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Gut Jan 2022In newly diagnosed paediatric patients with moderate-to-severe Crohn's disease (CD), infliximab (IFX) is initiated once exclusive enteral nutrition (EEN), corticosteroid... (Randomized Controlled Trial)
Randomized Controlled Trial
First-line treatment with infliximab versus conventional treatment in children with newly diagnosed moderate-to-severe Crohn's disease: an open-label multicentre randomised controlled trial.
OBJECTIVE
In newly diagnosed paediatric patients with moderate-to-severe Crohn's disease (CD), infliximab (IFX) is initiated once exclusive enteral nutrition (EEN), corticosteroid and immunomodulator therapies have failed. We aimed to investigate whether starting first-line IFX (FL-IFX) is more effective to achieve and maintain remission than conventional treatment.
DESIGN
In this multicentre open-label randomised controlled trial, untreated patients with a new diagnosis of CD (3-17 years old, weighted Paediatric CD Activity Index score (wPCDAI) >40) were assigned to groups that received five infusions of 5 mg/kg IFX at weeks 0, 2, 6, 14 and 22 (FL-IFX), or EEN or oral prednisolone (1 mg/kg, maximum 40 mg) (conventional). The primary outcome was clinical remission on azathioprine, defined as a wPCDAI <12.5 at week 52, without need for treatment escalation, using intention-to-treat analysis.
RESULTS
100 patients were included, 50 in the FL-IFX group and 50 in the conventional group. Four patients did not receive treatment as per protocol. At week 10, a higher proportion of patients in the FL-IFX group than in the conventional group achieved clinical (59% vs 34%, respectively, p=0.021) and endoscopic remission (59% vs 17%, respectively, p=0.001). At week 52, the proportion of patients in clinical remission was not significantly different (p=0.421). However, 19/46 (41%) patients in the FL-IFX group were in clinical remission on azathioprine monotherapy without need for treatment escalation vs 7/48 (15%) in the conventional group (p=0.004).
CONCLUSIONS
FL-IFX was superior to conventional treatment in achieving short-term clinical and endoscopic remission, and had greater likelihood of maintaining clinical remission at week 52 on azathioprine monotherapy.
TRIAL REGISTRATION NUMBER
ClinicalTrials.gov Registry (NCT02517684).
Topics: Adolescent; Anti-Inflammatory Agents; Azathioprine; Child; Child, Preschool; Crohn Disease; Female; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Infliximab; Male; Prednisolone; Remission Induction; Severity of Illness Index
PubMed: 33384335
DOI: 10.1136/gutjnl-2020-322339 -
Revista Espanola de Sanidad... 2022
Topics: Humans; Skin Diseases; Biopsy; Kidney Transplantation; Carcinoma, Squamous Cell; Azathioprine; Adrenal Cortex Hormones; Immunosuppressive Agents; Keratosis, Actinic
PubMed: 36256559
DOI: 10.18176/resp.00053 -
Molecular Diagnosis & Therapy Jan 2024The genetic background of inflammatory bowel disease, both Crohn's disease and ulcerative colitis, has been known for more than 2 decades. In the last 20 years,... (Review)
Review
The genetic background of inflammatory bowel disease, both Crohn's disease and ulcerative colitis, has been known for more than 2 decades. In the last 20 years, genome-wide association studies have dramatically increased our knowledge on the genetics of inflammatory bowel disease with more than 200 risk genes having been identified. Paralleling this increasing knowledge, the armamentarium of inflammatory bowel disease medications has been growing constantly. With more available therapeutic options, treatment decisions become more complex, with still many patients experiencing a debilitating disease course and a loss of response to treatment over time. With a better understanding of the disease, more effective personalized treatment strategies are looming on the horizon. Genotyping has long been considered a strategy for treatment decisions, such as the detection of thiopurine S-methyltransferase and nudix hydrolase 15 polymorphisms before the initiation of azathioprine. However, although many risk genes have been identified in inflammatory bowel disease, a substantial impact of genetic risk assessment on therapeutic strategies and disease outcome is still missing. In this review, we discuss the genetic background of inflammatory bowel disease, with a particular focus on the latest advances in the field and their potential impact on management decisions.
Topics: Humans; Genome-Wide Association Study; Inflammatory Bowel Diseases; Colitis, Ulcerative; Crohn Disease; Azathioprine
PubMed: 37847439
DOI: 10.1007/s40291-023-00678-7 -
Journal of Personalized Medicine Aug 2021Thiopurines, mercaptopurine, and azathioprine are used as immunosuppressants in the treatments of inflammatory bowel disease, rheumatoid arthritis, and organ... (Review)
Review
Thiopurines, mercaptopurine, and azathioprine are used as immunosuppressants in the treatments of inflammatory bowel disease, rheumatoid arthritis, and organ transplantation and as chemotherapeutic drugs for the treatment of acute leukemia and chronic myeloid leukemia. This drug class sometimes causes severe adverse reactions, including bone marrow suppression and hair loss. Genetic polymorphisms of the metabolizing enzyme thiopurine S-methyltransferase have been used for predicting these reactions in Caucasians, but these allele frequencies are less frequently observed in Asian populations. Recently, nudix hydrolase 15 () polymorphisms have been shown to play an important role in thiopurine-induced adverse reactions in Asians. In this review, we summarize the studies, mainly in Asian countries, and their implementation in several countries.
PubMed: 34442422
DOI: 10.3390/jpm11080778 -
The Korean Journal of Gastroenterology... Feb 2023Autoimmune hepatitis (AIH) is a chronic liver disease, characterized by elevated levels of transaminases, immunoglobulin G, and positive autoantibodies. The disease... (Review)
Review
Autoimmune hepatitis (AIH) is a chronic liver disease, characterized by elevated levels of transaminases, immunoglobulin G, and positive autoantibodies. The disease course is dynamic and presents heterogeneous disease manifestations at diagnosis. This review summarizes the issues regarding the treatment and monitoring of AIH in adult patients. Glucocorticoids and azathioprine are the first line of treatment. Alternative first-line treatments include budesonide or mycophenolate mofetil (MMF). Although no randomized controlled trials have been performed, MMF, cyclosporine, tacrolimus, 6-mercaptopurine, 6-thioguanine, allopurinol, sirolimus, everolimus, infliximab, or rituximab have been attempted in patients not responding to or intolerant to first-line treatments. Most patients require life-long special monitoring, with or without maintenance treatment.
Topics: Adult; Humans; Immunosuppressive Agents; Hepatitis, Autoimmune; Azathioprine; Tacrolimus; Mycophenolic Acid
PubMed: 36824035
DOI: 10.4166/kjg.2023.011 -
Cell Reports. Medicine Aug 2023Azathioprine (AZA) therapy failure, though not the primary cause, contributes to disease relapse and progression in inflammatory bowel disease (IBD). However, the role...
Azathioprine (AZA) therapy failure, though not the primary cause, contributes to disease relapse and progression in inflammatory bowel disease (IBD). However, the role of gut microbiota in AZA therapy failure remains poorly understood. We found a high prevalence of Blautia wexlerae in patients with IBD with AZA therapy failure, associated with shorter disease flare survival time. Colonization of B. wexlerae increased inflammatory macrophages and compromised AZA's therapeutic efficacy in mice with intestinal colitis. B. wexlerae colonization reduced 6-mercaptopurine (6-MP) bioavailability by enhancing selenium-dependent xanthine dehydrogenase (sd-XDH) activity. The enzyme sd-XDH converts 6-MP into its inactive metabolite, 6-thioxanthine (6-TX), thereby impairing its ability to inhibit inflammation in mice. Supplementation with Bacillus (B.) subtilis enriched in hypoxanthine phosphoribosyltransferase (HPRT) effectively mitigated B. wexlerae-induced AZA treatment failure in mice with intestinal colitis. These findings emphasize the need for tailored management strategies based on B. wexlerae levels in patients with IBD.
Topics: Animals; Mice; Mercaptopurine; Azathioprine; Immunosuppressive Agents; Biological Availability; Inflammatory Bowel Diseases; Colitis; Bacteria
PubMed: 37586320
DOI: 10.1016/j.xcrm.2023.101153 -
Neurology Feb 2023Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune condition, which can lead to significant disability, and up to 3%-5% of the cases have a pediatric...
BACKGROUND AND OBJECTIVE
Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune condition, which can lead to significant disability, and up to 3%-5% of the cases have a pediatric onset. There are limited studies to guide physicians in disease-modifying treatment (DMT) choices for children with NMOSD.
METHODS
This retrospective cohort study evaluated children with NMOSD cases followed at 12 clinics in the US Network of Pediatric MS Centers. Cases were classified as aquaporin-4 antibody positive (AQP4+) and double seronegative (DS) when negative for AQP4+ and for myelin oligodendrocyte glycoprotein (MOG) antibody. The effect of initial DMTs including rituximab, mycophenolate, azathioprine, and IV immunoglobulin (IVIg) on the annualized relapse rate (ARR) was assessed by negative binomial regression. Time to disability progression (EDSS score increase ≥1.0 point) was modeled with a Cox proportional-hazards model.
RESULTS
A total of 91 children with NMOSD were identified: 77 AQP4+ and 14 DS (85.7% females; 43.2% White and 46.6% African American). Eighty-one patients were started on a DMT, and 10 were treatment naive at the time of the analysis. The ARR calculated in all serogroups was 0.25 (95% CI 0.13-0.49) for rituximab, 0.33 (95% CI 0.19-0.58) for mycophenolate, 0.40 (95% CI 0.13-1.24) for azathioprine, and 0.54 (95% CI 0.28-1.04) for IVIg. The ARR in the AQP4+ subgroup was 0.28 (95% CI 0.14-0.55) for rituximab, 0.39 (95% CI 0.21-0.70) for mycophenolate, 0.41 (95% CI 0.13-1.29) for azathioprine, and 0.54 (95% CI 0.23-1.26) for IVIg. The ARR in the treatment-naive group was 0.97 (95% CI 0.58-1.60) in all serogroups and 0.91 (95% CI 0.53-1.56) in the AQP4+ subgroup. None of the initial DMT had a statistically significant effect on EDSS progression.
DISCUSSION
The use of DMTs, particularly rituximab, is associated with a lowered annualized relapse rate in children with NMOSD AQP4+.
CLASSIFICATION OF EVIDENCE
This study provides Class IV evidence that use of disease-modifying treatments is associated with a lowered annualized relapse rate in children with NMOSD AQP4+.
Topics: Female; Male; Humans; Neuromyelitis Optica; Aquaporin 4; Rituximab; Azathioprine; Retrospective Studies; Immunoglobulins, Intravenous; Immunoglobulin G; Autoantibodies; Immunosuppressive Agents; Enzyme Inhibitors; Recurrence; Myelin-Oligodendrocyte Glycoprotein
PubMed: 36460473
DOI: 10.1212/WNL.0000000000201625 -
Biomedicine & Pharmacotherapy =... Dec 2023Azathioprine is commonly used as an immunosuppressive antimetabolite in the treatment of acute lymphoblastic leukemia, autoimmune disorders (such as Crohn's disease and...
Azathioprine is commonly used as an immunosuppressive antimetabolite in the treatment of acute lymphoblastic leukemia, autoimmune disorders (such as Crohn's disease and rheumatoid arthritis), and in patients receiving organ transplants. Thiopurine-S-methyltransferase (TPMT) is a cytoplasmic trans-methylase catalyzing the S-methylation of thiopurines. The active metabolites obtained from thiopurines are hydrolyzed into inactive forms by the Nudix hydrolase 15 (NUDT15). The TPMT*2 (defined by rs1800462), *3A (defined by rs1800460 and rs1142345), *3B (defined by rs1800460), *3C (defined by rs1142345), *6 (defined by rs75543815), and NUDT15 rs116855232 genetic variant have been associated, with the highest level of evidence, with the response to azathioprine, and, the approved drug label for azathioprine and main pharmacogenetic dosing guidelines recommend starting with reduced initial doses in TPMT intermediate metabolizer (IM) patients and considering an alternative treatment in TPMT poor metabolizer (PM) patients. This study aims to assess the clinical impact of azathioprine dose tailoring based on TPMT genotyping studying the azathioprine toxicity and efficacy, treatment starts, and dose adjustments during follow-up, comparing TPMT IM/PM and normal metabolizer (NM) patients. It also studied the association of NUDT15 rs116855232 with response to azathioprine in patients receiving a tailored treatment based on TPMT and characterized the TMPT and NUDT15 studied variants in our population. Results show that azathioprine dose reduction in TPMT IM patients (TPMT*1/*2, *1/*3A, or *1/*3C genotypes) is related to lower toxicity events compared to TPMT NM (TPMT *1/*1 genotype), and lower azathioprine dose adjustments during follow-up without showing differences in the efficacy. The results support the hypothesis of existing other genetic variants affecting azathioprine toxicity.
Topics: Humans; Azathioprine; Pharmacogenetics; Immunosuppressive Agents; Genotype; Crohn Disease; Methyltransferases; Pyrophosphatases
PubMed: 37857254
DOI: 10.1016/j.biopha.2023.115706