OTHER AUTOIMMUNE DISORDERS
Systemic sclerosis: clinical
features and management
Emma C Derrett-Smith
Christopher P Denton
Abstract
Systemic sclerosis (SSc) is an autoimmune rheumatic disease within the
scleroderma spectrum of disorders. It is the prototypic multi-system fibrotic
disease with important complications that also result from vasculopathy
and inflammation. There have been substantial recent advances in under-
standing the pathogenic mechanisms underlying SSc, which has facilitated
more logical treatment approaches. While it remains the rheumatic disease
with the highest case-specific mortality, there have been important ad-
vances in the management of organ-specific complications, with emerging
clinical evidence supporting the use of immunosuppression, and novel
therapeutic approaches for the management of pulmonary arterial hyper-
tension (PAH). Systemic sclerosis should not be considered untreatable,
and patient and physician education about potential treatments is an
important aspect of management. However, therapies must be carefully
matched to disease subset and to the stage of disease.
Keywords Autoantibodies; pulmonary arterial hypertension; pulmonary
fibrosis; renal crisis; scleroderma; systemic sclerosis
The scleroderma spectrum encompasses a diverse range of
disorders that share clinical features, in particular, thickening of
the skin caused by dermal fibrosis and, in many cases, episodic
peripheral vasospasm (Raynauds phenomenon). These shared
features make it likely that common pathogenetic processes un-
derlie the various disorders.1 The spectrum ranges from purely
sclerotic manifestations (localized scleroderma) to purely
vascular features with cold-induced vasospasm (Raynauds); co-
existence of these two processes occupies the central sclero-
derma spectrum. Although the terms scleroderma and systemic
sclerosis (SSc) are often used synonymously, a distinction is
appropriate, with the latter describing a family of heterogeneous
conditions in which fibrosis of the skin and internal organs oc-
curs together with microvasculopathy and inflammation.
Localized scleroderma e adult-onset linear scleroderma and
morphoea are usually considered to be primarily of cosmetic
significance. Phototherapy and topical immunosuppression using
tacrolimus are useful therapies, though some cases warrant
systemic immunosuppression, particularly generalized mor-
phoea, when multiple plaques involve large areas of skin.
Emma C Derrett-Smith PhD MRCP is a Clinical Research Fellow at the
Centre for Rheumatology and Connective Tissue Diseases, UCL Medical
School, London, UK. Competing interests: none declared.
Christopher P Denton PhD FRCP is Professor of Experimental Rheuma-
tology at the Centre for Rheumatology and Connective Tissue Diseases,
UCL Medical School and Consultant Rheumatologist at the Royal Free
Hospital, London, UK. Competing interests: none declared.
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Whats new?
C Modern molecular biology and genetics techniques have
contributed significantly to the understanding of disease
pathogenesis
C Preclinical studies on the involvement of inflammatory cytokine
IL-6, are being translated into clinical trials using IL-6 receptor
inhibition
C Modern management of pulmonary arterial hypertension using
targeted therapies has dramatically improved prognosis
C Stem cell transplantation has emerged as a treatment option for
some patients with early and severe disease
C Several therapeutic options for treatment-resistant digital ul-
cers are now available
Localized scleroderma is also of major consequence in chil-
dren. There is often defective growth of underlying structures
with substantial morbidity and the need for effective pharma-
cological treatment is widely appreciated. At present, a combi-
nation of systemic corticosteroids and methotrexate is the most
frequently used therapy.2
Raynauds phenomenon e almost all patients with SSc
manifest Raynauds phenomenon. It is therefore conventional to
include other forms of isolated Raynauds phenomenon within
the scleroderma spectrum.
Systemic sclerosis e Despite its relative rarity, SSc is an
important clinical condition because of its high case-specific
mortality and pathological similarity to more common organ-
based fibrotic diseases. The two major subsets are designated
limited and diffuse cutaneous SSc, according to the extent of skin
involvement, though both forms are associated with internal
organ involvement. Other forms include overlap syndromes, in
which there are features of other connective tissue disorders,
such as systemic lupus erythematosus, polymyositis or inflam-
matory arthritis, and forms in which there is little or no skin
sclerosis despite other features of SSc (designated systemic
sclerosis sine scleroderma).3
Epidemiology of systemic sclerosis
The relative rarity and clinical heterogeneity of SSc have made
formal epidemiological studies difficult. The estimated preva-
lence from population-based studies is between 1 and 2 per
10,000 population, with a higher estimated prevalence in North
America. An incidence of 1 in 100,000 per year is considered
reasonably accurate.4 There are two peaks of disease onset e the
early 30s and mid50s e and, in common with most other auto-
immune diseases, there is a female predominance. One exception
to this is environmentally induced disease (for instance, due to
organic solvent exposure) which has a number of clinical dif-
ferences from idiopathic SSc.5
Evidence exists to support a genetic predisposition, though
genetic associations relate more to clinical phenotype than sus-
ceptibility to the disease per se. As in other complex diseases,
there are many conflicting reports of gene associations and it is
possible that ethnic or geographical factors confound the
demonstration of unifying genetic associations. The strongest
167 2013 Elsevier Ltd. All rights reserved.
 OTHER AUTOIMMUNE DISORDERS

genetic links are with autoantibody profiles and appear to relate
to class II MHC haplotype (reviewed in Romano et al.6). Many of
the gene products discovered are relevant to disease pathogen-
esis. For instance, studies of a genetically isolated Native
American population with a strikingly high frequency of the
disease show linkage to the fibrillin-1 locus and association of
fibrillin SNP haplotypes; together with similar findings in some
patients with idiopathic SSc, this strengthens the case for the
involvement of this gene in SSc. Familial associations of SSc are
statistically significant, though the absolute risk for any relative
of a patient remains less than 1%.7,8
Pathogenesis of systemic sclerosis
The pathogenesis of SSc involves the immune system, fibro-
blasts, the vasculature and epithelial structures in specialized
organs. All forms of SSc seem to involve these processes,
though their relative contribution can vary depending on dis-
ease subset and antibody profile. Fibrosis represents a common
pathological process and SSc is often regarded as a prototypic
fibrotic disease. The aetiology of SSc is multifactorial: whereas
genetics do have a role, environmental factors are also required
and the correct genetic/environmental combination occurs
infrequently.
Subsets of systemic sclerosis
Limited cutaneous systemic sclerosis (lcSSc)
Skin involvement is limited to areas distal to the knees and elbows,
and often just to the wrists and ankles. Additional changes in the
face and neck are usually present. There is typically a long ante-
cedent history of Raynauds phenomenon, often severe and asso-
ciated with recurrent digital ulceration and infarction. Other
manifestations include oesophageal dysmotility and gastro-
oesophageal reflux, and the hallmark features of cutaneous telan-
giectasia, generally seen on the palms and around the mouth, and
subcutaneous calcinosis. The term lcSSc is preferred to CREST
syndrome as it does not ignore the important internal organ mani-
festations of mid-gut disease (small bowel bacterial overgrowth),
pulmonary fibrosis and pulmonary arterial hypertension (PAH).

a b d

Figure 1 Clinical features of limited cutaneous systemic sclerosis (lcSSc) and diffuse cutaneous systemic sclerosis (dcSSc). (a) Typical facial features of lcSSc:
there is microstomia and accompanying radial furrowing with facial telangiectasia. (b) Typical features of established lcSSc. There are skin colour changes in
the digits due to vasospasm, alterations in pigmentation particularly over the metacarpo-phalangeal joints (MCPs), nail dystrophy, sclerodactyly and areas of
calcinosis (arrow). Pitting of the finger pulps has occurred at areas of previous ulceration. There is prominent palmar telangiectasia. (c) Skin thickening in
dcSSc extends proximally to the elbows and knees. (d) Typical features of dcSSc. Note the generalized skin tightening, inflammation, altered hair growth and
skin dryness in early dcSSc. Skin thickening and tendinopathy contribute to the development of fixed flexion deformities.

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 OTHER AUTOIMMUNE DISORDERS
Anticentromere antibodies are the hallmark antibodies in this
condition, although other antibodies may also be present.
Diffuse cutaneous systemic sclerosis (dcSSc)
The formal classification of dcSSc is determined by the presence of
skin sclerosis proximal to the knees and elbows, and usually
affecting the trunk; in practice, it has a number of characteristics
that distinguish it from lcSSc. The classical presentation is an
abrupt onset of inflammatory change in the skin and other struc-
tures. Pain and swelling of the extremities often occur and
expansion of tissues around the wrist often results in bilateral
carpal tunnel syndrome. Tendon friction rubs can be felt across
joints. Affected skin is often intensely pruritic and there is loss of
specialized skin structures, leading to changes in perspiration and
hair growth. Raynauds phenomenon develops simultaneously
with other features or once the disease is established. Oesophageal
involvement is almost universal and severe internal organ com-
plications tend to occur earlier in the course of disease compared
with lcSSc. Lung fibrosis or hypertensive renal crises are relatively
frequent, and some specific antibodies can be predictive of these.
PAH, myocardial involvement and lower gastrointestinal tract
involvement can each contribute to significant morbidity and
mortality. Hallmark reactivities are Scl-70, antifibrillarin, and anti-
RNA polymerases I and III; the anti-RNA polymerases are associ-
ated with the development of hypertensive scleroderma renal
crisis (SRC). Anti-Pm-Scl and anti-nRNP can be seen, particularly
in overlap with other connective tissue diseases. The natural
history of this condition is heterogeneous and skin sclerosis can
remit after several years, despite progression of internal organ
disease.
Hallmark autoantibodies in systemic sclerosis
Antigen Frequency
Centromere 60% lcSSc
25% primary biliary
cirrhosis
Topoisomerase 1 (Scl-70) 35% dcSSc
10e15% lcSSc
RNA polymerases I and III 20% dcSSc
Fibrillarin (U3-RNP) 5%
PM-Scl 3%
U1 RNP (nRNP) 10% SSc
5% dcSSc
14% lcSSc
dcSSc; diffuse cutaneous systemic sclerosis; lcSSc, limited cutaneous systemic sclerosis.
Table 1
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Typical features of lcSSc and dcSSc are shown in Figure 1.
Systemic sclerosis sine scleroderma
Some patients demonstrate typical vascular and serological fea-
tures of SSc together with visceral complications, such as lung
fibrosis, hypertensive renal crisis or severe bowel involvement,
but without any evidence of skin fibrosis. This clinical profile is
termed SSc sine scleroderma and probably accounts for less than
1% of cases, although it may well be under-diagnosed.
Diagnosis of systemic sclerosis
The preliminary classification criteria of the American College for
Rheumatology are directed towards identifying diffuse cutaneous
disease; it is widely appreciated that they are inadequate for the
diagnosis of, and exclude many patients with, lcSSc and even
those at the early stages of dcSSc.9 Up to 15% of cases of isolated
Raynauds phenomenon are associated with altered nailfold
capillaroscopy or positive antinuclear antibody (ANA) and/or
scleroderma hallmark antinuclear reactivity and may progress to
a defined connective tissue disease. These observations have led
to initiatives to develop more inclusive standards for the diag-
nosis of lcSSc and early dcSSc. These include the very early
diagnosis of scleroderma (VEDOSS) study,10 set up to identify,
investigate and treat early disease, and the EULAR ACR classifi-
cation criteria committee, whose purpose is to recommend
classification criteria for inclusion in research trials, with the
prerequisites that all currently diagnosed SSc patients will be
included, an acknowledgement to subset classification will be
made, early as well as late diagnoses can be made, and that these
criteria should be feasible in clinical practice.11
Immunofluorescence pattern Clinical association
Centromere Typical of lcSSc subset. These patients are at
risk of isolated pulmonary hypertension and
severe gut disease, but relatively protected
from lung fibrosis and renal crisis.
Nuclear (diffuse fine speckles) Although typical of diffuse skin involvement,
occurs in both subsets of SSc and is strongly
associated with lung fibrosis.
Nucleolar (punctate) Associated with diffuse skin involvement and
especially with renal involvement. Can occur in
limited subset.
Nucleolar (clumpy) staining Occurs in both major subsets. Associated with
coilin bodies poor outcome in dcSSc with cardiac disease,
pulmonary hypertension, renal involvement
and myositis.
Nucleolar (homogeneous) High frequency of myositis. In childhood may
associate with milder disease but renal
involvement increased in adult SSc.
Speckled antinuclear Higher frequency in Afro-Caribbean patients
with SSc. Associated with joint involvement
and lung fibrosis in SSc.
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 OTHER AUTOIMMUNE DISORDERS
Investigation of systemic sclerosis
Once the diagnosis is made, the stage, subset and pattern of organ
involvement need to be defined. It is important to identify overlap
syndromes, as these may impact on treatment approaches. In
addition to routine baseline investigations applicable to all the
autoimmune rheumatic diseases, there are specific tests that
should routinely be performed in SSc. Autoantibody testing often
reveals one of the hallmark reactivities of SSc and these are
summarized in Table 1. These are generally mutually exclusive
and useful in determining disease classification and risk stratifi-
cation, since certain internal organ complications appear to occur
with increased frequency with different serological reactivities.
Routine assessment of all of the organ systems likely to be
affected should be part of a thorough baseline description of SSc
cases. Recent studies have demonstrated that regular monitoring
and early detection and intervention have significantly improved
survival, particularly in diffuse disease.12 A recommended
schedule for SSc investigations is shown in Table 2.
Treatment of systemic sclerosis
In lcSSc, the main focus is on therapy for vascular complications
together with vigilant screening for important visceral disease.
DcSSc warrants a more comprehensive approach and the major
focus is presently on immunosuppression for active early stage
dcSSc. A practical approach to the management of SSc is shown
in Figure 2. In addition to pharmacological therapy, appropriate
advice and education, referral for physical therapy, podiatry and
occupational therapy form an important part of the management
of patients with SSc.
Pharmacological therapy in systemic sclerosis depends upon
disease subset, organ-based complications and overlap features
such as inflammatory arthritis or myositis. In general, treatments
can be divided into immunomodulatory, vascular and anti-
fibrotic strategies. Immunosuppressive therapies are reserved
for use in early diffuse disease and in pulmonary fibrosis, or
when there is overlap with inflammatory or vasculitic diseases.
There have been tangible advances in the management of
organ-based complications in SSc in particular. Two independent
studies have suggested that cyclophosphamide is superior to
placebo for the management of SSc-associated pulmonary
fibrosis,13,14 though it should be noted that the treatment effect
was extremely modest in both studies. The toxicity of cyclophos-
phamide should be considered in making decisions about its use in
scleroderma lung fibrosis or early diffuse disease, and there is
considerable interest in other agents, such as mycophenolate
mofetil and rituximab, which may be less toxic. Azathioprine is an
alternative or maintenance therapy still in current use for SSc lung
fibrosis. Methotrexate is of benefit when there is overlap myositis
or arthritis, and low-dose corticosteroid is used in combination
with other immunosuppressants in some contexts. Hydroxy-
chloroquine can be a useful therapy for skin and joint symptoms
that do not warrant stronger immunosuppression.
For the treatment of early diffuse disease, results from the
Autologous Stem Cell Transplantation International Scleroderma
(ASTIS) trial15 have recently been reported, which showed that
there were benefits to this treatment approach in some patients
when compared to standard treatment with cyclophosphamide.
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Investigation of patient with systemic sclerosis
General
Haematology
Anaemia
C Of chronic disease
C From gastrointestinal blood loss including gastric antral
vascular ectasia
C Effects of renal impairment
C Microangiopathic haemolytic anaemia in scleroderma renal
crisis
Serum biochemistry
C Creatine kinase high in myositis, myocarditis
C Renal impairment
C Raised troponin may indicate cardiac involvement
C N-terminal B-type natriuretic peptide elevated in left and right
ventricular dysfunction and pulmonary hypertension
C Indicators of malnutrition
Acute-phase markers
C Elevated erythrocyte sedimentation rate associates with poor
outcome, although acute-phase markers may be normal
Autoimmune serology
C Hallmark systemic sclerosis antibody status and evidence for
serological overlap with other autoimmune rheumatic diseases
Nailfold capillaroscopy
Organ-based
Renal
C Regular blood pressure checks, blood and urine monitoring
C Glomerular filtration rate estimation at baseline and annually
C Patient education paramount e home blood pressure moni-
toring desirable in diffuse cutaneous systemic sclerosis
Cardiac
C ECG/echocardiography scan annually. Estimate of right ventric-
ular systolic pressure useful (35 mmHg threshold)
C Pulmonary function tests (PFTs) important to identify pulmonary
hypertension (pulmonary diffusion capacity; DLco 55%
threshold)
C Exercise testing may help define borderline pulmonary hyper-
tension and provides prognostic information in established
pulmonary hypertension
C Cardiac MRI is investigation of choice for myocardial
involvement
C Right heart catheter if clinical features suggest PAH and echo/
PFT outside thresholds
Respiratory
C Chest X-ray at baseline e largely to exclude intercurrent
pathology
C PFTs every year e if abnormal e high-resolution CT scan,
consider DTPA, bronchoalveolar lavage or biopsy if clinically
indicated
Repeat non-invasive tests 3e6 monthly if borderline
Gut
C Barium swallow documents oesophageal involvement
C Other tests according to symptoms including hydrogen breath
test, gastroscopy, small or large bowel barium or Gastrografin
studies
Table 2
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 OTHER AUTOIMMUNE DISORDERS

A practical approach to the management of a patient with systemic sclerosis

Early and accurate diagnosis into subset, staging and assessment of organ-based disease

LcSSc DcSSc Overlap

Vascular therapy: Vascular Vascular

Angiotensin II receptor Proton pump inhibitor Proton pump inhibitor
inhibitors Immunosuppression: Manage features
Clopidogrel Cyclophosphamide of overlap
Fluoxetine Mycophenolate mofetil connective tissue
IV prostacyclin Methotrexate disease: arthritis,
Bosentan Hydroxychloroquine myositis, vasculitis
Sildenafil Low-dose corticosteroid
(stem cell transplant)
Proton pump inhibitor
In appropriate clinical
setting

Ongoing surveillance and early specific management of organ-based complications

Figure 2

Consensus recommendations for the treatment of pulmonary arterial

hypertension associated with systemic sclerosis

Symptomatic SSc-PAH

Supportive therapies: warfarin, digoxin, diuretics, oxygen,

exercise and diet advice, other lifestyle advice

1st: Bosentan
2nd: Sildenafil
Prostanoids

Serial monitoring

Symptoms WHO III or IV

Progression of breathlessness
6 minute walk test not improved
Refractory heart failure
Syncope

Combination therapy Refer for transplantation Balloon atrial septostomy

Adapted from Consensus statement on the management of pulmonary hypertension in clinical practice in
the UK and Ireland. National Pulmonary Hypertension Centres of the UK and Ireland.
Heart 2008;94(Suppl 1):i1-i41

Figure 3

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 OTHER AUTOIMMUNE DISORDERS

Preclinical investigation into the role of IL-6 activation in dcSSc
suggests a promising role for tocilizumab.
Vascular therapies are used in all disease contexts as Raynauds
phenomenon is ubiquitous. Angiotensin II blockers are first-line
therapy, with other vasodilators such as calcium channel
blockers, anti-platelet agents and selective serotonin reuptake in-
hibitors (SSRIs) useful in some patients. Intravenous prostacyclin
therapy, such as iloprost, is reserved for severe disease, including
digital ulceration and infarction. Bosentan, an endothelin receptor
antagonist, can prevent the development of new ischaemic digital
ulcers in SSc.16 Sildenafil and other phosphodiesterase 5 (PDE5)
inhibitors can be useful for refractory digital ulcers. Digital sym-
pathectomy (radical microarteriolysis) is considered preferable to
other surgical interventions, such as lumbar or cervical sympa-
thectomy. Another major area of advance is in the management of
PAH. Drawing from experience of PAH in other contexts there are
now several effective, licensed therapies for advanced PAH and
more are in development. These include prostacyclin analogues,17
endothelin receptor antagonists18,19 and PDE5 inhibitors.20 An
algorithm based on consensus recommendations about investi-
gation and treatment for PAH-SSc in the UK and Ireland is sum-
marized in Figure 3.21 Renal pathology in SSc shows several key
similarities to that of PAH. It is now well established that aggres-
sive treatment of hypertensive SRC can substantially reduce the
early mortality of this complication. Early diagnosis and treatment
remain essential as there is no firm evidence that drugs that are
effective in managing SRC also prevent it occurring. An algorithm
summarizing treatment approaches to established SRC is illus-
trated in Figure 4.22
Anti-fibrotic therapy is at present inadequate. An ideal agent
would probably be a non-peptide antagonist for one or more of
the activators of fibroblasts in SSc. Such approaches are some
way from being realized at present; early safety trials using an-
tibodies against the major profibrotic cytokine-transforming
growth factor-b have not been extended.23 Clinical trials of
imatinib mesylate, for which there were good preclinical and
early clinical data suggesting beneficial anti-fibrotic functions,
were disappointing due to drug toxicity. Endothelin antagonists
have not shown efficacy as anti-fibrotic agents in clinical trials.
Other inhibitors of matrix gene expression, such as halofuginone,
have also shown some promise experimentally.
Proton pump inhibitors generally relieve the symptoms of
reflux oesophagitis that are almost universal in SSc. Delayed
gastric emptying can be overcome by the use of dopamine re-
ceptor antagonists, such as metoclopramide or domperidone.
Broad-spectrum antibiotics can often reduce symptoms of small
intestinal bacterial overgrowth, such as diarrhoea, post-prandial
bloating and malabsorption.

Contemporary management of scleroderma renal crisis

Systemic sclerosis: diagnosis, stage and subset

Patient education, BP
Blood pressure elevated
monitoring, avoid
precipitants (high-dose
corticosteroid)
ACE inhibitors or
Follow up: renal function angiotensin II blockers
may improve for up to
24 months after renal Close observation, check
crisis for microangiopathic
haemolytic anaemia
Dialysis is initially
required in 50% but this Hospital admission:
is often not permanent Renal impairment ACE-inhibitors,
angiotensin II blockers,
Antihypertensive other oral
requirements often fall antihypertensive to
Other aspects of disease reduce BP slowly,
may improve prostacyclin analogues,
Occult cardiac disease renal biopsy, renal
may manifest support
Post-transplant
surveillance

Renal failure

Recovery Long-term renal replacement Transplant

ACE inhibitors remain the most important therapeutic intervention

Figure 4

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 OTHER AUTOIMMUNE DISORDERS
Conclusions
Systemic sclerosis is a multifaceted disease with a complex
pathogenesis. It offers a paradigm for immunologically triggered
fibrosis, which underlies many major medical problems, but the
complex nature of the underlying pathology, clinical heteroge-
neity and absence of clearly identifiable biomarkers have
hampered the development of effective therapies. In contrast, it
represents something of a success story with the improved
treatments of organ-based disease. Management of life-
threatening complications should be proactive, with screening
of at-risk patients and commencement of therapy at the earliest
opportunity. ACE inhibitors have substantially improved sur-
vival from hypertensive SRC, cyclophosphamide is effective in
scleroderma-associated fibrosing alveolitis, and advanced thera-
pies are showing benefit in patients with pulmonary hyperten-
sion. Effective acid-suppressive regimens, notably proton pump
inhibitors, have revolutionized the management of scleroderma-
associated oesophagitis. These interventions have contributed to
the significant improvement in mortality seen in survival studies
over the past 25 years but may also lead to changes in patterns of
disease and complications. For example, survival from pulmo-
nary hypertension may lead to more long-term complications
with severe gut disease. Systemic sclerosis should not be
considered untreatable, and patient and physician education
about potential treatments remains an important aspect of
management. A 17 Badesch DB, Tapson VF, McGoon MD, et al. Continuous intravenous
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22 Penn H, Howie AJ, Kingdon EJ, et al. Scleroderma renal crisis: patient
characteristics and long-term outcomes. QJM 2007; 100: 485e94.
23 Denton CP, Merkel PA, Furst DE, et al. on behalf of The Cat-192 Study
Group, the Scleroderma Clinical Trials Consortium. Recombinant
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Practice points
C Scleroderma should not be considered untreatable
C Appropriate diagnosis and staging of disease are prerequisites
to effective therapy
C Monitoring organ function for an early and accurate diagnosis
of organ-based complications with appropriate specialist
intervention improves prognosis
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