In a middle‑aged adult with Hashimoto’s thyroiditis (euthyroid) presenting with symmetric polyarthritis, morning stiffness, chronic fatigue, vertigo, nausea, gastrointestinal upset, peripheral neuropathy, nighttime delirium, leukopenia, low complement C4, speckled‑pattern antinuclear antibody 1:320 and modest IgG rheumatoid factor, what is the most likely diagnosis and what initial work‑up and management should be pursued?

Systemic Lupus Erythematosus (SLE) with Secondary Sjögren's Syndrome

This patient most likely has systemic lupus erythematosus (SLE) with secondary Sjögren's syndrome, and requires immediate comprehensive autoimmune workup including anti-dsDNA, extractable nuclear antigens (ENA panel), complement levels (C3), complete blood count, comprehensive metabolic panel, urinalysis with microscopy, and urgent rheumatology referral within 6 weeks. 1

Why SLE is the Primary Diagnosis

The constellation of findings strongly points toward SLE rather than rheumatoid arthritis or other inflammatory arthropathies:

• Speckled ANA 1:320 is highly characteristic of SLE, particularly when combined with low complement C4 (14 mg/dL, typically normal >16 mg/dL), which indicates active immune complex-mediated disease 1
• Low complement C4 with leukopenia (WBC 3.9) represents a classic SLE pattern reflecting immune consumption and bone marrow suppression, not seen in typical RA 1
• Multi-system involvement including neuropsychiatric symptoms (nighttime delirium, vertigo), peripheral neuropathy (numbness to arms and feet), gastrointestinal complaints, and chronic fatigue extends far beyond typical RA presentation 1
• Modest RF IgG of 34 (typically <40 IU/mL is negative) is non-specific; approximately 15-25% of healthy individuals and patients with other autoimmune diseases can have low-positive RF without having RA 1

The symmetric polyarthritis with morning stiffness could represent lupus arthritis, which occurs in 90% of SLE patients and can mimic RA clinically but is typically non-erosive 1.

Critical Distinguishing Features from Rheumatoid Arthritis

SLE is far more likely than RA in this case because:

• RA does not cause leukopenia and low complement simultaneously – RA typically shows leukocytosis during active disease, not leukopenia 2
• Neuropsychiatric manifestations (delirium, vertigo, peripheral neuropathy) are hallmark features of SLE but are not characteristic of RA 1
• The RF level of 34 is only modestly elevated and lacks the high-positive anti-CCP antibodies that would be expected in seropositive RA with this degree of systemic inflammation 1
• Speckled ANA pattern at 1:320 with low C4 strongly suggests SLE; while 47% of Hashimoto's patients can have positive ANA, the combination with low complement and cytopenias points to active lupus 3

Immediate Diagnostic Workup Required

Essential autoimmune serology (order immediately):

• Anti-dsDNA antibodies – highly specific for SLE (>95% specificity) and correlates with disease activity 1
• Extractable nuclear antigen (ENA) panel including anti-Sm (specific for SLE), anti-RNP, anti-SSA/Ro, anti-SSB/La (for secondary Sjögren's evaluation) 1
• Complement C3 level – typically low in active SLE alongside C4; both C3 and C4 depletion indicates severe immune complex disease 1

Baseline safety and organ assessment:

• Complete blood count with differential – already shows leukopenia (3.9); need to assess for anemia, thrombocytopenia, and lymphopenia which are common in SLE 1
• Comprehensive metabolic panel including liver enzymes, creatinine, and glucose to assess for lupus nephritis and baseline organ function 1
• Urinalysis with microscopy – essential to detect proteinuria, hematuria, or cellular casts indicating lupus nephritis, which occurs in 50% of SLE patients 1
• ESR and repeat CRP – typically ESR is markedly elevated in SLE while CRP may be normal or only modestly elevated (unlike RA where both are high) 1

Imaging studies:

• Bilateral hand, wrist, and foot X-rays – lupus arthritis is typically non-erosive, which would help distinguish from RA 1
• Chest X-ray – to evaluate for serositis (pleuritis/pericarditis) which occurs in 25-45% of SLE patients 2

Hashimoto's Thyroiditis Connection

The patient's euthyroid Hashimoto's thyroiditis is relevant but not the primary driver of symptoms:

• 47% of Hashimoto's patients have positive ANA, making autoimmune screening essential in this population 3
• 72% of Hashimoto's patients are positive for at least one additional autoimmunity parameter or have another autoimmune disease 3
• While euthyroid Hashimoto's can cause chronic fatigue and muscle pain, it does not explain the leukopenia, low complement, or multi-system neurological involvement 4
• The joint symptoms are not from hypothyroid arthropathy since the patient is euthyroid; hypothyroid arthropathy presents with non-inflammatory synovial fluid and resolves with thyroid replacement 5

Management Algorithm

Step 1: Immediate actions (within 48 hours)

• Order complete autoimmune workup as detailed above 1
• Refer to rheumatology urgently – target within 6 weeks, but given multi-system involvement, request expedited evaluation 2
• Document detailed 28-joint examination for swelling and tenderness 1
• Assess for malar rash, discoid lesions, photosensitivity, oral ulcers, and other SLE criteria 1

Step 2: Symptomatic management pending rheumatology evaluation

• NSAIDs (naproxen 500 mg twice daily) for joint pain and inflammation, after evaluating gastrointestinal and renal risks 2, 6
• Avoid starting corticosteroids before rheumatology evaluation unless severe symptoms warrant it, as this may mask diagnostic findings 2
• Do NOT start methotrexate – while it's first-line for RA, this patient likely has SLE which requires different immunosuppression 1

Step 3: If SLE confirmed by rheumatology

• Hydroxychloroquine is typically first-line for SLE with arthritis and constitutional symptoms 1
• Corticosteroids (prednisone 0.5-1 mg/kg/day) for moderate-to-severe disease 1
• Immunosuppressants (mycophenolate, azathioprine) if organ-threatening disease or inadequate response 1

Critical Pitfalls to Avoid

• Do not dismiss this as seronegative RA based on the modest RF elevation – the multi-system involvement, cytopenias, and low complement are not consistent with RA 1
• Do not attribute all symptoms to Hashimoto's thyroiditis – while euthyroid Hashimoto's can cause fatigue and myalgias, it does not cause leukopenia, low complement, or neuropsychiatric symptoms 4
• Do not delay workup waiting for symptoms to worsen – lupus nephritis can develop silently and early detection with urinalysis is critical for preventing irreversible kidney damage 1
• Do not start methotrexate empirically – if this is SLE rather than RA, methotrexate alone is insufficient and hydroxychloroquine is the cornerstone therapy 1

Monitoring Plan

• Repeat inflammatory markers (ESR, CRP) every 4-6 weeks after treatment initiation to monitor disease activity 1
• Serial complement levels (C3, C4) and anti-dsDNA correlate with SLE disease activity 1
• Urinalysis at every visit to monitor for development or progression of lupus nephritis 1
• CBC every 4-6 weeks to monitor cytopenias which may worsen with disease activity or improve with treatment 1