Tumor Necrosis Factor-α Inhibitors Research Articles

Association of Tumor Necrosis Factor-α Inhibitors with Incident Dementia: Analysis Based on Population-Based Cohort Studies.

Preliminary evidence suggests a possible preventive effect of tumor necrosis factor-α inhibitors (TNFi) on incident dementia. The objective of the analysis was to investigate the association between TNFi and the risk of incident dementia in a population undergoing treatment for rheumatological disorders. We followed patients aged ≥ 65years with dementia and rheumatological conditions in two cohort studies, DANBIO (N = 21,538), a Danish clinical database, and AOK PLUS (N = 7112), a German health insurance database. We defined incident dementia using diagnostic codes and/or medication use and used Cox regression to compare the associations of TNFi with other rheumatological therapies on the risk of dementia. To ensure that the patients were receiving long-term medication, we included patients with rheumatic diseases and systemic therapies. We observed similar trends towards a lower risk of dementia associated with TNFi versus other anti-inflammatory agents in both cohorts (hazard ratios were 0.92 [95% confidence interval 0.76, 1.10] in DANBIO and 0.89 [95% confidence interval 0.63, 1.24] in AOK PLUS, respectively). Tumor necrosis factor-α inhibitors may decrease the risk of incident dementia although the association did not reach statistical significance in this analysis. Further research, ideally with randomization, is needed to gauge the potential of repurposing TNFi for dementia prevention and/or treatment.

Concomitant Sjögren’s disease as a biomarker for treatment effectiveness in rheumatoid arthritis - results from the Swiss clinical quality management cohort

ObjectiveTo investigate the clinical phenotype and treatment response in patients with rheumatoid arthritis (RA) with and without concomitant Sjögren’s disease (SjD).MethodsIn this observational cohort study, patients with RA from the Swiss Clinical Quality Management in Rheumatic Diseases registry were categorised according to the presence or absence of SjD. To assess treatment effectiveness, drug retention of tumor necrosis factor-α-inhibitors (TNFi) was compared to other mode of action (OMA) biologics and Janus kinase-inhibitors (JAKi) in RA patients with and without SjD. Adjusted hazard ratios (HR) for time to drug discontinuation were compared in crude and adjusted Cox proportional regression models for potential confounders.ResultsWe identified 5974 patients without and 337 patients with concomitant SjD. Patients with SjD were more likely to be female, to have a positive rheumatoid factor, higher disease activity scores, and erosive bone damage. For treatment response, a total of 6781 treatment courses were analysed. After one year, patients with concomitant SjD were less likely to reach DAS28 remission with all three treatment modalities. Patients with concomitant SjD had a higher hazard for stopping TNFi treatment (adjusted HR 1.3 [95% CI 1.07–1.6]; OMA HR 1.12 [0.91–1.37]; JAKi HR 0.97 [0.62–1.53]). When compared to TNFi, patients with concomitant SjD had a significantly lower hazard for stopping treatment with OMA (adjusted HR 0.62 [95% CI 0.46–0.84]) and JAKi (HR 0.52 [0.28–0.96]).ConclusionRA patients with concomitant SjD reveal a severe RA phenotype, are less responsive to treatment, and more likely to fail TNFi.

Overcoming provider barriers to therapeutic drug monitoring of tumour necrosis factor inhibitors for rheumatoid arthritis: a qualitative analysis.

Therapeutic drug monitoring (TDM) of tumour necrosis factor-α inhibitors (TNFi), by measuring drug levels and/or anti-drug antibodies, is being considered by various international bodies to improve patient health outcomes and the value of care for people with rheumatoid arthritis. Rheumatology care providers may perceive barriers to adopting TNFi TDM within their own clinical practice, limiting the potential for patients and health care systems to benefit. This study aimed to explore the barriers perceived by rheumatologists that may reduce their uptake of TNFi TDM for rheumatoid arthritis. Semi-structured one-to-one telephone interviews were performed with a convenience sample of senior rheumatologists with experience of managing people with rheumatoid arthritis. The interviews explored the rheumatologists' understanding of TDM and their beliefs about how it can be integrated into their own routine practice. Interviews were audio recorded, transcribed verbatim and anonymized. Transcripts were coded inductively and barriers to using TNFi TDM were identified by thematic framework analysis. A sample of eleven senior rheumatologists were interviewed. The rheumatologists described five barriers to adopting TNFi TDM in routine practice: (i) observing clinical need; (ii) understanding how testing can improve practice; (iii) insufficient clinical evidence; (iv) insufficient resources to pay for testing; and (v) insufficient capability to deliver testing. Barriers to adopting TNFi TDM in routine care settings will restrict the ability for patients to benefit from effective monitoring strategies as they begin to emerge. Strategies to overcome these barriers are suggested which will require a coordinated response from stakeholders across health care systems.

Safety and Efficacy of Golimumab in Indian Patients with Active Spondyloarthritis of Ankylosing Spondylitis or Psoriatic Arthritis: A Multicenter, Noncomparative, Open-Label, Real-World Study.

The safety and efficacy of tumor necrosis factor-α (TNF-α) inhibitor therapy for most common rheumatological diseases, ankylosing spondylitis (AS), and psoriatic arthritis (PsA) in controlled clinical trials is well-studied. This study evaluated subcutaneous (SC) golimumab in Indian patients with active spondyloarthritis (SpA) of AS or PsA in a real-world setting. This phase 4, multicenter, prospective, non-comparative, interventional, 24-week study was performed in patients (age ≥18 years) with active SpA of AS or PsA (NCT03733925). Golimumab 50 mg was given subcutaneously to the patients every 4 weeks. Safety was assessed. The proportion of patients with AS and PsA achieving ≥20% improvement in the Assessment of SpA International Society 20 (ASAS20) criteria and American College of Rheumatology 20 (ACR20) responses, respectively, at weeks 14 and 24 were efficacy endpoints. Of the 100 patients enrolled (men: 78 [78.0%]; mean age: 36.7 [12.02] years), 94 (94.0%) patients completed the study. Treatment-emergent adverse events with golimumab were observed in 29/100 (29.0%) patients, and nasopharyngitis and upper respiratory tract infection (5.0% each) were the most common (≥5%). Deaths were not reported. At week 14, 74.5% (95% confidence interval [CI]: 59.7; 86.1%) of patients with AS and 84.6% (95% CI: 69.5; 94.1%) of patients with PsA achieved ASAS20 and ACR20 responses, which were sustained at week 24 (ASAS20: 66.0% [95% CI: 50.7, 79.1%]; ACR20: 93.2% [95% CI: 81.3, 98.6%]), respectively. Golimumab (50 mg) administered subcutaneously was safe and effective in Indian patients with active SpA of AS or PsA during the 24-week study period with no new safety signals.

Deep analysis of skin molecular heterogeneities and their significance on the precise treatment of patients with psoriasis.

Psoriasis is a highly heterogeneous autoinflammatory disease. At present, heterogeneity in disease has not been adequately translated into concrete treatment options. Our aim was to develop and verify a new stratification scheme that identifies the heterogeneity of psoriasis by the integration of large-scale transcriptomic profiles, thereby identifying patient subtypes and providing personalized treatment options whenever possible. We performed functional enrichment and network analysis of upregulated differentially expressed genes using microarray datasets of lesional and non-lesional skin samples from 250 psoriatic patients. Unsupervised clustering methods were used to identify the skin subtypes. Finally, an Xgboost classifier was utilized to predict the effects of methotrexate and commonly prescribed biologics on skin subtypes. Based on the 163 upregulated differentially expressed genes, psoriasis patients were categorized into three subtypes (subtypes A-C). Immune cells and proinflammatory-related pathways were markedly activated in subtype A, named immune activation. Contrastingly, subtype C, named stroma proliferation, was enriched in integrated stroma cells and tissue proliferation-related signaling pathways. Subtype B was modestly activated in all the signaling pathways. Notably, subtypes A and B presented good responses to methotrexate and interleukin-12/23 inhibitors (ustekinumab) but inadequate responses to tumor necrosis factor-α inhibitors and interleukin-17A receptor inhibitors. Contrastly, subtype C exhibited excellent responses to tumor necrosis factor-α inhibitors (etanercept) and interleukin-17A receptor inhibitors (brodalumab) but not methotrexate and interleukin-12/23 inhibitors. Psoriasis patients can be assorted into three subtypes with different molecular and cellular characteristics based on the heterogeneity of the skin's immune cells and the stroma, determining the clinical responses of conventional therapies.

Spirohypertones A and B as potent antipsoriatics: Tumor necrosis factor-α inhibitors with unprecedented chemical architectures

Tumor necrosis factor-α (TNF-α) is a promising target for inflammatory and autoimmune diseases. Spirohypertones A (1) and B (2), two unprecedented polycyclic polyprenylated acylphloroglucinols with highly rearranged skeletons, were isolated from Hypericum patulum. The structures of 1 and 2 were confirmed through comprehensive spectroscopic analysis, single-crystal X-ray diffraction and electronic circular dichroism calculations. Importantly, 2 showed remarkable TNF-α inhibitory activity, which could protect L929 cells from death induced by co-incubation with TNF-α and actinomycin D. It also demonstrated the ability to suppress the inflammatory response in HaCaT cells stimulated with TNF-α. Notably, in an imiquimod-induced psoriasis murine model, 2 restrained symptoms of epidermal hyperplasia associated with psoriasis, presenting anti-inflammatory and antiproliferative effects. This discovery positions 2 as a potent TNF-α inhibitor, providing a promising lead compound for developing an antipsoriatic agent.

Immune recovery uveitis in Whipple’s disease: an unusual ocular presentation

PurposeTo describe an unusual case of Whipple’s disease (WD) complicated by uveitis, and subsequent paradoxical worsening after effective antibiotic treatment targeting Tropheryma whipplei (TW).MethodsCase report.ResultsA 53-year-old male presented with bilateral knee arthritis, weight loss, chronic low-grade fever, and cognitive disorders. He was under treatment with tumor necrosis factor α inhibitors (TNFi) for seronegative spondyloarthritis. Given this unusual clinical presentation, further investigations were performed and revealed blood, saliva, stool, synovial fluid and cerebrospinal fluid positivity for TW, confirming the diagnosis of systemic WD. Ophthalmologic examination revealed bilateral posterior uveitis and an aqueous humor sample confirmed the presence of intraocular TW. TNFi were stopped, and the patient was subsequently treated with adequate antibiotics (ceftriaxone, followed by doxycycline and hydroxychloroquine), and subconjunctival corticosteroid injections. After a transient improvement of the ocular symptoms, he presented a recurrence of posterior segment inflammation, leading to repeated PCR testing for TW which were negative. Therefore, paradoxical worsening of the inflammation in the context of immune recovery uveitis (IRU) was thought to be the culprit. The patient was treated with systemic corticosteroid therapy, allowing for rapid improvement of the ocular findings.ConclusionsThis case underlines the possibility of IRU complicating WD. Ophthalmologists, rheumatologists, and internists should be aware of this rare complication, particularly in the context of previous immunosuppressive therapy.

Targeted therapies for uveitis in spondyloarthritis: A narrative review

Spondyloarthritis (SpA) encompasses a group of chronic inflammatory disorders of the joints frequently associated with uveitis in almost a quarter of cases. SpA-related uveitis typically affects the eye anterior chamber with sudden onset, causing pain, redness, photophobia, and blurred vision. Ophthalmologists will describe an acute anterior unilateral uveitis. Most patients present with episodic acute anterior non-granulomatous uveitis and retain excellent visual acuity. However, systemic treatments are recommended in the event of frequent relapses (2–3/year) or in rare cases of sight-threatening with ocular complications. The improved understanding of the pathogenesis of SpA has led to the management of this disease by biologics. Here, we review the main data regarding the opportunity to target specific components in inflammatory pathways for the treatment of SpA-related uveitis. These therapies are recommended for long-term control when uveitis relapses occur too frequently despite conventional systemic treatments. Significant benefits have been obtained with the tumor necrosis factor-α inhibitors (TNFis), particularly infliximab and adalimumab. Paradoxically, a high number of uveitis occurrences have been shown on etanercept. Mixed results have been demonstrated with interleukin-17 antagonists (secukinumab) and interleukin-12/interleukin-23 antagonists (ustekinumab) in cases of failure of TNFis. JAK inhibitors seem to be a valuable class of medications for these patients in the future. Although SpA-related uveitis is typically managed with conventional local and/or systemic treatments, these biological/targeted therapies may provide avenues to control both the underlying SpA and uveitis manifestations. Thus, a close collaboration between patients, rheumatologists, internists, and ophthalmologists is needed to optimally manage ocular inflammation in SpA.

Increased risk of malignancy in HLA-B27-positive patients with ankylosing spondylitis requiring biologics for sustained inflammation: A long-term, single-center retrospective study.

To assess the link between the administration of biologic disease-modifying antirheumatic drugs (bDMARDs) and the risk of malignancy in human leukocyte antigen B27 (HLA-B27)-positive patients with ankylosing spondylitis (AS) experiencing sustained inflammation. Between 2006 and 2021, 1445 HLA-B27-positive patients with AS were retrospectively evaluated. Among them, 112 patients required bDMARD therapy. The study compared conventional therapy with bDMARDs and investigated the risk factors for developing malignancies. During 8253 patient-years of follow-up, 38 (2.6%) patients developed various malignancies, including lung, liver, breast, and colon cancer. The risk of malignancy was significantly higher in the bDMARD-treated group compared to PS-matched groups receiving conventional synthetic DMARDs (csDMARD) and non-steroidal anti-inflammatory drugs. The cumulative risk of malignancies increased significantly after 6 years of follow-up. All patients who developed malignancy after bDMARD therapy received tumor necrosis factor-α inhibitors. Requiring bDMARD therapy, requiring bDMARDs in combination with csDMARD therapy, and being diagnosed with AS after 30 years of age were independent risk factors for developing malignancy. HLA-B27-positive AS patients with sustained inflammation requiring biologic therapy, particularly if diagnosed after age 30, may have an increased risk of malignancy. Regular cancer screenings are advisable for these patients while undergoing biologic treatment.

Cutaneous leishmaniasis in a patient with psoriatic arthritis treated with tumour necrosis factor-α inhibitor

Cutaneous leishmaniasis in a patient with psoriatic arthritis treated with tumour necrosis factor-α inhibitor

Ammonia‐‑nitrogen stress affects immune regulation via TNFα in yellow catfish (Pelteobagrus fulvidraco)

Ammonia‑nitrogen has become a global issue with feed-dependent intensive culture modes, which may cause toxicity in aquatic animals by affecting immune regulation. Although numerous studies have investigated the acute and short-term toxic effect of ammonia‑nitrogen in fish, there is a lack of research on the long-term effects of exposure to low concentration of ammonia‑nitrogen. In this study, yellow catfish (Pelteobagrus fulvidraco) were exposed to water supplemented with ammonia (NH4Cl was used as the ammonia source) at concentrations of 0 (control), 8, 10, 12, 14, 16 and 18 mg/L for eight-weeks, and the effects on growth performance, histopathology, antioxidant and immune capacities of yellow catfish were investigated. The results showed that long-term ammonia exposure resulted in decreased weight gain rate (WGR) and serum antioxidant capacity, increased feed coefficient (FC), serum and tissue ammonia levels. They caused extensive histopathological changes and significantly impaired inflammatory and immune responses. On the other hand, ammonia exposure significantly affected the respiratory burst and the content of reactive oxygen species (ROS) of head kidney macrophages. Still, the above phenomenon can be reversed by inhibiting tumor necrosis factor-α (TNFα), indicating that TNFα may play a key role in this process. In conclusion, our findings indicate that extended exposure to ammonia nitrogen, even at low concentrations, has a detrimental effect on the well-being of aquatic organisms. This finding underscores the necessity of long-term environmental toxicological investigations of ammonia‑nitrogen.

Screening of anti-inflammatory activities components of Angelica dahurica root based on spectrum-effect relationship analysis and NF-κB pathway.

Angelica dahurica root (ADR), a commonly utilized herbal medicine in China and other Asian nations, which has anti-inflammatory effects on diverse inflammatory ailments. However, the bioactive components and underlying mechanism responsible for the anti-inflammatory effect of ADR are still unclear. This work attempted to discover the anti-inflammatory bioactive compounds and explore their underlying mechanism in ADR based on spectrum-effect relationship analysis and NF-κB signaling pathway. Chromatographic fingerprints of ADR samples were established by high performance liquid chromatography with diode array detection (HPLC-DAD), and a total of eleven common peaks were selected. Then, high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (HPLC-Q/TOF-MS) was employed for identification of eleven common peaks in ADR Meanwhile, the anti-inflammatory activities of ADR samples were assessed by inhibition of NO, interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) production in LPS-induced RAW264.7 cells. The spectrum-effect relationships between the eleven common peaks in HPLC fingerprints and anti-inflammatory effects of ADR samples were investigated to identify the potential anti-inflammatory bioactive compounds by grey relational analysis (GRA) and partial least squares regression (PLSR). The spectrum-effect relationship analysis results indicated that six coumarin compounds, including bergapten, xanthotoxin, phellopterin, isoimperatorin, xanthotoxol and imperatorin could be potential anti-inflammatory bioactive compounds in ADR. The further validation experiments also showed that these six coumarins demonstrated significant inhibition of NO, IL-1β, IL-6, and TNF-α production in LPS-induced RAW264.7 cells. In addition, western blot analysis was conducted to explore the mechanisms of two potential anti-inflammatory bioactive compounds (phellopterin and isoimperatorin) by assessing the protein levels in the NF-κB signaling pathway. The western blot results illustrated that phellopterin and isoimperatorin could significantly down-regulate the phosphorylated NF-κB p65 (p-p65), phosphorylated IκBα (p-IκBα) and iNOS, and depress the pro-portion of p-p65/p65 and p-IκBα/IκBα, which indicated that these two coumarins in ADR could potentially exert anti-inflammatory effects by suppressing of NF-κB pathway.

Golimumab and certolizumab pegol for the treatment of hidradenitis suppurativa: a literature review and future perspective.

Hidradenitis suppurativa (HS) is an inflammatory skin condition with an underlying inflammatory process. Due to the limited efficacy of available treatments, HS remains a therapeutic challenge. The safety and efficacy of tumor necrosis factor-α (TNF-α) inhibitors, adalimumab, infliximab, and etanercept, are well studied in this patient population, and in some cases, HS was unresponsive to them. In recent years, evidence has been growing regarding the application of other anti-TNFs, including certolizumab pegol (CPZ) and golimumab. We sought to evaluate the overall safety and efficacy of golimumab and CPZ in the management of HS. A comprehensive search was performed on the PubMed, Scopus, Web of Science, and Ovid Embase databases, as well as the Google Scholar search engine from initiation to 31 August 2023. A total of nine and four studies used CPZ and golimumab to treat HS, respectively. Individuals with concomitant inflammatory immune-mediated diseases, pregnant females, and patients who were refractory to previous treatments achieved a Hidradenitis Suppurativa Clinical Response following CPZ administration. Also, golimumab showed promise in treating recalcitrant HS after the failure of other treatments, such as adalimumab and anti-interleukin-1. CPZ and golimumab can be efficacious treatment options for moderate-to-severe HS, especially in patients who are unresponsive to other TNF inhibitors, such as adalimumab.

Cardiovascular Adverse Events Associated with Tumor Necrosis Factor-Alpha Inhibitors: A Real-World Pharmacovigilance Analysis.

Evidence regarding the association between various tumor necrosis factor-α (TNF-α) inhibitors and cardiovascular adverse events (AEs) is both limited and contradictory. A retrospective pharmacovigilance study was conducted using the FDA Adverse Event Reporting System (FAERS) database. Cardiovascular AEs associated with TNF-α inhibitors (adalimumab, infliximab, etanercept, golimumab, and certolizumab) were evaluated using a disproportionality analysis. To reduce potential confounders, adjusted ROR and subgroup analyses were performed. After excluding duplicates, 9,817 cardiovascular reports were associated with the five TNF-α inhibitors. Only adalimumab had positive signals for myocardial infarction (ROR=1.58, 95%CI=1.51-1.64) and arterial thrombosis (ROR=1.54, 95%CI=1.49-1.58). The remaining four TNF-α inhibitors did not show a risk association with any type of cardiovascular event. Further analyses of specific indication subgroups and after adjusting for any confounding factors demonstrated that adalimumab was still significantly associated with cardiovascular events, especially in patients with psoriasis (adjusted ROR=2.16, 95%CI=1.95-2.39). This study revealed that adalimumab was the only TNF-α inhibitor associated with an elevated risk of thrombotic cardiovascular AEs, whereas the other four TNF-α inhibitors did not show any risk effect. However, given the limitations of such pharmacovigilance studies, it is necessary to validate these findings in prospective studies in the future.

Tumor necrosis factor-α inhibitor for successful treatment of toxic epidermal necrolysis with severe infection: a case series.

Toxic epidermal necrolysis (TEN) is a rare severe cutaneous adverse reaction that involves more than 30% of the body surface area. TEN can be accompanied by a series of systemic symptoms and has a high risk of death. Tumor necrosis factor (TNF)-α inhibitors such as adalimumab and etanercept have been shown to be safe and effective for the treatment of TEN in some cases. However, clinical data on the use of TNF-α inhibitors to treat TEN with severe systemic infection are scarce. In the present study, three adult patients who developed TEN with serious active infection were successfully treated with etanercept. One of the three patients had active open pulmonary tuberculosis, and the other two had septicemia and/or fungal sepsis. All patients' skin lesions significantly improved after several days, and none of the patients developed emerging or re-emerging infectious diseases, adverse reactions, or a similar rash during follow-up. TNF-α inhibitors may be an effective treatment choice for TEN with severe systemic infection. However, further studies with large samples are still required for validation because clinical experience is limited.

Interprofessional collaboration between general practitioners and community pharmacists to promote the safe and responsible use of TNF-α-inhibitors.

Introduction: Tumor necrosis factor α-inhibitors (TNF-α-inhibitors) are biological disease-modifying anti-rheumatic drugs (bDMARD’s) that are used in the treatment of different immune mediated inflammatory diseases (IMIDs) (eg. rheumatoid arthritis, psoriasis, Crohn’s disease…). TNF-inhibitors are generally well tolerated and safe, but some major challenges remain in the management of TNF-inhibitors. 
 First of all, only specific specialists (rheumatologist, dermatologist, ophthalmologist, gastro-enterologist) can prescribe these drugs. This implicates that GP’s often are not aware that patients use these drugs. Secondly, patients on TNF-therapy are more susceptible to opportunistic infections (eg influenza of bacterial infection). Recognizing symptoms to refer to the GP is essential and vaccination is highly recommended. Lastly, drug adherence is too low, which impacts the disease activity and clinical outcome. 
 Policy Context And Objective: In 2018, the Royal Association of Pharmacists in Antwerpen (KAVA) and Domus Medica have developed a quality improving program (QIP) in the context of Medical-Pharmaceutical Concertation (MPC). MPC is an initiative from the NIDHI in Belgium to promote the rational prescribing and dispensing of medication and the safe use of medication in general. The NIHDI provides financial incentives to general practitioners (GP) and community pharmacists (CP) to organize local MPC-projects, based on a QIP. A local MPC-project starts with a ‘kick-off meeting’, to make agreements of the rational use of medication. Most of the time, different cases are discussed in small interprofessional groups. After this meeting, the agreements are subsequently implemented into practice and can be evaluated with quality indicators. 
 This specific QIP focusses on four challenges: (1) to improve the influenza vaccination coverage in this group of patients, (2) to stimulate the communication between GP and CP, (3) to educate GP, CP and patients about the alarm symptoms of infections and (4) to improve patient adherence.
 Target Population: MPC targets the general practitioner and community pharmacist with mutual patients on TNF-therapy.
 Highlights: The Royal Association of Pharmacists in Antwerpen (KAVA) and the GP organization Domus Medica strongly believe in this initiative. Currently 13 local MPC-projects have been organized in which 68 CP and 118 GP participated. The three most important conclusions of these MPC-projects are;
 •GPs want to know which patients are on TNF-therapy, the CP can play an active role in the identification of these patients in the GP practice;
 •The influenza vaccination coverage is unknown in the pharmacy and GP practice. This will be checked after the MPC. Advocating and sensitization campaigns are useful and will he implemented and evaluated afterwards;
 •Referring to GP in case of alarm symptoms is necessary and should be done sooner.
 Conclusion: MPC is an initiative from the NIDHI in Belgium to promote the rational prescribing and dispensing of medication and the safe use of medication in general. KAVA and Domus Medica have developed a quality improving program, specifically targeted on TNF-inhibitors. Currently, 13 local MPC-projects have been organized. Further research is necessary to analyze the impact of the MPC-project.

Tumor necrosis factor-α inhibitor treatment of acne fulminans - a clinical and literature review.

Acne fulminans (AF) is a rare, serious, sudden-onset and long-lasting skin disease that causes scarring of face and body. Standard treatment with combined long-term isotretinoin and prednisolone is not always sufficient and has a well-known propensity for adverse effects leaving an unmet need for improved therapy. Case reports suggest that tumor necrosis factor (TNF)-α inhibitors may play a role in the management of AF. In a 3-year retrospective data collection from two dermatology centers and literature review of clinical cases of acne fulminans treated with anti-TNF-α therapy, three clinical cases and twelve literature cases were identified. A total of five different TNF-α inhibitors have been tested, with adalimumab being the most commonly used. Clinical response was seen after 1month in 2/3 (67%) clinical cases and 5/12 (42%) literature cases, respectively, and treatment was successful in 2/3 (67%) and 11/12 (92%) after a median 3-7months. All reported adverse effects were mild and reversible. Anti-TNF-α treatment may provide rapid improvement in patients with AF when initial treatment with isotretinoin and prednisolone fails. However, randomized controlled trials are lacking, and exact dosage and timing need to be explored before clinical implementation.

BET Protein Inhibitor JQ1 Ameliorates Experimental Peritoneal Damage by Inhibition of Inflammation and Oxidative Stress.

Peritoneal dialysis (PD) is a current replacement therapy for end-stage kidney diseases (ESKDs). However, long-term exposure to PD fluids may lead to damage of the peritoneal membrane (PM) through mechanisms involving the activation of the inflammatory response and mesothelial-to-mesenchymal transition (MMT), leading to filtration failure. Peritoneal damage depends on a complex interaction among external stimuli, intrinsic properties of the PM, and subsequent activities of the local innate-adaptive immune system. Epigenetic drugs targeting bromodomain and extra-terminal domain (BET) proteins have shown beneficial effects on different experimental preclinical diseases, mainly by inhibiting proliferative and inflammatory responses. However the effect of BET inhibition on peritoneal damage has not been studied. To this aim, we have evaluated the effects of treatment with the BET inhibitor JQ1 in a mouse model of peritoneal damage induced by chlorhexidine gluconate (CHX). We found that JQ1 ameliorated the CHX-induced PM thickness and inflammatory cell infiltration. Moreover, JQ1 decreased gene overexpression of proinflammatory and profibrotic markers, together with an inhibition of the nuclear factor-κB (NF-κB) pathway. Additionally, JQ1 blocked the activation of nuclear factor erythroid 2-related factor 2 (NRF2) and restored changes in the mRNA expression levels of NADPH oxidases (NOX1 and NOX4) and NRF2/target antioxidant response genes. To corroborate the in vivo findings, we evaluated the effects of the BET inhibitor JQ1 on PD patients' effluent-derived primary mesothelial cells and on the MeT-5A cell line. JQ1 inhibited tumor necrosis factor-α (TNF-α)-induced proinflammatory gene upregulation and restored MMT phenotype changes, together with the downmodulation of oxidative stress. Taken together, these results suggest that BET inhibitors may be a potential therapeutic option to ameliorate peritoneal damage.

Development of triple-functionalized calcium phosphate nanoparticles as an advanced drug delivery system for bone tissue repair

IntroductionDuring tissue repair or regeneration, several bioactive molecules are released and interact with each other and act as complex additives or inhibitors for tissue reconstruction. In this study, the bone-healing effects of the combination treatment with tumor necrosis factor-α (TNF-α) inhibition, vascular endothelial growth factor A (VEGF-A) and bone morphogenetic protein-7 (BMP-7) release by gene silencing, and gene transfection with calcium phosphate nanoparticles (CaP) in the rat femoral head was histologically, morphologically, and biochemically evaluated. MethodsA triple-functionalized paste of CaP carrying plasmid DNA encoding for BMP-7 and for VEGF), and siRNA against TNF-α was developed and denoted as CaP3mix. To compare the effects of 3mixCaP, CaP with plasmid DNA encoding BMP-7, VEGF, or siRNA encoding TNF-α was prepared and denoted as CaP/PEI/pBMP-7/SiO2, CaP/PEI/pVEGF/SiO2, or CaP/PEI/siRNA-TNF-α/SiO2, respectively. The bone healing in bone defects in the rat femoral head was investigated after 10 and 21 days of implantation. ResultsThe levels of bone formation-related markers OCN, Runx2, and SP7 increased at the protein and gene levels in 3mixCaP after 10 days, and 3mixCaP significantly accelerated bone healing compared with the other treatments after 21 days of implantation. ConclusionThe triple-functionalized CaP paste loading plasmid DNA encoding BMP-7 and VEGF and siRNA encoding TNF-α is a promising bioactive material for bone tissue repair.

Biologics targeting IL-17 and IL-23 maintain stability in patients with psoriasis during COVID-19 infection: a case-control study.

Psoriasis is a chronic and refractory skin disease. The emergence of biologics provides more options for the treatment of psoriasis, but the COVID-19 pandemic poses challenges for the management of psoriasis. The purpose of this study was to investigate the effect of different biologics on the stabilization of psoriasis during COVID-19 infection in China. This is a single-center, observational, retrospective, case-control study. Using our database, we conducted a remote dermatologic study by means of questionnaire follow-up or telephone follow-up to collect general information of patients, information related to COVID-19 infection and conditions of psoriasis for comparison and further analysis between groups. Our study ultimately included 274 patients for analysis. We found that the patients in this collection had mild symptoms of COVID-19 infection, and only 13 of them needed to go to the hospital for medical treatment. Further studies found that in biologics, relative to tumor necrosis factor-α inhibitors (TNF-αi), interleukin-17 inhibitors (IL-17i) and interleukin-23 inhibitors (IL-23i) are both protective factors in flare-up of psoriasis [IL-17i: OR (95% CI) = 0.412 (0.189-0.901); IL-23i: OR (95% CI) = 0.291 (0.097-0.876)]. In addition, we also found that the proportion of people with increased psoriasis developing long COVID-19 increased, and we speculated that increased psoriasis may be a potential risk factor for long COVID-19. Our study showed that the use of IL-17i and IL-23i was a protective factor for psoriasis compared with TNF-αi, and could keep the psoriasis stable.