Azathioprine

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Continuing Education Activity

Azathioprine (AZA) is a medication used in the management and treatment of active rheumatoid arthritis (RA) and the prevention of kidney transplant rejection. This activity reviews the indications, action, and contraindications for azathioprine as a valuable agent in treating RA and other disorders when applicable. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for members of the interprofessional team in the treatment of patients with RA and related conditions.

Objectives:

  • Describe the mechanism of action of azathioprine.
  • Identify the most common adverse events associated with azathioprine therapy.
  • Explain the importance of monitoring for patients on azathioprine therapy.
  • Outline the importance of collaboration and coordination among the interprofessional team to enhance patient care when monitoring azathioprine to improve patient outcomes.

Indications

Azathioprine (AZA) is approved by the Food and Drug Administration (FDA) for the symptomatic treatment of active rheumatoid arthritis. It also has approval as adjunctive therapy for the prevention of kidney transplant rejection.[1][2]

AZA used off-label for the treatment of inflammatory bowel disease,[3] Churg-Strauss syndrome, autoimmune hepatitis (for maintenance treatment along with steroids),[4][5] chronic ITP (second-line agent),[6] lupus nephritis,[1] connective tissue disease-associated ILD,[7] multiple sclerosis, severe myasthenia gravis, recurrent pericarditis,[8] psoriasis, non-infectious uveitis,[9] relapsing polychondritis,[10] dermatomyositis/polymyositis, erythema multiforme, severe and refractory atopic dermatitis, chronic actinic dermatitis, pyoderma gangrenosum, Behcet disease, cutaneous vasculitis, pityriasis rubra pilaris, lichen planus, bullous pemphigoid, and pemphigus vulgaris.[2][11] Of note, AZA or 6-MP are treatment options for Crohn disease in children as a maintenance treatment.[12]

Mechanism of Action

Azathioprine is a purine analog that converts to its active metabolites, mercaptopurine (6-MP) and thioguanine (6-TGN), by the action of hypoxanthine-guanine phosphoribosyltransferase (HPRT) and thiopurine methyltransferase (TPMT) enzymes. It then inhibits purine synthesis.[13] Its metabolites are incorporated into the replicating DNA and halt division. AZA metabolites may also mediate most of its immunosuppressive and toxic effects. AZA is absorbed rapidly through the GI system and does not penetrate the blood-brain barrier. It undergoes metabolism in the liver, and excretion is via the kidneys, which increases its toxicity in renal failure.[2]

Administration

The starting dose for AZA is 2 to 2.5 mg/kg/day, except for patients with TPMT or NUDT15 gene mutation, in which the starting dose is lower than normal.[14] Dose adjustments are necessary for hepatic and kidney disease.[11]

AZA tablets may be administered after meals to decrease adverse GI effects. Administration can be by IV push over 5 minutes, at a concentration not exceeding 5 mg/ml. It can be further diluted with NS or DW and administered by intermittent infusion over 30 to 60 minutes. However, it may also be infused over 5 minutes up to over 8 hours.

Adverse Effects

Complications occur in 15 to 28% of patients.[2]

Frequent Side Effects[15][16][13][4][17][18][19][20][21][22][23][24]

  • Nausea; is the most frequent side effect
    • Dose-dependent.
    • Early-onset nausea usually resolves without dose alteration
  • Fever
  • Fatigue
  • Arthralgias/myalgia
  • Bone marrow suppression causing pancytopenia, thrombocytopenia, leukopenia - there are reports of dose-dependent, life-threatening cases.
    • This complication correlates with the 6-TGN level
    • There is a higher risk of myelosuppression in patients who take allopurinol or ACEI and in renal insufficiency
    • An increase in the mean corpuscular volume of the red blood cells is also an expected side effect
  • Rash
  • Hepatotoxicity: Hepatic injury correlates with a 6-MMP level of more than 5700 pmol/8 x 10^8 RBC.
  • Hepatotoxicity categorizes into two groups.
    • Acute idiosyncratic liver injury happens in the early course and resolves with stopping the medication.  
    • Nodular regenerative hyperplasia occurs in IBD and organ transplant patients several years after therapy.
  • Infections (7.4%): Concomitant use of AZA and steroids will increase the risk of PCP in leukopenic patients.
  • Hypersensitivity: symptoms including fever, chills, arthralgia/myalgia, liver abnormalities, erythema nodosum
  • Kidney damage

Rare Side Effects[25][26][27][21][28][15][11][24]

  • Diarrhea
  • Carcinogenesis: cutaneous hyperkeratosis and nonmelanoma skin cancer (SCC) in myasthenia gravis (most likely due to increased risk of photosensitivity), solid-organ transplant and IBD patients/ lymphoma in transplant and IBD patients
  • Pancreatitis (3.3%): more in females with Crohn disease
    • Dose-dependent
    • Usually happens in the first six weeks
    • In the case of pancreatitis, discontinue AZA
  • Alopecia including telogen effluvium, anagen effluvium, and plica neuropathica
  • Macrocytic anemia
  • Sweet syndrome (acute febrile neutrophilic dermatosis)
  • Pneumonitis: in IBD and renal transplant patients
  • Upper airway edema
  • Tremor: in transplant and Crohn patient: dose-dependent

Contraindications

Contraindications[29][30][31][2][32]

  1. Hypersensitivity
  2. Pregnancy or plan for pregnancy: Contraception recommended. AZA can increase the risk of spontaneous miscarriage, low birth weight, and preterm delivery. Although data in systemic lupus erythematosus (SLE) and renal transplant patients showed safety in pregnancy. In some specific conditions like SLE and antiphospholipid antibody syndrome, the benefits of taking immunosuppressive medications are more than harms in keeping the mother safe.
  3. Breastfeeding as 6-MP was present in breast-milk of women who take azathioprine
  4. Unknown TPMT status or deficient TPMT activity due to the high risk of myelosuppression 
  5. Known malignancy
  6. Clinically active infection

Relative Contraindications[32]

  1. Allopurinol intake concomitantly with AZA due to severe myelosuppression 
  2. Cyclophosphamide or chlorambucil treatment in the past

Monitoring

  • It usually requires 6 to 8 weeks for AZA to work. The recommendation is to consider stopping the medication if there is no improvement in 3 months.[2]
  • Checking TPMT activity is suggested before starting the medication. Misclassification of TMPT phenotype can occur by prior blood transfusion.[12]
  • Test the patient for hepatitis B and C and PPD. A pregnancy test before treatment initiation is also a recommendation.[32]
  • Complete blood count (CBC) and liver function test (LFT) monitoring weekly are recommended initially for the first 4 to 8 weeks. CBC and LFT should get checked every three months for the rest of the treatment once the maintenance dose is achieved. However, it is advisable to check CBC and LFT more frequently in patients with kidney or renal diseases or elderly patients on high dosages of AZA or low TPMT activity. If labs show leukopenia (WBC less than 3 x 10^9/L), thrombocytopenia (platelet less than 120 x 10^9/L), or transaminitis (liver biochemistry more than half of the normal upper limit), the medication should be stopped.[21]
  • If patients have abdominal pain or severe nausea/vomiting, serum amylase requires checking to rule out pancreatitis. Lymph node and skin examination should be biannual.[32] If a generalized wart occurs, the AZA dose should be reduced or switched to another agent.
  • Some studies suggested monitoring the level of AZA metabolites (e.g., 6-TGN and 6-MP) to avoid specific complications.[4]

Toxicity

Toxicity symptoms include gastrointestinal symptoms, bradycardia, hepatotoxicity, myelosuppression.[33] Acute toxicity usually happens when more than 1.5 times of daily dose is taken by the patient. 

In the acute setting, activated charcoal may help with decreasing the symptoms within two hours of ingestion.[34] No specific antidote is known for AZA. In severe cases of toxicity, dialysis is permissible as AZA is dialysable.

In cases of hepatic sinusoidal obstruction syndrome, it must discontinue permanently. If severely leukopenic, thrombocytopenic, or infected, treatment should stop. 

Enhancing Healthcare Team Outcomes

Azathioprine is an immunomodulator associated with several serious adverse effects. Susceptibility to its toxicity varies with age, genetic differences, and medication dosage. Its adverse effects are a limiting factor in the patient's compliance. Therefore regular follow-up and frequent laboratory workups are crucial to avoiding its complications. Clinicians and pharmacists should be aware of potential adverse effects of AZA, even in asymptomatic patients. Pharmacists should verify dosing is appropriate to the condition treated and report any discrepancies to the rest of the healthcare team. Nursing will often function at the "front lines" in seeing the patients and are often the first to know about adverse events, which they can report to the team. Nursing will also be in charge of administration, so they should verify dosing to ensure optimal therapeutic results with minimal adverse effects.

In summary, azathioprine therapy requires an interprofessional team approach, including clinicians, specialists, mid-level practitioners, specialty-trained nurses, and pharmacists, all collaborating across disciplines to achieve optimal patient results. [Level 5]

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Author

Oranus Mohammadi

Editor:

Thamer A. Kassim

Updated:

5/1/2023 7:22:48 PM

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References

[1]

Ladrière M. [Current indications of azathioprine in nephrology]. Nephrologie & therapeutique. 2013 Feb:9(1):8-12. doi: 10.1016/j.nephro.2012.08.002. Epub 2012 Sep 28     [PubMed PMID: 23022291]

[2]

Anstey AV, Wakelin S, Reynolds NJ, British Association of Dermatologists Therapy, Guidelines and Audit Subcommittee. Guidelines for prescribing azathioprine in dermatology. The British journal of dermatology. 2004 Dec:151(6):1123-32     [PubMed PMID: 15606506]

[3]

Schmidt C, Herrlinger K, Siegmund B, Bokemeyer B, Schreiber S, Stallmach A, Kompetenznetz Darmerkrankungen. [Azathioprine in Crohn's disease therapy--guidance against the background of recent studies]. Zeitschrift fur Gastroenterologie. 2014 Dec:52(12):1423-30. doi: 10.1055/s-0034-1385650. Epub 2014 Dec 4     [PubMed PMID: 25474282]

[4]

Sheiko MA, Sundaram SS, Capocelli KE, Pan Z, McCoy AM, Mack CL. Outcomes in Pediatric Autoimmune Hepatitis and Significance of Azathioprine Metabolites. Journal of pediatric gastroenterology and nutrition. 2017 Jul:65(1):80-85. doi: 10.1097/MPG.0000000000001563. Epub     [PubMed PMID: 28272159]

[5]

Aljumah AA, Al Jarallah B, Albenmousa A, Al Khathlan A, Al Zanbagi A, Al Quaiz M, Al-Judaibi B, Nabrawi K, Al Hamoudi W, Alghamdi M, Fallatah H. The Saudi association for the study of liver diseases and transplantation clinical practice guidelines for management of autoimmune hepatitis. Saudi journal of gastroenterology : official journal of the Saudi Gastroenterology Association. 2018 Nov:24(7 Suppl):S1-S20. doi: 10.4103/sjg.SJG_159_18. Epub     [PubMed PMID: 30264737]

Level 1 (high-level) evidence

[6]

Cooper N. State of the art - how I manage immune thrombocytopenia. British journal of haematology. 2017 Apr:177(1):39-54. doi: 10.1111/bjh.14515. Epub 2017 Mar 10     [PubMed PMID: 28295192]

[7]

Oldham JM, Lee C, Valenzi E, Witt LJ, Adegunsoye A, Hsu S, Chen L, Montner S, Chung JH, Noth I, Vij R, Strek ME. Azathioprine response in patients with fibrotic connective tissue disease-associated interstitial lung disease. Respiratory medicine. 2016 Dec:121():117-122. doi: 10.1016/j.rmed.2016.11.007. Epub 2016 Nov 4     [PubMed PMID: 27888985]

[8]

Imazio M, Lazaros G, Brucato A, Gaita F. Recurrent pericarditis: new and emerging therapeutic options. Nature reviews. Cardiology. 2016 Feb:13(2):99-105. doi: 10.1038/nrcardio.2015.115. Epub 2015 Aug 11     [PubMed PMID: 26259934]

[9]

Touhami S, Diwo E, Sève P, Trad S, Bielefeld P, Sène D, Abad S, Brézin A, Quartier P, Koné Paut I, Weber M, Chiquet C, Errera MH, Sellam J, Cacoub P, Kaplanski G, Kodjikian L, Bodaghi B, Saadoun D. Expert opinion on the use of biological therapy in non-infectious uveitis. Expert opinion on biological therapy. 2019 May:19(5):477-490. doi: 10.1080/14712598.2019.1595578. Epub 2019 Apr 16     [PubMed PMID: 30888881]

Level 3 (low-level) evidence

[10]

Mathian A,Miyara M,Cohen-Aubart F,Haroche J,Hie M,Pha M,Grenier P,Amoura Z, Relapsing polychondritis: A 2016 update on clinical features, diagnostic tools, treatment and biological drug use. Best practice     [PubMed PMID: 27886803]

[11]

Meggitt SJ, Anstey AV, Mohd Mustapa MF, Reynolds NJ, Wakelin S. British Association of Dermatologists' guidelines for the safe and effective prescribing of azathioprine 2011. The British journal of dermatology. 2011 Oct:165(4):711-34. doi: 10.1111/j.1365-2133.2011.10575.x. Epub     [PubMed PMID: 21950502]

[12]

Ruemmele FM, Veres G, Kolho KL, Griffiths A, Levine A, Escher JC, Amil Dias J, Barabino A, Braegger CP, Bronsky J, Buderus S, Martín-de-Carpi J, De Ridder L, Fagerberg UL, Hugot JP, Kierkus J, Kolacek S, Koletzko S, Lionetti P, Miele E, Navas López VM, Paerregaard A, Russell RK, Serban DE, Shaoul R, Van Rheenen P, Veereman G, Weiss B, Wilson D, Dignass A, Eliakim A, Winter H, Turner D, European Crohn's and Colitis Organisation, European Society of Pediatric Gastroenterology, Hepatology and Nutrition. Consensus guidelines of ECCO/ESPGHAN on the medical management of pediatric Crohn's disease. Journal of Crohn's & colitis. 2014 Oct:8(10):1179-207. doi: 10.1016/j.crohns.2014.04.005. Epub 2014 Jun 6     [PubMed PMID: 24909831]

Level 3 (low-level) evidence

[13]

Wee JS, Marinaki A, Smith CH. Life threatening myelotoxicity secondary to azathioprine in a patient with atopic eczema and normal thiopurine methyltransferase activity. BMJ (Clinical research ed.). 2011 Mar 25:342():d1417. doi: 10.1136/bmj.d1417. Epub 2011 Mar 25     [PubMed PMID: 21441287]

[14]

Williet N, Roblin X. Trend towards dose reduction of azathioprine as monotherapy in inflammatory bowel disease patients: what about for combination therapy? Therapeutic advances in gastroenterology. 2017 Jan:10(1):5-10. doi: 10.1177/1756283X16670074. Epub 2016 Oct 10     [PubMed PMID: 28286554]

Level 3 (low-level) evidence

[15]

Joshi R, Singh S. Plica Neuropathica (Plica polonica) Following Azathioprine-induced Pancytopenia. International journal of trichology. 2010 Jul:2(2):110-2. doi: 10.4103/0974-7753.77523. Epub     [PubMed PMID: 21712900]

[16]

Steponaitiene R, Kupcinskas J, Survilaite S, Varkalaite G, Jonaitis L, Kiudelis G, Denapiene G, Valantinas J, Skieceviciene J, Kupcinskas L. TPMT and ITPA genetic variants in Lithuanian inflammatory bowel disease patients: Prevalence and azathioprine-related side effects. Advances in medical sciences. 2016 Mar:61(1):135-40. doi: 10.1016/j.advms.2015.09.008. Epub 2015 Dec 10     [PubMed PMID: 26674571]

Level 3 (low-level) evidence

[17]

. Guidelines for monitoring drug therapy in rheumatoid arthritis. American College of Rheumatology Ad Hoc Committee on Clinical Guidelines. Arthritis and rheumatism. 1996 May:39(5):723-31     [PubMed PMID: 8639168]

[18]

Melzer N, Ruck T, Fuhr P, Gold R, Hohlfeld R, Marx A, Melms A, Tackenberg B, Schalke B, Schneider-Gold C, Zimprich F, Meuth SG, Wiendl H. Clinical features, pathogenesis, and treatment of myasthenia gravis: a supplement to the Guidelines of the German Neurological Society. Journal of neurology. 2016 Aug:263(8):1473-94. doi: 10.1007/s00415-016-8045-z. Epub 2016 Feb 17     [PubMed PMID: 26886206]

[19]

Broekman MMTJ, Coenen MJH, van Marrewijk CJ, Wanten GJA, Wong DR, Verbeek ALM, Klungel OH, Hooymans PM, Guchelaar HJ, Scheffer H, Derijks LJJ, de Jong DJ, TOPIC Recruitment Team. More Dose-dependent Side Effects with Mercaptopurine over Azathioprine in IBD Treatment Due to Relatively Higher Dosing. Inflammatory bowel diseases. 2017 Oct:23(10):1873-1881. doi: 10.1097/MIB.0000000000001163. Epub     [PubMed PMID: 28644183]

[20]

Weinshilboum RM, Sladek SL. Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity. American journal of human genetics. 1980 Sep:32(5):651-62     [PubMed PMID: 7191632]

[21]

Nielsen OH, Vainer B, Rask-Madsen J. Review article: the treatment of inflammatory bowel disease with 6-mercaptopurine or azathioprine. Alimentary pharmacology & therapeutics. 2001 Nov:15(11):1699-708     [PubMed PMID: 11683683]

[22]

Saway PA, Heck LW, Bonner JR, Kirklin JK. Azathioprine hypersensitivity. Case report and review of the literature. The American journal of medicine. 1988 May:84(5):960-4     [PubMed PMID: 3284343]

Level 3 (low-level) evidence

[23]

González-Olivares M, Khedaoui R, Martínez-Morán C, Borbujo J. Azathioprine-Induced Hypersensitivity Reaction Presenting as Erythema Nodosum. Actas dermo-sifiliograficas. 2017 Jul-Aug:108(6):591-593. doi: 10.1016/j.ad.2016.12.006. Epub 2017 Mar 2     [PubMed PMID: 28262113]

[24]

Karaahmet F, Akinci H, Ayte R, Hamamci M, Coskun Y, Yuksel I. Tremor as dose dependent side-effect of azathioprine in remission patient with ileal Crohn's disease. Journal of Crohn's & colitis. 2013 Oct:7(9):e404. doi: 10.1016/j.crohns.2013.04.010. Epub 2013 Apr 26     [PubMed PMID: 23623283]

[25]

Fuggle NR, Bragoli W, Mahto A, Glover M, Martinez AE, Kinsler VA. The adverse effect profile of oral azathioprine in pediatric atopic dermatitis, and recommendations for monitoring. Journal of the American Academy of Dermatology. 2015 Jan:72(1):108-14. doi: 10.1016/j.jaad.2014.08.048. Epub 2014 Nov 4     [PubMed PMID: 25440430]

[26]

Trivedi CD, Pitchumoni CS. Drug-induced pancreatitis: an update. Journal of clinical gastroenterology. 2005 Sep:39(8):709-16     [PubMed PMID: 16082282]

[27]

van Geenen EJ, de Boer NK, Stassen P, Linskens RK, Bruno MJ, Mulder CJ, Stegeman CA, van Bodegraven AA. Azathioprine or mercaptopurine-induced acute pancreatitis is not a disease-specific phenomenon. Alimentary pharmacology & therapeutics. 2010 Jun:31(12):1322-9. doi: 10.1111/j.1365-2036.2010.04287.x. Epub 2010 Mar 6     [PubMed PMID: 20222913]

[28]

Gupta P, Shaffrali F. An unusual side effect of azathioprine. Clinical and experimental dermatology. 2015 Dec:40(8):929-30. doi: 10.1111/ced.12639. Epub 2015 Mar 21     [PubMed PMID: 25810100]

[29]

van der Woude CJ, Ardizzone S, Bengtson MB, Fiorino G, Fraser G, Katsanos K, Kolacek S, Juillerat P, Mulders AG, Pedersen N, Selinger C, Sebastian S, Sturm A, Zelinkova Z, Magro F, European Crohn’s and Colitis Organization. The second European evidenced-based consensus on reproduction and pregnancy in inflammatory bowel disease. Journal of Crohn's & colitis. 2015 Feb:9(2):107-24     [PubMed PMID: 25602023]

Level 3 (low-level) evidence

[30]

Provan D,Stasi R,Newland AC,Blanchette VS,Bolton-Maggs P,Bussel JB,Chong BH,Cines DB,Gernsheimer TB,Godeau B,Grainger J,Greer I,Hunt BJ,Imbach PA,Lyons G,McMillan R,Rodeghiero F,Sanz MA,Tarantino M,Watson S,Young J,Kuter DJ, International consensus report on the investigation and management of primary immune thrombocytopenia. Blood. 2010 Jan 14;     [PubMed PMID: 19846889]

Level 3 (low-level) evidence

[31]

Petri M. Immunosuppressive drug use in pregnancy. Autoimmunity. 2003 Feb:36(1):51-6     [PubMed PMID: 12765471]

[32]

Menter A, Korman NJ, Elmets CA, Feldman SR, Gelfand JM, Gordon KB, Gottlieb AB, Koo JY, Lebwohl M, Lim HW, Van Voorhees AS, Beutner KR, Bhushan R. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 4. Guidelines of care for the management and treatment of psoriasis with traditional systemic agents. Journal of the American Academy of Dermatology. 2009 Sep:61(3):451-85. doi: 10.1016/j.jaad.2009.03.027. Epub 2009 Jun 3     [PubMed PMID: 19493586]

[33]

Jack KL, Koopman WJ, Hulley D, Nicolle MW. A Review of Azathioprine-Associated Hepatotoxicity and Myelosuppression in Myasthenia Gravis. Journal of clinical neuromuscular disease. 2016 Sep:18(1):12-20. doi: 10.1097/CND.0000000000000133. Epub     [PubMed PMID: 27552384]

[34]

Gregoriano C, Ceschi A, Rauber-Lüthy C, Kupferschmidt H, Banner NR, Krähenbühl S, Taegtmeyer AB. Acute thiopurine overdose: analysis of reports to a National Poison Centre 1995-2013. PloS one. 2014:9(1):e86390. doi: 10.1371/journal.pone.0086390. Epub 2014 Jan 29     [PubMed PMID: 24489721]