Key Points
Disease summary:
Systemic lupus erythematosus (SLE) is a complex, autoimmune disease characterized by the presence of antibodies to nuclear components. An interplay of genetic and environmental factors contribute to the immunologic manifestations and disease pathogenesis, which can involve the skin, kidneys, hematologic system, nervous system, joints, mucosal and serosal membranes, and/or other organs.
Clinically, the disease spectrum is varied and affected individuals can experience periods of disease activity and remission.
Women are affected more frequently than men, with a reported ratio of up to 9:1, and diagnosis most often occurring in the third through fifth decades of life.
The diagnosis of SLE is clinical, and a typical presentation is often a young woman with constitutional, skin, and musculoskeletal complaints.
Organ involvement, such as kidney, central nervous system, or cardiopulmonary, can occur early in the disease course or at diagnosis, and can be severe and dominate the patient’s disease course.
Differential diagnosis:
Some important general considerations when evaluating an individual with potential SLE include drug-induced lupus, infection, malignancy, and other autoimmune conditions. Due to the number of possible clinical manifestations of SLE, it is beyond the scope of this review to fully summarize the differential diagnosis. However, if one organ manifestation dominates, then the differential will include related conditions. For example, in a patient presenting with seizures, considerations for diagnosis include new-onset epilepsy, metabolic abnormalities, drug toxicity or withdrawal, and hypoxia, among others.
Monogenic forms:
Several rare mutations that lead to either a deficiency of classical complement components, or impaired DNA degradation, clearance, and/or antigen signaling have been identified in small numbers of patients with SLE or lupus-like manifestations. The genes include C1Q (1p36), C1R/C1S (12p13), C4A&B (6p21.3), C2 (6p21.3), TREX1 (3p21.31), DNASE1 (16p13.3), ACP5 (19p13), SIAE (11q24), and DNASE1L3 (3p14.3).
Family history:
Most individuals with SLE do not have an affected family member. However, a familial prevalence of up to 12% has been reported. In families with clusters of members with SLE, the inheritance pattern does not follow a classic single-gene Mendelian pattern.
Twin studies:
The disease concordance rate is 2% to 5% for dizygotic twins and 24% to 58% for monozygotic twins. The rate of concordance in monozygotic twins supports the possibility that development of disease is multifactorial, which may include multiple genes, as well as environmental and hormonal factors.
Environmental factors:
Several infections have been associated with the development of SLE, with the strongest evidence linked to Epstein-Barr virus; the correlation of disease flares in patients with SLE who develop viral infections supports this possibility. Environmental exposures or contaminants, such as trichloroethylene (an industrial solvent) and various pesticides have all been suggested in epidemiologic studies as possible triggers of SLE in susceptible individuals, but further study in this area is necessary. Plausible biologic evidence links SLE and other autoimmune diseases to silica exposure, which can occur due to diverse occupations such as farming, construction, mining, and manufacturing. High silica exposure has been associated with the development of SLE (odds ratio [OR] 4.6, 1.4-15.4). Additionally, a number of medications have been implicated in precipitating SLE, including hydrochlorothiazide, antihistamines, calcium channel blockers, terbinafine, and naproxen. Antitumor necrosis factor-alpha therapy and interferon-alpha therapy have been associated with antinuclear antibodies (ANA)—typically anti–double-stranded DNA (dsDNA) antibodies—and the development of lupus manifestations. Furthermore, hormone-induced SLE may occur in some clinical settings.
Genome-wide associations:
In the vast majority of cases, SLE fits the common disease-common variant hypothesis, in which nonrare risk variants lead to a modest magnitude of risk (OR 1.1-2.5) and account for a portion of overall genetic susceptibility to disease. Genetic dissection of SLE utilizing the rapidly advancing technology applied in genome-wide association (GWA) studies have confirmed disease associations with previously established risk loci, and identified several novel risk loci. Up to 1 million single-nucleotide polymorphisms (SNPs) have been genotyped in each of six GWA studies, and in a series of large-scale replication studies of individuals of both European and Asian descent. Current understanding of SLE pathogenesis can group several of the identified genes into major immunologic pathways, such as defective clearance of immune complexes containing nuclear antigens (eg, TREX1, complement components, ITGAM, FCGRs); toll-like receptor activation with secretion of type I interferons (eg, TLRs, IRF5, STAT4, IRAK1); and amplification of the adaptive immune response (eg, PTPN22, BANK1, BLK, LYN, FCGR2B, TNFSF4). Certain immunologic pathways are common to multiple autoimmune disorders, which likely explains that a growing number of SLE-susceptibility genes also predispose to conditions including rheumatoid arthritis, Crohn disease, psoriasis, type 1 diabetes, and systemic sclerosis.
Pharmacogenomics:
Testing for TPMT (thiopurine methyltransferase) mutations can be utilized in clinical practice before initiation of a thiopurine drug such as azathioprine (Table 142-1). Defects in the TPMT gene can lead to increased levels of the pharmacologically active metabolite, with potential bone marrow toxicity.
Diagnostic Criteria and Clinical Characteristics
The diagnosis of SLE can be readily made in a young woman who presents with hallmark features of the disease, such as fatigue, fevers, malar rash or photosensitivity, alopecia, oral or nasal ulcerations, and/or arthralgias or arthritis. Hypertension, pleuritic chest pain with friction rub, purpura, hepatosplenomegaly, and/or lymphadenopathy may also be present at the initial evaluation.
Diagnostic evaluation should include
Laboratory testing: complete blood count, comprehensive metabolic panel, erythrocyte sedimentation rate or C-reactive protein, and urinalysis.
Autoantibody testing: ANA titer, anti-dsDNA titer, antiribosomal binding protein antibody titers (including anti-Smith, antiribonucleoprotein [RNP], anti-SSA/Ro, anti-SSB/La), and antiphospholipid antibody titers. Over 90% of individuals with SLE demonstrate ANA positivity, therefore the absence of ANAs would weigh strongly against a diagnosis of SLE.
Additional testing if indicated: protein and creatinine urine collection over 24 hours, Coombs antibody test, reticulocyte count, amylase or lipase, and lupus anticoagulant activity.
Organ involvement can be identified with evidence of nephritis or nephrosis, elevated liver enzymes, interstitial lung disease or pulmonary hypertension, cardiac valvular involvement, etc. Additional workup for the evaluation of specific organ involvement can include, when indicated
Biopsy: skin or kidney
Imaging: chest and/or joint radiographs, magnetic resonance imaging and/or angiography of the brain, computed tomography (CT) scan of the abdomen
Other: electrocardiogram, echocardiogram, pulmonary function test, lumbar puncture, scan for pulmonary embolism
The American College of Rheumatology has developed a set of criteria that differentiate individuals with SLE from other autoimmune diseases for the purposes of inclusion in clinical trials. When 4 of 11 criteria are present, serially or simultaneously, the sensitivity and the specificity for the classification of SLE are each 96%; these criteria include malar rash, discoid rash, photosensitivity, oral ulcers, arthritis, serositis (pleuritis or pericarditis), renal disorder (proteinuria of 500 mg/d or cellular casts present), neurologic disorder (seizures or psychosis), hematologic disorder (hemolytic anemia, leucopenia, lymphopenia, or thrombocytopenia), immunologic disorders, and an abnormal ANA titer.
Constitutional symptoms and/or specific organ symptoms can occur in the setting of an individual with SLE. A brief overview of major clinical characteristics at disease onset or at a time of increased disease activity is as follows:
Constitutional: Fatigue, malaise, and fever can occur.
Mucocutaneous: The most common skin lesion is the facial butterfly rash (sparing the nasolabial folds), with associated photosensitivity. Alopecia as well as oral and nasal ulcerations can be frequent. Discoid rash lesions (discrete plaques which tend to scar) are less common.
Arthritis: Arthritis is a common manifestation in SLE and is seen in over 60% of individuals. It tends to be symmetrical and nondeforming.
Renal: Renal involvement can develop in up to 75% of individuals diagnosed with SLE in the first or second decade of life, and usually complicates early stages of the disease. Adult-onset of SLE is associated with lower rates of renal involvement. There are a number of types of renal disease in SLE, which are typically differentiated by renal biopsy.
Pulmonary: Pleuritic chest pain is fairly common in SLE, with up to 50% involvement. Interstitial lung disease is less commonly seen, but can lead to pulmonary hypertension when untreated. Acute pneumonitis, pulmonary hemorrhage, and shrinking lung syndrome are rarely seen complications.
Hematologic: The major hematologic manifestations of SLE are anemia, leukopenia, thrombocytopenia, and the antiphospholipid syndrome.
Neuropsychiatric: The frequency of neuropsychiatric manifestations in SLE has been estimated anywhere between 10% and 90%. Cognitive dysfunction can be frequent, whereas seizures and psychosis are quite less common, although they remain a significant cause of morbidity. Headaches, neuropathies, and psychiatric abnormalities can also complicate the disease course in SLE.
Cardiovascular: Pericarditis, noninfectious valvular (Libman-Sacks) endocarditis, and increased risk of coronary artery disease are cardiac risks of SLE. Thromboembolic disease, vasculitis, and the antiphospholipid syndrome are additional important considerations in the disease course.
Gastrointestinal: Peritonitis and rarely pancreatitis can occur in SLE.
Screening and Counseling
There is no evidence supporting the routine screening of family members of individuals with SLE, in the absence of clinical signs or symptoms. The genetic testing of identified SLE susceptibility SNPs has not been validated in clinical studies in the general population or in relatives of patients with SLE. Because of the strong penetrance of C1q deficiency for development of immune deficiency and/or autoimmunity, some experts have advocated screening for the mutation identified in the index case among family members to identify C1q-deficient patients and carriers, and provide genetic counseling. This situation, however, is rare (SLE reported in less than 50 C1q deficiency cases worldwide), and often is offspring of consanguineous marriages.
The incidence of SLE or lupus-like manifestation in individuals with a complete deficiency, due to a homozygous mutation, in one of the classical complement pathway genes ranges from 10% to 93%. There is an extremely high genetic risk for SLE and glomerulonephritis in C1q-deficient (93% penetrant) individuals. Individuals deficient in both C4A and C4B genes have a high risk to develop SLE or a lupus-like manifestation (75% penetrant). Despite the strong association between C1q deficiency and development of SLE at an extremely young age, the clinical presentation of hereditary C1q deficiency can be very diverse, with symptoms ranging from mild recurrent infections to severe bacterial meningitis, sepsis, glomerulonephritis, and/or angioedema or SLE-like skin involvement.
The general sibling risk ratio for the development of SLE is approximately 30. Additionally, there seems to be familial aggregation of autoimmune disease in general in some families with SLE. Sporadic cases of SLE do not present with different disease features overall compared with familial cases; however, familial aggregates tend to display similar disease characteristics as well as immunologic manifestations.
Importantly, several recent GWA studies have begun to investigate the genotype-phenotype relationship in SLE with some interesting reported associations, particularly in regards to the development of autoantibody production as well as renal disease. Ongoing research into this area may ultimately provide uniquely personalized care and recommendations.
Management and Treatment
The basic management of individuals with SLE includes avoidance of known triggers of disease, and maintaining good general health.
Sun avoidance should be recommended to all patients, as ultraviolet radiation can promote disease activity likely through the stimulation of proinflammatory cytokines and increased generation of apoptotic material in the skin that can act as autoantigens.
Due to the recommended sun avoidance in all people with SLE, the assessment of circulating vitamin D levels with appropriate supplementation should be routine. Additionally, the use of calcium supplementation should be considered, particularly in patients with SLE who have required glucocorticoid therapy and would therefore be at increased risk for osteoporosis.
Routine vaccinations should be encouraged in individuals with SLE, especially prior to initiation of immune suppression (if possible), including the annual influenza vaccine. However, any individual on therapy with immune-modulating agents, with the exception of perhaps hydroxychloroquine, should avoid live virus vaccines.
No specific dietary recommendations exist for individuals with SLE, although a healthy and varied diet is encouraged. Weight loss should be recommended in any overweight individuals with SLE. Exercise is recommended for general health maintenance and for prevention of loss of muscle mass and bone demineralization in individuals with active disease. Smoking cessation is recommended in all individuals with SLE.
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