Printer Friendly

Side effects from the use of azathioprine in Crohn's disease: a systematic review.

INTRODUCTION

Crohn's disease (CD) is a disease of unknown cause, which creates inflammation to any point of the gastrointestinal tract wall, from the mouth all the way to the anus [1, 2].

However, the areas that are primarily affected are the small and large intestine and in particular the final section of the small intestine, the ileum, and the end portion of the colon, the rectum. The exact cause of CD remains a mystery. In the past, it was believed that diet and stress were the main causes of the disease. However, it is now known that although these factors can aggravate the disease, they aren't the main reason of cause. The latest surveys show that a number of factors, such as heredity and an abnormal functioning immune system may play a role in its development [1, 2].

The disease mainly affects people aged 1540 years and is equally found in both genders [3]. It is characterized by exacerbations and remissions, some of the symptoms in the phase of exacerbation are: A. Diarrhea; B. Abdominal pain and cramps; C. Blood in feces; D. Reduced appetite and weight loss; E. Hepatitis and cholangitis; F. Iridocyclitis; G. Arthritis; H. Fatigue; I. Dermatitis; J. Fever; K. Delayed development in children [3].

The drugs commonly used are corticosteroids, sulfasalazine and immunesuppressive drugs such as azathioprine (AZA). The goal of treatment is to reduce the inflammation of the intestine and other systems and organs that are probably affected by this systemic disease. The main aim is to bring remission and a symptomatic improvement of the patient. Surgical treatment is only used for severe complications of the CD [3, 4].

AZA, a medicine used for CD's treatment, is a chemical similar to that of purine. It competes with purine's metabolism and can inhibit the synthesis of DNA, RNA and proteins. It can also affect cellular metabolism and inhibit mitosis [5, 6].

The mechanism of its reaction is probably due to the incorporation of thiopurine in the structure of DNA, causing chain termination and cytotoxicity [5, 6].

AZA is not an active drug itself but is activated in the body. This happens in several steps. At first it is slowly and almost completely converted to 6-mercaptopourine (6-MP) by reductive cleavage of the thioether. This is mediated by glutathione and similar compounds in the intestinal wall, the liver and on red blood cells, without the aid of enzymes [7].

AZA is used to manage moderate, severe or chronic forms of the active disease and thus maintaining clinical remission. But the side effects that may result from it's treatment are numerous.

MATERIALS AND METHODS

For the construction of this study, the medical bibliography was searched using the electronic databases of PUBMED, GUT and ECCO, with the use of the following keywords: azathioprine in Crohn's disease, toxicity and side effects. In total, 85 primary studies were found. The criteria's of the articles chosen were:

* primary studies, reviews or meta-analyzes,

* available in full text,

* written in English,

* published in the period 1993-2016

* focused on humans.

Initially, a study of all the summaries of the articles was conducted in order to make a final choice. 75 articles from the searched bibliography were excluded and 10 were included, of which 9 were cohort studies and 1 was a systematic review.

RESULTS

Out of the 85 articles that appeared from the search, 28 were rejected after going through their titles and their summary, as they refer to the side effects of AZA in other diseases or to inflammatory diseases of the intestine in general and not specifically in CD. Moreover, 30 researches were excluded, after the examination of their full text, due to their lack of epidemiological and statistical data. Finally, 17 studies were not included for being descriptive reviews. Thus, the final research sample consisted of 10 articles.

During 2014, Guerra et al, published the results of a research, which took 9 years to complete at the university hospital of Spain Universitario de Fuenlabrada. In the cohort study conducted, 212 patients with CD were involved along with 57 patients with ulcerative colitis (UC) and 4 patients with indeterminate colitis, all of whom had been treated with AZA. 50% of the patients were men of an average age of 42, while the 40% of these were smokers. The indications for treatment with AZA were the following: 78% were dependent on Steroids, 10.8% were treating fistula created from CD, 4.8% for precaution after a bowel resection, 3% due to being irresponsive to steroids and 3.4% for other reasons. Treatment occurred 24 months after diagnosis of the disease and the average daily dose was 2.2mg/kg/ day. Side effects were observed in 43.6% of the patients, 91 with CD and 28 with ulcerative colitis (p=0.27). Due to having an intolerance to the drug, 58 patients discontinued the treatment with AZA. The most common side effects were: hepatotoxicity (11.7%), gastrointestinal intolerance (11.4%), myelotoxicity (7%), pyrexia (6.2%), acute pancreatitis (4.8%) and arthralgia/ myalgia (1.5%). The patients who discontinued the treatment with AZA, were treated with mercaptopurine. The results of this research showed that treatment with AZA proved efficient against idiopathic inflammatory diseases (IID), despite the side effects, which can be treated by replacing the drug with mercaptopurine [8].

During 2014, Estrada presented the results of a cohort study that was carried out in the hospital Vitoria-Alava in Spain. This study demonstrated the frequency of side effects and their type during treatment with AZA and also how the treatment was modified in order to deal with the side effects. The research included 198 patients of whom 50.5% were women, 43.4% with ulcerative colitis (5.8% proctitis, 43% with left colitis and 51.2% with pancolitis) and 56.6% with CD (ileitis 54%, 3% in the presence of the large intestine, 43% ileocolic disease). Side effects were observed in 42 patients of whom 54.7% were required to discontinue treatment with AZA. Side effects in patients with CD were as following [9]: dyspepsia (1 patient), cholestasis (4), hypertransaminasemia (2), acute pancreatitis (2), myelotoxicity (5), infections (3), alopecia (2). The results from the research indicated that the most common side effects were myelotoxicity (4.5%), hepatic abnormalities related to structural function (8%), indigestion (3%) and acute pancreatitis (2.5%). Cases of neoplasia or death were not found. They also concluded that therapy with AZA is effective against IID, despite the side effects, which can be treated by stopping this therapy or decreasing the dosage.

Dharmasiri et al. [10] during 2014, presented results from a cohort study, which took place at the Royal Bournemouth hospital in the United States. The goal of this research was to prove whether treatment with AZA was safe enough for elderly patients. There were 25 patients involved, 7 with CD and 18 with UC. The average age of the patients was 78 and 16 of the patients were male. All the patients were monitored for at least a year and 12 of the patients had an intolerance to AZA. The reasons for discontinuing treatment with AZA after 34 days of use were of the following: hepatitis (2 patients), vomiting (5), pancreatitis (1), myelosuppression (1), joint pain (1), infection (1), general malaise (1). At the same time, 13 patients tolerated the therapy and a group of these patients withdrew because the symptoms worsened. Furthermore, 4 deaths were noted, 2 in the group of patients that took AZA as part of their treatment and 2 in the group of patients that discontinued the treatment with AZA. Thus, it was shown from this research that treatment with AZA was effective with the elderly patients. However, intolerance to AZA was observed at a much higher level with the elderly than that of younger ages (48% intolerance in 3 months). It can be dealt with by decreasing the dosage of AZA or by administrating allopurinol together with AZA. But this has to be verified with further research [10].

Connell et al. conducted a cohort study at the St. Markos Hospital in London for 27 years, from 1964 to 1992 [11]. The aim of the study was to identify the side effects that treatment with AZA had on marrow bone. In this study 739 patients were involved, the average dosage of AZA given was 2 mg/kg/ day. 37 of the patients discontinued that therapy due to intolerance to the drug. Out of these patients 5 experienced symptoms and 32 were asymptomatic. The conclusion of this study was that myelotoxicity was unusual to occur when this drug was administrated in a controlled way even though it is dangerous [11].

During 2004, De Jong, Dj. et al. [12], worked on a cohort study at the University Hospital Medical Centre Nijimegen, in Holland. The purpose of this study was to assess the rate of side effects that lead to discontinuation of the therapy with the AZA drug and to define the prognostic factors lead to its termination. The results of 50 patients with CD who took the treatment were analyzed. Due to intolerance to AZA, 15 patients discontinued the therapy. At the start of the therapy, a small but significant decrease in white blood cells was observed within 6 weeks (From 10.6 to 9.5 * [10.sup.9]/l), while asymptomatic leucopenia (< 3.0 x [10.sup.9]/l) was noted in 2 patients. Moreover, 3 of the patients were hospitalized because of serious side effects. The condition was reversible as soon as the drug therapy stopped. The results of this study showed that 22% of the patients discontinued the therapy early due to the side effects it caused. These patients continued treatment with prednisolone, at low doses, which can be useful, if administrated together with AZA in order to prevent some of the side effects [12]..

Weersma et al. [13], during 2004 presented the result from a cohort study that took place in the University Hospital Groningen of Amsterdam in Holland. The aim of this study was to identify the side effects of the AZA therapy in the following diseases: Systemic lupus erythematosus, after liver and kidney transplant, Wegener Granulomatosis, autoimmune hepatitis, rheumatoid arthritis, UC and CD. 1564 patients took part in this study. 11 out of 224 patients that had CD showed signs of acute pancreatitis compared to 2/129 patients with autoimmune hepatitis, 2/388 after kidney transplant, 1/254 after liver transplant. Thus, acute pancreatitis was more prevalent in patients that suffered from CD. Discontinuation of treatment with AZA was followed after occurrence of toxicity: 73/317 patients with rheumatoid arthritis, 20/94 with ulcerative colitis, 52/224 with CD, 5/73 with SLE, 6/85 with Wegener granulomatosis, 8/129 with autoimmune hepatitis, 17/254 after liver transplantation and 22/388 following kidney transplantation. The main result of this research was that liver toxicity as a side effect of treatment with AZA occurs largely in CD compared to other diseases and discontinuation of the therapy is observed most often inflammatory bowel diseases (IBD) and rheumatoid arthritis [13].

Fraser et al. [14], during 2002 conducted a systematic review, taking data from the medical department of Auckland University in New Zealand. The purpose of this study was to show whether the long term use of AZA was associated with malignancy. The AZA was administered in 622 of 2204 patients (271 with CD and 355 with UC). The mean total duration of use of AZA was 27 months, the average time monitoring of the diagnosis of patients was 13.7 years and the mean follow-up time from the start of the treatment with azathioprine was 6.9 years. The data showed that 31 cancers were observed in 30 patients treated with AZA and 77 cancers in 70 patients not receiving. Moreover, 8 patients had lymphoma, of whom 3 were receiving AZA (p = NS). The main outcome of this study was that there was no increased risk for malignancy in patients treated with AZA, therefore, long term treatment with AZA does not associate with the development of malignancy [14].

Martinez et al. [15], during 2001, conducted a cohort study in the hospital La Fe of Valencia in Spain. The aim of the study was to determine the frequency and the type of side effects that come with the treatment with AZA in patients with IBD. They selected 70 patients, 55 with CD, 14 with ulcerative colitis and one patient with indeterminate colitis. There were 23 adverse events in 21 patients, who were blood related at a rate of 11.4%, digestive intolerance to 11.4%, inflammation in an amount of 7.1% and pancreatitis 2.8%. These side effects were observed at higher rates in patients with UC than with CD, with respective rates of 57.8% versus 21.8% (p=0.02). Specifically, the discomfort and pancreatitis occurred in the first half of the treatment of AZA and the hematological disorders were known within 3 months to 4 years from the start of treatment. The inflammation occurred within 8 months to 5 years from the start of the treatment [15].

Lopez-Martin et al. [16], during 2011, published a cohort study with data from the Spanish hospital Universitario de La Princesa in Madrid. The aim of the study was to determine the side effects caused by thiopurines namely AZA and 6MP to IBD. The survey included 377 patients diagnosed with the disease in 2008. 47% were male and 53% female with an average age of 43 years. 348 of these patients received AZA and 44 MP. 51 patients out of 377 experienced side effects, which are the following: myelotoxicity in 18 patients (incidence 16 months), acute pancreatitis in 10 patients [appeared in 27 days from the start of treatment with a statistically significant association with Crohn's disease (p=0.03) and smoking (p=0.01)], gastrointestinal intolerance in 10 patients, 9 patients with hepatotoxicity, hypersensitivity rash in 1 patient, bilateral deafness in 1 patient and a serious weakening in 1 patient. Discontinuation of therapy was performed in 84 patients. Also, there was a significant correlation between the incidence of side effects with CD (p=0.008). Therefore, they concluded that the thiopurines cause side effects in patients, which although relatively mild, are to be taken seriously [16].

Mazor et al. [17], published a cohort study, that was carried out in the hospital of Rambam Healthcare Campus of Haifa in Israel, in order to clarify the risk factors that increase the likelihood of a person with CD to develop side effects. Therefore, according to the article, the study included 176 patients with the above disease who were treated with thiopurines (45 patients with AZA and 131 with 6-MP). The factors considered in these patients were the specific genotypes GSTM1, GSTT1 and TPMT, age, ethnicity and smoking. The results showed that 24 patients developed side effects such as pancreatitis, myelosuppression and hepatotoxicity. The main risk factors seems to be smoking and GSTM1-null genotype for causing the side effects during treatment with thiopurines [17].

DISCUSSION

It is a fact that CD, is a chronic and idiopathic disease that accompanies the patient throughout his life from the moment it appears in his body. As mentioned before, there is no cure for the disease. AZA reduces both the symptoms of the disease and the possibility of surgery. However, there are doubts regarding its safety. A lot of side effects have been witnessed in significant levels in patients, with a prominent position given to hepatotoxicity, myelotoxicity and pancreatitis. If such complications are not immediately detected, they can be fatal to the patient's life.

During pregnancy, disease activity must be minimized. Most medications used to treat CD are considered low risk during pregnancy. AZA is a pregnancy category D drug. This means that there is evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks. Active disease poses more risk to the fetus than most CD's medications, so the benefits of treatment clearly outweigh the risks. Whatever medications helped maintain remission before pregnancy should be continued during pregnancy, except methotrexate or antibiotics. Vaginal delivery is recommended except in instances of active perianal disease or a history of fistulas. Breast-feeding should not be discouraged as most medications are considered safe [18]. According to remarkable surveys , use of AZA during pregnancy does not provoke preterm birth or teratogenicity [19,20].. Data has shown that 6-MP was undetectable in the neonatal blood [21].

AZA is well established for the maintenance of remission However, a significant proportion of patients are intolerant to AZA. It is not clear if this intolerance is a marker of poor prognosis for patients. AZA intolerance acts as a surrogate marker for patients with CD who in future have poorer symptom control. A few studies have indicated that mercaptopurine treat AZA's gastric intolerance in patients with IBD [22].

In conclusion, frequent rechecking are required during and even after therapy, so as to quickly perceive any negative changes. Further studies could be made regarding the combination of AZA with other drug for better results, as well as the relation between the dose of the drug and the side effects.

CONCLUSIONS

According to the results of the systematic review some conclusions can be generated regarding the nature of the side effects, as well as how frequently they appear. More specifically, hepatotoxicity is shown in six of the ten studies at a rate starting from 0.0022% and reaching up to 11.7%. Another equally as important side effect, myelotoxicity (as a generic term) is shown in six of the ten studies ranging from 0.01% to 7%. Then, leukopenia occurs at a rate from 0.03% to 0.8% and thrombocytopenia at 0.007%. Other blood disorders are presented at a rate of 11.7%. Furthermore, an equally important side effect is acute pancreatitis, which occurs in seven out of the ten studies with rates ranging from 2.5% to 4.9% and p-value <0.01. Also, symptoms associated with gastrointestinal intolerance occur at a rate ranging from 4% up to 11.4%. Specifically, dyspepsia corresponds to 3% of the total rate, nausea to 0.009%, diarrhea to 0.004%, vomiting from 0.009% to 10% and abdominal pain equal to 0.02%. Moreover, we observe that fever has a significant percentage that corresponds to 6.2%, arthralgia from 0.03% to 4%, while general malaise receives a rate starting from 0.01% up to 4%. In addition, generalized infection was observed without further definition, at a rate of 0.03% to 7.1%. Finally, pruritus as a symptom, corresponding to a small percentage of 0.01%.

Flowchart containing the method of reference selection:

* Total articles obtained after searching keywords (n = 85)

* Total studies that were excluded because of descriptive reviews (n = 17)

* Total studies that were rejected after reading the title and summary, and did not meet the criteria (n = 28)

* Total studies that were excluded after reading this entire article, due to lack of demographic and statistical data (n = 30)

The following table lists the characteristics of the studies included in the systematic review.

All 10 studies are then analyzed extensively so that, during the process, they can be compared to each other and to export the results.
                                           Country      Period
                               Type          of           of
    Author/Year/Title        of Study      conduct     conduct

Effectiveness and           Cohort       Spain         June
adverse events of           Study                      2004 -
azathioprine in                                        May
inflammatory bowel                                     2013
disease:
9-year follow-up
study

Guerra et al, 2014

Adverse effects of          Cohort       Spain         2014
azathioprine in             Study
patients with
inflammatory bowel
disease (IBD)

Estrada et al, 2014

Azathioprine in the         Cohort       United        June
elderly--Is it              Study        Kingdom       2005-
tolerated and is it                                    October
safe?                                                  2012

Dharmasiri et al,
2014

Bone marrow toxicity        Cohort       United        1964-
caused by                   Study        States        1991
azathioprine in
inflammatory bowel
disease: 27 years of
experience.

W R Connell,
M A Kamm,
J K Ritchie,
J E Lennard-Jones
1993

Side effects of             Cohort       The           2004
azathioprine in             Study        Netherlands
patients with Crohn's
disease

de Jong J, Goullet
M, Naber TH.
2004

Increased incidence         Cohort       The           1995-
of azathioprine-            Study        Netherlands   2002
induced pancreatitis
in Crohn's disease
compared with other
diseases

R. K. Weersma et al,
2004

Long-term risk of           Systematic   New           2002
malignancy after            review       Zealand
treatment of
inflammatory bowel
disease with
azathioprine

A. G. Fraser et al,
2002

Adverse effects of          Cohort       Spain         2001
azathioprine in the         study
treatment of
inflammatory bowel
disease

Martinez et al,
2001

Adverse events of           Cohort       Spain         2008
thiopurine                  study
immunomodulators
in patients with
inflammatory bowel
disease.
Lopez-Martin et al,
2011

Risk factors for            Cohort       Israel        2013
serious adverse             Study
effects of thiopurines
in patients with
Crohn's disease.
Mazor Y et al, 2013

    Author/Year/Title          Participants

Effectiveness and           Hospital
adverse events of           Universitario
azathioprine in             de Fuenlabrada
inflammatory bowel
disease:                    50% men
9-year follow-up
study                       40% smokers

Guerra et al, 2014          Average age 42
                            years.

Adverse effects of          Hospital in
azathioprine in             Vitoria-Alava,
patients with               Spain
inflammatory bowel
disease (IBD)               50,5% women

Estrada et al, 2014

Azathioprine in the         Royal
elderly--Is it              Bournemouth
tolerated and is it         Hospital,
safe?                       Department of
                            Gastro enterology
Dharmasiri et al,           United Kingdom
2014                        Average age 78
                            years.

                            16 were men.

                            Patients were
                            observed for at
                            least 1 year.

Bone marrow toxicity        St Mark's
caused by                   Hospital, London
azathioprine in
inflammatory bowel
disease: 27 years of
experience.

W R Connell,
M A Kamm,
J K Ritchie,
J E Lennard-Jones
1993

Side effects of             Department of
azathioprine in             Gastro enterology
patients with Crohn's       and Hepatology,
disease                     University
                            Medical Centre
de Jong J, Goullet          Nijmegen, The
M, Naber TH.                Netherlands
2004

Increased incidence         Information
of azathioprine-            System of the
induced pancreatitis        university
in Crohn's disease          hospital
compared with other         Groningen,
diseases                    Amsterdam
                            1564 patients
R. K. Weersma et al,        received AZA
2004                        due to: Lupus
                            erythematosus,
                            rheumatoid
                            arthritis,
                            Wegener
                            Granulomatosis,
                            autoimmune
                            hepatitis, Crohn's
                            disease,
                            ulcerative colitis,
                            kidney
                            transplantation
                            or liver
                            transplantation.

Long-term risk of           University of
malignancy after            Auckland, New
treatment of                Zealand Mean
inflammatory bowel          follow-up of
disease with                patients: 13.5
azathioprine                The mean
                            follow-up since
A. G. Fraser et al,         the start of the
2002                        treatment with
                            AZA was 6.9
                            years. The mean
                            total duration of
                            therapy was 27.1
                            months.

Adverse effects of          Hospital La Fe,
azathioprine in the         Valencia
treatment of
inflammatory bowel
disease

Martinez et al,
2001

Adverse events of           Hospital
thiopurine                  Universitario de
immunomodulators            La Princesa
in patients with            Madrid
inflammatory bowel          377 patients
disease.                    47% men
Lopez-Martin et al,         53% women
2011                        Average age: 43
                            Average daily
                            dose:
                            2.5mg/kg/day.

Risk factors for            Rambam Health
serious adverse             Care Campus,
effects of thiopurines      Haifa, Israel
in patients with
Crohn's disease.
Mazor Y et al, 2013

    Author/Year/Title              Identifier

Effectiveness and           212 patients with
adverse events of           Crohn's Disease (CD).
azathioprine in             57 patients with UC
inflammatory bowel          (Ulcerative Colitis)
disease:                    4 patients with
9-year follow-up            indeterminate colitis.
study

Guerra et al, 2014

Adverse effects of          198 patients. 43.4% with
azathioprine in             ulcerative colitis
patients with               (5.8% proctitis,
inflammatory bowel          43% left colitis
disease (IBD)               and
                            51.2% pancolitis),
Estrada et al, 2014         56.6% with CD (54%
                            ileitis,
                            43% ileocolonic disease,
                            3% colonic presentation)

Azathioprine in the         25 patients were
elderly--Is it              included,
tolerated and is it         (7 with Crohn's disease,
safe?                       18 with Ulcerative
                            colitis)
Dharmasiri et al,
2014

Bone marrow toxicity        739 patients took part in
caused by                   the study
azathioprine in             (422 with CD,
inflammatory bowel          284 with UC,
disease: 27 years of        33 with colitis
experience.                 indeterminate)
                            Average dose:
W R Connell,                2mg/kg/day
M A Kamm,                   From the 422,
J K Ritchie,                218 were women
J E Lennard-Jones           and 204 were men.
1993

Side effects of             112 patients with
azathioprine in             Crohn's Disease.
patients with Crohn's       50 of them,
disease                     who were under
                            treatment with AZA,
de Jong J, Goullet          were included in the
M, Naber TH.                study.
2004

Increased incidence         224 patients were
of azathioprine-            afflicted with Crohn's
induced pancreatitis        Disease.
in Crohn's disease          The average dose of
compared with other         AZA to those patients
diseases                    was 123 mg/day (1,75
                            mg/kg)
R. K. Weersma et al,        Men 79
2004                        Women 145
                            Average Age: 39 years

Long-term risk of           626 patients took part in
malignancy after            the study who received
treatment of                treatment with AZA.
inflammatory bowel          (271 with Crohn's
disease with                Disease and 355 with
azathioprine                Ulcerative colitis).

A. G. Fraser et al,
2002

Adverse effects of          70 patients were studied,
azathioprine in the         from who 55 were
treatment of                afflicted with Crohn's
inflammatory bowel          Disease and 14 with
disease                     Ulcerative colitis, while
                            there is also a chance of
Martinez et al,             indeterminate colitis.
2001

Adverse events of           377 patients under
thiopurine                  treatment with AZA
immunomodulators            (55% CD and 42% UC
in patients with            and 3% indeterminate
inflammatory bowel          colitis.)
disease.
Lopez-Martin et al,
2011

Risk factors for            176 patients with CD.
serious adverse             (45 with AZA and 131
effects of thiopurines      with 6MP.)
in patients with
Crohn's disease.
Mazor Y et al, 2013

    Author/Year/Title                  Results

Effectiveness and           Side effects were
adverse events of           observed in 43.6%
azathioprine in             (95%CI37-50%) of
inflammatory bowel          patients. 91 (42.9%) with
disease:                    CD, 28 (49.1%) with UC
9-year follow-up            (p=0.27)
study                       Hepatotoxicity: 11.7%

Guerra et al, 2014          Gastrointestinal
                            Intolerance: 11.4%
                            Myelotoxicity: 7%
                            Fever: 6.2%
                            Acute Pancreatitis: 4.8%

                            Arthralgia/Myalgia: 1.5%

Adverse effects of          21,2% of patients
azathioprine in             showed side effects.
patients with               The most common side
inflammatory bowel          effects were:
disease (IBD)               abnormal liver function
                            tests (8%),
Estrada et al, 2014         myelotoxicity (4,5%),
                            indigestion (3%),
                            acute pancreatitis
                            (2,5%).

Azathioprine in the         12 patients showed
elderly--Is it              intolerance to AZA.
tolerated and is it         Treatment was
safe?                       discontinued due to the
                            following side effects:
Dharmasiri et al,           hepatitis 8%,
2014                        vomiting 10%,
                            pancreatitis 4%,
                            myelosupression 4%,
                            pain in joints 4%,
                            infection 4%,
                            general hardship at 4%.
                            4 deaths were noted.
                            13 patients continued the
                            treatment and clinical
                            achieved and recession
                            gastrointestinal.

Bone marrow toxicity        16/422 showed signs of
caused by                   leukopenia
azathioprine in             (5 were men and 11 were
inflammatory bowel          women) during the first
disease: 27 years of        36 months since the start
experience.                 of treatment with AZA.
                            (0.03%)
W R Connell,                3/422 showed signs of
M A Kamm,                   thrombocytopenia (all 3
J K Ritchie,                were men) during the
J E Lennard-Jones           first 38 months since the
1993                        start of treatment with
                            AZA. (0.007%)

Side effects of             15/50 patients
azathioprine in             discontinued treatment
patients with Crohn's       with AZA due to side
disease                     effects.
                            A decrease in the number
de Jong J, Goullet          of white blood cells was
M, Naber TH.                noted in 6 weeks time
2004                        (median 10.6  [+ or -]
                            95 109/l), while asymptomatic
                            leukopenia (<3.0 109/l)
                            appeared in 2 patients.

Increased incidence         11/224 patients with
of azathioprine-            Crohn's Disease
induced pancreatitis        developed acute
in Crohn's disease          pancreatitis (4,9%)
compared with other         Other side effects:
diseases                    20/24 patients developed
                            nausea and vomiting.
R. K. Weersma et al,        6/224 developed
2004                        abdominal pain.
                            1/224 developed
                            diarrhea.
                            5/224 developed fever.
                            3/224 develo-ped
                            pruritus.
                            5/224 developed
                            hepatitis.
                            4 patients out of 224
                            developed
                            myelosupression,
                            while 8 of them
                            arthralgia.
                            3 patients out of 224
                            developed general
                            weakness.

Long-term risk of           31 cases of cancer were
malignancy after            noted in 30 patients who
treatment of                were treated with AZA
inflammatory bowel          and 77 cases of cancer
disease with                were noted in 70 patients
azathioprine                who were not treated
                            with AZA.
A. G. Fraser et al,         8 patients under
2002                        treatment with AZA had
                            lymphoma.
                            Thus proving that
                            treatment with AZA is
                            neither associated with
                            increase in cancer cases
                            (p=0.2), nor with the
                            appearance of specific
                            types of cancer:
                            colorectal (p=0.8),
                            bronchial (p=0.2),breast
                            (p=0.5) and lymphoma
                            (P=0,5).

Adverse effects of          23 types of side effects
azathioprine in the         were noted in 21 patients.
treatment of                Hematological 11.4%
inflammatory bowel          Intolerance of the
disease                     digestive system 11.4%
                            Infection 7.1%
Martinez et al,             Pancreatitis 2.8%
2001                        9 patients (12.8%)
                            discontinued the
                            treatment due to severe
                            intolerance.

Adverse events of           51 patients out of 377
thiopurine                  developed side effects.
immunomodulators            18 patients developed
in patients with            myelotoxicity (4.8%)
inflammatory bowel          15 patients developed
disease.                    gastrointestinal
Lopez-Martin et al,         intolerance (4%)
2011                        10 patients developed
                            acute pancreatitis
                            (2.7%).
                            Secondary liver toxicity
                            was developed in a
                            percentage of 2.4%.
                            From the 51 patients,
                            84% discontinued the
                            treatment with AZA.

Risk factors for            24 patients developed
serious adverse             side effects. Most
effects of thiopurines      important side effects:
in patients with            myelosuppression,
Crohn's disease.            hepatotoxicity and
Mazor Y et al, 2013         pancreatitis.

    Author/Year/Title           Confounders

Effectiveness and           Ulcerative colitis,
adverse events of           Mercaptopurine,
azathioprine in             Methyltransferase
inflammatory bowel          levels
disease:
9-year follow-up
study

Guerra et al, 2014

Adverse effects of          Ulcerative colitis
azathioprine in
patients with
inflammatory bowel
disease (IBD)

Estrada et al, 2014

Azathioprine in the         Ulcerative colitis
elderly--Is it              Methyltransferase
tolerated and is it
safe?

Dharmasiri et al,
2014

Bone marrow toxicity        Ulcerative colitis
caused by
azathioprine in
inflammatory bowel
disease: 27 years of
experience.

W R Connell,
M A Kamm,
J K Ritchie,
J E Lennard-Jones
1993

Side effects of             Prednisone 5-
azathioprine in             aminosalicylates
patients with Crohn's
disease

de Jong J, Goullet
M, Naber TH.
2004

Increased incidence         Lupus
of azathioprine-            erythematosus,
induced pancreatitis        rheumatoid
in Crohn's disease          arthritis, Wegener
compared with other         Granulomatosis,
diseases                    autoimmune
                            hepatitis, Crohn's
R. K. Weersma et al,        disease,
2004                        ulcerative colitis,
                            kidney
                            transplantation or
                            liver
                            transplantation

Long-term risk of           Ulcerative colitis
malignancy after
treatment of
inflammatory bowel
disease with
azathioprine

A. G. Fraser et al,
2002

Adverse effects of          Ulcerative colitis
azathioprine in the         6-mercaptopurine
treatment of
inflammatory bowel
disease

Martinez et al,
2001

Adverse events of           6-mercaptopurine
thiopurine                  Smoking
immunomodulators
in patients with
inflammatory bowel
disease.
Lopez-Martin et al,
2011

Risk factors for            Genotypes
serious adverse             Age
effects of thiopurines      Smoking
in patients with            Ulcerative colitis
Crohn's disease.
Mazor Y et al, 2013


Conflicts of interest

The authors declare that they have no conflicts interests.

REFERENCES

[1.] Ccfa. What is Crohn's Disease? 2016 [cited 2016 Apr 4]. Available from: http://www.ccfa.org/what-are-crohns-and-colitis/what-is-crohns-disease/.

[2.] Torres J, Boyapati RK, Kennedy NA, Louis E,

Colombel JF, Satsangi J. Systematic Review of Effects of Withdrawal of Immunomodulators or Biologic Agents From Patients With Inflammatory Bowel Disease. Gastroenterology. 2015 Dec;149(7):1716-30.

[3.] Park JR, Pfeil SA. Primary Care of the Patient with Inflammatory Bowel Disease. Med Clin North Am. 2015 Sep;99(5):969-87

[4.] Lee JL, Yu CS, Lim SB, Park IJ, Yoon YS, Kim CW, Yang SK, Kim JC. Surgical Treatment of Crohn Colitis Involving More Than 2 Colonic Segments: Long-Term Outcomes From a Single Institution. Medicine (Baltimore). 2016 May;95(22):e3793.

[5.] Nielsen OH, Coskun M, Steenholdt C, Rogler G. The role and advances of immunomodulator therapy for inflammatory bowel disease. Expert Rev Gastroenterol Hepatol. 2015 Feb;9(2):177-89

[6.] Maltzman JS, Koretzky GA. Azathioprine: old drug, new actions. J Clin Invest. 2003 Apr; 111(8):1122-4.

[7.] Neurath M. Thiopurines in IBD: What Is Their Mechanism of Action? Gastroenterol Hepatol (N Y). 2010 Jul;6(7):435-6.

[8.] Guerra I, Algaba A, Serrano A, Aullo C, Daniel Alcalde D, de Lucas M, Bonillo D, Zapatero A, Bermejo F. Effectiveness and adverse events of azathioprine in inflammatory bowel disease: 9-year follow-up study. Ecco. 2014;p 504.

[9.] Ramirez de la Piscina P ea. Adverse effects of azathioprine in patients with inflammatory bowel disease (IBD). Ecco. 2014;p 577.

[10.] Dharmasiri HJ, McLaughlin S, Weaver S. Azathioprine In The Elderly--Is It Tolerated And Is It Safe? Gut. 2014;63(A87):183.

[11.] 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(8):1081-5.

[12.] de Jong DJ, Goullet M, Naber TH. Side effects of azathioprine in patients with Crohn's disease. Eur J Gastroenterol Hepatol. 2004 Feb; 16 (2):207-12.

[13.] Weersma RK, Peters FT, Oostenbrug LE, van den Berg AP, van Haastert M, Ploeg RJ, Posthumus MD, Homan van der Heide JJ, Jansen PL, van Dullemen HM. Increased incidence of azathioprine-induced pancreatitis in Crohn's disease compared with other diseases. Aliment Pharmacol Ther. 2004 Oct 15;20(8): 843-50.

[14.] Fraser AG, Orchard TR, Robinson EM, Jewell DP. Long-term risk of malignancy after treatment of inflammatory bowel disease with azathioprine. Aliment Pharmacol Ther. 2002 Jul;16(7):1225-32.

[15.] Martinez F, Nos P, Pastor M, Garrigues V, Ponce J. Adverse effects of azathioprine in the treatment of inflammatory bowel disease. Revista espanola de enfermedades digestivas: organo oficial de la Sociedad Espanola de Patologia Digestiva. 2001;93(12):769-78.

[16.] Lopez-Martin C, Chaparro M, Espinosa L, Bejerano A, Mate J, Gisbert JP. Adverse events of thiopurine immunomodulators in patients with inflammatory bowel disease. Gastroenterologia y hepatologia. 2011;346):385-92.

[17.] Mazor Y, Koifman E, Elkin H, Chowers Y, Krivoy N, Karban A, Efrati E. Risk factors for serious adverse effects of thiopurines in patients with Crohn's disease. Curr Drug Saf. 2013 Jul;8 (3):181-5.

[18.] Austin J, Vaccaro A. Pregnancy, Crohn's Disease and Azathioprine: A Case Study and Literature Review. Aust Nurs Midwifery J. 2016 Apr; 23(9):28-31.

[19.] Sau A, Clarke S, Bass J, Kaiser A, Marinaki A, Nelson-Piercy C. Azathioprine and breastfeeding: is it safe? BJOG. 2007 Apr;114(4):498501.

[20.] Shim L, Eslick GD, Simring AA, Murray H, Weltman MD. The effects of azathioprine on birth outcomes in women with inflammatory bowel disease (IBD). J Crohns Colitis. 2011 Jun;5(3):234-8

[21.] Christensen LA, Dahlerup JF, Nielsen MJ, Fallingborg JF, Schmiegelow K. Azathio-prine treatment during lactation. Aliment Pharmacol Ther. 2008 Nov 15;28(10):1209-13.

[22.] Actis GC, Pellicano R, Rosina F. 6Mercaptopurine for Azathioprine Intolerant Inflammatory Bowel Disease: Literature Search and Reappraisal of Own Data. Inflamm Allergy Drug Targets. 2015;14(2):133-7.

Loutas Th. (1 A-D) *, Moutou A. (2 A-E), Theodosopoulou E. (3 AE-F)

(1.) Naval Hospital of Athens, Greece

(2.) General Hospital of Athens, Greece

(3.) University of Athens, Faculty of Nursing, Greece

(A)--Conception and study design, (B)--Data collection, (C) -Data analysis, (D)--Writing the paper, (E)--Review article, F--Approval of the final version of the article

* Corresponding author:

Loutas Theodoros

Naval Hospital of Athens, Greece

e-mail: theodorosloutas@hotmail.com

Received: 28.04.2016

Accepted: 12.06.2016
COPYRIGHT 2016 Medical University of Bialystok
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2016 Gale, Cengage Learning. All rights reserved.

Article Details
Printer friendly Cite/link Email Feedback
Author:Theodoros, Loutas; Moutou, A.; Theodosopoulou, E.
Publication:Progress in Health Sciences
Article Type:Report
Date:Jun 1, 2016
Words:5787
Previous Article:Mobile phone owners' health behaviors.
Next Article:Conscientious objection and European vision of human rights.
Topics:

Terms of use | Privacy policy | Copyright © 2019 Farlex, Inc. | Feedback | For webmasters