What is the diagnosis and treatment for a patient presenting with Raynaud phenomenon, non-blanching (NB) vasculitis on the foot, bilateral lung friction rub, microcytic (small red blood cells) microchromic (reduced hemoglobin) anemia, hematuria (blood in urine) and proteinuria (excess protein in urine), and symptoms of fatigue and weakness?

Diagnosis: Systemic Lupus Erythematosus (SLE) with Lupus Nephritis

This clinical presentation is most consistent with systemic lupus erythematosus (SLE) with renal involvement (lupus nephritis), requiring immediate initiation of high-dose corticosteroids combined with either mycophenolate mofetil or cyclophosphamide for induction therapy. 1

Clinical Reasoning for Diagnosis

The constellation of findings strongly points to SLE with multi-organ involvement:

• Raynaud phenomenon occurs in approximately 22% of early SLE patients 2
• Non-blanching vasculitis on the foot indicates active vascular inflammation, consistent with lupus vasculitis 1
• Bilateral lung friction rub suggests serositis (pleuritis), a classic SLE manifestation 3
• Hematuria and proteinuria indicate lupus nephritis, present in a significant proportion of SLE patients 1
• Microcytic microchromic anemia likely represents anemia of chronic disease or autoimmune hemolytic anemia, both common in SLE 2
• Fatigue and weakness are constitutional symptoms present in 28% of early SLE patients 2

This patient presents with features meeting both the 1997 ACR and 2012 SLICC classification criteria for SLE, including serositis, renal disorder, hematologic disorder, and likely positive immunologic markers 2.

Immediate Diagnostic Workup Required

Serologic testing must include:

• Anti-nuclear antibody (ANA)
• Anti-double-stranded DNA antibodies (highly specific for SLE) 2
• Complement levels (C3, C4) - hypocomplementemia is more common in early SLE 2
• Complete blood count with differential - looking for leukopenia, lymphopenia, or autoimmune hemolytic anemia 2
• Urinalysis with microscopy - to assess for active urinary sediment (RBC casts) 1
• 24-hour urine protein or spot urine protein-to-creatinine ratio 1
• Serum creatinine and estimated GFR 1
• Anti-Smith antibodies, anti-Ro/SSA, anti-La/SSB 3
• Antiphospholipid antibodies (lupus anticoagulant, anticardiolipin, anti-β2-glycoprotein I) 2
• Direct Coombs test 2

Renal biopsy is essential to determine the class of lupus nephritis (Class I-VI), as this directly determines treatment intensity and prognosis 1. The biopsy should be performed urgently given the presence of both hematuria and proteinuria 1.

Treatment Algorithm Based on Lupus Nephritis Class

For Class III or IV Lupus Nephritis (Most Likely Given Presentation)

Induction Therapy (First 6 months):

The American College of Rheumatology recommends either:

1. Mycophenolate mofetil (MMF) 2-3 g/day in divided doses PLUS high-dose corticosteroids 1
   • OR
2. Intravenous cyclophosphamide (CYC) PLUS high-dose corticosteroids 1

Corticosteroid regimen:

• Methylprednisolone 500-1000 mg IV daily for 3 days, followed by oral prednisone 0.5-1 mg/kg/day, tapered over several months 1

MMF is increasingly preferred over CYC due to comparable efficacy with fewer adverse effects, particularly regarding fertility preservation and infection risk 1. However, CYC may be considered for severe, rapidly progressive disease 1.

Maintenance Therapy (After 6 months):

• Continue MMF at lower doses (1-2 g/day) OR switch to azathioprine 2 mg/kg/day 1
• Low-dose prednisone (5-10 mg/day) 1
• Hydroxychloroquine should be added for all SLE patients as it reduces disease activity and flares 1

If Nephritis Worsens After 3 Months of Treatment

Switch to alternative therapy:

• If started on MMF, switch to CYC 1
• If started on CYC, switch to MMF 1
• Consider adding calcineurin inhibitors (tacrolimus or cyclosporine) 1
• Rituximab plus MMF may be considered for refractory cases 1

For Class V Lupus Nephritis (Membranous)

• If nephrotic syndrome with proteinuria >4 g/day persisting after 6 months of conservative therapy: initiate immunosuppression with alternating monthly cycles of oral and IV corticosteroids plus oral alkylating agents for 6 months 1

Management of Raynaud Phenomenon and Vasculitis

First-line for Raynaud phenomenon:

• Nifedipine (dihydropyridine calcium channel blocker) 30-60 mg extended-release daily 1, 4
• Avoid cold exposure, trauma, stress, smoking, and drugs that worsen Raynaud (bleomycin, clonidine, ergot alkaloids) 1

Second-line if inadequate response:

• Phosphodiesterase-5 inhibitors (sildenafil 20 mg three times daily or tadalafil 20 mg daily) 1, 4

Third-line for severe cases:

• Intravenous iloprost (prostacyclin analogue) 1, 4

For non-blanching vasculitis:

• The high-dose corticosteroids used for lupus nephritis will simultaneously treat the cutaneous vasculitis 1
• If vasculitis persists or worsens, consider increasing immunosuppression or adding rituximab 1

Management of Serositis (Pleuritis)

• NSAIDs or low-to-moderate dose corticosteroids (prednisone 0.5 mg/kg/day) for isolated serositis 3
• However, given this patient requires high-dose corticosteroids for nephritis, the pleuritis will be treated concurrently 1

Management of Anemia

• If autoimmune hemolytic anemia (positive Coombs test): the corticosteroids for nephritis will treat this 2
• If anemia of chronic disease: will improve with disease control 3
• If iron deficiency contributing: supplement with oral or IV iron as needed
• Monitor hemoglobin closely during treatment 1

Critical Monitoring Parameters

During induction therapy, monitor every 2-4 weeks:

• Serum creatinine and eGFR 1
• Urine protein-to-creatinine ratio 1
• Complement levels (C3, C4) 1
• Anti-dsDNA antibodies 1
• Complete blood count 1
• Blood pressure (risk of scleroderma renal crisis, though less common in SLE) 5

Response definitions:

• Complete remission: proteinuria <0.5 g/24 hours, normal serum albumin, normal or near-normal GFR 1
• Partial remission: ≥50% reduction in proteinuria to subnephrotic range, stable renal function 1
• No response: persistent nephrotic-range proteinuria after 6-12 months 1

Critical Pitfalls to Avoid

Do not delay renal biopsy - treatment intensity depends on histologic class, and empiric treatment without biopsy confirmation risks under- or over-treatment 1

Do not use belimumab as first-line therapy - while FDA-approved for SLE, it has not been adequately studied in severe active lupus nephritis and should not replace standard induction therapy 1

Do not stop treatment prematurely - patients may take up to 12 months to show complete response, with another 5-25% remitting by 24 months 1. Switching therapy before 3-6 months may be premature unless clear worsening occurs 1

Do not use anticoagulation routinely - only indicated if antiphospholipid syndrome is confirmed with thrombotic events 1

Do not use MMF, CYC, or methotrexate if pregnancy is possible - these are teratogenic; use hydroxychloroquine, corticosteroids, and azathioprine (≤2 mg/kg/day) in pregnant patients 1

Do not ignore infection risk - high-dose corticosteroids plus immunosuppression significantly increase infection risk; consider prophylaxis for Pneumocystis jirovecii if prolonged high-dose steroids are used 1

Do not assume thrombotic microangiopathy is lupus nephritis - if thrombotic microangiopathy is present on biopsy or clinically suspected, treat primarily with plasma exchange therapy 1