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Cutaneous Manifestations
Many SLE mimics manifest cutaneous changes that resemble the dermatologic effects of SLE observed in 50% to 85% of patients.[2],[7],[8] The Systemic Lupus International Collaborating Clinics classification criteria for SLE includes 4 types of cutaneous manifestations: acute or chronic cutaneous lupus, oral/nasal ulcers, and non-scarring alopecia.[9] In US studies of SLE, the most common cutaneous conditions were malar rash (58%), discoid lesions (28%), photosensitivity (60%), and oral ulcers (53%).[10] Additionally, subacute cutaneous lupus develops in 10% to 15% of patients with SLE.[4] Biopsy of a skin lesion with histopathologic study can often distinguish between SLE and other causes.[2] An SLE band test typically shows deposits of immunoglobulin and complement components at the dermal-epidermal junction in patients with SLE but can also be positive in people without SLE.[2] In addition, CD123 immunohistochemistry for plasmacytoid dendritic cells may help distinguish SLE from rosacea and other skin conditions.[2]
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Microbial Infection
Many viral, bacterial, parasitic, and fungal infections manifest features observed with SLE, such as fever, fatigue, rash, arthralgias, lymphadenopathy, mucosal ulcers, and positivity for ANA, anti-DNA antibodies, or direct Coombs’ test.[2],[11-13] Common viral infections like hepatitis C, Epstein-Barr, parvovirus B19, and cytomegalovirus have been misdiagnosed as SLE.[2] Several studies have implicated these and other viruses in the pathogenesis of SLE.[2],[13] Visceral leishmaniasis, a parasitic infection found in tropical countries and occasionally detected in US residents who traveled or lived abroad,[14] also mimics SLE.[11],[15],[16] Both can cause fever, weight loss, skin or mucosal lesions, and visceromegaly; positivity for ANAs and direct Coombs test also occurs with visceral leishmaniasis.[14-16] Patients with SLE are prone to infections, including disseminated gonorrhea, which should always be considered in the differential diagnosis for SLE flare.[17]
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Type I Interferonopathies
Type I interferonopathies (IFNs) are innate immune system disorders linked to elevated activity of type I interferons, which mediate antiviral response.[2],[18] Onset ranges from early infancy to adulthood, depending on the IFN.[2] Although the phenotypic spectrum of type I IFNs is broad, they are all associated with autoinflammation and autoimmunity.[18] At least 9 type I IFN genetic variants cause an SLE-like syndrome.[2] Some also have neurologic manifestations such as neonatal encephalopathy or cerebral calcification.[2] Other signs and symptoms include chilblain, glaucoma, paraparesis, skin lesions, vasculitis, and mental retardation.[2] A type I interferon signature has been linked to SLE,[18] and certain type I IFNs appear to increase the risk for SLE.[19] This has led to investigations of anti-interferon therapies for SLE.[18] If a patient with SLE also has symptoms of a type I IFN, diagnosing the type I IFN is important, albeit challenging.[2] Currently, only genetic screening can confirm a type I IFN diagnosis.[2]
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Hemophagocytic Lymphohistiocytosis
Hemophagocytic lymphohistiocytosis (HLH) refers to a group of hyperinflammatory syndromes and can be primary or secondary to another systemic infection, malignancy, or rheumatic disorder.[2] HLH in the setting of rheumatic disease is called macrophage activation syndrome (MAS). HLH/MAS can occur at any age and initiates a life-threatening cytokine storm.[2],[20] MAS may mimic or coincide with a disease flare in established or newly onset SLE.[20] Distinguishing MAS from SLE is difficult because they can both cause fever, lymphadenopathy, splenomegaly, rash, neurologic symptoms, and cytopenias.[2] Bone marrow aspirate showing hemophagocytosis is highly sensitive for MAS (83%) but has low specificity (60%).[2],[20] Clinical and biological features common with MAS but rare during an SLE flare include high fever (>39°C); neurologic symptoms; neutropenia (500 µg/L), and procalcitonin.[2]
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Autoimmune Lymphoproliferative Syndrome
Autoimmune lymphoproliferative syndrome (ALPS), also known as Canale-Schmitt syndrome, is a rare nonmalignant disorder frequently caused by germline or somatic FAS gene mutations (ALPS-FAS) that disrupt apoptotic mechanisms needed to maintain lymphocyte homeostasis.[2],[21] Expansion of double-negative T cells (CD3+, CD4- and CD8-) and progressive accumulation of autoreactive T and B lymphocytes contributes to a range of autoimmune symptoms.[2,21] Often, ALPS-FAS symptoms are evident in early childhood and overlap with symptoms of childhood SLE, such as lymphadenopathy, splenomegaly, and cytopenia.[2],[21] In a study of 150 patients with ALPS-FAS, 97% had lymphadenopathy, 95% had splenomegaly, and 69% had cytopenias.[21] Presumptive biomarkers of ALPS-FAS are an elevated double-negative T cell count (>1.5% of total lymphocytes or 2.5% of CD3+ lymphocytes) and increased serum levels of soluble FAS ligand, interleukin-10, and vitamin B12.[2],[21] Patients often test positive for ANAs and anti-dsDNA antibodies.[2] Molecular testing is required to confirm the diagnosis.[21]
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Primary Immunodeficiencies
Primary immunodeficiencies (PID) encompass hundreds of rare genetic disorders characterized by immune system impairment.[2] People with PID are more susceptible to recurrent or severe infections, autoimmune and autoinflammatory conditions, cancers, allergies, and skin disorders.[22],[23] Several mechanisms have been proposed for PID-related autoimmunity/autoinflammation, including increased production of type I interferon or interleukin-1; effects on regulation of T-cell or B-cell proliferation, function, and apoptosis, and dysregulation of apoptotic mechanisms.[23] The risk for autoimmune cytopenia is 120-fold higher for patients with PID relative to the general population, and early onset autoimmune hemolytic anemia or thrombocytopenia should arouse suspicion for PID.[23] Other indicators are unusual and recurrent infections, profound lymphopenia, hypogammaglobulinemia, or a suggestive family history.[2],[22] Some forms of PID manifest SLE-like symptoms, and SLE may occur in someone with PID, but it is not common.[2]
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Kikuchi Disease
Other names for Kikuchi disease (KD) are Kikuchi-Fujimoto disease and histiocytic necrotizing lymphadenitis.[2] The cause of KD is unknown, but it is commonly characterized by fever and cervical lymphadenopathy.[2] Less commonly, rash and ulcers, arthralgia, hepatosplenomegaly, and fatigue may occur.[2],[24] KD typically resolves on its own within a few months and recurs in less than 5% of patients.[24] The relationship between KD and SLE is unclear. In addition to overlapping clinical features, KD and SLE have similar predispositions for age and gender.[2] In approximately 20% of cases, the histologic and immunohistochemical features of SLE lymphadenopathy and KD are indistinguishable.[2],[24] Whereas ANAs are present in almost all patients with SLE, they are found in only 30% of patients with KD at diagnosis.[2] However, serologic tests for anti-dsDNA antibodies and rheumatoid factor are typically negative in patients with KD, and they may be useful for excluding SLE.[2],[24]
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Multicentric Castleman Disease
Castleman disease is a rare condition historically classified as unicentric or multicentric based on lymph node involvement.[25] Multicentric Castleman disease (MCD) may be idiopathic or associated with human herpesvirus-8.[25] Common clinical features of MCD are constitutional symptoms such as fever (>38°C), weight loss, night sweats, and fatigue; fluid accumulation, including edema and ascites; lymphadenopathy; hepatosplenomegaly; and skin changes.[2],[25] The overlapping clinical features between MCD and SLE and the similar histopathology in patients with enlarged lymph nodes make it easy to confuse the 2 diseases.[25] In addition, patients with MCD frequently test positive for ANAs, so an ANA test cannot be used to exclude it from the differential diagnosis.[2] Other laboratory findings consistent with MCD include an elevated level of C-reactive protein, an increased erythrocyte sedimentation rate, anemia, thrombocytopenia, hypoalbuminemia, renal dysfunction or proteinuria, and polyclonal hypergammaglobulinemia.[25]
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Angioimmunoblastic T-cell Lymphoma
Although rare, angioimmunoblastic T-cell lymphoma (AITL) is one of the most common subtypes of peripheral T-cell lymphoma.[26] It is an aggressive disease with a poor prognosis. Patients often present with fever, weight loss, night sweats, and lymphadenopathy.[26] Some also have hepatosplenomegaly at diagnosis.[26] Up to half of patients with AITL have cutaneous changes, such as urticarial rash or nodular lesions.[26] Other common features include pleural effusion, an elevated level of lactate dehydrogenase, polyclonal hypergammaglobulinemia, and ascites.[26] AITL is associated with immune deregulation, which can lead to positive test results for rheumatoid factor and anti-smooth muscle and a positive direct Coombs’ test.[26],[27] One-third of patients with AITL have autoimmune conditions, such as autoimmune hemolytic anemia, thrombocytopenic purpura, or vasculitis.[2] Lymph node biopsy is used to diagnose AITL and usually shows an admixture of tumor T cells plus B immunoblasts positive for the Epstein Barr virus.[27]
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Prolidase Deficiency
Prolidase deficiency (PD) is another rare genetic disorder that mimics SLE and is associated with increased risk for SLE.[2] More than 28 genetic mutations are linked with PD, which is characterized as an “autosomal recessive inborn error of amino acid metabolism that affects collagen degradation.”[28] It is typically diagnosed in early childhood. Approximately 80% of patients with PD experience dermatologic changes, the most common of which is chronic skin ulcerations; others include rash, photosensitivity, and dermatitis.[2],[28],[29] Other common clinical features include hepatosplenomegaly; recurrent respiratory, ear, and sinus infections; facial dysmorphism; intellectual disability; bone abnormalities; and joint dislocations.[2],[28],[29] An estimated 14% of patients with PD have comorbid SLE.[28] Laboratory findings of anemia, thrombocytopenia, hypergammaglobulinemia, and hypocomplementemia are also frequent and may lead to misdiagnosis of PD as SLE.[2] PD is diagnosed using chromatography to analyze the urine for iminodipeptides.[2]
