Types of Lupus

Introduction

On the basis of etiology and the extent of disease, lupus can be divided into several types, including systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), drug-induced lupus (DIL) and neonatal lupus (NL). Childhood-onset lupus (cSLE) is also sometimes considered a distinct type, although this is not universally accepted as it can also be understood as early-onset SLE. Even though each type of lupus has distinguishing characteristics, it is important to note that they may partially overlap in clinical or laboratory features and treatment approaches.

Systemic Lupus Erythematosus

Systemic LE is the most common type of lupus. It is an autoimmune inflammatory disorder that typically affects women 15 to 45 years of age. Systemic LE is markedly heterogeneous, often affecting multiple organ systems and causing constitutional, dermatologic, renal, neuropsychiatric, musculoskeletal and other symptoms (Figure 2-1). This heterogeneity has resulted in clinical division of SLE into manifestations characterized by specific management approaches. Lupus nephritis (LN) and neuropsychiatric lupus (NP SLE) are two of the most common manifestations of SLE.

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Cutaneous Lupus Erythematosus

Cutaneous manifestations occur in up to 80% of patients with lupus. Cutaneous LE may occur with SLE or independently, and can be seronegative for ANAs in the latter case. Cutaneous LE can be further subdivided into acute CLE, typified by a non-discoid malar rash (Figure 2-2A), subacute CLE, typified by nonindurated psoriasiform and/or annular polycyclic rash (Figure 2-2B), and chronic CLE, typified by discoid lesions (Figure 2-2C). Cutaneous LE may progress into SLE. A systematic review of 25 adult and 8 pediatric cohort studies reported a range of progression to SLE of 0-42% in the adult studies and 0-31% in the pediatric studies. In the largest adult cohorts, progression to SLE occurred in 11-14% of patients. Evolution into SLE also depends on CLE subtype, being most common in acute CLE (almost 100%), less common in subacute CLE (~30%) and rare in chronic or discoid CLE (~5%).

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As the name suggests, DIL is a form of lupus triggered by drug exposure. A universally-accepted definition of DIL does not (yet) exist; one proposal suggests four characteristics:

• Sufficient and continuous exposure to a specific drug
• A minimum of one symptom associated with SLE
• No prior history of SLE symptoms before starting the drug
• Resolution of symptoms within a certain time period (weeks or sometimes months) after discontinuation of the drug

Thus, DIL differs from SLE primarily in that it has a single cause and is typically reversible. However, a number of secondary differences arise from this, including demographics (the female:male ratio is as low as 1:1 with DIL, depending on the drug, compared to 9:1 in SLE; and the age of onset is typically higher for DIL than for SLE, reflecting a higher pharmacologic burden in older adults) and disease manifestations; see Table 2-1.

Various drugs have been associated with DIL; an analysis of >12,000 individual safety case reports from VigiBase, the WHO pharmacovigilance database, identified a total of 118 drugs and substances linked to DIL. This is likely to increase as the modern pharmacopoeia keeps growing. Drug classes with members associated with DIL include antiarrhythmics, antihypertensives, antimicrobials, anticonvulsants and immunomodulators.9 The older antiarrhythmic procainamide and the antihypertensive hydralazine carry the highest risk, with a 5-20% probability of inducing lupus-like symptoms.

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Neonatal Lupus

Neonatal lupus is a rare autoimmune disorder caused by transplacental passage of maternal autoantibodies to the fetus during gestation. Since the fetus is entirely dependent on a maternal source of immunoglobulin G, transplacental passage of antibodies is a normal process. Neonatal lupus may develop if autoantibodies against the Ro/SSA or La/SSB ribonucleoprotein complex components cross into the fetal blood. The term NL reflects the similarity between the cutaneous lesions that characterize NL and SLE. However, this is somewhat of a misnomer; anti-Ro/SSA and anti-La/SSB antibodies are also found in other autoimmune disorders, most notably Sjögren syndrome, which causes inflammation of exocrine glands. Among mothers of infants with SLE, only an estimated 30% have SLE (~15%) or SLE associated with Sjögren syndrome (~15%); the rest may be asymptomatic (~25%) or have an undifferentiated autoimmune disorder (~25%), Sjögren syndrome (~20%), or, rarely, rheumatoid arthritis (~1%).

Neonatal lupus is associated with a spectrum of manifestations, including cardiac, cutaneous, liver, hematologic and neurological abnormalities. Cardiac manifestations are characteristic and diverse, including complete heart block, cardiomyopathy, endocardial fibroelastosis and heart valve abnormalities. Because of the limited ability of heart tissue to regenerate, cardiac manifestations are typically irreversible. Cutaneous lesions (Figure 2-3) and most other non-cardiac manifestations, resolve after maternal antibodies are cleared from the bloodstream by ~8 months of age.

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Childhood-Onset Lupus

Childhood-onset lupus (cSLE), also known as juvenile-onset SLE or pediatric SLE, is typically defined as SLE that starts before the 18^th birthday. The median age at presentation is 11-12 years, and it rarely occurs in children under the age of 5 years. Like SLE in general, cSLE is more common in female patients, though less so than adult-onset SLE. The female:male ratio is 4:3 in the first decade of life and 4:1 in the second decade; in children <5 years of age, it is approximately 1:1. The pathogenesis of cSLE appears similar to SLE in that it involves a genetic predisposition and additional environmental, epigenetic and hormonal factors. Given the age-dependent increase in the sex ratio, cSLE with an early onset may be less dependent on hormonal factors. Anti-dsDNA antibodies are more common in cSLE than adult-onset SLE.

Childhood-onset SLE is even more diverse in presentation than adult-onset SLE, including a wide spectrum of severity (from life-threatening acute disease to a chronic course) and symptoms (including fever, weight loss, arthralgia/arthritis, cutaneous manifestations, LN and neuropsychiatric symptoms). The frequencies of specific manifestations of cSLE are shown in Table 2-2. Childhood-onset SLE is typically more severe than adult-onset SLE, with a more aggressive disease course and more flares. Severe disease manifestations, including LN and NP SLE, are more common in cSLE than adult-onset SLE. Mortality is ~3 times greater in cSLE than adult-onset SLE and is highest in patients in whom cSLE began before the age of 6.

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