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CASE REPORT |
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| Year : 2022 | Volume
: 67
| Issue : 1 | Page : 50-53 |
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| Azathioprine-induced marrow suppression in dermatology patients - Analysis of 18 patients |
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Vikrant V Saoji1, Sugat A Jawade1, Piyush Agrawal2, Shravya Rimmalapudi1
1 Department of Dermatology, Jawaharlal Nehru Medical College, Sawangi (Meghe), Wardha, Maharashtra, India
2 DDVL, Consultant Dermatologist, Skinzone, Raigarh, Chhattisgarh, India
| Date of Web Publication | 19-Apr-2022 |
Correspondence Address:
Vikrant V Saoji
Dr. Saoji Skin Clinic, Midas Height Building, Opposite Hotel Centre Point, Ramdaspeth, Nagpur - 440 012, Maharashtra
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/ijd.ijd_249_21
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 Abstract | | |
Background: Azathioprine is an immunosuppressant used to treat several immunological disorders. As a purine analog, it inhibits DNA synthesis and cell multiplication. However, marrow suppression is a serious complication associated with azathioprine. Aim: To analyze the marrow suppression caused by azathioprine in dermatology patients. Material and Method: This is a retrospective analysis of the records of 18 patients who presented with marrow suppression secondary to azathioprine which was used for the treatment of various dermatological diseases. Results: The analysis includes 18 patients, 15 females and 3 males with the average age being 25.88 years. All except two patients received 1 mg/kg of oral azathioprine once daily. Leukopenia was seen in 13 patients (with severe leukopenia in 7 patients), thrombocytopenia in 8, and low hemoglobin in 14 patients. Isolated low hemoglobin was seen in four patients, isolated leukopenia in four patients, and only one patient presented with isolated thrombocytopenia. Six patients had pancytopenia. The duration from the starting dose to reporting of marrow suppression ranged from 10 days to 1 year. Eight out of 18 patients presented with anagen effluvium, 2 patients with oral ulcers, and 1 patient with an upper respiratory tract infection. All the patients recovered within 1 month. Conclusion: Marrow suppression due to azathioprine can occur with a low dose of 1 mg/kg. Hair loss and oral ulcers serve as early warning signs for marrow suppression.
Keywords: Azathioprine, immunosuppressant, myelotoxicity
How to cite this article:
Saoji VV, Jawade SA, Agrawal P, Rimmalapudi S. Azathioprine-induced marrow suppression in dermatology patients - Analysis of 18 patients. Indian J Dermatol 2022;67:50-3 |
How to cite this URL:
Saoji VV, Jawade SA, Agrawal P, Rimmalapudi S. Azathioprine-induced marrow suppression in dermatology patients - Analysis of 18 patients. Indian J Dermatol [serial online] 2022 [cited 2023 Jun 4];67:50-3. Available from: https://www.e-ijd.org/text.asp?2022/67/1/50/343271 |
| Introduction | |  |
Azathioprine is used as an immunosuppressive agent in the treatment of many immunological diseases. Its dermatological use includes immunobullous disorders, atopic dermatitis, chronic actinic dermatitis, vasculitis, connective tissue disorders,[1] and vitiligo.[2] It is a purine analog which inhibits Deoxyribonucleic acid (DNA) synthesis and cell division. The rapidly dividing cells like hematopoietic cells are the most susceptible, accounting for its immunosuppressant action as well as the side effects. The most important and serious side effect of azathioprine is marrow suppression which may be life-threatening. This myelosuppression consists of leukopenia, thrombocytopenia, anemia, and sometimes pancytopenia of all three cell lineages.
A case series of 18 patients with marrow suppression due to azathioprine used for dermatological diseases is presented.
| Material and Methods | | |
This is a retrospective analysis of the records of the patients who developed marrow suppression secondary to the use of azathioprine and presented to the authors' OPD from January 2016 to December 2019. The marrow suppression is indicated by hemoglobin less than 10 gm, leukocyte count less than 3,000 cells/cm, and platelet count less than 1,00,000/cm.[1] Leukopenia is further classified as moderate (white blood count 2,000–3,000) or severe (less than 2,000).[1],[3] We maintain the records of all the patients of marrow suppression presenting to our OPD. Whenever a patient presents with signs and symptoms of marrow suppression to our OPD, a detailed history is taken with the help of proforma, and blood investigations are diligently recorded. The patients are treated on an OPD basis or hospitalized based on the severity of their marrow suppression. All the patients who are managed on an OPD basis were regularly contacted on the phone till the patient recovered completely.
This is an analysis of 18 patients which included 3 males and 15 females. The patient's age ranged from 7 to 45 years with a mean age of 25.88 years. The patient's details are shown in [Table 1]. These 18 patients included 16 patients of vitiligo and one each of pemphigus vulgaris and alopecia areata. All the patients, except two, received a 1 mg/kg oral daily dose of azathioprine. A case of pemphigus received a 2 mg/kg daily dose of azathioprine orally (50 mg once daily (OD) for the initial 15 days). A male patient of vitiligo tolerated a 1 mg/kg dose but he developed anemia when the dose was increased to 1.5 mg/kg. A female patient had received 50 mg OD for 1 year (without any problem) which was discontinued and when restarted after 8 months due to the spread of vitiligo, she developed marrow suppression with the same dose. | Table 1: Details of patients with azathioprine-induced immunosuppression
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Of these 18 patients, leukopenia was seen in 13 patients (severe leukopenia in 7), thrombocytopenia in 8, and anemia in 14 patients. Isolated low hemoglobin was seen in four patients, isolated leukopenia in four patients, and only one patient presented with isolated thrombocytopenia. Six patients had pancytopenia. Of the six patients with pancytopenia, five had severe leukopenia. The duration from the starting dose to reporting of marrow suppression ranged from 10 days to 8 months. Out of six patients with pancytopenia, five presented in less than 20 days. Eight out of the 18 patients presented with anagen effluvium. In all of them, hair loss was the first presentation, and upon further investigation, marrow suppression was noted. Except for one, all the patients who presented with hair loss had severe leukopenia with total leukocyte count (TLC) less than 2,000 and five patients had pancytopenia.
Two patients presented with oral ulcers and both these patients were also noted to have anagen effluvium. A 24-year-old female patient presented to the clinic with upper respiratory illness and fever and upon further investigation was noted to have marrow suppression with TLC 2,300. Only one patient had a TLC count of less than 1,000 [Table 1].
All vitiligo patients were also on oral psoralen (PUVA SOL). The pemphigus patient was on azathioprine and low-dose steroids for 4 months when presented with only leukopenia (2,800) with a lymphocyte count of 17%. This patient had received rituximab 3 months prior. All the patients had normal investigation reports before initiating this treatment. None of the patients had deranged renal or hepatic function. All the patients recovered. All the patients with a leukocyte count of less than 2,000 were admitted under a hematologist/intensivist. The patients with minor side effects (TLC count over 2,000, platelet count more than 50,000) were managed by the author with injectable vitamins (B complex injection containing folic acid 15 mg, cyanocobalamin 500 mcg, nicotine ice 200 mg) and supportive care without requiring admission to the inpatient setting. Thiopurine methyltransferase (TPMT) testing was not done in any of the patients.
| Discussion | | |
Azathioprine after absorption gets converted into 6-Mercaptopurine (6MP) which either gets converted into a pharmacologically active 6-Thioguanine (6TG) or gets metabolized into inactive metabolites by the enzyme thiopurine methyltransferase (TPMT) and to a minor extent by enzyme xanthine oxidase.[1] There is a polymorphism in the TPMT gene. A person with low TPMT activity has less inactivation of azathioprine and more diversion to the active pathway (6TG) leading to toxicity. It is advisable to do TPMT level testing before starting azathioprine.[1],[4] In a study from North India, 20 out of 114 patients with normal TPMT genotype developed marrow suppression.[5] No tests including TPMT genotype[5] or phenotype testing[6] can predict the risk of myelotoxicity by azathioprine accurately. Hence, regular monitoring of blood counts despite TPMT testing is essential.[7] It is recommended to test blood counts weekly for 4 weeks and then monthly or bi-monthly thereafter.[1],[7] Due to the financial constraints, TPMT testing was not done in our patients. It is likely that patients who presented with severe marrow suppression had a low level of TPMT and patients with relatively mild suppression had an intermediate level of TPMT. The usual dose of azathioprine used was 1–3 mg/kg. Without TPMT testing, the starting dose of azathioprine should not exceed 1 mg/kg.[7] The dose used in most of our patients was 1 mg/kg dose.
Our study Showed increased incidence in females with a female to male ratio of 15:3. We have not come across any other study of azathioprine-induced marrow suppression with female preponderance. It is theorized that a relatively low TPMT activity in females makes them more susceptible to the side effect of azathioprine. Blaker et al.[9] reported that the TPMT activity is lower in females than males.[8] Another study from the UK involving a multiracial group also showed that the TPMT enzyme activity was lower among the females, especially in South Asians.
All our vitiligo patients were on oral psoralen and betamethasone oral pulse therapy which are unlikely to affect the azathioprine metabolism. The pemphigus patient was on steroid and azathioprine for 1 month when she received rituximab and presented with isolated leukopenia (lymphopenia) which could be because of additive suppressive action on lymphocytes by both the drugs.
Azathioprine affects the rapidly dividing cells like hematopoietic cells, mucosal cells, and cells at the hair roots. Eight of our patients presented with anagen effluvium. Though all the patients regained hair in 3–4 months, it was very disturbing for the patients. In our patients, hair loss and oral ulcers were the initial presentation of the azathioprine toxicity—an early warning sign of marrow toxicity—cytopenia developed later. The hair loss was associated with severe marrow toxicity and presented early. In our cases, marrow suppression was seen from 10 days after the starting dose to 1 year indicating that regular Complete blood picture (CBC) monitoring throughout the course of azathioprine is very important to detect marrow suppression. The early presentation was associated with severe marrow suppression and the late-onset marrow suppression was associated with mild toxicity indicating that more frequent blood counts (weekly) in the first month are crucial to detect severe marrow toxicity.
Leukopenia increases the risk of infection and may lead to mortality. No fatality was seen in our study likely due to the use of low-dose (1 mg/kg) azathioprine.
Thrombocytopenia increases the risk of hemorrhages. Severe thrombocytopenia in our patients was seen as a part of pancytopenia. Only one patient presented with isolated thrombocytopenia which recovered within a week. None of our patients presented with bleeding manifestations.
The 6TG persists in the Red blood cells (RBCs) for a prolonged period and hence the recovery is slow.[9] In our patients, the recovery time ranged from 8 to 20 days. But the rising counts were reassuring.
Half of our patients were asymptomatic and only blood tests indicated the diagnosis. In one of the studies, 32 of the 37 patients of azathioprine-induced morrow suppression were asymptomatic.[3]
Since all the patients recovered after the withdrawal of azathioprine, other causes of myelosuppression are unlikely. The limitation of our study is that it includes only patients whose records were available to us, and some of the patients might not have reported to us.
The Naranjo scale score was calculated to be 5 which, according to the criteria, is interpreted as a probable adverse drug reaction that means the reaction followed a reasonable temporal sequence after a drug. It was confirmed by withdrawal but not by exposure to the drug and could not be reasonably explained by the known characteristics of the patient's clinical state.
| Conclusion | | |
Azathioprine is a very useful drug but can have serious side effects like myelosuppression. Since no tests can accurately predict the risk of myelotoxicity, regular monitoring of complete blood count is very important.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
| References | | |
| 1. | Badalamenti SS, Kerdel FA. Azathioprine. In: Wolverton SE. editors. Comprehensive Dermatologic Drug Therapy. Philadelphia: Saunders; 2013. p. 182-9.  |
| 2. | Radmanesh M, Saedi K. The efficacy of combined PUVA and low-dose azathioprine for early and enhanced repigmentation in vitiligo patients. J Dermatolog Treat 2006;17:151-3. |
| 3. | Connell WR, Kamm MA, Ritchie JK, Lennard-Jones JE. Bone marrow toxicity caused by azathioprine in inflammatory bowel disease: 27 years of experience. Gut 1993;34:1081-5. |
| 4. | Anstey AV, Wakelin S, Reynolds NJ. British Association of Dermatologists therapy, guidelines and audit subcommittee. Br J Dermatol 2004;151:1123-32. |
| 5. | Ambar G, Vandana A, Lalit D, Jyoti K. Thiopurine S-methyltransferase (TPMT) mutation prevalence and myelosuppression frequency in North Indian patients with autoimmune disorders. J Association Physicians India 2018;66:39-44. |
| 6. | Parkar SP, Dherai AJ, Desai DC, Ashavaid TF. Thiopurine metabolite level and toxicity in Indians with inflammatory bowel disease. JGH Open 2017;1:25-31. |
| 7. | Meggitt SJ, Anstey AV, Mohd Mustapa MF, Reynolds NJ, Wakelin S. British Association of Dermatologists' guidelines for the safe and effective prescribing of azathioprine. BJD 2011;165:711-34. |
| 8. | Blaker PA, Kariyawasam VC, Patel KV, Goel RM, Ward MG, Irving PM, et al. OC-015 The influence of gender and hemoglobin on TPMT activity. Gut 2013;62:A6-7. |
| 9. | Lennard L, Brown CB, Fox M, Maddocks JL. Azathioprine metabolism in kidney transplant recipients. Br J Clin Pharmac 1984;18:693-7. |
[Table 1] |
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