Tumor Necrosis Factor Blockers Research Articles

A multicentre, randomised, controlled, open-label pilot study on the feasibility of discontinuation of adalimumab in established patients with rheumatoid arthritis in stable clinical remission

ObjectivesTreatment with tumour necrosis factor (TNF) blockers, once started as therapy for rheumatoid arthritis (RA), is usually continued indefinitely. The aim of this trial was to assess the possibility of...

Mechanism and Clinical Significance of IL-6 Combined with TNF-α or IL-1 for the Induction of Acute Phase Proteins SAA and CRP in Chronic Inflammatory Diseases

Serum amyloid A (SAA) and C-reactive protein (CRP) are two major acute phase proteins whose serum concentrations increase in response to inflammation, though the exact mechanism underlying this induction remains unknown. Dysregulated production of interleukin (IL)-6 plays a pathogenic role in various inflammatory diseases such as rheumatoid arthritis, Castleman’s disease and systemic juvenile idiopathic arthritis. IL-6 blocking therapy with an anti-IL-6 receptor antibody (tocilizumab) can ameliorate clinical symptoms and abnormal laboratory findings, and completely normalize CRP and SAA levels in rheumatoid arthritis patients. Conversely, therapy for blocking tumor necrosis factor (TNF)-α, another key pathogenic factor in rheumatoid arthritis, barely lowers CRP and SAA to within their normal range, suggesting that IL-6 and TNF-α play different roles in the induction of acute phase protein expression. To clarify the different pathogenic roles and mechanisms of IL-6 and TNF-α or IL-1 in the induction of CRP and SAA in chronic inflammatory diseases, we investigated the transcriptional regulation mechanisms of SAA and CRP using hepatoma-derived cell lines in vitro, and related these mechanisms to the different effects of IL-6 and TNF-α blocking therapies on serum SAA and CRP in rheumatoid arthritis patients in vivo. We propose transcriptional regulation models for inflammatory cytokine-induced SAA and CRP expression that explain why IL-6 plays an essential role in the induction of SAA and CRP in the presence of inflammation.

Functional Comparison of Molluscum Contagiosum Virus vFLIP MC159 with Murine Cytomegalovirus M36/vICA and M45/vIRA Proteins.

Molluscum contagiosum virus (MCV) gene MC159 encodes a viral FLICE inhibitory protein (vFLIP) that inhibits caspase-8-mediated apoptosis. The MC159 protein was also reported to inhibit programmed necrosis (necroptosis) and modulate NF-κB activation by interacting with RIP1 and NEMO. The importance of MC159 during MCV infection has remained unknown, as there is no system for propagation and genetic manipulation of this virus. Here we investigated the functions of MC159 during viral infection using murine cytomegalovirus (MCMV) as a surrogate virus. MC159 was inserted into the MCMV genome, replacing M36 or M45, two MCMV genes with functions similar to those reported for MC159. M36 encodes a viral inhibitor of caspase-8-induced apoptosis (vICA) and M45 a viral inhibitor of RIP activation (vIRA), which inhibits RIP1/RIP3-mediated necroptosis. The M45 protein also blocks NF-κB activation by interacting with NEMO. When expressed by MCMV, MC159 blocked tumor necrosis factor alpha (TNF-α)-induced apoptosis of infected cells and partially restored MCMV replication in macrophages. However, MC159 did not fully replace M45, as it did not inhibit necroptosis in murine cells, but it reduced TNF-α-induced necroptosis in MCMV-infected human HT-29 cells. MC159 also differed from M45 in its effect on NF-κB. While MCMV-encoded M45 blocked NF-κB activation by TNF-α and interleukin-1β (IL-1β), MC159 inhibited TNF-α- but not IL-1β-induced NF-κB activation in infected mouse fibroblasts. These results indicate that the spectrum of MC159's functions differs depending on cell type and expression system and that a cell culture system for the propagation of MCV is needed to determine the biological relevance of presumed viral gene functions. MCV is a human-pathogenic poxvirus that cannot be propagated in cell culture or laboratory animals. Therefore, MCV gene products have been studied predominantly in cells expressing individual viral genes. In this study, we analyzed the function of the MCV gene MC159 by expressing it from a different virus and comparing its functions to those of two well-characterized MCMV genes. In this system, MC159 displayed some but not all of the previously described functions, suggesting that the functions of a viral gene depend on the conditions under which it is expressed. Until a cell culture system for the analysis of MCV becomes available, it might be necessary to analyze MCV genes in several different systems to extrapolate their biological importance.

Safety and efficacy of intra-articular anti-tumor necrosis factor α agents compared to corticosteroids in a treat-to-target strategy in patients with inflammatory arthritis and monoarthritis flare.

The aim of this study was to assess safety and efficacy of ultrasonography (US)-guided intra-articular injections using tumor necrosis factor (TNF) blockers compared to corticosteroids in rheumatoid arthritis (RA) or psoriatic arthritis (PsA) patients, experiencing refractory monoarthritis despite the current systemic therapy. Eighty-two patients were randomized to receive three intra-articular injections monthly of either corticosteroid or TNF blockers. Primary endpoints were the safety and an improvement greater than 20% for visual analogic scales of involved joint pain in patients injected with anti-TNFα. Further clinical, US, and magnetic resonance imaging (MRI) evaluations were considered secondary endpoints. Intra-articular TNF blockers are a safe strategy, determining a significant reduction of patient and physician reported clinical outcomes and US/MRI scores, in RA and PsA patients, when compared to intra-articular injections of corticosteroids. US guidance excluded the possibility to inject the drug in the wrong site, maximizing local effects, reducing systemic effects, and increasing the safety of the procedure. Patients with inflammatory monoarthritis could be successfully treated with US-guided intra-articular TNF blockers that are a safe and well tolerated procedure, to achieve a longstanding clinical and radiological good clinical response and/or disease remission.

Minimal Disease Activity and Remission in Psoriatic Arthritis Patients Treated with Anti-TNF-α Drugs.

A state of remission is the target of therapy in chronic arthritis. The aim of the present study was to assess the rate of minimal disease activity (MDA) and remission in patients with psoriatic arthritis (PsA) treated with tumor necrosis factor (TNF-α) blockers. Disease characteristics and predictors of MDA were also evaluated. Patients fulfilling the ClASsification for Psoriatic ARthritis (CASPAR) criteria and treated with TNF-α blockers adalimumab, etanercept, or golimumab were enrolled and prospectively followed every 4 months for 1 year in a clinical practice setting. Patients were considered in MDA when they met at least 5/7 of the criteria previously defined. Other remission criteria evaluated were 28-joint Disease Activity Score-C-reactive protein (DAS28-CRP) < 2.6 and Disease Activity in Psoriatic Arthritis (DAPSA) score ≤ 3.3. Patients achieving MDA were compared to non-MDA to identify outcome predictor factors. Of the 75 patients treated with TNF-α blockers, at baseline no patients were in MDA or had a DAPSA score ≤ 3.3, while 25 (21.3%) had a DAS28-CRP score < 2.6. Five patients (6%) discontinued treatment because of side effects or inefficacy during followup. After 12 months, MDA was achieved in 46 patients (61.3%). No difference was found among the 3 anti-TNF-α drugs. Predictors for MDA were found to be male sex, high CRP, high erythrocyte sedimentation rate, and low Health Assessment Questionnaire. In our prospective observational study, based on a clinical practice setting, MDA was achieved in 61.3% of patients treated with TNF-α blockers, identifying this as an achievable target for patients with PsA. Predictors of remission were also identified.

Summaries for Patients. Rashes in Patients With Ulcerative Colitis or Crohn Disease Being Treated With Drugs That Block Tumor Necrosis Factor.

Summaries for Patients. Rashes in Patients With Ulcerative Colitis or Crohn Disease Being Treated With Drugs That Block Tumor Necrosis Factor.

Cytokine and Chemokine Profile in Amicrobial Pustulosis of the Folds

Autoinflammation has recently been suggested in the pathogenesis of neutrophilic dermatoses but systematic studies on their cytokine profile are lacking. Notably, amicrobial pustulosis of the folds (APF), classified among neutrophilic dermatoses, has been studied only in small case series.In our University Hospital, we conducted an observational study on 15 APF patients, analyzing their clinical and laboratory features with a follow-up of 9 months to 20 years. Skin cytokine pattern of 9 of them was compared to that of 6 normal controls.In all patients, primary lesions were pustules symmetrically involving the skin folds and anogenital region with a chronic-relapsing course and responding to corticosteroids. Dapsone, cyclosporine, and tumor necrosis factor blockers were effective in refractory cases. In skin samples, the expressions of interleukin (IL)-1β, pivotal cytokine in autoinflammation, and its receptors I and II were significantly higher in APF (P = 0.005, 0.018, and 0.034, respectively) than in controls. Chemokines responsible for neutrophil recruitment such as IL-8 (P = 0.003), CXCL 1/2/3 (C-X-C motif ligand 1/2/3) (P = 0.010), CXCL 16 (P = 0.045), and RANTES (regulated on activation, normal T cell expressed and secreted) (P = 0.034) were overexpressed. Molecules involved in tissue damage like matrix metalloproteinase-2 (MMP-2) (P = 0.010) and MMP-9 (P = 0.003) were increased.APF is a pustular neutrophilic dermatosis with a typical distribution in all patients. The disorder may coexist with an underlying autoimmune/dysimmune disease but is often associated only with a few autoantibodies without a clear autoimmunity. The overexpression of cytokines/chemokines and molecules amplifying the inflammatory network supports the view that APF has an important autoinflammatory component.

Calcium-sensing receptor (CaSR)-mediated anti-inflammatory effects of L-amino acids in intestinal epithelial cells.

Calcium-sensing receptor (CaSR) plays an essential role in sensing nutrients and monitoring ion balance in the human gut. However, no discovery of CaSR-mediated anti-inflammatory effect of l-amino acids (l-AAs) on the gut system has been reported. The aim of this study is to screen and identify the anti-inflammatory activity of various l-AAs in intestinal epithelial cells (IECs) and stepwise illustrate a possible molecular mechanism for anti-inflammation. We used Caco-2 and HT-29 cell lines to evaluate the anti-inflammatory activity of l-AAs and revealed that l-tryptophan (l-Trp) and l-valine (l-Val) have strong anti-inflammatory activity consistent in both cell lines. l-Trp treatment (5 mM) reduced TNF-α-induced IL-8 secretion from HT-29 or Caco-2 cells to about 50 or 40%, respectively. l-Trp also significantly inhibited the expression of phosphorylation of JNK or IκBα to around 50% in HT-29 cells. However, the above inhibitory effects of l-Trp on inflammatory responses in TNF-α-induced HT-29 cells were abrogated by NPS-2143. The result of CaSR antagonist NPS-2143 pretreatment study suggests l-Trp exerts anti-inflammatory effects on IECs through CaSR activation. The involvement of β-arrestin2 was then found to block tumor necrosis factor (TNF)-α-induced signaling pathways after CaSR activated by l-Trp. These results validate a novel mechanism underlying CaSR agonistic l-AAs exerting anti-inflammatory effects on human intestinal epithelia.

Role of Agents other than Tumor Necrosis Factor Blockers in the Treatment of Psoriatic Arthritis.

Psoriatic arthritis (PsA) is a systemic inflammatory disease characterized by possible peripheral and axial joint involvement, enthesitis, dactylitis, and skin and nail disease. It affects up to one-third of psoriatic patients, and may be associated with comorbidities such as cardiovascular and metabolic diseases. The usually prescribed initial treatment of moderate-severe PsA is methotrexate, which may be accompanied or replaced by a tumor necrosis factor (TNF) inhibitor such as etanercept, infliximab, or adalimumab. However, some patients may become unresponsive (or have contraindications) to available anti-TNF agents and require alternative treatment. The aim of this review is to describe the potential role of some new immunomodulatory agents.

Study on the protective effect of the KIR3DL1 gene in ankylosing spondylitis.

Ankylosing spondylitis (AS) is an autoimmune disease that mainly affects the sacroiliac joints and the spine of the lower back. The disease is strongly associated with HLA-B27. Additional genes, single-nucleotide polymorphisms, and molecular components have been identified to be associated with AS, but the exact mechanism that drives disease development remains poorly understood. The killer cell immunoglobulin-like receptors (KIRs) are regulators of cytotoxicity of natural killer cells and T cell subsets and may be relevant in binding to HLA-B27 and the development of AS. We undertook this study to identify possible associations of KIR genotype with susceptibility to AS and disease characteristics including the presence of the HLA-B27 allele, disease severity, and uveitis. We performed complete genotyping of the KIR locus in 303 Caucasian AS patients, 119 randomly selected healthy Caucasian controls, and 50 HLA-B27-positive healthy Caucasian controls by multiplex ligation-dependent probe amplification assay for detection of gene presence and copy number. We did not observe a significant association of any specific KIR gene or haplotype with susceptibility to AS or any other clinical manifestation. Disease severity, as measured by fulfilling the criteria for treatment with tumor necrosis factor blocking therapy, was linked to a lower number of genes for the functional variant of KIR3DL1 (P = 0.007). Our exploratory study indicates that KIR genes are not a major risk factor for susceptibility to AS. However, the data do suggest a role for KIRs in progression of the disease, whereby KIR3DL1 has a protective effect against the more severe manifestations of AS.

Flare Rate in Patients with Rheumatoid Arthritis in Low Disease Activity or Remission When Tapering or Stopping Synthetic or Biologic DMARD: A Systematic Review.

To evaluate the risk of having a disease flare in patients with rheumatoid arthritis (RA) with low disease activity (LDA) or in remission when deescalating (tapering or stopping) disease-modifying antirheumatic drug (DMARD) therapy. A search in medical databases including publications from January 1950 to February 2015 was performed. Included were trials and observational studies in adults with RA who were in LDA or remission, evaluating ≥ 20 patients tapering or stopping DMARD. Flare rates had to have been reported. A metaanalysis was performed on studies deescalating tumor necrosis factor (TNF) blockers. Four studies evaluated synthetic DMARD. Flare rates ranged from 8% at 24 weeks to 63% at 4 months after deescalation. Fifteen studies reported on TNF blockers. Estimated flare rates by metaanalysis on studies tapering or stopping TNF blockers were 0.26 (95% CI 0.17-0.39) and 0.49 (95% CI 0.27-0.73) for good-quality and moderate-quality studies, respectively. Flare rates in 3 studies stopping tocilizumab were 41% after 6 months, 55% at 1 year, and 87% at 1 year. Flare rates in 3 studies deescalating abatacept were 34% at 1 year, 41% at 1 year, and 72% at 6 months. Five studies evaluating radiographic progression in patients deescalating treatment all found limited to no progression. Results suggest that more than one-third of patients with RA with LDA or in remission may taper or stop DMARD treatment without experiencing a disease flare within the first year. Dose reduction of TNF blockers results in lower flare rates than stopping and may be noninferior to continuing full dose. Radiological progression after treatment deescalation remains low, but may increase slightly.

The interleukin (IL)-23/IL-17 axis in ankylosing spondylitis: new advances and potentials for treatment.

Ankylosing spondylitis (AS), the most common form of spondyloarthropathy, is a chronic, progressive multi-system inflammatory disorder characteristically affecting the sacroiliac joints and axial skeleton. Although the exact mechanisms underlying the pathogenesis of AS remain to be elucidated, the presence of human leucocyte antigen (HLA)-B27 is known to markedly increase its risk of development. Current treatments include non-steroidal anti-inflammatory drugs (NSAIDs) and tumour necrosis factor (TNF) blockers. In recent years, the interleukin (IL)-23/IL-17 pathway has been shown to have significance in the pathogenesis of AS and treatment modalities targeting this pathway have been shown to be beneficial in various other inflammatory conditions. This review provides an overview of the IL-23/IL-17 pathway in the pathogenesis of AS and summarizes new potential treatments for AS and related inflammatory diseases.

Early Combined Immunosuppression in Crohn Disease: A Community-Based Trial

In treatment-naive patients with Crohn disease, early treatment with a combination of a tumor necrosis factor (TNF) blocker and an antimetabolite (azathioprine, 6-mercaptopurine, or methotrexate), or early combined immunosuppression (ECI), is recognized to result in the highest remission rates. In an industry-funded, cluster-randomized study of community practices, investigators tested the efficacy of ECI versus conventional step-up management. The primary outcome was the rate of steroid-free remission at month 12. Patients were followed for 24 months. In ECI-randomized practices, after initial mandated steroid trials (4 weeks in …

Long-term treatment with rituximab in severe juvenile idiopathic arthritis-associated uveitis

Background/aimsTo evaluate retrospectively the long-term efficacy of rituximab in patients with severe juvenile idiopathic arthritis (JIA)-associated uveitis.MethodsEight patients (15 eyes) with severe and longstanding JIA uveitis, who had an inadequate...

Brief Report: Clinical Course Over Two Years in Patients With Early Nonradiographic Axial Spondyloarthritis and Patients With Ankylosing Spondylitis Not Treated With Tumor Necrosis Factor Blockers: Results From the German Spondyloarthritis Inception Cohort.

To investigate the clinical course of disease over 2 years in patients with nonradiographic axial spondylarthritis (SpA) and patients with ankylosing spondylitis (AS). The study group comprised 303 patients with axial SpA (158 patients with AS and a symptom duration of ≤10 years and 145 patients with nonradiographic axial SpA and a symptom duration of ≤5 years) who did not receive tumor necrosis factor (TNF) blockers during 2 years of followup. The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) did not differ between patients with nonradiographic axial SpA and those with AS at any time point during followup. The Bath Ankylosing Spondylitis Functional Index was significantly higher in patients with AS at baseline only, but spinal mobility was generally better in patients with nonradiographic SpA compared with those with AS. At all time points, C-reactive protein (CRP) levels were significantly higher in patients with AS compared with patients with nonradiographic axial SpA. Accordingly, the Ankylosing Spondylitis Disease Activity Score (ASDAS) was significantly higher in the patients with AS at 2 of 4 time points. When patients with a BASDAI score of ≥4 plus an elevated CRP level at baseline were analyzed over time, there were no significant differences in the proportions of patients with nonradiographic axial SpA and those with AS who reached low disease activity status at ≥2 time points during 2 years of followup when a clinical definition of low disease activity was used (38% and 35%, respectively, achieved a BASDAI score of <4, and 13% and 15%, respectively, achieved a score of ≤2). When definitions that included the CRP level were used, however, a greater percentage of patients with nonradiographic axial SpA achieved low disease activity (25% of patients with nonradiographic axial SpA and 10% of patients with AS achieved a BASDAI score of <4 and a normal CRP level, and 13% of patients with nonradiographic axial SpA and 3% of those with AS achieved ASDAS-defined low disease activity). Patients with nonradiographic axial SpA and those with AS who were not treated with TNF blockers demonstrated a similar clinical disease course over 2 years. Patients with nonradiographic axial SpA achieved a status of low disease activity more frequently than those with AS if outcome parameters that included the CRP level were used.

Immunocompromised Travelers: Demographic Characteristics, Travel Destinations, and Pretravel Health Care from the U.S. Global TravEpiNet Consortium.

An increasing number of immunocompromised individuals are pursuing international travel, and a better understanding of their international travel patterns and pretravel health care is needed. We evaluated the clinical features, itineraries, and pretravel health care of 486 immunocompromised international travelers seen at Global TravEpiNet sites from January 2009 to June 2012. We used bivariate analyses and logistic regressions using random intercept models to compare demographic and travel characteristics, vaccines administered, and medications prescribed for immunocompromised travelers versus 30,702 immunocompetent travelers. Immunocompromised travelers pursued itineraries that were largely similar to those of immunocompetent travelers, with nearly one-third of such travelers visiting countries with low human development indices. Biological agents, including tumor necrosis factor blockers, were commonly used immunosuppressive medications among immunocompromised travelers. A strong collaboration between travel-medicine specialists, primary care doctors, and specialist physicians is needed to prepare immunocompromised people for international travel. Incorporating routine questioning and planning regarding travel into the primary care visits of immunocompromised people may be useful.

Fecal Diversion for Severe Perianal Crohn Disease

Tumor necrosis factor (TNF) blockers, with or without antibiotics such as ciprofloxacin and metronidazole, are commonly used to treat severe perianal

Increased Risk of Acute Pancreatitis in Patients with Rheumatoid Arthritis: A Population-Based Cohort Study.

The study was conducted to determine whether patients with rheumatoid arthritis (RA) are at increased risk of acute pancreatitis compared with those without RA and to determine if the risk of acute pancreatitis varied by anti-RA drug use. We used the large population-based dataset from the National Health Insurance (NHI) program in Taiwan to conduct a retrospective cohort study. Patients newly diagnosed with RA between 2000 and 2011 were referred to as the RA group. The comparator non-RA group was matched with propensity score, using age and sex, in the same time period. We presented the incidence density by 100,000 person-years. The propensity score and all variables were analyzed in fully adjusted Cox proportional hazard regression. The cumulative incidence of acute pancreatitis was assessed by Kaplan-Meier analysis, with significance based on the log-rank test. From claims data of one million enrollees randomly sampled from the Taiwan NHI database, 29,755 adults with RA were identified and 119,020 non- RA persons were matched as a comparison group. The RA cohort had higher incidence density of acute pancreatitis (185.7 versus 119.0 per 100,000 person-years) than the non-RA cohort. The adjusted hazard ratio (HR) was 1.62 (95% CI [confidence interval] 1.43–1.83) for patients with RA to develop acute pancreatitis. Oral corticosteroid use decreased the risk of acute pancreatitis (adjusted HR 0.83, 95% CI 0.73–0.94) but without a dose-dependent effect. Current use of disease modifying anti-rheumatic drugs or tumor necrosis factor blockers did not decrease the risk of acute pancreatitis. In conclusion, patients with RA are at an elevated risk of acute pancreatitis. Use of oral corticosteroids may reduce the risk of acute pancreatitis.

Effect of continuous versus on-demand treatment of ankylosing spondylitis with diclofenac over 2 years on radiographic progression of the spine: results from a randomised multicentre trial (ENRADAS)

BackgroundTo date, only a single controlled trial provided evidence that non-steroidal anti-inflammatory drugs (NSAIDs) given continuously reduce radiographic progression compared with an on-demand therapy over 2 years in patients with...

Acute Anterior Uveitis and Spondyloarthritis: More Than Meets the Eye.

Ankylosing spondylitis (AS) and related forms of spondyloarthritis (SpA) are associated with some extra-articular features, and the most common symptomatic association is with acute anterior uveitis (AAU). Thus, approximately 40 % of patients with AS will experience a sudden onset of a unilateral anterior uveitis sometime during the course of their disease. Patients with AAU, especially those who are HLA-B27 positive, should be questioned about inflammatory low back pain and also evaluated for other clinical features of SpA. Since a prolonged delay in diagnosis is common among SpA patients and occurrence of AAU may be the reason for their first interaction with medical care, occurrence of AAU presents a unique opportunity for identifying such undiagnosed SpA patients. Therefore, a novel evidence-based algorithm called Dublin Uveitis Evaluation Tool (DUET) has been proposed to guide ophthalmologists and primary care physicians to refer appropriate AAU patients to rheumatologists. In a large two-phase study, approximately 40 % of patients presenting with idiopathic AAU were noted to have undiagnosed SpA, and DUET algorithm was noted to have excellent sensitivity (96 %) and specificity (97 %). It has a positive likelihood ratio (LR) 41.5 and negative LR 0.03. In most instances, the eye inflammation responds well to corticosteroid and mydriatic eye drops and without the need for additional therapy. Use of oral corticosteroids is reserved for patients, especially with associated chronic inflammatory bowel disease or psoriatic arthritis presenting with bilateral, chronic, anterior, and/or intermediate uveitis, and this treatment is rarely needed for more than a couple of weeks. A very small percentage may be more refractory to such treatment and require potential novel therapies, including the use of tumor necrosis factor blockers.