What is the diagnosis and treatment plan for a patient with Raynaud's phenomenon, joint pain, proteinuria, and prior hepatosplenomegaly of unknown origin?

Diagnostic Assessment: Likely Systemic Lupus Erythematosus with Lupus Nephritis

This clinical presentation strongly suggests systemic lupus erythematosus (SLE) with active lupus nephritis, despite the negative ANA, and requires immediate confirmation with anti-dsDNA and anti-Sm antibodies followed by renal biopsy.

Key Diagnostic Features Supporting SLE

The constellation of findings creates a compelling picture for SLE:

• Raynaud's phenomenon in a 41-year-old with joint pain and systemic features is highly suggestive of connective tissue disease, particularly when combined with other manifestations 1
• Malar-like rash is a classic SLE feature 2
• Significant proteinuria (50-300 mg/dL) with multiple casts (granular, hyaline, and waxy) indicates active glomerulonephritis, most consistent with lupus nephritis 3
• Hepatosplenomegaly of unknown origin can occur in SLE 4
• Fluctuating CBC abnormalities suggest autoimmune cytopenias common in SLE 2
• Markedly elevated CRP (4.9-80.5) indicates significant systemic inflammation 2

Critical Point: ANA-Negative SLE

The negative ANA does not exclude SLE. Approximately 10-20% of patients with idiopathic pulmonary fibrosis have positive ANA, and conversely, some SLE patients can be ANA-negative, particularly early in disease or with certain antibody profiles 2. The urinalysis findings and clinical picture override the negative ANA in this case.

Immediate Diagnostic Workup Required

Essential Serologic Testing

• Anti-dsDNA antibodies (highly specific for SLE, sensitivity 72-85%) 2, 3
• Anti-Sm antibodies (highly specific for SLE) 3
• Complement levels (C3/C4) - low levels strongly suggest active lupus nephritis 3, 2
• Anti-phospholipid antibodies (lupus anticoagulant, anticardiolipin, anti-β2-glycoprotein I) given the risk of thrombotic complications and potential APS-associated nephropathy 2
• Rheumatoid factor and anti-CCP to exclude rheumatoid arthritis 2

Urinalysis Interpretation

The presence of waxy casts specifically indicates chronic kidney disease and is concerning for advanced nephropathy 2. The combination of proteinuria, leukocytes, and multiple cast types suggests active lupus nephritis, likely Class III, IV, or V 3.

Renal Biopsy Indication

Renal biopsy is mandatory to confirm lupus nephritis class and guide immunosuppressive therapy, as proteinuria exceeds 50 mg/mmol and there are multiple casts present 3, 2. This will differentiate between proliferative (Class III/IV) versus membranous (Class V) lupus nephritis, which have different treatment approaches 2.

Alternative Diagnoses to Consider

Cryoglobulinemic Vasculitis

• Can present with Raynaud's, proteinuria, and hepatosplenomegaly 2
• Check cryoglobulins, hepatitis C serology, and RF 2
• However, the malar rash and cast-predominant urinalysis favor SLE 3

Mixed Connective Tissue Disease

• Can present with Raynaud's and overlap features 5
• Check anti-U1-RNP antibodies 5
• Less likely given the severe renal involvement 5

Systemic Sclerosis

• Raynaud's is nearly universal in systemic sclerosis 2
• However, significant proteinuria with multiple casts is uncommon unless there is overlap syndrome or APS-associated nephropathy 2
• Check anti-Scl-70 and anti-centromere antibodies 2

Treatment Plan

Immediate Management (Pending Biopsy Results)

Do not delay treatment if lupus nephritis is strongly suspected clinically, as early intervention improves outcomes 2.

1. Initiate ACE inhibitor or ARB for proteinuria control (proteinuria >50 mg/mmol is an indication) 3
2. Blood pressure control to target <130/80 mmHg 2
3. Raynaud's management: Start nifedipine (dihydropyridine calcium channel blocker) 30-60 mg daily as first-line therapy 1, 2

Post-Biopsy Immunosuppressive Therapy

For Class III/IV Proliferative Lupus Nephritis

Mycophenolate mofetil (MMF) 3g/day in divided doses PLUS high-dose glucocorticoids (prednisone 0.5-1 mg/kg/day, maximum 60 mg/day) 3, 6. This has surpassed cyclophosphamide as initial treatment due to better tolerability and equivalent efficacy 2.

Alternative: IV cyclophosphamide (Euro-Lupus regimen: 500 mg every 2 weeks for 6 doses) PLUS high-dose glucocorticoids if MMF is contraindicated 3.

For Class V Membranous Lupus Nephritis

MMF or calcineurin inhibitors (tacrolimus or cyclosporine) PLUS moderate-dose glucocorticoids 2.

Glucocorticoid Dosing Strategy

• Initial: Prednisone 0.5-1 mg/kg/day (maximum 60 mg daily) for 4-6 weeks 6
• Taper: Reduce to ≤10 mg/day by 6 months to minimize toxicity 2, 6
• Consider pulse IV methylprednisolone (500-1000 mg daily for 3 days) for severe presentations 2

Raynaud's Phenomenon Management Algorithm

1. First-line: Nifedipine extended-release 30-60 mg daily (or other dihydropyridine calcium channel blocker) 1, 2
2. Second-line (if inadequate response): Add sildenafil 20 mg three times daily or tadalafil 20 mg daily 1, 2
3. Third-line (for severe/refractory cases): IV iloprost 0.5-2 ng/kg/min for 3-5 days 1
4. For digital ulcers: Consider bosentan 62.5 mg twice daily for 4 weeks, then 125 mg twice daily for prevention of new ulcers 1, 2

Monitoring Protocol

• Monthly for first 6 months: Serum creatinine, estimated GFR, spot urine protein-to-creatinine ratio, urinalysis with microscopy, CBC, C3/C4, anti-dsDNA 2
• Every 3 months thereafter: Same parameters if stable 2
• Reappearance of urinary casts has >80% sensitivity and specificity for renal flares 2

Critical Pitfalls to Avoid

• Do not dismiss the diagnosis based on negative ANA alone - proceed with anti-dsDNA and anti-Sm testing 2, 3
• Do not delay renal biopsy - it is essential for determining lupus nephritis class and guiding therapy 3, 2
• Do not use dexamethasone or betamethasone for long-term therapy as they have prolonged HPA axis suppression 6
• Do not ignore the slow capillary refill - this suggests significant peripheral vascular involvement requiring aggressive Raynaud's treatment 1
• Monitor for APS-associated nephropathy given the proteinuria and potential for thrombotic complications 2

Prognosis and Long-Term Considerations

With appropriate immunosuppression, complete renal response rates are 50-80% for lupus nephritis 2. However, 10-30% of patients progress to ESRD within 15 years despite treatment 2. Early aggressive therapy improves outcomes 3.