A 14 year old female presents with a 6 week history of fatigue and facial rash. Her rash seems to be exacerbated by sun exposure. She has recently developed pain and swelling in her fingers and wrists. She has no significant past illnesses. Family history is significant for an aunt with lupus and a grandmother with thyroid disease.
Exam: VS T 37.8, P 88, R 20, BP 110/66. Height and weight are at the 20th percentile. She is alert and cooperative. She has thinning hair over her front scalp with some fine short hairs. She has an erythematous maculopapular rash over her malar areas spanning the bridge of her nose, erythema of the hard palate and a few shallow gingival ulcers. Joint exam reveals mild swelling and tenderness to palpation and range of motion in the proximal interphalangeal joints of several of her fingers and both wrists. Heart, lung, abdomen, back and neurological examinations are within normal limits.
Laboratory: WBC 2.5 with 87% segs, 5% lymphs, 6% monos, 2% basophils. Hgb 10. Platelet count 167,000. ANA 1280. ESR 45. Urinalysis without protein or blood. No cellular casts or significant red or white cells.
Systemic Lupus Erythematosus (SLE) is a multisystem, inflammatory disease of autoimmune origin, characterized by the production of auto-antibodies directed against elements of the cell nucleus. The disease is often chronic with episodic flares of disease and remissions (1).
The etiology of lupus is unknown and thought to be complex and multifactorial. Many lines of evidence point to both host (endogenous and genetic) and environmental (e.g., environmental exposures and infection) factors, which contribute to development of disease. Although numerous susceptibility foci and genetic linkages or associations have been reported, there is no predominant or single one identified. Genetic associations found in one race may not apply to other races or even subsets within a particular race. Genes which confer susceptibility to developing the disease may differ from individual to individual and may result in different clinical manifestations and severity of disease.
Family studies offer compelling evidence of genetic predisposition. Connective tissue disease other than SLE has been reported in 10% of families of patients with SLE (1). There is an increased risk of developing SLE in first degree relatives of patients with SLE (2). A person with SLE has increased risk of having a sibling with SLE versus the general population having a sibling with SLE (2,3). Twin studies show higher rates of SLE in monozygotic versus dizygotic twins (4).
Studies have suggested that lupus is more prevalent in non-Caucasian ethnic groups such as African-American, Hispanic, Asian, Native American Indian, Alaskan Indian and Indian populations, which lends support for there being some genetic basis for disease susceptibility. We recently reviewed pediatric lupus patients in our rheumatology clinic in Hawaii, demonstrating that children of Samoan, Filipino and Japanese ancestry have increased odds ratio of developing SLE (5).
Other factors such as ultraviolet radiation, stress, and infection may also play a role in pathogenesis. Drugs such as hydralazine, isoniazid, sulfonamides, penicillin, beta-agonists and anticonvulsants have been associated with "drug-induced" lupus which is dependent upon the presence of the drug.
The true incidence and prevalence of lupus is not known, but is generally thought to be lower in children than in adults. Lupus is most common in women of child bearing years, but about 20% or more of patients with SLE are children. Lupus is rarely seen before the age of 5 years, is more common after 9 to 10 years, and tends to cluster around the age of puberty. Female predominance of the disease is less pronounced before puberty.
Clinical manifestations of lupus can vary widely. Lupus can present with non-specific and milder symptoms over an extended period of time, but children typically have a more acute onset. Constitutional symptoms are common, such as fever, fatigue, decreased appetite, and weight loss. High fevers should be suspect for an underlying infection in patients with lupus who are immunocompromised due to their disease and the immunosuppressive medications they are on.
Rash is common and variable. The classic malar "butterfly" rash is usually symmetric, spanning the bridge of the nose, but sparing the nasolabial folds. The rash may be photosensitive and involve other sun exposed areas such as the forehead, ears and the "V" of the neck and upper chest. Rash may involve other parts of the body, including the palms of the hands. Most heal without scarring or pigmentation. Severe vasculitis or thrombosis may result in ulcerations or even gangrene. Discoid lesions, which often lead to scarring, atrophy, and pigmentation changes, seem to be less frequent in children. Nail bed involvement with periungual erythema may occur. Livedo reticularis may also occur. Alopecia is common and is associated with active disease. It often involves the frontal scalp and may be generalized or patchy. Mucocutaneous lesions may include vasculitis and ulceration of the hard palate, aphthous stomatitis, and less frequently ulcers or perforation of the nasal mucosa or septum.
Vasculitis affects small blood vessels in lupus. Children with lupus may have Raynaud's phenomenon, manifested as sequential color changes (blanching to cyanosis and hyperemia) in their distal extremities often related to exposure to cold or stress. It can vary in severity. Ischemia may lead to pain and ulcers, and in severe cases, atrophy, necrosis and gangrene. Treatment may include biofeedback, behavior modification, vasodilators, and nerve blocks.
Arthritis and arthralgias are common. Arthritis is usually transient and usually does not result in permanent deformity, although it can be quite painful. Occasionally it can be persistent and erosive. Patients with lupus, especially those requiring long term corticosteroid therapy, are at risk for avascular necrosis particularly in weight bearing joints.
Myalgia and even myositis may occur often related to vasculitis. Corticosteroid therapy may also contribute to corticosteroid myopathy with weakness.
Nephritis is one of the most common complications of lupus and affects about 75-80 % of children with SLE. It usually is manifested in the first 1-2 years of disease. Microscopic hematuria is common. Proteinuria, including nephrotic syndrome and hypertension may occur. Acute renal failure at presentation is rare. Renal histology on tissue obtained on a renal biopsy allows classification of the type of glomerulonephritis based upon the World Health Organization Classification of Renal Nephritis.
The most common cardiopulmonary manifestations are pericarditis and pleural effusions. Pulmonary hemorrhage and acute lupus pneumonitis can occur. Pulmonary infection is also frequently encountered. Myocarditis can occur. Myocardial infarction and valvulitis (Libman-Sacks endocarditis) are less frequent in children than adults.
Lymphadenopathy is quite common in children with SLE, sometimes associated with splenomegaly. Hepatomegaly can also be present.
Gastrointestinal complaints frequently occur in children with SLE. Serositis, pancreatitis or bowel vasculitis can occur. Bowel vasculitis can be complicated by hemorrhage, perforation, ischemia, or infarction. Corticosteroids may mask or suppress symptoms, making the diagnosis difficult.
Central nervous system involvement is a major cause of morbidity and mortality in children with lupus. Some estimate that up to 50% of children and adolescents with SLE have CNS involvement at disease onset. CNS involvement is variable in severity and manifestation. Symptoms may be subtle and difficult to detect or diagnose. CNS problems include neuropsychiatric manifestations, headache, seizures, cerebrovascular accidents, chorea, peripheral neuropathy, papilledema, visual loss, vertigo, myelopathy. Depression and difficulty with memory and concentration are common. Psychosis with hallucinations and paranoia may also occur. Cognitive impairment may cause a child to have difficulty with school. Headache is a common problem. Difficulty in coping with the disease, its manifestations and side effects of medications is common, particularly for adolescent patients.
Associated phenomenon may include antiphospholipid syndrome characterized by episodes of thrombosis, spontaneous recurrent abortions, cardiovascular crises, and menorrhagia. Thrombocytopenic purpura (TTP) and Evans' Syndrome (acute hemolytic anemia) has been seen in association with SLE. Sjogren's syndrome is rare in children (keratoconjunctivitis sicca, xerostomia). Autoimmune thyroid disease may occur in children with lupus.
Laboratory Evaluation
Antinuclear antibodies (ANA) are a hallmark of SLE and present in virtually all children with active SLE. The most specific pattern of nuclear immunofluorescence is "peripheral" suggesting the presence of ds-DNA (double stranded DNA), however the "homogeneous" pattern is the most common. The ANA is a very non-specific test and may be present in other diseases or children without rheumatic disease.
Anti-ds DNA antibodies are more specific for SLE and are often found in children with active SLE, particularly those with active nephritis. Antibodies to extractable nuclear antigens (ENA) may be useful. Anti-Sm antibodies (pronounced anti-Smith) are strongly associated with SLE. Antibodies to SS-A/Ro and SS-B/La are strongly associated with SLE, neonatal lupus, and Sjogren's syndrome. Anti-RNP antibodies (anti-ribonuclear protein) may be present in SLE, but in high titers are associated with mixed connective tissue disease. Antihistone antibodies are present in children with SLE and drug-induced SLE.
LE cell preparations and false positive tests for syphilis (i.e., VDRL and RPR) have largely been replaced by the tests above for proof of the immunologic disorder in diagnosing SLE.
Antiphospholipid antibodies may also be associated with lupus in children. Laboratory testing for lupus anticoagulant and/or anti-cardiolipin antibodies is useful. Positive anticardiolipin antibodies are responsible for the false-positive VDRL seen in lupus. Antiphospholipid antibodies can prolong the partial thromboplastin time (PTT). These antibodies are associated with thrombosis (paradoxical since one would expect an anticoagulant to do the opposite), thrombocytopenia, livedo reticularis, and recurrent miscarriages. They can also be seen without the presence of SLE. Rheumatoid factor is present in some children with SLE, but high titers may suggest the presence of an overlap syndrome.
Immune complexes are thought to play a major role in the pathogenesis of SLE, however due to problems with reproducibility of assays and variability in correlating with disease activity, measuring immune complexes is of limited utility.
Decreases in serum complement particularly C3, C4, and CH50 may reflect active disease and are important in assessing disease activity, especially lupus nephritis.
Hematologic abnormalities such as anemia are common. Anemia may be secondary to chronic disease (normocytic, hypochromic) or due to autoimmune hemolysis with a positive Coombs test. Hypersplenism and drug sensitivity may complicate the anemia. Leukopenia, especially lymphopenia, and immune thrombocytopenia frequently occurs. Some patients may initially present as idiopathic thrombocytopenic purpura (ITP) with a positive ANA, and later progress to SLE.
Acute phase reactants such as ESR are often increased during disease activity. This is a non-specific test, however, and cannot distinguish between flares of disease and infection.
Urinalysis may show abnormal urinary sediment in patients with glomerulonephritis, as well as proteinuria. Determinations of urine protein and creatinine excretion are helpful in assessing renal disease.
The diagnosis of SLE is based upon clinical and laboratory findings. Classification criteria for SLE from the American College of Rheumatology, revised in 1982 have also been widely used for diagnosis (8). In adults, the presence of 4 out of 11 criteria are required for diagnosis with a sensitivity and specificity of 96% percent. In children, one study reported a sensitivity of 96% and a specificity of 100%, as compared with a rheumatic disease control group (7). The 11 criteria are: malar rash, discoid rash, photosensitivity, oral ulcers (oral or nasopharyngeal ulceration), arthritis, serositis (pleuritis or pericarditis), renal disorder (persistent proteinuria, cellular casts), neurologic disorder (seizures or psychosis), hematologic disorder (hemolytic anemia, leukopenia, lymphopenia, or thrombocytopenia), immunologic disorder (positive LE cell preparation, anti-DNA antibodies, anti-Sm antibodies, or false positive serologic test for syphilis), and antinuclear antibody.
Treatment
Corticosteroids (glucocorticoids) are indicated for the treatment of SLE with major organ involvement. Intravenous methylprednisolone may be useful in certain patients, particularly those with severe disease. Treatment is usually on a long term basis with tapering over a prolonged period of time raising concerns over potential complications such as growth suppression, susceptibility to infection, hyperlipidemia, hypertension, hyperglycemia, psychosis, myopathy, osteoporosis, cataracts, increased intra-ocular pressure, glaucoma, gastric irritation and Cushing's syndrome. Other effects may include hirsutism, acne, striae, and weight gain.
Nonsteroidal anti-inflammatory drugs (NSAIDs) may be used to manage musculoskeletal complaints, but may not be appropriate in children with renal disease. Hydroxychloroquine is an antimalarial which may be helpful as an adjunct to corticosteroid therapy and may allow tapering of the corticosteroids. It can be useful for treatment of the arthritis and rash of SLE. Children taking this medication should be closely monitored for retinal toxicity.
Immunosuppressive agents such as cyclophosphamide, azathioprine, methotrexate, cyclosporin, and mycophenolate mofetil have been used to treat SLE. Cyclophosphamide pulsing (intravenous) is important in the treatment of severe SLE, particularly lupus nephritis and CNS disease. It has contributed to the increased survival of patients with nephritis. Toxicity may limit use, particularly concerns over the increased risk of infertility, infection, and malignancy. The role of plasmapheresis in treating lupus is not well defined, although it has been used in severe life threatening disease.
Course of the disease
Over the past 30 years or so, the life expectancy of children with SLE has significantly increased. Improvements in therapy, monitoring, and supportive care have all contributed to this improvement. Long term quality of life and outcomes have become increasingly important. The course of lupus in any child is unpredictable and varies from individual to individual. Most have chronic disease with disease remissions and exacerbations, although some patients may remain in remission for long periods of time. Close monitoring and follow up is essential to prevent significant morbidity and mortality.
Infection is the one of the major causes of morbidity and mortality in children with SLE. Infection has surpassed renal disease as the most common cause of death. Children with SLE are susceptible to infection as a consequence of both the disease and therapy, particularly corticosteroids and other immunosuppressive agents.
Growth abnormalities due to lupus and long-term corticosteroid therapy may result in short stature and delayed onset of puberty. Corticosteroids may cause cushingoid facies, hirsutism, and increased appetite leading to significant weight gain. These factors may have significant impact on children and especially adolescents, who are often very concerned about body image and peer acceptance.
Many patients experience difficulty in coping, psychological distress, and even depression with their SLE and complications relating to the disease and therapy. This can complicate assessment of neuropsychiatric problems secondary to central nervous system lupus. Neuropsychiatric deficits can adversely impact a child or adolescent's functioning and quality of life. Mental health services can play an important role in positive outcomes.
With the improved survival of children with SLE, cardiovascular complications are becoming an important problem of the illness. Abnormal lipid metabolism, long term complications of corticosteroid therapy, hypertension, and cardiac involvement secondary to lupus may all be contributing factors.
Avascular necrosis is also a problem with childhood SLE. This can occur with or without long term corticosteroid treatment and may result in significant pain and disability, even requiring joint replacement. The availability of alternate immunosuppressive therapies to corticosteroids may help decrease the incidence of this complication. Potential ophthalmologic complications from SLE and treatment with drugs such as hydroxychloroquine and corticosteroids require monitoring by an ophthalmologist.
Sun avoidance and protection is important in management of SLE. Many patients are photosensitive resulting in exacerbation of their rash. UV rays from other sources besides sunlight, such as fluorescent and halogen lights can also aggravate lupus. Sunscreen, protective clothing, and other devices to block UV emissions are helpful. A well balanced and nutritious diet, physical rest, and reducing emotional stress are also important in maintaining health.
The outlook for children with lupus has markedly improved. The continuing development of new treatments, improved surveillance of disease activity, and advances in supportive care promise to further enhance not only survival, but the quality of life for these children. Early diagnosis and prompt, aggressive treatment are also important in managing the disease and its complications.
Questions
1. List at least 6 of the 11 diagnostic criteria for SLE.
2. Name 3 drugs which are used for the treatment of SLE.
3. Which of the following statements are false?
. . . . . a. Leading causes of morbidity and mortality for children with SLE are infection, renal disease, and CNS involvement.
. . . . . b. ANA, anti-ds DNA antibodies, anti-Sm antibodies are part of the criteria for diagnosis of lupus
. . . . . c. Ophthalmologic complications are infrequent in children with SLE
. . . . . d. UV emissions may exacerbate lupus
4. True/False: A positive ANA test is a useful screening test for SLE?
5. True/False: Patients with a lupus anticoagulant have a prolonged PTT and they have hemorrhagic tendencies similar to patients with hemophilia.
References
1. Petty RE, Cassidy JT. Chapter 18-Systemic Lupus Erythematosus. In: Cassidy JT, Petty RE (eds). Textbook of Pediatric Rheumatology, 4th edition. 2001, Philadelphia: W.B. Saunders, pp. 396-449.
2. Hochberg MC. The application of genetic epidemiology to systemic lupus erythematosus. J Rheumatol 1987;14:867-869.
3. Vyse TJ, Todd JA. Genetic analysis of autoimmune disease. Cell 1996;85:311-318.
4. Deapen D, Escalante A, Weinrib L, et al. A revised estimate of twin concordance in systemic lupus erythematosus. Arthritis Rheum 1992;35:311-318.
5. Kurahara D, Tokuda A, Grandinetti A, et al. Ethnic differences in risk for pediatric rheumatic illness in a culturally diverse population. J Rheumatol 2002;29:379-383.
6. Lindsley CB. Lupus: A brighter outlook, a continuing challenge. Contemp Pediatr 1992;9:19-44.
7. Ferraz MB, Goldenberg J, Hilario MO, et al. Evaluation of the 1982 ARA lupus criteria data set in pediatric patients. Clin Exp Rheumatol 1994;12:83-87.
8. Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus (SLE). Arthritis Rheum 1982;25:1271-1277.
Answers to questions
1. Malar rash, discoid rash, photosensitivity, oral ulcers, arthritis, serositis, renal disorder, neurologic disorder, hematologic disorder, immunologic disorder, antinuclear antibody
2. Corticosteroids, NSAIDs, hydroxychloroquine, cyclophosphamide, azathioprine, methotrexate, cyclosporine, and mycophenolate mofetil
3.c. Retinal toxicity may be a complication of hydroxychloroquine therapy. Long-termed corticosteroid therapy may be complicated by cataracts, glaucoma, and increased intra-ocular pressure. Rare cases of orbital/ocular vasculitis may occur.
4. The answer is true, depending on your interpretation. The ANA test is non-specific in that a positive ANA test by itself is not diagnostic of SLE. The ANA is frequently positive in normal individuals. However, a screening test is not a diagnostic test, but it is just used to screen. A negative ANA suggests that the patient does not have SLE. The answer to this question true, but it should be noted that the ANA is frequently ordered excessively and inappropriately.
5. False. It is true that patients with a lupus anticoagulant have a prolonged PTT. However, the lupus anticoagulant paradoxically is associated with and increased risk of thrombosis, rather than hemorrhage.