Tumor Necrosis Factor-alfa Inhibitors Research Articles

Cytochrome P450 activity in rheumatoid arthritis patients during continuous IL-6 receptor antagonist therapy

BackgroundInflammation suppresses cytochrome P450 (CYP) enzyme activity, and single-dose interleukin 6 receptor antagonists (anti-IL-6R) reverse this effect. Here, we assess the impact of continuous anti-IL-6R therapy in patients with rheumatoid arthritis.MethodsIn a clinical pharmacokinetic trial, the Basel cocktail was administered before and after 3 and 12 weeks of anti-IL-6R therapy to assess CYP enzyme activity (registered in the ClinicalTrials.gov database (identifier NCT04842981) on April 13th, 2021). In a retrospective study, the 4β-hydroxycholesterol/cholesterol ratio was measured as a biomarker for CYP3A4 activity before and after 3 and 6 months of anti-IL-6R therapy. The control group was patients initiating a tumor necrosis factor alfa (TNF-α) inhibitor.ResultsIn the clinical pharmacokinetic trial (n = 3), midazolam metabolic ratio (CYP3A4) was inconclusive due to the limited sample size. Midazolam AUC and Cmax indicate a weak impact on CYP3A4 activity after 3 weeks of anti-IL-6R therapy compared to baseline (AUC geometric mean ratio (GMR): 0.80, 95% CI: 0.64–0.99 and Cmax GMR: 0.58, 95% CI: 0.37–0.91), which returns to baseline levels after 12 weeks of therapy (AUC GMR 1.02, 95% CI: 0.72–1.46 and Cmax GMR 1.03, 95% CI 0.72–1.47). No effect on the 4β-hydroxycholesterol/cholesterol ratio was observed in the retrospective study.ConclusionBased on sparse data from three patients, continuous anti-IL-6R therapy seems to cause an acute but transient increase in CYP3A4 activity in rheumatoid arthritis patients, which may be due to a normalization of the inflammation-suppressed CYP activity. Further studies are warranted to understand the mechanism behind this putative transient effect.Trial registration Registered in the ClinicalTrials.gov database (identifier NCT04842981) on April 13th, 2021.

Overwhelming response to TNF-alfa inhibitor Infliximab “innovator” Vs. Adalimumab “Bio-similar” in a previously therapy naive adult

Therapeutic options for patients with Spondyloarthritis (SpA) are limited. The present-day pharmacotherapy for Spondyloarthritis comprises immunomodulator/suppressive drugs. In this case report, we describe a 29-year old Postgraduate resident in Medicine who was diagnosed with spondyloarthritis and was managed by a combination of various disease-modifying drugs like methotrexate and sulfasalazine and immunomodulators such as systemic corticosteroids as well as Tumor Necrosis Factor-alfa inhibitors. After a series of therapeutic trials with them, the chimeric TNF blocker Infliximab led to significant clinical improvement in symptoms and reduction in disease activity.

Comparison of Adverse Event Profiles of Tumor Necrosis Factor-Alfa Inhibitors: Analysis of a Spontaneous Reporting Database.

IntroductionConcerns over safety profiles of tumor necrosis factor (TNF)-alfa inhibitors have been raised. The purpose of this study was to clarify the adverse events associated with TNF-alfa inhibitors using a spontaneous reporting system database.Materials and MethodsA retrospective pharmacovigilance disproportionality analysis was conducted using the Japanese Adverse Drug Event Report (JADER) database. Adverse event reports submitted to the Pharmaceuticals and Medical Devices Agency between 2004 and 2017 were analyzed, and the reporting odds ratio (ROR) and 95% confidence interval (CI) for each adverse event were calculated.ResultsAmong the 34,031 reports of adverse events associated with TNF-alfa inhibitors, 65.8% were women, who were frequently in their 60s (28.2%). Signals were detected for pneumonia (ROR, 5.36; 95% CI, 5.14–5.6), interstitial lung disease (ROR, 2.04; 95% CI, 1.95–2.15), pneumocystis jirovecii pneumonia (ROR, 11.8; 95% CI, 11.1–12.5), and herpes zoster (ROR, 6.4; 95% CI, 5.92–6.91) for TNF-alfa inhibitors as a class. There was variability in their signal strength across individual TNF-alfa inhibitors.ConclusionThe strength of the associations of TNF-alfa inhibitors with adverse events is variable, and further studies are required to evaluate the identified signals.

Psoriatic arthritis and COVID ‐19 pandemic: Consequences in medical treatment?

The COVID‐19 pandemic has a strong negative impact on human society worldwide. Patients with immune‐mediated disease may be prone to an increased risk of infection and/or more severe course. We review the available data for patients with psoriatic arthritis (PSA) and systemic treatments. Current treatment options are summarized. Based upon the experience with COVID‐19, the following problems are addressed: (a) Can systemic treatment reduce comorbidities of PsA that are also comorbidities for COVID‐19? Does systemic medical treatment pose an increased risk of infection with SARS‐CoV‐2? Does systemic drug therapy have an impact on the risk of pulmonary fibrosis—a factor with strong negative impact on COVID‐19 outcome? Small molecules, inhibitors of tumor necrosis factor alfa, interleukin, and JAK inhibitors are considered. The data are inhomogeneous for the multiple drugs used in PsA. Although the risk for severe upper airway tract infections during clinical controlled trials was mostly in the range of placebo, these data have been obtained before the COVID‐19 pandemic and should be interpreted with caution. Some biologics demonstrated an antifibrotic activity in vitro and in animal disease models. None of the biologics is indicated during an active infection with fever. In nonsymptomatic PsA patients, systemic drug therapy can be continued.

JAAD Game Changers: Impact of effective tumor necrosis factor-alfa inhibitor treatment on arterial intima-media thickness in psoriasis: Results of a pilot study

Capsule Summary:•Due to common molecular pathways of psoriasis and atherosclerosis, psoriasis patients are at increased risk of cardiovascular morbidity.•Effective TNF-alpha inhibitor therapy might reduce arterial intima-media thickness (IMT), an accepted marker of subclinical atherosclerosis, in patients with severe psoriasis who do not have irreversible atherosclerotic plaques.•TNF-alpha inhibitors might have a beneficial impact on the cardiovascular morbidity rate of patients with severe psoriasis.How did this article change the practice of dermatology?Psoriasis is associated with a higher incidence of atherosclerotic comorbidities. In both psoriasis and rheumatoid arthritis, tumor necrosis factor-α inhibitors have shown to have a beneficial effect on endothelial function.1

JAAD Game Changers∗: Efficacy of switching between tumor necrosis factor-alfa inhibitors in psoriasis: Results from the Italian Psocare Registry

Capsule Summary•Some patients with psoriasis benefit from switching from one anti-tumor necrosis factor-alfa inhibitor to another.•In our series, response to the second anti-tumor necrosis factor-alfa inhibitor was lower in patients who exhibited primary inefficacy to the first anti-tumor necrosis factor-alfa agent than in those who developed drug resistance (secondary inefficacy).•When anticipating a change in therapy, physicians should consider the reason that led to the first drug being discontinued.How did this article change the practice of dermatology?Although each patient's biologic therapy regimen should be tailored individually, consider switching to a biologic medication that works by a different mechanism in cases where a patient experiences treatment failure with primary tumor necrosis factor-α–inhibitor therapy rather than switching to a second tumor necrosis factor-α inhibitor.1

Certolizumab pegol for induction of remission in Crohn's disease.

Crohn's disease (CD) is a chronic inflammatory disease of the gastrointestinal tract, and immune response modulation is the main treatment strategy to induce remission in active CD. Certolizumab pegol (CZP) is a tumor necrosis factor-alfa (TNF-α) inhibitor which regulates impaired immune response. The primary objectives were to evaluate the efficacy and safety of CZP for the induction of remission in CD. We searched MEDLINE, Embase, CENTRAL, the Cochrane IBD group specialized register, trials registers and other sources from inception to 28 January 2019. Moreover, we contacted the pharmaceutical company that manufactures CZP. We included randomized controlled trials comparing CZP with placebo or no treatment in active CD patients. We used standard Cochrane methodological procedures. The main outcomes selected for GRADE analysis were clinical remission at week 8 (Crohn's Disease Activity Index [CDAI] ≤150), clinical response at week 8 (CDAI reduction ≥ 100 or clinical remission), and serious adverse events. The Mantel-Haenszel random-effects method was applied for the statistical analyses. For dichotomous outcomes, we calculated the risk ratio (RR) and corresponding 95% confidence interval (95% CI). Four studies involving 1485 participants with moderate to severe CD met the inclusion criteria and were used in the meta-analyses. All studies included active CD patients with CDAI ranging from 220 to 450. Most patients were adults over 18 years of age. One study was identified as high risk of bias due to a non-identical placebo while the other studies were judged to be at low risk of bias.CZP (100 mg to 400 mg every 2 to 4 weeks) was shown to be superior to placebo for achieving clinical remission at week 8 (RR 1.36, 95% CI 1.11 to 1.66; moderate certainty evidence). The raw numbers of participants achieving clinical remission at week 8 were 26.9% (225/835) and 19.8% (129/650) in the CZP and the placebo groups, respectively.CZP was shown to be superior to placebo for achieving clinical response at week 8 (RR 1.29, 95% CI 1.09 to 1.53; moderate certainty evidence). In raw numbers, clinical response at week 8 was achieved in 40.2% (336/835) and 30.9% (201/650) of participants in the CZP and the placebo groups, respectively.In raw numbers, serious adverse events were observed in 8.7% (73/835) and 6.2% (40/650) of participants in the CZP and the placebo groups, respectively (RR 1.35, 95% CI 0.93 to 1.97; moderate certainty evidence). Serious adverse events included worsening Crohn's disease, infections, and malignancy. Moderate certainty evidence suggests that CZP is effective for induction of clinical remission and clinical response in participants with active CD patients. It is uncertain whether the risk of serious adverse events differs between CZP and placebo as the 95% CI includes the possibility of a small decrease or doubling of events. Future studies are needed to evaluate the long-term efficacy and safety of CZP in CD patients.

Severe Hypoglycemia Upon Initiation of Tumor Necrosis Factor Alfa Inhibitor for Crohnʼs Disease

Severe Hypoglycemia Upon Initiation of Tumor Necrosis Factor Alfa Inhibitor for Crohnʼs Disease

Protective Effect of Infliximab, a Tumor Necrosis Factor-Alfa Inhibitor, on Bleomycin-Induced Lung Fibrosis in Rats.

We aimed to investigate the preventive effect of Infliximab (IFX), a tumor necrosis factor (TNF)-α inhibitor, on bleomycin (BLC)-induced lung fibrosis in rats. Rats were assigned into four groups as follows: I-BLC group, a single intra-tracheal BLC (2.5 mg/kg) was installed; II-control group, a single intra-tracheal saline was installed; III-IFX + BLC group, a single-dose IFX (7 mg/kg) was administered intraperitoneally (i.p.), 72 h before the intra-tracheal BLC installation; IV-IFX group, IFX (7 mg/kg) was administered alone i.p. on the same day with IFX + BLC group. All animals were sacrificed on the 14th day of BLC installation. Levels of tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β, interleukin (IL)-6, periostin, YKL-40, nitric oxide (NO) in rat serum were measured, as well as, myeloperoxidase (MPO), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) activity, and reduced glutathione (GSH), hydroxyproline, malondialdehyde (MDA) content in lung homogenates. Lung tissues were stained with hematoxylin and eosin (H&E) for quantitative histological evaluation. The inducible nitric oxide synthase (iNOS) expression and cell apoptosis in the lung tissues were determined quantitatively by immunohistochemical staining (INOS) and by TUNNEL staining, respectively. BLC installation worsened antioxidant status (such as SOD, CAT, GPx, GSH, MPO), while it increased the serum TNF-α, TGF-β, IL-6, periostin, YKL-40, and lipid peroxidation, and collagen deposition, measured by MDA and hydroxyproline, respectively. IFX pretreatment improved antioxidant status as well as BLC-induced lung pathological changes, while it decreased the TNF-α, TGF-β, IL-6, periostin, YKL-40, lipid peroxidation and collagen deposition. Finally, histological, immunohistochemical, and TUNNEL evidence also supported the ability of IFX to prevent BLC-induced lung fibrosis. The results of the present study indicate that IFX pretreatment can attenuate BLC-induced pulmonary fibrosis.

Histopathologic analysis of tumor necrosis factor-alfa inhibitor therapy–induced psoriasiform eruptions

Histopathologic analysis of tumor necrosis factor-alfa inhibitor therapy–induced psoriasiform eruptions

Pyoderma gangrenosum: pathogenetic oriented treatment approaches.

Pyoderma gangrenosum (PG) shows features of autoimmune and autoinflammatory disorders. Genetic defects which affect the inflammasome, and in particular the NLRP3 zone, can cause an abnormal secretion of interleukin 1 (IL-1). IL-1 may be involved in clinical manifestation of certain (genetic) forms of PG. IL-1 receptor antagonists reduce the activity of IL-1α and IL-1β. Mutations in the PSTPIP1 gene have been identified in patients with pyogenic arthritis, pyoderma gangrenosum and acne syndrome. In patients with a pyoderma gangrenosum, acne, and suppurative hidradenitis syndrome these mutations cannot be found and the effect of IL-1 inhibition is questionable. Another upcoming opportunity is targeted therapy by tumor necrosis factor-alfa inhibitors in steroid-resistant patients. This review has been focused on (1) the modern pathogenetic concepts, (2) the currently accepted criteria for differentiating the disease, (3) the target therapy and (4) valuable advice to the clinicians regarding a number of medicaments capable of aggravating or inducing the PG.

ABATACEPT IN TREATMENT OF JUVENILE IDIOPATHIC ARTHRITIS: INTERNATIONAL DATA AND EXPERIENCE OF USAGE IN THE REPUBLIC OF MORDOVIA

The authors represent a review of modern views on abatacept usage in treatment of juvenile idiopathic arthritis emphasizing its high level of safety and possibility to use it in patients resistant to standard basic therapy and tumor necrosis factor alfa inhibitors. The results of clinical investigations on assessment of efficacy and safety of abatacept in treatment of various types of rheumatoid arthritis in adults and juvenile idiopathic arthritis in children are given. Among the advantages and prospects of abatacept usage in pediatric rheumatology is possibility to its administration as monotherapy, particularly in patients with intolerability or insufficient efficacy of methotrexate and/or tumor necrosis factor . The authors also show their own data on abatacept usage in 8 children with juvenile idiopathic arthritis in the Republic of Mordovia, among them — patients with high risk of tuberculosis infection activation. In 1 year 75% of children (half of them being resistant to genetically engineered biological agents) achieved 50% improvement according to the pediatric criteria of the American College of Rheumatology.

Systemic treatment and narrowband ultraviolet B differentially affect cardiovascular risk markers in psoriasis

Psoriasis is associated with a systemic inflammation and an increased frequency of the metabolic syndrome, both of which are believed to link psoriasis to an increased risk of cardiovascular disease. The study aimed to investigate the systemic expression of markers of cardiovascular risk and determine their response to ultraviolet B therapy and treatment with the tumor necrosis factor-alfa inhibitor, etanercept. Six markers of cardiovascular risk were measured in 28 patients with psoriasis and 28 control subjects. Five of the 6 investigated markers were elevated in patients with psoriasis. Four of these correlated to the body mass index and waist-hip ratio, suggesting a link to the metabolic syndrome. Total plasminogen activator inhibitor-1 remained elevated independently of these factors. The levels of the investigated risk markers decreased considerably after tumor necrosis factor-alfa inhibitor treatment but remained unaffected by ultraviolet therapy. A relatively limited study population and nonrandomization are limitations. These findings suggest that the choice of treatment in psoriasis may influence the cardiovascular risk in patients with psoriasis and the metabolic syndrome.

Cardiovascular event risk assessment in psoriasis patients treated with tumor necrosis factor-alfa inhibitors versus methotrexate

Cardiovascular event risk assessment in psoriasis patients treated with tumor necrosis factor-alfa inhibitors versus methotrexate

Efficacy of switching between tumor necrosis factor-alfa inhibitors in psoriasis: Results from the Italian Psocare Registry

Some studies have shown that switching patients from one tumor necrosis factor (TNF)-alfa inhibitor to another may be beneficial when they have an inadequate response or an adverse event. We sought to assess the variables predicting the efficacy of the second TNF-alfa inhibitor in patients discontinuing the first TNF-alfa inhibitor. Data from all 5423 consecutive patients starting TNF-alfa inhibitor therapy for psoriasis between September 2005 and September 2010 who were included in the Italian Psocare registry were analyzed. In 105 patients who switched to a second TNF-alfa inhibitor who had complete follow-up data, 75% improvement in the Psoriasis Area Severity Index score (PASI 75) was reached by 29% after 16 weeks and by 45.6% after 24 weeks. Patients who switched because of secondary loss of efficacy (loss of initial PASI 75 response) or adverse events/intolerance were more likely to reach PASI 75 than those who switched as a result of primary inefficacy (PASI 75 never achieved) (hazard ratio 2.7, 95% confidence interval 1.3-5.5 vs hazard ratio 2.0, 95% confidence interval 1.0-3.9 and 1, respectively). There was a small number of patients with complete follow-up data. PASI 75 response in patients who switched from one anti-TNF-alfa agent to another was significantly reduced in patients who showed primary inefficacy of the first anti-TNF-alfa.

From the Medical Board of the National Psoriasis Foundation: Recommendations for screening for hepatitis B infection prior to initiating anti–tumor necrosis factor-alfa inhibitors or other immunosuppressive agents in patients with psoriasis

No consensus exists regarding the optimal laboratory screening for hepatitis B infection that should be performed before initiating therapy with tumor necrosis factor-alfa inhibitors or other immunosuppressive agents. We sought to give guidelines on which tests to order for hepatitis B screening. We review the pathophysiology and serology of hepatitis B infection and provide recommendations for screening for hepatitis B infection in patients with psoriasis before beginning anti-tumor necrosis factor-alfa therapy or other immunosuppressive agents. We propose the standardized use of triple serology testing: hepatitis B surface antigen, hepatitis B surface antibody, and hepatitis B core antibody in combination with liver function tests as screening. Conclusions based on review of available literature is a limitation. All patients with psoriasis who are candidates for tumor necrosis factor-alfa inhibitor should undergo screening for hepatitis B virus infection using the triple serology: hepatitis B surface antigen, hepatitis B surface antibody, and hepatitis B core antibody. It is advisable that patients, who are candidates for ustekinumab, cyclosporine, or methotrexate undergo the same screening.

Impact of effective tumor necrosis factor-alfa inhibitor treatment on arterial intima-media thickness in psoriasis: Results of a pilot study

Psoriasis is associated with higher incidence of atherosclerotic comorbidities. Sustained arterial wall inflammation mediated by common cytokines of psoriasis and atherogenesis precedes atherosclerotic plaque development. Increased intima-media thickness (IMT) is an accepted indicator of subclinical atherosclerosis and has been reported in severe psoriasis. This pilot study aimed to clarify whether effective long-term tumor necrosis factor-alfa inhibition decreases IMT in psoriasis. In 16 patients with severe psoriasis, the Psoriasis Area and Severity Index score was calculated before therapy (etanercept, infliximab, adalimumab) and after 6-month treatment. Simultaneously, carotid and brachial IMT was measured by high-resolution, B-mode ultrasonography. Difference between initial and 6-month IMT values was determined for monitored arteries collectively and separately in carotid and brachial arteries. All of 16 patients achieved Psoriasis Area and Severity Index 75, and 14 of 16 achieved Psoriasis Area and Severity Index 90 improvement. In the group of patients without initial calcified atherosclerotic plaques (13 of 16) significant IMT decrease was detected when arteries were measured collectively (P= .0002). Initial and follow-up data differed significantly also at individual analysis of carotid (P= .011) and brachial (P= .006) arteries. Eleven of 13 patients had initial carotid IMT exceeding age-adjusted normal values. The other group (3 of 16) with initial manifest plaques showed increasing IMT tendency. Their baseline ultrasonography revealed carotid IMT above the upper limit of healthy adults' age-adjusted values. Study limitation involves small patient numbers, self-controlled study design, and lack of patients' stratification according to common cardiovascular risk factors. In our pilot study effective tumor necrosis factor-alfa inhibition was found to decrease IMT in psoriatic patients without irreversible atherosclerotic plaques. Further analysis is recommended to confirm and complete our primary observations.

Review on the Influence of Protocol Design on Clinical Outcomes in Rheumatoid Arthritis Treated with Rituximab

To critically analyze the influence of protocol design on clinical outcome in patients with rheumatoid arthritis (RA) treated with rituximab. A PubMed and EMBASE search (January 2000-January 2012) using the key words rheumatoid arthritis and rituximab was performed. A search of English-language studies from the data sources was conducted for randomized, double-blind, placebo-controlled studies with 100 patients or more assessing the efficacy and safety of rituximab in the treatment of RA. From these studies, 2 authors independently extracted, compiled, and aggregated the data. Eight studies met the inclusion criteria. In these studies, some patients had not been treated with tumor necrosis factor-alfa (TNF-α) inhibitors, while most did not respond to it. The variables compared included dose (500 vs 1000 mg), duration of study (24 vs 48 weeks), and number of cycles (1 vs 2). They were statistically analyzed using the χ(2) test. There was a statistically significant difference in the response to rituximab compared to the control (methotrexate) (p < 0.001). In patients who were studied for only 24 weeks, given 500 or 1000 mg for 1 or 2 cycles, a 90% or greater response rate was reported in those who achieved an ACR 20, but no statistically significant differences were observed (p = 0.75). In patients studied for 48 weeks who received 2 cycles of either 500 mg or 1000 mg of rituximab and achieved an ACR 20, a statistically significant difference (p < 0.001) was observed in those who received a dose of 1000 mg for 2 cycles (42.77% vs 67.49%). In patients who are nonresponsive to disease-modifying antirheumatic drugs and TNF-α inhibitors, rituximab may be a promising and well-tolerated biologic agent. The capacity of rituximab to produce long-term, sustained remissions could not be evaluated because the duration of the studies was limited to 24 weeks or 48 weeks. Studies with longer periods of observation are warranted.

Effect of tumor necrosis factor–alfa inhibitor and methotrexate therapy on total cholesterol, high-density lipoprotein, and low-density lipoprotein in psoriasis/psoriatic arthritis and rheumatoid arthritis patients

Effect of tumor necrosis factor–alfa inhibitor and methotrexate therapy on total cholesterol, high-density lipoprotein, and low-density lipoprotein in psoriasis/psoriatic arthritis and rheumatoid arthritis patients

Treatment of refractory chronic urticaria with tumor necrosis factor–alfa inhibitors

To the Editor: Chronic urticaria is a physically and emotionally debilitating condition that often fails to respond adequately to antihistamines. Systemic therapy with glucocorticoids, sulfasalazine, colchicine, intravenous immunoglobulin, dapsone, or other immunosuppressants including cyclosporine, cyclophosphamide, and methotrexate are used in many patients with the associated risks of renal and hepatic toxicity and anemia. Unfortunately, some patients have disease recalcitrant to these treatments.