Castleman disease mimicking systemic lupus erythematosus: the importance of vigilance in diagnosing autoimmune mimickers

Introduction

CD is a rare and heterogeneous lymphoproliferative disorder characterized by lymph node enlargement and a spectrum of systemic inflammatory manifestations. It is classified into unicentric (UCD) and multicentric (MCD) forms, with the idiopathic variant (iMCD) often presenting with constitutional symptoms, cytopenias, and multiorgan involvement (1). Due to its protean clinical features and occasional autoantibody positivity, CD can closely resemble SLE, an autoimmune disease defined by immune dysregulation and broad clinical variability (2). This editorial highlights the diagnostic challenges of this overlap and underscores the importance of considering Castleman disease in the differential diagnosis of lupus-like syndromes. Key distinguishing features between iMCD and SLE are summarized in Table 1, and representative misleading clinical scenarios are summarized in Table 2.

Table 2. Minicase series from the literature (selected reports).

Table 1. Comparison between iMCD and SLE.

iMCD, idiopathic multicentric Castleman disease; TAFRO, thrombocytopenia, anasarca, fever, reticulin fibrosis, renal dysfunction, organomegaly; NOS, not otherwise specified; IL-6, interleukin-6; VEGF, vascular endothelial growth factor; sIL-2R, soluble interleukin-2 receptor; FDC, follicular dendritic cell; ANA, antinuclear antibody; anti-dsDNA, anti–double-stranded DNA antibody; anti-Sm, anti-Smith antibody; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein; HHV-8, human herpesvirus 8.

Clinical overlap and diagnostic challenges

Both iMCD and SLE can present with fever, lymphadenopathy, anemia, thrombocytopenia, nephrotic-range proteinuria, serositis, and elevated inflammatory markers such as ESR or CRP (1, 3). In a striking case, a 46-year-old man met the 2012 SLICC criteria for SLE but repeatedly tested negative for ANA and anti-dsDNA, prompting further investigation (4). Similarly, Radhakrishnan, Shalini, et al. reported a woman initially diagnosed with SLE due to lymphadenopathy, oral ulcers, and fatigue, but ultimately reclassified as having CD after lymph node biopsy and steroid nonresponse (5). Another woman initially diagnosed with SLE was later found to have CD after her symptoms—including lymphadenopathy, oral ulcers, and rash—persisted despite corticosteroids.

While SLE is a prototypical autoimmune disease mediated by a loss of tolerance to nuclear antigens, CD is fundamentally driven by interleukin-6 (IL-6)–mediated hypercytokinemia and polyclonal lymphoproliferation (1, 3). This divergence is clinically crucial even within a shared cytokine-driven inflammatory milieu, as iMCD requires cytokine-targeted therapy rather than conventional lupus-directed immunosuppression.

Marked systemic inflammation with generalized lymphadenopathy can be the presenting phenotype in both conditions, prompting initial evaluation for iMCD versus an SLE flare (5, 6, 13). Hypermetabolic lymph nodes on PET/CT have been reported in lupus presentations later reclassified as iMCD (and vice versa), underscoring that imaging alone cannot separate the entities (6, 9). Cytopenias, serositis, renal involvement/proteinuria, and hypergammaglobulinemia are repeatedly described as shared overlap features that can bias clinicians toward SLE, particularly when rash/arthralgia co-exist (4, 7, 10). TAFRO-spectrum presentations (thrombocytopenia, anasarca, fever, reticulin fibrosis/renal dysfunction, organomegaly) may overlap with SLE activity and have been described in lupus patients with Castleman-like pathology (11, 12).

Autoantibody positivity in castleman disease

Autoantibodies such as ANA, anti-dsDNA, and antiphospholipid antibodies have been documented in up to 37% of iMCD cases (3). These antibodies may emerge as an epiphenomenon of cytokine-driven B-cell hyperactivity, rather than true autoimmune pathogenesis. In one review, ANA positivity was noted in 14 of 38 patients with HHV-8–negative iMCD, while other studies report even higher rates (1, 3). This overlap contributes to diagnostic confusion and reinforces the need to contextualize serologic findings within the broader clinical picture.

Autoantibody positivity can occur in Castleman disease and may create a false sense of diagnostic certainty for SLE. Conversely, early SLE can present with Castleman-like lymphadenopathy before a complete serologic profile emerges, so longitudinal reassessment is often necessary.

Case reports of CD/iMCD initially approached as SLE note positive ANA and/or anti-dsDNA at presentation, which can misdirect the diagnostic pathway if clinicopathologic correlation is not pursued (4, 10, 13). Some Castleman-like lupus cases emphasize that serologies may evolve over time; repeating autoantibodies and complement, and reassessing classification criteria during follow-up, can be decisive (6, 9). In suspected overlap, the pattern of inflammatory markers and immunoglobulins (e.g., disproportionate IL-6-driven inflammation, marked polyclonal hypergammaglobulinemia) should prompt reconsideration of iMCD even when lupus serology is positive (11, 13).

Histopathological clues

Lymph node biopsy remains the most definitive method for distinguishing CD from SLE. In the case presented by Wang et al., the excisional biopsy revealed florid follicular hyperplasia, interfollicular plasmacytosis, and increased CD138+ plasma cells—hallmarks of the plasma cell variant of CD (4). Similarly, in the BMJ case, CD was confirmed only after identifying vascular proliferation and follicular dendritic cell prominence on node histology.

These findings contrast with SLE lymphadenitis, which typically shows necrosis, hematoxylin bodies, and a paucity of vascular structures (2). Given the limitations of fine-needle aspiration in capturing architectural features, excisional biopsy should be prioritized in lupus-like cases with lymphadenopathy and treatment resistance (1).

Several reports highlight classic CD patterns (hyaline vascular features with regressed germinal centers and prominent follicular dendritic cell networks; or plasmacytic features with interfollicular plasmacytosis) in patients clinically suspected of SLE (4, 7).

A key pitfall is Castleman-like reactive follicular hyperplasia in SLE lymphadenitis; small series and modern case reports emphasize that necrosis/hematoxylin bodies support lupus lymphadenitis, whereas prominent vascular proliferation and follicular dendritic cell dysregulation favor CD/iMCD (5, 8, 9). When available, integrating lymph node pathology with systemic features (e.g., HHV-8 status, cytokine-driven inflammatory phenotype, organomegaly) improves diagnostic confidence and reduces misclassification (11, 13).

In addition, the diagnosis of iMCD in the present case was established based on the international consensus criteria, including multicentric lymphadenopathy, characteristic histopathology, exclusion of HHV-8 infection, and the absence of an alternative malignant or autoimmune cause.

Therapeutic implications

Failure to recognize CD in SLE-like patients may result in prolonged and ineffective immunosuppression. While corticosteroids and cytotoxic drugs can transiently reduce inflammation, they do not address the IL-6–driven pathogenesis of iMCD. A systematic review by Fajgenbaum et al. of over 300 published iMCD cases demonstrated that response rates to immunosuppressive therapy were inconsistent, and mortality remained high without IL-6–targeted treatment (3). In the reported case, the patient responded poorly to SLE therapy but achieved remission with CHOP chemotherapy, supporting the importance of early and accurate diagnosis (4).

Anti–IL-6 therapy (e.g., siltuximab, tocilizumab) has shown increasing efficacy in recent studies and is now considered the standard of care in non–HHV-8 iMCD (1).

Multiple cases demonstrate symptomatic improvement with corticosteroids, which may temporarily fit either diagnosis; sustained remission with standard lupus therapy supports SLE, while relapse or steroid-dependence should trigger reassessment for iMCD (6, 9). In iMCD, anti-IL-6-directed therapy is a cornerstone strategy and has been used successfully in reported mimicker cases; missing the diagnosis can delay appropriate cytokine-targeted treatment (11, 13). Conversely, labeling Castleman-like lymphadenopathy as refractory lupus may lead to unnecessary escalation to intensive immunosuppression; clinicopathologic confirmation (including repeat biopsy when the course is atypical) is repeatedly advocated (5, 7). TAFRO-like presentations require careful phenotyping because management may diverge (supportive care and cytokine targeting versus lupus-directed immunosuppression), and overlap cases have been reported (11, 12). Serum IL-6 level was not available, which represents a limitation; however, the diagnosis was supported by the characteristic clinical and pathologic features.

Discussion

The relationship between SLE and iMCD may not be purely a matter of differential diagnosis. Lupus-associated immune dysregulation could theoretically create a cytokine milieu that resembles iMCD. However, the presence of characteristic lymph node architecture, the clinical course, and the response to IL-6–directed therapy support the concept that iMCD remains a distinct therapeutic entity. Therefore, correct classification is essential for treatment selection.

Castleman disease, particularly its idiopathic multicentric form, may mimic systemic lupus erythematosus both clinically and serologically. In patients with lupus-like presentations, ANA negativity, lymphadenopathy, systemic inflammation, and suboptimal response to immunosuppression should prompt consideration of CD. Early lymph node biopsy and recognition of histopathological hallmarks are essential for diagnosis. Rather than representing a simple differential diagnosis, the relationship between Castleman disease and systemic lupus erythematosus may reflect a spectrum of immune dysregulation in which accurate classification is essential for therapeutic decision-making and optimal patient outcomes.

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Footnotes

Edited by: Jian Liu, University of Bristol, United Kingdom

Reviewed by: Brugós Boglárka, University of Debrecen, Hungary

Kriti Chauhan, Metropolis Health Care Ltd, India