Can Azathioprine be used to treat a patient with relapsing-remitting Multiple Sclerosis (MS) who has not responded to or has contraindications to preferred disease-modifying therapies (DMTs)?

Azathioprine for Relapsing-Remitting Multiple Sclerosis

Azathioprine can be used as a maintenance treatment for relapsing-remitting MS patients who frequently relapse, but it should be considered a second-line option when preferred disease-modifying therapies have failed or are contraindicated.

Evidence for Efficacy in MS

Azathioprine demonstrates modest but consistent benefit in reducing MS disease activity:

• Relapse reduction: Azathioprine reduces the proportion of patients experiencing relapses by 20% at one year, 23% at two years, and 18% at three years compared to placebo 1
• Disability progression: A 42% relative risk reduction in disability progression was observed at three years, though this was based on limited data from only 87 patients 1
• MRI activity: Monthly MRI monitoring demonstrated that azathioprine at lymphocyte-suppressing doses (2.6-2.8 mg/kg daily) reduced gadolinium-enhancing lesion number and volume to zero in the median patient, with 50% or more reduction in 12 of 14 patients 2
• New T2 lesions: Equivalent reductions in new T2 lesion formation were sustained throughout treatment 2

Dosing and Monitoring Strategy

Optimal dosing requires individualized adjustment based on lymphocyte suppression:

• Start at 1-2 mg/kg/day orally, titrating up to 2.5-3 mg/kg daily as tolerated 1, 2
• Target blood lymphocyte count reduction to approximately 57% of baseline value for therapeutic effect 2
• Mandatory pre-treatment testing: Check thiopurine S-methyltransferase (TPMT) enzyme levels before initiating therapy 3
  • Patients with intermediate TPMT levels require lower starting doses
  • Azathioprine is contraindicated in patients lacking functional TPMT enzyme 3
• Monitor complete blood counts and liver function tests weekly for the first 4 weeks, then minimum every 3 months during maintenance 4

Safety Profile and Risk Management

The safety profile is acceptable with appropriate monitoring, though specific risks require attention:

Common Adverse Effects (manageable with dose adjustment):

• Gastrointestinal disturbances occur in >10% of patients, primarily during the first year 1, 5
• Leukopenia affects >10% of patients 5
• Bone marrow suppression and hepatic toxicity are anticipated but easily managed with monitoring 1
• Withdrawal due to adverse effects occurs in approximately 5%, mainly from gastrointestinal intolerance 1

Serious Long-Term Risks:

• Malignancy risk: The critical threshold is cumulative doses above 600 grams or treatment duration exceeding 10 years 1, 5
• Myelodysplastic syndrome: Four cases have been reported in MS patients after long-term azathioprine therapy, suggesting time- and dose-dependent risk 6
• Infection risk: Azathioprine increases susceptibility to infections even without neutropenia, with mild lymphopenia commonly contributing 4

Critical Management Points:

• Do not exceed 600 grams cumulative dose to minimize malignancy risk 1
• Immediately discontinue azathioprine if sepsis or serious infection develops; hold until infection completely resolves 4
• Lifelong monitoring is necessary even after discontinuation, as 50-90% of patients relapse after withdrawal, typically within 12 months 7

Clinical Context and Positioning

Azathioprine represents a fair alternative to interferon beta when:

• Patients have frequent relapses requiring steroids 1
• Preferred DMTs (interferons, glatiramer acetate, newer agents) have failed or are contraindicated 1
• Cost considerations favor less expensive options 1
• The drug is "usually well tolerated and compatible with normal daily activities" with minimal monitoring requirements 8

Key advantages over other immunosuppressants:

• Better therapeutic index than cyclophosphamide for maintenance therapy 3
• Does not significantly increase cancer risk within the first 5 years at conventional 2.5 mg/kg daily dosing 8
• Rapidly reversible activity if adverse effects occur 8

Treatment Duration

Maintain therapy for at least 18 months in the absence of toxicity 3, but recognize that:

• Most benefit occurs during active treatment 1
• After discontinuation, monitor clinically every 1-3 months during the first year, then every 3-6 months lifelong 7
• Prompt reinitiation is crucial if relapse occurs after withdrawal 7