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The Lancet. Gastroenterology &... May 2024Management strategies and clinical outcomes vary substantially in patients newly diagnosed with Crohn's disease. We evaluated the use of a putative prognostic biomarker... (Randomized Controlled Trial)
Randomized Controlled Trial
A biomarker-stratified comparison of top-down versus accelerated step-up treatment strategies for patients with newly diagnosed Crohn's disease (PROFILE): a multicentre, open-label randomised controlled trial.
BACKGROUND
Management strategies and clinical outcomes vary substantially in patients newly diagnosed with Crohn's disease. We evaluated the use of a putative prognostic biomarker to guide therapy by assessing outcomes in patients randomised to either top-down (ie, early combined immunosuppression with infliximab and immunomodulator) or accelerated step-up (conventional) treatment strategies.
METHODS
PROFILE (PRedicting Outcomes For Crohn's disease using a moLecular biomarker) was a multicentre, open-label, biomarker-stratified, randomised controlled trial that enrolled adults with newly diagnosed active Crohn's disease (Harvey-Bradshaw Index ≥7, either elevated C-reactive protein or faecal calprotectin or both, and endoscopic evidence of active inflammation). Potential participants had blood drawn to be tested for a prognostic biomarker derived from T-cell transcriptional signatures (PredictSURE-IBD assay). Following testing, patients were randomly assigned, via a secure online platform, to top-down or accelerated step-up treatment stratified by biomarker subgroup (IBDhi or IBDlo), endoscopic inflammation (mild, moderate, or severe), and extent (colonic or other). Blinding to biomarker status was maintained throughout the trial. The primary endpoint was sustained steroid-free and surgery-free remission to week 48. Remission was defined by a composite of symptoms and inflammatory markers at all visits. Flare required active symptoms (HBI ≥5) plus raised inflammatory markers (CRP >upper limit of normal or faecal calprotectin ≥200 μg/g, or both), while remission was the converse-ie, quiescent symptoms (HBI <5) or resolved inflammatory markers (both CRP ≤ the upper limit of normal and calprotectin <200 μg/g) or both. Analyses were done in the full analysis (intention-to-treat) population. The trial has completed and is registered (ISRCTN11808228).
FINDINGS
Between Dec 29, 2017, and Jan 5, 2022, 386 patients (mean age 33·6 years [SD 13·2]; 179 [46%] female, 207 [54%] male) were randomised: 193 to the top-down group and 193 to the accelerated step-up group. Median time from diagnosis to trial enrolment was 12 days (range 0-191). Primary outcome data were available for 379 participants (189 in the top-down group; 190 in the accelerated step-up group). There was no biomarker-treatment interaction effect (absolute difference 1 percentage points, 95% CI -15 to 15; p=0·944). Sustained steroid-free and surgery-free remission was significantly more frequent in the top-down group than in the accelerated step-up group (149 [79%] of 189 patients vs 29 [15%] of 190 patients, absolute difference 64 percentage points, 95% CI 57 to 72; p<0·0001). There were fewer adverse events (including disease flares) and serious adverse events in the top-down group than in the accelerated step-up group (adverse events: 168 vs 315; serious adverse events: 15 vs 42), with fewer complications requiring abdominal surgery (one vs ten) and no difference in serious infections (three vs eight).
INTERPRETATION
Top-down treatment with combination infliximab plus immunomodulator achieved substantially better outcomes at 1 year than accelerated step-up treatment. The biomarker did not show clinical utility. Top-down treatment should be considered standard of care for patients with newly diagnosed active Crohn's disease.
FUNDING
Wellcome and PredictImmune Ltd.
Topics: Adult; Humans; Male; Female; Crohn Disease; Infliximab; Azathioprine; Biomarkers; Immunologic Factors; Inflammation; Leukocyte L1 Antigen Complex
PubMed: 38402895
DOI: 10.1016/S2468-1253(24)00034-7 -
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 -
Clinical Rheumatology Sep 2023Idiopathic granulomatous mastitis (IGM) is a rarely seen chronic and benign disease of the breast. IGM usually emerges in women between 30 and 45 years of age and...
INTRODUCTION
Idiopathic granulomatous mastitis (IGM) is a rarely seen chronic and benign disease of the breast. IGM usually emerges in women between 30 and 45 years of age and within the first 5 years after lactation. There is no consensus on the treatment of the disease. Steroids, immunosuppressive agents such as methotrexate and azathioprine, antibiotics, and surgical and conservative treatments can be preferred. In the present study, it was aimed to demonstrate the treatment options and follow-up data of the patients with IGM and to investigate the effective factors on recurrence if developed in the follow-up period.
MATERIALS AND METHOD
The data of 120 patients diagnosed with idiopathic granulomatous mastitis were evaluated for this cross-sectional retrospective study. The demographic, clinical, treatment, and follow-up features of the patients were obtained from the file records.
RESULTS
The median age value of the 120 female patients included in the study was 35 (24-67) years. Of the patients, 45%, 79.2%, 49.2%, and 15% had a past history of surgical intervention, steroid use, methotrexate use, and azathioprine use, respectively. Recurrent lesion developed after the treatment in 57 (47.5%) patients. The recurrence rate was 66.1% in the patients who underwent surgical intervention in the initial treatment. There was a statistically significant difference between the patients with and without recurrence regarding the presence of abscess, the presence of recurrent abscess, and having surgical intervention as the initial treatment in the past history. The rate of having surgery was statistically significantly higher compared with the administration of steroid therapy alone and the combination of steroid and immunosuppressive therapy in the initial treatment of the patients who developed recurrence. The rate of having surgery together with the administration of steroid and immunosuppressive therapy was statistically significantly higher than the administration of steroid and immunosuppressive therapies.
DISCUSSION
Our study showed that surgical intervention and the presence of abscess increased recurrence in the treatment of IGM. Key Points • This study has shown that surgical intervention and the presence of abscess increase recurrence. • A multidisciplinary approach to the treatment of IGM and management of the disease by the rheumatologists may be critical.
Topics: Female; Humans; Adult; Middle Aged; Aged; Methotrexate; Granulomatous Mastitis; Retrospective Studies; Azathioprine; Abscess; Cross-Sectional Studies; Treatment Outcome; Steroids; Immunoglobulin M; Recurrence
PubMed: 37301771
DOI: 10.1007/s10067-023-06651-3 -
Diagnostics (Basel, Switzerland) Feb 2024Autoimmune hepatitis is an immune-mediated inflammatory condition of the liver of undetermined cause that affects both sexes, all ages, races, and ethnicities. Its... (Review)
Review
Autoimmune hepatitis is an immune-mediated inflammatory condition of the liver of undetermined cause that affects both sexes, all ages, races, and ethnicities. Its clinical presentation can be very broad, from having an asymptomatic and silent course to presenting as acute hepatitis, cirrhosis, and acute liver failure potentially requiring liver transplantation. The diagnosis is based on histological abnormalities (interface hepatitis), characteristic clinical and laboratory findings (increased aspartate aminotransferase, alanine aminotransferase, and serum IgG concentration), and the presence of one or more characteristic autoantibodies. The large heterogeneity of these clinical, biochemical, and histological findings can sometimes make a timely and proper diagnosis a difficult task. Treatment seeks to achieve remission of the disease and prevent further progression of liver disease. First-line therapy includes high-dose corticosteroids, which are later tapered to decrease side effects, and azathioprine. In the presence of azathioprine intolerance or a poor response to the standard of care, second-line therapy needs to be considered, including mycophenolate mofetil. AIH remains a diagnostic and therapeutic challenge, and a further understanding of the pathophysiological pathways of the disease and the implementation of randomized controlled trials are needed.
PubMed: 38396421
DOI: 10.3390/diagnostics14040382 -
Dermatologie (Heidelberg, Germany) Sep 2023Pemphigoid diseases are a group of bullous autoimmune diseases characterized by autoantibodies against structural proteins of the dermal-epidermal junction. With... (Review)
Review
Pemphigoid diseases are a group of bullous autoimmune diseases characterized by autoantibodies against structural proteins of the dermal-epidermal junction. With a steadily growing aging population, pemphigoid diseases are emerging as a significant medical challenge, because they occur primarily in older individuals. The by far most common disease is bullous pemphigoid, which is clinically characterized by tense blisters, erosions, erythema or urticarial plaques, while severe pruritus is the leading subjective symptom. Mucous membrane pemphigoid predominantly affects surface-close mucous membranes with painful erosions and blisters as well as frequently scarring usually in the mouth, nose, and eyes. Anti-p200 pemphigoid clinically resembles bullous pemphigoid but is much less common. Diagnosis of these diseases involves the combination of clinical evaluation, lesional histopathology, direct immunofluorescence microscopy of a perilesional biopsy and serology. Topical and systemic corticosteroids are the mainstay of pemphigoid diseases treatment. Depending on the severity of the disease, various potentially corticosteroid-sparing therapies, such as dapsone, doxycycline, methotrexate, azathioprine and mycophenolate may be used. In severe courses, treatment with rituximab, cyclophosphamide, intravenous immunoglobulins or immunoadsorption are second- or third-line treatment options. Patients are best managed in centers experience with the management of pemphigoid diseases. Updated national and international guidelines for the diagnosis and treatment of bullous pemphigoid and mucous membrane pemphigoid have recently been published.
Topics: Humans; Aged; Pemphigoid, Bullous; Blister; Pemphigoid, Benign Mucous Membrane; Autoimmune Diseases; Immunosuppressive Agents
PubMed: 37594515
DOI: 10.1007/s00105-023-05209-3 -
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 -
Seminars in Arthritis and Rheumatism Aug 2023Neurologic involvement in Behçet's disease (BD) represents a major cause of disease morbidity and mortality. Early recognition and timely treatment represent crucial... (Review)
Review
BACKGROUND
Neurologic involvement in Behçet's disease (BD) represents a major cause of disease morbidity and mortality. Early recognition and timely treatment represent crucial aspects that aim at preventing long-term disability. The absence of robust and evidence-based studies further complicates the management of neuro-BD (NBD). In this review we aim at collecting the best available evidence and suggest a treatment algorithm for an optimal and personalized management of NBD.
EVIDENCE ACQUISITION
PubMed (NLM) database for papers written in English language was used to retrieve relevant articles for this review.
RESULTS AND CONCLUSIONS
Neurologic involvement in BD is one of the most serious and challenging aspects to manage, particularly in its chronic progressive form. It is important to distinguish between acute and chronic progressive NBD, as treatment may vary considerably. Currently, no standardized treatment guidelines support physicians in the decision-making process that therefore relies on low-level evidence. High dose corticosteroids remain the cornerstone for managing acute phase both in the parenchymal and non-parenchymal involvement. Prevention of relapses and control of disease progression represent crucial goals for acute and chronic progressive NBD respectively. In this regard, mycophenolate mofetil and azathioprine are valuable options in the acute NBD. On the other hand, low weekly dose methotrexate has been suggested for chronic progressive NBD. Refractory cases or intolerant patients to conventional therapies may benefit from biologic agents, particularly infliximab. First-line infliximab may be preferred in severe patients with high risk of damage. Other agents including tocilizumab, interleukin-1 inhibitors, B-cell depletion therapy and to a lesser extent, interferon-α and intravenous immunoglobulins are potential options in severe and multidrug resistant cases. Due to multiple organ involvement in BD, long-term treatment should be determined by a multidisciplinary approach. Therefore, multicenter collaborations in the context of international registry-based projects could promote data sharing, standardization of more clinical outcomes and knowledge diffusion that hopefully may optimize therapy and personalize the management of patients with such a complex syndrome.
Topics: Humans; Behcet Syndrome; Infliximab; Adrenal Cortex Hormones; Azathioprine; Central Nervous System; Multicenter Studies as Topic
PubMed: 37172497
DOI: 10.1016/j.semarthrit.2023.152206 -
BMJ Open Respiratory Research Feb 2024Mycophenolate mofetil (MMF) and azathioprine (AZA) are immunomodulatory treatments in interstitial lung disease (ILD). This systematic review aimed to evaluate the... (Meta-Analysis)
Meta-Analysis
OBJECTIVES
Mycophenolate mofetil (MMF) and azathioprine (AZA) are immunomodulatory treatments in interstitial lung disease (ILD). This systematic review aimed to evaluate the efficacy of MMF or AZA on pulmonary function in ILD.
DESIGN
Population included any ILD diagnosis, intervention included MMF or AZA treatment, outcome was delta change from baseline in per cent predicted forced vital capacity (%FVC) and gas transfer (diffusion lung capacity of carbon monoxide, %DLco). The primary endpoint compared outcomes relative to placebo comparator, the secondary endpoint assessed outcomes in treated groups only.
ELIGIBILITY CRITERIA
Randomised controlled trials (RCTs) and prospective observational studies were included. No language restrictions were applied. Retrospective studies and studies with high-dose concomitant steroids were excluded.
DATA SYNTHESIS
The systematic search was performed on 9 May. Meta-analyses according to drug and outcome were specified with random effects, I evaluated heterogeneity and Grading of Recommendations, Assessment, Development and Evaluation evaluated certainty of evidence. Primary endpoint analysis was restricted to RCT design, secondary endpoint included subgroup analysis according to prospective observational or RCT design.
RESULTS
A total of 2831 publications were screened, 12 were suitable for quantitative synthesis. Three MMF RCTs were included with no significant effect on the primary endpoints (%FVC 2.94, 95% CI -4.00 to 9.88, I=79.3%; %DLco -2.03, 95% CI -4.38 to 0.32, I=0.0%). An overall 2.03% change from baseline in %FVC (95% CI 0.65 to 3.42, I=0.0%) was observed in MMF, and RCT subgroup summary estimated a 4.42% change from baseline in %DL (95% CI 2.05 to 6.79, I=0.0%). AZA studies were limited. All estimates were considered very low certainty evidence.
CONCLUSIONS
There were limited RCTs of MMF or AZA and their benefit in ILD was of very low certainty. MMF may support preservation of pulmonary function, yet confidence in the effect was weak. To support high certainty evidence, RCTs should be designed to directly assess MMF efficacy in ILD.
PROSPERO REGISTRATION NUMBER
CRD42023423223.
Topics: Humans; Azathioprine; Immunosuppressive Agents; Lung Diseases, Interstitial; Lung; Mycophenolic Acid; Enzyme Inhibitors; Observational Studies as Topic
PubMed: 38413120
DOI: 10.1136/bmjresp-2023-002163 -
International Immunopharmacology Oct 2023Immunosuppression is an integral part of treating chronic spontaneous urticaria (CSU), but there is no literature to evaluate the efficacy of multiple immunosuppressive... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Immunosuppression is an integral part of treating chronic spontaneous urticaria (CSU), but there is no literature to evaluate the efficacy of multiple immunosuppressive agents.
OBJECTIVE
The comparison of the efficacy, safety, and incidence of adverse effects of four immunosuppressive medicines (tripterygium glycosides, methotrexate, cyclosporine A, and azathioprine) in combination with antihistamines in treating CSU provides a clinical reference and evidence-based medicine for treating CSU.
METHODS
PUBMED, The Cochrane Library, EMBASE, WANFANG, CNKI, CBM, and clinical trial registration platform were searched to collect relevant randomized controlled trials (RCT) and cohort studies of four immunosuppressive medicines combined with antihistamines for treating CSU. The primary outcomes were the efficacy of weekly urticaria activity score 7 (UAS7) and adverse effects.
RESULTS
This study pooled data from seven randomized clinical trials with 410 participants. The standardized mean differences for change in UAS7 were 0.10 (95% confidence interval (CI), 0.01 to 0.68) for cyclosporine A plus antihistamine; 0.03 (95% CI, 0.00 to 0.23) for azathioprine plus antihistamine; 0.52 (95% CI, 0.32 to 0.85) for tripterygium glycosides plus antihistamine; and 1.54 (95% CI, 0.64 to 3.67) for methotrexate plus antihistamine. There were no significant differences in side effects between these medicines in the limited number of trials and clinical samples.
CONCLUSION
Our results indicate that cyclosporine A combined with antihistamine resulted in greater improvements regarding the UAS7 in CSU patients and that tripterygium glycosides are also effective in treating CSU.
Topics: Humans; Immunosuppressive Agents; Cyclosporine; Methotrexate; Azathioprine; Network Meta-Analysis; Chronic Disease; Chronic Urticaria; Histamine H1 Antagonists; Urticaria; Histamine Antagonists; Drug-Related Side Effects and Adverse Reactions; Glycosides; Treatment Outcome; Omalizumab; Anti-Allergic Agents; Randomized Controlled Trials as Topic
PubMed: 37567010
DOI: 10.1016/j.intimp.2023.110577 -
Annals of the Rheumatic Diseases Jan 2024To compare the long-term efficacy and safety of azathioprine (AZA), 18-month fixed-schedule rituximab (RTX), 18-month tailored RTX and 36-month RTX in preventing...
OBJECTIVE
To compare the long-term efficacy and safety of azathioprine (AZA), 18-month fixed-schedule rituximab (RTX), 18-month tailored RTX and 36-month RTX in preventing relapses in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis who achieved a complete remission after induction therapy. Patients treated with 36-month RTX received either a fixed or a tailored regimen for the first 18 months and a fixed regimen for the last 18 months (36-month fixed/fixed RTX and 36-month tailored/fixed RTX, respectively).
METHODS
The Maintenance of Remission using Rituximab in Systemic ANCA-associated Vasculitis (MAINRITSAN) trials sequentially compared: 18-month fixed-schedule RTX versus AZA (MAINRITSAN); 18-month fixed-schedule RTX versus 18-month tailored-RTX (MAINRITSAN2); and extended therapy to 36 months with four additional RTX infusions after MAINRITSAN2 versus placebo (MAINRITSAN3). Patients were then followed prospectively through month 84 and their data were pooled to analyse relapses and adverse events. The primary endpoint was relapse-free survival at month 84.
RESULTS
277 patients were enrolled and divided in 5 groups: AZA (n=58), 18-month fixed-schedule RTX (n=97), 18-month tailored-RTX (n=40), 36-month tailored/fixed RTX (n=42), 36-month fixed/fixed RTX (n=41). After adjustment for prognostic factors, 18-month fixed-schedule RTX was superior to AZA in preventing major relapses at month 84 (HR 0.38, 95% CI 0.20 to 0.71). The 18-month tailored-RTX regimen was associated with an increased risk of major relapse compared with fixed-schedule regimen (HR 2.92, 95% CI 1.43 to 5.96). The risk of major relapse was similar between 36-month fixed/fixed and 18-month fixed-RTX (HR 0.69, 95% CI 0.38 to 1.25).
CONCLUSIONS
According to these results, it appears that the 84-month remission rate is higher with an 18-month fixed RTX regimen compared with AZA and 18-month tailored RTX. Also, extending RTX to 36 months does not appear to reduce the long-term relapse rate compared with the 18-month fixed RTX regimen. However, as this study was underpowered to make this comparison, further prospective studies are needed to determine the potential long-term benefits of extending treatment in these patients.
Topics: Humans; Rituximab; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Azathioprine; Antibodies, Antineutrophil Cytoplasmic; Recurrence; Remission Induction; Treatment Outcome; Immunosuppressive Agents
PubMed: 37918894
DOI: 10.1136/ard-2023-224623