Uncommon Mimickers of Systemic Lupus Erythematosus - Rheumatology Advisor

Uncommon Mimickers of Systemic Lupus Erythematosus


  • 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]

  • 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]

  • 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]

  • 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]

  • 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]

  • 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]

  • 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]

  • 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]

  • 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]

  • 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]


Systemic lupus erythematosus (SLE) can be associated with many diagnostic challenges. Although SLE was first recognized as a systemic disease more than a century ago,1 there is still no definitive test for this complex, multisystemic, autoimmune disease.2 Instead, SLE is diagnosed based on a battery of clinical features and laboratory test results, none of which is exclusive to SLE.2 For example, while antinuclear antibodies (ANAs) are highly sensitive for SLE, patients with other diseases may also test positive for ANAs, and a small percentage of patients with SLE will test negative.2,3

Another confounding factor is SLE’s highly heterogeneous presentation.4,5 Patients may have a mild variant characterized primarily by mucocutaneous manifestations, or they may have life-threatening disease involving multiple organ systems.5 SLE may take a relapsing-remitting course in some patients or a progressive one in others.5 Thus, someone with new-onset SLE may have different signs and symptoms than someone with longstanding, undiagnosed disease.4,6The high heterogeneity of SLE combined with overlap between its clinical presentation and that of many other medical disorders has complicated efforts to develop unambiguous classification criteria.4 The diverse array of conditions that share signs and symptoms with SLE are collectively called SLE mimickers.2 SLE mimickers span several categories, such as cutaneous or rheumatic disorders, infectious diseases, malignancies, primary immunodeficiencies, or other autoimmune disorders.2 They may be misdiagnosed as new-onset SLE or mistaken for an SLE flare. Maintaining suspicion for rare diseases included in the broad differential diagnosis for SLE may help prevent misdiagnosis and facilitate more prompt management of a patient’s illness.

Compiled by Christin Melton, ELS


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2. Chasset F, Richez C, Martin T, Belot A, Korganow A-S, Arnaud L. Rare diseases that mimic systemic lupus erythematosus (Lupus mimickers). Joint Bone Spine. 2019;86(2):165-171.

3. Leuchten N, Hoyer A, Brinks R, et al. Performance of antinuclear antibodies for classifying systemic lupus erythematosus: a systematic literature review and meta-regression of diagnostic data. Arthritis Care Res (Hoboken). 2018;70(3):428-438.

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8. Salinas M, Saurit V, Alvarellos A, et al. Cutaneous manifestations in patients with systemic lupus erythematosus: data from a multiethnic Latin American Cohort (GLADEL). J Dermatol Res Ther. 2016;2:034.

9. Petri M, Orbai A-M, Alarcón GS, et al. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum. 2012;64(8):2677-2686.

10. Cervera R, Khamashta MA, Font J, et al. Morbidity and mortality in systemic lupus erythematosus during a 10-year period: a comparison of early and late manifestations in a cohort of 1,000 patients. Medicine (Baltimore). 2003;82(5):299-308.

11. Bueno GCL, Koerich ATS, Burg LB, Kretzer SL, Moral J, Pereira IA. Visceral leishmaniasis mimicking systemic lupus erythematosus. Rev Soc Bras Med Trop. 2019;52:e20180208.

12. Rekvig OP. Systemic lupus erythematosus: definitions, contexts, conflicts, enigmas. Front Immunol. 2018;9:387.

13. Rigante D, Esposito S. Infections and systemic lupus erythematosus: binding or sparring partners? Int J Mol Sci. 2015;16(8):17331-17343.

14. US Centers for Disease Control and Prevention. Parasites – Leishmaniasis. About Leishmaniasis. https://www.cdc.gov/parasites/leishmaniasis/gen_info/faqs.html. Updated July 26, 2018. Accessed April 8, 2019.

15. Santana IU, Dias B, Nunes EA, Rocha FA, Silva FS Jr, Santiago MB. Visceral leishmaniasis mimicking systemic lupus erythematosus: case series and a systematic literature review. Semin Arthritis Rheum. 2015;44(6):658-665.

16. Santos Silva AF, Figueiredo Dias JPBC, Nuak JMNGS, Rocha Aguiar F, Araújo Pinto JA, Sarmento ACEM. Visceral leishmaniasis in a patient with systemic lupus erythematosus. IDCases. 2015;2(4):102-105.

17. To U, Kim J, Chia D. Lupus flare: an uncommon presentation of disseminated gonorrhea. Case Rep Med. 2014;2014:626095.

18. Rodero MP, Crow YJ. Type I interferon-mediated monogenic autoinflammation: the type I interferonopathies, a conceptual overview. J Exp Med. 2016;213(12):2527-2538.

19. Rice GI, Del Toro Duany Y, Jenkinson EM, et al. Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling. Nat Genet. 2014;46(5):503-509.

20. Thornton CS, Minoo P, Schneider M, Fifi-Mah A. Severe skin disease in lupus associated with hemophagocytic lymphohistiocytosis: case reports and review of the literature. BMC Rheumatol. 2019;3:7.

21. Price S, Shaw PA, Seitz A, et al. Natural history of autoimmune lymphoproliferative syndrome associated with FAS gene mutations. Blood. 2014;123(13):1989-1999.

22. de Wit J, Brada RJK, van Veldhuizen J, Dalm VASH, Pasmans SGMA. Skin disorders are prominent features in primary immunodeficiency diseases: a systematic overview of current data. Allergy. 2019;74(3):464-482.

23. Fischer A, Provot J, Jais J-P, et al. Autoimmune and inflammatory manifestations occur frequently in patients with primary immunodeficiencies. J Allergy Clin Immunol. 2017;140(5):1388-1393.e8.

24. Perry AM, Choi SM. Kikuchi-Fujimoto disease: a review. Arch Pathol Lab Med. 2018;142(11):1341-1346.

25. Fajgenbaum DC, Uldrick TS, Bagg A, et al. International, evidence-based consensus diagnostic criteria for HHV-8-negative/idiopathic multicentric Castleman disease. Blood. 2017;129(12):1646-1657.

26. Lunning MA, Vose JM. Angioimmunoblastic T-cell lymphoma: the many-faced lymphoma. Blood. 2017;129(9):1095-1102.

27. Moskowitz AJ. Practical treatment approach for angioimmunoblastic T-cell lymphoma. J Oncol Pract. 2019;15(3):137-143.

28. Hintze JP, Kirby A, Torti E, Batanian JR. Prolidase deficiency in a Mexican-American patient identified by array CGH reveals a novel and the largest PEPD gene deletion. Mol Syndromol. 2016;7(2):80-86.29. Klar A, Navon-Elkan P, Rubinow A, et al. Prolidase deficiency: it looks like systemic lupus erythematosus but it is not. Eur J Pediatr. 2010;169(6):727-732.

29. Klar A, Navon-Elkan P, Rubinow A, et al. Prolidase deficiency: it looks like systemic lupus erythematosus but it is not. Eur J Pediatr. 2010;169(6):727-732.