Version May 2024
INTRODUCTION — Azathioprine (AZA) is an immunosuppressive agent that acts through its effects as an antagonist of purine metabolism, resulting in the inhibition of deoxyribonucleic acid (DNA), ribonucleic acid (RNA), and protein synthesis. It has been used as an immunosuppressive agent for the treatment of a variety of disorders; these include a number of rheumatic diseases, such as rheumatoid arthritis, systemic lupus erythematosus (SLE), dermatomyositis and polymyositis, systemic sclerosis, and systemic vasculitis; inflammatory bowel disease; the prevention of organ transplant rejection; and for other conditions.
The pharmacology and adverse effects of AZA, particularly when used in the context of the rheumatic diseases, will be reviewed here. The role of AZA in the management of the different rheumatic diseases and other autoimmune and immune-mediated disorders, and for the prevention and management of transplant rejection, is presented in detail separately in the topic reviews covering the treatment of these individual conditions (see appropriate topic reviews).
PHARMACOLOGY AND BIOLOGIC EFFECTS
Structure and metabolism — Azathioprine (AZA), the 1-methyl-4-nitro-5-imidazolyl derivative of thioguanine, is a purine-mimic antimetabolite [1]. It is well-absorbed from the gastrointestinal tract and has a serum half-life of 0.2 to 0.5 hours and a biologic half-life of approximately 24 hours [2]. AZA is a prodrug, which is approximately 30 percent protein-bound. Forty-five percent of the drug is excreted in the urine, and the remainder is metabolized to its principal metabolite, 6-mercaptopurine (6-MP), which is formed by the action of glutathione in red blood cells [1]. The 6-MP is then further metabolized along competing routes:
●Xanthine oxidase-dependent metabolism – 6-MP undergoes catabolic oxidation to 6-thiouric acid, which is an inactive metabolite. This reaction is catalyzed by xanthine oxidase, which is concentrated in the intestine and liver.
●Thiopurine S-methyltransferase and hypoxanthine phosphoribosyl transferase-dependent metabolism – 6-MP is also metabolized along an anabolic pathway to several metabolites including 6-methylmercaptopurine (6-MMP), 6-methyl-thioinosine 5'-monophosphate, and 6-thioguanine (6-TG). Two enzymes are responsible for catalyzing these reactions: thiopurine S-methyltransferase (TPMT) and hypoxanthine phosphoribosyl transferase (also termed hypoxanthine-guanine phosphoribosyl transferase [HGPRT]).
Additionally, nucleoside triphosphate diphosphatase NUDT15 (nudix hydrolase 15, NUDT15) metabolizes the active thiopurine metabolite thioguanosine triphosphate (TGTP) to inactive thioguanosine monophosphate (TGMP); loss-of-function mutations in the NUDT15 gene are associated with increased hematologic toxicity [3,4]. (See 'Pharmacogenetics and azathioprine toxicity' below.)
Mechanism of action — AZA, through the effects of 6-MP and its metabolites, causes a reduction in intracellular purine synthesis, which results in decreased numbers of circulating B and T lymphocytes [5,6], reduced immunoglobulin synthesis [6], and diminished interleukin (IL) 2 secretion [7]. This occurs through the intracellular metabolism of 6-MP by HGPRT, which produces thioinosinic and thioguanylic acid. These compounds suppress intracellular inosinic acid synthesis, thereby interfering with adenine and guanine ribonucleotide production and resulting in the effects upon lymphoid cells [1,8]. AZA does not reduce serum levels of IL-6 or soluble IL-2 receptor [9].
Another pathway that is inhibited by thioguanine is the intracellular signaling downstream of the necessary costimulatory binding by CD28 on the surface of CD4+ T cells to CD80 and CD86 (B7-1 and B7-2) molecules on antigen-presenting cells [10] (see "Transplantation immunobiology", section on 'CD28, B7, and CTLA4'). Specifically, the metabolite 6-thioguanine triphosphate (6-thio-GTP) diminishes the activity of the small GTPase Rac1 in T lymphocytes. 6-thio-GTP blocks the interaction between Rac1 and its guanosine exchange factor Vav1 and inhibits activation of NF-kappaB and STAT3, thereby inducing apoptosis of activated T lymphocytes [11].
The inhibition of purine metabolism and induction of T-cell apoptosis both depend upon intracellular metabolites for the antineoplastic and immune-modulating effects of AZA [12]. Therefore, serum drug levels are of little value in monitoring treatment.
CONSIDERATIONS DURING TREATMENT
Pharmacogenetics and azathioprine toxicity — The relative accumulation of azathioprine (AZA) metabolites depends upon genetic polymorphisms of the genes for the individual enzymes, including thiopurine S-methyltransferase (TPMT) and nucleoside triphosphate diphosphatase NUDT15 (see 'Structure and metabolism' above); hematologic toxicity due to AZA and 6-mercaptopurine (6-MP) is predominantly related to the activity of TPMT and/or NUDT15 genetic variants, with the frequency of risk variants differing depending upon genetic background. (See "Overview of pharmacogenomics", section on 'Thiopurines and polymorphisms in TPMT and NUDT15'.)
Risk variants of TPMT and NUDT15 affect various population groups to different degrees:
●TPMT – Deficiency of thiopurine S-methyltransferase (TPMT), which is responsible for the metabolism of thiopurines, including AZA and mercaptopurine, causes 6-MP to be preferentially metabolized toward 6-thioguanine (6-TG) nucleotides, which appears to account for much of the hematologic toxicity related to AZA and 6-MP in some populations; there is large interindividual variability in the activity of TPMT. An inactive metabolite, 6-methylmercaptopurine (6-MMP), is associated with hepatotoxicity.
In European and African individuals, inherited TPMT deficiency is the primary genetic cause of thiopurine intolerance; as an example, White Americans show a trimodal distribution, with 89 to 94 percent possessing high enzyme activity, 6 to 11 percent intermediate activity due to heterozygosity at the TPMT locus, and 0.33 percent low activity [13-16]. However, a unimodal distribution of TPMT activity in various Chinese populations was found, indicating considerable differences between population groups in TPMT activity [17].
●NUDT15 – In contrast to TPMT polymorphisms, NUDT15 (nucleoside diphosphate-linked moiety X motif 15, NUDIX 15) variants of concern have been described most often in persons from several Asian populations, as well as in Hispanic individuals [3,4,18,19], although one study from Germany has also reported these variants among individuals described as being of European ancestry [20].
The poor metabolizer phenotype for NUDT15 appears in approximately 2 percent of studied East Asian populations, which is more prevalent than the poor metabolizer phenotype of TPMT among Europeans. (See "Overview of pharmacogenomics", section on 'Thiopurines and polymorphisms in TPMT and NUDT15' and 'Pharmacology and biologic effects' above.)
Variants of NUDT15, particularly NUDT15 c.415C>T, have been associated, especially in East Asian populations, with increased risk for hematologic toxicity (eg, leukopenia) with AZA/6-MP [18]. In more limited studies using genetic analyses of ancestry, the NUDT15 variant was common in East Asian populations and found to a lesser degree in patients from Hispanic populations, but was rare in Europeans and not observed in Africans [19]. Although most reports of toxicity related to NUDT15 polymorphisms have been in patients with inflammatory bowel disease and in acute lymphocytic leukemia, cases have been reported in other disorders, including a Chinese patient with Sjögren's disease [21].
Data on other genetic polymorphisms are emerging that may help identify patients at risk for AZA-related adverse effects [22,23]. (See "Overview of pharmacogenomics", section on 'Thiopurines and polymorphisms in TPMT and NUDT15'.)
TPMT and NUDT15 testing — There is uncertainty regarding the benefits of routine testing for thiopurine S-methyltransferase (TPMT; OMIM 187680) or NUDT15 (OMIM 615792) deficiency before beginning AZA; both genotyping and functional assays for these enzymes are available commercially. As with TPMT, genotyping for NUDT15 polymorphisms has not been universally adopted, and the optimal clinical circumstances in which to perform routine testing are not well defined. (See "Overview of pharmacogenomics", section on 'Thiopurines and polymorphisms in TPMT and NUDT15' and 'Pharmacology and biologic effects' above.)
Although some clinicians routinely perform TPMT and/or NUDT15 testing prior to initiating AZA, the author does not perform such testing but rather initiates therapy at a low dose with close monitoring as the dose is gradually increased. (See 'Dose titration and monitoring' below.)
Variation in the TPMT gene can result in functional inactivation of the enzyme and in a markedly increased risk of life-threatening myelosuppression. For this reason, the US Food and Drug Administration (FDA) recommends that "consideration be given to either genotype or phenotype patients for TPMT" prior to treatment with AZA. However, TPMT genotyping has not been universally adopted, and the cost effectiveness and optimal clinical circumstances in which to perform routine testing are not well-defined. Poor metabolizing TPMT gene variants are uncommon among East Asian populations when compared with NUDT15 variants. (See "Overview of pharmacogenomics", section on 'Thiopurines and polymorphisms in TPMT and NUDT15' and 'Pharmacogenetics and azathioprine toxicity' above.)
Expert opinions differ regarding the role of TPMT or NUDT15 genotyping prior to the administration of thiopurines for treatment of inflammatory and autoimmune disorders. In one study, among patients who developed hematologic toxicity within three months of treatment, 53 percent could be attributed to TPMT and/or NUDT15 polymorphisms, but 38 percent remained unexplained [20]. Therefore, some advocate routine testing, while others disagree with this approach, based upon the low frequency of homozygous variants among patients of White European genetic background, low frequency of any genetic risk across all races and ethnicities, the risk of a false sense of security that may arise with testing, and that there are many patients who develop myelosuppression while taking AZA who do not have detectable TPMT or NUDT15 gene variants. (See "Overview of pharmacogenomics", section on 'Thiopurines and polymorphisms in TPMT and NUDT15' and 'Pharmacology and biologic effects' above.)
Examples of the clinical observations regarding such testing include the following:
●In 1 study among 67 patients given AZA, 5 of 6 individuals heterozygous for a mutant allele (as assessed by polymerase chain reaction-based assays) discontinued therapy within 1 month of drug initiation because of low leukocyte counts [24]. AZA was given for a significantly longer period to those with wild-type alleles compared with patients with gene variants (39 versus 2 weeks, respectively). By contrast, there was no association between TPMT alleles and AZA toxicity in a study of 342 patients with systemic lupus erythematosus (SLE) in Korea [25].
●Similar considerations to those with AZA apply to the use of 6-MP. In a series of 180 children with acute lymphoblastic leukemia, the cumulative incidence of dose reductions in 6-MP due to drug toxicity was 7 percent in the 161 children with 2 wild-type TPMT alleles, 35 percent in the 17 children with 1 variant allele, and 100 percent in the 2 children with 2 variant alleles [26]. Lowering the 6-MP dose in the last 2 groups permitted administration of the full protocol.
Target serum levels of the metabolite 6-TG can provide information to help predict efficacy and toxicity. In an open-label study of AZA therapy for 50 patients with active SLE, pretreatment TPMT status facilitated dosing of AZA necessary to achieve appropriate serum levels of 6-TG [27]. However, this observation requires further validation and more readily available testing for 6-TG levels before it can be applied to routine clinical practice.
Drug interactions
Xanthine oxidase inhibitors — The major drug interactions with AZA are with allopurinol and febuxostat, which slow the elimination of 6-MP by inhibiting xanthine oxidase, the mechanism by which allopurinol and febuxostat reduce uric acid levels in patients with hyperuricemia and gout, consequently increasing the risk of adverse effects from use of AZA [28].
Thus, the dose of AZA should be reduced significantly (by 50 to 75 percent) in patients who require treatment with allopurinol, but this combination should be avoided if possible. In patients receiving both agents, the white blood cell count should be carefully monitored. When AZA is combined with either xanthine oxidase inhibitor (even with appropriate dose reduction), a complete blood count (CBC) should be performed at two weeks and monthly for three months, and this testing regimen should be repeated any time the dose is increased. TPMT and NUDT15 testing are recommended for patients in populations likely to be at increased risk of genetic variants conveying greater risk of toxicity (see 'Pharmacogenetics and azathioprine toxicity' above) when receiving a combination of AZA with allopurinol or febuxostat, and an alternative agent should be considered in the setting of heterozygous or homozygous deficiency.
There is insufficient experience combining AZA and febuxostat to make specific dosing reduction recommendations; this combination should be avoided [29]. (See 'Bone marrow suppression' below.)
Other medications — Specific interactions may be determined using the drug interactions program included in UpToDate. This tool can also be accessed from the UpToDate online search page or through the individual drug information topics in the section on drug interactions. (See "Azathioprine: Drug information".)
Dose titration and monitoring — For most rheumatic disease indications, we generally use an initial dose of AZA of 25 to 50 mg/day, and we obtain a CBC after two weeks of therapy to ensure that the counts are stable because toxicity can be seen even at low doses. We then usually increase the daily dose by 50 mg (or approximately 0.5 mg/kg/day) every four weeks to 1.5 mg/kg/day. In patients with a higher target dose for a given medical condition or with an inadequate response after three months of therapy, we increase the dose as tolerated up to a maximum typically of 3 mg/kg/day. A lower dose is indicated in patients with renal insufficiency. For dose adjustment in kidney impairment, refer to the drug information for azathioprine included within UpToDate.
A CBC and platelet count should be monitored every two weeks during dose escalation and every four to six weeks after a stable dose is achieved. Some experts suggest liver enzyme testing every six to eight weeks during AZA therapy. For patients on a stable testing routine, surveillance testing may be reduced after the first year to every three months.
In patients who develop leukopenia (white blood cells <4000/microL) or thrombocytopenia (platelet count <150,000/microL) during therapy, the AZA dose should be reduced by 50 percent or the drug should be discontinued. If a 50 percent reduction in the dose is associated with persistent cytopenia, then AZA should generally be permanently discontinued. Patients who develop macrocytosis should be closely monitored with more frequent CBCs (eg, initially every two weeks for a month) once other major causes of macrocytosis have been excluded, including vitamin B12 and folate deficiency. Stable mild macrocytosis in the absence of vitamin deficiency is a potential side effect that is well-tolerated and does not require discontinuation of medication.
Reproductive health concerns — AZA can generally be continued during pregnancy in patients with rheumatic disease and does not appear to reduce male fertility. The evidence and recommendations are described in detail separately. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Azathioprine and 6-mercaptopurine' and "Effects of antiinflammatory and immunosuppressive drugs on gonadal function and teratogenicity in men with rheumatic diseases".)
ADVERSE EFFECTS
Overview — Although the frequency of toxicity in patients with rheumatic diseases treated with azathioprine (AZA) is comparable with that of other conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and mycophenolate mofetil, AZA must still be administered with caution [2,30,31].
The most common side effects of AZA at doses typically used in the treatment of rheumatic diseases include gastrointestinal intolerance, bone marrow suppression, and infection. (See 'Gastrointestinal' below and 'Bone marrow suppression' below and 'Infection' below.)
Other concerns include malignancy and risks related to increased drug levels with the concomitant use of xanthine oxidase inhibitors. (See 'Malignancy risk' below and 'Reproductive health concerns' above and 'Xanthine oxidase inhibitors' above.)
Gastrointestinal — Anorexia, nausea, and vomiting occur in up to 23 percent of patients treated with AZA; these symptoms usually begin soon after the initiation of therapy [14]. In contrast to hematologic toxicity, TPMT deficiency or NUDT15 variants are poor predictors of gastrointestinal side effects. In our experience, starting the AZA at a low dose sometimes abrogates the nausea and vomiting. By comparison, diarrhea occurs in less than 1 percent of patients, and a mild elevation of liver enzymes occurs in approximately 5 percent. Progression to cirrhosis has not been described [2].
Dramatic gastrointestinal hypersensitivity reactions have been reported in a few patients, characterized by nausea, vomiting, and often diarrhea and fever. Other nonspecific symptoms that should alert the clinician to this hypersensitivity syndrome include rash, myalgias, malaise, elevation of liver enzymes, and occasional hypotension, all occurring within the first few weeks of therapy.
Drug-induced pancreatitis is a rare adverse effect of AZA and 6-mercaptopurine (6-MP) [32,33]; evidence from patients with inflammatory bowel disease suggests that increased risk of this side effect is associated with the presence of specific human leukocyte antigen (HLA) class II variants, with an association seen in these patients with the HLA-DQA1*02:01-HLA-DRB1*07:01 haplotype [34]. AZA-induced pancreatitis is less frequently reported in autoimmune rheumatic connective tissue diseases, such as rheumatoid arthritis and systemic lupus erythematosus (SLE), than in inflammatory bowel disease or antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis [33,35].
Hematologic complications and malignancies
Bone marrow suppression — Dose-related marrow suppression results in leukopenia in up to 27 percent of patients and thrombocytopenia in up to 5 percent [2,14]. Mild leukopenia usually responds to a reduction in the daily dose of AZA, which is done mostly when the absolute neutrophil count is less than 1000 cells/microL and/or the absolute lymphocyte count (ALC) is less than 600 cells/microL [2]. Use of AZA in addition to glucocorticoids with a low ALC is a risk factor for opportunistic infections such as Pneumocystis jirovecii pneumonia (PCP), and on a case-by-case basis, a decision is required to determine if the risk is warranted and if antibiotic prophylaxis is appropriate. Thrombocytopenia occurs in up to 5 percent of patients [14]. Unless platelets are below 50,000/microL, which is uncommon, clinical bleeding or need for concurrent antiplatelet drug therapy dose reduction is typically not required.
Genetically determined abnormalities that reduce thiopurine S-methyltransferase (TPMT) and nucleoside triphosphate diphosphatase NUDT15 (NUDT15) may reduce AZA metabolism and result in a significant risk for myelosuppression and a macrocytic anemia [14,15,36]. (See 'Pharmacogenetics and azathioprine toxicity' above.)
The risk of AZA accumulation and possibly severe bone marrow toxicity is much greater when AZA is given with allopurinol [37] or febuxostat. As a result, we generally avoid this combination. Dose reduction and close monitoring are required if it is necessary to use these drugs together. (See 'Xanthine oxidase inhibitors' above.)
Malignancy risk — There is some evidence suggesting a possible but small increased risk of malignancy in patients with rheumatoid arthritis treated with AZA [5,38,39]. However, in one study, a trend for an increase in risk of hematologic malignancy compared with control patients not treated with AZA was no longer significant after adjusting for confounding variables, including other drug therapies [38]. In another study, with a 20-year follow-up of patients with rheumatoid arthritis treated with 300 mg daily of AZA, the absolute increase in risk for lymphoproliferative malignancy with the drug was estimated at 1 case per 1000 patient-years of exposure [39]. The study could not exclude an increased risk of other cancers, but no dose-dependent or site-specific increase was seen in the cases identified. One report has described a possible increase in hematologic malignancies in patients with SLE exposed to immunosuppressive agents, although the increase was not limited to patients receiving AZA [40].
Although an initial report appeared to show an increased risk of neoplasms in patients with rheumatoid arthritis using AZA [41], a subsequent study found that high rheumatoid arthritis disease activity conferred greater risk of lymphoma than did treatment [42].
The risk of malignancy is much higher, by comparison, in patients being treated to prevent organ transplant rejection. Renal transplant recipients who have been treated with protocols including AZA have demonstrated a 50- to 100-fold increase in the relative risk of malignant disease [5,43]. The most common tumors are squamous cell carcinomas of the skin, non-Hodgkin lymphoma, Kaposi sarcoma, in situ carcinomas of the uterine cervix, and carcinomas of the vulva and perineum [43]. Skin cancer is most common, occurring in 20 to 37 percent of patients, depending in part upon sun exposure. (See "Malignancy after solid organ transplantation".)
One study using mutational signature analysis revealed an association between the presence of a novel signature (signature 32) and cutaneous squamous cell carcinoma in patients with chronic exposure to AZA [44].
Infection — Infections occur overall in up to 9 percent of patients [2,5]. Bacterial infections usually occur in the clinical setting of leukopenia [45,46]. Viral infections, especially herpes zoster, occur in up to 6 percent of treated patients [5,46]. Exacerbation of chronic viral hepatitis may also occur [47]. There are no established guidelines to indicate the severity or frequency of infection(s) that necessitates discontinuing AZA, and this decision should be determined on an individual basis, depending upon the severity of the infection, comorbidities, other medications, and general medical status.
Patients who will receive AZA should receive appropriate immunizations to help prevent infectious complications. Recommendations may be affected by the underlying illness and other medications being employed (table 1). (See "Immunizations in autoimmune inflammatory rheumatic disease in adults".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Side effects of anti-inflammatory and anti-rheumatic drugs".)
SUMMARY AND RECOMMENDATIONS
●Azathioprine (AZA) is a derivative of thioguanine, a purine-mimic antimetabolite, which is well-absorbed from the gastrointestinal tract. AZA is a prodrug; the action of glutathione in red blood cells causes the formation of the principal metabolite, 6-mercaptopurine (6-MP). The prodrug AZA is approximately 30 percent protein-bound, and 45 percent of the drug is excreted in the urine; the remainder is metabolized to 6-MP, which is then further metabolized. (See 'Structure and metabolism' above.)
●The metabolism of 6-MP is by competing routes: catabolic oxidation to 6-thiouric acid, which is catalyzed by xanthine oxidase, and metabolism along an anabolic pathway to several metabolites, for which two enzymes are responsible: thiopurine S-methyltransferase (TPMT) and hypoxanthine-guanine phosphoribosyl transferase (HGPRT). (See 'Structure and metabolism' above.)
●The relative accumulation of 6-MP metabolites depends upon genetic polymorphisms of several enzymes. The toxicity of AZA and 6-MP is substantially affected by the activity of TPMT. Deficiency of this enzyme causes 6-MP to be preferentially metabolized toward 6-thioguanine (6-TG) nucleotides, which appear to account for much of the toxicity related to 6-MP. Depending upon the ethnicity, low TPMT activity has been observed in up to 11 percent of the population, with 0.3 percent having negligible activity. Analysis of the TPMT gene by use of commercially available genotyping or functional assays for the enzyme prior to the administration of AZA may help predict those individuals at risk for severe toxicity. Other genes (eg, NUDT15 genetic variants in East Asian and Hispanic populations) also have a role in determining and predicting AZA toxicity. (See 'Pharmacogenetics and azathioprine toxicity' above.)
●Intracellular metabolites of 6-MP are responsible for a reduction in intracellular purine synthesis and for the antineoplastic and immune-modulating effects of AZA. Serum drug levels are, therefore, of little value in monitoring treatment. AZA causes decreased numbers of circulating B and T lymphocytes, reduced immunoglobulin synthesis, diminished interleukin (IL) 2 secretion, and inhibition of the intracellular signaling downstream of T-cell costimulation involving CD28-mediated pathways. (See 'Mechanism of action' above.)
●The major drug interaction with AZA is with allopurinol and febuxostat, which slow the elimination of 6-MP by inhibiting xanthine oxidase. Thus, the dose of AZA needs to be reduced significantly (50 to 75 percent) in patients treated with allopurinol, but this combination should be avoided if possible. Use of AZA with febuxostat should also be avoided. (See 'Xanthine oxidase inhibitors' above.)
●In the treatment of rheumatic diseases, AZA is generally begun at a dose of 25 to 50 mg/day for two weeks to test for drug hypersensitivity and serve as a screen for TPMT homozygous deficiency and other causes of diminished AZA/6-MP metabolism. The dose is then increased incrementally by 0.5 mg/kg/day every four weeks until the desired response is seen or until a maximal total dose of 3 mg/kg/day is reached. A lower dose is indicated in patients with renal insufficiency. (See 'Dose titration and monitoring' above and 'TPMT and NUDT15 testing' above.)
●A complete blood count (CBC) and platelet count should be monitored every two weeks during dose escalation and every four to six weeks after a stable dose is achieved. Some experts suggest liver enzyme testing every six to eight weeks during AZA therapy. The AZA dose should be reduced or discontinued in patients who develop leukopenia or thrombocytopenia. Patients who develop macrocytosis should be more closely monitored once the usual causes, such as vitamin B12 deficiency, have been excluded. After one year on a stable dosing routine, surveillance laboratory testing can be reduced to every three months. (See 'Dose titration and monitoring' above.)
●The frequency of toxicity of AZA in patients with rheumatoid arthritis and other rheumatic diseases is comparable with that of other conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), and AZA must be administered with great caution. The most common side effects of AZA at doses typically used in the treatment of rheumatic diseases include gastrointestinal intolerance, bone marrow suppression, and infection. The increase in relative risk of malignancy in patients with rheumatoid arthritis is small in contrast with the effects of AZA in renal transplant recipients. (See 'Adverse effects' above.)
ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge William Wilke, MD, who contributed to an earlier version of this topic review.
آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟
