2780 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

skin involvement, severe gastroesophageal reflux, and presence of

topoisomerase-I (Scl-70) autoantibodies, whereas anti-centromere

antibody–positive patients have a reduced risk of ILD. Additional risk

factors for significant ILD include low forced vital capacity (FVC)

or single-breath diffusing capacity of the lung for carbon monoxide

(DLCO) at initial presentation. Esophageal dilatation with chronic acid

reflux in SSc causes recurrent micro-aspiration, a risk factor for the

development and progression of ILD. The most rapid progression in

ILD generally occurs early in the disease course (within the first 3–5

years), when the FVC can decline by 30% per year. In contrast, new

onset of ILD is rare in SSc patients with long-standing disease.

Pulmonary involvement can remain asymptomatic until it is

advanced. The most common presenting respiratory symptoms—

exertional dyspnea, fatigue, and reduced exercise tolerance—are subtle

and slowly progressive. A chronic dry cough may be present. Physical

examination may reveal fine inspiratory “Velcro” crackles at the lung

bases. Pulmonary function testing (PFT) is relatively insensitive for

detecting early pulmonary involvement. In patients with established

SSc-ILD, PFT typically shows a restrictive ventilatory defect (FVC

<70% predicted and/or forced expiratory volume in 1 s [FEV1

]/FVC

ratio >0.8) and reduced total lung capacity (TLC) and diffusing capacity (DLCO). A reduction in DLCO that is significantly out of proportion

to the reduction in lung volumes should raise suspicion for pulmonary

vascular disease but may also be due to anemia. Oxygen desaturation

with exercise is common.

Chest radiography can be used as an initial screening tool to rule

out infection and other causes of respiratory symptoms in SSc, but

compared to HRCT, it is relatively insensitive for detection of early ILD.

Characteristic imaging findings include lower lobe subpleural reticular

linear opacities and ground-glass opacifications with an apicobasal gradient, even in asymptomatic patients with normal PFTs (Fig. 360-12).

Additional HRCT findings include mediastinal lymphadenopathy,

pulmonary nodules, traction bronchiectasis, and uncommonly, honeycomb changes. The extent of interstitial changes on chest HRCT at

baseline is a predictor of ILD progression and mortality. While bronchoalveolar lavage (BAL) can demonstrate inflammatory cells in the

lower respiratory tract and may be useful for ruling out tuberculosis

and other infections, it does not appear to be useful for SSc diagnosis

or for identifying reversible alveolitis. Surgical lung biopsy in SSc is

FIGURE 360-11 Calcinosis cutis in systemic sclerosis. A. Note calcific deposit

breaking through the skin in a patient with limited cutaneous systemic sclerosis

(lcSSc). B. Dual-energy computed tomography showing calcific deposits at the

proximal interphalangeal joints.

A

B

FIGURE 360-12 High-resolution chest CT findings in systemic sclerosis. Top

panel: Early interstitial lung disease with subpleural reticulations and ground-glass

opacities in the lower lobes. Patient in supine position. Bottom panel: Extensive lung

fibrosis with coarse reticular honeycombing and traction bronchiectasis. (Courtesy

of Rishi Agrawal, Northwestern University.)

overlying skin with drainage of chalky white material and secondary infections. Paraspinal sheet calcifications may cause neurologic

complications.

■ PULMONARY FEATURES

The two principal forms of lung involvement in SSc, ILD and pulmonary vascular disease, are frequent and together account for a majority

of SSc-related deaths. Survival is particularly poor in SSc patients with

concurrent presence of these two processes. Less common pulmonary

complications of SSc include aspiration pneumonitis complicating

chronic gastroesophageal reflux, pulmonary hemorrhage due to endobronchial telangiectasia, obliterative bronchiolitis, pleural reactions,

restrictive physiology due to chest wall fibrosis, spontaneous pneumothorax, and drug-induced lung toxicity. The incidence of lung cancer is

increased in SSc.

Interstitial Lung Disease While evidence of ILD can be found

in up to 65% of SSc patients by high-resolution computed tomography (HRCT), clinically significant ILD develops in 16–43%; the frequency varies depending on the detection method used. Risk factors

for significant ILD include male sex, African-American race, diffuse

Systemic Sclerosis (Scleroderma) and Related Disorders

2781CHAPTER 360

TABLE 360-6 Prominent Gastrointestinal Manifestations of Systemic

Sclerosis and Their Management

SITE PRINCIPAL MANIFESTATION MANAGEMENT

Oropharynx Diminished oral aperture

Dry mouth

Periodontitis, gingivitis

Swallowing difficulty

Periodontal care

Artificial saliva

Swallowing therapy

Esophagus Reflux

Dysphagia

Strictures

Barret’s metaplasia

Lifestyle modifications

Prokinetic drugs

Proton pump inhibitors

Endoscopic procedures

Stomach Gastroparesis

Gastric antral vascular

ectasia (GAVE, watermelon

stomach)

Prokinetic agents

Endoscopic laser cryotherapy

Small and large

intestines

Bacterial overgrowth (SIBO)

Diarrhea/constipation

Pseudo-obstruction

Pneumatosis intestinalis

Malabsorption

Colonic pseudodiverticula

Laxatives

Prokinetic agents

Rotating antibiotics

Octreotide

Parenteral nutritional support

Anorectum Sphincter incompetence Biofeedback, sacral nerve

stimulation, surgery

Abbreviation: SIBO, small intestinal bacterial overgrowth.

indicated only in patients with atypical findings on chest imaging. The

histologic pattern on lung biopsy may predict the risk of progression of

ILD, with the NSIP pattern having a better prognosis than UIP.

Pulmonary Arterial Hypertension PAH results from vascular

remodeling of small (<500 μm) pulmonary arteries. PAH develops

in 8–12% of patients with SSc as a late complication and can be an

isolated abnormality or associated with ILD. PAH is defined as a mean

pulmonary artery pressure ≥20 mmHg with a pulmonary capillary

wedge pressure ≤15 mmHg and pulmonary vascular resistance >3

Wood units. The natural history of SSc-associated PAH is variable but

often follows a progressive course leading to right heart failure. The

3-year survival of SSc patients with untreated PAH is <50%. Risk factors include limited cutaneous disease, older age at disease onset, high

numbers of cutaneous telangiectasia, and antibodies to centromere,

U3-RNP (fibrillarin), and B23. Mutations in the BMPR2 gene implicated in idiopathic PAH are not associated with SSc-PAH.

In SSc, PAH is often asymptomatic in early stages. Patients present

with exertional dyspnea and reduced exercise capacity. With progression, angina, near-syncope, and symptoms and signs of right-sided

heart failure appear. Physical examination may show tachypnea, a

loud pulmonic component of the S2 heart sound, pulmonic/tricuspid

regurgitation murmur, palpable right ventricular heave, elevated jugular venous pressure, and dependent edema. Doppler echocardiography

is a noninvasive screening method for estimating the pulmonary

arterial pressure. In light of the poor prognosis of untreated PAH

and better therapeutic response in patients with early diagnosis, SSc

patients should be screened for PAH at initial evaluation and annually

thereafter. Estimated pulmonary artery systolic pressure >40 mmHg

at rest or tricuspid regurgitation jet velocities >3 m/s suggest PAH.

Pulmonary function testing may show a reduced DLCO in isolation or

out of proportion with the severity of restriction. Because echocardiography can over- or underestimate pulmonary artery pressures, cardiac

catheterization is required to confirm the diagnosis of suspected PAH;

assess its severity, including the degree of right heart dysfunction; rule

out veno-occlusive disease and other cardiac (postcapillary) causes

of pulmonary hypertension; and provide prognostic parameters.

Distinguishing PAH in SSc patients from pulmonary hypertension

secondary to pulmonary fibrosis and hypoxia can be difficult. Serum

levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) correlate with the presence and severity of PAH, as well as survival. While

NT-proBNP can be useful in PAH screening and in monitoring the

response to treatment, elevated levels are not specific for PAH and also

occur in other forms of right and left heart disease. Despite more favorable hemodynamics of SSc-associated PAH, its prognosis is worse and

treatment response poorer than for idiopathic PAH. This is most likely

due to frequent concurrence of ILD and cardiac disease in patients.

■ GASTROINTESTINAL INVOLVEMENT

Variable involvement of the gastrointestinal (GI) tract, which can affect

any level, is the most common internal organ manifestation of SSc,

seen in up to 90% of SSc patients with both limited and diffuse cutaneous disease (Table 360-6). Severe GI tract involvement is associated

with male sex and specific autoantibodies. The pathologic findings of

GI involvement in SSc include fibrosis, smooth-muscle atrophy, and

obliterative small vessel vasculopathy throughout the length of the GI

tract. Together they have major impact on quality of life, malnutrition,

and mortality.

Upper Gastrointestinal Tract Involvement Decreased oral

aperture interferes with regular dental hygiene. Loss of periodontal

ligament attaching teeth to the alveolar bone leads to teeth loosening.

Additional oropharyngeal manifestations due to a combination of

xerostomia, shortened frenulum, and resorption of the mandibular

condyles cause much distress. Most SSc patients show symptoms of

GERD (heartburn, regurgitation, and dysphagia) due to a combination

of reduced lower esophageal sphincter pressure resulting in reflux,

impaired esophageal clearance of refluxed gastric contents due to

diminished motility, and delayed gastric emptying. Calcium channel

antagonists and phosphodiesterase inhibitors commonly used to treat

Raynaud’s phenomenon in SSc can further aggravate reflux. Esophageal manometry shows abnormal motility in most patients, even in

the absence of symptoms. Common extraesophageal GERD manifestations in SSc include hoarseness, cough, and chronic microaspiration,

which can aggravate underlying ILD. Characteristic chest CT findings

include dilated patulous esophagus with intraluminal air. Esophageal

dilation is associated with the severity of ILD. Endoscopy may be

indicated in patients with dysphagia in order to rule out opportunistic

infections with Candida, herpes virus, and cytomegalovirus. Severe

erosive esophagitis may be found in patients with minimal symptoms.

Esophageal strictures and Barrett’s esophagus may complicate chronic

GERD in SSc patients. Because Barrett’s metaplasia is associated with

increased risk of adenocarcinoma, these patients require regular surveillance endoscopy with biopsy.

Gastroparesis with early satiety, abdominal distention, and aggravated reflux symptoms is common. Barium contrast studies are neither

sensitive nor specific for evaluation of gastric involvement in SSc.

Gastric antral vascular ectasia (GAVE) in the antrum may occur. These

subepithelial lesions, reflecting the widespread small vessel vasculopathy of SSc, are called “watermelon stomach” due to their endoscopic

appearance. GAVE may present with recurrent episodes of GI bleeding, resulting in chronic unexplained anemia. Patients with SSc show

increased prevalence of Helicobacter pylori infection in the stomach.

Lower Gastrointestinal Tract and Anorectal Involvement

Weight loss and malnutrition due to a combination impaired intestinal

motility, malabsorption, and chronic diarrhea secondary to bacterial

overgrowth are common. Fat and protein malabsorption and vitamin

B12 and vitamin D deficiency ensue and may be further exacerbated by

pancreatic insufficiency. Disturbed intestinal motor function can also

lead to episodic intestinal pseudo- obstruction, with symptoms that

are indistinguishable from those of delayed gastric emptying. Patients

present with acute abdominal pain, nausea, and vomiting, and radiographic studies show acute intestinal obstruction. A major diagnostic

challenge is differentiating pseudo-obstruction, which responds to

supportive care and intravenous nutritional supplementation, from

mechanical obstruction. Colonic involvement in SSc may result in

constipation, occasionally complicated by sigmoid volvulus, fecal

incontinence, GI bleeding from telangiectasia, and rectal prolapse. In

late-stage SSc, wide-mouth sacculations or diverticula occur in the

2782 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

colon and occasionally cause perforation and bleeding. An unusual radiologic finding is pneumatosis cystoides

intestinalis, which is due to air trapping

in the bowel wall that may rarely rupture and cause benign pneumoperitoneum. Studies of the fecal microbiota

in SSc show a reduction in protective

butyrate-producing bacteria, potentially

promoting a proinflammatory intestinal

microenvironment. Although the liver is

rarely affected in patients with SSc, primary biliary cirrhosis may occur, particularly in patients with limited cutaneous

disease.

■ RENAL INVOLVEMENT:

SCLERODERMA RENAL

CRISIS

Scleroderma renal crisis presents with

accelerated hypertension accompanied

by acute kidney injury and progressive failure. This acute life-threatening complication occurs in <15% of SSc patients, almost always

within 4 years of disease onset. Scleroderma renal crisis can occasionally even be the presenting manifestation of SSc. While short-term

survival in scleroderma renal crisis was <10% prior to the advent of

angiotensin-converting enzyme (ACE) inhibitors, outcomes for this

serous complication have shown great improvement. The pathogenesis

involves obliterative vasculopathy of the renal arcuate and interlobular arteries, with consequent intravascular hemolysis (Fig. 360-13).

Progressive reduction in renal blood flow, aggravated by vasospasm,

leads to increased juxtaglomerular renin secretion and angiotensin II

generation, with further renal vasoconstriction resulting in a vicious

cycle that culminates in accelerated hypertension. Risk factors for

scleroderma renal crisis include African-American race, male sex, and

diffuse or progressive skin involvement. Up to 50% of patients with

scleroderma renal crisis have antibodies to anti-RNA polymerase III,

whereas patients with anti-centromere antibodies appear protected.

Palpable tendon friction rubs, pericardial effusion, new unexplained

anemia, and thrombocytopenia may be harbingers of impending scleroderma renal crisis. High-risk patients with early-stage SSc should

monitor their blood pressure daily. Because glucocorticoid use is

associated with scleroderma renal crisis, prednisone in high-risk SSc

patients should be taken only when absolutely required and at low

doses (<10 mg/d).

Patients with scleroderma renal crisis characteristically present with

accelerated hypertension (generally >150/90 mmHg) and progressive

oliguric renal insufficiency. However, ~10% of patients present with

blood pressure in the normal range. Normotensive renal crisis is

generally associated with a poor outcome. Headache, blurred vision,

congestive heart failure, and pulmonary edema may accompany elevation of blood pressure. Moderate thrombocytopenia and microangiopathic hemolysis with fragmented red blood cells can be seen,

and urinalysis typically shows mild proteinuria, granular casts, and

microscopic hematuria. Progressive oliguric renal failure over several

days generally follows. Scleroderma renal crisis is sometimes misdiagnosed as thrombotic thrombocytopenic purpura (TTP) or other

forms of thrombotic microangiopathy. In such cases, renal biopsy

and determination of serum von Willebrand factor–cleaving protease

activity may be of benefit. The presence of oliguria or a creatinine

>3 mg/dL at initial presentation predicts poor outcome (permanent

hemodialysis and mortality), as do vascular thrombosis and glomerular ischemic collapse on renal biopsy. Crescentic glomerulonephritis in the setting of SSc has been described and may be associated

with myeloperoxidase-specific antineutrophil cytoplasmic antibodies

(ANCAs). Membranous glomerulonephritis may occur in patients

treated with D-penicillamine. Asymptomatic renal impairment can

occur in up to half of SSc patients, is commonly associated with other

vascular manifestations, and rarely progresses to end-stage renal

failure.

■ CARDIAC INVOLVEMENT

Although it is often silent, cardiac involvement is detected in 10–50%

of SSc patients screened with sensitive diagnostic tools. Clinical cardiac involvement is more frequent in dcSSc than in lcSSc and may

be primary or secondary to PAH, ILD, or renal involvement. Cardiac

involvement in SSc is associated with poor outcomes. The endocardium, myocardium, and pericardium may each be affected separately

or together. Pericardial involvement is manifested as pericarditis,

pericardial effusions, constrictive pericarditis, and rarely, cardiac tamponade. Conduction system fibrosis is common and may be silent

or manifested by heart block. Other arrhythmias include premature ventricular contractions, atrial fibrillation, and supraventricular

tachycardia. Microvascular involvement, recurrent vasospasm, and

ischemia-reperfusion injury contribute to patchy myocardial fibrosis,

and the resulting systolic or diastolic left ventricular dysfunction may

progress to overt heart failure. Acute or subacute myocarditis leading

to left ventricular dysfunction may occur, best diagnosed by cardiac

magnetic resonance imaging or endomyocardial biopsy. While conventional echocardiography has low sensitivity for detecting preclinical

heart involvement in SSc, newer modalities such as tissue Doppler

echocardiography (TDE), cardiac MRI, and nuclear imaging (singlephoton emission CT [SPECT]) reveal a high prevalence of abnormal

myocardial function or perfusion. The serum levels of NT-proBNP, a

ventricular hormone elevated in SSc-PAH, may also have utility as a

marker of primary cardiac involvement.

■ MUSCULOSKELETAL COMPLICATIONS

Musculoskeletal complications are commonly seen in SSc. Carpal tunnel syndrome may be a presenting disease manifestation, and generalized arthralgia and stiffness are prominent in early disease. Mobility

of both small and large joints is progressively impaired, and fixed contractures at the proximal interphalangeal joints and wrists ensue. Large

joint contractures occur in patients with dcSSc and are frequently

accompanied by tendon friction rubs. These are characterized by

coarse leathery crepitation heard or palpated upon passive joint movement and are caused by fibrosis and adhesion of the tendon sheaths and

fascial planes at the affected joint. The presence of tendon friction rubs

is associated with increased risk for renal and cardiac complications

and reduced survival. Synovitis seen on ultrasound or MRI is common;

occasional SSc patients develop erosive polyarthritis in the hands,

and some may have a seropositive rheumatoid arthritis overlap. Muscle weakness is common and multifactorial; deconditioning, disuse

A B

b

a

FIGURE 360-13 Biopsy and hematologic findings in scleroderma renal crisis. A. Renal biopsy demonstrating intimal

proliferation and myxoid changes in medium-sized renal arteries. B. Fragmentation of red blood cells due to intravascular

hemolysis. (Courtesy of Drs. Edward Stern and Christopher Denton, Royal Free Hospital, London, UK.)