutic management of these
complications.
Assessment of skin disease
Skin fibrosis is a hallmark feature of SSc. Depending on
the extent of skin sclerosis, the disease is classified into two
major subsets—limited cutaneous SSc (limited SSc) when
only skin distal to the elbows and knees (with or without
face involvement) is affected and diffuse cutaneous SSc
(diffuse SSc) when the skin thickening includes distal areas
and also spreads proximally (Figure 1). These patients are
also at risk from other complications of SSc.
classified to the diffuse subset as there is almost always
progression to involve proximal limbs or trunk. Neverthe-
less, it is important to consider that almost all cases will at
some point have less extensive skin involvement. For this
reason determining the duration of disease, as defined by the
first non-Raynaud disease sign or symptom (such as joint
pain and swelling, reflux disease, digital ulcer, etc.) is criti-
cal to the assessment of SSc cases. Predictors of rapidly
progressive SSc are detailed in Figure 2. For diffuse SSc, it
includes anti-Scl-70 antibody, anti-RNA polymerase III anti-
body and presence of tendon friction rubs (TFR), a “leathery
crepitus” on palpation of knees, wrists, fingers and ankles
during motion.1,2
Patients with early diffuse SSc tend to have worsening
of their skin thickness over the first 3–5 years after disease
onset. During this phase of skin thickening, patients have a
greater likelihood of developing internal organ involvement
(Table 1). In addition, worsening skin thickness is a predic-
tor of morbidity and mortality. Therefore, current efforts are
directed toward the early diagnosis of internal organ involve-
ment and institute therapies. After 3–5 years of worsening
skin thickening, the skin tends to soften irrespective of the
treatment.3,4 This has been noted both in clinical practice
and randomized controlled trials of diffuse SSc.5 Although
softening of skin is associated with improved survival,6 this

UCLA Scleroderma Program, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Correspondence: Dr. Dinesh Khanna, email: dkhanna@mednet.ucla.edu
70 Indian Journal of Rheumatology 2010 June; Vol. 5, No. 2
Limited Diffuse
Figure 1 Limited and diffuse SSc–skin involvement.
Predictors of diffuse SSc*
Anti-SCL-70 or anti-RNA-polymerase III antibodies, presence of
tendon friction rubs
Renal crisis*
Anti-RNA-polymerase III antibody, presence of tendon friction
rubs, diffuse SSc, rapidly worsening skin thickening, recent
history of prednisone (> 15 mg/day)
Interstitial pulmonary fibrosis*
Anti-SCL-70 antibody, moderate-to-severe fibrosis on HRCT,
FVC percentage ≤ 70% at presentation
Pulmonary hypertension†
Anti-centromere antibody, anti-nucleolar antibody, DLCO
< 55%, FVC/DLCO ratio > 1.4
Myocardial involvement*
Early diffuse SSc
Digital ulcers
Smoking
*Usually occurs during the first 5 years of signs and symptoms
attributed to SSc.
†
Can occur either in early or late disease.
Figure 2 Predictors of rapidly progressive SSc.
relationship between change in skin score and internal organ
involvement is not straightforward. The modified Rodnan
skin score (MRSS), a measure of skin thickness has been
used as the primary outcome measure in most of these tri-
als, as it is feasible, reliable, valid and responsive to change
in multicentre clinical trials7 and is routinely performed in
Khanna
Table 1 Diffuse vs. limited scleroderma—distinguishing features
Diffuse Limited
ILD (severe in 15%) ILD (severe in 15%)
Heart (severe in 10%) Minimal heart
Pulmonary hypertension Pulmonary arterial hypertension
(5–10%) (10–15%)
Kidney (severe in 10–15%) Minimal kidney
Large joint contractures Concurrent Primary biliary
cirrhosis (6–8%)
Worse survival overall
clinical practice at scleroderma centres (Figure 3). It assesses
skin thickness in 17 body surface areas (face, chest and ab-
domen, and right and left fingers, hands, forearms, upper
arms, thighs, lower legs and feet).8 The thickness of each
area was assessed on a 0–3 scale (0 = normal, 1 = mild but
definite thickening, 2 = moderate skin thickening and 3 =
severe skin thickening). The total score (the sum of scores
from all 17 body areas) ranged from 0 to 51; a score of ≥ 20
is associated with poor prognosis.
Treatment of rapidly progressive skin disease
No treatment has been found to be effective for skin involve-
ment in limited SSc although methotrexate (MTX) and other
disease-modifying anti-rheumatic agents can be used for con-
comitant inflammatory polyarthritis. For diffuse SSc, two
randomized controlled trials have shown that oral MTX is
more effective than placebo in patients with active SSc in
improving skin thickness.9,10 Based on these studies, recent
guidelines recommend the use of MTX in the treatment of
skin manifestations in early (defined as first 3–5 years from
first sign or symptom attributed to SSc) diffuse SSc.11 Dose
of MTX is similar to that used in patients with RA and can
be given orally or subcutaneously. If improvement is not seen
within 3–6 months, then consider switching to mycopheno-
late mofetil (2–3 g/day)3 or use low-dose pulse intravenous
CYC. Other drugs (such as imatinib, anti-CD20 therapies)
should be considered investigational at this time.
The next sections discuss the involvement of internal
organs. Figure 4 presents suggested monitoring for internal
organ involvement in patients with SSc that can lead to
timely intervention to tackle organ-based complications.
Renal involvement in SSc
The pattern of kidney manifestations in SSc may be divided
into scleroderma renal crisis (SRC), chronic kidney disease
and inflammatory renal pathology. However, SRC is the
most important renal complication in SSc and occurs in
Diagnosis and management of systemic sclerosis Review Article 71

Subject Initials ________________

Subject Number ________________
DISEASE ASSESSMENTS Date of Exam ________________
(Weeks 0,12, 24, 36 and 56 or early termination)
Modified Rodnan Skin Score
It is essential to have the same examiner for each subject throughout the study
0 = UNINVOLVED THICKENING 1 = MILD THICKENING 2 = MODERATE THICKENING 3 = SEVERE

RIGHT LEFT
FINGERS ___0 ___1 ___2 ___3 ___0 ___1 ___2 ___3
HANDS ___0 ___1 ___2 ___3 ___0 ___1 ___2 ___3
FORE-ARMS ___0 ___1 ___2 ___3 ___0 ___1 ___2 ___3
UPPER-ARMS ___0 ___1 ___2 ___3 ___0 ___1 ___2 ___3
FACE ___0 ___1 ___2 ___3
ANTERIOR CHEST ___0 ___1 ___2 ___3
ABDOMEN ___0 ___1 ___2 ___3
THIGHS ___0 ___1 ___2 ___3 ___0 ___1 ___2 ___3
LEGS ___0 ___1 ___2 ___3 ___0 ___1 ___2 ___3
FEET ___0 ___1 ___2 ___3 ___0 ___1 ___2 ___3

Name of Examiner ____________________

Figure 3 Modified Rodnan skin score.

Systemic sclerosis

• Activity/severity of skin disease – MRSS and tendon friction rubs

• Subset – limited vs. diffuse
Risk stratification
• Autoantibody profile – ACA, ATA, ARA
• Disease duration – < 3 yr vs. ≥ 3 yr

Renal Lung fibrosis PAH/Cardiac GIT

• If anti-RNA polymerase • PFT with DLCO at • EKG and Echo with • Symptom based
III or early diffuse SSC baseline and every doppler every year investigation such as
• BP monitoring three 6 months during first • PFT/DLCO yearly barium swallow with
times a week during 5 years • RHC to confirm small bowel follow
first 3–5 years • HRCT if any new diagnosis of PAH through, gastric emptying
• Prednisone > 15 mg/day respiratory symptoms study, endoscopy and
with caution or reduction in PFT breath test.
• Estimated creatinine • Baseline HRCT if • Upper GI endoscopy and
clearance and vanti-topoisomease-1 manometry if persistent
urinalysis at least positive dyspepsia
every 3 months

• Subset classification important as severe progressive skin disease associates with increased risk of renal crisis
and cardiac involvement
• Disease duration reflects risk of major internal organ disease. Renal crisis in early dcSSc and severe lung fibrosis
more likely in severe SSc of early onset; both less likely after 5 years. Gastrointestinal involvement, cardiac disease
and PAH can occur in early and later disease.

Figure 4 Algorithm for regular screening of severe progressive systemic sclerosis.

72 Indian Journal of Rheumatology 2010 June; Vol. 5, No. 2
10–15% of patients with diffuse SSc and very rarely
(1–2%) in limited SSc.12 Physicians should remember this
equation.
SSc patient + New onset rise in BP + rising serum
creatinine = SCLERODERMA
RENAL CRISIS
The typical features of SRC comprise new onset of signifi-
cant systemic hypertension (> 150/85 mmHg) and decreased
renal function (≥ 30% reduction in calculated glomerular fil-
tration rate). In approximately 10–15% of patients, the diag-
nosis of SRC precedes the diagnosis of SSc; therefore, early
identification of SSc is highly important.12 Risk factors
include early diffuse SSc, presence of anti-RNA polymerase
III antibody, rapidly progressive skin thickening and pres-
ence of tendon friction rubs. A recent history of medium-
dose corticosteroid use (e.g. prednisolone or equivalent at
> 15 mg/day) may precede SRC diagnosis13 and studies sug-
gest that even low doses of corticosteroids may be associ-
ated with SRC.14 Although there is no evidence of a causal
effect, this observation necessitates extreme caution in using
corticosteroids in diffuse SSc.
Treatment
Angiotensin converting enzyme (ACE) inhibitors are corner-
stone for the treatment of SRC.15 They have a favourable
impact on morbidity and mortality.
My approach is to initiate short-acting ACE inhibitors
and continue the dose every 4–6 hours with a goal of achiev-
ing normal blood pressure or maximum dose. If the BP is
still elevated, add calcium channel blocker or furosemide.
Patient may need to be hospitalized. Initiate dialysis, if
needed but increasing serum creatinine is NOT an indication
to stop ACE inhibitors. If a patient goes on dialysis, wait at
least 18 months before contemplating renal transplant since
some patients may come off dialysis.16
Interstitial pulmonary fibrosis
Interstitial lung disease occurs in 70% of patients with SSc,
but only 40% develop moderate-to-severe lung fibrosis.17
Because the greatest decline in lung function occurs in
early disease, PFT with DLCO should be performed at
baseline and every 6 months during first 5 years of disease,
irrespective of limited or diffuse SSc. HRCT of lungs is a
useful tool to characterize fibrosis, as recent studies showed
Khanna
Table 2 Indication for immunosppression in ILD. Modified
from Ref. 20
Limited or diffuse SSc with dyspnea AND 7 years after onset of
signs or symptoms attributable to SSc associated with
A. Decline in their FVC percentage predicted by ≥ 10% in the
preceding 3–12 months and/or
B. FVC percentage predicted of ≤ 70% at time of presentation
and/or
C. Moderate fibrosis on baseline HRCT (defined as > 20%
lung involvement)
a positive association of degree of baseline lung fibrosis
and subsequent decline in FVC percentage predicted and
mortality.18 Bronchoalveolar lavage is not useful in clinical
care for diagnosis of pulmonary fibrosis, but may be impor-
tant to rule out atypical infections in a patient with ground
glass appearance.19
Table 2 lists patients who should be offered immuno-
suppressive therapy for their ILD. It is important to rule out
atypical infections before initiating these therapies.
Treatment
Recent studies have shown that the oral/intravenous cyclo-
phosphamide (CYC) is superior to placebo in stabilizing
FVC percentage.21,22 In addition, CYC was associated with
improvement in dyspnea and quality of life.23 My approach
is to use pulse CYC monthly at 500–750 mg/m2 (assuming
normal renal function) for 6–12 months. Repeat PFTs every
3–4 months while on CYC. On completion of CYC infu-
sions, switch to mycophenolate mofetil 2–3 g/day orally
and plan to continue this drug for several years. If a patient
cannot tolerate mycophenolate mofetil, then consider aza-
thioprine 2–3 mg/kg/day. Oral prednisone has not been shown
to be effective in the treatment of SSc-ILD and has an asso-
ciation with developing SRC. Therefore, oral prednisone
has been avoided for the treatment of SSc-ILD.
Pulmonary arterial hypertension
Pulmonary hypertension (PH), defined as an elevation in the
mean pulmonary artery pressure > 25 mmHg at rest is a
haemodynamic observation and occurs in both limited and
diffuse cutaneous forms of SSc.24 PAH is a subset of PH.
PAH is defined as PH in addition to pulmonary capillary
wedge pressure (PCWP) ≤ 15 mmHg (the absence of elevated
PCWP rules out the presence of left-sided heart disease as a
cause of PH). PAH has a prevalence of approximately
10–15% and it is important to consider other causes of PH
Diagnosis and management of systemic sclerosis
such as left heart disease, diastolic dysfunction and PH in
association with pulmonary interstitial fibrosis. Because
treatment of PH vs. PAH is different, diagnosis should be
based on right heart catheterization, only modality that can
reliably differentiate PAH from PH. The 5-year cumulative
survival of SSc related to PAH is 10%, compared with 80%
in a control population of patients with SSc without PAH.25
Predictors of PAH include declining DLCO% in the setting
normal or near normal FVC percentage (DLCO < 55% or
FVC/DLCO ratio of 1.4:1.6), presence of anti-centromere
antibodies and nucleolar pattern on ANA. Although consid-
ered a late complication, recent data show PAH is associated
with both early and late SSc26 and yearly echocardiogram with
Doppler should be performed. A recent review by the author
details PAH associated with connective tissue diseases.24
Treatment
PAH-specific therapies are available and include endothelin-
1 receptor blockers (bosentan and ambrisentan), phospho-
diesterase (PDE)-5 inhibitor (sildenafil and tadalafil) and
prostacyclin derivatives (epoprostenol, iloprost and trepros-
tinil). Of these, sildenafil, tadalafil and bosentan are avail-
able in India. These therapies are associated with delay
in clinical worsening and improvement in haemodynamics.
In addition, there appears to be survival benefit compared
to historical cohorts.
Cardiac involvement
Cardiac involvement is a major factor determining mortal-
ity in SSc. Myocardial involvement is rare but associated
with early diffuse SSc. Pericardial effusion can occur and is
associated with early diffuse SSc and PAH.
Treatment
In patients with early diffuse SSc and impaired LV function
(ejection fraction < 45%), consider immunosuppressive ther-
apy. In addition, if there are documented tachyarrhythmias or
conduction defects, implantable defibrillator or pacemaker
devices may be considered.
Gastrointestinal manifestations
The gastrointestinal tract is the most commonly involved
internal organ system (approximately 90%) in SSc and
gastro-oesophageal manifestations are the most frequent.27
Despite major morbidity, only a minority of cases have life-
threatening complications. Major involvement of the small in-
testine typically occurs in patients with established SSc. At its
Review Article 73
most severe, small intestinal involvement leads to recurrent
episodes of intestinal pseudo-obstruction due to ileus with
dilated small bowel loops. Small bowel bacterial over-
growth complicating hypomotility results in recurrent diar-
rhoea and bloating, and in more severe cases leads to
malabsorption, weight loss, malnutrition and cachexia. A
detailed review was recently published by this author in the
current journal.28
Treatment
Management of advanced bowel disease includes rotating
antibiotics, stimulation of intestinal motility with prokinetic
agents such as metoclopramide, erythromycin or domperidone
and supplemental alimentation. In the short term, nocturnal
feeding to maintain nutrition and a nasogastric or nasojeju-
nal feeding tube may be effective. Longer term nutritional
supplementation requires percutaneous jejunostomy. When
malnutrition is the major problem, intermittent parenteral
hyperalimentation may be required.29 Treatment with rotat-
ing antibiotics and prokinetics is necessary. In resistant cases,
daily subcutaneous octreotide (50 mg twice to three times a
day) may be helpful.
Digital ulcers and severe Raynaud’s
phenomenon
Digital ulcers (DU) occur in approximately 30% of the pa-
tients with SSc.30 DUs are associated with substantial mor-
bidity that can escalate to gangrene and amputation. A large
minority require hospitalization for their complicated DU.
For severe Raynaud’s phenomenon (cold blue finger)
and digital necrosis, I initiate intravenous iloprost or another
prostacyclin in the hospital setting. PDE-5 inhibitors may
be used in addition to prostacyclin therapy. Consider anti-
platelet therapy and systemic broad-spectrum antibiotic ther-
apy. Always use liberal opioids to provide adequate analgesia.
Surgical debridement may be necessary, but avoid emergent
amputation. Bosentan may be helpful in the prevention of re-
current DUs, especially in patients with high DU burden.31
TARGETED THERAPIES
Tyrosine kinase inhibitors
TGF-β and platelet-derived growth factor (PDGF) are
thought to be key mediators of fibrosis in SSc. Imatinib
mesylate is a tyrosine kinase inhibitor that binds to the c-abl
and blocks its tyrosine kinase activity efficiently.32,33 In
74 Indian Journal of Rheumatology 2010 June; Vol. 5, No. 2
addition, imatinib mesylate interferes with PDGF signalling
by blocking the tyrosine kinase activity of PDGF receptors.
In an in vitro model of bleomycin-induced pulmonary fibro-
sis, imatinib prevented TGF-β induced extracellular matrix
gene expression, transformation and proliferation of fibrob-
lasts.33 An ongoing open-label study is assessing oral daily
imatinib in patients with SSc-ILD. Preliminary data from 15
patients with SSc-ILD was recently reported.34 The inclusion/
exclusion criteria were similar to Scleroderma Lung Study.
Of 15 patients, seven completed the study and eight dropped
out due to side effects. In patients who completed the study,
statistically significant improvements were seen in total lung
capacity and skin score. Side effects such as lower extremity
and generalized oedema, nausea/vomiting and diarrhoea led
to drop out in this trial. The majority of these adverse events
can be managed by lowering the dose of imatinib, giving
divided dose or addition of a diuretic. Other ongoing open-
label studies of imatinib for skin disease in SSc will provide
preliminary data for possible future RCTs and should be
considered investigational at this time.
Anti-CD 20 therapies
B-cell depletion with rituximab (RTX) may also be a suc-
cessful future therapeutic agent. In an open-label study of
14 patients with SSc, eight patients were randomized to re-
ceive two cycles of RTX at baseline and 24 weeks (each cycle
consisted of four weekly infusions at 375 mg/m2—fix this)
of standard treatment, while six control patients received stan-
dard treatment only.35 After one year, the RTX group had sig-
nificant increases in FVC and DLCO compared to controls.
In addition, skin thickening in the RTX group improved sig-
nificantly. Larger scale, multicentre, RCTs are needed to
confirm these possible beneficial effects of RTX in SSc.
CONCLUSION
Although SSc can be fatal, early recognition of internal
organ involvement is critical to achieve better outcomes.
This review provides up-to-date strategies for screening and
managing patients with SSc.
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