Cardiovascular disease is a chronic inflammatory disease with high mortality rates. TNF-alpha is pro-inflammatory and associated with the disease, but current medications have adverse effects. Therefore, efficient inhibitors are urgently needed as alternatives. This study represents a structural-activity relationship investigation of TNF-alpha, curated from the ChEMBL database. Exploratory data analysis was performed to visualize the physicochemical properties of different bioactivity groups. The extracted molecules were subjected to PubChem and SubStructure fingerprints, and a QSAR-based Random Forest (QSAR-RF) model was generated using the WEKA tool. The QSAR random Forest model was built based on the SubStructure fingerprint with a correlation coefficient of 0.992 and 0.716 as the respective tenfold cross-validation scores. The variance important plot (VIP) method was used to extract the important features for TNF-alpha inhibition. The Substructure-based QSAR-RF (SS-QSAR-RF) model was validated using molecules from PubChem and ZINC databases. The generated model also predicts the pIC50 value of the molecules selected from the docking study followed by molecular dynamic simulation with the time step of 100 ns. Through virtual reverse pharmacology, we determined the main drug targets from the top four hit compounds obtained via molecular docking study. Our analysis included an integrated bioinformatics approach to pinpoint crucial targets like EGRF, HSP900A1, STAT3, PSEN1, AKT1, and MDM2. Further, GO and KEGG pathways analysis identified relevant cardiovascular disease-related pathways for the hub gene involved. However, this study provides valuable insights, it is important to note that it lacks experimental application. Future research may benefit from conducting in-vitro and in-vivo studies.

Generalized pustular psoriasis of pregnancy (GPPP) is a rare dermatological condition that significantly affects maternal health and pregnancy outcomes. The treatment of this disease might be very challenging, as only a limited number of effective therapeutic options are available. If the use of systemic drugs is considered, they should ideally effectively control the systemic inflammation without harming the fetus. Here, we report the successful treatment of a severe case of GPPP in a 28-year-old woman using the tumor necrosis factor-alpha inhibitor (TNFi) certolizumab pegol. Additionally, we review the existing literature on the use of this class of drugs for treating GPPP. To date, there are only 11 reported cases of this severe skin condition treated with a TNFi. We also discuss the pathogenesis of GPPP and the rationale behind using TNFi for its treatment.

UNASSIGNED: Topical therapies for nail lichen planus (clobetasol propionate, topical tacrolimus, bath-PUVA), intralesional treatment (triamcinolone), and systemic treatment (corticosteroids, retinoids, small molecule inhibitors (jak/stat inhibitors)), TNF-alpha inhibitors (etanercept), systemic immunomodulators (oral calcineurin inhibitors, mycophenolate mophetil), and antimalarials (chloroquine), each with unique safety profiles and considerations. Herein, we discuss common and uncommon adverse events, as well as utilization for special populations, including pregnant and pediatric patients.

BACKGROUND: Rheumatoid arthritis (RA) patients seropositive for hepatitis B core antibody (HBcAb) and negative for hepatitis B surface antigen (HBsAg) are at risk of hepatitis B virus (HBV) reactivation when treated with biologic or targeted synthetic (b/ts) disease-modifying antirheumatic drugs (DMARDs). The study aims to investigate the risk in this population.
METHODS: From January 2004 through December 2020, 1068 RA patients undergoing b/tsDMARDs therapy and 416 patients with HBsAg-/HBcAb+ were enrolled. Factors associated with HBV reactivation were analysed.
RESULTS: During 2845 person-years of follow-up, 27 of 416 (6.5%,9.5 per 1000 person-years) patients developed HBV reactivation, with a cumulative rate of HBV reactivation of 3.5% at 5 years, 6.1% at 10 years and 24.2% at 17 years. The median interval from beginning b/tsDMARDs to HBV reactivation was 85 months (range: 9-186 months). The risk of HBV reactivation varied by type of b/tsDMARD, with rituximab having the highest risk (incidence rate: 48.3 per 1000 person-years), followed by abatacept (incidence rate: 24.0 per 1000 person-years). In multivariate analysis, rituximab (adjusted hazard ratio [aHR]: 15.77, 95% confidence interval [CI]: 4.12-60.32, p = .001), abatacept (aHR: 9.30, 1.83-47.19, p = .007), adalimumab (aHR: 3.86, 1.05-14.26, p = .04) and negative baseline HBV surface antibody (anti-HBs, <10 mIU/mL) (aHR: 3.89, 1.70-8.92, p < .001) were independent risk factors for HBV reactivation.
CONCLUSIONS: HBsAg-/HBcAb+ RA patients are susceptible to HBV reactivation during b/tsDMARD therapy. Those with negative baseline anti-HBs and those on certain b/tsDMARDs, such as rituximab, abatacept and adalimumab, have high reactivation risks. Risk stratification and management should be based on the patient\'s baseline anti-HBs titre and type of therapy.

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BACKGROUND: Necrobiosis lipoidica (NL) is a chronic granulomatous dermatosis usually affecting the lower limbs, although less common sites have been described. Herein we report a series of cases of NL located on the elbow, with an unusual presentation and occurring after trauma or surgery.
METHODS: Our series includes three men and one woman, with a mean age of 64 years. Three had undergone surgery for elbow bursitis and one had had trauma after a fall from a horse, with exposure of subcutaneous tissue prior to healing. Within 5 years, they had all developed an atrophic erythematous annular plaque with papular and telangiectatic edges, with recurrent episodes of ulceration and scarring. Repeated tests for infectious agents were negative. Histological examinations showed granulomas and necrobiosis with palisading or early-stage palisading. Partial healing was achieved in two patients after 6 months of doxycycline. Treatment with adalimumab resulted in disappearance of the ulcers at 6 months in one patient.
CONCLUSIONS: Unusual sites of NL impose consideration of other types of palisading granuloma or mycobacterial infections, which we were able to rule out. Two other cases of NL of the elbow similar to ours are reported in the literature. These cases, involving multiple ulcerations over a very long period of time, probably constitute a distinct entity because of the very distinct character of these 6 cases. Tetracyclines are partially active and tumour necrosis factor alpha (TNF)-alpha inhibitors may offer an option.

Generalized pustular psoriasis (GPP) is a rare but severe form of psoriasis. An early onset of the diseases is correlated with mutations among IL36RN, CARD14, AP1S3, MPO and SERPINA3 genes. Systemic biological agents including anti-TNF-α, anti-IL-17, anti-IL-12/IL-23, anti-IL1R, anti-IL1β and anti-IL-36R act as novel treatment methods for GPP. Herein we report a female infant clinically diagnosed with GPP since she was 10-month-old. Results of whole-exome sequencing (WES) and Sanger sequencing revealed a reported heterozygous IL36RN (c.115+6T>C) and another reported heterozygous SERPINA3 frame-shifting variant (c.1247_1248del). Initial cyclosporin treatment for the patient led to a partial remission of the symptoms. However, the patient reached nearly total remission of pustules and erythema after anti-TNF-α inhibitor etanercept treatment. Results of further RNA sequencing (RNA-seq) done on peripheral blood mononuclear cells correlated with the clinical responses, showing that cyclosporin suppressed a portion of the neutrophil-related genes, while most genes associated with neutrophil activation, neutrophil-mediated immunity and degranulation were downregulated by the subsequent etanercept treatment. We report this case to demonstrate WES and RNA-seq in combination could come in handy in reaching a precise diagnosis and in evaluating or even predicting the molecular alterations underlying clinical treatment effectiveness.

Although targeted immunomodulatory medications are increasingly utilized for inflammatory skin conditions like plaque psoriasis, little is known of the trends in the adoption of newly Federal Drug Administration (FDA)-approved immunomodulators by dermatologists. We performed a retrospective, cross-sectional analysis of Medicare Part D Prescriber datasets to identify dermatologists filing Medicare prescription claims for immunomodulatory drugs FDA-approved for plaque psoriasis between 2013 and 2018. Differences in dermatologist characteristics were determined between dermatologists prescribing a psoriasis treatment within two years of its FDA approval, \"early adopters\" and non-prescriber dermatologists over the same time period. Biologics approved for psoriasis from 2013 to 2018 included certolizumab pegol, secukinumab, brodalumab, ixekizumab, guselkumab, and apremilast. Early adopter dermatologists (n = 783) accounted for 5% of all Medicare Part D prescribing dermatologists. Early adopters were more likely to be male, in practice longer, and had a greater number of average annual beneficiaries than dermatologists who did not. Only six (< 1%) early adopters practiced in a small town or rural areas. We believe these data show that the adoption of novel biologic treatments for psoriasis by dermatologists to Medicare beneficiaries may be associated with clinician experience and practice volume. Additionally, we identified low absolute numbers of dermatologists prescribing biologics overall in non-metropolitan areas, which may represent delayed access to novel psoriasis treatments for many Medicare beneficiaries.

With anti-PD-1 antibodies serving as a representative drug, immune checkpoint inhibitors (ICIs) have become the main drugs used to treat many advanced malignant tumors. However, immune-related adverse events (irAEs), which might involve multiple organ disorders, should not be ignored. ICI-induced myocarditis is an uncommon but life-threatening irAE. Glucocorticoids are the first choice of treatment for patients with ICI-induced myocarditis, but high proportions of steroid-refractory and steroid-resistant cases persist. According to present guidelines, tumor necrosis factor alpha (TNF-α) inhibitors are recommended for patients who fail to respond to steroid therapy and suffer from severe cardiac toxicity, although evidence-based studies are lacking. On the other hand, TNF-α inhibitors are contraindicated in patients with moderate-to-severe heart failure. This review summarizes real-world data from TNF-α inhibitors and other biologic agents for ICI-induced myocarditis to provide more evidence of the efficacy and safety of TNF-α inhibitors and other biologic agents.

BACKGROUND: Certolizumab pegol (CZP) is a TNF-ɑ inhibitor used to treat moderate-to-severe plaque psoriasis (PsO) in adult patients, including women of childbearing potential (WOCBP) and patients with psoriatic arthritis (PsA). There are currently limited real-world data on CZP for treatment of PsO.
OBJECTIVE: To examine the use of CZP for treatment of PsO in clinical practice at two dermatology clinics in Canada.
METHODS: We conducted a retrospective chart analysis of 59 patients with moderate-to-severe psoriasis receiving CZP. Clinical efficacy was measured using the Psoriasis Area and Severity Index (PASI), Body Surface Area (BSA), and Physician Global Assessment (PGA). Drug survival was analyzed using Kaplan-Meier plots.
RESULTS: Of the 59 patients, 36 (61%) were female, of whom 23 (63.9%) were WOCBP. Twenty-three (39.0%) patients received CZP as their first biologic treatment. The main reasons for choosing CZP were its efficacy in both PsO and PsA, and for WOCBP due to little or no cross-placental transfer. Improvement of symptoms was observed after 3 months of treatment and was maintained for the 12-month analysis period. After 12 months of treatment, the patients\' mean PASI score decreased from 13.0 (±5.8) at baseline to 2.3 (±4.3), mean BSA score from 13.1% (±6.7%) to 1.7% (±2.6%), and mean PGA score from 3.0 (±0.6) to 0.8 (±0.6). Overall CZP drug survival rate was 76.3% at 12 months, with no difference between biologic-naive and biologic-experienced patients.
CONCLUSIONS: CZP was effective and well tolerated in this cohort of patients with moderate-to-severe PsO in a real-world setting.