Chapter 204. Systemic Lupus Erythematosus, Overlap Connective Tissue Disease, and Mixed Connective Tissue Disease

Systemic lupus erythematosus (SLE) represents the prototype of a pediatric autoimmune disease with the presence of autoantibodies as its hallmark. The incidence of SLE diagnosed prior to age 18 is approximately 10 to 20 new cases per 100,000 population per year with an overall prevalence of 1 to 2 cases per 1000 adolescents ages 12 to 18. Both the incidence and prevalence rates are higher in African Americans, Asians, Southeast Asians, and Hispanics. The female predominance (4–4.5:1) in pediatric patients is lower than in adults (9:1).1 The mean age at diagnosis is approximately 12 to 13 years, but presentation as young as age 3 or 4 is routinely reported.2 Presentation prior to age 1 is very rare and may manifest as congenital nephrotic syndrome.

Neonatal lupus erythematosus (NLE) must not be mistaken for early-onset SLE. NLE is a disease caused by the transplacental passage of maternal autoantibodies, and the fetus/neonate is an innocent bystander with a normal immune system that is not actively producing autoantibodies. However, some of these children may develop true SLE many years later. Early-onset pediatric SLE is a disease in which the child produces autoantibodies and the immune abnormalities are intrinsic to the child’s immune system.

Etiology

Although the triggering mechanisms are not fully defined, the production of autoantibodies is the hallmark of SLE. These autoantibodies are usually directed against histone, nonhistone, RNA-binding, cytoplasmic, and nuclear proteins. Antinuclear antibody (ANA) occurs in most, if not all, patients with SLE. With more sensitive detection systems, ANA-negative SLE is very rare but still does occur (<5% of cases). Anti-DNA antibodies are present in approximately 50% to 60% of patients, while antibodies directed against the small nuclear ribonuclear proteins (anti-Sm and anti-70kDa RNP antibodies) occur in 40% to 50% of patients.3 Antibodies directed against small cytoplasmic ribonuclear proteins (anti-Ro and/or anti-La antibodies) occur in 30% to 40% of patients, anticardiolipin antibodies in 40% to 50% of patients, and rheumatoid factor 15% to 20% of patients. Antiribosomal P antibodies are present in approximately 25% to 30% of patients and may be associated with psychosis and depression.4,5

Antiphospholipid and anticardiolipin antibodies are detected in approximately 50% of patients.6 One specific antiphopholipid antibody worth noting is the lupus anticoagulant (LAC), an antibody that reacts with phospholipids in the reagent used in the partial thromboplastin time (PTT) determination. The LAC is often seen in conjunction with anticardiolipin antibodies. Patients with LAC do not bleed; instead, they have an increased incidence of deep vein thrombosis, thromboemboli, or, less commonly, arterial thrombosis. Antiphospholipid antibodies are associated with multiple neurologic manifestations including stroke, seizures, chorea, and other movement disorders; pseudotumor cerebri; and migraine headache; as well as with nonneurologic disorders such as thrombosis, thrombocytopenia, or recurrent abortion.6–9 Most, if not all, pediatric patients with evidence of venous thromboembolic disease will have evidence of LAC.

Clinical Presentations

In 1997 the American College of Rheumatology (ACR) revised the criteria for classification of SLE (Table 204-1).10 These criteria were not to be used to diagnosis and separate SLE patients from normal individuals but for classification of patients with an autoimmune into SLE as opposed to another autoimmune disease. The purpose is to compare one group of patients with another. Patients are classified as having definite SLE if they meet 4 out of 11 criteria, but most series report 10% to 15% of patients who have only 3 criteria.

Arthritis, dermatitis, and nephritis are the most common manifestations, but any organ may be affected (Table 204-2). Systemic symptoms reflecting a generalized inflammatory process (fever, malaise, weight loss, and lethargy) are very common. In 80% to 90% of patients, a disease manifestation either occurs within the first year of diagnosis or it fails to arise. The exception is central nervous system (CNS) disease, in which up to 25% of patients will have their first episode of CNS involvement more than one year after diagnosis. Flares of SLE tend to be similar to the initial presentation but generally less with systemic inflammation in patients that are followed closely.

Renal Disease

The incidence of renal involvement varies between 48% to 90% of patients.11-13 An extensive discussion of the diagnosis and management of renal complications of SLE is provided in Chapter 472.

Central Nervous System

Central nervous system (CNS) disease or neuropsychiatric (NP-SLE) involvement occurs in 20% to 40% of patients and is associated with significant morbidity and mortality.18-21 Both the central and/or the peripheral nervous systems may be involved with multiple syndromes and presentations (eTable 204.1). In 1999 the American College of Rheumatology developed a new nomenclature and case definition for neuropsychiatric SLE (eTable 204.1).22

Psychiatric illnesses range from mood disorders to depression to frank organic brain syndrome. Neurocognitive testing detects impairments in cognitive function or learning difficulties in a high percentage of patients, but the true incidence is unknown.

Depression secondary to active disease must be differentiated from a secondary depression arising from environmental factors or from medication side effects. Overt psychosis or organic brain syndrome occurs in approximately 10% of all patients with SLE and may be attributed to endogenous CNS disease, metabolic imbalance, or infection, the latter sometimes precipitated by steroid therapy. In most patients with psychosis or organic brain syndrome, a lumbar puncture is indicated.

Seizures, seen in approximately 10% to 20% of patients, may be the presenting sign of more significant organic brain disease, the result of an infarction, or the sole manifestation of CNS involvement. Movement disorders encompass cerebellar ataxia, hemiballismus, tremor, parkinsonian-like movements, and chorea. SLE, or antiphospholipid antibody syndrome, is currently the most common cause of chorea in developed countries.23

Cranial nerve involvement is more common than peripheral neuropathy. Rarely, hemiparesis or transverse myelitis may occur. Although not studied in children, the incidence of autonomic dysfunction in adults is 40% to 50%, is usually mild, and may lead to changes in heart rate.

Headache occurs in up to 25% of patients with SLE. The typical headache responds to mild analgesia.24 However, a severe, unremitting headache, sometimes referred to as a lupus headache, usually reflects active disease or CNS vasculitis, or it may represent cerebral vein thrombosis. In all cases of unremitting headache, appropriate investigations must be performed to rule out cerebral vein thrombosis or infection.25 A more benign cause of headache is pseudotumor cerebri ascribable either to the underlying disease or to steroid medication. Migraine-like headaches are common and likely reflect active CNS SLE.

Examination and culture of cerebrospinal fluid (CSF) are performed to rule out the possibility of CSF infection or hemorrhage. An elevated CSF protein and/or CSF white blood cell count in the absence of infection is suggestive of cerebritis.20 Neuroradiologic investigation of the central nervous system (CT or MRI scan) may demonstrate specific structural lesions such as infarction, embolus, cerebral vein thrombosis, and subdural or intracranial hemorrhage, but these modalities are generally not helpful in measuring overall CNS disease activity.2 6 MRI is the imaging modality of choice in patients suspected of having CNS involvement. Levels of complement proteins and anti-DNA antibodies, which may correlate with disease activity at other sites, may be normal with CNS involvement.

The therapy of CNS disease varies with the manifestation. Most clinicians do not treat isolated cognitive impairment. Active psychosis and/or organic brain syndrome are potentially life-threatening complications and should be treated aggressively with an immunosuppressive regimen that includes high-dose corticosteroids and azathioprine, MMF, or cyclophosphamide. Psychotropic drugs serve as adjunctive, but not primary, therapy.

Dermatologic Disease

Skin involvement manifesting as malar rash, discoid rash, or photosensitivity occurs in 60% to 90% of patients with SLE.27 A rash in the malar area involving cheeks and nasolabial folds is quite specific; dermatomyositis is the only other disease in the differential diagnosis (Figs. 204-1 and 205-1). A discoid rash is rarer than a malar rash. Although isolated discoid lupus is commonly seen in adults, all pediatric patients with a discoid rash must be followed for the development of true SLE. Many but not all patients exhibit photosensitivity, and sun exposure may lead to a flare of skin and/or systemic disease. Sun-exposed areas should be protected with light clothing and a sunscreen with a high ultraviolet (UV) light protection rating against both UVA and UVB. The rash of subacute cutaneous SLE appears as an annular rash with a raised border and central sparing; it, too, has a photosensitive component and is often associated with anti-Ro and anti-La antibodies. Alopecia, listed in the original classification, occurs in 25% to 35% of patients. In pediatric patients, alopecia in the presence of a systemic autoimmune disease is quite specific for SLE. A vasculitic rash consisting of oral or nasal erosions or ulcers on the arms, legs, or ears may occur in up to 25% of patients and is often associated with systemic involvement (eFig. 204.1).

Musculoskeletal Involvement

As many as 90% of patients exhibit joint involvement, typically a polyarticular arthritis that affects both large and small joints; severe pain and significant morning stiffness occur in half the patients, whereas in the other 50% polyarthritis may produce few symptoms. Control of extra-articular sites of disease activity is frequently sufficient to treat the arthritis. An arthritic flare may herald a more generalized flare. Therapy with nonsteroidal anti-inflammatory agents and antimalarial agents may control arthritis as an isolated symptom, but low-dose corticosteroid therapy is frequently required.

Patients with SLE are at a high risk for the development of avascular necrosis (AVN) of many joints; this complication is likely secondary to a combination of the disease process, to antiphospholipid antibodies, and/or to the use of corticosteroids. AVN occurs in 5% to 10% of patients who present with acute pain, joint tenderness, and effusion. Septic arthritis and osteomyelitis must always also be considered if a fever is present.

Hematologic Involvement

Anemia, thrombocytopenia, and leukopenia occur in 50% to 75% of patients. Only a Coomb-positive hemolytic anemia satisfies the diagnostic criteria of the American College of Rheumatology, but both normochromic, normocytic anemia and microcytic, hypochromic anemia are more common in SLE. The Coomb test is positive in approximately 30% to 40% of patients, but less than 10% of patients have overt hemolysis.28 Thrombocytopenia is present in 30% to 45% and may precede the diagnosis of SLE. SLE should be considered in all children and adolescents with chronic thrombocytopenia.28-30 Leukopenia occurs in 20% to 40% of cases (lymphopenia and/or granulocytopenia). Pancytopenia may also occur, and when present one must consider the concomitant presence of a herpes family viral infection or macrophage activation syndrome.

Anticardiolipin antibodies are the most common antiphospholipid antibody seen in pediatric SLE.31,32 Lupus anticoagulant (LAC), is seen in approximately 20% of cases as discussed above. Up to 50% of patients with the LAC will present with or develop evidence of a thromboembolic event.33

Although 20% to 30% of patients have splenomegaly on physical examination, of more importance is the presence of functional asplenia, which may increase the incidence of sepsis.

Cardiac Involvement

Although cardiac tamponade is rare, symptomatic pericarditis occurs in approximately 20% to 25% of patients and is commonly associated with pleurisy. In contrast, clinically important myocarditis or endocarditis is uncommon (<10% of patients). Longer survival times and the use of corticosteroid therapy have led to an increase in atherosclerotic heart disease and myocardial infarction.34,35 Other factors predisposing to atherosclerotic heart disease include hypertension, hyperlipidemia, antiphospholipid antibodies, and coronary vasculitis. Coronary arteritis can be associated with acute myocardial infarction. Valvular cardiac involvement is commonly seen in autopsy studies, but it is rarely clinically significant.

Pulmonary Disease

The reported incidence of pulmonary involvement varies between 25% and 75% of all patients with SLE. There are protean pulmonary manifestations ranging from severe life-threatening pulmonary hemorrhage or infection to a chronic interstitial lung disease to asymptomatic abnormalities on pulmonary function tests. Decreased diffusion capacity is the most common abnormality. Abnormalities of pulmonary function tests account for the 75% incidence of lung disease. In the acutely ill patient with severe lung disease, the differential diagnosis includes acute lupus pneumonitis, pulmonary hemorrhage, or pulmonary infection; the latter may be present even prior to steroid or immunosuppressive treatment. Pleural involvement occurs in up to 30% of cases, is commonly seen in association with pericarditis, and is usually easy to treat.

Gastrointestinal Disease

Gastrointestinal (GI) involvement occurs in 20% to 40% of patients. Abdominal pain is the most common GI symptom and can be the result of peritoneal inflammation (serositis), vasculitis, pancreatitis, and/or direct bowel wall involvement (enteritis). Peritoneal inflammation of underlying SLE must be differentiated from an infective peritonitis. Pancreatitis is a rare cause of abdominal pain in pediatric SLE and may arise from the use of corticosteroids and azathioprine.

Hepatomegaly occurs in 40% to 50% of patients. Abnormalities on liver function tests are seen in up to 25% of patients, but are usually mild and transient. When jaundice is a prominent feature in a patient with SLE, then a second disease, such as obstruction, hemolysis, or viral hepatitis, is the likely cause. Patients with SLE are at an increased risk to develop drug hepatotoxicity.

Endocrine Involvement

The thyroid is the most common endocrine organ involved in SLE, with antithyroid antibodies present in 40% to 50% of patients and clinical hypothyroidism in 10% to 20%. Grave disease is much less common than hypothyroidism. Steroid-induced diabetes mellitus occurs in as many as 10% of patients, but a lower percentage require insulin treatment. Rarely, hypoparathyroidism and growth hormone deficiency have been reported.

Complications of Treatment

Although steroids are the mainstay of therapy in patients with severe disease, side effects are frequent and include avascular necrosis (described above); osteoporosis with fracture or vertebral body collapse; growth failure; cataracts; glaucoma; steroid-induced diabetes mellitus; hyperlipidemia; hypertension; and premature atherosclerosis.34-37 Unfortunately, patients with pediatric-onset SLE generally require steroids more frequently and at higher doses than adults.1,38 Therefore, although steroids can be lifesaving in SLE, every attempt should be made to avoid their use or to use the minimal dose required.

The rational use of cytotoxic agents is limited by the lack of good clinical studies; their use should be reserved for severe and/or life-threatening disease. Azathioprine has a good safety profile, but leukopenia and increased susceptibility to infection must be considered in all patients using this medication. In addition to all the side effects of azathioprine, long-term use of cyclophosphamide is associated with an increased risk of malignancy and infertility. Mycophenolate mofetil (MMF) has been successfully used in large trials of adults with proliferative lupus nephritis. The outcome of these patients is equal or superior to that of patients treated with cyclophosphamide with less toxicity. Smaller pediatric cases have shown similar good results with MMF. Many pediatric rheumatologists will treat almost all patients with hydroxychloroquine (5–6 mg/kg/day) because studies suggest that its use is associated with fewer disease flares and an improved lipid profile. Because the major toxicity is ophthalmologic, patients require retinal examinations every 6 to 9 months.

Patients with overlap syndromes have features of more than one defined connective tissue disease. There are no true definitions and no estimates of how frequently they occur in pediatric patients. The diagnosis may be confounded by the acceptance of atypical features within the definitions of defined connective tissue diseases. Examples of this phenomenon include the presence of myositis in patients with SLE and arthritis in patients with dermatomyositis. In addition patients with overlap syndromes should be differentiated from patients with diseases in evolution that do not yet meet the criteria for a defined connective tissue disease. Two recognized overlap syndromes are mixed connective tissue disease (MCTD) and a scleroderma/polymyositis overlap. These latter patients have features of definite scleroderma and significant myositis. They frequently have the specific autoantibody anti-PM/Scl (polymyositis/scleroderma) antibody.

Mixed connective tissue disease, the most controversial of the rheumatic illnesses, is the prototype of an overlap syndrome. The controversy centers on its definition and its existence as a unique, separate disease. It has been suggested that a defined overlap syndrome must include a distinct constellations of clinical signs and/or serologic features. The main reason for defining MCTD as a separate entity is its association with antibodies against U1RNP extractable nuclear antigen; features of more than one connective disease; and in particular features of systemic lupus erythematosus (SLE), polymyositits/dermatomyositis, scleroderma (SSc), and rheumatoid arthritis or, in children, juvenile idiopathic arthritis (JIA). In 1972, Sharp described, in adults, a series of patients with very high levels of anti-U1RNP antibodies, and the common features included arthritis, swollen fingers, tight skin, abnormal esophageal motility, Raynaud phenomenon, and myositis, but in contrast to SLE, anti-DNA antibodies were not detected; these patients were corticosteroid responsive and free of renal disease.39 Although circulating antibodies were thought to be specific for the U1RNP autoantigen, these antibodies are found in 30% to 40% of patients with SLE.40 Currently there are at least 43 classification criteria of MCTD in adults (Table 204-3),43,44 of which 3 are most commonly used: Sharp, Kasukawa, and Alacron-Segovia.39,43,44 One adult study using the Alcaron-Segovia showed that 92% also met the Kasukawa but only 70% met the Sharp criteria (the original criteria).43 Similar studies have not been performed in the pediatric age group. It is still controversial whether MCTD is a distinct disease or a disease in transition that will differentiate into a defined illness. Even advocates of the disease acknowledge that up to 50% of patients will differentiate into SLE, SSc, or myositis within 5 years of diagnosis. It is not clear yet how many of the other patients with eventually “declare” themselves. The first reports of MCTD in the pediatric age group was from Singsen et al. in 1977 and Fraga et al. in 1978.41,42.

The pediatric literature is even more confusing than the adult literature. The earliest series described children with significant cardiac and renal involvement and thrombocytopenia in the presence of high-titer speckled ANA and anti-RNP antibodies.41,42,45,46 In this regard, pediatric patients more closely resembled the clinical and laboratory features of a subgroup of patients with SLE with anti-RNP antibodies, although some patients had myositis. Some of these patients also had anti-Sm and/or anti-DNA antibodies, which many authors feel are specific for SLE. Indeed, many pediatric patients will meet criteria for the diagnosis of definite SLE or scleroderma. Both the uniqueness of the clinical syndrome and the specificity of anti-U1RNP antibodies in pediatric patients are questionable. However, there is a subgroup of patients with high-titer anti-U1RNP antibodies who have a disease that meets the criteria for MCTD. This is not to be confused with patients with overlap symptoms without anti-U1RNP antibodies, as less than 50% of children with overlap symptoms have these autoantibodies. Conversely, most pediatric patients with anti-U1RNP antibodies do not have clinical features consistent with MCTD, but instead have clinical features that meet the classification criteria for SLE.

Epidemiology

Because the definition of the disease may vary, the true incidence of pediatric MCTD is difficult to obtain. The youngest reported patient with MCTD was age 5, and the number of patients increases with an increase in age. A nationwide study from Finland showed an annual incidence rate of 0.10, which compares to 0.37 for SLE, 0.05 for scleroderma, and 0.30 for inflammatory myositis in children. It has been estimated that less than 1% of patients followed in pediatric rheumatology clinics have MCTD.48

Clinical Features and Diagnosis

There is a female predominance (80%), with Raynaud phenomenon, fever, arthritis, skin rashes, sclerodermatosus-like skin changes, and myositis the most common features (see eTable 204.2). Although originally described as a relatively benign disorder, subsequent reports have found involvement of multiple internal organs. Central nervous system involvement is rare but aseptic meningitis may be seen, particularly after the use of nonsteroidal anti-inflammatory medications. Clinically significant eye involvement is very rare. Acute pericarditis and/or pericardial effusion and mitral valve prolapse are the most common cardiac features, whereas myocarditis and cardiomyopathy (uncommon manifestations) tend to be severe, progressive, and life threatening. Pulmonary involvement is common clinically, and pulmonary function tests frequently show small airway obstruction early in the disease course, with a progressive impairment of alveolar gas exchange. A restrictive airway disease may be seen in more than 50% of patients, and pulmonary hypertension, when present, tends to be severe. The characteristic pulmonary pathologic finding is intimal proliferation and hypertrophy of the pulmonary arterioles with sparing of the interstitial areas.

Gastrointestinal abnormalities similar to those found in patients with SLE, myositis, or SSc are frequent. Any area of the GI tract may be affected, but the esophagus is the most common location, with incidence rates of up to 85% for esophageal symptoms including heartburn and dysphagia, and/or abnormal esophageal function as demonstrated by manometric abnormalities. Liver disease is uncommon. GI abnormalities are not related to disease duration nor to the presence of Raynaud phenomenon.54,55 Renal involvement is seen in 45% to 50% of pediatric patients and up to 33% of adults. The lesions are consistent with membranous, membranoproliferative, or mesangioproliferative nephritis.56 Arthritis is common and a loss in joint function may be seen in up to one third of the cases.5 Vasculitis may present with splenic vasculitis and oral, digital, GI, or genital ulceration. The development of other autoimmune diseases may occur, including Hashimoto thyroiditis, myasthenia gravis, and cold agglutinin syndrome.

Typical patients exhibit positive, speckled ANA, All patients have high-titer anti-U1RNP antibodies, and typically have rheumatoid factor, and hypergammaglobulinemia (see eTable 204.3). Other laboratory abnormalities may include elevated muscle enzymes, thrombocytopenia, lymphopenia, a mild anemia, an elevated ESR, and hypocomplementemia. Human leukocyte antigen-DR4 (HLA-DR4) has been reported to occur more frequently in patients who continue to have features of MCTD as compared with the patient groups who differentiate, although definite RA may develop in HLA-DR4-positive patients.

Treatment

As originally described, MCTD was said to be a corticosteroid-responsive illness with a good prognosis. However, more recent reports suggest that only a subgroup of patients is persistently steroid responsive, and some may require high-dose intravenous methylprednisolone. In the other patients, the outcome and therapy are directed to the disease into which the patient differentiates. The outcome in the patients who develop SLE is similar to most patients with SLE, as is the therapy. Unfortunately, the same is true for the patients who develop systemic scleroderma. These patients are usually unresponsive to therapy, although there have been reports of the efficacy of immunosuppression.

However, the long-term prognosis is guarded. Of note in adults, esophageal dysfunction has been reported to improve with corticosteroid therapy. Overall, given the wide variety of manifestations, therapy must be individualized to treat the important organ involvement in the individual patient. A large review of pediatric patients demonstrated that patients who were initially diagnosed with MCTD had a worse 5-year prognosis than those diagnosed with SLE.49

Prognosis

Initially described as a benign disease, follow-up studies demonstrated that many patients developed either severe disease or differentiation into definite SSc or SLE in the majority of pediatric patients. A large review of pediatric patients demonstrated that patients who were initially diagnosed with MCTD had a worse 5-year prognosis than those diagnosed with SLE.49 Large prospective and retrospective studies of adult patients with high-titer anti-RNP antibodies in the absence of anti-Sm and anti-DNA antibodies reported that only 25% to 50% of patients followed for 7 years or more still had features of an overlap, rather than another defined rheumatic disease.40,49,50-53 The transformation occurred at a mean of 2 to 3 years, but there was a large standard deviation (3 years or more). A review at five large pediatric rheumatology centers in England and the United States found only a minority of patients still carried the diagnosis after follow-up of more than 5 years.

Mortality rates as high as 25% have been reported, and the highest mortality was associated with severe Raynaud phenomenon and clinical features of scleroderma at presentation. Infection is the leading cause of death, followed by cardiac complications or pulmonary hypertension and renal failure.