Systemic Sclerosis (Scleroderma) and Related Disorders

2783CHAPTER 360

atrophy, malnutrition, inflammation, and fibrosis may all contribute. A

chronic noninflammatory form of myopathy characterized by atrophy

and fibrosis with mildly elevated muscle enzymes occurs in late-stage

SSc. Bone resorption in the terminal phalanges causes the characteristic loss of the distal tufts (acro-osteolysis) (Fig. 360-5). Resorption

of the mandibular condyles can lead to bite difficulties. Osteolysis can

also affect the ribs and distal clavicles.

■ LESS RECOGNIZED DISEASE MANIFESTATIONS

Dry eyes and dry mouth (sicca complex) are common in SSc. Biopsy of

the minor salivary glands in these cases shows fibrosis rather than focal

lymphocytic infiltration characteristic of primary Sjögren’s syndrome

(Chap. 361). Hypothyroidism resulting from Graves’ or Hashimoto’s

disease is common, particularly in lcSSc, and may be underrecognized.

Whereas the central nervous system is generally spared in SSc, unilateral or bilateral sensory trigeminal neuropathy can occur. Erectile

dysfunction is a frequent and occasionally initial disease manifestation.

Inability to attain or maintain penile erection is due to vascular insufficiency and fibrosis of corporeal smooth muscle and responds poorly

to medical therapy. Sexual performance is also adversely affected in

women. While fertility is not impaired in SSc, pregnancy is associated

with a higher risk of adverse fetal outcomes. Furthermore, cardiopulmonary involvement may worsen during pregnancy, and new onset of

scleroderma renal crisis has been described.

Cancer Epidemiologic studies indicate an increased cancer risk

in SSc. Lung cancer and esophageal adenocarcinoma typically occur

in the setting of long-standing ILD or GERD and may be linked to

chronic inflammation and tissue repair. In contrast, breast, lung, and

ovarian carcinomas and lymphomas tend to occur in close temporal

association with the onset of SSc, particularly in patients who have

autoantibodies to RNA polymerase III. In this scenario, SSc may represent a paraneoplastic syndrome that is triggered by the antitumor

immune response.

■ LABORATORY EVALUATION AND BIOMARKERS

Mild microcytic anemia is frequent and may indicate recurrent GI

bleeding caused by GAVE or chronic esophagitis. Macrocytic anemia

may be caused by folate and vitamin B12 deficiency due to smallbowel bacterial overgrowth and malabsorption or by drugs such as

methotrexate. Microangiopathic hemolytic anemia caused by mechanical fragmentation of red blood cells during their passage through

microvessels coated with fibrin or platelet thrombi is a hallmark of

scleroderma renal crisis. The erythrocyte sedimentation rate (ESR) is

generally normal in SSc; an elevation may signal coexisting myositis

or malignancy.

Antinuclear autoantibodies are detected in almost all patients with

SSc. Anti-topoisomerase I (Scl-70) and anti-centromere antibodies

are mutually exclusive and highly specific for SSc. Topoisomerase I

(Scl-70) antibodies are associated with increased risk of ILD and poor

outcomes. Anti-centromere antibodies are associated with PAH, but

only infrequently with significant cardiac, pulmonary, or renal involvement. Nucleolar immunofluorescence pattern may indicate antibodies

to U3-RNP (fibrillarin), Th/To, or PM/Scl, whereas speckled immunofluorescence indicates antibodies to RNA polymerase III, associated with increased risk of scleroderma renal crisis and malignancy

(Fig. 360-14).

■ DIAGNOSIS, STAGING, AND MONITORING

The diagnosis of SSc is made primarily on clinical grounds and is generally straightforward in patients with established disease. Diagnostic

criteria developed for classification are >90% specific and sensitive for

SSc. The presence of skin induration with a characteristic symmetric

distribution pattern associated with typical visceral organ manifestations establishes the diagnosis with a high degree of certainty. In

lcSSc, a history of Raynaud’s phenomenon and GERD symptoms,

coupled with sclerodactyly and nailfold capillary changes, often in

combinations with cutaneous telangiectasia and calcinosis cutis, helps

to establish the diagnosis. Primary Raynaud’s disease is a benign condition that must be differentiated from early or limited SSc. Nailfold

microscopy is particularly helpful in this situation, because in contrast

to SSc, nailfold capillaries are normal. Diagnosing SSc at an early stage

may be a challenge. In dcSSc, initial symptoms are often nonspecific,

Raynaud’s phenomenon may be absent, and physical examination may

only show upper extremity edema and puffy fingers. Early-stage SSc

might be initially misdiagnosed as arthritis, SLE, myositis, or, most

commonly, undifferentiated connective tissue disease leading to delays

in diagnosis. Within weeks to months, Raynaud’s phenomenon and

advancing skin induration appear. SSc-specific autoantibodies provide

a high degree of diagnostic certainty. Raynaud’s phenomenon with

fingertip ulcerations or other evidence of digital ischemia, coupled

with telangiectasia, distal esophageal dysmotility, unexplained ILD or

PAH, or accelerated hypertension with renal failure in the absence of

clinically evident skin induration, suggests the diagnosis of SSc sine

scleroderma. Patients with a new diagnosis of SSc should be screened

for ILD, followed by regular pulmonary monitoring for several years

(Fig. 360-15).

MANAGEMENT OF SYSTEMIC SCLEROSIS

■ OVERVIEW: GENERAL PRINCIPLES

To date, no therapy has been shown to significantly alter the natural

history of SSc. In contrast, numerous interventions are effective in

alleviating the symptoms, slowing the progression of the cumulative

organ damage, and reducing disability. Moreover, a significant decrease

in disease-related mortality has been noted during the past 25 years. In

light of the marked heterogeneity in disease manifestations, course, and

outcomes, optimized care for patients with SSc requires a thoughtful

“precision medicine” approach that is tailored specifically to each individual patient’s unique needs.

The following general principles should guide management

(Table 360-7): prompt and accurate diagnosis; patient subclassification and risk stratification based on clinical, radiologic, and laboratory evaluation, including autoantibody profiles and prognostic and

predictive biomarkers; early recognition of organ-based complications

and assessment of their extent, severity, and likelihood of deterioration; regular monitoring for disease progression, new complications,

and response to and side effects of therapy; adjusting therapy; and

patient education. In order to minimize the risk of irreversible organ

damage, management should be individualized and proactive, with

regular screening and initiation of appropriate intervention at the earliest possible opportunity. In light of the complex and multisystemic

nature of the SSc, a team-oriented management approach integrating

appropriate specialists should be pursued. Most patients are treated

with a combination of drugs that impact different aspects of the disease. Patients should be encouraged to become familiar with potential

complications and therapeutic options, including interventional trials,

and natural history and should be empowered to partner with their

treating physicians. This requires a long-term relationship between

patient and physician, with ongoing counseling, encouragement, and

two-way dialogue.

■ DISEASE-MODIFYING THERAPY:

IMMUNOSUPPRESSIVE AGENTS

Immunosuppressive agents used in other autoimmune diseases have

generally shown modest or no benefit in SSc. Glucocorticoids alleviate

stiffness and aching in early inflammatory-stage dcSSc but do not

influence the progression of skin or internal organ involvement. Since

their use is associated with an increased risk of scleroderma renal crisis,

glucocorticoids should be given only when absolutely necessary, at the

lowest dose possible, and for brief periods only.

Cyclophosphamide has been extensively studied in light of its efficacy in the treatment of vasculitis (Chap. 363), SLE (Chap. 356), and

other autoimmune diseases (Chap. 355). Both oral and intravenous

cyclophosphamide have been shown to reduce the progression of

SSc-associated ILD, with stabilization and, rarely, modest improvement

2784 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

of pulmonary function, HRCT findings, respiratory symptoms, and

skin induration. These benefits of cyclophosphamide need to be balanced against its potential toxicity, including bone marrow suppression, opportunistic infections, hemorrhagic cystitis and bladder cancer,

premature ovarian failure, and late secondary malignancies.

Methotrexate had modest effect on SSc skin involvement in small

studies. Mycophenolate mofetil was evaluated in both open-label and

randomized controlled trials. Both skin induration and ILD improved

in patients treated with mycophenolate mofetil, and the drug was well

tolerated. Tocilizumab, a monoclonal antibody that blocks IL-6 receptor signaling, also showed benefit on both skin and lung involvement

in randomized SSc trials. Open-label studies and small clinical trials

provide some support for rituximab, a monoclonal antibody directed

against the mature B-cell marker CD20, along with extracorporeal

photopheresis, IV immunoglobulin, and abatacept, a fusion protein

that inhibits T-cell co-stimulation and function. The use of cyclosporine, azathioprine, hydroxychloroquine (Plaquenil), thalidomide,

and rapamycin for SSc therapy is currently not well supported by the

literature. Intensive immune ablation using high-dose chemotherapy,

followed by autologous hematopoietic stem cell reconstitution therapy

(HSCT), was associated with durable remission and improved longterm survival in multiple randomized clinical trials. Currently, HSCT

is indicated for selected patients with severe SSc but carries potential morbidity and mortality, as well as significant cost. Additional

forms of potentially disease-modifying cellular therapies are under

investigation.

Antifibrotic Therapy Because tissue fibrosis underlies organ damage

in SSc, drugs that interfere with the fibrotic process represent a rational

therapeutic approach. In older retrospective studies, D-penicillamine

was shown to stabilize skin induration, prevent new internal organ

involvement, and improve survival. However, a randomized controlled

clinical trial in early active SSc found no difference in the extent of skin

involvement between patients treated with standard-dose (750 mg/d)

or very low-dose (125 mg every other day) D-penicillamine. Recent

clinical trials show benefit of the tyrosine kinase inhibitor nintedanib,

alone or in combination with mycophenolate, in patients with SSc-ILD,

with significant slowing of the loss of lung function.

Vascular Therapy The goal of Raynaud’s therapy is to control

episodes, prevent and enhance the healing of ischemic complications,

and slow the progression of obliterative vasculopathy. Patients should

dress warmly, minimize cold exposure, and avoid drugs that precipitate

or exacerbate vasospastic episodes. Extended-release dihydropyridine

calcium channel blockers such as amlodipine and nifedipine, as well

as diltiazem, ameliorate Raynaud’s phenomenon, but their use is often

limited by side effects (palpitations, dependent edema, worsening

gastroesophageal reflux). While ACE inhibitors do not reduce the

A B

C D

E F

FIGURE 360-14 SSc-associated autoantibodies: immunofluorescence. Indirect immunofluorescence of SSc serum samples using HEp-2 substrate. Representative images

show (A) anti-centromere; (B) anti-Scl-70/topoisomerase I; (C) anti-PM/Scl; (D) anti-Th/To; (E) anti-RNA polymerase III; and (F) anti-fibrillarin/U3RNP antibodies. Variations

in immunostaining are clues to autoantibody specificity, but immunoassays with purified autoantigens are needed to confirm antigen specificity. (Courtesy of Marvin Fritzler

and Susan Copple, Inova Diagnostics Inc., San Diego, CA.)

Systemic Sclerosis (Scleroderma) and Related Disorders

2785CHAPTER 360

frequency or severity of episodes, angiotensin II receptor blockers such

as losartan are effective and well tolerated. Patients with Raynaud’s phenomenon unresponsive to these therapies may require the addition of

α1

-adrenergic receptor blockers (e.g., prazosin), phosphodiesterase-5

inhibitors (e.g., sildenafil), topical nitroglycerine, and intermittent IV

infusions of prostaglandins. Low-dose aspirin and dipyridamole prevent platelet aggregation and may have a role as adjunctive agents. In

patients with ischemic digital tip ulcerations, the endothelin-1 receptor

antagonist bosentan reduces the risk of new ulcers. Digital sympathectomy and intradigital injections of botulinum type A (Botox) may be

considered in patients with severe ongoing ischemia. Empirical longterm therapy with statins and antioxidants may retard the progression

of vascular damage and obliteration. There is limited evidence-based

New SSc diagnosis

ILD screening

PFT, HRCT

No evidence of ILD Limited radiologic ILD

Mild-moderate restriction (>70% predicted)

Extensive radiologic ILD

Severe restrictive changes (FVC <70% predicted)

Initiate therapy

Monotherapy or combination

MMF, cyclophosphamide

Nintedanib

Evidence of ILD

progression

Rescue therapy

HSCT, lung Tx

Palliative care

High risk for

ILD progression

Monitoring

PFT every 6 months

for 3–5 years

No Yes

FIGURE 360-15 Proposed algorithm for screening, monitoring, and treatment of systemic sclerosis (SSc)-associated interstitial lung disease (ILD). FVC, forced vital

capacity; HRCT, high-resolution computed tomography; HSCT, hematopoietic stem cell transplantation; MMF, mycophenolate mofetil; PFT, pulmonary function testing; Tx,

transplantation. (Adapted from A Perelas et al: Lancet Respir Med 8:304, 2020.)

TABLE 360-7 Key Principles in Management

• Establish early and accurate diagnosis.

• Detect and evaluate internal organ involvement.

• Define clinical disease stage and activity.

• Tailor individualized therapy to each patient’s unique needs.

• Assess treatment response, and adjust therapy as needed; monitor for

disease activity, progression, and new complications.

information for the treatment of cardiac complications of SSc, which

should be guided by specialists experienced in their diagnosis and

management. While selective beta blockers such as metoprolol can precipitate vasospasm, nondihydropyridine calcium channel blockers can

be used for rate control in atrial arrhythmias, and nonselective alpha/

beta blockers such as carvedilol can be used for improving myocardial

perfusion and left ventricular systolic function.

TREATMENT

SSC-ASSOCIATED INTERSTITIAL LUNG DISEASE

ILD is a leading cause of death in patients with SSc. However,

because the course of SSc-associated ILD is highly variable, it is

important to identify patients who are at high risk for disease

progression. The extent of ILD on HRCT and the FVC at initial

evaluation and the decline in FVC during the preceding 12-month

period are helpful in identifying these patients. Additionally, male

sex, older age at initial presentation, progressive skin involvement,

and myocardial disease may be risk factors for ILD progression.

Patients at high risk for ILD should be monitored by performing

PFTs every 6 months (Fig. 360-15); serial HRCT imaging is not recommended. Cyclophosphamide, given IV or orally for 6–12 months,

2786 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

and mycophenolate mofetil slow the decline in lung function and

improve respiratory symptoms, but cyclophosphamide is associated

with more frequent side effects. The efficacy and optimal duration of antifibrotic therapy with nintedanib, which was recently

approved for SSc-associated ILD, are currently under investigation.

In patients who show continued progression of ILD despite medical therapy, lung transplantation might be considered as a lifeprolonging procedure, although significant GERD contributing to

organ rejection is a concern in SSc. Recurrence of SSc-ILD in transplanted lung allografts has not been reported.

TREATMENT OF GASTROINTESTINAL COMPLICATIONS

Because oral problems, including decreased oral aperture,

decreased saliva production, gum recession, periodontal disease,

and teeth loss, are common, regular dental care is recommended.

Gastroesophageal reflux is very common in SSc and may occur in

the absence of symptoms. Patients should be instructed to elevate

the head of the bed, eat frequent small meals, and avoid alcohol,

caffeine, known reflux exacerbants, and meals before bedtime.

Proton pump inhibitors to reduce acid reflux may need to be

given in relatively high doses. Prokinetic agents such as metoclopramide, erythromycin (a motilin agonist), and domperidone

may occasionally be helpful in SSc but are frequently associated

with side effects. Botulinum toxin injection sometimes ameliorates

impaired gastric emptying. Antireflux procedures such as Nissen

fundoplication can result in secondary achalasia and generally

should be avoided. Episodic bleeding from GAVE (watermelon

stomach) may be treated with endoscopic ablation using laser or

argon plasma photocoagulation, although it commonly recurs. In

some patients, enteral feeding and/or decompression via percutaneous gastrostomy or jejunostomy may become necessary. Small

intestinal bacterial overgrowth secondary to gut dysmotility causes

abdominal bloating and diarrhea and may lead to malabsorption

and severe malnutrition. Short courses of rotating broad-spectrum

antibiotics such as metronidazole, erythromycin, and rifaximin

can eradicate bacterial overgrowth. Small bowel hypomotility may

respond to octreotide, but pseudo-obstruction is difficult to treat.

Fecal incontinence, a frequent but underreported complication,

may respond to antidiarrheal medication, biofeedback, sphincter

augmentation, and sacral neuromodulation. Potential malnutrition

should be routinely assessed.

TREATMENT OF PULMONARY ARTERIAL HYPERTENSION

In SSc, PAH carries an extremely poor prognosis and accounts

for 30% of deaths. Because PAH is asymptomatic until advanced,

patients with SSc should be screened at initial evaluation and

regularly thereafter. Treatment is generally started with an

oral endothelin-1 receptor antagonist such as bosentan or a

phosphodiesterase-5 inhibitor such as sildenafil. Recently, the soluble guanylate cyclase stimulator riociguat, which acts by increasing

the production of nitric oxide, and the selective IP prostacyclin

receptor agonist selexipag were shown to improve PAH symptoms

and survival. Patients may also require diuretics and digoxin. If

hypoxemia is documented, supplemental oxygen should be prescribed in order to avoid secondary pulmonary vasoconstriction.

Prostacyclin analogues such as epoprostenol or treprostinil can

be given by continuous IV or SC infusion or via intermittent nebulized inhalations. Combination therapy with different classes of

agents acting additively or synergistically is often necessary. Lung

transplantation remains an option for selected SSc patients with

PAH who fail medical therapy, and 2-year survival rates (64%) are

comparable to those of idiopathic ILD or PAH.

MANAGEMENT OF RENAL CRISIS

Scleroderma renal crisis represents a medical emergency. Since

its outcome is largely determined by the extent of renal damage at

the time that aggressive therapy is initiated, prompt recognition of

impending or early scleroderma renal crisis is essential, and efforts

should be made to avoid its occurrence. High-risk SSc patients

(early disease, extensive and progressive skin involvement, tendon

friction rubs, and anti-RNA polymerase III antibodies) should be

instructed to monitor their blood pressure daily and report significant alterations immediately. Potentially nephrotoxic drugs should

be avoided, and glucocorticoids should be used only when absolutely necessary and at low doses. Patients presenting with scleroderma renal crisis should be immediately hospitalized. Once other

causes of acute renal disease are excluded, treatment should be

started promptly with titration of short-acting ACE inhibitors, with

the goal of rapid normalization of the blood pressure. In patients

with persistent hypertension, addition of angiotensin II receptor

blockers, calcium channel blockers, endothelin-1 receptor blockers,

prostacyclins, and direct renin inhibitors should be considered. In

light of evidence for intrarenal complement pathway activation in

some patients with scleroderma renal crisis, addition of eculizumab

to ACE inhibitors may be considered. Up to two-thirds of patients

with scleroderma renal crisis necessitate dialysis. Substantial renal

recovery can occur following an episode of scleroderma renal crisis, and renal replacement therapy can be ultimately discontinued

in 30–50% of patients. Kidney transplantation is appropriate for

patients unable to discontinue dialysis after 2 years. Survival of

transplanted SSc patients is comparable to that of other diseases,

and recurrence of renal crisis is rare.

SKIN CARE

Because skin involvement in SSc is never life-threatening and stabilizes, and may even regress spontaneously, disease management

should not be dictated by its cutaneous manifestations. The inflammatory symptoms of early skin involvement can be controlled with

antihistamines and short-term use of low-dose glucocorticoids

(<5 mg/d of prednisone). Cyclophosphamide and methotrexate

have modest effects on skin induration. Because the skin is dry,

the use of hydrophilic ointments and bath oils is encouraged, and

regular skin massage is helpful. Telangiectasia, which presents

a cosmetic problem, especially on the face, can be treated with

pulsed dye laser. Ischemic digital ulcerations should be protected

by occlusive dressings to promote healing and prevent infection.

Infected skin ulcers are treated with topical antibiotics and surgical

debridement. While no therapy has been shown to be effective in

preventing soft-tissue calcific deposition or promoting its dissolution, reports support the use of minocycline, bisphosphonates,

and topical or IV sodium thiosulfate (STS). Additional approaches

include carbon dioxide laser treatment, extracorporeal shock-wave

lithotripsy, and surgical high-speed microdrilling.

TREATMENT OF MUSCULOSKELETAL COMPLICATIONS

Arthralgia and joint stiffness are very common and distressing

manifestations in early-stage disease. Short courses of nonsteroidal

anti-inflammatory agents, methotrexate, and cautious use of lowdose glucocorticoids alleviate symptoms. Physical and occupational

therapy can be effective for preventing loss of musculoskeletal function and joint contractures and should be initiated early.

COURSE

The natural history of SSc is highly variable and difficult to predict,

especially in early stages of the disease. Patient with dcSSc tend to have

a more rapidly progressive course and worse prognosis than those with

lcSSc. Inflammatory symptoms of early dcSSc, such as fatigue, edema,

joint pain, and pruritus, subside, and skin thickening reaches a plateau

at 2–4 years after disease onset. It is during the early edematous/inflammatory stage that life-threatening visceral organ involvement may

develop. While existing visceral organ involvement, such as ILD, may

progress even after skin involvement peaks, new organ involvement is

rare. Scleroderma renal crisis generally occurs within the first 4 years

of disease. In late-stage disease (>6 years), the skin is usually soft and

atrophic. Skin regression characteristically occurs in an order that is the

reverse of initial involvement, with softening on the trunks followed

by proximal and finally distal extremities; however, sclerodactyly and

Sjögren’s Syndrome

2787CHAPTER 361

fixed finger contractures generally persist. Relapse or recurrence of skin

thickening after peak skin involvement has been reached is uncommon.

Patients with lcSSc follow a clinical course that is markedly different

than that of dcSSc. Raynaud’s phenomenon typically precedes other

disease manifestations by years or even decades. Visceral organ complications such as PAH generally develop late and progress slowly.

PROGNOSIS

SSc confers a substantial increase in the risk of premature death.

Age- and gender-adjusted mortality rates are five- to eightfold higher

compared to the general population, and more than half of all patients

with SSc die from their disease. In one population-based study of

SSc, the median survival was 11 years. In patients with dcSSc, 5- and

10-year survival rates are 70% and 55%, respectively, whereas in

patients with lcSSc, 5- and 10-year survival rates are 90% and 75%,

respectively. The prognosis correlates with the extent of skin involvement, which itself is a surrogate for visceral organ involvement. Major

causes of death are PAH, pulmonary fibrosis, GI involvement, and

cardiac disease. Scleroderma renal crisis is associated with a 30%

3-year mortality. Lung cancer and excess cardiovascular deaths also

contribute to increased mortality. Markers of poor prognosis include

male gender, African-American race, older age at disease onset,

extensive skin thickening with truncal involvement, palpable tendon friction rubs, and evidence of significant or progressive visceral

organ involvement. Laboratory predictors of increased mortality at

initial evaluation include an elevated ESR, anemia, proteinuria, and

anti–topoisomerase I (Scl-70) antibodies. In one study, SSc patients

with extensive skin involvement, lung vital capacity <55% predicted,

significant GI involvement (pseudo-obstruction or malabsorption),

clinical cardiac involvement, or scleroderma renal crisis had a 9-year

survival <40%. The severity of PAH predicts mortality, and patients

with mean pulmonary arterial pressure ≥45 mmHg had a 33% 3-year

survival. The advent of ACE inhibitors in scleroderma renal crisis had a

dramatic impact on survival, increasing survival from <10% at 1 year in

the pre–ACE inhibitor era to >70% 3-year survival at the present time.

Moreover, 10-year survival in SSc improved from <60% in the 1970s to

>66–78% in the 1990s, a trend that reflects both earlier detection and

better management of complications.

LOCALIZED SCLERODERMA

The term scleroderma describes a group of localized skin disorders

(Table 360-1). These occur more commonly in children than in

adults and, in marked contrast to SSc, are generally not complicated

by Raynaud’s phenomenon or significant internal organ involvement.

Morphea presents as solitary or multiple circular patches of thick skin

or, rarely, as widespread induration (generalized or pansclerotic morphea); the fingers are generally spared. Linear scleroderma may affect

subcutaneous tissues, leading to fibrosis and atrophy of supporting

structures, tendons, muscle, and even bone. In children, the growth of

affected long bones can be retarded. When linear scleroderma crosses

large joints, significant contractures can develop.

MIXED CONNECTIVE TISSUE DISEASE

Patients who have lcSSc coexisting with features of SLE, polymyositis,

and rheumatoid arthritis may have mixed connective tissue disease

(MCTD). This overlap syndrome is generally associated with the

presence of high titers of autoantibodies to U1-RNP. The characteristic

initial presentation is Raynaud’s phenomenon associated with puffy

fingers and myalgia. Over time, sclerodactyly, soft-tissue calcinosis,

and cutaneous telangiectasia may appear. Skin rash suggestive of SLE

(malar erythema, photosensitivity) or dermatomyositis (heliotrope

rash on the eyelids, erythematous rash on knuckles) occurs. Arthralgia

is common, and some patients develop erosive polyarthritis. Pulmonary fibrosis and isolated or secondary PAH may develop. Other

manifestations include esophageal dysmotility, pericarditis, Sjögren’s

syndrome, and renal disease, especially membranous glomerulonephritis. Laboratory evaluation shows elevated ESR and hypergammaglobulinemia. While anti-U1RNP antibodies are detected in high titers,

SSc-specific autoantibodies are absent. In contrast to SSc, MCTD often

responds to glucocorticoids, and the long-term prognosis is better than

that of SSc. Whether MCTD is truly a distinct entity or is a subset of

SLE or SSc remains controversial.

EOSINOPHILIC FASCIITIS (DIFFUSE

FASCIITIS WITH EOSINOPHILIA)

Eosinophilic fasciitis is a rare idiopathic disorder of adults associated with abrupt skin induration. The skin characteristically shows

a coarse cobblestone “peau d’orange” appearance. In contrast to SSc,

Raynaud’s phenomenon and SSc-associated internal organ involvement and autoantibodies are absent. Furthermore, skin involvement

spares the fingers. Full-thickness biopsy of the lesional skin reveals

fibrosis of the subcutaneous fascia, with variable inflammation and

eosinophil infiltration. In the acute phase of the illness, peripheral

blood eosinophilia may be prominent. MRI appears to be a sensitive

tool for the diagnosis of eosinophilic fasciitis. Eosinophilic fasciitis

can occur in association with, or preceding, various myelodysplastic

syndromes or multiple myeloma. Although glucocorticoids cause

prompt resolution of eosinophilia, the skin shows slow and variable

improvement. The prognosis of patients with eosinophilic fasciitis is

generally good.

■ FURTHER READING

Allanore Y et al: Systemic sclerosis. Nat Rev Dis Primers 1:15002,

2015.

Herzog EL et al: Interstitial lung disease associated with systemic

sclerosis and idiopathic pulmonary fibrosis: How similar or distinct?

Arthritis Rheum 66:1967, 2014.

Joseph CG et al: Association of the autoimmune disease scleroderma

with an immunologic response to cancer. Science 343:152, 2014.

Martyanov V, Whitfield ML: Molecular stratification and precision

medicine in systemic sclerosis from genomic and proteomic data.

Curr Opin Rheumatol 28:83, 2016.

Tashkin DP et al: Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): A

randomised controlled, double-blind, parallel group trial. Lancet

Respir Med 4:708, 2016.

■ DEFINITION, INCIDENCE, AND PREVALENCE

Sjögren’s syndrome is a prototype autoimmune disease characterized by lymphocytic infiltration of the exocrine glands resulting in

xerostomia, dry eyes (keratoconjunctivitis sicca), and profound B-cell

hyperactivity. The syndrome has unique features since it presents with

a wide clinical spectrum from organ-specific to systemic disease; can

occur alone or in association with other systemic rheumatic diseases,

more commonly rheumatoid arthritis, limited scleroderma, and

systemic lupus erythematosus; and displays high probability of the

development of lymphoma. Because of all these characteristics, it is

an ideal model to study not only autoimmunity but also lymphoid

malignancy.

Middle-aged women (female-to-male ratio 10-20:1) are primarily

affected, although Sjögren’s syndrome may occur at any age, including

childhood. Patients with earlier disease onset express a more aggressive disease phenotype manifested by a high occurrence of systemic

manifestations and serum autoantibodies. The prevalence of Sjögren’s

syndrome is ~0.5–1%, while 5–20% of patients with other autoimmune

diseases can express sicca manifestations.

361 Sjögren’s Syndrome

Haralampos M. Moutsopoulos,

Clio P. Mavragani

2788 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

■ PATHOGENESIS

The autoimmune phenomena observed in Sjögren’s syndrome include

lymphocytic infiltration of the exocrine glands (primarily salivary

and lachrymal glands) and B lymphocyte hyperreactivity. The latter

is mainly manifested by hypergammaglobulinemia and the presence

of serum autoantibodies toward non-organ-specific antigens such

as immunoglobulins (rheumatoid factors) and extractable cellular

antigens (Ro52, Ro60, and La). The major infiltrating cells in the

affected exocrine glands are activated T lymphocytes. In labial minor

salivary gland tissues with extensive lymphocytic infiltrations, B-cell

populations prevail. Other cellular subsets detected in the labial minor

salivary gland histopathologic lesion of Sjogren’s syndrome include

follicular, myeloid, and plasmacytoid dendritic cells, as well as macrophages. Inflammasome activation and macrophages positive for

interleukin (IL) 18 in the salivary gland lesion have been shown to be

associated with adverse predictors for lymphoma development.

The interplay of endogenous (e.g., intracellular stress, inappropriate

overexpression of endogenous nucleic acids) and exogenous triggers

(e.g., viruses, hormonal triggers, stressful life events) in a background

of a genetically determined hyperactive immune response seems to be

crucial for the initiation and perpetuation of the disease. Ductal and

acinar epithelial cells appear to play a significant role in the initiation

and perpetuation of autoimmune injury. These cells (1) express inappropriately costimulatory molecules and the intracellular autoantigens

Ro and La on their cell surfaces, acquiring the capacity to provide signals essential for lymphocytic activation; (2) produce proinflammatory

cytokines and lymphocyte-attracting chemokines necessary for sustaining the autoimmune lesion and allowing the formation of ectopic

germinal centers; (3) express functional receptors of innate immunity,

particularly Toll-like receptors (TLRs) 3, 7, and 9 molecules, which

may account for the initiation of the autoimmune reactivity; and (4)

display immunoregulatory molecules such as ICAM and CD40. Glandular epithelial cells also seem to have an active role in the production

of B cell–activating factor (BAFF), which is induced after stimulation

with type I and II interferons. Circulating BAFF has been found to be

elevated also in the serum of Sjögren’s syndrome patients, especially

those with hypergammaglobulinemia and serum autoantibodies, and

probably accounts for the antiapoptotic effect on B lymphocytes.

In contrast to B and T lymphocytes, glandular epithelial cells display increased rates of apoptotic death. Established risk genetic loci

implicated in Sjögren’s syndrome include the human leukocyte antigen

DQA1*

0501 allele, as well as variants involved in the interferon/BAFF

axis (IRF 5, STAT 4, BAFF), B-cell function (EBF1, BLK), and chronic

inflammation (TNFAIP3).

CLINICAL MANIFESTATIONS

The majority of patients with Sjögren’s syndrome have symptoms

related to impaired exocrine gland, particularly lacrimal and salivary

gland, function. The disease evolution is slow and, in the majority of

patients, runs a benign course. Studies have shown that prior to disease

onset, patients with Sjögren’s syndrome experience major stressful life

events with which they cannot cope adequately.

The principal oral symptom of Sjögren’s syndrome is dryness (xerostomia). Patients report difficulty in swallowing dry food, a burning

mouth sensation, an increase in dental caries, and problems in wearing

complete dentures. Physical examination shows a dry, erythematous,

sticky oral mucosa. There is atrophy of the filiform papillae on the

dorsum of the tongue, and saliva from the major glands is either not

expressible or cloudy. Intermittent or persistent enlargement of the

parotid or other major salivary glands occurs in two-thirds of patients

with Sjögren’s syndrome. Diagnostic tests include sialometry and several imaging techniques, including ultrasound, MRI, and magnetic resonance sialography of the major salivary glands. In particular, salivary

gland ultrasound is an emerging tool of both diagnostic and prognostic

utility. Biopsy of the labial minor salivary gland allows histopathologic

confirmation of focal lymphocytic infiltrates.

Ocular involvement is the other major manifestation of Sjögren’s

syndrome. Patients usually report a sandy or gritty feeling under

TABLE 361-1 Prevalence of Extraglandular Manifestations in Primary

Sjögren’s Syndrome

CLINICAL

MANIFESTATION PERCENT REMARKS

Nonspecific

Fatigability/myalgias 25 Fibromyalgia

Arthralgias/arthritis 60 Usually nonerosive, leading to

Jaccoud’s arthropathy

Raynaud’s phenomenon 37 In one-third of patients, precedes

sicca manifestations

Periepithelial

Lung involvement 14 Small airway disease/lymphocyte

interstitial pneumonitis

Kidney involvement 9 Interstitial kidney disease is usually

asymptomatic

Liver involvement 6 Primary biliary cirrhosis stage I

Immune complex–mediated

Small vessel vasculitis 9 Purpura, urticarial lesions

Peripheral neuropathy 2 Polyneuropathy, either sensory or

sensorimotor

Glomerulonephritis 2 Membranoproliferative

Lymphoma

Lymphoma 6 Glandular MALTa

 lymphoma

is most common

a

Mucosa-associated lymphoid tissue.

the eyelids. Other ocular symptoms include burning, accumulation

of secretions in thick strands at the inner canthi, decreased tearing,

redness, itching, eye fatigue, and increased photosensitivity. These

symptoms are attributed to the destruction of corneal and bulbar

conjunctival epithelium, a pathology termed keratoconjunctivitis sicca.

Diagnostic evaluation of keratoconjunctivitis sicca includes measurement of tear flow by Schirmer’s I test, determination of tear composition by tear breakup time or tear lysozyme content, and slit-lamp

examination of the cornea and conjunctiva after lissamine green or

Rose Bengal staining that reveals punctuate corneal and bulbar conjunctival ulcerations and attached filaments.

Involvement of other exocrine glands, which occurs less frequently,

includes a decrease in mucous gland secretions of the upper and lower

respiratory tree, resulting in dry nose, throat, and trachea (xerotrachea). In addition, diminished secretion of the exocrine glands of the

gastrointestinal tract leads to esophageal mucosal dysmotility and atrophic gastritis. Dyspareunia, in premenopausal women, due to dryness

of the external genitalia and dry skin also may occur.

Extraglandular (systemic) manifestations are seen in one-third of

patients with Sjögren’s syndrome (Table 361-1) and can be classified as

follows: nonspecific, periepithelial (surrounding of epithelial tissues

by lymphocytes), immune complex–mediated, and lymphoma. Nonspecific manifestations include fatigability, low-grade fever, Raynaud’s

phenomenon, myalgias, arthralgias, and arthritis. Arthritis in patients

with primary Sjögren’s syndrome is nonerosive. Periepithelial pathology due to periepithelial accumulation of lymphocytes results from the

involvement of parenchymal organs such as the lungs, kidneys, and

liver. On the basis of this observation, one of the authors (H.M.M.) has

coined the term autoimmune epithelitis. Lung involvement is usually

manifested with dry cough and rarely with dyspnea. The underlying

lung pathology includes peribronchial infiltrates (bronchitis sicca)

and interstitial pneumonitis. Renal involvement includes interstitial

nephritis, clinically manifested by hyposthenuria and renal tubular dysfunction with or without acidosis. Untreated acidosis may lead to nephrocalcinosis. Immune complex–mediated disease is expressed with

vasculitis affecting primarily small-sized vessels, mainly manifested

with purpura and rarely with urticarial rash, skin ulcerations, mononeuritis multiplex, and membranoproliferative glomerulonephritis