What is the best course of treatment for a patient with Primary Sjögren’s syndrome, IgA (Immunoglobulin A) nephropathy, acute on chronic kidney disease, and liver injury due to leflunomide (generic name) poisoning?

Management of Primary Sjögren's Syndrome with IgA Nephropathy, Acute-on-Chronic Kidney Disease, and Leflunomide-Induced Liver Injury

Immediately discontinue leflunomide and initiate drug elimination with cholestyramine or activated charcoal, then treat the acute kidney injury with corticosteroids while managing the liver injury supportively.

Immediate Leflunomide Management

Leflunomide must be stopped immediately and an active drug elimination procedure initiated given the severe hepatotoxicity and the context of acute-on-chronic kidney disease 1.

• Administer cholestyramine 8g three times daily or activated charcoal 50g four times daily to accelerate elimination of the active metabolite 1
• Monitor ALT/AST closely during the elimination process, as rare cases of severe liver injury with fatal outcomes have been reported with leflunomide, particularly within the first 6 months of therapy 1
• The drug elimination procedure is critical because leflunomide's active metabolite has a prolonged half-life and continued presence will worsen both hepatic and renal toxicity 1

Acute Kidney Injury Treatment in Sjögren's Syndrome

Corticosteroids are the first-line treatment for acute tubulointerstitial nephritis in primary Sjögren's syndrome, which is the most common renal manifestation 2, 3.

• Initiate prednisone 1 mg/kg/day (maximum 80 mg daily) for acute tubulointerstitial nephritis, as this represents the acute component of the kidney injury 2, 3
• The combination of full-dose corticosteroids with cyclophosphamide (100 mg/day) has demonstrated good outcomes in pSS-associated acute tubulointerstitial nephritis, with documented creatinine improvement of 0.28 mg/dL over 3 months 2
• Treatment with glucocorticoids or other immunosuppressive agents appears to slow progression of renal disease in pSS, with 14 of 16 patients maintaining or improving renal function through long-term follow-up 3

IgA Nephropathy Considerations

The presence of IgA nephropathy complicating primary Sjögren's syndrome represents a rare but serious manifestation requiring aggressive treatment 4.

• IgA nephropathy associated with Sjögren's syndrome and systemic vasculitis presents a more diverse outcome and may require hemodialysis 4
• Renal biopsy findings should guide the intensity of immunosuppression, particularly if crescentic glomerulonephritis is present 4
• The combination of tubulointerstitial nephritis (the predominant Sjögren's lesion) with IgA nephropathy requires treatment addressing both pathologies 3, 4

Liver Injury Management

Supportive care is the mainstay for leflunomide-induced hepatotoxicity while the drug elimination procedure removes the offending agent 1.

• Monitor ALT, AST, and serum albumin at least weekly during the acute phase of liver injury 1
• Avoid all other hepatotoxic medications during recovery 1
• The liver injury should improve once leflunomide levels decline with cholestyramine/charcoal treatment 1

Alternative Immunosuppression Strategy

Once leflunomide is eliminated and liver function stabilizes, mycophenolate mofetil or azathioprine should be considered as steroid-sparing agents rather than reintroducing leflunomide 5.

• Mycophenolate mofetil (MMF) or azathioprine are recommended as first-line steroid-sparing agents for Sjögren's-related systemic disease 5
• Methotrexate should be avoided given the existing liver injury and the risk of drug-induced interstitial lung disease in Sjögren's patients 5
• Rituximab should be considered for severe, refractory systemic disease, as it has the highest level of evidence among biologics tested in Sjögren's syndrome 5

Monitoring Parameters

Close monitoring of renal function, electrolytes, and liver enzymes is essential during the acute management phase 1, 3, 6.

• Check serum creatinine, cystatin C, and alpha-1-microglobulin (α1-MG) regularly, as the combination of creatinine and α1-MG provides the best assessment of renal function in pSS 6
• Monitor for renal tubular acidosis with serum bicarbonate and potassium levels, as this is common in Sjögren's-related kidney disease 2, 7
• Screen for urinary abnormalities with urinalysis to detect proteinuria and hematuria 3
• Platelet count, white blood cell count, and hemoglobin should be monitored given the immunosuppression and prior leflunomide exposure 1

Critical Pitfalls to Avoid

• Do not restart leflunomide given the severe hepatotoxicity and availability of safer alternatives for Sjögren's syndrome 5, 1
• Do not delay the drug elimination procedure with cholestyramine or charcoal, as this is essential for preventing further organ damage 1
• Do not use methotrexate as an alternative immunosuppressant given the existing liver injury and pulmonary risk in Sjögren's patients 5
• Do not underestimate the severity of acute-on-chronic kidney disease in pSS, as 7 patients presenting in stage IV chronic kidney disease maintained function with treatment and none progressed to stage V 3

Long-Term Management

After stabilization, the patient will require ongoing immunosuppression for both the Sjögren's syndrome and IgA nephropathy 2, 3.

• Corticosteroids should be tapered gradually over 6 months once clinical improvement is documented 2
• A steroid-sparing agent (mycophenolate mofetil or azathioprine) should be introduced as corticosteroids are tapered 5
• Regular monitoring for disease activity and renal function should continue indefinitely, as renal involvement significantly reduces quality of life in pSS patients 7