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Expert Review of Clinical Immunology Mar 2024Atopic dermatitis is a prevalent skin condition causing dry, pruritic, inflammatory skin lesions that can result in patient distress. Various emerging classes of... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
Atopic dermatitis is a prevalent skin condition causing dry, pruritic, inflammatory skin lesions that can result in patient distress. Various emerging classes of therapy, including biologics and Janus kinase inhibitors, have been developed in recent years.
AREAS COVERED
A literature search of PubMed was conducted to explore existing literature and clinical trials. Treatment options and adverse effects were summarized by class and severity. JAK inhibitors and biologics are efficacious options for adults with severe atopic dermatitis. Using the Eczema Area and Severity Index (EASI) from 11 randomized control trials, the highest efficacy was seen with upadacitinib 30 mg with 70% of patients achieving EASI-75. Older, immune-inhibiting treatment options are still appropriate options to improve patient conditions. A meta-analysis of 39 randomized control trials concluded high dose cyclosporine is more effective at improving quality of life and itch when compared to azathioprine and methotrexate. Newly developed topical and systemic medications improve disease and itch severity and can be considered in patients without adequate control with their initial treatment regimen. Adverse effects must be considered when using the newer options, although major adverse events were not seen.
EXPERT OPINION
Current management options are efficacious, but adherence is required for any effect.
Topics: Adult; Humans; Dermatitis, Atopic; Quality of Life; Cyclosporine; Methotrexate; Biological Products; Treatment Outcome; Severity of Illness Index
PubMed: 38037822
DOI: 10.1080/1744666X.2023.2291038 -
World Journal of Gastroenterology Jul 2023There is no consensus on the recommended duration of and optimal time to stop azathioprine (AZA) therapy in inflammatory bowel disease (IBD). Determining the optimal...
BACKGROUND
There is no consensus on the recommended duration of and optimal time to stop azathioprine (AZA) therapy in inflammatory bowel disease (IBD). Determining the optimal duration and cessation time can help to balance the risks of long-term intake with the possibility of relapse after cessation.
AIM
To describe the events following AZA cessation.
METHODS
Retrospective analysis was performed to examine data from adult patients affected by IBD who were followed at the University of Padua and had started but then discontinued AZA between 1995 and 2022. Data on therapy duration, reasons for cessation, and type of relapse after cessation were collected. Cox regression models were used to estimate the risk of relapse in different subgroups.
RESULTS
A total of 133 ulcerative colitis patients and 141 Crohn's disease patients were included. Therapy with AZA was stopped in the 1 year in approximately 34% of patients but was continued for more than 10 years in approximately 10% of cases. AZA discontinuation was due to primary failure or disease relapse in 30% of patients and due to disease remission in 25.2% of patients. Most of the remaining cases stopped AZA therapy due to side effects (primarily clinical intolerance, cytopenia, and pancreatic disease). Patients who stopped AZA for clinical remission had an 83% lower risk of relapse during the observation time than other groups, with a relapse-free rate of 89% after 1 year and 79% after 2 years.
CONCLUSION
AZA administration is effective and safe, but it requires careful monitoring for potential minor and major side effects. Only 10% of patients who achieved remission with AZA needed a new treatment within 1 year of drug interruption.
Topics: Adult; Humans; Azathioprine; Immunosuppressive Agents; Retrospective Studies; Inflammatory Bowel Diseases; Colitis, Ulcerative; Remission Induction
PubMed: 37545640
DOI: 10.3748/wjg.v29.i27.4334 -
The Lancet. Neurology Mar 2024Myasthenia gravis is an autoimmune disorder of the neuromuscular junction. Treatment typically includes symptomatic oral cholinesterase inhibitors, immunosuppression,...
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.
Topics: Adolescent; Adult; Humans; Azathioprine; Immunosuppressive Agents; Myasthenia Gravis; Mycophenolic Acid; Prospective Studies; Quality of Life
PubMed: 38365379
DOI: 10.1016/S1474-4422(24)00028-0 -
Journal of Clinical Medicine Oct 2023This study focuses on the use of thiopurines for treating inflammatory bowel diseases (IBD). These drugs undergo enzymatic changes within the body, resulting in active... (Review)
Review
This study focuses on the use of thiopurines for treating inflammatory bowel diseases (IBD). These drugs undergo enzymatic changes within the body, resulting in active and inactive metabolites that influence their therapeutic effects. The research examines the role of genetic polymorphisms in the enzyme thiopurine S-methyltransferase (TPMT) in predicting the therapeutic response and adverse effects of thiopurine treatment. The TPMT genotype variations impact the individual responses to thiopurines. Patients with reduced TPMT activity are more susceptible to adverse reactions (AEs), such leukopenia, hepatotoxicity, pancreatitis, and nausea, which are common adverse effects of thiopurine therapy. The therapeutic monitoring of the metabolites 6-thioguanine nucleotides (6-TGN) and 6-methyl mercaptopurine (6-MMP) is proposed to optimize treatment and minimize AEs. Patients with higher 6-TGN levels tend to have better clinical responses, while elevated 6-MMP levels are linked to hepatotoxicity. Genotyping for TPMT before or during treatment initiation is suggested to tailor dosing strategies and enhance treatment efficacy while reducing the risk of myelosuppression. In conclusion, this study highlights the importance of considering genetic variations and metabolite levels in optimizing thiopurine therapy for IBD patients, focusing on balance therapeutic efficacy with the prevention of adverse effects and contributing to personalized treatment and better patient outcomes.
PubMed: 37959208
DOI: 10.3390/jcm12216742 -
Respiratory Medicine Jan 2024Interstitial pneumonia with autoimmune features (IPAF) has features of connective tissue disease-associated interstitial lung disease (CTD-ILD), but without meeting...
BACKGROUND
Interstitial pneumonia with autoimmune features (IPAF) has features of connective tissue disease-associated interstitial lung disease (CTD-ILD), but without meeting criteria for a specific CTD. We compared baseline characteristics, survival, and response to treatment of IPAF to both CTD-ILD and unclassifiable ILD.
METHODS
Measurements were extracted from a prospective registry. Baseline features and survival were compared in IPAF against both CTD-ILD and unclassifiable ILD. Linear trajectory of lung function decline (%-predicted forced vital capacity [FVC%] and diffusion capacity of the lung for carbon monoxide [DLCO%]) before and after initiation of mycophenolate or azathioprine were compared in IPAF against both CTD-ILD and unclassifiable ILD using linear mixed models.
RESULTS
Compared to CTD-ILD (n = 1240), patients with IPAF (n = 128) were older, more frequently male, and had greater smoking history. Compared to unclassifiable ILD (n = 665), patients with IPAF were younger, more frequently female, and had worse baseline lung function. IPAF had higher mortality compared to CTD-ILD and similar risk of mortality compared to unclassifiable ILD. Mycophenolate initiation was associated with stabilization of FVC% and DLCO% in all ILD subtypes except for FVC% in patients with IPAF, and azathioprine initiation with stabilization of FVC% and DLCO% in all ILD subtypes except for FVC% decline in IPAF and DLCO% decline in CTD-ILD.
CONCLUSION
Patients with IPAF had worse survival compared to those with CTD-ILD and similar mortality to unclassifiable ILD, with treatment being associated with stabilization in lung function in all three ILDs. It is uncertain whether IPAF should be considered a distinct ILD diagnostic subgroup.
Topics: Humans; Male; Female; Azathioprine; Lung Diseases, Interstitial; Lung; Connective Tissue Diseases; Immunosuppressive Agents; Risk Factors
PubMed: 38142756
DOI: 10.1016/j.rmed.2023.107500 -
Revue Neurologique Mar 2024Neuromyelitis optica spectrum disorder (NMOSD) is a rare but debilitating autoimmune disease of the central nervous system (CNS) for which several biotherapies have... (Review)
Review
Neuromyelitis optica spectrum disorder (NMOSD) is a rare but debilitating autoimmune disease of the central nervous system (CNS) for which several biotherapies have recently been approved on the market. Historically, NMOSD disease-modifying treatments relied on wide-spectrum off-label immunosuppressants, such as azathioprine, mycophenolate mofetil, and cyclophosphamide. Since 2015, evidence has accumulated to support off-label biotherapies (rituximab and tocilizumab) and to approve satralizumab, inebilizumab, eculizumab, and ravulizumab. This next generation of drugs provides several targeted disease-modifying treatment options for NMOSD. Here, we review this modern panel. We first review the mechanistic rationales associated with their specific targets. We then review the pivotal evidence supporting their use in practice and their respective regimens. Lastly, we discuss the positioning of each therapeutic class. The current therapeutic options in NMOSD comprise three targeted mechanisms at different stages of a unique tissue-injury cascade: B-cell depleting, anti-cytokine, and anti-complement therapies. One drug has been approved on the market in each class. The current consensus proposes positioning the approved drugs as first-line treatments for newly-diagnosed patients and as alternative therapies in case of failure of historical treatment. Yet, there has been limited acceptance in practice due to high drug prices.
PubMed: 38553270
DOI: 10.1016/j.neurol.2024.01.008 -
Neuroimaging Clinics of North America Feb 2024Primary central nervous system vasculitis (PCNSV) is a vasculitis limited to the brain and spinal cord. Induction therapy often consists of steroids and... (Review)
Review
Primary central nervous system vasculitis (PCNSV) is a vasculitis limited to the brain and spinal cord. Induction therapy often consists of steroids and cyclophosphamide. Maintenance therapy includes a prednisone taper and may be combined with medications such as azathioprine or mycophenolate mofetil. Relapse is common in PCNSV and an increased dose of steroids is often given, sometimes with a change in therapy. Medications such as rituximab and mycophenolate mofetil may be good alternatives in those who do not respond to initial treatment or who have relapse of disease. Mortality rates of 8% to 9% are reported in the literature.
Topics: Humans; Immunosuppressive Agents; Mycophenolic Acid; Vasculitis, Central Nervous System; Steroids; Recurrence
PubMed: 37951702
DOI: 10.1016/j.nic.2023.07.008 -
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 -
Journal of Clinical Medicine Jan 2024Despite advances in the treatment of patients with systemic lupus erythematous (SLE), outcomes have remained suboptimal. Persistent disease activity, patient... (Review)
Review
Despite advances in the treatment of patients with systemic lupus erythematous (SLE), outcomes have remained suboptimal. Persistent disease activity, patient comorbidities and drug toxicities contribute to the accrual of progressive irreversible damage and high rates of morbidity and mortality. Currently, similar drug doses and regimens are promulgated in the treatment guidelines for all SLE patients, despite the vast differences in patient and environmental factors that affect the drugs' metabolism and blood concentrations. This causes a disconnect between drug dosing and drug blood concentrations, which can then result in unpredictability in drug toxicities and therapeutic effects. In this review, we discuss commonly used oral immunosuppressive medications in SLE, their pharmacogenomics, and factors affecting their metabolism and blood concentrations. Further, we highlight the role of therapeutic drug monitoring in SLE, which is the first accessible step to individualising therapy.
PubMed: 38256585
DOI: 10.3390/jcm13020451 -
BMJ Case Reports Sep 2023A young male presented with intermittent high-grade fever, asymmetric polyarthritis and erythematous, tender nodules over left shin for 2 months duration. He had a...
A young male presented with intermittent high-grade fever, asymmetric polyarthritis and erythematous, tender nodules over left shin for 2 months duration. He had a history of alcohol dependence with multiple episodes of acute pancreatitis. With polyarthritis progressing relentlessly, unresponsive to non-steroidal anti-inflammatory drugs and steroids, a provisional diagnosis of sarcoidosis was considered. Indeed, he was treated with azathioprine and rituximab with no effect. Biopsy of the skin nodule revealed subcutaneous fat necrosis, foam cells, deposition of eosinophilic amorphous material and calcification. Synovial fluid aspiration from the arthritic knee obtained purulent but surprisingly culture-negative material, rich in triglycerides. Abdominal CT confirmed chronic pancreatitis. Final diagnosis of pancreatitis, panniculitis and polyarthritis (PPP) syndrome was made. He underwent surgical pancreatic ductal drainage leading to complete remission of symptoms. PPP syndrome triad occurs due to leakage of pancreatic enzymes into systemic circulation and subsequent fat necrosis. Surgical drainage of pancreatic duct is often curative.
Topics: Humans; Male; Pancreatitis; Acute Disease; Panniculitis; Arthritis; Subcutaneous Fat; Fat Necrosis
PubMed: 37751979
DOI: 10.1136/bcr-2023-254732