Clinical and serologic features
of systemic sclerosis
Christopher P. Denton • Voon H. Ong
Key Points
■ The updated classification criteria for systemic sclerosis reflect disease heterogeneity
and improve diagnostic sensitivity and specificity of systemic sclerosis (SSc) subsets.
■ Autoantibodies help to characterize disease subsets and stratify risks of visceral
involvement.
■ Pulmonary complications, in particular interstitial lung disease, are leading causes of
death, and management is determined by the pattern and extent of disease to
stratify those at high risk of progression and thus guide treatment decisions.
■ Screening and early recognition of suspected pulmonary arterial hypertension in
patients with SSc are critical because sequential combination goal-oriented
treatment strategy is now the standard of care for this complication.
■ Gastrointestinal involvement can affect any or all of the alimentary tract and is a
prominent symptom in nearly all patients with SSc.
■ Psychological aspects of SSc, in particular depression and anxiety, are often
overlooked but remain pervasive in patients with SSc.
INTRODUCTION
The clinical features of systemic sclerosis (SSc) are diverse and responsible
for the major clinical challenge of the disease. They also underpin the diagnosis
and classification of the disease; these issues are discussed elsewhere in the
textbook. One of the hallmarks of SSc is clinical heterogeneity, and this is
reflected in the variety and severity of the clinical features. These also form
the basis of differentiation of the major clinical subsets of the disease. The
development of major organ disease determines the outcome and especially
survival from SSc. However, the burden of nonlethal manifestations is also
important because it has a major impact on patients and because many of
the nonlethal aspects are much more prevalent. Even for the individual
manifestations, there is substantial variation in the severity, and this forms
an important aspect of clinical assessment of SSc that is described elsewhere.
In this chapter, the major clinical features of SSc are summarized for each
of the affected organ systems and manifestations. An overview of presentation,
symptoms, signs, and investigational findings is given; the specific management
of these aspects of SSc is described elsewhere (see Chapter 153).
DIAGNOSIS AND CLASSIFICATION
Systemic sclerosis is clinically heterogeneous and can be classified into distinct
subsets based on the pattern and extent of disease. The major subgroups of
patients are summarized in Box 150.1. This takes account of the extent of
skin involvement and the presence of overlapping features with other
autoimmune rheumatic diseases. The detailed aspects of disease classification
and diagnosis are dealt with elsewhere in this textbook but are firmly based
on clinical and serologic manifestations of the disease. This is much more
complete reflected in the 2013 European League Against Rheumatism/American
College of Rheumatology (EULAR/ACR) Classification criteria1 than in the
earlier 1980 preliminary classification criteria.2 The classification criteria
permit most cases of SSc to be reliably classified for the purposes of clinical
research and operationally the 2013 EULAR/ACR classification criteria are
often used for diagnosis. The criteria are summarized in Table 150.1.
CLINICAL FEATURES
SKIN
Involvement of skin represents a hallmark feature of SSc. The most important
and frequent manifestation is skin thickening, and this can be assessed using
the modified Rodnan skin score (Fig. 150.1). Skin sclerosis also is used in
the current subset definition whereby proximal involvement defines the
diffuse cutaneous form of SSc.3 The skin is less markedly involved in limited
cutaneous disease, and the extent of involvement is more varied.
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150  
Pruritus represents another important skin manifestation of SSc and has
a number of different causes.4,5 It tends to be most prominent in early-stage
diffuse disease but can be persistent and also occur in late disease associated
with skin dryness. The practical approaches to managing this disease are
important, and it represents one of the largely neglected clinical features
that many patients experience.6,7
Telangiectasias are a frequent cutaneous feature of SSc, and a number of
patterns are recognized. These include the classical lesions seen on the palms
and face with a predilection for the lips and upper body. Other patterns
include a much more extensive serpiginous pattern of telangiectasia that
may be seen in later stage diffuse SSc. There has been the observation that
these cutaneous vascular lesions may often be a reflection of disease
duration.
MUSCULOSKELETAL
It is no surprise that musculoskeletal manifestations are frequent in SSc, but
the diversity and pattern of involvement need particular attention. Manifesta-
tions include arthritis, tendinitis, and severe contractural arthropathy. These
patterns of involvement may occur at different times and in a distinct subgroups
of patients. The main musculoskeletal features of SSc together with relevant
assessment techniques are summarized in Table 150.2.
Arthritis has been associated with anti–cyclic citrullinated protein antibody
(ACPA) and rheumatoid factor (RF) positivity and may occur in the context
of an overlap connective tissue disease.8,9 It may on occasion be symmetric
and rheumatoid-like, but some patients have a more destructive arthropathy
with bone resorption. In addition, there is a propensity to deformity that
may be compounded by contractural tendinopathy in SSc. In addition, the
fibrotic changes in the skin and other soft tissues may result in a much
greater degree of permanent deformity than is typical of a Jaccoud pattern
of arthritis that may be a hallmark of systemic lupus erythematosus (SLE).10,11
Tendon involvement can occur in a number of contexts. In diffuse cutaneous
disease, especially with anti-RNA polymerase III positivity, it is common to
have tendon friction rubs that occur at many sites, including the ankle,
wrists, and fingers.12 This is a peculiar musculoskeletal manifestation of SSc
and is characterized by stiffness or resistance to passive movement and to
a grating roughness on passive movement that may be felt or heard by
auscultation with a stethoscope over the affected site. Typically, a tendon
will exhibit a “rub” on three or four occasions and then move more normally
for a period of time, so careful assessment is important. Tendon friction rubs
have been associated with an increased risk of scleroderma renal crisis.13
Contractures of the hands and sometimes the large joints or feet are a
hallmark of severe SSc and may be especially prominent in some defined
subgroups. There appears to be an association with antireticulin antibody
(anti-RNA polymerase III [ARA]) positivity, and this pattern of disease has
been especially reported in paraneoplastic cases of SSc.14 The contracture
often develops over a short period of time in the early stages of disease and
when established may be a major cause of long-term morbidity. Examples
of musculoskeletal and soft tissue manifestations of SSc are shown in
Fig. 150.2.
GASTROINTESTINAL TRACT
The gastrointestinal (GI) tract can be involved in many ways and is the most
frequent internal organ manifestation of the disease. Although involvement
can be considered anatomically and this has value in disease assessment, it
is also useful to take a problem-oriented approach that integrates the various
overlapping causes for some important symptoms. GI manifestations of SSc
are summarized in Fig. 150.3.
The mouth and teeth are affected, including a very high frequency of
xerostomia. These sicca symptoms may be seen especially in those with
limited cutaneous SSc and clinical overlap with Sjögren syndrome. Vascular
lesions occur and can bleed and require local treatment (Fig. 150.4). In
addition, there are problems with mouth opening and with connective tissue
1237
1238 SECTION 12  Systemic Sclerosis

BOX 150.1  CLINICAL FEATURES OF THE MAJOR SUBSETS OF Table 150.1 

SYSTEMIC SCLEROSIS
The 2013 European League Against Rheumatism/American College of
Limited SSc Rheumatology criteria for the classification of systemic sclerosis
■ Skin sclerosis distal limbs and face Item Subitem(s) Weight/score*
■ Long preexisting RP symptoms Skin thickening of the fingers — 9
■ Lower frequency of severe lung fibrosis and renal crisis of both hands extending
■ High burden of nonlethal morbidity proximal to the
metacarpophalangeal joints
Diffuse SSc
(sufficient criterion)
■ Proximal skin sclerosis Skin thickening of the fingers Puffy fingers 2
■ Shorter preexisting RP history (only count the higher score) Sclerodactyly of the fingers 4
■ High frequency of severe lung fibrosis (distal to the MCP joints
■ Increased risk of scleroderma renal crisis but proximal to the PIP
■ Inflammatory skin changes and pruritus common for first 1–3 years joints)
Sine SSc Fingertip lesions (only count Digital tip ulcers 2
the higher score) Fingertip pitting scars 3
■ Features of RP with scleroderma-associated ANA reactivity and at least Telangiectasia — 2
one internal organ manifestation of SSc Abnormal nail-fold capillaries — 2
■ Frequency uncertain because of likely underdiagnosis PAH, ILD, or both (maximum PAH 2
Overlap SSc score, 2) ILD 2
Raynaud phenomenon — 3
■ Cases that fulfill classification criteria for SSc and are diagnosed as SSc SSc-related autoantibodies Anticentromere 3
but also show features of another autoimmune rheumatic disease (anticentromere, anti– Antitopoisomerase I
■ Most often myositis
topoisomerase I [anti–Scl- Anti–RNA polymerase III
■ Other cases of lupus, arthritis, or vasculitis
70], anti–RNA polymerase
■ Comprise up to 20% of SSc cohorts
III) (maximum score is 3)
ANA, Antinuclear antibody; RP, Raynaud phenomenon; SSc, systemic sclerosis. *Patients with a total score of ≥9 are classified as having definite systemic sclerosis (SSc).
ILD, Interstitial lung disease MCP, metacarpophalangeal; PAH, pulmonary arterial hypertension; PIP,
proximal interphalangeal.
(From van den Hoogen F, Khanna D, Fransen J, et al. 2013 classification criteria for systemic sclerosis:
an American college of rheumatology/European league against rheumatism collaborative initiative. Ann
Rheum Dis. 2013 Nov;72(11):1747-55. Tab 1)

ASSESSING SKIN SEVERITY IN SYSTEMIC SCLEROSIS BY THE MRSS

a Histologic correlation of skin score grades c Standard recording of MRSS Date_______

ID_________
1 - Uninvolved
0 1 2 3 Face
2 - Mild thickening
3 - Moderate thickening 0 1 2 3 Abdomen
4 - Severe thickening 0 1 2 3 Chest
1 2 3
Skin score grade
Upper arm 0 1 2 3 0 1 2 3 Upper arm

b Palpation of skin to assess MRSS Forearm 0 1 2 3 0 1 2 3 Forearm

Hand 0 1 2 3 0 1 2 3 Hand

Fingers 0 1 2 3 0 1 2 3 Fingers
Thigh 0 1 2 3 0 1 2 3 Thigh

Leg 0 1 2 3 0 1 2 3 Leg

Foot 0 1 2 3 0 1 2 3 Foot

Total ___/51

FIG. 150.1  Assessing skin severity in systemic sclerosis (SSc) by the modified Rodnan Skin Score (MRSS). The MRSS is used in routine assessment of SSc and
in clinical trials in which it is a validated endpoint for diffuse SSc. The score assesses estimated skin thickness, which correlates with the skin biopsy thickness,
weight, and collagen content (a). The thickness is assessed by palpation at 17 sites (b), and the sites are recorded on a standard assessment sheet, with an
example shown (c). (Adapted from Denton CP. A 30 year old woman with puffy hands, Raynaud’s phenomenon and carpal tunnel syndrome. In: Silver RM,
Denton CP, editors. Case studies in systemic sclerosis. London: Springer-Verlag; 2011.)

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 CHAPTER 150  Clinical and serologic features of systemic sclerosis 1239

a b c

FIG. 150.2  Musculoskeletal and soft tissue manifestations of systemic sclerosis. (a) Focus of soft tissue calcification anterior to the tibial tuberosity. (b) Acro-osteolysis of all
distal phalanges, which is worst on the little and index fingers. (c) Contractural changes affecting the digits with foci of calcification and isolated telangiectasia.

Table 150.2 
MANIFESTATIONS OF SSc AFFECTING THE GI TRACT
Overview of musculoskeletal complications of systemic sclerosis
Serologic
Manifestation Clinical features associations History, trial of PPI therapy, endoscopy,
Contractures Typical feature of dcSSc ARA, ATA, RF, Baseline assessment
manometry, MUST evaluation
Associated with ARA positivity ACPA
Palmar fibrosis
Tendonitis or Overlap arthritis ARA Gastroesophageal
tendon friction SSc manifestations
Orodental complications reflux and dysphagia
rubs
Arthritis May resemble RA in overlap U1RNP, ACPA,
Associated with RF positivity and RF Distention and bloating GAVE or anemia Diarrhea
ACPA positivity
More with U1RNP reactivity
Contributes to deformity and Weight loss and malnutrition Exocrine pancreatic insufficiency
contractures
May have Jaccoud pattern but
with fixed deformity Constipation Anorectal incontinence
Myositis Minor elevation in CK common, U1RNP,
especially in dcSSc PM-Scl,
Weakness and loss of muscle bulk U3RNP Common comorbidities Barrett metaplasia Rectal prolapse
Severe myositis less frequent
Overlap syndromes with myositis
most common Diverticular disease Sigmoid volvulus
Serologic associations include
anti–PM-Scl, anti-U1RNP,
anti-fibrillarin
Acro-osteolysis More common in environmentally ACA, ATA FIG. 150.3  Manifestations of systemic sclerosis within the gastrointestinal (GI) tract
triggered SSc are frequent and require careful assessment. The major features are summarized
Association with vasculopathy and for the upper, mid, and lower GI tract together with important comorbidities that
Raynaud phenomenon may need additional assessment and treatment. GAVE, Gastric antral vascular ectasia;
Possible association with calcinosis MUST, Malnutrition Universal Screening Tool; PPI, proton pump inhibitor.

ACA, Anticentromere; ACPA, anti–cyclic citrullinated protein antibody; ARA, anti-RNA polymerase III
antibody; ATA, antitopoisomerase; CK, creatine kinase; dcSSc, diffuse cutaneous systemic sclerosis;
PM-Scl, anti-polymyositis scleroderma antibody; RA, rheumatoid arthritis; RF, rheumatoid factor; SSc,
systemic sclerosis; U1RNP, anti-U1-ribonucleoprotein antibody; U3RNP, anti-U3-ribonucleoprotein
antibody.

loss in the lips and buccal tissues.15 These problems all lead to difficulty
with dental caries and other aspects of gingival disease. Management of oral
and dental issues requires expert assessment and multidisciplinary care,
including dental, oral surgery, and oral medicine colleagues.
The esophageal involvement in SSc is well recognized and seems to be
almost universal. Patients have substantially impaired motility and reduced
lower esophageal sphincter pressure that leads to reflux. This is seen clearly
with high-resolution manometric assessment compared with a healthy
individual (Fig. 150.5). Esophagitis can be treated with proton pump inhibitors
and other approaches, but other manifestations include dysphagia and volume
reflux. On occasion, there may be stricture formation from scarring, and
this can respond to treatment with endoscopic dilatation. Barrett esophagus
can develop, and there is an increased risk of malignancy in affected patients,
although some metaplastic changes may resolve during follow-up.16
Gastric manifestations include outflow obstruction, slow gastric emptying,
and vascular complications with ectasia (gastric antral vascular ectasia
[GAVE]). Clinically, these manifestations translate into subjective postprandial
bloating and early satiety that can contribute to poor nutritional intake and
a b c
Telangiectasiae on the GAVE GAVE after argon
oral mucosa plasma treatment
FIG. 150.4  Mucosal vascular involvement in the gastrointestinal tract. Superficial
vascular lesions occur on the buccal mucosa in some cases of systemic sclerosis
(SSc) and can be associated with local bleeding. (a) Typical lesions in a patient with
limited cutaneous SSc. In the stomach, a typical appearance is that of gastric antral
vascular ectasia (GAVE, or watermelon stomach). This is shown at diagnosis (b) and
after a first treatment with argon plasma photocoagulation (c).
weight loss. In addition, the retention of gastric contents is a contributory
mechanism for gastroesophageal reflux. Gastritis may develop in association
with other manifestations but is generally controlled by acid suppressive
therapy. Candida infection may occur in the stomach and esophagus and
lead to painful dysphagia.17 Vascular abnormalities with antral vascular ectasia

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1240 SECTION 12  Systemic Sclerosis

a Normal peristalsis Good LES relaxation Normal LES pressure b Aperistalsis with preserved amplitudes in proximal esophagus

FIG. 150.5  High-resolution manometry for assessment of esophageal motility in systemic sclerosis. High-resolution manometry catheter
via a transnasal approach monitors the pressure bands across both the upper and lower esophageal sphincters (LESs) in response
to a series of wet swallows on the color contour to assess esophageal motility. (a) This trace demonstrates normal manometric
responses with appropriate relaxation of the LES with peristaltic follow-through wave response on swallowing. (b) Hypotensive LES
and the band of pressure reflect diaphragmatic pressure. Aperistaltic activity in response to wet swallows with some preserved
amplitudes in the proximal esophagus.

is an important cause for recurrent blood loss and secondary iron-deficiency

anemia. Typically, GAVE presents with recurrent severe anemia without
any symptoms of hematemesis or melena; the profound degrees of anemia
often require regular blood transfusion or parenteral iron infusion.18-20 The
baseline and posttreatment appearances of GAVE are demonstrated in
Fig. 150.4. a
Small bowel complications include dysmotility, small bowel obstruction
(SBO), and vascular abnormalities, reflecting that similar mechanisms of
damage can occur throughout the GI tract.21 In addition there may be functional
impairment and malabsorption caused by effects on the submucosa and local
fibrosis, inflammation, and vasculopathy. Exocrine pancreatic insufficiency
has been demonstrated and can contribute to malnutrition as well as symptoms
of bloating and diarrhea.22,23 Mid gut diverticular formation is a recognized
manifestation.24,25
Large bowel complications lead to constipation and may predispose to
sigmoid volvulus and rectal prolapse. This is more likely in the later stages
of SSc. These manifestations occur particularly in well-established disease,
and this can be especially challenging because of other complications such
as cardiorespiratory disease that increase risks associated with definitive
treatment and impact of abdominal distention. Small and large bowel involve-
b c
ment can lead to ileus with intestinal pseudo-obstruction. Whenever possible,
this should be managed conservatively. Patients with SSc generally cope
poorly with major abdominal surgery with increased risks of ileus and slow FIG. 150.6  Clinical and radiologic features of abdominal distention in systemic sclerosis
healing. (SSc). Abdominal distention and bloating is a common clinical feature of SSc.
Other gut complications include pneumatosis coli and diverticular disease, (a) This can be associated with bowel dysmotility and pseudo-obstruction. (b) Protuber-
although the precise role of SSc in the development of some of these features ant abdomen with fecal loading associated with dilated bowel loops in the computed
is often uncertain. These manifestations are often regarded as incidental tomography (CT) scan of the abdomen. No mechanical colonic obstruction was
findings on imaging or other assessment techniques and may not require demonstrated on CT scan of the abdomen. (c) There is clear evidence of constipation
specific therapy or intervention.26,27 The clinical and radiologic features of with dilated bowel on the plain radiograph. Excessive fecal loading within the colon,
small and large bowel involvement are shown in Fig. 150.6. with dilation with no mechanical obstruction.

HEART
Cardiac involvement is important and may be life threatening; unfortunately,
it can also be difficult to detect and assess. The assessment and clinical
features of cardiac complications are summarized in Fig. 150.7. It is likely
that current estimates of the frequency of serious cardiac involvement
understate the prevalence because the clinical significance of investigational
abnormalities in imaging studies, including nuclear medicine, magnetic
resonance imaging (MRI) and positron emission tomography (PET) scans,
and electrophysiologic testing, is unclear. Future studies will likely elucidate
the value of different modalities and help to stratify risk and the need for
treatment.
Arrhythmias and conduction defects
The most frequent clinically important cardiac manifestations of SSc relate
to abnormalities in heart rhythm and rate.28 Ventricular extrasystoles are
common and may be associated with paroxysmal of sustained tachyarrhythmia.
These may reflect cardiac fibrosis with intrinsic conduction defects and
inflammatory processes or local vascular disturbance and ischemia. The first
challenge is to detect these events. Often they are not seen on routine 12-lead
electrocardiograms (ECGs) and require more prolonged monitoring. This
can include 24-hour or longer monitoring. One approach that is now being
evaluated is placement of implantable loop recorders that allow events to
be assessed over a long period of time and with normal everyday activity.
Treatment of arrhythmias depends on their pattern and hemodynamic sig-
nificance, and the same approach to these clinical events in the general
population is applied. This can include recommendation of pacemaker or
implantable cardioverter defibrillator (ICD) devices in some cases, and this
has been associated with better outcomes.29
Conduction defects also may reflect intracardiac fibrosis from scleroderma
and lead to resting ECG abnormalities. Management of conduction defects
follows the principles used in general cardiology and includes the use of
pacing and medical approaches. It has been suggested that later stage lcSSc
cases may be especially at risk and that aortic valve disease may be a contribu-
tory factor. This is difficult to assess as an independent factor in the typical
demographic of SSc.30

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 CHAPTER 150  Clinical and serologic features of systemic sclerosis 1241

ASSESSMENT AND TREATMENT OF CARDIAC INVOLVEMENT IN SSc

Background therapy; consider:

Suspected cardiac disease Role of CCBs uncertain
FIG. 150.7  Cardiac manifestations of systemic sclerosis Syncope Diastolic dysfunction: diuretics
(SSc) are common but can be challenging to diagnose Hypotension Systolic dysfunction: ACEi, ?carvedilol, ?selective beta blocker
ECG abnormality
and manage. This is because minor changes in rate or
Chest pain (pericarditic)
with imaging may not be significant, and other Troponin T, Nt-pro BNP LVEF less than 50%
manifestations can be unpredictable. Cardiac involvement Left heart catheter, endomyocardial biopsy
should be investigated systematically, and
hemodynamically significant disease may be treated as Elevated troponin
outlined in the figure. The use of loop recording reveal Immunosuppression (cyclophosphamide, MMF)
devices in cases with suspected sporadic significant Dual-chamber pacemaker
arrhythmias may be considered to identify patients who
may benefit from an implantable defibrillator (ICD). ACEI,
Angiotensin-converting enzyme inhibitor; CCB, calcium Consider implantable loop recorder
channel blocker; ECG, electrocardiogram; LVEF, left
ventricular ejection fraction; MMF, mycophenolate
mofetil; MRI, magnetic resonance imaging; Nt-pro BNP,
N-terminal pro b-type natriuretic peptide. Echocardiogram Significant ventricular arrhythmia
24-hour tape Reduced systolic function and ICD
Cardiac catheterization
Cardiac MRI Significant bradycardia
Endomyocardial biopsy Pacemaker

FIG. 150.8  Cardiac magnetic

resonance (CMR) imaging
abnormalities in systemic sclerosis
(SSc). In this case of SSc
complicated by cardiac
involvement leading to group II
pulmonary hypertension, features
of enlargement of the left and right
atria are clearly demonstrated with
associated severe tricuspid
regurgitation and flattening of the
interventricular septum despite
good preservation of systolic
function (a). Late gadolinium
enhancement shows the presence
of myocardial fibrosis that delays
clearance of this contract a b
medium (b).

Myocarditis
Inflammatory myocardial disease is important because it can be very serious
through the associated impact of systolic function and the associated cardiac
arrhythmias. In addition, it represents a potentially treatable cardiac manifesta-
tion of SSc. It may be suspected based on the presence of myositis in skeletal
muscle. Elevated cardiac enzymes and troponin are supportive of the diagnosis
but not specific. Investigation by cardiac MRI is now generally performed,
and signs of inflammation are helpful in making the diagnosis and selecting
patients for treatment with immunosuppressive or antiinflammatory
strategies.31
Cardiac fibrosis
Autopsy studies point toward a very high prevalence of cardiac involvement
with increased fibrillary collagen and other extracellular matrix components
being deposited in patients with SSc. Interestingly, although these studies
have included patients with SSc who have had no evidence of MRI abnormal-
ity,32 cardiac MRI is generally considered an important tool for detection of
potential myocardial fibrosis, and the presence of late enhancement with
gadolinium is taken as evidence of fibrosis. It is likely that intracardiac
fibrosis contributes to systolic and especially diastolic dysfunction and may
also contribute to arrhythmias.33-35 Typical MRI abnormalities seen in patients
with SSc are demonstrated in Fig. 150.8.
Valvular heart disease
Although it is well recognized for scleroderma patients to have valvular heart
disease, it is not clear that this is an intrinsic manifestation of the disease.36,37
It is equally likely that it is coincidental based on the age and demographics
of the population that is affected.
Systolic and diastolic dysfunction
Systolic and diastolic cardiac functional abnormalities are important in SSc.
Diastolic dysfunction is one of the most frequent abnormalities and may
reflect intracardiac fibrosis. It contributes to the high prevalence of postcapillary
pulmonary hypertension (PH). Systolic impairment is generally considered
to be more significant and a much more ominous prognostic event. In general,
patients with reduced ejection fraction and arrhythmias may be considered
for ICD placement if they are considered to be at risk of significant cardiac
arrhythmias. In addition, any significant evidence of myocarditis should be
treated with immunosuppression, and other approaches such as intravenous
immunoglobulin or rituximab may also be considered.38,39
LUNGS
Pulmonary complications of SSc are among the most frequent and important
internal organ manifestation. They are also an important cause of respiratory
symptoms that include cough and dyspnea. There are many potential causes
for breathlessness in SSc; they are summarized in Fig. 150.9. The most frequent
is cardiorespiratory and musculoskeletal deconditioning, but this must be
a diagnosis of exclusion after other potentially serious and treatable causes
have been excluded. It is common in SSc to have multiple potential factors
contributing the dyspnea, and this must be considered in assessing patients. For
example, pulmonary fibrosis, pulmonary vascular disease, anemia, and cardiac

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1242 SECTION 12  Systemic Sclerosis

MULTIPLE CAUSES OF SYMPTOMATIC BREATHLESSNESS IN SSc

Overlap features
SLE, vasculitis, myositis
Consider muscle weakness, organizing
pneumonia, pulmonary hemorrhage,
ARDS/DAD
Pulmonary embolus
Interstitial lung disease
Usually NSIP pattern
also UIP and
organizing pneumonia
Pulmonary hypertension
Group 1 (PAH)
Group 1’ (PVOD)
Group 2 (cardiac)
Group 3 (lung disease)
Group 4 (thromboembolic)
Cardiorespiratory or
musculoskeletal
deconditioning
FIG. 150.9  There are many potential causes for breathlessness in
systemic sclerosis (SSc). The most frequent is cardiorespiratory
Gastrointestinal
and musculoskeletal deconditioning but this must be a diagnosis
Anemia from GI blood loss (GAVE,
gastritis, mucosal telangiectasis) of exclusion once other potentially serious and treatable causes
Diaphragmatic splinting from pseudo- have been excluded. Important causes to exclude are pulmonary
obstruction, bloating fibrosis, pulmonary vascular disease, anemia, and cardiac
dysfunction, which all contribute to symptoms of exertional
breathlessness; this can be clinically challenging. ARDS, Acute
Serositis
SSc Pleural or pericardial effusion
respiratory distress syndrome; DAD, diffuse alveolar damage;
GAVE, gastric antral vascular ectasia; GI, gastrointestinal; NSIP,
nonspecific interstitial pneumonitis; PAH, pulmonary arterial
hypertension; PVOD, pulmonary venoocclusive disease; SLE,
Renal systemic lupus erythematosus; UIP, interstitial pneumonitis.
Hypertensive renal
Cardiac crisis: pulmonary
Significant arrhythmia edema, anemia
conduction defect
Cardiac fibrosis
Myocarditis

Table 150.3 
Patterns of parenchymal lung involvement in systemic sclerosis
Classification HRCT appearance Frequency (%) Outcome Treatment
NSIP Homogeneous interstitial shadowing with 50 Variable depending on extent of Supportive
traction bronchiectasis and predilection for disease Antireflux
bases and subpleural locations MMF or CYC
RTX
Experimental agents
UIP Heterogeneous interstitial shadowing with 15 Variable depending on extent of Supportive
architectural distortion, traction disease and may have worse Antireflux
bronchiectasis, and cystic changes outcome than NSIP but not as MMF or CYC
much as in IPF RTX
Experimental agents
OP Patchy and asymmetric changes with 5 Potential for improvements and Steroids and antiinfective treatment
homogeneous appearance and later patchy recovery if treated effectively MMF or CYC if associated significant
scarring fibrosis
PF with Interstitial fibrotic change that may have 10 Variable depending on extent and Supportive
emphysema NSIP or UIP features and is associated with severity Antireflux
airspace enlargement and concurrent MMF or CYC
emphysematous change RTX for fibrosis
Manage airways disease according
to severity and responsiveness
Pleuroparenchymal Interstitial fibrosis with additional pleural- 1 Progressive and difficult to treat Supportive
fibroelastosis based dense fibrosis and scarring with poor outcome Antireflux
extending to the upper zones MMF or CYC
RTX for fibrosis
Aspiration Asymmetric changes often associated with 20 Potential for improvements and Vigorous antireflux and acid
pneumonia esophageal dilatation; leaves patchy recovery if treated effectively; suppressive therapy
scarring may be aggravated by Prophylactic antibiotics and prompt
immunosuppression treatment of intercurrent infection

CYC, Cyclophosphamide; IPF, Idiopathic pulmonary fibrosis; MMF, mycophenolate mofetil; NSIP, nonspecific interstitial pneumonia; OP, organizing pneumonia; PF, pulmonary fibrosis; RTX, rituximab; UIP, usual interstitial
pneumonia.

dysfunction may all contribute to symptoms of exertional breathlessness,
and this can be clinically challenging. A systematic and practical approach
to identify potentially important and reversible factors is required.
Upper airways
The larynx is mostly affected by sicca symptoms and the effect of chronic
reflux, which may lead to inflammation. These features may lead to hoarseness
of the voice and chronic cough. In addition, there may be fibrotic thickening
of the vocal cords. It is important to investigate new-onset symptoms that
may reflect laryngeal involvement by referral and assessment in an otolar-
yngologic clinic. Mucosal telangiectatic lesions occur on occasion and may
be a cause of epistaxis or hemoptysis. All symptoms should be evaluated in
view of the potential for comorbidity or for SSc to occur as a paraneoplastic
phenomenon.40,41
Parenchymal lung disease
Lung fibrosis is a leading cause for SSc-associated mortality and an important
complication. It has been extensively characterized, and management is
based on the severity, progressivity, and risk of future decline. The commonest
histologic pattern associated with SSc is nonspecific interstitial pneumonitis
(NSIP). However, usual interstitial pneumonitis (UIP) and other patterns of
disease may also occur.42 The patterns of parenchymal involvement are shown
in Table 150.3. Although the classification is based on biopsy appearance,
it has now been established that the pattern can be reliably determined in

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 CHAPTER 150  Clinical and serologic features of systemic sclerosis
FIG. 150.10  Patterns of lung
fibrosis observed in systemic
sclerosis. Nonspecific interstitial
pneumonitis pattern (NSIP) (a)
with traction bronchiectasis in
contrast to another patient with an
NSIP pattern with prominent cysts
of variable size up to 2 cm with
basal reticulation (b). Some a b
patients have a pattern with more
extensive honeycombing
reminiscent of interstitial
pneumonitis (c). Recently, a less
common subgroup of patients has
been recognized (d) with more
apical pleurally based change that
resembles the newly described
entity of pleuroparenchymal
fibroelastosis.
c d
most cases through careful examination of cross-sectional imaging by high-
resolution computed tomography (HRCT); representative images of SSc-
associated lung fibrosis are shown in Fig. 150.10. The assessment of lung
fibrosis in SSc must be multifaceted to determine the pattern and extent and
to stratify cases according to the risk of progression. Lung fibrosis with the
NSIP pattern is characterized by a relatively homogeneous change and
preservation of lung architecture. There is a predilection for basal and
subpleural distribution, and there may be elements of homogeneous ground-
glass appearance that may represent fine fibrosis or inflammatory change.
This contrasts with UIP patterns that occur in a minority of cases and have
more disrupted lung architecture with dense areas of fibrosis and often
associated cavitation and cystic change.43 Both patterns of lung fibrosis are
associated with traction bronchiectasis, and the extent of disease is reflected
in risk of progression and outcome. Thus, an operational staging system can
be used that determines the extent of disease with an approximate 20%
threshold for a higher risk of progression.44 This is often used for making
treatment decisions. Other patterns of lung parenchymal disease include
organizing pneumonia, which is more frequent in scleroderma–myositis
overlap syndromes. Other factors to consider are cases in which there is
coexistent emphysematous change.45 This has an impact on assessment and
outcome and may also reflect some of the common pathogenetic processes
that link fibrosis and emphysema. Finally, an uncommon group of
cases has recently been described with pleurally based fibrosis and greater
involvement of the upper lobes; these are designated pleuro-parenchymal
fibroelastosis. Thus, all patterns of parenchymal disease that may occur in
SSc also occur in other contexts, although in general, the outcomes of SSc-
associated diseases are better than those of idiopathic parenchymal lung
disease.46
Pleural and pericardial disease
The development of pleural and pericardial effusions occurs and always
requires careful assessment. It can occur in the context of cardiac failure,
fluid overload, or pulmonary arterial hypertension that leads to pericardial
transudate effusion. Transudates are generally not of any hemodynamic
significance in the pericardial sac; exudates are more important because they
can cause diastolic collapse and tamponade. These are treated aggressively
in conjunction with interventional cardiologists. Inflammatory pleural effusions
occur and require treatment with immunoinflammatory drugs but are relatively
uncommon. In cases of SLE overlap, pleural effusions are more common.
However, noticing an antinuclear antibody (ANA) pattern and autoimmune
serology is not a robust method of assessing or predicting the development
of these serositis presentations. Massive pericardial effusion occurs and may
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1243
requires more specific intervention on occasion. The causes of pleural or
pericardial effusions are included in the associated table and figures in this
chapter.
Pulmonary vascular disease
Pulmonary hypertension occurs as a long-term risk in SSc, and the disease
could perhaps be regarded as a susceptibility phenotype. Thus, in a screened
SSc population, between 1% and 2% of patients will develop PH per year
after the disease is established.46 This has been shown in several recent
studies, and the time-dependent nature of the risk of PH developing is the
most likely explanation for the variation in prevalence of PH reported in
cross-sectional studies. It seems that PH is very unusual when it develops
in SSc of less than 3 years’ duration, but there is a steady accrual of cases
after this time that seems to remain over the duration of SSc. Of those who
develop PH, most are precapillary pulmonary arterial hypertension (PAH);
that is, they fall into group 1 of the standard classification for PH. The
remaining cases are split evenly between those with cardiac causes of PH
that are postcapillary and associated with an elevated pulmonary artery
wedge pressure (group 2) and those with significant concurrent lung fibrosis
that are classified as group III PH. These distinctions are important because
they have implications for management that are discussed elsewhere in this
textbook. Management or PH is directed by expert recommendation, including
those of the European Society of Cardiology and the European Respiratory
Society (ESC/ERS), which were updated in 2015.47 These also make recom-
mendations about screening for PAH. This is important considering the high
risk of this complication in SSc. However, the precise approach to screening
is less clear.48,49 The different strategies used include the use of the DETECT
(detection of pulmonary hypertension) algorithm in relevant patients who
have no previous diagnosis of PH, a significantly impaired gas exchange on
pulmonary function tests (PFTs) (diffusing capacity of the lungs for carbon
monoxide [DLCO] <60%), and an estimated disease duration of at least 3
years from the onset of the first non-Raynaud manifestation of SSc.50 One
consequence of an active screening program is that group with borderline
elevation of the mean PA pressure will be identified; these are important
cases because they will include a group of patients who will progress to
PAH. This has been defined, and the best strategies for predicting progression
are being determined, including a number of risk scores that require further
validation. In addition to the forms of PH already described, it is also important
to consider two other potential mechanisms. The first is thromboembolic
disease, which may occur because of comorbidity related to vasculopathy;
these cases must be identified because they may be amenable to curative
surgical intervention and because management is different from PAH.
1244 SECTION 12  Systemic Sclerosis
The other important mechanisms for PH is the group of pulmonary
venoocclusive disease (PVOD), or pulmonary capillary angiomatosis.51 These
are forms of PH that include a greater proportion of the postcapillary vas-
culature, and there may be overlap with more classical PAH cases. The
cooccurrence of PVOD is a potential reason for single-agent PAH therapies
having reduced efficacy in some cases because the use of vasodilators in
PVOD may be detrimental and lead to clinical worsening or pulmonary
edema caused by the increase in blood delivery in the context of postcapillary
vascular resistance being increased.52
RENAL SCLERODERMA
It is important to consider the range of renal manifestations of SSc that
include chronic kidney disease that may not be clinically significant in many
cases but likely reflects background fibrosis and vasculopathy that are hallmarks
of the disease. The most important renal manifestation is scleroderma renal
crisis (SRC). Interstitial nephritis is well recognized and may relate to
medication or other factors.53 Inflammatory glomerular disease or vasculitis
is typically associated with clinical or serologic features of overlap syndrome,
including SLE or antineutrophil cytoplasmic antibody (ANCA)–associated
vasculitis.54-56
Scleroderma renal crisis is characterized by accelerated hypertension and
has some similarities with other forms of thrombotic microangiopathy.55
Scleroderma renal crisis usually develops in early stage diffuse SSc. It has
a varied frequency depending on geographic or genetic or ethnic factors and
overall is seen more often in North America and Northern European patient
cohorts than in Southern European or Asian patients. The estimated frequency
is up to 14% in recent cohort studies in diffuse SSc and a much lower frequency
of 1% to 2% in cases of limited cutaneous SSc. In up to one fifth of cases,
SRC may be the presenting feature of SSc in that there will not be a preexisting
diagnosis even though in such cases, there often could be features present
that are attributable to SSc over the previously 12 months.53 There is a
well-recognized temporal association with prednisolone or other glucocorticoid
use, although the precise mechanisms and role of this are unclear. Analysis
is confounded by the fact that more aggressive or active cases of SSc that
may have independently increased risk of SRC are also the cases that may
receive glucocorticoids. Current classification criteria for the diagnosis of
SRC are indicated in Table 150.4.
DIGITAL VASCULOPATHY
It is now appreciated that digital vascular complications of SSc are frequent
and may be severe. Operationally, it is helpful to differentiate the effects of
vasospasm (Raynaud phenomenon); severe or critical digital ischemia; and
the commonest complication of digital vasculopathy, ischemic digital ulceration
(DU). These different aspects of digital vascular involvement are outlined
in Box 150.2. Raynaud phenomenon is essentially universal, but in SSc,
there is fixed vascular insufficiency that compounds tissue perfusion. This
is associated with complications including ischemic pain, DU, trophic changes,
and in the most extreme situations with critical digital ischemia.57 Recent
work has suggested that cases can be stratified by severity, and this may be
helpful in planning therapy, especially in the context of limited treatment
Table 150.4 
Clinical features and diagnosis of scleroderma renal crisis
Diagnostic criteria (essential)
New-onset BP >150/85 mm Hg or obtained at least twice over 24 hr
Increase ≥20 mm Hg from usual systolic BP
AKI stage 1 or higher: >50% increase in serum creatinine from stable baseline
or an absolute increase of 26.5 µmol/L
Supportive evidence (desirable)
Microangiopathic hemolytic anemia on blood film, thrombocytopenia, and
other biochemical findings consistent with hemolysis
Findings consistent with accelerated hypertension on retinal examination
Microscopic hematuria on urine dipstick or RBCs on urine microscopy
Oliguria or anuria
Renal biopsy with typical features of SRC, including onion-skin proliferation
within the walls of intrarenal arteries and arterioles, fibrinoid necrosis, and
glomerular shrinkage
Flash pulmonary edema
AKI, Acute kidney injury; BP, blood pressure; RBC, red blood cell; SRC, scleroderma renal crisis.
Reproduced from Lynch BM, Stern EP, Ong V, Harber M, Burns A, Denton CP. UK Scleroderma Study
Group (UKSSG) guidelines on the diagnosis and management of scleroderma renal crisis. Clin Exp
Rheumatol 2016;34(suppl 1005):106-9.
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options and the need to use combination approaches in those most at risk.
One important point is that critical digital ischemia can be a medical emergency
leading to severe pain and requiring urgent hospital based treatments.
Registry data have led to subclassification of digital ulcer disease into
categories of different severity.58,59 This is analogous to other manifestations
of SSc with severely affected cases having much greater disease burden and
increased risk of complications that include infection, pain, and functional
impairment. Overall, more than half of SSc cases are affected by DU at some
point in their disease course, and this has a major impact on quality of life
and may predict the development of other vascular manifestations of disease.60
Severe digital vasculopathy leads to gangrene and amputation (Fig. 150.11)
as well as ulceration and complications of infection. These include soft tissue
infection and in more severe cases osteomyelitis. MRI can be a valuable
BOX 150.2  DIGITAL VASCULOPATHY IN SYSTEMIC SCLEROSIS
Raynaud phenomenon
■ Intermittent vasospasm with triphasic color changes induced by cold or
emotional stress
■ Long-standing precursor in some cases of lcSSc
■ Component of VEDOSS
■ In severe dcSSc, can occur simultaneous to or after onset of other disease
features
■ Clinical diagnosis based on history and clinical photographs or
examination
■ Confirm with infrared thermography
■ Stratify early cases by nail-fold capillaroscopy
Critical digital ischemia
■ Severe persistent ischemia often with abrupt onset
■ Threatened tissue
■ Medical emergency
■ Consider inpatient management
■ Vasodilator therapy
■ Antiplatelet agents
■ Analgesia
■ Minimize surgical intervention
■ Arterial reconstruction
■ Proximal vascular disease may be concurrent and amenable to
revascularization
Digital ulcer disease
■ Digital ulcers occur in lcSSc and dcSSc
■ Trophic ulcers on extensor locations with contractures in dcSSc
■ Treatment includes local and systemic therapy
■ Treat infection and optimize vascular supply
■ Link between severity of DU disease and major complications
■ Chronic or recurrent subgroups have greatest risk and burden
■ Important impact on quality of life and high socioeconomic costs
DU, Digital ulceration; dcSSc, diffuse cutaneous systemic sclerosis; lcSSc, limited cutaneous systemic
sclerosis; VEDOSS, Very Early Diagnosis of Systemic Sclerosis.
a b c
FIG. 150.11  Severe digital vasculopathy with amputation. These clinical images
demonstrate the serious sequelae of severe digital vasculopathy. Progressive digital
gangrene as a consequence of significant vascular disease initially affecting the
middle phalange (a) followed by both index finger and thumbs (b), resulting in
autoamputation of the middle finger and subsequent loss of two other digits
(c) caused by surgical amputation for severe pain and progressive vasculopathy
despite maximal medical therapy.
 CHAPTER 150  Clinical and serologic features of systemic sclerosis 1245

FIG. 150.12  Digital ulceration and

deep infection as complications of
digital vasculopathy. These clinical
photographs show flexion
deformity associated with soft
tissue calcinosis over the volar
aspect of left index finger (a and a b
b) with no focal bony abnormality
on plain radiography (c). Magnetic
resonance image of a finger
demonstrated loss of T1 marrow
signal within the head of the
middle phalanx of the left index
finger (d) consistent with clinical
suspicion of underlying
osteomyelitis.

c d

PATTERNS OF NEUROLOGIC INVOLVEMENT IN SSc

Clinical manifesation Investigations

• Cranial neuropathy • EMG
 Especially trigeminal nerve with • NCS
sensory loss • Bloods and ANA
• Skin biopsy
FIG.150.13  Although less frequent than other features, a • Nerve biopsy
range of neurologic manifestations of systemic sclerosis • Neuralgia • Muscle biopsy

(SSc) are seen. Those affecting the peripheral and  Trigeminal or glossopharyngeal most • Fluoroscopic screening for diaphragmatic
autonomic nervous systems are more common and may frequent weakness
have a multifactorial basis. Central nervous system
involvement is rare and most often seen in the context of • Peripheral neuropathy
an overlap connective tissue disease with features of SLE  Suggests overlap connective tissue
or Sjögren syndrome in which cognitive features are more disease or vasculitis
typical. ANA, Antinuclear antibody; CSF, cerebrospinal  Lower GI involvement impacts on
fluid; CT, computed tomography; EEG, anorectal disease
electroencephalography; EMG, electromyography; GI,
• Autonomic function testing
gastrointestinal; MRI, magnetic resonance imaging; NCS, • Autonomic dysregulation • Nerve biopsy
nerve conduction study; POTS, postural orthostatic  May underlay cardinal manifestations of • Thermographic assessment of Raynaud’s
tachycardia syndrome. SSc, including esophageal dysmotility GI phenomenon
abnormities
 Can lead to more classical features,
including postural hypotension or POTS • CT with contrast
• MRI imaging
• Psychometric testing
• Encephalopathy • EEG
 Especially in scleroderma renal crisis • Lumbar puncture with CSF examination

imaging modality to define the presence of osteomyelitis, although plain
radiography is also used for longer term monitoring of bone infection and
response to treatment. It is particularly critical to consider osteomyelitis as
a complication of digital vasculopathy that are not easily detected either
clinically or on plain radiography as demonstrated in Fig. 150.12.
NEUROLOGIC MANIFESTATIONS OF SYSTEMIC SCLEROSIS
Systemic sclerosis can affect the nervous system in a variety of ways (Fig.
150.13). Although central nervous system (CNS) involvement is much less
frequent in SSc than other systemic autoimmune rheumatic diseases, it is
important to consider the ways that neurologic manifestations occur. In
cases of overlap SSc with features of SLE, vasculitis, or Sjögren syndrome,
the CNS manifestations of these other diseases may occur. These require
assessment and treatment along the lines of other situations with appropriate
neurologic imaging, electroencephalography, and spinal fluid analysis. It is
important to exclude any infective process, including opportunistic pathogens,
that may cause encephalomyelitis or meningitis.61
Intrinsic CNS pathology is very unusual in SSc, but vascular disease may
occur; complex migraines may be seen as comorbidity, and venous sinus
disease may lead to intracranial hypertension and headache.62
Serious and significant neurologic complications may occur in the context
of SRC. The combination of accelerated hypertension and microvascular
disease may explain the predilection for hypertensive encephalopathy that
may be associated with headache, cognitive impairment, and seizures. In
undiagnosed SRC, this is a classical presenting feature and an important part
of evaluation of any case of unexplained generalized seizure, especially in
the context of severe hypertension or acute kidney injury. Another consequence
can be posterior reversible encephalopathy syndrome, which may reflect
altered autoregulation of posterior cerebral circulation in the context of
severe hypertension and its treatment. It is important not to be too aggressive
in reducing systemic blood pressure in established SRC.63

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1246 SECTION 12  Systemic Sclerosis
Other neurologic features include autonomic neuropathy together with
peripheral neuropathy. This should be a diagnosis of exclusion, and other
causes that may coexist should be sought.
Cranial neuropathy is well recognized and tends to be associated with
anti-U1 ribonucleoprotein antibody (RNP) disease. It typically manifests as
trigeminal neuropathy with loss of sensation in the distribution of one or
more branches of the fifth cranial nerve.64 In some cases, the pain can be
bilateral and sufficiently severe, leading to weight loss. Sometimes this may
also be seen with other cranial nerves so that some patients may present
with painful glossopharyngeal neuralgia. The mechanism of these symptoms
is unclear, and treatment may be challenging.
Neuromodulatory agents can be helpful in some cases, including for the
treatment of ischemic rest pain related to severe digital vasculopathy, suggesting
that even in this context, there is an intrinsic neural dysfunction.61
CALCINOSIS
This is likely to arise by different mechanisms, and a number of distinct
clinical patterns are recognized. Thus, some cases have small calcific deposits
at the fingertips and sites of minor tissue trauma or pressure.65 These deposits
can coalesce or become larger and overlap with a group of cases that develop
tumorous calcinosis, especially over the pressure areas of the buttocks,
ischiogluteal region, and elbows. This may resemble some cases of dermato-
myositis, especially juvenile-onset disease.66,67 In other patients, especially
with severe diffuse SSc in the later stages that are often associated with
regression or improvement of skin involvement, there can be a diffuse fascial
calcinosis that can occur in many sites and be especially debilitating in the
wrists. This may lead to calcific periarthritis with limited range of movement
and severe pain. Calcinosis is an important cofactor in the development of
digital ulcers in SSc.68
SEXUAL DYSFUNCTION
Recent studies have highlighted the frequency of both male and female
sexual dysfunction in the disease, and this aspect requires careful and sensitive
attention.69 In general, the approaches that are helpful are similar to other
diseases and include addressing the psychological aspects and impact as well
as physical or practical aspects. Erectile dysfunction is almost universal in
men and can respond to phosphodiesterase type 5 (PDE5)-inhibitors, although
more prolonged treatment may be required than in other circumstances.
Studies suggest that vasculopathy similar to other affected organs is a key
factor. Penile implants and other local approaches may also be considered.
Female sexual complications are most often related to perineal and vaginal
trophic changes or fibrosis leading to dyspareunia.70
SEROLOGIC FEATURES OF
SYSTEMIC SCLEROSIS
Systemic sclerosis is an immune-mediated disease in which there is adaptive
immune system involvement that leads to the near universal presence of
circulating autoantibodies. The most clearly defined antibodies are against
specific nuclear antigens.71,72 A number of reactivities are considered scle-
roderma specific; these have common clinical associations and can be a
considerable value in disease assessment. In addition, some patients with
SSc demonstrate ANA patterns that are also present in other diseases. These
include serologic markers of other autoimmune rheumatic diseases such as
SLE or myositis, especially in patients with overlap syndromes.73 The typical
ANA profiles seen in overlap SSc are listed in Fig. 150.14. Autoantibodies
that occur in other organ-specific autoimmune diseases may also be present;
these include antimitochondrial antibodies and antithyroid antibodies that
are associated with primary biliary cirrhosis and autoimmune thyroid disease,
most often hypothyroidism, respectively. Similarly, there is a recognized
association between SSc and celiac disease that will be associated with
antitransglutaminase antibody reactivity if patients are not on a strict gluten-
free diet. ANCA is seen in some cases and associates with vasculitis. In these
cases, atypical as well as anti-PR3 or anti-MPO reactivity occurs. RF and
ACPAs occur in RA/SSc overlap syndromes and appear to be more common
in SSc patients with arthropathy.
Another important serologic feature in SSc is the presence of antibodies
against cell surface proteins that may include receptors.74,75 The first set of
such antibodies were identified against platelet-derived growth factor (PDGF)
receptors, and a plausible mechanistic link that may involve reactive oxygen
species (ROS) and intracellular signaling to drive fibroblast activation was
described. Recently, antibodies with putative agonist function have been
detected against angiotensin and endothelin receptors.75 This would provide
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TYPICAL ANA PATTERN AND CLINICAL ASSOCIATIONS IN SSc
• Centromere (~30%) ACA
 lcSSc, isolated PAH, bad gut disease
• Topoisomerase-1 (~25%)
 Interstitial lung disease
 dcSSc, renal crisis
• RNApol I, III (~20%)
 Renal crisis
 dcSSc
 Concurrent malignancy ATA
• PM-Scl (~5%)
 Myositis mild skin
 Subgroup with severe disease
including renal crisis
• Fibrillarin (~5%) ARA PM-ScI
 PH, myositis
• Th/To (~3%)
 lcSSc with respiratory involvement
PAH and PF
• U11/U12 (~2%)
 Lung fibrosis AFA
• eIF2B (~1%)
 Lung fibrosis
 dcSSc
 Overlap syndrome
FIG. 150.14  The hallmark antinuclear reactivities are summarized together with their
main clinical associations. These reactivities are generally mutually exclusive and
have specific immunogenetic associations. Thus, a patient will almost always just
have one of these antinuclear antibody (ANA) patterns. Not all are in routine clinical
use, but the three main patterns of anticentromere (ACA), antireticulin antibodies
(ARAs), and antitopoisomerase (ATA) should be part of the initial assessment of any
patient suspected of having SSc and are part of the 2013 European League Against
Rheumatism/American College of Rheumatology classification criteria. AFA, anti-
fibrillarin antibody; dcSSc, diffuse cutaneous systemic sclerosis; IcSSc, limited
cutaneous systemic sclerosis; PF, pulmonary fibrosis; PM-Scl, anti-polymyositis
scleroderma antibody.
a possible pathogenic link between immune and vascular cell dysfunction
in SSc. Finally, it is reported that antibodies against extracellular matrix
components occur, and this seems to associate with severity of disease in
some cases. Table 150.5 summarizes the functional autoantibodies with
target antigen, clinical associations, and putative mechanisms.
More recently, the association of antibodies to variant forms of the target
antigens expressed by tumor cells with malignancy in SSc has been described,
and this might give a mechanistic link potentially relevant to SSc pathogenesis
in general.76,77 It has also been reported that SSc target autoantigens are
overexpressed or selectively fragmented in SSc. Thus, there may be an
antigen-driven process in SSc that contributes to autoantibody generation,
and this may be involved in the initiation or maintenance of cardinal disease
features.
AUTOIMMUNE SEROLOGY
Systemic sclerosis is an autoimmune disease, and one of the hallmarks is
the presence of distinct ANAs. These are largely disease restricted, and the
clinical overlap between cases manifesting the various ANA patterns is striking;
in this way, the ANA pattern can be used to identify cases at increased risk
of specific SSc-related complications. The serologic landscape of SSc is one
of the most compelling aspects to the disease that separates SSc from other
conditions. Mutual exclusivity of the ANA subtypes is generally seen and
appears to reflect the immunogenetic background of affected cases. These
class II major histocompatibility haplotypes may predict the development
of particular antibodies, and in vitro studies have clarified the mechanism
that are involved and epitopes that are targeted.
In genetic studies, there are often stronger relationships with ANA-defined
subtypes than the clinically defined subsets. Fig. 150.14 summarizes the
main SSc ANA subtypes and associations. The immunofluorescence patterns
on Hep2 cells are shown, although bead-based or immunoblot solid phase
assays are now more widely used with confirmation by counter-
immunoelectrophoresis (CIE) or immunoprecipitation.
The hallmark ANA patterns of anticentromere (ACA), antitopoisomerase
(ATA), and antireticulin antibodies (ARAs) that are pathognomonic of SSc
are included in the 2013 ACR/EULAR classification criteria for the disease,
 CHAPTER 150  Clinical and serologic features of systemic sclerosis 1247

Table 150.5 
Summary of potential functional autoantibodies in systemic sclerosis
Antibody
Antibody to angiotensin II type 1
receptor and endothelin type A
receptor
Antibody to muscarinic type 3
receptor
Antibody to PDGF
Anti-endothelial antibody
Anti-fibroblast antibody
Anti–estrogen receptor antibody
Putative target antigen(s) Clinical association Plausible mechanism(s)
AT1R and ETAR on cells Associates with vasculopathy and lung Acts agonistically to increase expression of TGF-β
of vascular system fibrosis; predicts death in PH with other cytokines and induce ERK1/2
phosphorylation in endothelial cells
Neural and myogenic GI dysmotility Mediates enteric cholinergic neurotransmission
receptors
PDGFR Increased local expression of PDGF in Selective induction of ROS in cells expressing
lesional skin and lung in SSc PDGFR by SSc-purified IgG and dimerization of
PDGFR by anti-PDGFR antibodies mediates both
receptor binding and activation
Novel antigen 2, ICAM-1, Associated with vascular involvement Activation of endothelial cell with modulation of
ETAR, topoisomerase I, (digital vasculopathy and PH) fibroblast dysfunction, ADCC with endothelial
CENP-B apoptosis
Intracellular antigens, Higher levels in diffuse subset than Associated with upregulation of ICAM-1 and IL-6
including α-enolase, limited and associated with PAH production with induction of ECM protein synthesis
G6PD, and caldesmon
Not known Possible association with disease Induction of apoptosis of resting lymphocytes and
activity and diffuse subset with proliferation of anti-CD3–activated T cells
anti-Scl70 antibody

ADCC, Antibody-dependent cell-mediated cytotoxicity; AT1R, Angiotensin II type 1 receptor; CENP-B, anti-centromere protein B antibody; ETAR, Endothelin type A receptor; G6PD, glucose-6-phosphate dehydrogenase;
GI, gastrointestinal; ICAM, intercellular adhesion molecule; IgG, immunoglobulin G; IL-6, interleukin-6; PAH, pulmonary arterial hypertension; PDGF, platelet-derived growth factor;
PDGFR, platelet-derived growth factor receptor; PH, pulmonary hypertension; ROS, reactive oxygen species; TGF, transforming growth factor.

although other less common SSc-specific reactivities are not part of the
formal classification criteria.
RISK STRATIFICATION
Autoantibodies provide valuable information about the risk of specific organ-
based complications of SSc because they are generally present at the time
of diagnosis, and the mutual exclusivity of hallmark ANA patterns in SSc
means that association studies have provided clear indication about which
antibodies are associated with specific complications. There have been studies
that examine the levels of these antibodies longitudinally. These are interesting
in that some associations have been observed, but these may be confusing
because the levels do not predict organ complications or disease outcome.
CONCLUSIONS
The diagnosis and classification of SSc are the cornerstones of evaluation
and management. The clinical and serologic profiles that have emerged provide
a framework for subclassification, and although the clinical associations are
not so strong that they can override other factors in assessment, they are
useful in interpreting and pursuing profiles. The diverse clinical features of
SSc make classification and staging difficult and endow the disease with a
high mortality rate. Although long-term outcomes have improved and
management of individual complications has progressed, there is still an
overall association between outcome and clinical features and serologic
reactivity.

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