Association of TPMT and NUDT15 gene polymorphisms with azathioprine-induced leukopenia: A case-control study in Eastern India.

BACKGROUND: Azathioprine (AZA) is a widely used immunosuppressant drug. Leukopenia is a serious adverse effect of the drug which often necessitates dose reduction or drug withdrawal. Predictors of leukopenia include genetic and nongenetic factors. Genetic polymorphism of AZA-metabolizing enzyme, thiopurine S-methyltransferase (TPMT) is well established. There is inconclusive evidence about the role of Nudix hydrolase (NUDT15) gene polymorphism. This case-control study assessed the association of genetic polymorphisms of NUDT15 and TPMT with leukopenia induced by AZA. MATERIALS AND METHODS: Cases were patients on AZA who developed leukopenia (white blood cell count <4000/µl) within 1 year of treatment initiation that necessitated dose reduction or drug withdrawal. Age and gender-matched patients without leukopenia within 1 year of treatment with AZA served as controls. TPMT (3 loci: c238G to C, c460G to A, c719A to G) and NUDT15 (c 415C to T, rs116855232) genotyping were done using TPMT strip assay and polymerase chain reaction-restriction fragment length polymorphism, respectively. Genotype frequencies were noted, and the odds ratio was calculated to determine the association between genotypes and leukopenia. RESULTS: Twenty-nine subjects (15 cases and 14 controls) were enrolled. Statistically significant differences were not observed in the TPMT genotype (*1/*1 and *1/*3C) (P = 0.23) between cases and controls. NUDT15 genotypes (*1/*1 and *1/*3) (P = 0.65) also showed no statistically significant difference between cases and controls. CONCLUSION: The above genotypes do not appear to be associated with AZA-induced leukopenia in an eastern Indian population.

Comparison of efficacy and safety of tofacitinib and azathioprine in patients with alopecia areata and variants: a double-blind, randomized controlled trial.

BACKGROUND: Alopecia areata (AA) is an autoimmune pathology manifested by loss of hair. OBJECTIVE: To evaluate and compare the efficacy and safety of tofacitinib and azathioprine in patients with AA and variants. METHODS: In this double-blind randomized controlled trail (RCT) carried out at the Department of Dermatology, Medical Teaching Institute-Lady Reading Hospital (MTI-LRH), Peshawar, Pakistan, patients aged ≥ 12 years diagnosed with AA, alopecia totalis (AT) or alopecia universalis (AU) with minimum 50% scalp hair loss for a period ≥ 06 years were included. Patients were randomly assigned to receive oral tofacitinib 5 mg twice daily (Group I) or oral azathioprine 2 mg/kg body weight once daily (Group II). The primary endpoint was Severity of Alopecia Tool (SALT) score, evaluated at baseline and 06 months follow-up. Safety was consistently assessed during the study. RESULTS: A total of 104 patients underwent random allocation into either the tofacitinib group (n = 52) or the azathioprine group (n = 52). The mean (SD) age of patients was 20.23 (7.14) years and 22.26 (8.07) years, while the mean (SD) disease duration was 6.59 (4.01) years and 7.98 (4.40) years in in Group I and II, respectively. Overall, 40 (38.5%) patients were adolescents while 70 (67.3%) were male. 52 (50%) had AA, 37 (35.5%) had AT and 15 (14.5%) had AU. Mean baseline SALT score in tofacitinib group was 91.02 ± 10.21 and azathioprine group was 91.02 ± 10.63, which at 06 months follow-up improved to 14.1 ± 24.6 and 63.9 ± 33.9, respectively (difference, 11.5 points; 95% confidence interval, 38.3-61.3, p < 0.0001). Overall, no major adverse effects and no difference among the minor adverse effects in the two groups (04 adverse events for tofacitinib group and 08 for azathioprine group: p = 0.23) was observed. CONCLUSIONS: Efficacy of tofacitinib was significantly higher than azathioprine, whilst both drugs were well-tolerated in patients with AA and variants.

Predictive role of ITPA genetic variants in thiopurine-related myelotoxicity in Crohn's disease patients.

Thiopurines, an effective therapy for Crohn's disease (CD), often lead to adverse events (AEs). Gene polymorphisms affecting thiopurine metabolism may predict AEs. This retrospective study in CD patients (n = 114) with TPMT activity > 5 Units/Red Blood Cells analyzed TPMT (c.238 G > C, c.460 G > A, c.719 A > G), ITPA (c.94 C > A, IVS2 + 21 A > C), and NUDT15 (c.415 C > T) polymorphisms. All patients received azathioprine (median dose 2.2 mg/kg) with 41.2% experiencing AEs, mainly myelotoxicity (28.1%). No NUDT15 polymorphisms were found, 7% had TPMT, and 31.6% had ITPA polymorphisms. AEs led to therapy modifications in 41.2% of patients. Multivariate analysis identified advanced age (OR 1.046, p = 0.007) and ITPA IVS2 + 21 A > C (OR 3.622, p = 0.015) as independent predictors of AEs. IVS2 + 21 A > C was also associated with myelotoxicity (OR 2.863, p = 0.021). These findings suggest that ITPA IVS2 + 21 A > C polymorphism and advanced age predict AEs during thiopurine therapy for CD with intermediate-normal TPMT activity.

Filgrastim Use in the Treatment of Azathioprine-Induced Myelosuppression Toxicity After Prescription Error in the Feline.

Only one report on the successful use of filgrastim (granulocyte colony-stimulating factor) in cats for severe neutropenia following azathioprine toxicity exists. Here, we report on a case in which a cat was prescribed methimazole but the medication was filled incorrectly with azathioprine tablets and the prescription label indicated a methimazole dosing regimen that was administered for three days before recognition of the error. On presentation, the cat's physical examinations were consistent with previous examinations before ingestion of azathioprine. A complete blood cell count revealed neutropenia and leukopenia. The cat later developed hyporexia, dehydration, and vomiting. Treatment included antinausea and appetite stimulant medications, filgrastim, and antibiotics. Filgrastim given as subcutaneous injections over the course of treatment increased neutrophil cell counts after suppression. The cat made a full recovery after responding to the treatment protocol. Based on the perceived response to filgrastim in this single feline case report, its use can be considered for the treatment of azathioprine-induced neutropenia in cats.

Real-world NUDT15 genotyping and thiopurine treatment optimization in inflammatory bowel disease: a multicenter study.

BACKGROUND: This study evaluated the effectiveness of NUDT15 codon 139 genotyping in optimizing thiopurine treatment for inflammatory bowel disease (IBD) in Japan, using real-world data, and aimed to establish genotype-based treatment strategies. METHODS: A retrospective analysis of 4628 IBD patients who underwent NUDT15 codon 139 genotyping was conducted. This study assessed the purpose of the genotyping test and subsequent prescriptions following the obtained results. Outcomes were compared between the Genotyping group (thiopurine with genotyping test) and Non-genotyping group (thiopurine without genotyping test). Risk factors for adverse events (AEs) were analyzed by genotype and prior genotyping status. RESULTS: Genotyping test for medical purposes showed no significant difference in thiopurine induction rates between Arg/Arg and Arg/Cys genotypes, but nine Arg/Cys patients opted out of thiopurine treatment. In the Genotyping group, Arg/Arg patients received higher initial doses than the Non-genotyping group, while Arg/Cys patients received lower ones (median 25 mg/day). Fewer AEs occurred in the Genotyping group because of their lower incidence in Arg/Cys cases. Starting with < 25 mg/day of AZA reduced AEs in Arg/Cys patients, while Arg/Arg patients had better retention rates when maintaining ≥ 75 mg AZA. Nausea and liver injury correlated with thiopurine formulation but not dosage. pH-dependent mesalamine reduced leukopenia risk in mesalamine users. CONCLUSIONS: NUDT15 codon 139 genotyping effectively reduces thiopurine-induced AEs and improves treatment retention rates in IBD patients after genotype-based dose adjustments. This study provides data-driven treatment strategies based on genotype and identifies risk factors for specific AEs, contributing to a refined thiopurine treatment approach.

Mycophenolate and methotrexate are better tolerated than azathioprine in myasthenia gravis.

Azathioprine is recommended as the first-line steroid-sparing immunosuppressive agent for myasthenia gravis. Mycophenolate and methotrexate are often considered as second-line choices despite widespread consensus on their efficacy. We aimed to gather real-world data comparing the tolerability and reasons for discontinuation for these agents, by performing a national United Kingdom survey of side effects and reasons for discontinuation of immunosuppressants in myasthenia gravis. Of 235 patients, 166 had taken azathioprine, 102 mycophenolate, and 40 methotrexate. The most common side effects for each agent were liver dysfunction for azathioprine (23 %), diarrhoea for mycophenolate (14 %), and fatigue for methotrexate (18 %). Women were generally more likely to experience side effects of immunosuppressants. Azathioprine was significantly more likely to be discontinued than mycophenolate and methotrexate due to side effects. There was no significant difference in treatment cessation due to lack of efficacy. This study highlights the significant side-effect burden of treatment for myasthenia gravis. Mechanisms to reduce azathioprine toxicity should be utilised, however mycophenolate and methotrexate appear to be good treatment choices if teratogenicity is not a concern. Women are disadvantaged due to higher frequency of side effects and considerations around pregnancy and breastfeeding. Treatments with improved tolerability are needed.

Comparative effectiveness of azathioprine and mycophenolate mofetil for myasthenia gravis (PROMISE-MG): a prospective cohort study.

BACKGROUND: Myasthenia gravis is an autoimmune disorder of the neuromuscular junction. Treatment typically includes symptomatic oral cholinesterase inhibitors, immunosuppression, and immunomodulation. In addition to corticosteroids, azathioprine and mycophenolate mofetil are the most frequently used immunosuppressants in North America. We aimed to evaluate the comparative effectiveness of these two drugs, and to assess the effect of the dose and duration of treatment. METHODS: We did a prospective cohort study at 19 academic centres in Canada and the USA. We included patients (aged ≥18 years) with autoimmune myasthenia gravis, who were never treated with immunosuppressants. Treating clinicians determined the choice of medication, dose, follow-up intervals, and drug monitoring. Outcome measures and adverse events were recorded at each visit. We assessed two co-primary outcomes. The first was the patient-reported Myasthenia Gravis-Quality of Life 15-revised (MGQOL-15r) score, measured as the mean change from treatment initiation to the follow-up visit with the lowest score. A clinically meaningful reduction (CMR) in MGQOL-15r was defined as a 5-point decrease. The second was a composite clinical outcome of disease improvement (Myasthenia Gravis Foundation of America Post-Intervention Status Minimal Manifestations or better) and low adverse event burden (defined as grade ≤1 Common Terminology Criteria for Adverse Events). We also compared these outcomes in patients receiving an adequate dose and duration of azathioprine (≥2 mg/kg per day for at least 12 months) or mycophenolate mofetil (≥2 g per day for at least 8 months) and a lower dose or shorter duration of these agents. We used propensity score weighting with generalised linear regression models. This study is registered with ClinicalTrials.gov (NCT03490539). FINDINGS: Between May 1, 2018, and Aug 31, 2020, 167 patients were enrolled; 85 did not receive azathioprine or mycophenolate mofetil and were excluded. Four were excluded from outcome analyses because they had scores of 0 on an outcome measure at treatment initiation. Of the 78 patients included in analyses, 47 received mycophenolate mofetil (median follow-up 25 months [IQR 13·5-31·5]) and 31 received azathioprine (median follow-up 20 months [IQR 13-30]). The mean change in MG-QOL15r was -10·4 (95% CI -18·9 to -1·3) with mycophenolate mofetil and -6·8 (-17·2 to 3·6) with azathioprine (mean difference -3·3, 95% CI -7·7 to 1·2; p=0·15). 38 (81%) of 47 patients receiving mycophenolate mofetil and 18 (57%) of 31 receiving azathioprine had a CMR in MG-QOL15r (risk difference 24·0%; 95% CI -0·2 to 48·0; p=0·052). The clinical composite outcome was achieved in 22 (47·7%) of 47 patients who received mycophenolate mofetil and nine (28·1%) of 31 who received azathioprine (risk difference 19·6%, 95% CI -4·9 to 44·2; p=0·12). Descriptive analysis did not find a difference in the proportion of patients reaching a CMR in MG-QOL15r between the adequate dose and duration group and the lower dose or shorter duration group. Adverse events occurred in 11 (32%) of 34 patients who received azathioprine and nine (19%) of 48 who received mycophenolate mofetil. The most frequent adverse events were hepatotoxicity with azathioprine (five [15%] of 34) and gastrointestinal disturbances (seven [15%] of 48) with mycophenolate mofetil. There were no study-related deaths. INTERPRETATION: More than half of patients treated with azathioprine and mycophenolate mofetil felt their quality of life improved; no difference in clinical outcomes was noted between the two drugs. Adverse events associated with azathioprine were potentially more serious than those with mycophenolate mofetil, although mycophenolate mofetil is teratogenic. Lower than recommended doses of azathioprine might be effective, with reduced dose-dependent adverse events. More comparative effectiveness studies are required to inform treatment choices in myasthenia gravis. FUNDING: Patient-Centered Outcomes Research Institute, Myasthenia Gravis Foundation of America.

Thiopurine Metabolite Shunting in Late Pregnancy Increases the Risk of Intrahepatic Cholestasis of Pregnancy in Women With Inflammatory Bowel Disease, and Can be Managed With Split Dosing.

BACKGROUND AND AIMS: The risk of intrahepatic cholestasis of pregnancy [ICP] is increased in thiopurine-exposed pregnancies. Thiopurine 'shunting', with a 6-methylmercaptopurine [MMP] to 6-thioguanine [TGN] ratio of >11, progresses over pregnancy, and may promote ICP development. We aimed to explore the association between thiopurine exposure and ICP, including the hypothesised impact of thiopurine shunting, and identify risk minimisation strategies. METHODS: This prospective multicentre cohort study compared thiopurine and biologic monotherapy-exposed pregnant participants. Disease activity and obstetric outcome data, thiopurine metabolites, bile acids, and transaminases were obtained before conception, in each trimester, at delivery, and postpartum. Thiopurine dose management was at the discretion of the treating physician. RESULTS: Included were 131 thiopurine and 147 biologic monotherapy-exposed pregnancies. MMP/TGN ratio increased from preconception to third trimester [p <0.01], with approximately 25% of participants shunting in pregnancy. Second trimester split dosing led to a decrease in the median MMP/TGN ratio from 18 (interquartile range [IQR] 6-57) to 3 [IQR 2-3.5] at delivery [p = 0.04]. The risk of ICP was increased in thiopurine-exposed pregnancies (6.7% [7/105] vs 0% [0/112], p <0.001), with all ICP cases occurring in the setting of antenatal thiopurine shunting. Thiopurine dose increases (risk ratio [RR] 8.10, 95% confidence interval [CI] 1.88-34.85, p = 0.005) and shunting in third trimester [6.20, 1.21-30.73, p = 0.028] and at delivery [14.18, 1.62-123.9, p = 0.016] were associated with an increased risk of ICP. CONCLUSIONS: Thiopurine exposure is associated with an increased risk of ICP, particularly following dose increases antenatally and with shunting in late pregnancy. The latter may be effectively managed with split dosing, although further studies are warranted.

[Successful cord blood transplantation for refractory gamma-delta hepatosplenic T-cell lymphoma developed during treatment of Crohn's disease].

The patient was a 21-year-old man who had been diagnosed with Crohn's disease and received infliximab and azathioprine six years earlier. He was admitted with fever and fatigue. Peripheral blood examination showed LDH 2,473 U/l and thrombocytopenia, and contrast-enhanced computed tomography (CT) showed hepatosplenomegaly. Bone marrow biopsy and liver biopsy showed CD4+CD56+TCRγδ＋CD8- atypical cells, leading to a diagnosis of hepatosplenic T-cell lymphoma (HSTCL). The patient was refractory to CHOP and DA-EPOCH, and therefore received cord blood transplantation with myeloablative conditioning. CT showed reduced in hepatosplenomegaly and peripheral blood examination showed LDH 165 U/l and plt 180,000/µl, so the patient was discharged on day117. HSTCL is a tumor of immature γδT cells with a Vδ1 mutation in the spleen, and immunodeficiency has been implicated in its pathogenesis. Patients with inflammatory bowel disease treated with azathioprine are known to have an increased risk of lymphoproliferative disease. In this case, use of immunosuppressive drugs for Crohn's disease may have caused malignant transformation of γδ cells in the intestinal epithelium. Although the patient was refractory to chemotherapy, he was able to achieve remission with early cord blood transplantation and long-term survival is expected.

Immunosuppressant Medications in Pregnancy.

Pregnant patients are often on immunosuppressant medications, most commonly to manage transplantation or autoimmune disorders. Most immunosuppressant agents, including tacrolimus, corticosteroids, azathioprine, and calcineurin inhibitors, are safe during pregnancy and lactation. However, mycophenolic acid is associated with higher risks of birth defects and should be avoided in pregnancy. Tacrolimus, the commonly used drug in transplantation medicine and autoimmune disorders, requires monitoring of serum levels for dose adjustment, particularly during pregnancy. Although no pregnancy-specific therapeutic range exists, the general target range is 5-15 ng/mL, and pregnant patients may require higher doses to achieve therapeutic levels. Adherence to prescribed immunosuppressive regimens is crucial to prevent graft rejection and autoimmune disorder flare-ups. This review aims to provide essential information about the use of immunosuppressant medications in pregnant individuals. With a rising number of pregnant patients undergoing organ transplantations or having autoimmune disorders, it is important to understand the implications of the use of these medications during pregnancy.

Comparison of outcomes of azathioprine, leflunomide and allergen avoidance in patients with patch test-positive pigmented contact dermatitis: a randomized comparative study.

BACKGROUND: Pigmented contact dermatitis (PCD) is a noneczematous form of allergic contact dermatitis characterized by dermal hyperpigmentation. Allergen avoidance is the cornerstone of therapy, but it is difficult to achieve. The use of immunosuppressives seems rational, but data are lacking. OBJECTIVES: To compare outcomes with azathioprine (AZA), leflunomide and allergen avoidance (AA) in patients with PCD. METHODS: A comparative study was conducted on 28 patients with patch test-positive PCD who were randomly allocated to one of three treatment groups: AZA 2 mg kg-1 daily for 24 weeks + AA (n = 10); leflunomide (LEF) 20 mg daily for 24 weeks + -AA (n = 8); AA alone (n = 10). Patients were followed up for an additional 24 weeks. The Dermal Pigmentation Area and Severity Index (DPASI) score and Hindi Melasma Quality of Life scale (MELASQOL) were used to assess hyperpigmentation and quality of life (QoL). respectively. RESULTS: Hair colorants (n = 12) and paraphenylenediamine (n = 8) were the most common allergens. Mean (SD) DPASI score decreased from 30.97 (3.69), 32.35 (3.90) and 31.86 (3.47) to 13.78 (4.25), 21.67 (2.99) and 20.64 (3.82) at 48 weeks in the three groups, respectively (P < 0.001); the maximum percentage decline was seen with AZA (56%). Mean (SD) MELASQOL score was reduced in the three treatment groups from 48.0 (6.46), 46.75 (3.69) and 46.6 (4.65) to 19.6 (6.98), 24.5 (5.80) and 24.0 (5.49), respectively, at 48 weeks (P < 0.001). Reductions in DPASI and Hindi MELASQOL scores were significantly correlated. The most frequent adverse event was transaminitis in both the AZA and LEF groups. CONCLUSIONS: Patients on AZA achieved a statistically significantly greater reduction in DPASI and MELASQOL score; therefore, AZA may fulfil an unmet need in PCD treatment. An objective reduction in hyperpigmentation was paralleled by an improvement in QoL score, reiterating the need for active management of this disease.

Clinical trial: Combination allopurinol-thiopurine versus standard thiopurine in patients with IBD escalating to immunomodulators (the DECIDER study).

BACKGROUND: Thiopurines are established treatments for inflammatory bowel disease (IBD), yet concerns remain regarding their safety. AIM: To evaluate the use of thiopurine-allopurinol combination therapy compared to standard thiopurine therapy in IBD. METHODS: We performed a multicentre, randomised, placebo-controlled trial to compare the efficacy and safety of thiopurine-allopurinol versus thiopurine with placebo for adults commencing a thiopurine for IBD. Patients had active disease at baseline; dosing of therapy was based on a pre-specified regimen and subsequent metabolites. The primary outcome was the proportion of patients achieving a composite of symptomatic disease activity remission (Harvey Bradshaw Index <5 for Crohn's disease, Simple Clinical Colitis Activity Index <4 for ulcerative colitis) and a faecal calprotectin <150 µg/g after 26 weeks of treatment. RESULTS: The trial was terminated early due to slow recruitment. We randomised 102 participants (54 thiopurine-allopurinol, 48 thiopurine with placebo) with similar age (median 42 vs 48 years) and sex distribution (46% women per group). A higher proportion achieved the primary outcome in the thiopurine-allopurinol group (50% vs 35%, p = 0.14) and fewer participants stopped their allocated therapy due to adverse events (11% vs 29%, p = 0.02). Also, within the thiopurine-allopurinol group, thiopurine dose adjustments were less frequent (69% vs 92%, p = 0.03), a higher proportion achieved an early therapeutic 6-TGN level at week 6 (71% vs 53%, p = 0.19), and adverse events attributed to therapy were less frequent (15% vs 44%, p = 0.002). CONCLUSION: Thiopurine-allopurinol therapy is safe and mitigates thiopurine adverse effects, thus enhancing tolerability without compromising efficacy (ACTRN12613001347752).

Drug-Related Adverse Reactions in Pediatric Inflammatory Bowel Disease.

The therapeutic approach to inflammatory bowel disease (IBD) is complex, often involving multiple pharmacologic classes. We aimed to evaluate the prevalence of drug-related adverse reactions (ARs) associated with therapies used in pediatric IBD. We conducted a retrospective study of pediatric patients with IBD followed in a tertiary hospital from 2010 to 2022. Ninety-nine patients were included (62.6% were male), with a median age at diagnosis of 13 years (interquartile range [IQR] 11-15 years). The majority had Crohn's disease (69.7%), followed by ulcerative colitis (21.2%) and unclassified IBD (9.1%). The most prescribed therapies were: immunomodulators (n = 75, 75.8%), exclusive enteral nutrition (n = 61, 61.6%), and biologics (n = 58, 58.6%). During a median follow-up time of 31 months (IQR 11-51 months), the incidence of ARs was 16.2% (16 ARs occurred in 14 patients). The main drug involved was azathioprine (12/16) and the most frequent AR was hepatitis (5/16). Drug discontinuation was necessary in all but 1 case. Of the ARs recorded, 75% were mild to moderate and 81.3% did not require specific treatment; all patients had clinical and/or analytical normalization. There was a positive association between the cumulative number of prescribed drugs and the occurrence of ARs (P = .044). The incidence of ARs was similar to the rates reported in the few existing previous studies. The majority of ARs were mild, but implied the discontinuation of therapy or dose reduction, with a possible impact on disease control.

Key factors associated with 6-thioguanine and 6-methylmercaptopurine nucleotide concentrations in children treated by thiopurine for acute leukaemia and inflammatory bowel disease.

AIMS: Azathioprine (AZA) and 6-mercaptopurine are prescribed in acute lymphoblastic leukaemia (ALL) and inflammatory bowel diseases (IBD). Metabolism to active 6-thioguanine (6TGN) and 6-methylmercaptopurine nucleotides (6MMPN) is variable but therapeutic drug monitoring (TDM) remains debatable. This study reports on factors impacting on red blood cell (RBC) metabolites concentrations in children to facilitate TDM interpretation. METHODS: The first paediatric TDM samples received during year 2021 were analysed, whatever indication and thiopurine drug. Target concentration ranges were 200-500, <6000 pmol/8 × 108 RBC for 6TGN and 6MMPN. RESULTS: Children (n = 492) had IBD (64.8%), ALL (22.6%) or another autoimmune disease (12.6%): mean ages at TDM were 7.5 in ALL and 13.7 years in IBD (P < .0001). ALL received 6-mercaptopurine (mean dose 1.7 mg/kg/d with methotrexate), IBD received AZA (1.9 mg/kg/d with anti-inflammatory drugs and/or monoclonal antibodies). Median 6TGN and 6MMPN concentrations were 213.7 [interquartile range: 142.5; 309.6] and 1144.6 [419.4; 3574.3] pmol/8 × 108 RBC, 38.8% of patients were in the recommended therapeutic range for both compounds. Aminotransferases and blood tests were abnormal in 57/260 patients: 8.1% patients had high alanine aminotransaminase, 3.4% of patients had abnormal blood count. Factors associated with increased 6TGN were age at TDM and thiopurine methyltransferase genotype in ALL and AZA dose in IBD. The impact of associated treatment in IBD patients was also significant. CONCLUSION: TDM allowed identification of children who do not reach target levels or remain over treated. Including TDM in follow-up may help physicians to adjust dosage with the aim of reducing adverse effects and improve treatment outcome.

Tumor Necrosis Factor Inhibitors in Inflammatory Bowel Disease and Risk of Immune Mediated Inflammatory Diseases.

BACKGROUND & AIMS: Tumor necrosis factor inhibitors (anti-TNF) are effective therapies for several immune-mediated inflammatory diseases (IMIDs). However, case reports have identified the paradoxical occurrence of IMIDs in patients treated with anti-TNF. We studied the risk of rheumatoid arthritis, psoriasis, and hidradenitis suppurativa after the initiation of anti-TNF therapy for inflammatory bowel disease (IBD). METHODS: We conducted 2 nationwide cohort studies comprising all patients with IBD in Denmark (2005-2018) and France (2008-2018). We obtained individual-level information on exposure to anti-TNF, diagnoses of IMIDs including rheumatoid arthritis, psoriasis, and hidradenitis suppurativa, and potential confounders from healthcare registers in the respective countries. We used Cox models to estimate hazard ratios (HRs) for the association between anti-TNF exposure and IMIDs and then pooled the estimates from the 2 cohorts. To test the robustness of our results, we performed an active comparator analysis of anti-TNF monotherapy vs azathioprine monotherapy. RESULTS: The Danish and French cohorts comprised 18,258 and 88,786 subjects with IBD, respectively, contributing a total of 516,055 person-years of follow-up. Anti-TNF was associated with an increased risk of rheumatoid arthritis, psoriasis, and hidradenitis suppurativa in both the Danish (HR, 1.66; 95% confidence interval [CI], 1.34-2.07) and the French cohort (HR, 1.78; 95% CI, 1.63-1.94), with a pooled HR of 1.76 (95% CI, 1.63-1.91). Anti-TNF was also associated with an increased risk of the outcomes when compared with azathioprine (pooled HR, 2.94; 95% CI, 2.33-3.70). CONCLUSIONS: In 2 nationwide cohorts of IBD patients, anti-TNF therapy was associated with an increased risk of rheumatoid arthritis, psoriasis, and hidradenitis suppurativa.

Azathioprine hypersensitivity: A Sweet-like syndrome.

INTRODUCTION: Azathioprine hypersensitivity can occasionally present as Sweet-like syndrome, a dose-independent side effect characterized by the unanticipated onset of macules, papules, and pustules. CASE PRESENTATION: A 35-year-old woman with systemic lupus erythematosus presented with complaints of generalized maculopapular rash, facial swelling, and bilateral lower extremity edema with a duration of 4 days and a 2-day history of constitutional symptoms within 2 weeks of the beginning of azathioprine therapy to treat existing lupus nephritis (class 2/3). DISCUSSION: Patients who experience azathioprine hypersensitivity syndrome can present with erythema nodosum, small-vessel vasculitis, acute generalized exanthematous pustulosis, Sweet syndrome, and nonspecific dermatosis. The following signs and symptoms are used as criteria to diagnose drug-induced Sweet syndrome: (a) abrupt onset of painful erythematous plaques, (b) histopathological evidence of dense neutrophilic infiltrate without evidence of leukocytoclastic vasculitis, (c) temperature higher than 39.7°C, (d) temporal relationship between drug ingestion and clinical presentation, and (e) temporal resolution of lesions after drug withdrawal. Our patient met three out of five criteria and was diagnosed with Sweet-like syndrome. CONCLUSION: Our case highlights the uncommonly presented azathioprine-induced Sweet-like syndrome that occurs abruptly after the commencement of the offending drug. This diagnosis can be established through basic laboratory workup and skin biopsy findings.