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Pediatric Neurology Aug 2023To evaluate the clinical features, demographic features, and treatment modalities of pediatric-onset chronic inflammatory demyelinating polyneuropathy (CIDP) in Turkey.
BACKGROUND
To evaluate the clinical features, demographic features, and treatment modalities of pediatric-onset chronic inflammatory demyelinating polyneuropathy (CIDP) in Turkey.
METHODS
The clinical data of patients between January 2010 and December 2021 were reviewed retrospectively. The patients were evaluated according to the Joint Task Force of the European Federation of Neurological Societies and the Peripheral Nerve Society Guideline on the management of CIDP (2021). In addition, patients with typical CIDP were divided into two groups according to the first-line treatment modalities (group 1: IVIg only, group 2: IVIg + steroid). The patients were further divided into two separate groups based on their magnetic resonance imaging (MRI) characteristics.
RESULTS
A total of 43 patients, 22 (51.2%) males and 21 (48.8%) females, were included in the study. There was a significant difference between pretreatment and post-treatment modified Rankin scale (mRS) scores (P < 0.05) of all patients. First-line treatments include intravenous immunoglobulin (IVIg) (n = 19, 44.2%), IVIg + steroids (n = 20, 46.5%), steroids (n = 1, 2.3%), IVIg + steroids + plasmapheresis (n = 1, 2.3%), and IVIg + plasmapheresis (n = 1, 2.3%). Alternative agent therapy consisted of azathioprine (n = 5), rituximab (n = 1), and azathioprine + mycophenolate mofetil + methotrexate (n = 1). There was no difference between the pretreatment and post-treatment mRS scores of groups 1 and 2 (P > 0.05); however, a significant decrease was found in the mRS scores of both groups with treatment (P < 0.05). The patients with abnormal MRI had significantly higher pretreatment mRS scores compared with the group with normal MRI (P < 0.05).
CONCLUSIONS
This multicenter study demonstrated that first-line immunotherapy modalities (IVIg vs IVIg + steroids) had equal efficacy for the treatment of patients with CIDP. We also determined that MRI features might be associated with profound clinical features, but did not affect treatment response.
Topics: Male; Female; Child; Humans; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating; Immunoglobulins, Intravenous; Azathioprine; Retrospective Studies; Methotrexate
PubMed: 37245275
DOI: 10.1016/j.pediatrneurol.2023.04.018 -
Clinical Gastroenterology and... Oct 2023The aim of this study was to assess how 6-thioguanine nucleotide (6-TGN) levels and use of oral methotrexate relate to the pharmacokinetics of biologics.
BACKGROUND AND AIMS
The aim of this study was to assess how 6-thioguanine nucleotide (6-TGN) levels and use of oral methotrexate relate to the pharmacokinetics of biologics.
METHODS
This was a prospective cohort study including patients with inflammatory bowel diseases on maintenance doses of infliximab, vedolizumab, or ustekinumab on monotherapy or combination with a thiopurine or oral methotrexate. We collected 6-TGN concentrations, biomarker levels, and clinical and endoscopic disease activity. The primary outcomes were infliximab, vedolizumab, and ustekinumab concentrations as well as anti-drug antibodies (ADAs).
RESULTS
A total of 369 patients were recruited (113 infliximab, 133 vedolizumab, and 123 ustekinumab). Patients with 6-TGN levels ≥146 pmol per 8 × 10 red blood cells (RBCs), and those receiving combination therapy with thiopurine or oral methotrexate had significantly higher infliximab concentrations when compared with monotherapy (median levels of 17.4 μg/mL on thiopurine with 6-TGN ≥146 pmol per 8 × 10 RBCs, 17.1 on methotrexate, and 3.9 on infliximab monotherapy; P = .001 for both comparisons). However, there was no association between the use of immunomodulators and 6-TGN concentrations with vedolizumab (median levels of 8.8 on thiopurine with 6-TGN ≥152 pmol per 8 × 10 RBCs, 6.8 on methotrexate, and 10.5 on vedolizumab monotherapy; P > .05 for both comparisons) or ustekinumab median concentrations (median levels of 5.0 on thiopurine with 6-TGN ≥154 pmol per 8 × 10 RBCs, 5.2 on methotrexate and 7.0 on ustekinumab monotherapy; P > .05 for both comparisons). Fourteen (12%) patients had anti-infliximab antibodies, while 1 patient had ADAs in each of the other drug cohorts.
CONCLUSIONS
Achieving higher 6-TGN levels or the use of methotrexate improved the pharmacokinetics of infliximab. Conversely, these data do not support the use of combination therapy to augment pharmacokinetics with vedolizumab or ustekinumab.
Topics: Humans; Infliximab; Azathioprine; Ustekinumab; Mercaptopurine; Methotrexate; Prospective Studies; Immunologic Factors; Antibodies, Monoclonal, Humanized; Inflammatory Bowel Diseases; Immunosuppressive Agents
PubMed: 36280102
DOI: 10.1016/j.cgh.2022.10.016 -
Nanomaterials (Basel, Switzerland) Sep 2023Many purine derivatives are active pharmaceutical ingredients of significant importance in the therapy of autoimmune diseases, cancers, and viral infections. In many... (Review)
Review
Many purine derivatives are active pharmaceutical ingredients of significant importance in the therapy of autoimmune diseases, cancers, and viral infections. In many cases, their medical use is limited due to unfavorable physicochemical and pharmacokinetic properties. These problems can be overcome by the preparation of the prodrugs of purines or by combining these compounds with nanoparticles. Herein, we aim to review the scientific progress and perspectives for polymer-based nanoparticles as drug delivery systems for purines. Polymeric nanoparticles turned out to have the potential to augment antiviral and antiproliferative effects of purine derivatives by specific binding to receptors (ASGR1-liver, macrophage mannose receptor), increase in drug retention (in eye, intestines, and vagina), and permeation (intranasal to brain delivery, PEPT1 transport of acyclovir). The most significant achievements of polymer-based nanoparticles as drug delivery systems for purines were found for tenofovir disoproxil in protection against HIV, for acyclovir against HSV, for 6-mercaptopurine in prolongation of mice ALL model life, as well as for 6-thioguanine for increased efficacy of adoptively transferred T cells. Moreover, nanocarriers were able to diminish the toxic effects of acyclovir, didanosine, cladribine, tenofovir, 6-mercaptopurine, and 6-thioguanine.
PubMed: 37836288
DOI: 10.3390/nano13192647 -
Journal of Hepatology Apr 2024
Topics: Humans; Hepatitis, Autoimmune; Immunosuppressive Agents; Azathioprine
PubMed: 38309440
DOI: 10.1016/j.jhep.2024.01.021 -
Biomedicine & Pharmacotherapy =... Jun 2024The interaction between the gut microbiota and mercaptopurine (6-MP), a crucial drug used in pediatric acute lymphoblastic leukemia (ALL) treatment, has not been...
The interaction between the gut microbiota and mercaptopurine (6-MP), a crucial drug used in pediatric acute lymphoblastic leukemia (ALL) treatment, has not been extensively studied. Here we reveal the significant perturbation of gut microbiota after 2-week 6-MP treatment in beagles and mice followed by the functional prediction that showed impairment of SCFAs production and altered amino acid synthesis. And the targeted metabolomics in plasma also showed changes in amino acids. Additionally, targeted metabolomics analysis of feces showed changes in amino acids and SCFAs. Furthermore, ablating the intestinal microbiota by broad-spectrum antibiotics exacerbated the imbalance of amino acids, particularly leading to a significant decrease in the concentration of S-adenosylmethionine (SAM). Importantly, the depletion of gut microbiota worsened the damage of small intestine caused by 6-MP, resulting in increased intestinal permeability. Considering the relationship between toxicity and 6-MP metabolites, we conducted a pharmacokinetic study in pseudo germ-free rats to confirm that gut microbiota depletion altered the methylation metabolites of 6-MP. Specifically, the concentration of MeTINs, a secondary methylation metabolite, showed a negative correlation with SAM, the pivotal methyl donor. Additionally, we observed a strong correlation between Alistipes and SAM levels in both feces and plasma. In conclusion, our study demonstrates that 6-MP disrupts the gut microbiota, and depleting the gut microbiota exacerbates 6-MP-induced intestinal toxicity. Moreover, SAM derived from microbiota plays a crucial role in influencing plasma SAM and the methylation of 6-MP. These findings underscore the importance of comprehending the role of the gut microbiota in 6-MP metabolism and toxicity.
PubMed: 38925017
DOI: 10.1016/j.biopha.2024.116975 -
Journal of the European Academy of... Jan 2024Treating atopic dermatitis (AD) in pregnant or breastfeeding women, and in women and men with AD aspiring to be parents is difficult and characterized by uncertainty, as... (Review)
Review
Treating atopic dermatitis (AD) in pregnant or breastfeeding women, and in women and men with AD aspiring to be parents is difficult and characterized by uncertainty, as evidence to inform decision-making on systemic anti-inflammatory treatment is limited. This project mapped consensus across dermatologists, obstetricians and patients in Northwestern Europe to build practical advice for managing AD with systemic anti-inflammatory treatment in men and women of reproductive age. Twenty-one individuals (sixteen dermatologists, two obstetricians and three patients) participated in a two-round Delphi process. Full consensus was reached on 32 statements, partial consensus on four statements and no consensus on four statements. Cyclosporine A was the first-choice long-term systemic AD treatment for women preconception, during pregnancy and when breastfeeding, with short-course prednisolone for flare management. No consensus was reached on second-choice systemics preconception or during pregnancy, although during breastfeeding dupilumab and azathioprine were deemed suitable. It may be appropriate to discuss continuing an existing systemic AD medication with a woman if it provides good disease control and its benefits in pregnancy outweigh its risks. Janus kinase (JAK) inhibitors, methotrexate and mycophenolate mofetil should be avoided by women during preconception, pregnancy and breastfeeding, with medication-specific washout periods advised. For men preconception: cyclosporine A, azathioprine, dupilumab and corticosteroids are appropriate; a 3-month washout prior to conception is desirable for methotrexate and mycophenolate mofetil; there was no consensus on JAK inhibitors. Patient and clinician education on appropriate (and inappropriate) AD treatments for use in pregnancy is vital. A shared-care framework for interdisciplinary management of AD patients is advocated and outlined. This consensus provides interdisciplinary clinical guidance to clinicians who care for patients with AD before, during and after pregnancy. While systemic AD medications are used uncommonly in this patient group, considerations in this article may help patients with severe refractory AD.
Topics: Pregnancy; Male; Humans; Female; Cyclosporine; Methotrexate; Breast Feeding; Dermatitis, Atopic; Azathioprine; Mycophenolic Acid; Consensus; Anti-Inflammatory Agents
PubMed: 37818828
DOI: 10.1111/jdv.19512 -
Clinical Rheumatology Nov 2023Cardiovascular disease in patients with systemic lupus erythematosus (SLE) remains one of the most common causes of death and is caused by several factors, including... (Review)
Review
Cardiovascular disease in patients with systemic lupus erythematosus (SLE) remains one of the most common causes of death and is caused by several factors, including both traditional and disease-specific risk factors. We aimed to systematically appraise the evidence of cardiovascular disease risk factors focusing on the SLE population. The protocol for this umbrella review is registered in PROSPERO (registration no. CRD42020206858). A systematic literature search was conducted in PubMed, Embase, and the Cochrane Library from database inception to June 22, 2022, for systematic reviews and meta-analyzes that examined cardiovascular disease risk factors in patients with SLE. Two reviewers independently extracted data and assessed the quality of the included studies using the "Assessing the Methodological Quality of Systematic Reviews 2 (AMSTER 2)" tool. Of the 102 identified articles, nine systematic reviews were included in this umbrella review. All included systematic reviews were assessed as critically low quality according to the AMSTER 2 tool. The traditional risk factors identified in this study were older age, male sex, hypertension, dyslipidemia, smoking, and a family history of cardiovascular disease. SLE-specific risk factors were long-term disease duration, lupus nephritis, neurological disorders, high disease activity, organ damage, use of glucocorticoids, azathioprine, and antiphospholipid antibodies, including anticardiolipin antibodies and lupus anticoagulant. This umbrella review identified some cardiovascular disease risk factors in patients with SLE; however, the study quality of all included systematic reviews was critically low. Key Points • We examined the evidence of cardiovascular disease risk factors focusing on patients with systemic lupus erythematosus. • We found that long-term disease duration, lupus nephritis, neurological disorders, high disease activity, organ damage, use of glucocorticoids, azathioprine, and antiphospholipid antibodies, including anticardiolipin antibodies and lupus anticoagulant, were cardiovascular disease risk factors among patients with systemic lupus erythematosus. • The review indicates the need for well-validated and high-quality future reviews that assess major adverse cardiovascular events as an outcome in patients with systemic lupus erythematosus.
Topics: Humans; Male; Cardiovascular Diseases; Lupus Coagulation Inhibitor; Lupus Nephritis; Antibodies, Anticardiolipin; Azathioprine; Systematic Reviews as Topic; Lupus Erythematosus, Systemic; Antibodies, Antiphospholipid; Risk Factors; Antiphospholipid Syndrome; Nervous System Diseases
PubMed: 37142864
DOI: 10.1007/s10067-023-06608-6 -
Pharmacoepidemiology and Drug Safety Nov 2023To detect the possible safety signal of purine antimetabolites associated with Pneumocystis jirovecii pneumonia through disproportionality analysis in the FDA Adverse...
PURPOSE
To detect the possible safety signal of purine antimetabolites associated with Pneumocystis jirovecii pneumonia through disproportionality analysis in the FDA Adverse Event Reporting System (FAERS) Database.
METHODS
A case/non-case retrospective disproportionality analysis was performed in the publicly available FAERS database using AERSmine (2004Q1-2021Q3). Four models were developed to explore the signal strength of PAs among different populations with possible confounding factors. Reporting odds ratio (ROR) and Proportional reporting ratio (PRR) was used as the data mining algorithm for the analysis. A value of ROR-1.96SE > 1 and PRR ≥ 2 with an associated X value of 4 or more was considered the threshold for a signal.
RESULTS
A total of 7073 reports associated with Pneumocystis jirovecii pneumonia were present in the database, of which 899 reports were associated with purine antimetabolites. A crude signal strength of ROR 15.76(14.70-16.91) was obtained for purine antimetabolites associated PJP, with the highest signal strength reported with fludarabine and thioguanine [ROR 19.63(17.42-22.13); 19.45(13.21-28.63)]. Stratifying the cases based on autoimmune disorders and the cancer population revealed an ROR of 3.33(2.46-4.50) and 2.93(2.26-3.79) respectively. The highest risk of PJP with use of PAs was observed amongst children with a higher risk of nearly 2 times than the adult population [ROR 11.57(9.16-14.62)].
CONCLUSIONS
Our study provided evidence on the occurrence of PJP with the use of purine antimetabolites among the autoimmune and cancer population. We identified signals for PJP with azathioprine, mercaptopurine, thioguanine, cladribine, fludarabine, and clofarabine. More research with a superior epidemiological study design of a defined population is required to validate these findings.
Topics: Adult; Child; Humans; Pneumonia, Pneumocystis; Retrospective Studies; Thioguanine; Neoplasms; Antimetabolites
PubMed: 37265365
DOI: 10.1002/pds.5647 -
Arthritis & Rheumatology (Hoboken, N.J.) Nov 2023B-cell depletion using the anti-CD20 monoclonal antibody rituximab is a cornerstone in the therapeutic concept of multiple autoimmune diseases. B-cell depletion is... (Observational Study)
Observational Study
OBJECTIVE
B-cell depletion using the anti-CD20 monoclonal antibody rituximab is a cornerstone in the therapeutic concept of multiple autoimmune diseases. B-cell depletion is associated with a higher risk for severe infections, and the time span of B-cell repopulation differs greatly between individuals. Data on factors influencing B-cell repopulation kinetics are limited. This study aims to identify patient-specific and therapy-associated covariates that modulate B-cell repopulation.
METHODS
This single-center retrospective observational study presents data of 839 subjects receiving 2,017 courses of rituximab for autoimmune diseases. Assessed covariates are patient-specific factors (sex, age, kidney function, and underlying disease) and co-immunosuppression with common agents (azathioprine, cyclosporine A, cyclophosphamide, hydroxychloroquine, methotrexate, mycophenolate mofetil, tacrolimus, and corticosteroids). The primary end point is the time to B-cell repopulation (≥5/μl). The secondary end point is the time to B-cell reconstitution (≥50/μl). Multivariate time-to-event analysis and logistic regression models were applied to estimate the influence of covariates.
RESULTS
Age over 60 years (hazard ratio [HR] 0.71 for repopulation, P = 0.008), impaired kidney function (HR 0.72, P = 0.001), antineutrophil cytoplasmic antibody-associated vasculitis (HR 0.61, P < 0.001), solid organ transplantation (HR 0.4, P < 0.001), and co-immunosuppression with corticosteroids (HR 0.64, P < 0.001) or azathioprine (HR 0.49, P < 0.001) were associated with impaired B-cell repopulation and reconstitution. Effects of corticosteroids (P = 0.043) and azathioprine (P = 0.025) were dose dependent.
CONCLUSION
Prolonged rituximab dosing intervals may be effective to achieve B-cell depletion and reduce risk of infection in advanced age or patients with impaired kidney function. Co-medication with corticosteroids or azathioprine prolongs B-cell recovery, which may increase therapeutic effects but also the rate of adverse events.
Topics: Humans; Middle Aged; Rituximab; Azathioprine; Cyclophosphamide; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Adrenal Cortex Hormones; Immunosuppressive Agents
PubMed: 37276446
DOI: 10.1002/art.42625 -
International Immunopharmacology Oct 2023Inflammasome has been reported to play an important role in the pathogenesis and progression of hematologic malignancies. As one of the backbone drugs for treating acute...
BACKGROUND
Inflammasome has been reported to play an important role in the pathogenesis and progression of hematologic malignancies. As one of the backbone drugs for treating acute lymphoblastic leukemia (ALL), the anti-inflammatory effect of mercaptopurine (6-MP) and the impact of gut microbiome changes caused by 6-MP on anti-inflammasome remain unclear.
OBJECTIVE
We aimed to explore the association between 6-MP therapeutic effects and microbiome-involved inflammatory responses in ALL mice models.
STUDY DESIGN
ALL murine model was built by i.v. injecting murine L1210 cells into DBA/2 mice (model group). Two weeks after cell injections, 6-MP was orally administrated for 14 days (6-MP group). Fecal samples of mice were collected at different time points. Cecum short-chain fatty acids (SCFAs) concentrations were determined by LC-MS/MS method. Serum cytokines were measured using a cytometric bead array. Gut microbiota composition in mice was explored using 16S rRNA gene sequencing.
RESULTS
The anti-tumor effect of 6-MP was proved in ALL mice models. The levels of pro-inflammatory factors IL-6 and TNFα significantly decreased after the administration of 6-MP. Cecum contents' acetate, propionate, and butyrate levels were negatively correlated with IL-6 (correlation coefficient: acetate, -0.24; propionate, -0.26; butyrate, -0.17) and TNFα (correlation coefficient: acetate, -0.45; propionate, -0.42; butyrate, -0.31) changes. Relative abundance changes of f_Lachnospiraceae.g_ASF356 and f_Peptococcaceae.g_uncultured were in accordance with the changes of butyrate levels and opposite to the changes of pro-inflammatory levels.
CONCLUSION
The anti-inflammatory response of 6-MP influenced by intestinal microbiota and its metabolites SCFAs, especially butyrate, played an essential role in improving ALL progression.
Topics: Mice; Animals; Propionates; Tumor Necrosis Factor-alpha; Mercaptopurine; Interleukin-6; RNA, Ribosomal, 16S; Chromatography, Liquid; Mice, Inbred DBA; Tandem Mass Spectrometry; Fatty Acids, Volatile; Microbiota; Butyrates; Acetates; Anti-Inflammatory Agents; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 37573688
DOI: 10.1016/j.intimp.2023.110782