What is the likely diagnosis and recommended evaluation for a 31-year-old woman with intermittent cervical lymphadenopathy, mildly low C‑reactive protein, elevated lactate dehydrogenase and transaminases, positive antinuclear antibody with homogeneous pattern, positive anti‑RNP/Sm antibodies, and negative anti‑smooth muscle and anti‑mitochondrial antibodies?

Likely Diagnosis: Mixed Connective Tissue Disease (MCTD) or Early Systemic Lupus Erythematosus (SLE)

This 31-year-old woman with intermittent cervical lymphadenopathy, elevated LDH and transaminases, positive ANA with homogeneous pattern, and positive anti-RNP/Sm antibodies most likely has either MCTD or early SLE, and requires immediate rheumatologic evaluation with complete serologic workup, imaging, and consideration of lymph node biopsy to exclude lupus lymphadenopathy or other serious conditions.

Diagnostic Reasoning

Serologic Profile Points to Connective Tissue Disease

• Anti-RNP antibodies are present in 25-47% of SLE patients, while high titers are diagnostic of MCTD. 1
• Anti-Sm antibodies have 5-30% prevalence in SLE and are highly specific for the disease, included in diagnostic criteria. 1
• The positive anti-RNP/Sm antibody screen with homogeneous ANA pattern strongly suggests either SLE or MCTD as the underlying diagnosis. 1
• Anti-RNP antibodies are associated with Raynaud's phenomenon and milder renal involvement, while anti-Sm antibodies correlate with severity and activity of renal disease. 1

Lymphadenopathy in Autoimmune Disease

• Lupus lymphadenopathy has an estimated prevalence of 5-7% at disease onset and 12-15% at any stage, though it is not included in diagnostic criteria. 2
• Isolated cervical lymphadenopathy can rarely be the first presentation of SLE, requiring high clinical suspicion. 2
• In patients with SLE and cervical lymphadenopathy, the differential includes lupus lymphadenopathy, Kikuchi-Fujimoto disease, lymphoma, and secondary infection from immunosuppression. 2

Elevated LDH as a Key Indicator

• LDH ≥400 U/L has an adjusted odds ratio of 3.78 for cervical lymphadenopathy requiring clinical intervention, with 82% of such cases being infectious mononucleosis or necrotizing lymphadenitis. 3
• Elevated LDH, transaminases (AST, ALT), and aldolase can indicate muscle inflammation in autoimmune myositis. 4
• Complete blood count with differential, ESR, CRP, LDH, and liver function tests are essential initial blood tests for evaluating cervical lymphadenopathy. 5

Required Diagnostic Workup

Immediate Laboratory Studies

• Obtain complete blood count with differential to assess for pancytopenia, lymphopenia, or hemolytic anemia seen in SLE. 2
• Measure ESR and CRP to quantify inflammatory response. 5
• Check complement levels (C3, C4) as low complements suggest active SLE. 2
• Order anti-double-stranded DNA antibodies, which are elevated in active SLE. 2
• Perform direct and indirect antiglobulin tests if anemia is present to detect autoimmune hemolytic anemia. 2
• Measure creatine kinase to evaluate for concurrent myositis, as CK, AST, ALT, and LDH can all be elevated in muscle inflammation. 4

Imaging and Tissue Diagnosis

• CT scan of neck with contrast is the primary imaging modality for evaluating cervical lymphadenopathy. 5
• CT chest, abdomen, and pelvis with contrast is required when malignancy is suspected or to assess for systemic lymphadenopathy. 5
• Lymph node biopsy (excisional preferred, with >95% diagnostic yield) is necessary to differentiate lupus lymphadenopathy from Kikuchi-Fujimoto disease and lymphoma. 6, 2
• Histology showing moderate reactive follicular hyperplasia with scattered plasma cells, immunoblasts, and varying degrees of coagulative necrosis suggests lupus lymphadenopathy. 2
• Immunohistochemistry with Bcl2 staining is essential to exclude lymphoma. 2

Risk Stratification Features

• Age >40 years, supraclavicular location, size >2 cm, fixed or firm consistency, and duration ≥2 weeks are high-risk features for malignancy. 5
• Constitutional symptoms including unexplained weight loss >10%, night sweats, and fever are high-risk features requiring urgent evaluation. 5
• Lymph nodes that are larger than 2 cm, hard, or matted/fused to surrounding structures may indicate malignancy or granulomatous disease. 7

Critical Management Considerations

Avoid Common Pitfalls

• Never prescribe multiple courses of antibiotics without clear infectious etiology, as this significantly delays cancer diagnosis and masks underlying autoimmune disease. 5
• Do not assume partial resolution after antibiotics excludes malignancy or autoimmune disease; infection may occur in underlying malignancy or immunosuppression. 5
• Corticosteroids should be avoided before tissue diagnosis because they can mask the histologic diagnosis of lymphoma or other malignancy. 7

Specific Exclusions in This Case

• Kikuchi-Fujimoto disease typically presents with fever, cervical lymphadenopathy, elevated inflammatory markers, and high LDH and ferritin, but the positive anti-RNP/Sm antibodies point more toward SLE or MCTD. 8
• Infectious mononucleosis would present with exudative tonsillitis, massive bilateral cervical adenopathy, and splenomegaly, not typically with positive autoantibodies. 9
• Autoimmune hepatitis is excluded by negative anti-smooth muscle and anti-mitochondrial antibodies. 2

Urgent Rheumatology Referral Required

• Refer immediately to rheumatology for definitive diagnosis and treatment planning, as early intervention in SLE improves outcomes. 2
• If lupus lymphadenopathy is confirmed, treatment with hydroxychloroquine, corticosteroids, and immunosuppressants (such as mycophenolate mofetil) typically results in symptom improvement and lymphadenopathy regression. 2
• Monitor closely for development of lupus nephritis, as this patient's serologic profile (anti-Sm positive) is associated with more severe renal involvement. 1

Follow-Up Protocol

• Re-evaluate at 2 weeks after initial presentation; if cervical lymphadenopathy persists or worsens, escalate diagnostic workup immediately. 9, 5
• When lymphadenopathy persists beyond 4 weeks or is accompanied by systemic symptoms, imaging and appropriate laboratory studies must be obtained. 7
• If cervical lymphadenopathy has not completely resolved at 2-week follow-up, proceed to definitive imaging (CT) to exclude underlying malignancy. 9