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Clinical Manifestations and Diagnosis of Systemic Sclerosis (Scleroderma) in Adu
Clinical Manifestations and Diagnosis of Systemic Sclerosis (Scleroderma) in Adu
Clinical Manifestations and Diagnosis of Systemic Sclerosis (Scleroderma) in Adu
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jan 2020. | This topic last updated: Jan 03, 2020.
INTRODUCTION
The term scleroderma is used to describe the presence of thickened, hardened skin
(from the Greek "scleros") [1]. Scleroderma is the hallmark feature of systemic sclerosis
(SSc).
This topic will review the clinical manifestations and diagnosis of SSc in adults.
Localized scleroderma, scleroderma-like conditions, and scleroderma disorders in
childhood are presented separately. (See "Localized scleroderma in childhood" and
"Juvenile systemic sclerosis (scleroderma): Classification, clinical manifestations, and
diagnosis".)
BACKGROUND
Patients with dcSSc are more likely to have a rapid progression of skin thickening
with early development of lung fibrosis and an increased risk of renal crisis and
cardiac involvement.
● Systemic sclerosis with overlap syndrome – Patients with SSc (of any of the
above subsets) may have overlap or features of another systemic rheumatic
disease such as systemic lupus erythematosus (SLE), rheumatoid arthritis,
polymyositis, or Sjögren's syndrome.
Epidemiology — The reported incidence and prevalence rates of SSc vary widely
across studies. This may be due in part to the differences in disease classification as
well as possibly true temporal and geographic differences. The overall incidence rates
range globally from 8 to 56 new cases per million persons per year, and the prevalence
rates fall between 38 and 341 cases per million persons per year [3].
The majority of patients with SSc are female. There are differences in disease
presentation, with women trending towards more limited disease, younger age of onset,
increased peripheral vascular disease, and risk for pulmonary arterial hypertension
(PAH). Men have an increased risk of diffuse disease, more severe interstitial lung
disease (ILD), and increased cardiovascular complications [4].
African Americans tend to have earlier-onset disease and more severe disease
phenotypes with increased risk of pulmonary fibrosis and scleroderma renal crisis
(SRC) [5].
In addition to the major organ involvement discussed in detail below, patients with
systemic sclerosis (SSc) often experience pain and fatigue [6]. The level of fatigue that
has been described is comparable to that in rheumatoid arthritis, systemic lupus
erythematosus (SLE), or cancer patients in active treatment [7]. The presence of fatigue
has been associated with poorer physical function and greater pain [6]. Causes of pain
include skin-related discomfort, joint pain, Raynaud phenomenon (RP), and ischemic
digital ulcers.
The distribution of skin lesions forms the basis for the widely used binary classification
Only a small percentage of patients with SSc have no skin induration (termed SSc sine
scleroderma) [9]. Although there is no clinically evident skin sclerosis, these patients
have characteristic vascular and/or fibrotic features of systemic disease, including RP,
nailfold capillary alterations, gastrointestinal involvement, renal crisis, pulmonary
hypertension, and/or interstitial lung disease (ILD).
Digital vasculopathy — RP is virtually always present in patients with SSc and can
predate other disease symptoms by years, particularly in limited SSc. RP is classically
viewed as reversible vasospasm due to functional changes in the digital arteries of the
hands and feet. However, over time, many patients with SSc develop progressive
structural changes in the small blood vessels, with permanently impaired flow. In such
patients, episodes of RP may be prolonged, lasting 30 minutes or even longer, and can
result in ischemic pain, digital ulceration, trophic changes, and in extreme cases,
refractory or progressive ischemia and infarction. (See "Clinical manifestations and
diagnosis of Raynaud phenomenon".)
Joint pain, immobility, and contractures of both small and large joints develop as the
result of fibrosis around tendons and other periarticular structures. Contractures of the
fingers are common, but large joint contractures involving the wrists, elbows, and
ankles may also occur. The process is sometimes associated with palpable and/or
audible deep tendon friction rubs. Tendon friction rubs occur predominantly in patients
Several studies suggest that the presence of tendon friction rubs in patients with SSc is
a marker for aggressive disease and increased risk of internal organ involvement
including renal crisis [13-15]. Destructive joint disease in a patient with SSc may
suggest an overlap syndrome with rheumatoid arthritis. (See "Undifferentiated systemic
rheumatic (connective tissue) diseases and overlap syndromes".)
Radiographs of the hands may reveal soft tissue calcifications (calcinosis cutis) (image
1) and resorption of the distal phalangeal tufts (acro-osteolysis). Articular erosions, joint
space narrowing, and demineralization are less common radiographic findings [16].
PAH is typically progressive and, if severe, can lead to cor pulmonale and right-sided
heart failure. Thrombosis of the pulmonary vessels is a common late-stage complication
and is a frequent cause of death. (See "Pulmonary hypertension due to lung disease
Renal disease in SSc, including SRC, is discussed in detail separately. (See "Renal
disease in systemic sclerosis (scleroderma), including scleroderma renal crisis".)
Women with SSc may also have sexual dysfunction. This is related to decreased
vaginal lubrication or constriction of the vaginal introitus. In one study, dyspareunia was
present in 56 percent of 60 women with SSc [28].
● Cancer risk – There have been several reports demonstrating an increased risk of
malignancy in patients with SSc [29-36]. The most significant association appears
to be with lung cancer, which accounts for approximately one-third of the cancers
seen in SSc patients [31]; however, a significantly increased incidence was not
noted in a population with a high background rate of lung cancer [34]. In a study of
632 Australian patients with SSc, 19 developed lung cancer [37]. Those who
smoked were seven times as likely to develop cancer as those who did not.
Pulmonary fibrosis and antitopoisomerase antibodies were not risk factors for lung
cancer.
The cause of an increased cancer risk in SSc is not well understood. The
association with lung and skin cancers suggests that sites of disease activity may
be prone to malignant transformation.
A close temporal relationship between the onset of cancer and SSc has been
observed among patients with autoantibodies to RNA polymerase I/III [38,39]. One
study demonstrated that tumors harboring somatic mutations in the POLR3A gene
may trigger the development of SSc [40].
● Puffy swollen fingers and/or nonpitting edema of the hands (figure 1). This is more
commonly observed in the early stages of the disease.
● Skin thickening, either diffuse or limited to the hands, feet, face, and forearms. The
assessment of skin involvement includes semiquantitative estimation of skin
thickness, pliability (hardness), and fixation to underlying structures (tethering). The
modified Rodnan skin score is commonly used as an outcome measure in clinical
trials (figure 2A-B). This semiquantitative score rates the severity of these features
from 0 (normal) to 3 (most severe) in 17 distinct areas of the body and shows an
acceptable degree of intra-rater variability.
● Digital pitting with loss of fingertip tissue and superficial digital ulcerations under or
close to the nailbed due to underlying vascular disease. Ulcerations over the distal
or proximal interphalangeal joints may also be observed, but these are usually due
to trauma as a complication of avascular or thinned skin (figure 4).
● Calcinosis cutis (of the hands, elbows, and knees), mucocutaneous telangiectasias
(figure 3), and/or cutaneous hyperpigmentation.
● Tendon friction rubs, which can be felt as coarse crepitus over joints or areas with
adjacent joint involvement. The most common sites of involvement are the tendons
of the fingers and wrists, elbows, knees, and ankles.
Laboratory testing — We obtain the following routine laboratory tests, some of which
may provide information about specific organ involvement:
We also perform the following serologic tests (table 4), which may support the diagnosis
if positive:
● Anti-RNA polymerase III antibody. Antibodies to RNA polymerase III are found in
patients with dcSSc and are generally associated with rapidly progressive skin
involvement as well as an increased risk for scleroderma renal crisis (SRC) [24,48].
These patients may also be at increased risk for concomitant cancer [39,40].
The antitopoisomerase I (anti-Scl-70), ACA, and anti-RNA polymerase III tests are
highly specific (>99.5 percent in some studies) for SSc but are only moderately
sensitive (20 to 50 percent) [46,49,50]. The autoantibodies are almost always mutually
exclusive. Among those with RP but without definite SSc or a related autoimmune
rheumatic disease, the presence of these antibodies predicts an increased risk of
progression to SSc, particularly in combination with puffy fingers and/or abnormal
nailfold capillaroscopy [51]. (See "Clinical manifestations and diagnosis of Raynaud
phenomenon".)
To help in the differential diagnosis of SSc, we also may order the following when
appropriate:
Since these antibodies are relatively uncommon in patients with SSc, their presence
points toward overlap syndromes with other systemic rheumatic diseases. These
syndromes are characterized by a more prominent arthritis than seen in SSc [52]. (See
"Undifferentiated systemic rheumatic (connective tissue) diseases and overlap
syndromes".)
A variety of other SSc-associated serologic tests may also inform the diagnosis, but
their availability is generally limited to specialized research centers (table 5). These
autoantibodies have distinct clinical associations and prognostic implications.
All patients with suspected SSc should be evaluated for ILD and pulmonary
hypertension, which are the most frequent types of lung involvement in SSc patients. A
more detailed discussion of the initial evaluation for lung disease in patients with SSc is
presented separately (see "Clinical manifestations, evaluation, and diagnosis of
interstitial lung disease in systemic sclerosis (scleroderma)", section on 'Evaluation').
However, we will briefly present here the studies that we obtain as part of the initial
diagnostic workup:
● Pulmonary function testing (PFT) – This should be done to assess for the presence
In some patients with SSc, visceral organ involvement may be the predominant clinical
manifestation at the time of presentation. As an example, a patient may present with
SRC even prior to developing characteristic skin changes (see "Renal disease in
systemic sclerosis (scleroderma), including scleroderma renal crisis", section on
'Clinical features'). However, in our experience, these clinical scenarios are atypical and
often represent cases in which the cutaneous findings were subtle or overlooked.
Skin biopsy in selected cases — Skin biopsy is rarely indicated for making the
diagnosis of SSc. However, in some cases, a skin biopsy may be necessary to help
differentiate SSc from other syndromes such as eosinophilic fasciitis, scleredema, or
scleromyxedema. (See 'Causes of scleroderma-like skin changes' below.)
Additional common features include atrophic eccrine and pilosebaceous glands, and
loss of intradermal fat. In patients with early-stage disease, sparse mononuclear cell
infiltrates may be found around the dermal blood vessels [57]. Direct
immunofluorescence studies are usually negative in SSc patients. These lesions may
be histologically indistinguishable from other diseases characterized by collagen
deposition, such as morphea.
DIAGNOSIS
● Any one of the following: pulmonary interstitial fibrosis, primary PAH without
fibrosis, characteristic esophageal motility alterations, or renal failure consistent
with scleroderma renal crisis (SRC)
● An observational study compared the clinical and laboratory features of 507 lcSSc
patients with 48 SSc sine scleroderma patients [9]. Other than the absence of skin
thickening, there were no significant differences in the type of individual internal
organ involvement, serum autoantibodies, or survival rate.
CLASSIFICATION CRITERIA
The 2013 criteria incorporate disease manifestations of the three hallmarks of SSc:
fibrosis of the skin and/or internal organs, production of specific autoantibodies,
and evidence of vasculopathy. Skin thickening of the fingers extending proximal to
the metacarpophalangeal joints is sufficient for the patient to be classified as
having SSc. If that is not present, seven additive items with varying weights for
each should be used: skin thickening of the fingers, fingertip lesions, telangiectasia,
abnormal nailfold capillaries, interstitial lung disease (ILD) or pulmonary arterial
hypertension (PAH), Raynaud phenomenon (RP), and SSc-related autoantibodies.
The sensitivity and specificity for the 2013 criteria were 0.91 and 0.92, respectively.
However, these criteria have yet to be validated in ethnic groups that are not
common in North America and in Europe.
It must be noted that strict adherence to these classification criteria will still exclude
some patients in whom a clinical diagnosis of SSc would likely be made. As an
example, a patient with early-stage SSc presenting with RP, an SSc-specific
autoantibody (described above), and abnormal nailfold capillaroscopy would not
have enough features to be classified as SSc.
● Preliminary criteria for early diagnosis – Preliminary criteria for very early
diagnosis of SSc (VEDOSS) have been proposed in order to identify features of
early disease that may precede characteristic skin thickening and internal organ
involvement, and facilitate earlier diagnosis [67]. Key features (or "red flags")
whose presence should raise suspicion for early SSc include RP, puffy swollen
digits, and the presence of a positive antinuclear antibody (ANA). The prevalence
DIFFERENTIAL DIAGNOSIS
Raynaud phenomenon — RP occurs in over 90 percent of patients with SSc but does
not occur in the other disorders associated with scleroderma-like skin changes
discussed above (see 'Causes of scleroderma-like skin changes' above). On the other
hand, cold-induced digital vasospasm associated with characteristic color changes may
occur in isolation (primary RP, also called Raynaud disease), in other disease states,
and in response to drugs and/or environmental exposures (see "Clinical manifestations
and diagnosis of Raynaud phenomenon"). Primary RP occurs in up to 5 percent of the
general population and more commonly in women; in these individuals, it generally
develops in the first three decades of life, is frequently familial, and is not associated
with ischemic digital ulcers or infarction.
Here are the patient education articles that are relevant to this topic. We encourage you
to print or e-mail these topics to your patients. (You can also locate patient education
articles on a variety of subjects by searching on "patient info" and the keyword(s) of
interest.)
● Major clinical manifestations of SSc include the following (see 'Clinical features'
above):
• All anatomic domains of the heart can be affected in patients with SSc,
including the myocardium, pericardium, and conduction system. Cardiac
manifestations can also occur secondary to PAH, ILD, or scleroderma renal
crisis (SRC). (See 'Cardiac involvement' above.)
• SSc in men is very commonly associated with erectile dysfunction, which can
be an early and even initial manifestation of disease. Women with SSc may
also have sexual dysfunction. (See 'Genitourinary involvement' above.)
● The diagnosis of SSc should be suspected in patients with skin thickening, puffy or
swollen fingers, RP, hand stiffness, and/or painful distal finger ulcers. Symptoms of
gastroesophageal reflux are often present. (See 'Evaluation for suspected systemic
sclerosis' above.)
● We obtain the following routine laboratory tests in patients with suspected SSc,
some of which may provide information about specific organ involvement (see
'Laboratory testing' above):
• Complete blood count and differential, which may reveal anemia due to
malabsorption of iron or gastrointestinal blood loss
• Serum creatinine level, which may indicate renal dysfunction
• Creatine kinase (CK), which may be elevated in patients with myopathy or
myositis
• Urinalysis
● We also perform the following serologic tests (table 4), which may support the
diagnosis if positive:
● We diagnose limited or diffuse SSc in patients with skin thickening of the fingers of
both hands extending proximal to the metacarpophalangeal joints. Among patients
with such involvement, the presence of the following additional findings and/or
abnormalities support the diagnosis of SSc (see 'Diagnosis' above):
• Ischemic fingertip ulcerations (digital tip pitting scars) (figure 4), calcinosis
cutis, hyperpigmentations, and/or mucocutaneous telangiectasia (figure 3).
However, these findings are often absent in patients with early disease.
• Characteristic nailfold capillary changes.
• Heartburn and/or dysphagia of new onset.
• Erectile dysfunction in men.
• RP.
• Acute onset of hypertension and renal insufficiency.
• Dyspnea on exertion associated with evidence of interstitial pulmonary
changes on radiography or HRCT.
• Dyspnea on exertion associated with evidence of PAH on Doppler
echocardiography.
• Diarrhea with malabsorption or intestinal pseudo-obstruction.
• Positive antitopoisomerase I (anti-Scl-70) antibody, ACA, and/or anti-RNA
polymerase III antibody; or a positive ANA with a nucleolar pattern.
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