Tumor Necrosis Factor Alpha Inhibitors Research Articles

Biologic therapies committee. What does it provide?

ObjectiveTo assess the general healthcare impact of a Biological Therapies Commitee (immune-mediated inflammatory diseases) through prescription habits, pre-biological studies and immunization. MethodA quasi-experimental study was conducted on all naive patients of legal age who started treatment with a biological agent for an immune-mediated inflammatory disease the year before and the year after the creation of the Biological Therapies Committee. ResultsA total of 31 patients treated in 2016 and 40 patients treated in 2018 were included. Prescriptions of tumor necrosis factor alpha inhibitor drugs decreased in 2018 (from 80.6% to 45.0%, p < 0.05), while prescriptions of interleukin 12/23 inhibitors increased (from 12.9% to 35.0%, p < 0.05). Tuberculosis screening was statistically different between the two periods: the number of interferon gamma release assays performed was higher in 2018 (from 9.7% to 80.0%, p < 0.01) and the proportion of patients who successfully underwent chemoprophylaxis was higher in 2018 (from 36.4% to 81.8%, p < 0.05). The proportion of tests requested for the study of viral pathologies and the number of vaccines administered were also higher in 2018. ConclusionsThe development of a specific Biological Therapies Committee allows healthcare improvements, contributing to a deeper understanding of the medications and to preventing the infection-related adverse events. It would therefore seem advisable to develop specialized committees akin to the Biological Therapies Committee in other domains.

Comparative binding effects of celecoxib/ poly(lactic-co-glycolic acid) microparticles with enhancing anti-inflammatory and anti-cancer activities: Density functional theory, molecular Docking, and ADMET calculations

This study is to evaluate the enhancement of anti-inflammatory and anti-cancer activities of celecoxib (CXB) in a dichloromethane (DCM) environment by poly(lactic-co-glycolic acid) (PLGA), using density functional dispersion correction (DFT-D), time-dependent density functional theory (TDDFT), molecular docking (MD), and ADMET calculations. The CXB, via its sulfonamide (-NH2SO2) group contact with the PLGA in state B through hydrogen bonds, is stronger than in states A and C, according to our computed analyses based on binding energy and chemical reactivity parameters. According to the theoretical analysis of IR spectra, the interaction of CXB with PLGA causes shifts in both the pure PLGA and the CXB. In the presence of stronger negative Gibbs free solvation energy (Gsolv) values, the CXB interaction with PLGA results in the increment of dipole moment, higher solubility, and the energy gap (Eg) reduction. Further, MD calculations on states A, B, and C were able to inhibit tumor necrosis factor-alpha (TNF-α), interleukin 1 beta (IL-1β), cyclooxygenase-2 (COX-2), and human epidermal growth factor receptor 2 (HER2). Based on the MD calculations, the obtained data illustrated a strong interaction with the target binding pocket (CXB via the sulfonamide group interacting with PLGA in the state B), leading to the improvement of the anti-inflammatory and anti-cancer activities in comparison with the pure CXB.

A clinical case of pyoderma gangrenosum as a severe extraintestinal manifestation of Crohn’s disease

Pyoderma gangrenosum is a rare neutrophilic dermatosis associated with a number of immune-mediated disorders, most frequently with inflammatory bowel disease and rheumatoid arthritis. Despite significant success in the treatment in inflammatory bowel disease, the problem of multidisciplinary management of patients with extraintestinal manifestations in routine medical practice remains unsolved. The paper presents a clinical case of a 32-year old female patient with a life-threatening extraintestinal manifestation of Crohn's disease, i. e. pyoderma gangrenosum. Late diagnosis of Crohn's disease, underestimation of the inflammation activity in the gut and respective lack of disease-modifying treatment were the reasons for the occurrence of pyoderma gangrenosum and its uncontrolled course. The untimely diagnosis of the skin purulent wound as an extraintestinal manifestation of Crohn's disease has led to delay in the immunosuppressive therapy required. The patient needed an intensive course of systemic glucocorticosteroids, prompt addition of a tumor necrosis factor-alpha inhibitor and surgery as a circulatory autodermoplasty.

Efficacy of TNF-Alpha Inhibitors to Control Inflammation and Prevent Secondary Complications in Non-Infectious Uveitis: A Real-Life Experience from Switzerland

ABSTRACT Purpose To evaluate the efficacy of systemic tumor necrosis factor-alpha inhibitors (TNFi) in the treatment of non-infectious uveitis (NIU). Methods This Swiss multicenter retrospective cohort study included patients with NIU requiring TNFi during the period from 2001 to 2018. Risk factors for the occurrence of new complications were identified using Cox regression analysis and hazard ratios (HR). Results Seventy-one patients (126 eyes; mean age 40.6 ± 14.4 years, mean duration of uveitis 46.0 ± 61.8 months) were followed for 40.2 ± 17.3 months after addition of TNFi. Under TNFi, visual acuity improved from 0.2 ± 0.3 to 0.1 ± 0.3 logMAR (p < 0.001). The portion of patients under systemic corticosteroids decreased from 81.7% to 25.4% (p < 0.001), while that for conventional synthetic disease-modifying anti-rheumatic drugs insignificantly decreased from 63.4% to 50.7% (p > 0.05). In 80.2% of eyes, complications were present at baseline with epiretinal gliosis (39.7%), cataract (41.3%) and macular edema (ME; 27.8%) being the most common. New complications under TNFi were encountered in 49.2% of eyes, also including recurrence (5 eyes) or new onset of ME (14 eyes). The need for switching of TNFi was associated with further complications (HR 3.78, p = 0.012). Conclusion Although the efficacy and tolerability of TNFi in a real-life setting are favorable, treatment is often initiated late, i.e., after many eyes have already developed complications. Even with TNFi, new complications, particularly ME, cannot be completely avoided. Further research is needed to assess the impact of earlier initiation of TNFi therapy.

Compliance level to Tuberculosis prophylaxis in patients undergoing therapy with tumor necrosis factor-alpha inhibitors: a cross-sectional study.

Tumor necrosis factor-alpha (TNF-α) inhibitors are used to treat autoimmune diseases such as rheumatoid arthritis, ankylosing spondylitis, and inflammatory bowel disease. However, patients using TNF-α inhibitors are at a high risk of developing tuberculosis. Therefore, this study aimed to evaluate the compliance level of patients who were prescribed TNF-α-based tuberculosis prophylactic treatment. The study included 135 patients who were followed up at a tuberculosis dispensary between December 2020 and June 2021 and agreed to participate in the study. The study was conducted after obtaining necessary permissions from the institution, ethics committee, and patients. Data were collected using a questionnaire and evaluated using the Medication Adherence Report Scale (MARS). The MARS scale scores range from 5 to 25, with high scores indicating a high level of "medication compliance level". Of the included patients, 42.2% were females, 46.7% were primary school graduates, and their mean age was 43.75±11.86 years. Additionally, 35.6% of patients had ankylosing spondylitis, among whom 54.1% had a disease duration of 1-5 years and 57.8% had been using TNF-α inhibitors for a year. Of the patients taking isoniazid (INH) for tuberculosis prophylaxis, 47.4% missed their prescribed INH doses, with "forgetfulness" being the reason in 28.9% of these patients. The patients had a mean MARS score of 15.71±6.18. Patients using TNF-α inhibitors were found to have "moderate" compliance levels for INH-based prophylactic therapy. It is recommended that the compliance levels of patients and factors influencing their compliance should be regularly monitored.

Infliximab Ameliorates Methotrexate-Induced Nephrotoxicity in Experimental Rat Model: Impact on Oxidative Stress, Mitochondrial Biogenesis, Apoptotic and Autophagic Machineries

Accumulating data confirms that Methotrexate (MTX), a well-known immunosuppressive and anticancer drug, causes nephrotoxicity. Infliximab (INF), the inhibitor of tumor necrosis factor-alpha (TNF-α), was proven to have anti-inflammatory properties. Thus, it may have potential in preventing MTX-induced nephrotoxicity. Therefore, this study aimed to inspect the prospective nephroprotective effect of INF on MTX-induced rat nephrotoxicity through investigating the possible molecular mechanisms, including its interference with different death routes, oxidative stress as well as mitochondrial biogenesis. Rats received an INF intraperitoneal single dose of 7 mg/kg 72 h prior to a single 20 mg/kg MTX injection. MTX nephrotoxicity was demonstrated by significantly increased serum levels of the renal indicators urea and creatinine as well as renal inflammatory markers TNF-α and Interleukin-6 (IL-6) and the renal oxidative stress marker malondialdehyde (MDA), while renal antioxidant enzyme superoxide dismutase (SOD) was significantly decreased compared to control. INF injection prior to MTX markedly reversed these MTX-induced effects. Besides, MTX impaired mitochondrial biogenesis, while INF attenuated this impairment, as indicated by increased expression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). Finally, MTX triggered apoptotic and autophagic cascades in renal tissues as evidenced by reduced anti-apoptotic Bcl-2 protein expression as well as elevated expression of the pro-apoptotic protein Bax and both key regulators of autophagy; beclin-1 and LC-3, whereas INF pretreatment counteracted these apoptotic and autophagic effects of MTX. Summarily, these results suggest that INF provides protection against MTX-induced nephrotoxicity which could be elucidated by its antioxidant, anti-inflammatory, anti-apoptotic and anti-autophagic effects as well as upregulating mitochondrial biogenesis.

A retrospective analysis of mortality risk and immunosuppressive therapy for Stevens-Johnson Syndrome and toxic epidermal necrolysis syndrome using the TriNetX research network

Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) exist on a spectrum of autoimmune conditions which cause epidermal detachment and keratinocyte necrosis. Due to the rare incidence of these conditions, a dramatic heterogeneity in treatment algorithms exists. To better appreciate pharmacologic immunosuppressive therapies' impact on survival, the authors queried a multi-institutional data network. Data for this study was extracted from TriNetX Research Network, a platform that contains ICD-9/ICD-10 coding data from a consortium of international healthcare organizations. Seventy-one institutions were queried to identify adult patients diagnosed with SJS, TEN or SJS-TEN Overlap. Cohorts were created based on the therapy received: systemic steroids (SS), diphenhydramine (DH), cyclosporine (CS), intravenous immunoglobulin (IVIG), tumor necrosis factor alpha inhibitors (TNFαi), or a combination of treatments. Cohorts were then propensity matched with patients who received supportive care. Patients who only received one of the above treatments showed no significant reduction in 90-day mortality. Patients who received CS or IVIG as part of their multitherapy showed a significantly increased risk of death when compared to supportive care (CS: RR = 1.583, 95% CI [1.119, 2.240]; IVIG: RR = 2.132, 95% CI [1.485, 3.059]). Despite their frequent utilization, this study’s analysis suggests that none of these therapies confer significant 90-day mortality survival over supportive care alone. These results highlight the heterogeneity of therapies and emphasize the need for critical prospective appraisal of their outcomes in SJS and TEN.

An Insight on the Possible Association between Inflammatory Bowel Disease and Biologic Therapy with IL-17 Inhibitors in Psoriasis Patients.

Psoriasis is a chronic, inflammatory, multisystemic disease which affects approximately 2-3% of the population globally, whose onset is triggered by genetic and environmental factors which activate both dendritic cells and keratinocytes, resulting in the production of proinflammatory cytokines such as tumor necrosis factor alpha, interleukin 17, interleukin 23, interleukin 22, and interleukin 1β. An in-depth understanding of the pathophysiology of psoriasis led to significant advances in the development of safe and efficient novel therapeutic options, with four classes of biologic therapy being approved for the management of moderate to severe psoriasis: tumor necrosis factor alpha inhibitors, interleukin 23 inhibitors, anti-interleukin 12/23 agents, anti-interleukin 17 agents, as well as small-molecule inhibitors, such as apremilast. Psoriasis is associated with comorbid conditions, namely psoriatic arthritis, cardiovascular disease, metabolic syndrome, psychiatric disorders, malignancy, as well as inflammatory bowel disease. For patients affected by both psoriasis and inflammatory bowel disease, there is a strong recommendation to avoid IL-17 inhibitors since they may play a part in the exacerbation of the gastrointestinal disease. Our aim was to perform a thorough literature review regarding the development of inflammatory bowel disease lesions in psoriasis patients treated with IL-17 inhibitors, along with a case presentation to emphasize the need for close follow-up of these patients.

Tofacitinib in the treatment of rheumatoid arthritis: real-life practice and randomized clinical trial data

The article justifies the need for a large arsenal of drugs to treat perennial rheumatoid arthritis. The authors present randomized controlled trial data showing high efficacy of tofacitinib at different doses as monotherapy, or in combination with methotrexate, or other conventional synthetic disease-modifying anti-inflammatory drugs in suppressing the activity and progression of the disease in various groups of patients, both non-responders to methotrexate, and non-responders to tumour necrosis factor-alpha inhibitors. Extension-phase data of randomized clinical trials demonstrated sustained efficacy of tofacitinib for up to 9.5 years. The authors presented the real-world evidence confirming high efficiency of the drug and noted the rapidity of onset of the effect and its high analgesic activity. The safety issues of tofacitinib with an emphasis on the cardiovascular safety of the drug, taking into account updates to the latest 2022 EULAR Recommendations on the need to consider risk factors for the development of cardiovascular adverse events when planning therapy with Janus kinase inhibitors are discussed. It is reported that slightly increased risk of such adverse events during use of tofacitinib, as compared with inhibitors of tumour necrosis factor alpha, was observed in elderly patients who have at least one risk factor for the development of cardiovascular events. Tofacitinib safety data were obtained from meta-analyses, systematic reviews, national registries, open observational studies, as well as outcomes of the use of the drug in real clinical practice. The launch of a domestic generic of the original drug was noted in the Russian Federation.

Rituximab for rheumatoid arthritis-related interstitial lung disease: A systematic review and meta-analysis

Objectives: This systematic review and meta-analysis aimed at summarizing the evidence of efficacy and safety of rituximab in rheumatoid arthritis- related interstitial lung disease (RA-ILD). Materials and methods: PubMed and Embase databases were searched until June 22, 2022, to identify studies on RA-ILD treated with rituximab, confined to predefined inclusion and exclusion criteria. A systematic review and meta-analysis were performed on the included studies to assess the overall stabilization or improvement in ILD, changes in percent-predicted (%-predicted) forced vital capacity (FVC), and %-predicted diffusion capacity of lungs for carbon monoxide (DLCO) following rituximab therapy. Results: A total of 15 studies (4 prospective and 11 retrospective studies) were included, with a total of 314 patients. There were 105 (60.7%) females out of 173 subjects for whom sex details were available from seven studies. The overall pooled proportion of patients with stabilization or improvement in ILD was 0.88 [95% confidence interval (CI): 0.76-0.96, p=0.02]. Rituximab improved FVC from baseline by 7.50% (95% CI: 1.35-13.65; p=0.02, fixed effect). Similarly, rituximab improved DLCO by 6.39% (95% CI: 1.366-14.43; p=0.12, random-effect). Two retrospective studies reported reduced mortality with rituximab therapy compared to tumor necrosis factor-alpha inhibitors. Conclusion: Treatment with rituximab in RA-ILD was associated with a significant improvement in %-predicted FVC, as well as stabilization or improvement in ILD after one year of treatment.

Predictors of functional and morphological arterial wall properties in coronary artery disease patients with increased lipoprotein (a) levels before and after treatment with proprotein convertase subtilisin-kexin type 9 inhibitors

BackgroundIn addition to proatherogenic properties, lipoprotein (a) (Lp(a)) has also pro-inflammatory, antifibrinolytic and prothrombogenic features. The aim of the current study was to identify the predictors of functional and morphological properties of the arterial wall in patients after myocardial infarction and increased Lp(a) levels at the beginning and after treatment with proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors.MethodsSeventy-six post-myocardial infarction patients with high Lp(a) levels were included in the study. Ultrasound measurements of flow-mediated dilation of brachial artery (FMD), carotid intima-media thickness (c-IMT) and pulse wave velocity (PWV) were performed initially and after 6 months of treatment. At the same time points lipids, Lp(a), inflammatory and hemostasis markers were measured in blood samples.ResultsIn linear regression model FMD significantly correlated with age at first myocardial infarction (β = 0.689; p = 0.022), high-sensitivity C-reactive protein (β = -1.200; p = 0.009), vascular cell adhesion protein 1 (VCAM-1) (β = -0.992; p = 0.006), overall coagulation potential (β = 1.428; p = 0.014) and overall hemostasis potential (β = -1.473; p = 0.008). c-IMT significantly correlated with age at first myocardial infarction (β = 0.574; p = 0.033) and Lp(a) (β = 0.524; p = 0.040). PWV significantly correlated with systolic blood pressure (β = 0.332; p = 0.002), tumor necrosis factor alpha (β = 0.406; p = 0.002), interleukin-8 (β = -0.315; p = 0.015) and plasminogen activator inhibitor 1 (β = 0.229; p = 0.031). After treatment FMD reached statistical significance only in univariant analysis with systolic blood pressure (r = -0.286; p = 0.004) and VCAM-1 (r = -0.229; p = 0.024). PWV and c-IMT correlated with age (r = 0.334; p = 0.001 and r = 0.486; p < 0.0001, respectively) and systolic blood pressure (r = 0.556; p < 0.0001 and r = 0.233; p = 0.021, respectively).ConclusionsOur results suggest that age, systolic blood pressure, Lp(a) levels and other biochemical markers associated with Lp(a) are predictors of functional and morphological properties of the arterial vessel wall in post-myocardial patients with high Lp(a) levels initially. However, after 6 months of treatment with PCSK9 inhibitors only age and systolic blood pressure seem to be predictors of these properties.Trial registrationThe protocol for this study was registered with clinicaltrials.gov on November, 3 2020 under registration number NCT04613167.Graphical

In silico screening of potential Tumor necrosis factor alpha (TNF-α) inhibitors through molecular modeling, molecular docking, and pharmacokinetics evaluations

The multifunctional cytokine TNF-α serves as a key biological mediator for several important immune processes, such as inflammation, infection, and antitumor responses. It is crucial for both acute and chronic neuroinflammation, as well as several neurodegenerative diseases. For the treatment of inflammatory diseases, the synthetic antibodies etanercept, adalimumab, and the generic medication Diclophenac directly bind to TNF-α, preventing it from interacting with the tumor necrosis factor receptor (TNFR). These approved drugs have detrimental side effects. There is therefore a lot of interest in the scientific world to identify new small-molecule-based TNF-α inhibition therapies. In this study, a set of molecular modeling techniques have been applied including the QSAR model, docking, and pharmacokinetics prediction to identify and optimize novel TNF-α inhibitors. Based on the modeling techniques applied, the QSAR shows (R2= 0.9534, Q2 = 0.8707, Rpred2= 0.8599, cRr2= 0.8994, SEE = 0.1067). The results showed that the function of these discovered compounds was not connected to lipophilicity, whereas less lengthy NN bonds and long substituents might lead to quite bioactive molecules. The discovered hits indicate promising inhibition against TNF-α and lacked harmful effects. Most of the discovered molecules had higher TNF-binding affinity than the reference substance. Furthermore, comparing the reference drug grading (ds) of 0.38, molecule 74 with PubChem ID 2998055 exhibits superior properties with a drug grading (ds) of 0.76. As a whole, the discovered molecules have favorable pharmacokinetics, pharmacodynamics, and drug interaction properties that suggest promising TNF- inhibition and lacked toxicity, suggesting that they are potential drug candidates.

Platelet-rich fibrin therapy as an adjuvant treatment in the management of metastatic Crohn’s disease: A case series

Abstract Metastatic or cutaneous Crohn’s disease (MCD) is a rare manifestation of Crohn’s disease and presents with ulcers, nodules, edema, fissures, and fistula. The genital involvement is seen in almost 50% patients and linear ulcers (knife-cut ulcers) are characteristic clinical features. The histopathological findings of skin lesions are similar to gastrointestinal involvement and is diagnostic. The treatment options for the management of MCD include topical and oral steroids, oral metronidazole, as well as immunosuppressants such as methotrexate, azathioprine, cyclosporine, and tumor necrosis factor alpha inhibitors. We present three cases of MCD who were treated with platelet-rich fibrin therapy as adjuvant and resulted in rapid healing of ulcers.

Maternal and neonatal antibody levels on pertussis vaccination in pregnant women on immune-modulating therapy for rheumatic disease

ObjectivesWhile protection against pertussis following maternal tetanus-diphtheria-and-acellular-pertussis (Tdap) vaccination was demonstrated in healthy term-born infants, no evidence is available on Tdap vaccination in combination with immune-modulating therapy during pregnancy. In...

Paradoxical Tumor Necrosis Factor-Alpha (TNF-α) Inhibitor-Induced Psoriasis: A Systematic Review of Pathogenesis, Clinical Presentation, and Treatment.

Tumor necrosis factor-alpha (TNF-α) inhibitors have been shown to be well tolerated among patients with rheumatoid arthritis, inflammatory bowel disease, and psoriasis. Meanwhile, more recently, clinical practice and research efforts have uncovered increasing cases of psoriatic lesion development tied to initiating treatment with a TNF-α inhibitor. The underlying mechanisms associated with this occurrence have yet to be fully elucidated. A review and analysis of cases of paradoxical psoriasis currently published in the literature is warranted. In addition, exploring possible mechanisms of action and potential treatment options associated with favorable outcomes is much needed. A systematic literature review was performed utilizing PubMed and Google Scholar databases (1992-present), in which 106 cases of paradoxical psoriasis were reviewed. The most common morphology developed was plaque psoriasis vulgaris. There was a female predominance (61.3%), and the most common underlying autoimmune disease was rheumatoid arthritis (45.3%). In addition, the most commonly associated drug with the onset of psoriatic lesions was infliximab (62.3%). Furthermore, the findings suggest that the most well-supported mechanism of action involves the uncontrolled release of interferon-alpha (IFN-α) from plasmacytoid dendritic cells (pDCs) after TNF-α inhibition. While TNF-α inhibitors have been shown to have great benefits to patients with rheumatologic diseases, cases of paradoxical psoriasis demonstrate the importance of close monitoring of patients on TNF-α inhibitors to allow for early recognition, treatment, and potentially change to a different mechanism of action of the medication used to prevent further progression of the inflammatory lesions.

COVID-19 outcomes in patients with rheumatoid arthritis with biologic or targeted synthetic DMARDs

ObjectivesWe aimed to investigate the role of rheumatoid arthritis (RA) with biologic or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARD) exposure in COVID-19 outcomes.MethodsOur study retrieved data from the US Collaborative...

Insight Of Engineered Nano-Based Biologics Approaches Used To Combat Autoimmune Disease Using Tnf-Α & Il Inhibitors.

Autoimmune disease is increasing widely, and the biologicals in autoimmune disease play a vital role in the cure. Biologicals have an affinity to bind the specific target molecule and suppress inflammation. The different biologicals are used to treat various autoimmune diseases by preventing the cytokines from unlocking cells and causing inflammation. Each biologic targets a different cytokine. The common classes of biologic that are used to treat autoimmune disease are i) Tumor Necrosis Factor-alpha (TNFα) inhibitors and ii) Interleukin Inhibitors (IL). Along with biologics, nanomedicine has shown to be a successful method for creating customized nanomaterials with the potential to deliver medicinal agents to particular organs or tissues drugs without causing immunosuppressive or immunostimulatory adverse effects. This article reviews biologics used in treating Autoimmune Disease (AD) and the mechanism involved. The examination of current developments that have been made to create innovative nanoparticle-based therapies for autoimmune illnesses and their inclusion in vaccines. Also, recent clinical trials display nanosystem strategies for treating AD.

Current and Emerging Therapies for Chronic Spontaneous Urticaria: A Narrative Review.

Chronic spontaneous urticaria (CSU) is a condition in which wheals, angioedema, and pruritus occur spontaneously and recurrently for at least 6weeks. The etiology of this disease is partially dependent on production of autoantibodies that activate and recruit inflammatory cells. Although the wheals can resolve within 24h, symptoms have a significant detrimental impact on the quality of life of these patients. Standard therapy for CSU includes second-generation antihistamines and omalizumab. However, many patients tend to be refractory to these therapies. Available treatments such as cyclosporine, dapsone, dupilumab, and tumor necrosis factor alpha (TNFa) inhibitors have been used with success in some cases. Furthermore, various biologics and other novel drugs have emerged as potential treatments for this condition, and many more are currently under investigation in randomized clinical trials.

P-503 Immunological therapies in women undergoing assisted conception: a systematic review and meta-analysis

Abstract Study question What is the effectiveness and safety of immunological therapies in women undergoing assisted conception? Summary answer The evidence on the overall effectiveness and safety of immunomodulators was scarce and uncertain, although some drugs may lead to improved outcomes in selected women. What is known already Embryo implantation is a pre-requisite for pregnancy success. It requires a state of immune tolerance within the maternal endometrium permitting the attachment and subsequent invasion into the decidua of the semi-allogenic blastocyst. Mechanistic data suggesting that heightened immune responses may impair implantation have led to the widespread use of immunomodulatory therapies in clinical practice. These include drugs such as aspirin, heparin, corticosteroids, intralipid and intravenous immunoglobulin (IVIG). However, despite the common use of immunomodulatory drugs in women having in vitro fertilisation (IVF), there is no consensus on their effectiveness and safety, owing to a paucity of well-designed interventional studies. Study design, size, duration We searched MEDLINE, EMBASE, PubMed and CENTRAL until September 2022. We selected randomised controlled trials (RCTs) investigating immunological therapies in women undergoing IVF, including aspirin, heparin, corticosteroids, granulocyte-colony stimulating factor (G-CSF), intralipid, intravenous immunoglobulin (IVIG), tumour necrosis factor-alpha inhibitors and peripheral blood mononuclear cells (PBMCs), evaluated alone or in combination, versus no intervention, placebo or any other immunomodulator(s). The primary outcomes were the rates of live birth or ongoing pregnancy (LBR/OPR) and miscarriage per participant. Participants/materials, setting, methods Two reviewers independently selected studies and extracted data. We conducted pairwise meta-analyses according to participants’ phenotypes as reported by the trialists, including: good prognosis, previous implantation failure, autoimmunity, high inflammation, thin endometrium, and low ovarian reserve. Using the Cochrane-RoB-1 tool, we restricted our primary analyses to RCTs at low risk of selection and other biases. We presented effect estimates as risk ratio (RR) with 95% confidence interval (CI) and considered I2&amp;gt;50% as representing substantial heterogeneity. Main results and the role of chance Our searches identified 14,893 records. We included a total of 84 studies in the qualitative synthesis, of which 43 contributed to the meta-analyses, evaluating in total 7,301 participants and 12 treatment comparisons. The primary analysis showed that aspirin resulted in little to no difference in LBR (RR 0.97, 95% CI 0.94-1.23; n = 688 women; moderate-certainty evidence) and MR (RR 1.20, 95% CI 0.73-1.99; n = 988 women; low-certainty evidence) compared with placebo. The data did not identify a difference in LBR/OPR in women using subcutaneous heparin (RR 1.30, 95% CI 0.80-2.12; n = 150 women; very low-certainty evidence) or IVIG (RR 1.28, 95% CI 0.32-5.16; n = 51 women; very low-certainty evidence) versus placebo. For the remaining interventions, the primary analysis was uncertain of an effect or insufficient for quantitative synthesis. However, the sensitivity analysis including all studies, irrespective of risk of bias, showed that corticosteroids may improve LBR in women with thyroid autoimmunity (RR 2.33, 95% CI 1.04-5.25; n = 60 women; very low-certainty evidence); intrauterine G-CSF may improve LBR in women with a thin endometrium (RR 2.57, 95% CI 1.24-5.29; n = 304 women; very low-certainty evidence); and intrauterine PBMCs may improve LBR in women with previous implantation failure (RR 2.03, 95% CI 1.33-3.10; n = 312 women; very low-certainty evidence). Limitations, reasons for caution For most of the interventions under study, the evidence was of low or very-low certainty, owing to limitations in study design, imprecision, indirectness and inconsistency. Further, very few studies reported on adverse events, highlighting a worrying lack of data on the safety of immunological therapies for women undergoing assisted conception. Wider implications of the findings A scarcity of well-designed RCTs limits the evidence on immunomodulators in women undergoing IVF. However, we identified positive signals for some therapies in specific conditions (e.g. corticosteroids for thyroid autoimmunity, intrauterine G-CSF for thin endometrium, and PBMCs in women with previous implantation failure). This merits further investigation in high-quality trials. Trial registration number PROSPERO registration number CRD42021294031

A case of perifolliculitis capitis abscedens et suffodiens and acne conglobata effectively treated with a tumor necrosis factor α inhibitor.

Perifolliculitis capitis abscedens et suffodiens (PCAS) and acne conglobate (AC) are often treated with isotretinoin and tumor necrosis factor alpha (TNF-α) inhibitors in Europe and the United States. Treatment with these drugs is uncommon in Asia, and alternative treatment options are limited. In this paper, we report the case of a Japanese patient who presented with PCAS and AC and was treated successfully with adalimumab.