Lupus Through the Ages: Neonatal, Childhood, Adolescence, and Elderly
When antibodies to Ro (SSA) cross the placenta, they infrequently settle in fetal tissue. Anti-SSB and anti-RNP may do this as well. Neonatal lupus occurs when the infant is born with a discoid or subacute cutaneous rash that disappears within weeks, often without treatment1 (Fig. 8.1). This occurs in 7% of infants born to anti-Ro-positive mothers. Two percent of the time, this antibody settles in other tissues. Of those with pathology, 54% have varying degrees of myocardial dysfunction, and 7% have hepatic, hematological, or neurological complications. Pregnant mothers with anti-Ro should undergo serial fetal echocardiograms between weeks 18 and 24; dexamethasone or intravenous immunoglobulin may be advised to prevent or ameliorate congenital heart block.
Somewhere between 5,000 and 10,000 people in the United States have childhood lupus. Of these, 20% to 40% are male. Nearly 70% have organ-threatening disease, as opposed to 40% to 50% of adults. Special considerations are taken into account to minimize the use of drugs that interfere with growth and development, interact with an incomplete immune system, or influence potential fertility issues. Despite the severity of childhood lupus, mortality rates are surprisingly low and only slightly worse than with adult lupus.2,6
Adolescents with lupus have a high treatment nonadherence rate, especially with corticosteroids and other agents that alter mood, behavior, or appearance. Noncompliance with sun avoidance is also a problem. Fragile social relationships should not take second place to patients’ being honest with their physician and family.
Lupus in the elderly is usually a milder, bland process that is more focused on musculoskeletal activity, constitutional symptoms, and Sjögren’s-related signs. The symptoms are often difficult to differentiate from primary Sjögren’s syndrome, rheumatoid arthritis (RA), or polymyalgia rheumatica. Only 2% of cases of lupus develop in patients over the age of 70. Organ-threatening disease is rare, and patients are frequently responsive to low doses of corticosteroids. Mortality studies suggest a poorer prognosis for lupus in older patients; in this author’s opinion, it relates to non-lupus-associated comorbidities.
Figure 8.1 Neonatal lupus. ©1972–2004 American College of Rheumatology Clinical Slide Collection. Used with permission.
Overlapping Syndromes
Defined in Chapter 2, mixed connective tissue disease and overlap syndromes occur when a patient has another defined rheumatic process in addition to systemic lupus erythematosus. Once thought to be a benign process, MCTD has a 20-year mortality rate of over 50%. Patients should be screened for pulmonary hypertension, nutritional problems related to dysmotility or malabsorption, myositis, and malignant hypertension. Elevated titers of anti-RNP must be present by definition. One case of MCTD is reported for every 20 persons with SLE. Overlap syndrome patients lack anti-RNP and are managed in the same manner as patients with lupus and other rheumatic disease.
Undifferentiated Connective Tissue Disease
It has been estimated that lupus is the “tip of the iceberg” and that for every patient with SLE, seven patients have an undifferentiated connective tissue disease. Many report a spontaneous disappearance of the process, or a palindromic course where the symptoms wax and wane or signs disappear for months or years at a time. Nonsteroidal anti-inflammatory drugs, antimalarial therapies, and intermittent low-dose corticosteroids are usually effective. Of the one-third with UCTD who evolve an American College of Rheumatology-defined autoimmune processes, 70% develop RA and only 20% develop SLE.
Drug-Exacerbated and -Induced Lupus
Some patients with established lupus experience exacerbations of the disease when given certain agents. These agents include sulfa-containing drugs, nonsteroidal drugs, and tetracyclines, among others. It is thought that this occurs via a sun-sensitizing mechanism (see Table 8.1).3
Many drugs can induce a positive antinuclear antibody in some patients; only a small percentage of these patients ever develop a clinically evident lupus-like reaction. For only six agents is the development of SLE reported in at least 1 in 1000 users. They account for 90% of cases of drug-exacerbated and -induced lupus and include hydralazine, procainamide, minocycline, tumor necrosis factor (TNF) inhibitors, methyldopa, and D-penicillamine. Organ-threatening disease is almost unheard of, and musculoskeletal, serositis, and constitutional presentations predominate. Resolution of the process occurs in over 90% within three months of discontinuation of the drug. Some of the patients given anti-TNF agents may have had lupus to begin with, because early lupus and RA are difficult to differentiate. Nonsteroidal drugs, salicylates, and low doses of corticosteroids may be needed in some patients and are very effective.
Table 8.1 Drug-exacerbated and -induced lupus: A partial list of causal agents
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1. Drugs proven to induce clinical lupus in at least 1 of 1000 cases • Hydralazine • Procainamide • Methyldopa • D-penicillamine • Tumor necrosis factor (TNF) blockers • Minocycline 2. Drugs proven to induce clinical lupus in at least 1 of 10,000 cases • Isoniazid • Sulfasalazine • Carbamazepine • Phenothiazines • Quinidine • Griseofulvin 3. Drugs that infrequently exacerbate but do not cause lupus • Antibiotics (e.g., arylamine sulfas, tetracyclines) • Nonsteroidal anti-inflammatory drugs (e.g., ibuprofen, piroxicam) • Oral contraceptives and other hormones 4. Mechanisms of drug-induced lupus • Drug promotes autoreactive T cells (e.g., phenytoin) • Drug is sun-sensitizing (e.g., phenothiazines) • Drug alters DNA and renders it immunogenic (e.g., procainamide) • Metabolic breakdown products in slow acetylators are immunogenic (e.g., hydralazine) • Drugs promote altered DNA repair via hypomethylation 5. Drugs shown to induce subacute cutaneous lupus rashes • Thiazide diuretics • Cimetidine • Calcium channel blockers • Angiotensin-converting enzyme inhibitors |
Antiphospholipid Syndrome
Defined in Chapter 2, 11% of persons with SLE have a hypercoagulable state. An equal number of patients without SLE develop the same process. A variety of factors allow lupus patients to be at an increased risk for developing thromboembolic disease, such as a protein cofactor to anti–β2 glycoprotein, endothelial exposure, and aberrations in the prostacyclin pathway.5 Over 90% of APS cases can be diagnosed by performing a specialized partial thromboplastin time, anti–β2 glycoprotein, anticardiolipin antibody, and circulating anticoagulant. A list of proteins and antibodies found more commonly in SLE that are associated with thromboembolic events is given in Table 8.2. Higher titers of IgG isotype phospholipid antibodies increase thromboembolic risks. The overwhelming majority of patients with an antiphospholipid antibody never experience an event. However, some of these patients have recurrent miscarriages and are only at risk during pregnancy.
Patients deemed to be at high risk for a thromboembolic event but who have never had one may benefit from daily low-dose aspirin. Antiphospholipid syndrome (APS) patients should be on lifelong anticoagulation, usually in the form of warfarin. Warfarin resistance warrants low-molecular-weight heparin; patients with arterial events sometimes benefit from the addition of low-dose aspirin, clopidogrel, or dipyramidole.
One percent of APS patients sustain recurrent events despite adequate therapy. These patients have catastrophic antiphospholipid syndrome (CAPS). This serious complication has a 50% mortality rate within two years and mandates anti-inflammatory interventions as well (e.g., immunosuppressives, apheresis).
Pregnancy
Lupus patients are normally fertile. However, only 67% of pregnancies in SLE patients are successful, compared to 85% in the general population.4 There are several contraindications to pregnancy wherein the life of the mother is jeopardized: myocarditis, renal failure, malignant hypertension, pulmonary hypertension, or recurrent thromboembolic events. Certain medications commonly used in SLE are also contraindicated. These include methotrexate, cyclophosphamide, mycophenolate mofetil, cyclosporine, angiotensin-converting enzyme inhibitors, warfarin, and rituximab. Antimalarial therapies are safe and decrease pregnancy-related disease exacerbations. Corticosteroids and occasional nonsteroidal anti-inflammatory drugs are permitted. Apheresis and intravenous immunoglobulin can be safely used if indicated.
Table 8.2 Clinical associations of anticardiolipin antibody
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Immunology/rheumatology • Antiphospholipid antibody syndrome • Systemic lupus erythematosus • Lupus anticoagulant • Chronic biological false positive test for syphilis • Rheumatoid arthritis • Sjögren’s syndrome • Ulcerative colitis • Behçet’s syndrome • Drug-induced lupus erythematosus • Other autoimmune disorders |
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Obstetrics • Recurrent fetal loss |
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Hematology • Arterial and venous thrombosis • Thrombocytopenia • Coombs’ positive hemolytic anemia • Evan’s syndrome |
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Neurology • Cerebral thrombosis • Transient ischemic attack • Chorea • Transverse myelopathy • Epilepsy • Migraine |
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Cardiology • Libman Sacks endocarditis • Coronary thrombosis • Labile hypertension |
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Pulmonary • Pulmonary emboli • Pulmonary hypertension |
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Dermatology • Livedo reticularis • Digital gangrene • Chronic leg ulcers |
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Miscellaneous • Drugs • Chlorpromazine • Pronestyl • Others • Infections • AIDS • Mononucleosis • Others • Malignancies |
Low-risk mothers are those with chronic cutaneous (discoid) lupus, drug-induced lupus, and non-organ-threatening disease with slight to no activity. Most pregnancy flares occur during the first trimester; afterward, the fetus, the placenta, and the mother’s stressed adrenal gland make extra corticosteroids. Blood pressure, urinary protein, blood sugars, and weight should be carefully monitored. A drop in C3 complement is associated with increased disease activity and a poorer pregnancy outcome. The prevalence of preeclampsia is increased in SLE. APS patients usually benefit from low-molecular-weight heparin and low-dose aspirin. Low-dose aspirin should be discontinued at week 28 to allow the patent ductus arteriosus to close. After delivery, postpartum flares occur in as many as 30% of patients between weeks 2 and 8. Short or increased doses of corticosteroids usually are efficacious. Breastfeeding is usually allowed in those taking all permissible medications.
References
1. Izmirly PM, Rivera TL, Buyon JP. Neonatal lupus syndromes. Rheum Dis Clin N Am. 2007;33:267–285.
2. Arkachaisri T, Lehman TL. Systemic lupus erythematosus and related disorders of childhood. Curr Opin Rheumatol. 1999;11:384–392.
3. Vasoo S. Drug-induced lupus erythematosus: an update. Lupus. 2006;15:757–761.
4. Clowse ME. Lupus activity in pregnancy. Rheum Dis Clin N Am. 2007;33:237–252.
5. Bertolaccini ML, Khamashta MA, Hughes GR. Diagnosis of antiphospholipid syndrome. Nat Clin Prac Rheumatol. 2005;1:40–46.
6. Lehman TJA. SLE in childhood and adolescence. In: DJ Wallace and BH Hahn. Dubois’ Lupus Erythematosus and Related Disorders, 8th ed. Philadelphia, PA: Elsevier; 2013:495–505.