What is the management approach for hematuria in patients taking tofacitinib (Xeljanz)?

Management of Hematuria in Patients Taking Tofacitinib

Immediately investigate any hematuria in patients on tofacitinib with urinalysis, urine microscopy, complete blood count, comprehensive metabolic panel including creatinine, and urologic evaluation to exclude urinary tract pathology, malignancy, or drug-induced glomerulonephritis.

Initial Diagnostic Approach

When hematuria develops in a patient taking tofacitinib, the evaluation must distinguish between three primary etiologies:

Urologic Causes (Most Common)

• Urinary tract infection is the most common serious infection associated with tofacitinib and should be ruled out first with urinalysis and urine culture 1
• Obtain urologic consultation for cystoscopy and imaging, as tofacitinib increases serum creatinine levels in a dose-related manner 1
• Consider bladder malignancy evaluation, as patients on immunosuppressive therapy have elevated cancer risk, with lung and breast cancer being the most common nonhematologic malignancies in tofacitinib-treated patients 1

Drug-Induced Glomerular Disease (Rare but Serious)

• Tofacitinib can induce ANCA-associated vasculitis with crescentic glomerulonephritis, presenting with hematuria, proteinuria, and acute kidney injury 2
• Send p-ANCA and c-ANCA testing if there is concurrent proteinuria, declining renal function, or systemic symptoms 2
• Perform urine microscopy with phase contrast to identify dysmorphic red blood cells and red cell casts, which indicate glomerular bleeding 3
• If ANCA-vasculitis is confirmed by kidney biopsy, immediately discontinue tofacitinib and initiate pulse-dose corticosteroids and rituximab 2

Monitoring-Related Detection

• Hematuria may be detected during routine monitoring, as baseline and ongoing renal function tests are recommended every 3 months in patients on tofacitinib 4
• Tofacitinib causes dose-related elevations of serum creatinine that stabilize after initial increases 1

Risk Stratification

High-Risk Features Requiring Urgent Evaluation

• Gross (macroscopic) hematuria warrants immediate urologic assessment 3
• Concurrent proteinuria (especially nephrotic-range) suggests glomerular disease 2
• Rising creatinine or declining GFR indicates potential renal parenchymal involvement 5
• Systemic symptoms (fever, weight loss, malaise) raise concern for vasculitis or malignancy 2

Medication-Specific Considerations

• For patients with severe renal impairment (CrCl <30 mL/min), tofacitinib dose must be reduced to 5 mg once daily 1, 5
• Patients with moderate renal impairment (CrCl 30-50 mL/min) require more frequent monitoring for infections and cytopenias 5
• Consider drug interactions: reduce tofacitinib to 5 mg once daily when used with potent CYP3A4 inhibitors 5

Management Algorithm

Step 1: Immediate Laboratory Assessment

• Complete blood count with differential to assess for cytopenias 4
• Comprehensive metabolic panel including creatinine and liver enzymes 4
• Urinalysis with microscopy (preferably phase contrast) 3
• Urine culture to exclude infection 1
• Spot urine protein-to-creatinine ratio 2

Step 2: Determine Hematuria Source

• If dysmorphic RBCs or RBC casts present: Proceed to glomerular workup including ANCA, ANA, complement levels, and nephrology referral 2, 3
• If normal RBC morphology: Proceed to urologic evaluation with cystoscopy and imaging (CT urography or renal ultrasound) 3

Step 3: Tofacitinib Management Decision

• Continue tofacitinib if hematuria is clearly from urologic cause (UTI, stones) that is being appropriately treated 1
• Temporarily hold tofacitinib pending workup if glomerular source suspected or if gross hematuria with unclear etiology 1
• Permanently discontinue tofacitinib if ANCA-vasculitis confirmed or if malignancy diagnosed requiring alternative immunosuppression 2

Step 4: Ongoing Monitoring After Resolution

• Repeat CBC and CMP at 4-8 weeks after any dose adjustment or medication change 4
• Continue routine monitoring every 3 months with CBC, CMP, and urinalysis 4
• If persistent microscopic hematuria continues beyond 2 weeks, refer to nephrology for potential kidney biopsy 3

Critical Pitfalls to Avoid

• Do not attribute hematuria solely to tofacitinib's known effects on creatinine without excluding serious urologic or glomerular pathology 1, 5
• Do not continue full-dose tofacitinib in patients with declining renal function without dose adjustment per guidelines 1, 5
• Do not delay ANCA testing in patients with concurrent proteinuria and hematuria, as tofacitinib-induced vasculitis requires urgent immunosuppressive therapy 2
• Do not overlook malignancy screening, particularly in older patients (>65 years) who already have increased infection and cardiovascular risks on tofacitinib 1, 4
• Do not restart tofacitinib after confirmed ANCA-vasculitis without rheumatology/nephrology consultation regarding alternative JAK inhibitors or other immunosuppression 2