10 Chapter 63 :: Systemic Sclerosis
:: Pia Moinzadeh, Christopher P. Denton,
Carol M. Black, & Thomas Krieg
AT-A-GLANCE
■ Scleroderma (systemic sclerosis [SSc]) is a
multisystemic autoimmune disease characterized
by vasculopathy, inflammation, and fibrosis of the
Part 10
skin and many other organs.
■ Differential diagnosis of SSc includes severe forms
of localized scleroderma, as well as many other
::
scleroderma-like conditions.
Autoimmune Connective Tissue and Rheumatologic Disorders
■ Raynaud phenomenon, circulating autoantibodies,
and skin sclerosis are almost always present and
are important for the early diagnosis.
■ Patients with SSc are classified into 2 major subtypes
depending on the extent of skin sclerosis (diffuse
cutaneous systemic sclerosis and limited cutaneous
systemic sclerosis).
■ Patients with an overlap syndrome, including
mixed connective tissue disease, are characterized
by additional clinical features of other rheumatic
diseases.
■ Involvement of internal organs (digestive tract, lung,
kidney, and heart) can lead to severe dysfunction
and determines the prognosis.
■ The heterogeneity and clinical course of SSc and
SSc overlap syndromes require the urgent need
of interdisciplinary collaborations and regular
followup visits.
■ Although the disease is still not curable, there
have been substantial advances in developing new
therapeutic approaches and treating organ-based
complications based on a better understanding of
the pathophysiology.
DEFINITIONS
Scleroderma (systemic sclerosis [SSc]) is a multisystem
disease, characterized by autoimmunologic processes,
vascular endothelial cell injury, inflammation, and
an extensive activation of fibroblasts. There is a large
individual variability in the extent of skin and organ
involvement, as well as in disease progression and
prognosis. Skin, esophagus, lung, heart, and kidneys
are the most frequently affected organs.
EPIDEMIOLOGY
Women are more frequently affected by SSc, with a
female-to-male ratio between 3:1 and 14:1.1-4 The age
of disease onset ranges between 30 and 50 years.1
Kang_CH063_p1086-1105.indd 1086
However, male patients have earlier onset than female
patients. Blacks with SSc are frequently younger than
whites.
SSc is a rare disease; however, incidence rates
increased from 0.6 to 16 patients per million inhabit-
ants and prevalence rates rose from 2 to 233 patients
per million inhabitants per year,2-5 depending on
methodologic differences in case definition and ascer-
tainment as well as the investigated time period. It can
be assumed that these numbers represent an under-
estimation as patients with mild disease remain often
undiagnosed.
SSc has the highest case-specific mortality of any
of the autoimmune rheumatic diseases, but it var-
ies individually, depending on racial or ethnic differ-
ences, presence and severity of organ involvement,
SSc subsets, age at diagnosis, and gender differences.
Although not curable, there have been substantial
advances in treatment options for organ-based compli-
cations of SSc.
CLINICAL FEATURES OF
SYSTEMIC SCLEROSIS
SSc usually starts with a Raynaud phenomenon, which
can precede the disease for many years. The clinical
manifestations depend to a large extent on the subset
and stage of disease. The clinical features of established
SSc are diverse with severe fibrosis of the skin and all
additional cutaneous manifestations. These include
hardening of the skin, development of contractures,
digital ulcerations and calcifications. They also reflect
the multiple patterns of internal organ involvement
and the consequences of progression of the underly-
ing pathologic processes of vasculopathy, inflamma-
tion, and fibrosis. Particular consideration must be
given to the hallmark complications of hypertensive
scleroderma renal crisis (SRC), pulmonary arterial
hypertension (PAH), pulmonary fibrosis (PF), and GI
dysmotility.
CLASSIFICATION AND
DEFINITION OF DIFFERENT
SSc SUBSETS
The heterogeneity of SSc arises from the range of dis-
ease manifestations that vary in extent and severity of
organ involvement between patients. However, some
03/12/18 9:17 am
 clinical features that are almost always present are
Raynaud phenomenon (RP) and skin sclerosis. The
extent of skin sclerosis defines each major disease sub-
set, each of which has particular clinical characteristics,
although there are also common features to each.
In 1980, the American College of Rheumatology
(ACR) published preliminary classification criteria for
SSc for patients with established disease,6 which cri-
teria showed 97% sensitivity and 98% specificity for
SSc. According to the criteria, the diagnosis is proven,
if either 1 major criterion or at least 2 minor criteria are
found. The major criterion are scleroderma proximal
to the metacarpophalangeal or metatarsophalangeal
joints; the minor criteria include sclerodactyly, digital
ulcerations and/or pitting digital scars, and bibasilar
PF. Although these criteria have been used for many
years they do not allow the inclusion of patients with
early SSc and some patients with limited cutaneous
systemic sclerosis. As a result, new ACR/European
League Against Rheumatism criteria were developed,
which are based on a score system and consider sev-
eral additional criteria such as abnormal nailfold cap-
illaries, fingertip lesions, and autoantibodies. These
new criteria now allow early diagnosis of patients and
include those patients in clinical trials before extensive
fibrosis develops.7
In 1988, a descriptive subclassification of limited
versus diffuse SSc was introduced by LeRoy,8 which
was primarily associated with the extent of cutane-
ous involvement. This classification has been widely
accepted and used in clinical practice. In 2001, LeRoy
and Medsger9 published amended criteria, with
the additional presence of autoantibodies and nail-
fold capillaroscopic alterations. Furthermore, these
criteria include a separate group of patients with
early onset of SSc, with minimal skin thickening.
It was mandatory that patients with early (limited)
SSc have evidence of RP plus scleroderma-specific
autoantibodies and/or nailfold capillaroscopic
manifestations.10,11 Although there are several other
classifications published, for example, by Nadash-
kevich and colleagues and by Maricq and Valter,10,12
the initial LeRoy classification is still widely used in
daily clinical practice.
Diffuse cutaneous SSc is defined as a progressive
form of SSc with an early onset of RP, usually within
1 year of onset of skin thickening. This subset is
characterized by rapid skin involvement of trunk,
face, upper arms, and thighs, showing very fre-
quently, anti–scleroderma 70 (antitopoisomerase-I)
or anti-RNA polymerase III antibodies.8 Further-
more, there is a higher propensity to develop PF,
cardiac involvement, and SRC (Fig. 63-1).
Limited cutaneous SSc is characterized by a long
preexisting history of RP and skin changes of the
extremities distal to the knee and elbow joints, includ-
ing facial skin.8 This SSc-subset variant often (50% to
70% of cases) presents with anticentromere antibodies
and is frequently associated with isolated PAH. The
traditional acronym CREST (calcinosis, RP, esopha-
geal dysmotility, sclerodactyly, and telangiectasias) is
assigned to the limited form of SSc (Fig. 63-2).
Kang_CH063_p1086-1105.indd 1087
Patients suffering from early SSc, also known as
undifferentiated SSc, are defined by positive RP and
10
at least 1 additional feature of SSc (positive nailfold
capillary alterations, puffy fingers, pulmonary hyper-
tension) and/or detectable scleroderma-associated
autoantibodies without fulfilling the ACR criteria.1,13,14
A very small proportion of cases (1.5%) develop
vascular (RP and/or PAH), immunologic (most com-
monly anticentromere antibodies), and organ-based
fibrotic features of SSc, but do not show skin sclerosis.15
Patients suffering from this subset are classified as SSc
sine scleroderma.
Patients with features of scleroderma together
with those of another autoimmune rheumatic disease
Chapter 63 :: Systemic Sclerosis
are designated SSc overlap syndrome (Fig. 63-3 and
Table 63-1). SSc overlap syndrome is defined as a dis-
ease occurring with clinical aspects of SSc (according to
the ACR criteria) or main symptoms of SSc simultane-
ously with those of other connective tissue diseases or
other autoimmune diseases, such as dermatomyositis,
Sjögren syndrome, systemic lupus erythematosus, vas-
culitis, and polyarthritis. These patients present mostly
high titers of anti-U1RNP, anti-nRNP, antifibrillarin, or
anti-PmScl antibodies.16
This group of patients includes well-defined
patients suffering from mixed connective tissue dis-
ease (MCTD), characterized by high titers of circulat-
ing anti-U1RNP antibodies (Table 63-2). There is still
an ongoing discussion, whether MCTD represents
a distinct disease entity or may be an early form of
another connective tissue disease. These MCTD
patients have varying clinical features with symp-
toms of systemic lupus erythematosus or rheumatoid
arthritis with Raynaud syndrome, and later develop-
ing sclerodermatous lesions. They have swollen fin-
gers and puffy hands. Non-Raynaud symptoms are
skin sclerosis at acral regions and internal manifesta-
tions that occur later. There are often intense inflam-
matory symptoms with heavy arthralgia. MCTD
patients can develop pericarditis, pleuritis, and
pulmonary hypertension. However, there is a good
response to antiinflammatory/anti-immune therapy
and the prognosis is clearly better than in patients
with classic scleroderma.17,18
Another already well-defined subset within the
overlap syndromes are patients with scleroderma-
tous lesions, who also suffer from an intense myositis.
These patients are usually characterized by specific
Pm-Scl autoantibodies, have typical mechanic hands,
and develop early intense subcutaneous calcifications.
Similar to MCTD patients, they respond well to an
early antiinflammatory treatment (eg, methotrexate/
glucocorticosteroids).19
Other overlap syndromes include patients with
Raynaud and lupus erythematosus or rheumatoid
arthritis symptoms, who later develop scleroderma-
tous lesions. Many of these patients have specific circu-
lating autoantibodies that probably represent distinct
disease entities. However further studies using molec-
ular markers are still required to clarify their disease
identity within the spectrum of scleroderma-related 1087
diseases.19
03/12/18 9:17 am
10

A
Part 10
::
Autoimmune Connective Tissue and Rheumatologic Disorders

Figure 63-1 Extensive skin involvement in patients with

diffuse cutaneous systemic sclerosis. A, Sclerodactyly
with dermatogenous contractures (restricted mobility of
digital joints) and salt-and-pepper hyperpigmentations
and hypopigmentations. B, Microstomia (radial furrow-
ing around the mouth) with frenulum sclerosis. C, Skin
thickening proximal of the metacarpophalangeal joints.
D, Typical scleroderma facial physiognomy with hyper-
C mimia, microstomia, telangiectasias, and a beaked nose.

A B

Figure 63-2 Clinical feature of patients with early disease. A, Raynaud phenomenon with typical discoloration (blue-white
1088 pallor), localized mostly at fingers and/or toes as the result of vasospasm. Coldness and emotional stress are the most
frequent triggers for these attacks. B, Limited disease with puffy fingers.

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 Clinical spectrum of systemic sclerosis overlap syndromes
10
SSc overlap syndromes

Mixed connective SSc/polymyositis

tissue disease syndrome
(U1snRNP+) (PmScl+)

SSc/myositis SSc/dermatomyositis
overlap overlap
syndrome (Ku+) syndrome

Chapter 63 :: Systemic Sclerosis

SSc/SLE SSc/rheumatoid
overlap arthritis overlap
syndrome syndrome

Figure 63-3 Clinical spectrum of systemic sclerosis (SSc) overlap syndromes. Patients with clinical features of scleroderma
together with features of at least 1 additional autoimmune rheumatic disease are designated SSc overlap syndromes. SLE,
systemic lupus erythematosus.

In addition, the frequency and timing of different autoantibody reactivity has been well described, lead-
visceral manifestations of SSc differs between major ing to the suggestion that the serologic subsets may be
subsets. However, there is some overlap between sub- more genetically homogeneous than unselected SSc
sets in terms of organ-based disease and the extent and cases or clinically defined subsets of SSc. Large-scale
severity of skin sclerosis. studies in multinational patient cohorts using molecu-
In all patients, the extent and severity of skin sclero- lar and clinical markers are probably required to revise
sis can be assessed by the modified Rodnan skin score. the current classification system of this heterogeneous
Skin score at baseline correlates with disease severity spectrum of diseases.
and outcome in diffuse cutaneous SSc. Thickening
and fibrosis of the skin as one of the first recognized
phenomenon in SSc still forms the basis of most clas-
sification criteria and proposed subsets of this disease
spectrum.
ORGAN MANIFESTATION
It also has to be mentioned that another classifica-
tion of SSc-related diseases, which is completely based RAYNAUD PHENOMENON
on autoantibodies, has been proposed. There is evi-
Distinctive for this disease is the initial onset of RP,
dence from association studies that this may be clini-
which appears in more than 90% of SSc patients (see
cally meaningful, as indicated in Table 63-3. Moreover,
Fig. 63-2).1 It is defined by recurrent attacks of vaso-
genetic association analysis using a candidate gene
spasm of small digital arterioles/arteries at fingers
approach has demonstrated an association between
and toes, usually caused by cold and/or other stimuli,
serologically based subsets of SSc that are stronger
for example, emotional stress. RP clinically appears
than with SSc overall. The significance of this is uncer-
tain, and it should be noted that a genetic basis for

TABLE 63-2
Clinical Features of Mixed Connective
TABLE 63-1 Tissue Disease17,18
Clinical Features of Systemic Sclerosis/Myositis
Overlap Syndrome ■ Raynaud phenomenon
■ Puffy fingers/hands
■ Raynaud phenomenon ■ Sclerodactyly
■ Sclerodactyly ■ Oesophageal involvement
■ Mechanic hands ■ Pulmonary hypertension/interstitial lung disease
■ Myositis ■ Myositis
■ Pulmonary involvement ■ Arthritis and arthralgia
■ Calcinosis cutis ■ Serositis
■ Serositis ■ Anemia/lymphopenia
■ PmScl autoantibodies ■ High titers of U1RNP antibodies 1089

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10 TABLE 63-3
Clinical Association of Hallmark Autoantibodies in Systemic Sclerosis47
REACTIVITY TARGET ANTIGEN FREQUENCY IN SSc (%) HLA ASSOCIATION CLINICAL ASSOCIATION

Centromere CENP proteins 20 to 30 HLA-DRB1 HLA-DQB1 Limited skin sclerosis, severe gut disease, isolated PAH,
speckled pattern calcinosis
Scl-70 Topoisomerase-1 15 to 20 HLA-DRB1 HLA-DQB1 Diffuse skin sclerosis, pulmonary fibrosis and secondary
speckled pattern HLA-DPB1 PAH, increased SSc-related mortality rate
RNAP III RNA polymerase III 20 HLA-DQB1 Diffuse skin sclerosis, hypertensive renal crisis, corre-
speckled pattern lated with a higher mortality rate
nRNP U1RNP speckled 15 HLA-DR2, HLA-DR4 Overlap features of SLE, arthritis
pattern HLA-DQw5, DQw8
Pm-Scl Polymyositis/Scl 3 HLA-DQA1 HLA-DRB1 Limited skin sclerosis, myositis–sclerosis overlap,
Part 10

nuclear staining calcinosis

pattern
Fibrillarin U3RNP nuclear 4 HLA-DQB1 Diffuse skin sclerosis, myositis, PAH, renal disease
::

staining pattern
Th/To 7-2RNP nuclear 2–5 HLA-DRB1 Limited skin sclerosis, pulmonary fibrosis
Autoimmune Connective Tissue and Rheumatologic Disorders

staining pattern

PAH, pulmonary arterial hypertension; SLE, systemic lupus erythematosus; SSc, systemic sclerosis.

suddenly and is clearly restricted and is accompanied
by painful pallor/ischemia of single or several digits/
toes, followed by reactive hyperemia after reheating at
the end of a RP attack, in some cases cyanosis (tripha-
sic RP) also ensues (see Fig. 63-2).
SKIN INVOLVEMENT
Skin involvement is a cardinal feature of SSc and usu-
ally appears first in the fingers and hands. Within
time, patients develop nonpitting edema of the fingers
(puffy fingers), hands, and extremities, followed by
an increasing induration and skin thickening (sclero-
dactyly) (see Figs. 63-1 and 63-2). Depending on the
localization of skin thickening, restricted mobility of
joints (dermatogenous contractures), and/or restricted
breath excursion may be present. Typical facial fea-
tures include telangiectasias, a beak-shaped nose, and
reduced mouth aperture (microstomia). The typical
facial appearance of SSc patients is characterized by
a radial furrowing around the mouth, no expression,
a stiff and mask-like facial appearance, and sclerosis
of the frenulum. Besides cosmetic/aesthetic problems,
this causes considerable difficulties regarding eating
and oral hygiene (see Fig. 63-1).
The abnormal deposition of cutaneous and/or subcu-
taneous calcium (calcinosis cutis), usually occurs over
pressure points (acral, joints) (Fig. 63-4). Calcinosis
cutis next to joints is Thibierge-Weissenbach syn-
drome. Further skin manifestations include hypopig-
mented and hyperpigmented (salt-and-pepper) skin
(see Fig. 63-1), and loss of hair follicles and sweat
glands (hypohidrosis/anhydrosis).20
Approximately 50% of patients with SSc are affected
by digital ulceration associated with vasculopathy at
1090 some point in their disease. This is the major exter-
nal feature of structural vessel disease, probably
attributable to thickened intima and lumen-occluded
vessels. Tender and painful pitting scars are very fre-
quent and, on occasion, progress to ulcers. These occur
on the finger- or toe-tips, over the extensor surfaces
of the joints as a result of microtrauma or in associa-
tion with the abovementioned calcinosis cutis. Digi-
tal ulcers are associated with strong, local pain and
a major impact on quality of life regarding all-day
functions (eg, dressing, eating). Other complications
include critical digital ischemia, paronychia, infec-
tions, gangrene, osteomyelitis, and finger pulp loss or
amputation.
CARDIOPULMONARY
MANIFESTATIONS
There are different ways that the cardiopulmonary
system may be involved, most often appearing as
fibrosis and PAH. The differentiation between these
manifestations is often clinically difficult because of
similar overlapping clinical features, such as dyspnea,
nonproductive cough, disturbed diffusion capacity,
and cyanoses. PAH is currently the most common
cause of disease-related death in SSc.21 It occurs in
both limited and diffuse cutaneous subsets, although
the most typical cases are those of limited SSc associ-
ated with isolated PAH. This condition has substan-
tial similarities to idiopathic PAH. Thus, 2 patterns of
disease occur in SSc. Most cases have PAH, but there
are some patients with late-stage extensive intersti-
tial lung fibrosis in SSc that develop a true secondary
pulmonary hypertension.22 Besides the right-heart
worsening caused by PAH, the heart could also be
involved by diffuse or focal fibrosis or from inflam-
matory myocarditis. This may lead to diastolic or
systolic dysfunction, as well as a restricted contract-
ibility of the myocardium. These patients clinically

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 10

A B

Chapter 63 :: Systemic Sclerosis

C D

Figure 63-4 Digital alterations with complications. A, Digital ulcerations at the fingertips. B, Digital ulcerations and necro-
sis of the fingertips. C, Severe calcifications with deposition of subcutaneous masses. D, Multiple ulcerations at bone
protuberants with inflammation in the surrounding sclerotic skin.

present cardiac arrhythmia, paroxysmal tachycardia, SSc can also affect the intestine, and includes atonic
incomplete or complete right-heart blocks, and heart dilation, constrictions, malabsorption, pseudoobstruc-
insufficiency.23 tion, diarrhea, constipation, fecal incontinence, and
severe malnutrition.

GI INVOLVEMENT
GI involvement is the most common internal organ
involvement in patients suffering from both limited
and diffuse SSc (>60%).1 Many parts of the GI tract
may be impaired, affecting motility, digestion, absorp-
tion, and excretion.24
Esophageal involvement includes symptoms like
dysphagia, heartburn resulting from reflux, nau-
sea, and/or vomiting. A weakened lower esopha-
geal sphincter and impaired peristalsis increase the
risk for esophagitis. If untreated, this could lead to
peptic esophagitis, gastric/esophageal ulcerations,
peptic stricture formations, and fistulae. Chronic gas-
troesophageal reflux can be complicated after a time
by a higher risk for Barrett esophagus, which may
progress into an adenocarcinoma.
Possible gastric manifestations include atrophy of
mucous membrane–associated ulcerations and delayed
gastric emptying. Gastric antral vascular ectasia is also
an important complication in some SSc patients and
needs to be detected by endoscopy because it can lead
to severe, often not recognized, bleeding.25
KIDNEY INVOLVEMENT
SRC appears in 5% to 10% of SSc patients, and may
cause an abrupt onset of significant systemic hyperten-
sion (>140/90 mm Hg, or a rise in systolic/diastolic
blood pressure ≥30/≥20 mm Hg), together with an
increase in serum creatinine, proteinuria, hematuria,
thrombocytopenia, or hemolysis followed by an acute
renal failure.26 Studies suggest that a chronic vascu-
lopathy with reduced glomerular filtration rate is
frequent. In addition, there is evidence of an increase
in fibrillar collagen deposition within the renal inter-
stitium in SSc. Many cases occur within the first
12 months of disease, and in up to 25% of patients with
SRC, the diagnosis of SSc is made at the time of the
renal presentation. End-organ damage can result in
encephalopathy with generalized seizures or flash pul-
monary edema. Microangiopathic anemia is common,
and sometimes disseminated, intravascular coagula-
tion develops. Nephrotoxic drugs and high-dose pred-
nisolone (>7.5 mg/day) should be avoided in patients 1091
suffering from SSc.27

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10 ETIOLOGY AND
PATHOGENESIS
The pathogenesis of this complex autoimmune dis-
ease involves multiple cell types (endothelial cells,
epithelial cells, fibroblasts, and lymphocytic cells)
interacting through a variety of mechanisms that are
dependent on their microenvironment and several
key mediators.
Major facets of the disease include inflammation,
vasculature, and the activation of connective tissue-
producing cells (Fig. 63-5). The clinical heterogeneity
of SSc makes it likely that distinct pathogenetic mecha-
nisms predominate in particular patients or subsets of
disease. Similarly, the key pathways are not necessarily

The pathophysiology of scleroderma

Injury
Part 10

EC
damage
::
Autoimmune Connective Tissue and Rheumatologic Disorders

Inflammation

IL-4/ IL-13
Innate immune cells T cells B cells Autoantibodies
Cytokines
CTGH Profibrotic
PDGF macrophages
Growth
factors TGF-β
TGF-β
RELM-β
TGF-βR
Endothelial PDG-R
cells
TGF-β
Circulating ET-R Mechanical
precursors tension
Resting
fibroblast

Adipocytes Activated myofibroblast

Growth
factors
Lysyt
hydroxylase
Other fibrogenic Fibrillin, collagens,
cytokines FN, COMP, etc.

Stiff fibrous matrix

Genetic predisposition

Figure 63-5 Pathogenesis of systemic sclerosis. The schematic shows how the development of systemic sclerosis results
from a complex interplay between cells within the immune system, including adaptive and innate compartments, the
vasculature, and the connective tissue. Cell–matrix interactions are important regulators of cellular functions. Early vas-
cular events lead to later development of an autonomous population of activated fibroblasts and myofibroblasts that
contract soft tissue and deposit excessive extracellular matrix proteins. These cells may develop from resident connective
tissue fibroblasts; transdifferentiation from other cell types, including activated microvascular pericytes; and recruitment
of circulating progenitor cells (fibrocytes). The contribution of each lineage to the fibrotic lesion is still unclear. Many
growth factors and cytokines are implicated as mediators of this process, and complex reciprocal networks may lead to a
profibrotic microenvironment. Potential disease-modifying therapies could target individual mediators alone or in com-
bination (eg, tumor growth factor-β [TGF-β], endothelin [ET-1], connective tissue growth factor [CTGF], platelet-derived
growth factor [PDGF]) or modulate immune cells (eg, cyclophosphamide) or the endothelial cell (eg, prostacyclin analogs).
The extracellular matrix is an important repository for mediators that are later released and play a key role in pathogenesis.
CCL, CC chemokine ligand; COMP, cartilage oligomeric matrix protein; EC, extracellular; ET-R, endothelin receptor; FN,
1092 fibronectin; Ig, immunoglobulin; IL, interleukin; RELM-β, resistin like molecule-β.

Kang_CH063_p1086-1105.indd 1092 03/12/18 9:17 am

 the same at different stages of SSc. Although a genetic
component to etiopathogenesis is likely and evidence
supports genetic factors determining severity and sus-
ceptibility, there are also strong arguments, supporting
environmental and chemical factors as triggers for the
disease.28
GENETIC FACTORS
The best evidence for a genetic contribution to SSc and
related diseases comes from studies that report famil-
ial clustering and from the limited twin studies that
have been undertaken. Although the absolute risk for
familial-occurring SSc is relative low, the relative risk
for first-degree relatives is 13-fold higher compared
to the normal population.29 Several studies suggest
that a positive family history for SSc is the strongest
risk factor, but ethnicity also contributes.29 Assassi
and colleagues suggest that members of SSc-affected
families tend to show concordant scleroderma-
specific autoantibodies.30 Further support is provided
from genetic association studies with candidate gene
approaches. Most success has been observed in genetic
analysis of individual components of the disease such
as autoantibody profiles. These appear to have a strong
genetic determinant, and this may underlie the appar-
ent mutual exclusivity of the SSc hallmark reactivities.
It has been demonstrated that the ability to mount an
immune response to a particular SSc-associated anti-
gen is restricted by major histocompatibility complex
haplotype. Several studies suggest an association of
HLA-DRB1∗1302 and HLA-DQB1∗0604/0605 haplo-
types with antifibrillarin-positive patients,31 while
HLA-SRB1∗0301 occurs in patients with anti–Pm-Scl
antibodies.32 Observation from a large number of stud-
ies examining genetic markers has identified a num-
ber of candidate genes (eg, anemia-inducing factor
[AIF]-1, cluster of differentiation [CD] 19, CD22, CD86,
cytotoxic T-lymphocyte antigen [CTLA]-4, CCL-2,
CCL-5, chemokine ligand [CXCL]-8, chemokine-related
receptor [CXCR]-2, interleukin [IL]-1α, IL-1β, IL-2,
IL-10, IL-13, macrophage migration inhibitory factor
(MIF), protein tyrosine phosphatase non-receptor 22
(PTPN22) tumor necrosis factor [TNF]-α).29,33 Most
of the more recent genome-wide association studies
have identified loci relevant for the innate immune
system; some of these associations are already rather
robust and might lead to new therapeutic approaches.
Others reflect the altered connective tissue response.
However, as with other complex diseases, in very
many instances, it has not always possible to replicate
initially promising data. Studies of genetically homo-
geneous populations have been especially informa-
tive, including those of the Choctaw Nation of Native
Americans. However, it is of interest that some of the
associations are very plausible in terms of molecular
pathogenesis. It is likely that epistasis and the effect
of multiple modifier genes confound simple genetic
association studies in SSc, just as in other complex
diseases.34 There is increasing evidence that epigenetic
Kang_CH063_p1086-1105.indd 1093
mechanisms by modulating chromatin structure and
gene expression of cytokines/growth factors critical
10
for the activation of the immune response and/or the
fibrotic reaction are important additional factors con-
tributing to the development of scleroderma.
ENVIRONMENTAL FACTORS
Scleroderma-like syndromes have been reported in
association with numerous environmental toxins and
drugs. These agents include solvents (vinyl chloride,
benzene, toluene, epoxy resins), drugs (bleomycin, car-
Chapter 63 :: Systemic Sclerosis
bidopa, pentazocine, cocaine, docetaxel, metaphenyl-
enediamine), and miscellaneous substances.35
SSc was reported to occur in underground coal and
gold miners. In male patients with silicosis who were
older than 40 years of age, the likelihood of developing
SSc was approximately 190 times greater than in males
not exposed to silica, and 50 times greater than in males
without silicosis but exposed to silica dust.36 The role of
silicone gel implants and other silicone products in the
development of scleroderma has been questioned.37
However, most epidemiologic studies have failed to
show a significant association. An unusual form of
scleroderma characterized by RP, morphea-like skin
changes, capillary abnormalities of the nailfold (simi-
lar to those in SSc), osteolysis of the distal phalanges,
and hepatic and PF may occur in workers exposed to
polyvinyl chloride. Bleomycin also produces PF, RP,
and cutaneous changes indistinguishable from those of
SSc.37 The development of these changes appears to be
dose-dependent and is reversible on discontinuation
of the drug. Collectively, chemical exposures account
for a small fraction of scleroderma-like diseases. Large
epidemiologic studies have not yet revealed a signifi-
cant role for toxins and drugs in scleroderma.
HISTOPATHOLOGY
The histopathology of SSc shows fibrosis of the lower
two-thirds of the dermis and the subcutaneous fibrous
trabeculae, because of excessive deposition of extra-
cellular matrix (ECM) proteins, most notably collagen
Types I and III (Fig. 63-6).28
Panniculitis and mucoid edema also may be promi-
nent features in the early stages, whereby subcutane-
ous fat is replaced by a fibrous connective tissue. It is
possible to differentiate histologically an early cellular
stage on the one hand and a later fibrotic stage on the
other hand. In the early stages, the dermis presents
pathologically collagen bundles within the reticular
dermis, and appear pale, homogenous, running paral-
lel to the skin surface, and swollen, and there is often
a perivascular lymphocytic infiltrate. These inflamma-
tory cell infiltrates are localized between the collagen
bundles but mainly around the vessels, and can also
spread into subcutaneous fat tissue. The infiltrate can 1093
also entrap sweat glands. The epidermis often becomes
03/12/18 9:17 am
10
Figure 63-6 Histologic appearance of skin in early and
late-stage diffuse cutaneous systemic sclerosis (SSc). In
Part 10
SSc, there is perivascular mononuclear cell infiltrate at the
early stages of disease. This precedes the development
of skin sclerosis. Perivascular changes are shown at high
power in the left panel. Later stage disease is accompa-
::
nied by skin sclerosis, a low density of blood vessels, and
Autoimmune Connective Tissue and Rheumatologic Disorders
absence of inflammatory cells. At this stage, there may be
associated epidermal changes with thickening and loss
of secondary skin structures, including hair follicles and
sweat glands. Absence of the rete ridges is also charac-
teristic at the later stages of diffuse cutaneous SSc. Similar
changes are predicted in localized cutaneous SSc, but this
is rarely biopsied because of limited skin sclerosis and con-
cerns about healing.
atrophic in the overlying areas. Vessels of all sizes may
be involved in SSc. In the early stages, there may only
be dilation of capillaries, then endothelial prolifera-
tion and complete occlusion of vessels occur. With the
progression of scleroderma, the involved skin becomes
more avascular and inflammation decreases. In later
stages, pilosebaceous units and eccrine glands disap-
pear, collagen bundles appear to be packed closely,
and there may be an effacement of the rete ridges.20
VASCULOPATHY
Vasculopathy in SSc is an early event and is based on
inappropriate vascular remodeling and repair pro-
cesses. It involves the microcirculation and arterioles
and is very likely a primary event in the pathogenetic
processes of the disease. Vascular abnormalities are
characterized by vasoconstriction, adventitial and inti-
mal proliferation, inflammation, and thrombosis.28 The
earliest signs of vascular dysfunction are represented
by enhanced vascular permeability with an imbal-
ance between vasodilatory (nitric oxide, prostacyclin,
calcitonin gene-related peptide) and vasoconstric-
tive mediators (endothelin-1, angiotensin II, α2-
adrenoreceptors). Consequently, the impaired blood
flow leads to tissue hypoxia, which induces strong
expression of vascular endothelial growth factor and
its receptors, associated with a defect of vasculogen-
esis. However, inflammatory cytokines like TNF-α
1094 may stimulate or inhibit angiogenesis depending on
the duration of the stimulus.38
Kang_CH063_p1086-1105.indd 1094
In addition to these functional abnormalities, intra-
vascular and structural changes contribute to overt
RP, and in the course of time to progressive reduction
of vessels and blood flow. This pattern of obliterative
vasculopathy may clinically manifest in all vessels of
virtually all organs. Early lesions in the microcircula-
tion because of structural damage are initially seen in
the nailfold capillaries and as vasospastic responses in
RP. Furthermore, vascular changes, that is, overgrowth
of the endothelium and deposition of scar tissue, pro-
duce some of the major complications of SSc, including
PAH, SRC, and digital vasculopathy.
IMMUNE EVENTS
There are early inflammatory changes in the skin and
lung of patients with SSc. The first inflammatory infil-
trates in lesional skin are predominantly cells of the
monocyte lineage (T cells, macrophages, B cells, and
mast cells).39 There are several lines of evidence for the
crucial role of the innate immune system in SSc. This is
underlined by the association of interferon regulatory
factor-5 variants with scleroderma.40,41 Several studies
also demonstrate the role of macrophages as important
contributors of cytokines, which influence the fibrotic
response.42
Later, T lymphocytes predominate and are detect-
able in both the circulation and affected organs. These
T cells are predominantly CD4+, bear markers of acti-
vation, exhibit oligoclonal expansion, which suggests
an antigen-driven proliferation, and show a predomi-
nant T-helper 2 phenotype.43,44 Consequently, increased
serum levels of T-helper 2 cell–derived cytokines (IL-2,
IL-4, IL-10, IL-13, and IL-17) have been observed in
scleroderma patients.45,46
In addition to T cells, B cells are also found in
involved skin. Several studies suggest that B cells are
able to induce ECM production through secretion of
IL-6 and transforming growth factor-β (TGF-β) and are
involved in the production of autoantibodies.
Several of these autoantibodies are associated with
defined subsets of the disease and are important diag-
nostic markers (see Table 63-3).47 The potential role of
autoantibodies in pathogenesis is a fascinating and
exciting area. The majority of SSc cases have circulat-
ing antibodies. These include a number of hallmark
reactivities, as well as autoantibodies, that occur in
other autoimmune rheumatic diseases (eg, anticy-
clic citrullinated peptide, rheumatoid factor) but also
antibodies that may have functional significance, as
they are directed against cell-surface antigens (eg,
antiendothelial cell antibodies, antifibrillin antibod-
ies, anti–platelet-derived growth factor [PDGF] recep-
tor antibodies) (Table 63-4).48-50 However, functional
impact of these antibodies remains an area of inves-
tigation. There is growing evidence of functional sig-
nificance for antiendothelial cell autoantibodies and
for antifibroblast-reacting antibodies. Reports also
suggest the presence of antifibrillin autoantibodies
and stimulatory autoantibodies reacting with PDGF
03/12/18 9:17 am
 TABLE 63-4
10
Functional Autoantibodies in Systemic Sclerosis and Their Association to Pathophysiology48-50
FREQUENCY IN
FUNCTIONAL ANTIBODY SYSTEMIC SCLEROSIS CLINICAL ASSOCIATION

Anti–platelet-derived 33% to 100% ■ Seem to induce skin fibrosis as a result of activation of fibroblasts into myofibroblasts and
growth factor receptor fibroblast-like cells
■ First functional antibodies discovered in systemic sclerosis (SSc)
Antiendothelial cell 44% to 84% ■ Mediates endothelial cell damage and activation of fibroblasts resulting from stimulation
antibodies of proinflammatory and fibrotic cytokines
■ Associated with severe organ manifestation
■ Associated with perivascular, vascular (digital ulcers [DUs]) and lung involvement
(pulmonary arterial hypertension [PAH])
■ Also found in other rheumatic diseases

Chapter 63 :: Systemic Sclerosis

Antifibroblast antibodies 26% to 58% ■ Associated with Scl-70 antibodies and the prevalence of interstitial lung disease and PAH
■ Increased prevalence in diffuse cutaneous SSc compared to limited cutaneous SSc
Antifibrillin-1 >50% ■ Activates fibroblasts by stimulation of the release of transforming growth factor-ββ
Anti–matrix metallo- 49% to 52% ■ Inhibits the degradation of extracellular matrix proteins, because of an inhibition of MMP
proteinase (MMP) 1, collagenase activity
anti-MMP3 ■ Correlates with the extent of fibrosis (skin, lung, kidney)
Angiotensin II Type 1 82% to 83% ■ Simultaneous presence has been described in SSc patients (cross-reactivity)
receptor and endothelin ■ Associated with early and severe disease, PAH, DUs, renal crisis, diffuse cutaneous SSc, and
Type A receptor lung fibrosis

receptors.48-50 Microchimerism and graft-versus-host
disease mechanisms have been suggested in some
cases, although the relatively high frequency of micro-
chimerism in healthy individuals or other disease
states suggests that this may be contributory rather
than causal if it has a role in SSc.
Careful clinical studies have identified a subset of
SSc patients (characterized by RNA polymerase anti-
bodies), who develop the disease in association with
the occurrence of malignancies.51-53 This led to the
hypothesis that fibrosis may represent an immune
response against tumor antigens and initiated a dis-
cussion on the relationship of autoimmunity and
malignancy in general. Further studies are required to
clarify this issue.
FIBROSIS
SSc is a multisystem fibrotic disease. The initial
inflammation and hypoxia induces in fibroblasts the
production of several proteins that are involved in
ECM remodeling as, for example, thrombospondin-1,
fibronectin-1, lysylhydroxylase-2, and TGF-β–induced
proteins.54 At the same time there is a disturbed bal-
ance between synthesis and degradation mechanisms
leading to the excess of ECM in specialized organs,
which is then responsible for much of the morbid-
ity and mortality of the disease. The key event in the
development of fibrosis is the induction of fibroblasts
into activated myofibroblasts. Alternatively, also other
cell types (eg, circulating precursor cells, endothelial
cells, and epithelial cells) can be converted into myo-
fibroblasts. The initiation of this process includes a
number of key cytokines and growth factors that may
represent logical therapeutic targets. These include
fibrogenic cytokines such as TGF-β, connective tissue
growth factor, PDGF, and endothelin-1.28,55-57 Especially
TGF-β has been shown to play a central role,58 which
is also underscored by extensive expression profiling
studies using skin biopsies from scleroderma patients
in different stages of the diseases.59 This has already
led to therapeutic approaches using antibodies against
TGF-β in early clinical studies.60
Myofibroblasts are characterized by a high con-
tractility, ECM production, and cytokine release.
This function together with altered biophysical
properties of the resulting connective tissue lead to
persistent activation of fibroblasts with an excessive
deposition of ECM components. However, crucial
for understanding the mechanisms of this disease is
the close connection between autoimmunity, vascu-
lopathy, and fibrosis. This was recently demonstrated
in a mouse model characterized by downregulation
of the transcription factors Friend leukemia integra-
tion 1 (Fli1) and Kruppel-like factor 5 (KLF5), which
develop a scleroderma like disease with the produc-
tion of autoantibodies.61
Figure 63-5 is a schematic that summarizes the
pathogenetic mechanisms.
DIAGNOSIS
RAYNAUD PHENOMENON
Patients presenting only with RP should be studied
for capillary alterations as well as autoantibody status.
All these are predictors for the development of SSc, 1095
which together make the diagnosis of SSc rather likely.

Kang_CH063_p1086-1105.indd 1095 03/12/18 9:17 am

10 TABLE 63-5
Recommended Diagnostic Procedures in Systemic Sclerosis71
ORGAN INVOLVEMENT CLINICAL FEATURE DIAGNOSTIC PROCEDURES

Vascular system Raynaud phenomenon ■ Coldness provocation

■ Nailfold capillaroscopy
■ Antinuclear antibody levels
Skin Scleroderma ■ Clinical assessment regarding puffy fingers, telangiectasias, mechanic hands, hypopigmen-
Calcinosis cutis tations/hyperpigmentations, digital ulcerations, dermatogenous contractures
■ Modified Rodnan skin score
■ 20-MHz ultrasonography
■ Radiography (X-ray, MRI, CT)
Musculoskeletal system Arthralgia ■ Clinical assessment regarding fist closure deficiency, joint contractures, tendon friction rub,
Part 10

Synovitis muscle weakness

Muscle weakness ■ Laboratory parameters: erythrocyte sedimentation rate, rheumatoid factor, antinuclear
autoantibodies
■ Creatine kinase (greater than threefold?)
■ MRI, electromyography
::

■ Muscle biopsy
Autoimmune Connective Tissue and Rheumatologic Disorders

GI tract Reflux ■ Gastro-/esophageal endoscopy

Dysphagia ■ Esophageal scintigraphy, esophagus manometry
Gastric antral vascular ■ Gastro-/esophageal endoscopy with laser coagulation, if necessary
ectasia ■ Colonoscopy
Diarrhea, obstipation
Respiratory system Dyspnea ■ Lung function test (carbon monoxide transfer factor corrected for hemoglobin [TLCOc]
single breath (SB), total lung capacity [TLC], forced vital capacity [FVC])
■ Radiography (X-ray or high resolution CT)
■ Bronchioalveolar lavage (BAL) (optional)
Cardiac system Dyspnea, arrhythmia ■ Electrocardiography (conduction blocks?)
■ Echocardiography (mean pulmonary artery pressure, diastolic dysfunction?, ventricular
ejection fraction)
■ (Spiro-)Ergometry
■ 24-Hour blood pressure controls
■ Right-heart catheterization
■ Cardio MRI
Kidney Renal function failure ■ Regular blood pressure controls (>140/90 mm Hg)
■ Ultrasonography
■ Serum levels of creatinine, urine analyses (protein, albuminuria, microelectrophoresis)

To identify and visualize vascular cutaneous altera-
tions caused by SSc, nailfold capillaroscopy is a non-
invasive, simple, and one of the most useful diagnostic
and prognostic methods (Table 63-5). Furthermore, it is
a useful tool to categorize capillary changes into early,
active, and late patterns. Laser Doppler perfusion
imaging is also a noninvasive microvascular imaging
technique able to provide maps of the cutaneous blood
flow.62
to the modified Rodnan skin score,63 the 20-MHz
ultrasonography,64 MRI,65 and plicometer66 methods
are useful for assessing skin thickening (recommended
diagnostic procedures are listed in Table 63-5). Further
physical procedures to monitor skin fibrosis are the
durometer,67 cutometer,68 and elastometer.69 In addi-
tion to these noninvasive methods, skin biopsy with
histologic evaluation of the dermal skin thickness is an
appropriate but invasive method. This method enables
the characterization of the inflammatory infiltrates.

SKIN SCLEROSIS
Skin involvement should be evaluated using the modi-
fied Rodnan Skin Score. Usually, 17 sites are assessed
and skin thickness is categorized to grade 1, 2, or 3,
corresponding to mild, medium, and severe, accord-
ing to palpation of the skin by a trained examiner
1096 (Fig. 63-7). Newer techniques for calculating skin
thickening also have been evaluated. In addition
CARDIOPULMONARY
INVOLVEMENT
Individuals with SSc and cardiopulmonary symptoms
should be followed up at least annually using pulmo-
nary function tests, echocardiography, a 6-minute walk
test, and high-resolution CT (HRCT).70 Pulmonary

Kang_CH063_p1086-1105.indd 1096 03/12/18 9:17 am

 Modified Rodnan skin score
10
Face:

Upper arm ri: Upper arm le:

Trunk/thorax:

Abdomen:

Forearm ri: Forearm le:

Chapter 63 :: Systemic Sclerosis

Hand ri: Hand le:

Fingers ri: Fingers le:

Thigh ri: Thigh le:

Lower leg ri: Lower leg le:

Foot ri: Foot le:

Sum of scores:

Figure 63-7 Modified Rodnan skin score (mRSS). Skin hardening evaluation using the modified mRSS is usually performed
by assessing the skin thickness at 17 different areas. The skin sclerosis is categorized by palpation to grade 1, correspond-
ing to mild, grade 2, corresponding to moderate, and grade 3, corresponding to severe. le, Left; ri, right.

function tests are the most important techniques to
determine possible cardiopulmonary involvement,
because of impaired diffusion capacity of the lung for
carbon monoxide (DLCO ≤75%) being an early marker
of both lung fibrosis and PAH.71
To determine the presence of interstitial lung
involvement, that is, subpleural localized line opaci-
ties, ground-glass opacities, and subpleural cysts with
honeycomb formations, HRCT and/or thoracic radi-
ography should be used.
Followup should also include transthoracic Doppler
echocardiography, a noninvasive procedure, that can
indicate a hypertrophy with or without enlargement of
the right ventricle, paradoxical motion of the interven-
tricular septum, tricuspid valve insufficiency, and peri-
cardial effusion. Right-heart catheterization is indeed the
gold standard, but is an invasive diagnostic procedure to
determine PAH. PAH is defined as a mean pulmonary
artery pressure of ≥25 mm Hg at rest together with a pul-
monary capillary wedge pressure of ≤15 mm Hg as deter-
mined by right-heart catheterization.70,72,73
Cardiac MRI is also a potential strategy for assess-
ing myocardiac involvement in SSc. Besides imaging
procedures, there is also some promise for the use of
N-terminal brain natriuretic peptide to detect right
ventricular impairment (see Table 63-5). Early detec-
tion of cardiac involvement is crucial to prevent and to
allow early treatment of cardiomyopathy and severe
cardiac arrhythmias.70
GI INVOLVEMENT
The presence of esophagitis can be determined by
upper GI endoscopy with histologic evaluations.
Impaired motility of the esophagus can usually
be diagnosed by scintigraphic evaluation follow-
ing a radiolabeled meal or 24-hour pH manometry
(see Table 63-5).71
KIDNEY INVOLVEMENT
Early diagnosis is the key role in improving the out-
come of SRC using regular blood pressure monitoring,
urine analysis microelectrophoresis, and determina- 1097
tion of creatinine clearance (see Table 63-5).26

Kang_CH063_p1086-1105.indd 1097 03/12/18 9:17 am

10 DIFFERENTIAL DIAGNOSIS
The diagnosis of SSc is clinical. Although there are
criteria that were developed to facilitate the distinc-
tion of SSc from other connective tissue diseases, no
formal diagnostic criteria have been developed. How-
ever, determination of the correct subset of the disease,
including the SSc overlap syndromes, is required to
enable judging of prognosis and involvement of certain
organs and for determining the therapeutic approach.
There are several differential diagnoses that imitate
scleroderma: circumscript (localized) scleroderma;
eosinophilic fasciitis; sclerodermiform genodermato-
ses; acrodermatitis chronica atrophicans; scleroderma-
Part 10
like syndromes induced by environmental factors;
scleroderma adultorum Buschke; scleroderma diabeti-
corum; scleromyxedema; nephrogenic fibrosing der-
mopathy; porphyria cutanea tarda; graft-versus-host
::
disease; and scleroderma-like lesions in malignancies.
Autoimmune Connective Tissue and Rheumatologic Disorders
These certainly have to be excluded. Table 63-6 out-
lines the differential diagnosis of SSc.
CLINICAL COURSE AND
PROGNOSIS
The development of the disease depends very much
on the specific subset. Patients with the limited form
develop RP already many years prior to the onset of
other organ manifestations. Skin fibrosis remains local-
ized to the acral areas and the main complications are
the development of digital ulcerations and pulmonary
hypertension. In the diffuse form, however, fibrosis
occurs early and together with inflammation, joint
pain and shows a rapid spreading to almost all parts
of the integument. In these patients, manifestations of
the lung (lung fibrosis), heart, and kidney occur early
in the disease course and often determine the prog-
nosis. There is still a high number of deaths associ-
ated with this disease subset. Several studies indicate
that the diffuse cutaneous SSc patients show a rapid
TABLE 63-6
Differential Diagnosis of Systemic Sclerosis
Differential Diagnosis
■ Circumscript (localized) scleroderma (morphea)
■ Eosinophilic fasciitis
■ Lichen sclerosus et atrophicans
■ Sclerodermiform genodermatoses (eg, progeria, acrogeria)
■ Sclerodermiform acrodermatitis chronica atrophicans
■ Scleroderma adultorum Buschke
■ Scleroderma diabeticorum
■ Scleroderma amyloidosus
■ Scleromyxedema
■ Mixed connective tissue disease (MCTD)
■ Nephrogenic fibrosing dermopathy
■ Sclerodermiform porphyria cutanea tarda
■ Sclerodermiform chronic graft-versus-host disease
1098 ■ Eosinophilia-myalgia syndrome
Kang_CH063_p1086-1105.indd 1098
worsening of the disease in the initial years. In later
years, the activity of the disease is reduced and symp-
toms can improve. Surprisingly, the sclerotic skin also
can become softer and contractures can be diminished.
Although SSc is still a life-threatening disease, a
multidisciplinary management of the patients with
early detection and treatment of complications may
lead to a much-improved prognosis during the
patient’s life.
MANAGEMENT
DISEASE-MODIFYING
TREATMENT
Three facets of SSc are potentially amenable to thera-
peutic modulation, which raises the possibility of true
disease-modifying treatment. At present, vascular ther-
apies and immunomodulation have the widest range
of candidate therapies. Tables 63-7 and 63-8 summa-
rize these approaches. General immunosuppression
can be of benefit by improving skin involvement and
interstitial lung disease. The best evidence is available
for cyclophosphamide but more recently mycophe-
nolate mofetil (MMF) has been shown to be as effec-
tive as oral cyclophosphamide and is used by many
centers.74,75 There is also evidence that rituximab can
lead to improvement of the disease course in a select
group of patients, if standard immunosuppression
has failed.76 Efficiency of immunosuppression in gen-
eral is demonstrated by trials from the United States
and Europe using high-intensity immunosuppression
with autologous hemopoietic stem cell transplantation
in some selected patients.77-80 However, side effects
always have to be considered (Table 63-9).
Antifibrotic treatment remains still a challenge,
although during the last few years a number of new
approaches have been generated mainly based on
the better understanding of the underlying mecha-
nisms. A newer study using a new antibody against
TGF-β led to an improvement of the severity of skin
involvement and a reduction of the expression of sev-
eral TGF-β–dependent genes.60 Some encouragement
is also provided by newer clinical trials of idiopathic
PF. However, at present there is no proven antifi-
brotic agent. Figure 63-8 is a simplified schematic for
integrating putative disease-modifying therapy with
programs of screening and surveillance that permit
timely intervention in SSc with organ-based strate-
gies that currently form the basis of the majority of
SSc therapeutics. Possibilities for targeted disease
modifying therapy depend on the availability of ther-
apeutic agents and a clear understanding of their role
in pathogenesis.
There has been much more success in the field of
organ-based therapeutics in SSc, which already had a
high impact especially on the quality of life of many
patients. Early detection of these organ-specific com-
plications is required to enable early intervention.
03/12/18 9:17 am
 TABLE 63-7
10
Recommended Therapeutic Strategies for Internal Organ Involvement in Systemic Sclerosis105
ORGAN INVOLVEMENT CLINICAL FEATURE THERAPEUTIC OPTIONS

Vasculopathy Raynaud phenomenon Consistent warm keeping, paraffin-bath, patient education

Calcium channel blockers (eg, nifedipine) by mouth
Angiotensin receptor antagonists
Alternatives: selective serotonin reuptake inhibitors (SSRIs), α-blockers, sympathectomy
with or without botulinum toxin injection
Digital ulcers Prostacyclin (eg, iloprost) IV87,88
Endothelin receptor blockade (eg, bosentan by mouth)81,106
Phosphodiesterase Type 5 inhibitors (off-label)90

Chapter 63 :: Systemic Sclerosis

Wound dressing (hydrocolloid membrane, Mepilex)
Musculoskeletal system Synovitis/myositis Methotrexate (by mouth, IM), rituximab (off-label)
GI tract Reflux Proton pump inhibitors, prokinetics
Dysphagia H2-receptor antagonists
Diarrhea, obstipation Change habit of eating, parenteral nutrition
Antibiotics (eg, ciprofloxacin)
Symptomatic management with antidiarrheal agents or laxatives
Respiratory system Dyspnea Oxygen, if necessary
Alveolitis/lung fibrosis Cyclophosphamide IV
Mycophenolate mofetil by mouth (used as an alternative or after cyclophosphamide)
Glucocorticoids (short dated, if necessary)
Cardiac system Pulmonary arterial Oxygen, if necessary
hypertension
Diuretics
Endothelin receptor blockade (eg, bosentan by mouth, macitentan)107
Inhaled iloprost107
Phosphodiesterase Type 5 inhibitors (eg, sildenafil by mouth, tadalafil)107,108
Epoprostenol by mouth107
Combination of different agents
Systolic heart failures Immunosuppression with or without pacemaker
Cardioverter defibrillator
Angiotensin-converting enzyme inhibitors and carvedilol (selective β-blockers may be
considered, but consider worsening of Raynaud phenomenon)
Diastolic heart failure Diuretics
Calcium channel inhibitors
Kidney Scleroderma renal crisis Angiotensin-converting enzyme–Hemmer (high-dosed)

Therapy requires a close interaction between

DIGITAL VASCULOPATHY
AND ITS COMPLICATIONS
Simple but important recommendations for reduc-
ing the frequency of Raynaud attacks include reduc-
ing vasoconstriction by avoiding precipitating
factors like nicotine, sympathomimetics, emotional
stress and coldness, and instead to have good home
heating, thick and airtight clothes, thermochemical
or microwaveable hand warmers, electrically heated
gloves, soles, or infrared hyperthermy, regular par-
affin wax bath treatments, and minimizing finger
trauma.
several medical disciplines applying topical and
systemic therapies. Current local management of
digital ulcers includes a combination of nonphar-
macologic care, antibiotics (in case of infection),
analgesia, and individually applied wound dress-
ings, if necessary.
Potential pharmacologic treatment requires optimal
therapy for RP, including agents that have the poten-
tial for vascular remodeling and/or dilation, such as
calcium channel blockers and angiotensin II receptor
antagonists,81,82 which should be considered first-line
therapy. The results have been contradictory with
other pharmacologic treatment options, such as diltia- 1099
zem and angiotensin-converting enzyme inhibitors.83-86

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10 TABLE 63-8
Algorithm summarizing current approach to
management of systemic sclerosis
Therapeutic Options for Skin Involvement in
Systemic Sclerosis20,105
Systemic slerosis
CLINICAL FEATURE THERAPEUTIC OPTIONS

Skin hardening ■ Lymphatic drainage lSSc dSSc Overlap SSc

■ Physiotherapy
■ Topical treatment with steroids or calcineu-
rin inhibitors Therapy: Therapy: Manage according
to severity and
■ Systemic treatment with steroids (short
Vascular Vascular
Immunosupressive activity of overlap
dated) and/or immunosuppressants features -
■ Phototherapy (psoralen and ultra-
Antifibrotic arthritis, myositis,
violet A, ultraviolet A1, extracorporeal lupus
photochemotherapy)
Part 10

Identification and treatment of

Dryness and ■ Topical treatment with steroids, capsaicin organ-based complications
itching ■ Cannabinoid agonists
■ Emollients
■ Phototherapy (psoralen and ultraviolet A, Figure 63-8 Algorithm summarizing the current approach
::

ultraviolet A1) to management of systemic sclerosis (SSc). The principles

■
Autoimmune Connective Tissue and Rheumatologic Disorders

Systemic treatment with antihistamines or of therapy for SSc include accurate diagnosis and treat-
gabapentin ment according to the disease subset, the presence of
Digital ulcerations ■ IV iloprost overlap features, and the likely predominant pathologic
■ Bosentan by mouth process according to the stage of disease. In all cases,
■ Hydrocolloid dressings screening for and treatment of organ-based complications
■ Skin substitutes has a major role in successful management. Education of
■ Physical therapy patients and a multidisciplinary team, including special-
ist nurses, physiotherapists, occupational therapists and
Calcifications ■ Bisphosphonate by mouth
many subspecialty physicians, and surgeons, are central to
■ Local corticosteroid injection
providing appropriate care for severe cases of SSc. dSSc,
■ Laser therapy
Diffuse cutaneous systemic sclerosis; lSSc, limited cutane-
■ Surgery
ous systemic sclerosis.
Telangiectases ■ Laser therapy
■ Camouflage
Hyperpigmentation ■ Bleaching agents, camouflage, sunscreens large, controlled trials, bosentan, an oral dual-spec-
and hypopig- ■ Salicylic acid and chemical peelings ificity endothelin receptor antagonist, was shown
mentation ■ Hydroquinone, retinoids, corticosteroids to significantly reduce the number of new digital
ulcers, compared with placebo.89 However, no posi-
tive effect on healing of established ulcers was dem-
Parenteral prostacyclin derivatives, in particular ilo- onstrated. Other agents, such as phosphodiesterase
prost, are widely used, and help to heal digital ulcers Type 5 inhibitors sildenafil and tadalafil, also have
and may prevent recurrent lesions. Prostacyclin deriv- been used for treatment of RP and digital ulcers,
atives by IV infusion are the mainstay of therapy for but prospective clinical trial data are not available.90
critical digital ischemia.87,88 Antiplatelet agents, such Surgical treatments include digital microarterioly-
as aspirin and clopidogrel, are also used, especially in sis, which can benefit single fingers with refractory
critical digital ischemia. ulcers. Whenever possible, surgical amputation of
There has been enthusiasm about therapies that are digits is avoided, and prolonged treatment with par-
effective for PAH in digital vasculopathy. Thus, in 2 enteral prostacyclin in combination with phosphodi-
esterase Type 5 inhibitors and potent analgesia may
help with this. Lumbar sympathectomy may be help-
ful for lower-limb RP or ulceration. Generally, a tem-
TABLE 63-9 porary procedure is performed initially to determine
Stem Cell Transplantation (ASCT) for Early the likely benefit from a definitive sympathectomy.
Diffuse Cutaneous Systemic Sclerosis78-80 In cases of critical digital ischemia, antiplatelet ther-
apies are often given, with anecdotal reports of the
■ Recommended in poor-prognosis diffuse cutaneous systemic benefit of clopidogrel in preventing digital infarction
sclerosis (SSc) (see Table 63-7).
■ Patients should not have severe organ manifestations, which
render this option highly toxic
Pro Contra
■ Improved long-term ■ 10% Transplant-related mortality SKIN INVOLVEMENT
survival ■ Patients with cardiopulmonary
■ Improved event-free disease have to be excluded
1100 Key elements in the management of skin manifesta-
survival
tions of SSc are physical therapy and regular exercise

Kang_CH063_p1086-1105.indd 1100 03/12/18 9:17 am

 to maintain circulation, joint mobility, and muscle
strength, all aimed at improving the quality of life of
SSc patients. Skin affected by scleroderma tends to be
very dry, taut, and susceptible to trauma.
Skin hardening can be improved by physical therapy
and exercise, lymphatic drainage, topical treatment
with steroids, calcineurin inhibitors, and moisturizing
crèmes. Systemic therapies include immunosuppres-
sive drugs, systemic steroids (for just a short time),
and phototherapy (ultraviolet A1 or psoralen and
ultraviolet A). Ultraviolet A1 phototherpay appears to
inhibit fibrotic and inflammatory processes and reduce
the amount of sclerotic skin.91
Dry and itching skin should be treated topically with
corticosteroids, cannabinoid agonists, capsaicin, emol-
lients, and phototherapy (see above). Local steroid
injections and laser or surgical therapies could also be
tried for the treatment of calcinosis cutis.
Laser therapies or noninvasive methods like cam-
ouflage have been used for telangiectases. Bleaching
agents, salicylic acids, and chemical peels, as well
as camouflage, retinoids, and corticosteroids, may
have the potential to improve hyperpigmentation or
hypopigmentations (see Table 63-8).
Two randomized clinical trials have shown that
methotrexate improves the skin score in early diffuse
SSc, while positive effects on other organ manifesta-
tions have not been established.92,93 On the other hand,
in two randomized clinical trials, cyclophosphamide
improved skin sclerosis.94,95 For balancing efficacy
and side effects, MMF might be an interesting option
to influence skin fibrosis.74 Protein kinase inhibitors
(eg, imatinib) have been used, but as of this writing,
controlled clinical trials have been mixed and suggest
poor tolerability.96,97
CARDIOPULMONARY
MANIFESTATIONS
It is increasingly appreciated that a group of patients
with some lung fibrosis have predominantly PAH and
that this group may respond to standard PAH therapies.
There have been substantial advances in the treatment of
PAH over the past decade. Most cases are treated with
oral agents, either an endothelin receptor antagonist
(eg, bosentan, ambrisentan) or a phosphodiesterase 5
inhibitor (eg, sildenafil, tadalafil), once the PAH is signifi-
cantly functionally limited (New York Heart Association
class III). Later, if progression takes place, a combination
of oral treatment or introduction of parenteral prosta-
cyclin is used, by either the IV or subcutaneous route.
Inhaled delivery systems for iloprost are available.
Although PAH is probably responsible for more
deaths than lung fibrosis in SSc, lung fibrosis remains
an important complication. Treatment of SSc-PF remains
challenging.98 Adding to a substantial body of uncon-
trolled or retrospective data suggesting benefit for
cyclophosphamide in SSc-PF, the results of 2 random-
ized, double-blind, placebo-controlled trials have been
Kang_CH063_p1086-1105.indd 1101
reported. Both show a modest placebo-subtracted ben-
efit for cyclophosphamide.99-101 For change in forced
10
vital capacity (percent predicted), this was statistically
significant for the Scleroderma Lung Study comparing
oral cyclophosphamide with placebo, showing a strong
trend (p = 0.06) in the trial of IV cyclophosphamide fol-
lowed by oral azathioprine. At present, most centers use
cyclophosphamide as treatment for severe or progressive
SSc-PF, defining the extent and severity by pulmonary
function tests and HRCT. The extent of disease by HRCT
and a history of progressive restrictive abnormality on
pulmonary function tests is the best predictor of future
decline in lung function and is generally used to make
decisions about therapy. Newer clinical trials have shown
Chapter 63 :: Systemic Sclerosis
equal efficacy in the treatment of both MMF and cyclo-
phosphamide for stabilizing lung function of patients
with scleroderma and ILD.74 MMF therapy is associated
with a stability of lung function for up to 36 months, with
a better side-effect profile than in patients treated with
azathioprine.102 Other therapies that are in use include
carbocysteine and low-dose corticosteroids. The place
of other immunosuppressive strategies remains uncer-
tain and requires evaluation in prospective multicenter
clinical trials. It is noteworthy that despite there being a
strong theoretic rationale for using the endothelin recep-
tor antagonist bosentan as a therapy for lung fibrosis,
bosentan was not superior to placebo in a recent large
multicenter study of SSc-PF cases.
Cardiac involvement from SSc is also an important
contributor to mortality but remains one of the least-well
understood and poorly recognized of the internal organ
complications of SSc. A large number of studies confirm
that radionuclide imaging, electrophysiologic, and func-
tional abnormalities are frequent in SSc, but the signifi-
cance of these findings is uncertain. Hemodynamically
significant cardiac involvement occurs in up to 10% of
cases of diffuse cutaneous SSc. An inflammatory compo-
nent of myocarditis may respond to immunosuppressive
treatment, and so an operational approach to manage-
ment of cardiac scleroderma. Although this is not yet
based on sufficient reliable data, it could form a basis for
prospective evaluation of the significance of impaired left
ventricular ejection fraction and elevated circulating tro-
ponin levels in SSc.
There have been many advances in SSc, including
a better appreciation of the diversity of the condition,
improved understanding of the underlying pathologic
mechanisms, and major progress in treating organ-
based complications. This includes the accumulation
of robust clinical trial data that demonstrate effective-
ness or lack of benefit of individual therapies and in
validation of measures of disease assessment.103
GI INVOLVEMENT
Involvement of the GI tract occurs frequently in SSc.
Esophageal symptoms can respond very well to pro-
ton pump inhibitors and agents that increase lower
esophageal sphincter tone such as domperidone,
although high-dose treatment may be associated 1101
with an increased risk of cardiac arrhythmia. Midgut
03/12/18 9:18 am
10 involvement takes many forms. Pseudoobstruction
requires conservative management initially, but sub- TABLE 63-10
sequently may require parenteral nutritional supple- Frequency of Organ Involvement in Two
mentation. Small intestinal bacterial overgrowth can Networks for Systemic Sclerosis (Germany
be treated using broad-spectrum antibiotics, and and United Kingdom)
pancreatic insufficiency may require enzyme supple-
DIFFUSE CUTANEOUS LIMITED CUTANEOUS
ments. Large bowel involvement is a major challenge.
SYSTEMIC SCLEROSIS SYSTEMIC SCLEROSIS
Anorectal incontinence sometimes responds well to an
implanted sacral nerve stimulator or to less-elaborate UNITED UNITED
CLINICAL GERMANY KINGDOM GERMANY KINGDOM
approaches, such as bioplastic injection to increase the
FEATURES (n = 780) (n = 741) (n = 1190) (n = 1505)
internal anal sphincter bulk. Associated rectal prolapse
may require additional surgical intervention. Chronic Raynaud phe- 95.3% 97% 96.3% 99%
constipation, sometimes with overflow diarrhea, is nomenon
a common problem. An adjustment to diet and judi- Skin 95.9% 100% 90% 90%
Part 10

cious use of stimulating, softening, or bulking aperi- Hardening

ents is recommended, but an individualized approach Digital 36% 28% 24.3% 13%
with substantial patient involvement is generally the ulcerations
most successful approach. On occasion, defunctioning PAH 20.2% 12% 14% 15%
::

colostomy is needed, but this is only appropriate in a

Lung fibrosis 62.9% 38% 26.7% 16%
Autoimmune Connective Tissue and Rheumatologic Disorders

very limited number of cases.

GI tract 65.2% 90% 60.7% 90%
involvement
Heart 20% 3% 9.9% 1%
SCLERODERMA involvement

RENAL CRISIS Kidney

involvement
15.9% 19% 9.7% 3%

Musculo- 48.8% 45% 38.8% 35%

Overall, approximately two-thirds of the cases of SRC
that present to a specialist center require renal replace-
ment therapy. Of these, approximately one-half of cases
eventually recover sufficiently to discontinue dialysis.
This can occur over 24 months after the renal crisis,
and so decisions about renal transplantation should be
postponed depending on the outcome. The possibility
of late recovery distinguishes SRC from other causes
of end-stage renal failure. These outcomes are possible
through the use of angiotensin-converting enzyme
inhibitors as routine therapy for SRC. Before their
availability, the mortality from established SRC was
greater than 90% at 12 months. The most critical aspect
of management of SRC is prompt identification and
treatment of significant hypertension in the context of
scleroderma, with initiation of angiotensin-converting
enzyme inhibitors. This is a medical emergency and
any features of renal impairment or end-organ dam-
age should prompt hospitalization.104
Table 63-10 illustrates the frequency of organ
involvement in 2 networks for SSc (Germany and
United Kingdom).
OTHER SUPPORTIVE
PROCEDURES
All these organ-specific therapeutic approaches have
to be supported by several general measures to help
the patients. These general measures include recom-
mendations for keeping the home and the body warm,
and for optimizing nutritional status. Paraffin waxing
1102 and physical therapy has to be provided. Patients need
to be taught to deal with the complications of daily life
skeletal
involvement
and to recognize early those symptoms that indicate
disease progression and new organ involvement.
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