Search

Tumor necrosis factor-alpha (TNFα) may promote neuroinflammation prompting tinnitus. This retrospective cohort study evaluated whether anti-TNFα therapy influences incident tinnitus risk among adults with autoimmune disorders and no baseline tinnitus selected from a US electronic health records database (Eversana; 1 January 2010–27 January 2022). Patients with anti-TNFα had ≥90-day history pre-index (first autoimmune disorder diagnosis) and ≥180-day follow-up post-index. Random samples (n = 25,000) of autoimmune patients without anti-TNFα were selected for comparisons. Tinnitus incidence was compared among patients with or without anti-TNFα therapy, overall and among at-risk age groups or by anti-TNFα category. High-dimensionality propensity score (hdPS) matching was used to adjust for baseline confounders. Compared with patients with no anti-TNFα, anti-TNFα was not associated with tinnitus risk overall (hdPS-matched HR [95% CI]: 1.06 [0.85, 1.33]), or between groups stratified by age (30–50 years: 1 [0.68, 1.48]; 51–70 years: 1.18 [0.89, 1.56]) or anti-TNFα category (monoclonal antibody vs. fusion protein: 0.91 [0.59, 1.41]). Anti-TNFα was not associated with tinnitus risk among those treated for ≥6 months (hdPS-matched HR [95% CI]: 0.96 [0.69, 1.32]) or ≥12 (1.03 [0.71, 1.5]), or those with RA (1.16 [0.88, 1.53]). Thus, in this US cohort study, anti-TNFα therapy was not associated with tinnitus incidence among patients with autoimmune disorders.

Here, we report two cases of cutaneous adverse effects possibly induced by the use of tumor necrosis factor-alpha (TNF-α) inhibitors. The first case presented alopecia areata (AA) and atopic dermatitis (AD) that developed during the treatment of ulcerative colitis using infliximab; the other case presented urticaria and AD that developed during the treatment of rheumatoid arthritis using etanercept. AA, AD, and urticaria are relatively common skin diseases; however, they are not well known as adverse effects of TNF-α inhibitors. Although immunological studies were not performed, the clinical courses suggested that these skin disorders might have developed as a result of an immune four-way imbalance in T helper 1 (Th1), Th2, Th17, and regulatory T cells by the administration of TNF-α inhibitors.

Background: This study aimed to investigate the molecular mechanism of Radix Paeoniae Alba (white peony, WP) in treating immune inflammatory diseases of rheumatoid arthritis (RA) and tumor necrosis factor-alpha (TNF-α) inhibitors (TNFis) by using network pharmacology and molecular docking.Methods: In this study, the ingredient of WP and the potential inflammatory targets of RA were obtained from the Traditional Chinese Medicine Systematic Pharmacology Database, GeneCard, and OMIM databases, respectively. The establishment of the RA–WP-potential inflammatory target gene interaction network was accomplished using the STRING database. Network maps of the WP–RA-potential inflammatory target gene network were constructed using Cytoscape software. Gene ontology (GO) and the biological pathway (KEGG) enrichment analyses were used to further explore the RA mechanism and therapeutic effects of WP. Molecular docking technology was used to analyze the optimal effective components from WP for docking with TNF-α.Results: Thirteen active ingredients and 71 target genes were screened from WP, and 49 of the target genes intersected with RA target inflammatory genes and were considered potential therapeutic targets. Network pharmacological analysis showed that the WP active ingredients such as mairin, DPHCD, (+)-catechin, beta-sitosterol, paeoniflorin, sitosterol, and kaempferol showed better correlation with RA inflammatory target genes such as PGR, PTGS1, PTGS2, NR3C2, TNFSF15, and CHRM2, respectively. The immune-inflammatory signaling pathways of the active ingredients for the treatment of RA are the TNF-α signaling pathway, Toll-like receptor signaling pathway, cell apoptosis, interleukin-17 signaling pathway, C-type lectin receptor signaling pathway, mitogen-associated protein kinase, etc. Molecular docking results suggested that mairin was the most appropriate natural TNFis.Conclusion: Our findings provide an essential role and basis for further immune-inflammatory studies into the molecular mechanisms of WP and TNFis development in RA.

Background: Risk factors for sepsis have not been assessed in patients receiving tumor necrosis factor-alpha inhibitors (TNFi) for immune-mediated inflammatory diseases (IMIDs) who are vulnerable to serious/hospitalized infections. Methods: Data from 2003–2017 were obtained from Taiwan’s National Health Insurance Research Database to identify patients receiving TNFi, including etanercept, adalimumab, and golimumab, for IMIDs including rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriasis (PsO), psoriatic arthritis (PsA), Crohn’s disease (CD), and ulcerative colitis (UC). To investigate risk factors for sepsis, we used the Sepsis-3 definition and calculated hazard ratios (HRs) with 95% confidence intervals (CIs) using Cox regression analysis. Results: There were 17,764 patients (mean age 49.3 ± 14.3 years; females, 57.6%) receiving TNFi for IMIDs, including RA (58.6%), AS (19.1%), PsO (15.1%), PsA (2.5%), CD (3.0%), and UC (1.7%). The overall incidence rate of sepsis was 1088 per 100,000 person-years. After adjustment for potential confounders, recent sepsis within 3 months before TNFi initiation (HR, 2.35; 95% CI, 1.73–3.20), CD (HR, 3.36; 95% CI 2.11–5.34; reference group: AS) and glucocorticoid use (prednisolone-equivalent dose, mg/day HR, 1.05; 95% CI, 1.05–1.06) were associated with the risk of sepsis. Intriguingly, golimumab users appeared to have a lower risk of sepsis compared with etanercept users (HR, 0.56; 95% CI, 0.38–0.83). In addition, socioeconomic status, including urbanization level and insured amount, was associated with sepsis in a dose-response manner. Conclusions: Recent sepsis, CD, concomitant glucocorticoid use, and low socioeconomic status, which were associated with an increased risk of sepsis, are crucial for individualized risk management plans.

Authors present a response to therapy followed by adverse effects in a 21-year-old patient with DGS and hypogammaglobulinemia suffering from polyarticular type of JIA, treated simultaneously with intravenous immunoglobulins (IVIGs) and tumor necrosis factor-alpha inhibitor (TNFi).

Objective: to describe a case of the total development of alopecia in a female patient with psoriatic arthritis during treatment with a tumor necrosis factor-αlpha (TNF-α) inhibitor. Materials and methods. Patient I., aged 36 years has been followed up at the Kazan’ Center of Rheumatic Diseases and Osteoporosis since 1998. At approximately the same time, the patient noted the appearance of skin eruptions behind the ears, on the skin of the scalp. She was examined by a dermatologist who diagnosed psoriasis. In 2005, she was admitted to Kazan’ Rheumatology Center, City Clinical Hospital Seven, for the development of obvious synovitis of the knee joint and for the inefficiency of therapy with nonsteroidal anti-inflammatory drugs and diagnosed with psoriatic arthritis. During the prescribed therapy with methotrexate 10 mg/week, evident menstrual irregularities were observed in the patient who stopped using the drug herself. The second pregnancy occurred in 2008. Articular syndrome progression and eruptive psoriasis were recorded in the lactation period. After lactation cessation in 2009, she was hospitalized again. Her examination revealed high laboratory activity (erythrocyte sedimentation rate, as high as 40 mm/hr); magnetic resonance imaging of the knee joints showed the signs of bilateral synovitis; lumbar spine radiography exhibited grade II sacroiliitis. Leflunomide 20 mg/day was recommended as a basic drug. In 2012, the patient used leflunomide, her condition worsened; joint pain progressed; new joints were involved into the process, and cutaneous manifestations were aggravated. To verify a diagnosis and to choose therapy, the patient was referred to a consultation at the Moscow Research Institute of Rheumatology. Results. In connection with the high activity of the disease and with no response to the performed therapy, it was recommended to initiate therapy with biologics, such as infliximab, the drug of choice. Seven infliximab injections were well tolerated: the patient reported lower intensity of joint pains and regression of the skin manifestations of psoriasis. In 2013, after the eighth infliximab injection the patient sought medical advice because of complaints about an obvious exacerbation of psoriasis affecting the trunk, upper and lower extremities, and the development of total alopecia within a week. Discontinuation of cytostatics and biologics was recommended; whether ustekinumab therapy should be used was considered. Conclusion. Practical interest in this clinical case is due to the development of a rare (3.3 %) adverse event in the patient with psoriatic arthritis – hair loss (total development of alopecia) during treatment with a TNF-α inhibitor.

Objectives: To compare the efficacy and safety of certolizumab pegol (CZP) with and without loading dose (LD) in a post-hoc analysis of two Japanese clinical studies. Methods: Data from the double-blind trials (DBT) J-RAPID and HIKARI, and their open-label extension (OLE) studies, were used. Patients randomized to CZP 200 mg every 2 weeks (Q2W) groups starting with LD (400 mg Weeks 0/2/4; LD group; J-RAPID: n = 82, HIKARI: n = 116) and patients randomized to placebo groups who subsequently started CZP Q2W without LD in the OLEs (No-LD group; J-RAPID: n = 61, HIKARI: n = 99) were analyzed. Efficacy and pharmacokinetics were assessed during 24 weeks. Adverse events were reported from all studies. Results: In both trials, the LD groups showed more rapid initial ACR20/50/70 kinetics, and maintained higher ACR50/70 responses until 24 weeks, compared with the No-LD groups. Anti-CZP antibody development was less frequent in the LD groups (J-RAPID: 1.2% versus 4.9%; HIKARI: 17.2% versus 27.3%). Similar safety profiles were reported between LD and No-LD groups (any AEs: 281.8 versus 315.7 [J-RAPID], 282.6 versus 321.3 [HIKARI] [incidence rate/100 patient-years]). Conclusions: Despite limitations, including comparing DBT and OLE studies, these results suggest that a CZP LD improves clinical response in active rheumatoid arthritis without altering the safety profile.

Objectives. This 24-week, multicenter, double-blind, randomized, placebo-controlled study (NCT00791999) compared efficacy and safety of certolizumab pegol (CZP) in combination with methotrexate (MTX) vs placebo plus MTX in Japanese rheumatoid arthritis (RA) patients with inadequate response to MTX. Methods. In total, 316 patients were randomized 1:1:1:1 to subcutaneous CZP 100, 200, or 400 mg (induction dose: 200 mg or 400 mg CZP at Weeks 0, 2, and 4) plus MTX or placebo plus MTX every 2 weeks. Primary endpoint was ACR20 response at Week 12. Results. ACR20 response rates were 62.5%, 76.8%, 77.6%, and 28.6% at Week 12, and 61.1%, 73.2%, 71.8%, and 24.7% at Week 24 for CZP 100, 200, and 400 mg, and placebo groups, respectively, with statistical significance between each CZP group and placebo. Change in Total Sharp Score over 24 weeks was significantly smaller in CZP 200 and 400 mg groups vs placebo. Improvements in health-related quality of life (HRQoL) were observed in all three CZP groups vs placebo. Incidence of adverse events was similar between CZP groups. Conclusions. CZP plus MTX resulted in rapid, sustained reductions in RA signs and symptoms in Japanese patients with inadequate response to MTX, with significant inhibition of radiographic progression and improved HRQoL.

Hyperhidrosis is a disorder caused by overactivity of the eccrine glands and characterized by excessive sweating beyond what is essential for thermoregulation.1 Its prevalence is 3% in the US population and affects men and women equally.1, 2 Hyperhidrosis can be classified as either primary, which tends to be focal, or secondary, which tends to be more generalized.2 Primary hyperhidrosis specifically affects the palms, soles, axillae, and face in a bilateral, symmetric distribution; begins in adolescence; and does not occur during sleep. In contrast, secondary hyperhidrosis typically presents in adults, affects a wider distribution of the body asymmetrically during both waking and sleeping hours, and is caused by either underlying medical conditions or medications.2

Objective. This 24-week, placebo-controlled, double-blind, randomized study (NCT00791921) investigated efficacy and safety of certolizumab pegol (CZP) in Japanese rheumatoid arthritis (RA) patients in whom methotrexate (MTX) cannot be administered. Methods. A total of 230 patients were randomized to subcutaneous CZP 200 mg (induction dosing: 400 mg at Weeks 0, 2 and 4) or placebo every 2 weeks. Results. ACR20 responses with CZP were rapid and significant versus placebo at Week 1, sustained to Week 12 (67.2% vs. 14.9%) and Week 24 (63.8% vs. 11.4%). Week 24-modified Total Sharp Score (mTSS) change from baseline (CFB) was 0.48 (CZP) versus 2.45 (placebo). CZP treatment was associated with higher Week 12 ACR20 responses versus placebo (with non-MTX disease modifying antirheumatic drugs [DMARDs], 74.2% vs. 20.0%; without [monotherapy], 59.3% vs. 8.2%) and inhibition of radiographic progression at Week 24 (mTSS CFB; with non-MTX DMARDs, 0.24 vs. 1.61; monotherapy, 0.68 vs. 3.65). Incidences of serious adverse events were 11.2% (CZP) and 2.6% (placebo); one CZP patient died of dissecting aortic aneurysm. Conclusion. CZP treatment with and without non-MTX DMARDs in Japanese patients in whom MTX cannot be administered resulted in rapid, sustained reductions in RA signs and symptoms. Notably, CZP monotherapy showed significant inhibition of radiographic progression.

A 65-year-old man was admitted to our hospital with a temperature of 39.3 C, cough, sputum, and pharyngeal discomfort that had persisted for 3 days. He had been treated with methotrexate and adalimumab (a tumor necrosis factor-alpha [TNF-α] inhibitor) for rheumatoid arthritis for 2 years, and he had also been treated with S-1 (tegafur, gimeracil, and oteracil potassium) for pancreatic metastasis of gastric cancer for 2 months. Regardless of the underlying pathologies, his general condition was good and he had worked as an electrician until 2 days before admission. However, his appetite had suddenly decreased from the day before admission, and high fever and hypoxia were also evident upon admission. A chest X-ray and computed tomography scan revealed left pleural effusion and consolidation in both lungs. The pneumonia severity index score was 165 and the risk class was V. Accordingly, we started to treat the pneumonia with a combination of levofloxacin and meropenem. Thereafter, we received positive urinary antigen test findings for Legionella pneumophila. After hospitalization, hypoxia was progressed and hypotension was emerged. Despite the application of appropriate antibiotics, vasopressors, and oxygenation, the patient died 8 h after admission. Even after his death, blood cultures were continued to consider the possibility of bacterial co-infection. Although no bacteria were detected from blood cultures, Gimenez staining revealed pink bacteria in blood culture fluids. Subsequent blood fluid culture in selective medium revealed L. pneumophila serogroup 1. Recently, TNF-α inhibitors have been described as a risk factor for Legionnaires' disease. In consideration of the increased frequency of TNF-α inhibitors, we may need to recognize anew that L. pneumophila might be a pathogen of severe community-acquired pneumonia., Journal of Infection and Chemotherapy, 19(1), pp.166-170; 2013

Background Tumor necrosis factor-alpha inhibitors are widely used agents in the treatment of immune disorders such as rheumatoid arthritis and inflammatory bowel disease. Despite their anti-inflammatory action, paradoxical drug-induced inflammatory events have been occasionally associated with the use of infliximab, etanercept, and in a lesser extent adalimumab. However, eye involvement is uncommon and anterior uveitis is the only reported ocular adverse manifestation. It can be induced by etanercept, but has also been described during adalimumab therapy. We present here the first report of recurrent peripheral corneal infiltrates following subcutaneous injections of adalimumab. Case presentation A 34 year-old Caucasian woman with Crohn’s disease presented to the emergency department with bilateral red eyes and discomfort 36 hours after she received her bimonthly dose of subcutaneous adalimumab. Examination revealed bilateral peripheral corneal infiltrates with characteristic features of immune infiltrates. Symptoms and infiltrates regressed after topical corticosteroid therapy, but recurred after each adalimumab injection over the following weeks. Conclusion Paradoxical immune reactions associated with tumor necrosis factor-alpha inhibitors may result either from hypersensitivity mechanisms, or from immune-complex deposition via anti-adalimumab antibodies. Both mechanisms could explain this newly described manifestation. Care should be taken to search for corneal infiltrates in the event of red eye symptoms during adalimumab therapy since they respond to topical corticosteroids and do not necessarily prompt the discontinuation of the immunosuppressive therapy. Electronic supplementary material The online version of this article (doi:10.1186/s12886-015-0047-6) contains supplementary material, which is available to authorized users.

This was an exploratory analysis comparing the safety and efficacy of tocilizumab monotherapy with those of tocilizumab in combination with disease-modifying anti-rheumatic drugs (DMARDs). Data were from a single-arm, nonrandomized, open-label, 24-week study in patients with rheumatoid arthritis in which patients with inadequate responses to DMARDs or tumor necrosis factor-α inhibitors received tocilizumab 8 mg/kg intravenously every 4 weeks plus methotrexate/other DMARD(s) combination therapy. If they were intolerant of methotrexate/other DMARD, patients received tocilizumab monotherapy. Effectiveness endpoints included American College of Rheumatology (ACR) responses (ACR20/50/70/90) and disease activity score using 28 joints (DAS28). Of 1,681 patients, 239 received tocilizumab monotherapy, and 1,442 received combination therapy. Methotrexate was the most common DMARD (79 %) used in combination therapy. The frequency of adverse events (AEs), serious AEs, and AEs leading to withdrawal were similar between tocilizumab monotherapy (82.4, 7.9, and 5.4 %, respectively) and combination therapy (76.6, 7.8, and 5.1 %, respectively). No differences in ACR20/50/70/90 responses were observed between treatment groups (66.9 %/43.5 %/23.8 %/10.0 % vs 66.9 %/47.2 %/26.8 %/8.5 %, respectively; p > 0.12 for all individual comparisons, including ACR50 propensity score analyses). The decrease in DAS28 was also similar between treatment groups (mean ± standard deviation: −3.41 ± 1.49 for tocilizumab monotherapy vs −3.43 ± 1.43 for combination therapy; p > 0.33 all analyses, including propensity score analyses). Tocilizumab had a comparable safety profile, and was similarly effective, when used as monotherapy or in combination with DMARDs in a broad population of patients with rheumatoid arthritis. Electronic supplementary material The online version of this article (doi:10.1007/s10067-014-2857-y) contains supplementary material, which is available to authorized users.

Idiopathic pneumonia syndrome (IPS) is a fatal non-infectious respiratory complication that develops after hematopoietic stem cell transplantation (HSCT). Because of the poor prognosis of post-HSCT patients with IPS requiring mechanical ventilatory support, performing extracorporeal membrane oxygenation (ECMO) has been regarded as relatively contraindicated in these patients. A tumor necrosis factor-alpha inhibitor, etanercept, has been reported to be a promising treatment option for post-HSCT patients with IPS; however, the phase III clinical trial of etanercept has recently been terminated without definitive conclusion. If post-HSCT patients with IPS really benefit from etanercept, mechanical ventilation (MV)-dependent IPS patients might be worth receiving ECMO treatment in line with the protective lung strategy. We therefore performed veno-venous ECMO (VV-ECMO), which substantially acted as an extracorporeal carbon dioxide removal, on a 56-year-old post-HSCT male with severe MV-dependent IPS due to graft-versus-host disease. Although a serious bleeding complication due to post-HSCT thrombocytopenia occurred, the VV-ECMO was continued for 11 days. The patient successfully entered remission of the IPS and was finally extubated on the 12th MV day. However, the patient soon complained of dyspnea, probably due to cytomegalovirus infection and/or exacerbation of the IPS, and was reintubated after 3 days of extubation. The patient then rapidly developed irreversible type II respiratory failure despite the administration of etanercept and an anti-cytomegalovirus agent and died on the eighth re-MV day. The autopsy findings of the patient revealed diffuse alveolar damage and alveolar hemorrhage, accompanied with bronchitis obliterans in his lungs, as well as whole body cytomegalovirus infection, which were compatible with the clinical diagnosis of the patient. We think that the legitimacy of this treatment strategy is dependent on the overall prognosis of IPS, which is influenced by the complications induced by immunosuppressants and ECMO, especially infections and bleeding. Electronic supplementary material The online version of this article (doi:10.1186/s40560-014-0048-1) contains supplementary material, which is available to authorized users.

Aim To study the effects of the tumor necrosis factor alpha inhibitor adalimumab on rabbit retina after injection into the vitreous body. Methods Forty-eight rabbits of mixed strain (9–12 months old, weighing ≈ 3.5 kg) were randomized into four groups. Adalimumab was injected at one of two concentrations (1.25 mg or 2.5 mg) into the eyes of two groups, and balanced salt solution into the eyes of the third group. The fourth group acted as controls. Full-field electroretinography (ffERG) was performed before injection and 1 and 6 weeks post-injection. At 6 weeks post-injection the rabbits were euthanized and the sectioned retinas were studied. Retinal histology was studied with hematoxylin–eosin staining. Immunohistochemical analysis was performed on rods, cones, rod bipolar cells, horizontal cells, amacrine cells and Müller cells. Results No significant difference in ffERG amplitudes or implicit times was observed between the four groups at any time point. Histological and immunohistochemical findings were similar in all groups. Conclusions Injection of adalimumab into the vitreous body of healthy rabbits, at doses up to 2.5 mg, does not appear to be toxic to the rabbit retina.