What rheumatologic diagnoses can exhibit lymphadenopathy?

Rheumatologic Diagnoses Associated with Lymphadenopathy

Lymphadenopathy occurs commonly in systemic lupus erythematosus (SLE), Sjögren's syndrome, rheumatoid arthritis (RA), sarcoidosis, IgG4-related disease, and adult-onset Still's disease, with SLE and Sjögren's being the most frequent rheumatologic causes. 1, 2

Primary Rheumatologic Conditions with Lymphadenopathy

Systemic Lupus Erythematosus (SLE)

• Lymphadenopathy can be the presenting and sole manifestation of SLE for up to 6 months before other features emerge, making early diagnosis challenging 3
• Generalized diffuse lymphadenopathy occurs in SLE patients, though less frequently now than historically reported 3
• When present, lymph nodes typically show follicular hyperplasia on biopsy without necrosis, calcification, or conglomerate formation 2
• Average lymph node size is approximately 13.5 mm in short axis diameter 2
• SLE-associated lymphadenopathy responds favorably to corticosteroids 2
• Consider SLE when lymphadenopathy occurs with constitutional symptoms, cytopenias, proteinuria, positive ANA, anti-dsDNA antibodies, and low complement levels 3, 4

Sjögren's Syndrome

• Sjögren's syndrome is one of the two most common rheumatologic causes of lymphadenopathy alongside SLE 1, 2
• Lymph node enlargement represents a hallmark clinical finding within the disease spectrum 1
• Sicca syndrome induced by checkpoint inhibitors presents with dry mouth and possible lymphadenopathy, with lower prevalence of autoantibodies (52% ANA, 20% Ro/SS-A) compared to classic Sjögren's 5
• Biopsy typically reveals follicular hyperplasia without specific distinguishing features 2

Sarcoidosis

• Bilateral hilar lymphadenopathy is the characteristic pattern in sarcoidosis, particularly in stage 1 disease 5
• Sarcoidosis accounts for 85% of cases presenting with bilateral hilar lymphadenopathy on imaging 5
• Mediastinal and axillary lymph nodes may also be involved 5
• In patients with Löfgren's syndrome (erythema nodosum, fever, arthralgia), lupus pernio, or Heerfordt's syndrome, lymph node sampling is not recommended due to high clinical certainty 5
• Sarcoid-like reactions can occur with checkpoint inhibitor therapy, presenting with new hilar lymphadenopathy or pulmonary nodules requiring biopsy confirmation 5

Rheumatoid Arthritis (RA)

• Lymphadenopathy occurs in RA patients, though less commonly than in SLE or Sjögren's 2
• Lymph node enlargement in RA typically shows reactive follicular hyperplasia 2
• Responds to corticosteroid therapy 2

IgG4-Related Disease

• IgG4-related disease must be considered in the differential diagnosis of lymphadenopathy as effective targeted treatments can impact prognosis 1
• Elevated serum IgG4 levels (high IgG4:IgG ratio) are present in approximately 66% of patients 5
• Pathology can differentiate IgG4-related disease from sarcoidosis 5
• Testing IgG4 levels is recommended when this diagnosis is suspected 6

Kawasaki Disease

• Cervical lymphadenopathy (≥1.5 cm diameter, usually unilateral) is one of the five principal diagnostic criteria for Kawasaki disease 5
• Lymphadenopathy is the least common of the principal clinical features 5
• Imaging frequently demonstrates multiple enlarged nodes without suppuration 5

Rosai-Dorfman-Destombes Disease (RDD)

• Most patients present with bilateral, massive, painless cervical lymphadenopathy with or without fevers, night sweats, and weight loss 5
• Mediastinal, axillary, and inguinal nodes may be involved, but retroperitoneal lymphadenopathy is uncommon 5
• Prognosis correlates with the number of nodal groups involved 5
• Histology shows large histiocytes with emperipolesis (intact leukocytes within cytoplasm), S100 positivity, and CD68 positivity 5

Diagnostic Approach to Lymphadenopathy in Rheumatologic Disease

Key Clinical Features Suggesting Rheumatologic Etiology

• Absence of elevated lactate dehydrogenase (LDH) and splenomegaly favors rheumatologic over malignant causes 2
• Systemic symptoms (fever, weight loss, night sweats) occur in 68% of rheumatologic lymphadenopathy cases 2
• Lymph nodes averaging 13.5 mm in short axis without necrosis, calcification, or conglomerate formation suggest rheumatologic origin 2
• No specific or predictable localization pattern except in sarcoidosis (bilateral hilar) 2

Laboratory Evaluation

• Complete blood count to assess for cytopenias (leukopenia, lymphocytopenia) 3, 4
• Autoantibody panel including ANA, anti-dsDNA, anti-Smith, anti-Ro, anti-La, RF 3
• Complement levels (C3, C4) - low in active SLE 3
• Erythrocyte sedimentation rate and C-reactive protein 3
• Serum IgG4 levels if IgG4-related disease suspected 5, 6
• Angiotensin-converting enzyme (ACE) level for suspected sarcoidosis 6

Imaging Strategy

• High-resolution CT scan should be performed to characterize lymphadenopathy and assess for additional abnormalities 6
• Bilateral symmetric hilar lymphadenopathy strongly suggests sarcoidosis 6
• Unilateral or asymmetric lymphadenopathy requires tissue diagnosis due to higher malignancy risk 6

When to Pursue Tissue Diagnosis

• Lymph node biopsy is mandatory for unilateral or asymmetric lymphadenopathy to exclude malignancy 6
• EBUS-guided transbronchial needle aspiration is the preferred first-line approach with 87% diagnostic yield and minimal complications (<0.1%) 6
• Core needle biopsy is preferred over fine-needle aspiration to enable histological examination 6
• In sarcoidosis with classic presentation (Löfgren's syndrome, lupus pernio, Heerfordt's syndrome), biopsy can be deferred with close clinical follow-up 5

Critical Differential Diagnoses to Exclude

Malignant Causes

• Lymphoma must be excluded, particularly in asymmetric or unilateral lymphadenopathy 6
• Lymphoma accounts for 25% of alternative diagnoses in suspected sarcoidosis cases 5

Infectious Causes

• Tuberculosis accounts for 38% of alternative diagnoses in suspected sarcoidosis 5
• Syphilis, particularly in patients with rheumatologic features 3
• Kikuchi histiocytic necrotizing lymphadenitis 3

Other Rheumatologic Mimics

• Castleman disease - requires consideration as effective targeted treatments are available 1, 3
• Mixed connective tissue disease 2
• Checkpoint inhibitor-induced rheumatic immune-related adverse events with lymphadenopathy 5

Common Pitfalls to Avoid

• Do not rely on chest X-ray alone - mediastinal widening may be subtle and CT is necessary for proper evaluation 6
• Do not assume ANA-negative status excludes SLE - approximately 10-20% of SLE patients can be ANA-negative 7
• Do not skip tissue diagnosis in asymmetric or unilateral disease - these patterns have higher malignancy risk requiring pathologic confirmation 6
• Do not overlook the possibility of coexisting conditions - sarcoidosis and SLE can occur simultaneously in the same patient 8
• Consider that lymphadenopathy may precede other manifestations of rheumatologic disease by months, requiring close follow-up 3, 4