Other Systemic Autoimmune Diseases

This section covers the following systemic autoimmune diseases:

• Systemic Sclerosis

• Sjögren Syndrome

Systemic Sclerosis

Systemic sclerosis (SSc) is a chronic, multisystem disease characterized by skin fibrosis and widespread extracutaneous involvement, including the synovium, digital arteries, esophagus, intestinal tract, heart, lungs, and kidneys. SSc can be subdivided according to the extent of the skin disease:

• diffuse cutaneous systemic sclerosis (dSSc)

• limited cutaneous systemic sclerosis (lSSc), previously designated as the CREST syndrome (calcinosis cutis, Raynaud phenomenon [RP], esophageal dysfunction, sclerodactyly, telangiectasia)

The localized forms of scleroderma, including morphea and linear scleroderma, are less often associated with systemic manifestations and are not reviewed in this section.

Pathophysiology

The cause of SSc is unknown. It is characterized as a tripartite process involving dysfunction of the immune system, endothelium, and fibroblasts that lead to a heterogenous phenotype characterized prominently by fibrosis (see figure below).

• autoimmunity: circulating disease-specific autoantibodies and multiple abnormalities of T-cell function → inflammation in skin and lungs

• endothelial cell dysfunction/vasculopathy: Raynaud phenomenon, capillary dropout, digital ischemia, pulmonary hypertension, renal crisis

• fibroblast dysfunction: increased synthesis and deposition of extracellular matrix proteins, resulting in fibrosis → interstitial lung disease (ILD), upper/lower gastrointestinal dysmotility, myocardial fibrosis

Clinical Features of Systemic Sclerosis

Onset of SSc is often insidious and characterized by Raynaud phenomenon; tightening, thinning, and atrophy of skin on hands and face; or cutaneous telangiectasias on face, upper trunk, and hands.

Cutaneous involvement:

• nonpitting edema of extremities and face (for weeks to months) → induration and sclerosis

• sclerotic phase: skin has waxy texture and becomes “bound down” or tethered to underlying soft tissues; absence of forehead wrinkling and diminished aperture of mouth

• telangiectasias: fine macular dilations of cutaneous or mucous membrane blood vessels; periungual nail fold is most obvious location early in disease course

• digital pitting in pulp of fingertips due to ischemia; sometimes with ulceration and gangrene

• calcinosis: subcutaneous calcification, especially over joints; can ulcerate

Raynaud phenomenon:

• key clinical manifestation of SSc (affects 90% of children with SSc) and can precede other manifestations of SSc by years

• can lead to digital infarcts

• precipitated by cold, stress, temperature change, or vibration

• vasospasm (white) → deoxygenation (blue) → reactive hyperemia (red)

• can be primary (no underlying systemic autoimmune condition) or secondary (underlying autoimmune condition such as SSc, systemic lupus erythematosus [SLE], or primary Sjögren syndrome [pSS])

  • clues to secondary RP: onset in childhood, year-round symptoms, digital ulcerations, asymmetry

Triphasic color change (white → blue/purple → red) (Source: Primary Raynaud's Phenomenon. N Engl J Med 2013.)

Musculoskeletal involvement:

• arthralgias/arthritis

• joint contractures

• myositis

Gastrointestinal involvement:

• affects 70%-90% of patients with SSc

• esophageal complications most common

  • esophageal dysmotility → dysphagia and gastroesophageal reflux disease [GERD] → Barrett esophagus, esophagitis with ulceration and stricture

• gut hypotonia → pseudo-obstruction, pneumatosis intestinalis, megaduodenum

• small-bowel bacterial overgrowth → malabsorptive diarrhea

Cardiac involvement:

• rare but associated with high morbidity

  • in adults, cardiac involvement is the cause of death in 25%

• pericardial effusions, cardiomyopathy

• cardiac ischemia due to equivalent of Raynaud phenomenon of the coronary arteries; can lead to myocardial fibrosis

Pulmonary involvement:

• associated with poor prognosis: median survival of SSc patients with ILD is 5 to 8 years

• as many as 90% of adults with SSc develop ILD

• usually diagnosed via pulmonary function testing (PFT) as opposed to symptoms; PFTs show a restrictive pattern with reduced forced vital capacity (FVC) and diffusing capacity of the lungs for carbon monoxide (DLCO)

• high-resolution chest CT shows bilateral ground-glass opacities most prominent in lower lobes

• pulmonary arterial hypertension is associated with a worse prognosis and can occur secondary to pulmonary fibrosis or as isolated pulmonary arterial hypertension

Scleroderma renal crisis:

• accelerated-phase hypertension and/or rapidly deteriorating renal function, frequently accompanied by microangiopathic hemolysis

• treat with high-dose angiotensin-converting-enzyme (ACE) inhibitors

• in adults, presence of anti-topoisomerase I (anti-Scl-70) antibody and rapidly progressing skin involvement are predictors of early and often fatal renal and cardiac involvement

Sicca syndrome:

• xerostomia (dry mouth) and keratoconjunctivitis sicca (dry eyes) are common

• can have parotitis and salivary gland enlargement

Diagnosis

• Clinical exam: Diagnosis of SSc is primarily based on clinical features (as detailed above).

• Laboratory evaluation:

  • CBC with differential: can reveal anemia of chronic disease or due to malabsorption

  • antinuclear antibody (ANA): high titer is common (positive in 81%-97% of children with SSc)

  • anti-topoisomerase I antibodies (anti-Scl-70): positive in about 30% of patients and associated with increased risk for interstitial pulmonary fibrosis (specificity for SSc is 99.5%)

  • anti-centromere antibodies: not common in children (7%), more common in adults with SSc and limited SSc; associated with an increased risk of pulmonary hypertension and severe GI involvement

  • anti-RNA polymerase III antibodies: associated with renal crisis (specificity for SSc is 99.5%)

• Echocardiogram: may show pericardial effusions, left ventricular hypertrophy, and decreased left ventricular compliance

• Pulmonary function tests: monitor routinely (every 6-12 months) for decreased FVC and diffusing capacity of the lungs for carbon monoxide (DL_CO)

  • if abnormal, obtain high-resolution chest CT

• High-resolution chest CT: obtain at diagnosis and as needed based on either symptoms or abnormal PFTs; findings of bilateral ground-glass opacities, most prominent in lower lobes

• Radiographs: hands are often abnormal with marked decrease in soft tissue and resorption of tufts of distal phalanges (acro-osteolysis), especially in patients with severe Raynaud phenomenon

• Barium esophagography: shows decreased or absent peristalsis in lower part of esophagus, stricture

• Esophageal manometry and pH probe monitoring: can detect low sphincter tone and presence of reflux, which are common in SSc

Classification

In 2013, a joint committee of the ACR and the European League Against Rheumatism (EULAR) developed the following classification criteria for SSc:

Treatment

No uniformly effective therapy exists for SSc. Most treatment is targeted at specific organ involvement as follows:

• supportive measures: maintain core and extremity warmth, especially in cold climates; avoid excessive sun exposure and heat; encourage physical activity

• Raynaud phenomenon and digital ulcers: treated with vasodilators (e.g., calcium-channel blockers [amlodipine], phosphodiesterase type 5 inhibitors [sildenafil], prostacyclin synthetic analogues [iloprost, sildenafil, bosentan])

• fibrosing ILD: requires aggressive immunosuppression, standard of care often involves mycophenolate mofetil (MMF) and glucocorticoids for induction and MMF for maintenance therapy ; newer evidence is emerging for the efficacy of rituximab and tocilizumab for lung function and skin fibrosis

• pulmonary arterial hypertension: treated with prostanoids, sildenafil, or bosentan

• gastroesophageal reflux: treatment with proton-pump inhibitors (PPIs) or prokinetics

• midgut disease: rotate antibiotic therapy for bacterial overgrowth

• musculoskeletal involvement: treated with methotrexate

• renal disease: treated with ACE inhibitors

• skin involvement: treated with methotrexate or MMF

Disease Course and Prognosis

• ranges from mild and stable to rapidly progressive and fatal

• poor prognosis is associated with:

  • younger age at disease onset

  • male sex

  • positive Scl-70 antibody test

  • extensive skin, cardiopulmonary, and renal disease

• morbidity

  • estimated 10-year survival rate in childhood-onset SSc is 80%-87%

  • most common causes of death are related to involvement of cardiac, renal, and pulmonary systems

Sjögren Syndrome

Sjögren syndrome (SjS) is a chronic autoimmune disease characterized by inflammation of the exocrine glands, principally the salivary and lacrimal, resulting in recurrent parotitis and dryness of the mucosal surfaces of the mouth and eyes. Additionally, patients can have extraglandular or systemic features. Sjögren syndrome can occur as a primary disorder (pSjS) or secondary to another systemic autoimmune condition (e.g., SSc or SLE). This review focuses on the diagnosis, clinical features, and management of pSjS.

Pathogenesis

The proposed model of the pathogenesis of pSjS is that genetically predisposed individuals are exposed to environmental factors (e.g., viral infection), which leads to a protracted autoimmune response in the epithelial cells of exocrine glands. The relation between initial autoimmune disease in exocrine glands and further extraglandular disease is unknown. Anti-Ro (SSA) and anti-La (SSB) antibodies may have a pathogenic role based on presence in saliva of patients with pSjS and infiltrating B cells with intracytoplasmic immunoglobulin directed against Ro and La.

Clinical Features

Oral manifestations:

• parotitis: most common presenting feature in children; may be unilateral but often becomes bilateral; can be painful or painless

• xerostomia (dry mouth): affects 90% of adults but less common in children because it emerges after glandular damage has occurred

  • leads to increase in dental caries

Ocular manifestations:

• keratoconjunctivitis sicca (dry eyes): burning sensation in eye, foreign-body sensation

Extraglandular manifestations:

• systemic symptoms: fatigue, low-grade fever, myalgias, arthralgias

• skin: Raynaud phenomenon, pernio, vasculitic skin lesions

• arthralgias and arthritis

• pulmonary involvement

  • dry cough due to dryness of epithelium of trachea

  • small-airway obstructive disease and hyperactivity due to lymphocytic infiltration

  • ILD in 8% of adults

Renal manifestations:

• interstitial nephritis due to lymphocytic infiltration of tubular epithelium

• glomerulonephritis due to immune complex deposition (associated with higher mortality or progression to lymphoma)

• renal tubular acidosis (more common in children than adults)

Neurologic manifestations:

• many neurologic manifestations overlap with central nervous system (CNS) lupus

  • neuropathies: purely sensory neuropathy, sensorimotor polyneuropathy, mononeuritis multiplex

  • neuromyelitis optica (NMO) and NMO spectrum disorders (NMOSD) have a higher incidence in patients with pSjS

Diagnosis

Widely accepted diagnostic criteria for pSjS do not exist, especially in children, because of differences in presenting symptoms compared to adults. The general approach to diagnosis involves the following:

• history and exam noting the presenting clinical features of pSjS (described above)

• focused laboratory testing if suspicion for pSjS

• confirmation of diagnosis with minor salivary gland biopsy, dry eye testing, and/or parotid ultrasound

  • minor salivary gland biopsy: lymphocytic infiltration; focal aggregates of lymphocytes, plasma cells, and macrophages suggestive of pSjS

Laboratory testing (none of the following tests are specific for identifying pSjS):

• ANA: sensitive but not specific for pSjS (similar to SLE)

  • ANA profile: anti-Ro (SSA) and anti-La (SSB) found in 60%-90% of patients

• erythrocyte sedimentation rate (ESR): often very elevated, in part due to significant hypergammaglobulinemia

• rheumatoid factor: positive in 57%-87.5% of pediatric patients

• amylase: often elevated due to exocrine gland damage

• complement levels: low or normal C3 and C4

• urinalysis: to monitor for renal disease (e.g., renal tubular acidosis, glomerulonephritis)

Imaging:

• parotid ultrasound: ultrasound score based on parotid gland homogeneity and presence of hypoechoic lesions; highly accurate for diagnosing pSjS in adults (90% specificity, 87% sensitivity); noninvasive and easy to perform in children

• sialometry: measures salivary flow, difficult to obtain in younger children and age-matched normal values are not available

Dry eye testing:

• fluorescein and lissamine-green staining of conjunctiva and cornea to demonstrate degree of ocular surface damage

• Schirmer test: length of paper strip moistened by tears in 5 minutes (≤5 mm is abnormal in adults)

Treatment and Management

• Symptom relief:

  • Dry mouth is relatively uncommon in children with pSjS

  • Use artificial tears and avoid smoking and anticholinergic medications

  • Use sugar-free lozenges or chewing gum to stimulate salivary flow

  • Schedule more-frequent dental checkups to prevent or detect caries

  • Pilocarpine hydrochloride may help increase salivary secretion

• Hydroxychloroquine may help relieve constitutional symptoms, arthralgia, and fatigue.

• Immunosuppression can be used for extraglandular organ manifestations or severe ocular or mucosal symptoms; it has a theoretical benefit of preventing glandular damage in patients who have not yet developed sicca symptoms.

  • Glucocorticoids can decrease parotid swelling episodes and improve systemic complaints.

  • Methotrexate can decrease frequency of parotitis and arthritis/arthralgias.

  • Mycophenolate mofetil reduces hypergammaglobulinemia and increases complement levels and white blood cell count.

  • Rituximab might improve systemic symptoms and cryoglobulin-associated vasculitis; can also be used in cases of overlap with NMO and in Sjögren syndrome-related lymphoma.

  • Belimumab, a monoclonal anti-BAFF antibody, had a modest positive effect on sicca symptoms and pSjS disease activity in one trial.

• Counseling: Close monitoring is needed during pregnancy because of risk for neonatal lupus erythematosus (NLE) in the developing fetus and neonate due to transplacental passage of anti-Ro (SSA) and/or anti-La (SSB) antibodies. The most common clinical features of NLE include congenital heart block, cutaneous lesions, and hepatic dysfunction.

Prognosis

• Prognosis is very good in most adult patients with stable and benign course of disease (long-term prognosis in pediatric patients has not been studied).

• Adverse outcomes associated with purpura, glomerulonephritis, low C4, or mixed monoclonal cryoglobulinemia.

• Relative risk of lymphoma in adults with pSjS is 44 times greater than age-matched adults; elevated quantitative IgG is a risk factor for development of lymphoma; lymphoma risk in children has not been established.