Systemic Medications for the Dermatology Toolbox: Azathioprine

Transcription

1 Systemic Medications for the Dermatology Toolbox: Azathioprine Wynnis Tom, M.D. Associate Clinical Professor University of California, San Diego and Rady Children s Hospital

2 Faculty Disclosure Information Wynnis Tom, M.D. Investigator for Celgene, Dermira, Incyte, Janssen, Medimetriks, Pfizer, Regeneron **Off-label use of medications discussed

3 Azathioprine and the Skin FDA approved for prevention of renal transplant rejection and rheumatoid arthritis In dermatology, it is used for: o Autoimmune bullous disorders o Atopic dermatitis and other eczematous dermatitis o Photodermatoses o Connective tissue disorders incl. SLE o Psoriasis o Behcet s disease o GVHD

4 Pharmacokinetics Mechanism of action o 6-mercaptopurine analog that inhibits purine synthesis lymphocytes rely on de novo synthesis and more selectively affected o Also affects T-cell activation by blocking the CD28 costimulatory signal Well-absorbed after oral intake, extensively metabolized in RBCs and liver, small remainder excreted in urine Clinical improvement - at least 6-8 weeks

5 Overview of Thiopurine Metabolism IMPDH TPMT Adapted from Camilleri, M. Nat. Rev. Gastroenterol. Hepatol :

6 Azathioprine Concern for profound marrow suppression genetic polymorphisms in Thiopurine Methyl Transferase (TPMT) are important o 1 in 300 individuals homozygous for low activity alleles, 10% have intermediate activity o Low activity correlates with higher risk of suppression Use red blood cell TPMT activity to guide dosing o Normal activity: start 2.5mg/kg/d, by 0.5mg/kg/d prn o Intermediate: start 1 mg/kg/d, by 0.25mg/kg/d prn o Low: generally not recommended to use, although this has been done with careful monitoring of cell counts

7 Drug Dosing Basing on TPMT activity level appears to significantly reduce myelosuppression risk 50mg increments to mg sometimes adults may not need as high a dose as children Maximum dose that I use is 3.5, and rarely, 4.0 mg/kg/d Monitoring o Baseline: CBC, renal and liver function, TB testing, hepatitis B and C, HIV o Follow-Up: CBC, renal and liver function at 2-4 weeks then monthly x 2-3 months, once dose stable Q 3-4 months; repeat infectious tests annually

8 Contraindications Demonstrated hypersensitivity to azathioprine o Fever, malaise, diarrhea, rash, myalgias, liver enzymes, occ hypotension; usually in the first several weeks of tx Pregnancy Category D, generally avoid during lactation Drug Interactions o Dose reduction needed with allopurinol o May have higher risk of cytopenia with aminosalicylates, cotrimoxazole, ACE inhibitors, ribavirin o Can inhibit warfarin effect

9 Black Box Warning

10 Black Box Warning Hepatosplenic T-cell lymphoma median survival 10 mo. o More cases with using AZA and TNF-α inhibitors concomitantly for IBD esp Crohn s, cases with AZA alone were generally with >3years of tx (median duration 6 years, range of 2 17 y) o Also reported with CsA use in transplant patients, few cases in RA patients were with TNF-α inhibitors + MTX o No cases when used for skin disorder as a primary indication so how much concern should we have? Thai and Prindiville. J Crohns Colitis. 2010;4: Kotlyar et al. Am J Gastroenterol. 2010;105: Yabe et al. Ann Diagn Pathol Feb;26:16-22.

11 Other Adverse Effects GI side effects (mild nausea, diarrhea, discomfort) most common can divide doses, take with food Secondary infection Other malignancy squamous cell carcinoma Pancreatitis more often when given for GI disorders/ibd Cases of Sweet s syndrome reported

12 Pharmacogenomics Still more to Learn! Severe refractory cases of pemphigus and pemphigoid had increases in TPMT activity during therapy 12 children with AD with repeat measurements of TPMT activity o o 9 responders with stable levels 2 responders had decreasing TMPT activity, correlating with additional clinical improvement. One case with increasing activity, correlating with poor control. Changes in TPMT activity can occur after therapy begins and appear to inversely relate to azathioprine efficacy o May consider repeat assessment if not responding or change in response to therapy El-Azhary et al. Arch Dermatol Jun;145(6): Caufield and Tom. JAAD Jan;68(1):29-35.

13 El-Azhary et al. Arch Dermatol Jun;145(6):644-52