Azathioprine

Azathioprine (AZA)

Azathioprine:

  • It is a cytotoxic immunosuppressant, a purine analog. Its metabolite is 6-mercaptopurine is a purine antagonsit.

  • Inhibits cell cycle: resting (G1) and DNA synthesis (S) phases through suppression of GTPase Rac1 activation.

  • It acts against T cells and is efficacious in T-cell dependent antibody-mediated disorders of MG.

  • It reduces T cell numbers, immunoglobulins derived from B-cells and IL-2. It suppresses T and B cells by interfering with purine biosynthesis, disrupting the antigen processing and presentation (RNA synthesis dependent), as well as proliferation and differentiation of immunocompetent cells (DNA and RNA synthesis dependent).

  • Effective in 70% to 90% of MG patients.

  • Therapeutic latency: 5-15 months. Full effect by 2 years.

  • FDA label for anti-rejection agent (transplant), RA, and inflammatory bowel disease.

  • Also used in DM, PM, CIDP, MMN, LEMS, DADS, vasculitic neuropathy, Isaac's syndrome, and sarcoidosis. None of these have FDA approval.

  • Randomized clinical trial evidence support azathioprine as a first-line immunosuppressive agent in myasthenia gravis. A randomized, double blinded, placebo controlled study of azathioprine versus placebo in myasthenia gravis patients already treated with prednisolone showed that, after 12 to 15 months on a prednisone taper protocol, azathioprine conferred a clear a steroid sparing effect compared with placebo. Retrospective data also suggests that azathioprine may have a steroid sparing effect and ocular MG and that the drug may reduce the risk of conversion from ocular to generalized MG.

  • Azathioprine's steroid sparing effect may take 12 months or more to emerge. 25% of patients with CIDP who would not respond to conventional therapies such as IVIG, PLEX and corticosteroids responded to azathioprine if given over a long duration.

  • The data on effectiveness of azathioprine and idiopathic inflammatory myopathies are limited. Again the steroid sparing effect emerges after a long period of time. Current consensus guidelines recommend the use of azathioprine and prednisone in the IMNM patients who are intolerant to methotrexate. In some severe cases, IV corticosteroids and azathioprine may be combined with IVIG for anti-HMGCR antibody positive cases and with rituximab and anti-SRP-ab positive cases although the strength of evidence in support of these approaches remain weak.

  • Advantage: steroid sparing immunosuppressant. Beneficial if used with prednisone.

  • Disadvantage: neoplasia risk, immunosuppression, pancytopenia, pancreatitis, hepatotoxicity. Not to be used in pregnancy. increases the risk of skin cancer.

    • 10% of patients do not tolerate the drug.

    • It causes flu like sx, bone marrow suppression, LFTs abnormalities.

    • Thiopurine methyltransferase (TPMT) is responsible for methylation of thiopurine compounds including azathioprine. Failure to methylate azathioprine results in accumulation of the medication and increases the risk for myelotoxicity, including fatal myelosuppression. Alternative immunosuppressants should be considered for patients with a low TPMT level. Check TPMT (thiopurine methyltransferase) enzyme activity. If individual is homozygous for TPMT (1:300), do not give azathioprine. If individual is heterozygous for TPMT, given azathioprine in smaller doses and monitor carefully.

    • Not to be used with allopurinol - bone marrow suppression

      • Concurrent administration of allopurinol can increase azathioprine toxicity by interfering with its metabolism by xanthine oxidase, an important degradative pathway. Thus azathioprine dose must be reduced by as much as 75% in patients who take allopurinol.

    • Weekly CBC to check WBC for the first few months of starting treatment.

  • Improvement may be slow, seen after 6 months, and full affect occur after 1-2 years.

  • Azathioprine is a useful and generally well-tolerated agent in MG. The usual dosage is 2 to 3 mg/kg/day. Approximately 5% to 10% of individuals have idiosyncratic reaction with fever, nausea, and vomiting, sometimes accompanied by eosinophilia or increased hepatocellular enzymes at the initiating dose. This may occur in patients treated with azathioprine within the first 3 weeks of treatment. The reaction resolves within 1 day of stopping azathioprine and will recur upon rechallenge with azathioprine. I obtain a baseline complete blood count (CBC) and differential, platelet count, and serum glutamic pyruvic transaminase (SGPT) and alkaline phosphatase levels levels. If the patient is not already receiving corticosteroids, obtain an anergy panel, including a PPD, and check that a recent x-ray film has been taken.

    • Therapy starts with 50 mg/day for 5 days, blood tests are checked, and the dosage is increased by 50 mg/day every 5 days. After reaching 150 mg/day, increase 25 mg/day every 5 days, checking the blood studies. At 2 to 2.5 mg/kg/day, observe the patient for 3 to 4 months. If the patient has not started to show clinical improvement and an increase in red blood cell (RBC) mean cell volume (MCV; increase in MCV of >100 fL is a useful indicator of a therapeutic dose, in the absence of concomitant iron deficiency), increase again by 25 mg/day to 3 mg/kg/day.

    • CBC with diff, CMP (transaminases, GGT) q2 weekly until patient is on a stable dose, then q3-6 months x 2 years, then qyear.

    • Macrocytosis is not an indication of discontinuation of therapy. WBC 4K/mm3 is a safe endpoint. If WBC falls <4K/mm3, decrease dose. If WBC falls <2.5K/mm3 or the absolute neutrophil count is less than 1000/mm3, azathioprine should be briefly discontinued, then reintroduced at a lower dose. This measure cannot be used in patients receiving prednisone, because of the steroid-induced leukocytosis. In that situation, an absolute lymphocyte count of 5% to 10% is an appropriate target. If transaminases increased 2 x to 3x normal - stop AZA.

    • Leukopenia resolves in 1 month. Hepatotoxicity resolves in several months.

    • Side effects that may respond to lowering of the dose or dividing the daily dose to twice or three times a day include a queasy feeling, nausea and vomiting, stomatitis, oral thrush, increased susceptibility to infections, marrow suppression, or increase in hepatocellular or obstructive liver chemistries. The majority of patients benefit from the drug and tolerate it long term (years).

    • Very little evidence has shown an increased incidence of neoplasm from azathioprine in the doses generally used in MG. In MG patients, a retrospective analysis of large MG cohort treated with azathioprine showed that hepatotoxicity occurred in 15.2% of patients in myelosuppression and 9.1% and a small proportion had both. The major disadvantage of azathioprine is the delay in therapeutic effect; it takes 3 to 4 months to see a clinical effect, and it may take more than 12 months for maximal effect.

    • An adequate therapeutic trial with Azathioprine should last at least 1-2 years, since the lag to onset of effect may range from 3-12 months, and the point of maximum benefit may be delayed 1 to 3 years.

    • No Class 1 evidence exists for prednisone and azathioprine.

    • Azathioprine when taken in therapeutic doses can result in photosensitivity due to DNA damage when DNA 6-TG interacts with UVA.

Azathioprine

  • Dose: Initial: 50 mg/d, increase by 50 mg every 1-2 wk; maintenance: 2-3 mg/kg/d (single daily dose or divided twice daily if GI upset)

  • Onset of action: 6-12 mo; peak 24 months.

  • Adverse events: Flu-like reaction within 4 weeks from initiation, hepatoxicity, pancreatitis, leukopenia (WBC ≤4000 cells/mm3), myelosuppression, malignancy, infection, teratogenicity

  • Monitoring parameters: CBC and LFTs: weekly × 4, then monthly for 1 year, then quarterly; age appropriate malignancy screening; consider skin cancer screening exam annually