What are the next steps for a patient with a rash on both hands after a month of methotrexate (methotrexate) treatment, with negative test results for pancytopenia (low blood cell count)?

Management of Hand Rash in Patient on Methotrexate with Normal Blood Counts

Immediately discontinue methotrexate and evaluate for methotrexate-induced cutaneous toxicity, as skin ulceration can occur even without pancytopenia and may signal impending severe toxicity. 1

Immediate Assessment and Workup

Characterize the rash urgently to distinguish between methotrexate-induced cutaneous toxicity versus other etiologies:

• Examine for erosions, ulcerations, or painful lesions on hands, palms, and other sites (oral mucosa, genitals, feet), as these are hallmark features of methotrexate toxicity 2, 1, 3
• Document presence of psoriatic plaques - methotrexate-induced erosion of psoriatic plaques is a rare but recognized sign of impending pancytopenia 2
• Assess for systemic symptoms including fever, malaise, nausea, vomiting, or stomatitis, which indicate more severe toxicity 4, 3

Repeat complete blood count with differential immediately despite the recent negative pancytopenia screen, as hematologic toxicity can develop rapidly:

• Pancytopenia can occur as early as 3 days after methotrexate ingestion and may develop suddenly even after one month of therapy 3, 2
• Monitor for WBC <3.5×10⁹/L, neutrophils <2×10⁹/L, or platelets <100×10⁹/L 4
• Check MCV for early folate deficiency (MCV >105 fL suggests developing toxicity) 5

Obtain comprehensive metabolic panel focusing on:

• Renal function (creatinine, BUN, creatinine clearance) - renal insufficiency is the primary risk factor for methotrexate toxicity 4, 6
• Liver function tests (AST, ALT, albumin) - hypoalbuminemia increases toxicity risk 4, 6
• Serum methotrexate level if available 3

Risk Factor Assessment

Identify high-risk features that increase likelihood of methotrexate toxicity:

• Advanced age (>50-70 years) significantly increases toxicity risk 4
• Renal impairment - even mild dysfunction impairs drug clearance 4, 6
• Lack of folate supplementation - verify patient is taking folic acid 1-5 mg daily (except on methotrexate day) 4, 5
• Drug interactions - review for NSAIDs, trimethoprim-sulfamethoxazole, penicillins, or other interacting medications 4, 5
• Hypoalbuminemia - increases free methotrexate levels 4, 6
• Concurrent infection - increases myelotoxicity risk 6

Immediate Management

Stop methotrexate immediately regardless of whether pancytopenia is present, as cutaneous ulceration alone warrants discontinuation 1, 3:

• Methotrexate-induced skin ulcers can occur without hematologic toxicity 1
• Early discontinuation prevents progression to life-threatening complications 4

Consider leucovorin (folinic acid) rescue therapy even without pancytopenia if high-risk features present:

• Administer leucovorin 15 mg orally or IV every 6 hours for at least 24-48 hours 4, 7
• Leucovorin significantly shortens recovery time (5.5 days vs 10 days without it) 7
• Do not use folic acid - only leucovorin (folinic acid) bypasses methotrexate's metabolic block 4

Initiate supportive care:

• Aggressive IV hydration to enhance renal elimination 4
• Monitor for infection given potential subclinical immunosuppression 6
• Wound care for any ulcerated areas 1

Monitoring and Follow-up

Intensive monitoring for 2 weeks minimum:

• CBC with differential every 2-3 days initially, then weekly for 2 weeks 5, 6
• Watch for delayed pancytopenia development (can occur up to 6 weeks post-exposure) 5
• Monitor renal and liver function weekly 5

If pancytopenia develops:

• Administer leucovorin immediately (15 mg IV/PO every 6 hours) 4, 7
• Consider G-CSF (filgrastim 5 µg/kg daily SC) for severe neutropenia (<1×10⁹/L) 4, 6, 7
• Combined leucovorin + G-CSF achieves fastest recovery (4 days average) 7
• Hospitalize for neutropenic fever risk and transfusion support 4, 6

Dermatologic Evaluation

Obtain skin biopsy of rash if diagnosis unclear:

• Rule out vasculitis, infection, or alternative diagnoses 1
• Methotrexate-induced ulcers show no vasculitis on histopathology 1
• Biopsy helps distinguish from psoriatic flare or other drug reactions 1

Critical Pitfalls to Avoid

• Do not assume normal blood counts exclude methotrexate toxicity - cutaneous manifestations can precede or occur independently of hematologic toxicity 2, 1
• Do not restart methotrexate until complete resolution of rash and confirmation of normal blood counts for at least 2 weeks 8
• Do not delay leucovorin if clinical suspicion is high - efficacy decreases dramatically after 24 hours 4
• Do not confuse folic acid with folinic acid (leucovorin) - only leucovorin is effective for acute toxicity 4

Long-term Considerations

If methotrexate rechallenge considered (generally not recommended after cutaneous toxicity):

• Ensure adequate folate supplementation was in place initially 4, 5
• Correct any identified risk factors (renal function, drug interactions) 4
• Use lower dose with more intensive monitoring 8
• Consider alternative DMARD therapy instead 1