TNF-α Blocking Therapy Research Articles

Predictive values of circulating miR-146a and miR-155 for disease activity and clinical response to TNF-α blocking therapy in patients with ankylosing spondylitis.

Ankylosing spondylitis is an insidiously progressive and debilitating form of arthritis involving the axial skeleton. MicroRNAs have been reported to act as candidate biomarkers for ankylosing spondylitis diagnosis and progression. The study aimed to assess the roles of circulating miR-146a and miR-155 in ankylosing spondylitis and their prediction to clinical response to TNF-α blocking therapy. The study included 62 ankylosing spondylitis patients who were given originator TNFi with a 6-month period. Responders to anti-TNF treatment were defined as those reaching the Assessment of SpondyloArthritis international Society 40 (ASAS40) response at the 6-month interval, and nonresponders were defined those not (n = 24). The ankylosing spondylitis patients at M0 (before beginning TNFi treatment) had higher serum levels of miR-146a and miR-155 than the healthy controls (p < .0001). Lower serum levels of miR-146a and miR-155 were noted in the responders (n = 38) compared with the nonresponders (n = 24) at different time points after anti-TNF treatment (p < .0001). The serum levels of miR-146a and miR-155 alone or in combination used to predict treatment outcomes produced AUCs of 0.884, 0.902, and 0.936, respectively. We submitted the following variables: miR-146a and miR-155 levels, BASDAI, ASDASCRP, ESR (mm/h), and CRP (mg/L) into multivariate logistic regression analysis, and results showed that higher levels of miR-146a (OR: 13.75, 95%CI: 1.32 to 143.57, p = .029), miR-155 (OR: 5.74, 95% CI: 1.63 to 20.20, p = .006), and ESR (OR: 1.08, 95% CI: 1.01 to 1.15, p = .022) were independent baseline predictors of ASAS40 response at 6-month anti-TNF-a treatment. These findings obtained from the study suggest that high serum levels of miR-146a and miR-155 could aid in prediction of poor treatment outcomes after TNF-α blocking therapy.

Incidence of histoplasmosis in patients receiving TNF-alpha inhibitors: A systematic review and meta-analysis.

Immunobiological drugs such as TNF-α inhibitors are valuable in rescue therapy for autoimmune diseases such as rheumatoid arthritis and inflammatory bowel disease (IBD), but they increase the risk of infectious complications. Histoplasmosis is a significant concern in patients living in endemic regions, however, few studies have assessed the incidence of Histoplasma infection during therapy, and classic estimates may underestimate the risk. This study aimed to produce an updated risk estimate of histoplasmosis in patients on TNF-α blocking therapy. This is a systematic review and meta-analysis of studies that contain parameters for calculating the risk of histoplasmosis in people who use TNF-α inhibitors, to produce a risk estimate. We identified 11 studies with the necessary parameters for inclusion in the meta-analysis, most of which were from North America. The incidence rate of histoplasmosis found was 33.52 cases per 100,000 patients treated with TNF-ɑ inhibitors (95% CI 12.28-91.46). Considering only studies evaluating monoclonal antibodies, the calculated incidence was 54.88/100,000 patients treated (95%CI 23.45-128.34). In subgroup analysis, the incidence was much higher in patients with IBD compared to rheumatic diseases. There was significant heterogeneity among the studies. The risk of histoplasmosis during TNF-α inhibitory therapy may be considerably higher than that found in classical estimates, especially in patients with IBD. There is a lack of studies evaluating histoplasmosis in large endemic areas, such as Central and South America.

Predictive Values of Blood Type I and Type II Interferon Production for Disease Activity and Clinical Response to TNF-α Blocking Therapy in Patients with Ankylosing Spondylitis.

Tumor necrosis factor-α (TNF-α) blocking therapy is recommended to treat ankylosing spondylitis for patients who fail to respond to nonsteroidal anti-inflammatory drugs (NSAIDs). Herein, we attempt to dissect whether blood type I and II interferon (IFN) production can be predictive of ankylosing spondylitis progression and treatment response to the tumor necrosis factor inhibitor (TNFi). A total of 50 ankylosing spondylitis patients receiving originator TNFi with a 6-month period were retrospectively analyzed. The patients who reached the Assessment of SpondyloArthritis international Society 40 (ASAS40) response at the 6-month interval were classified as responders (n = 29) to TNFi treatment, otherwise as non-responders (n = 21). The serum type I IFN activity, and the serum levels of IFN-α and IFN-γ in the patients at baseline were notably greater than the healthy controls. Pearson correlation analysis showed positive correlations in the patients between the serum type I IFN activity or the serum levels of IFN-α and IFN-γ, and BASDAI scores, ASDASCRP or pro-inflammatory factor production. The responders were demonstrated with reduced serum type I IFN activity concomitant with lower serum levels of IFN-α and IFN-γ compared to the non-responders after anti-TNF treatment. The serum type I IFN activity, and the serum levels of IFN-α and IFN-γ used as a test to predict responders and non-responders to anti-TNF treatment produced an area under the curve (AUC) of 0.837, 0.814, and 0.787, respectively. In conclusion, the study demonstrates that blood type I and II IFN production may be correlated with disease activity, inflammatory cytokine production, and indicative of unsatisfying response to TNFi treatment in ankylosing spondylitis patients.

High prevalence of hip involvement and decrease in inflammatory ultrasound lesions during tumour necrosis factor-α blocking therapy in ankylosing spondylitis.

To assess the prevalence of clinical, US and radiographic hip involvement in AS patients with active disease and to explore the associations between these assessments. Furthermore, to evaluate the effect of 6 months of TNF-α blocking therapy on tender and inflammatory power Doppler US lesions of hip joints. Consecutive AS patients starting TNF-α blocking therapy were evaluated for hip joint involvement. At baseline, patient-reported history of hip involvement was assessed and radiographic evaluation (BASRI-hip) was performed. Clinical examination (tender hip joints) and US examination took place before and after 6 months of treatment. Of the 111 included patients, 20% reported a history of hip involvement. At baseline, tender hip joints were present in 23% of patients. US examination showed inflammatory lesions in 17% of patients, of which 74% had positive power Doppler. Structural lesions were present in 20% of patients, of which 55% had osteophytes. Structural radiographic damage was seen in 10% of patients. Highest concordance was found between history of hip involvement and radiographic hip involvement (phi coefficient 0.333). After 6 months of TNF-α blocking therapy, significant decrease was found in tender hip joints (from 29 to 11), total number of inflammatory US lesions (from 29 to 9) and positive power Doppler (from 22 to 6). The prevalence rate of hip involvement in AS patients varies from 10 to 23%, depending on the type of hip assessment. TNF-α blocking therapy significantly improved tender hip joints, and inflammatory US lesions including positive power Doppler.

The effects of golimumab treatment on systolic and diastolic left ventricular function in ankylosing spondylitis.

BackgroundDiastolic left ventricular (LV) dysfunction appears more prevalent in ankylosing spondylitis (AS). The effects of tumor necrosis factor alpha (TNF-α) blocking therapy, a strong and effective anti-inflammatory drug, on diastolic LV function in AS are unknown. The objective of the study was to find the effects of 1-year treatment with golimumab 50 mg subcutaneously once per month on systolic and diastolic LV dysfunction in AS patients.MethodsForty consecutive AS patients were treated with TNF-α blocking therapy for 1 year. Transthoracic echocardiography was performed in all patients at baseline and after 1 year of treatment.ResultsDiastolic LV function improved after treatment in four out of six (67%) AS patients who completed follow-up (P=0.125), and did not develop or worsen in any of the other patients. Treatment with TNF-α blocking therapy had no effect on systolic LV function.ConclusionThese findings give support to the hypothesis that diastolic LV dysfunction improves during treatment with TNF-α blocking therapy.

Anti-TNF-α restricts dengue virus-induced neuropathy.

Proinflammatory TNF-α facilitates dengue virus (DENV) infection in endovascular dysfunction and neurotoxicity. The introduction of TNF-α blocking therapy with Abs is performed to test its therapeutic effect in this study. In DENV-infected mice, TNF-α production in the brain accompanied the progression of neurotoxicity and encephalitis. DENV infection caused the loss of hippocampal neurons with TNF-α expression around damaged regions, and immunostaining showed the induction of apoptosis in hippocampal neurons. TNF-α was expressed in active microglia and astrocytes in DENV-infected mice. TNF-α facilitated DENV-induced neurotoxicity in vitro in murine Neuro-2a cells. Using a currently established encephalitic mouse model in which DENV infection causes progressive hunchback posture, limbic seizures, limbic weakness, paralysis, and lethality 7 days postinfection, we showed that TNF-α transgenic mice represented the progressive disease development and administration of neutralizing TNF-α Ab reduced dengue encephalitis and mortality. These results demonstrate an immunopathogenesis of TNF-α for mediating DENV-induced encephalitis-associated neurotoxicity and that targeting TNF-α can be used as a strategy against dengue encephalitis.

Targeting TNF-α against dengue virus-induced neurotoxicity and acute viral encephalitis-like symptoms

Abstract Pro-inflammatory tumor necrosis factor α (TNF-α) facilitates dengue virus (DENV) infection in endovascular dysfunction and neurotoxicity. The introduction of TNF-α blocking therapy with antibodies and antagonists is performed for testing its therapeutic effects in this study. In DENV-infected mice, TNF-α was produced in the brains accompanied by the progression of neurotoxicity and encephalitis. DENV infection caused loss in hippocampal neurons with TNF-α expression around the damaged regions. Additionally, immunostaining showed the induction of apoptosis in hippocampal neurons. TNF-α was expressed in active microglia as well as astrocytes of DENV-infected mice. TNF-α facilitated DENV-induced neurotoxicity in vitro in murine Neuro-2a cells. By using a currently established encephalitic mice model that DENV infection caused progressive hunchback posture, limbic seizures, limbic weakness, paralysis, and lethality 7 days post-infection, TNF-α transgenic mice represented the progressive disease development while administration of neutralizing TNF-α antibody reduced dengue encephalitis and mortality. These results demonstrate an immunopathogenesis of TNF-α for mediating DENV-induced encephalitis-associated neurotoxicity and targeting TNF-α can be used as a strategy against dengue encephalitis.

Incidence of human cytomegalovirus infection and T-cell response in patients with psoriasis before and during antitumour necrosis factor-α therapy

psoriasis is a chronic inflammatory skin disease that affects approximately 2-3% of the world population.1 Among the cytokines produced by T cells, TNF-α has a crucial role in psoriasis.2 Thus, TNF-α blocking therapy is efficient in the treatment of psoriasis. This article is protected by copyright. All rights reserved.

Ultrasound Evaluation of the Entheses in Daily Clinical Practice during Tumor Necrosis Factor-α Blocking Therapy in Patients with Ankylosing Spondylitis.

To assess structural and inflammatory ultrasound (US) lesions of entheses in ankylosing spondylitis (AS) patients with active disease and to evaluate inflammatory lesions after 6 months of tumor necrosis factor (TNF-α) blocking therapy, in daily clinical practice. Consecutive patients with AS were clinically evaluated and underwent US examination of 9 bilateral entheses before and after 6 months of TNF-α blocking therapy. US examination included the following as inflammatory lesions: bone erosions/cortical irregularities, enthesophytes, calcifications as structural lesions; adjacent bursitis, effusion, increased tendon hypoechogenicity or thickness; and positive power Doppler (PD) signal. At baseline, 105 (95%) of 111 included patients showed US abnormalities. Structural lesions were seen in 74 patients (67%) and inflammatory lesions in 88 (79%). Enthesophytes and positive PD signal were the most prevalent structural and inflammatory lesions, respectively. Most lesions were found at the lower extremities. Additionally, inflammatory lesions occurred at the lateral epicondyle of the elbow. Patients with structural lesions at baseline were significantly older, had longer disease duration, higher modified Stoke AS Spine score, and higher C-reactive protein. Individually, there was a great diversity in changes of inflammatory entheseal lesions during treatment, but on the group level no significant decrease was found. This prospective observational cohort study in daily clinical practice shows a high prevalence of structural and inflammatory US lesions in AS patients with longstanding and active disease. Positive PD signal was the most common inflammatory feature. No significant change in inflammatory US lesions was found after 6 months of TNF-α blocking therapy.

抗TNF-α製剤使用下における関節リウマチ大関節破壊予測 : FDG-PET/CTとARASHIスコアによる検討

抗TNF-α製剤使用下における関節リウマチ大関節破壊予測 : FDG-PET/CTとARASHIスコアによる検討

Radiographic damage and progression of the cervical spine in ankylosing spondylitis patients treated with TNF-α inhibitors: Facet joints vs. vertebral bodies.

To investigate radiographic damage and 4-year progression of the cervical facet joints in a prospective observational cohort of AS patients treated with TNF-α inhibitors, to compare this with damage and progression of the cervical vertebral bodies, and to study the relation with patient characteristics and clinical outcome. Patients from the Groningen Leeuwarden AS (GLAS) cohort starting TNF-α inhibitors with baseline and 4-year radiographs were included. Cervical facet joints and vertebral bodies were scored by two independent readers according to the method of de Vlam and mSASSS, respectively. At baseline, 25 of 99 (25%) AS patients had partial or complete ankylosis of the cervical facet joints, whereas 51 (52%) patients had non-bridging or bridging syndesmophytes of cervical vertebral bodies. During 4 years, 13 (13%) patients developed new (partial) ankylosis of the facet joints, whereas 26 (26%) developed new (bridging) syndesmophytes. Facet joint damage and progression without involvement of the vertebral bodies were seen in 5 (5%) and 8 (8%) patients, respectively. Damage of facet joints was associated with longer disease duration, history of IBD/uveitis/psoriasis, higher disease activity, larger occiput-to-wall distance, higher mSASSS, and presence of syndesmophytes. Progression of the facet joints was associated with larger occiput-to-wall distance and more facet joint damage at baseline. Cervical facet joints were frequently involved in AS. During 4 years of TNF-α blocking therapy, 13% of the patients showed radiographic progression of cervical facet joints of which the majority did not show progression of vertebral bodies.

Long-term outcome of inflammatory bowel disease patients with deep remission after discontinuation of TNFα-blocking agents

Background: Little data exist on the long-term prognosis of patients with inflammatory bowel disease (IBD) after stopping TNFα-blocking therapy in deep remission. Existing data indicate that approximately 50% of patients on combination therapy who discontinued TNFα-blockers are still in remission 24 months later. The aims of this follow-up analysis were to evaluate the long-term remission rate after cessation of TNFα-blocking therapy, the predicting factors of a relapse and the response to restarting TNFα blockers.Methods: The first follow-up data of 51 IBD patients (17 Crohn’s disease [CD], 30 ulcerative colitis [UC] and four inflammatory bowel disease type unclassified [IBDU]) in deep remission at the time of cessation of TNFα-blocking therapy have been published earlier. The long-term data was collected retrospectively after the first follow-up year to evaluate the remission rate and risk factors for the relapse after a median of 36 months.Results: After the first relapse-free year, 14 out of the remaining 34 IBD patients relapsed (41%; 5/12 [42%] CD and 9/22 [41%] UC/IBDU). Univariate analysis indicated no associations with any predictive factors. Re-treatment was effective in 90% (26/29) of patients.Conclusion: Of IBD patients in deep remission at the time of cessation of TNFα-blocking therapy, up to 60% experience a clinical or endoscopic relapse after a median follow-up time of 36 months (95% CI 31–41 months). No individual risk factors predicting relapse could be identified. However, the initial response to a restart of TNFα-blockers seems to be effective and well tolerated.

Alterations in the mucosa-associated bacterial composition in Crohn's disease: a pilot study.

Changes in the intestinal bacterial composition seem to play a major role in the pathogenesis and in the clinical course of inflammatory bowel diseases (IBD), which consist of Crohn's disease (CD), and ulcerative colitis (UC). Mutations in the NOD2 gene are the most important genetic risk factors for the development of CD. In this study, the association between mucosal biopsies and the mucosa-associated bacterial composition from CD and UC patients regarding their genetic risk factors (mutations in the NOD2 gene), their endoscopic activity, and their medical therapy (TNF-α blocking therapy) was examined. Seventy biopsies from routine colonoscopies from 33 IBD patients (26 CD and 7 UC) were obtained. Disease activity and clinical characteristics were assessed. Seven different bacterial strains (Bacteroides fragilis, Escherichia coli, Prevotella melaninogenica, Clostridium coccoides, Clostridium difficile, Bifidobacterium bifidum, and Faecalibacterium prausnitzii) were quantified using real-time PCR. NOD2 genotyping from patients with CD was performed. Five of the 24 patients were positive for at least one mutation in the NOD2 gene. The bacterial composition was different in CD compared to UC, in macroscopic healthy compared to macroscopic inflamed biopsies, in NOD2 mutated compared to NOD2 wildtype patients, and in patients receiving TNF-α blocking therapy compared to patients without this treatment. This study further characterizes the mucosa-associated bacteria in IBD patients. Different clinical situations lead to an altered mucosa-associated bacterial composition. The analyzed bacteria could be promising targets for cost-effective surveillance or therapies in IBD patients.

Spinal radiographic progression in patients with ankylosing spondylitis treated with TNF-α blocking therapy: a prospective longitudinal observational cohort study.

ObjectivesTo evaluate spinal radiographic damage over time and to explore the associations of radiographic progression with patient characteristics and clinical assessments including disease activity in ankylosing spondylitis (AS) patients treated with tumor necrosis factor-alpha (TNF-α) blocking therapy in daily clinical practice.MethodsConsecutive outpatients from the Groningen Leeuwarden AS (GLAS) cohort were included based on the availability of cervical and lumbar radiographs before start of TNF-α blocking therapy and after 2, 4, and/or 6 years of follow-up. Clinical data were assessed at the same time points. Radiographs were scored by two independent readers using the modified Stoke AS Spine Score (mSASSS). Spinal radiographic progression in relation to clinical assessments was analyzed using generalized estimating equations.Results176 AS patients were included, 58% had syndesmophytes at baseline. Median mSASSS increased significantly from 10.7 (IQR: 4.6–24.0) at baseline to 14.8 (IQR: 7.9–32.8) at 6 years. At the group level, spinal radiographic progression was linear with a mean progression rate of 1.3 mSASSS units per 2 years. Both spinal radiographic damage at baseline and radiographic progression were highly variable between AS patients. Male gender, older age, longer disease duration, higher BMI, longer smoking duration, high CRP, and high ASDAS were significantly associated with syndesmophytes at baseline. Significantly more radiographic progression was seen in patients with versus without syndesmophytes (2.0 vs. 0.5 mSASSS units per 2 years) and in patients >40 versus ≤40 years of age (1.8 vs. 0.7 mSASSS units per 2 years). No longitudinal associations between radiographic progression and clinical assessments were found.ConclusionsThis prospective longitudinal observational cohort study in daily clinical practice shows overall slow and linear spinal radiographic progression in AS patients treated with TNF-α blocking therapy. At the individual level, progression was highly variable. Patients with syndesmophytes at baseline showed a 4-fold higher radiographic progression rate than patients without syndesmophytes.

Does fecal calprotectin predict short-term relapse after stopping TNFα-blocking agents in inflammatory bowel disease patients in deep remission?

This prospective multicenter study examined whether elevated fecal calprotec tin (FC) concentrations after stopping TNFα-blocking therapy can predict clinical or endoscopic relapse. In addition, we evaluated the impact of histological remission on the relapse risk. We enrolled inflammatory bowel disease (IBD) patients who were in clinical, endoscopic, and FC-based (< 100 μg/g) remission after a minimum 11 months of TNFα-blocking therapy. The patients were followed-up for 12 months after the discontinuation of TNFα-blocking therapy. FC was collected monthly for the first 6 months and thereafter every second month. Ileocolonoscopy was performed at inclusion, at 4 months, at the study end, and at the time of clinical relapse. Of 52 enrolled patients, 49 (16 Crohn's disease, 33 ulcerative colitis/IBD unclassified) provided the stool samples requested and comprised the study group. During the follow-up, 15/49 (31%) relapsed, whereas 34 (69%) remained in remission. Patients relapsing showed constantly elevated FC levels for a median of 94 (13-317) days before the relapse. Significant increase in median FC levels was seen 2 (p = 0.0014), 4 (p = 0.0056), and 6 (p = 0.0029) months before endoscopic relapse. Constantly normal FC concentrations during the follow-up were highly predictive for clinical and endoscopic remission. Normal FC concentrations in patients with remission were associated with histological remission. FC seems to increase and remain elevated before clinical or endoscopic relapse, suggesting that it can be used as a surrogate marker for predicting and identifying patients requiring close follow-up in clinical practice.

AB0662 Inflammatory Power Doppler Ultrasound Lesions of the Entheses and Hip Joints in Patients with Ankylosing Spondylitis before and after 6 Months of Tnf-α Blocking Therapy in Daily Clinical Practice

BackgroundInflammatory entheseal and hip involvement are characteristic extra-spinal manifestations of ankylosing spondylitis (AS). In clinical studies these manifestations are commonly evaluated by enthesitis indexes such as the Maastricht AS Enthesitis...

SAT0343 Spinal Radiographic Progression during 6 Years of Tnf-Alpha Blocking Therapy in Patients with Ankylosing Spondylitis: Results from the GLAS Cohort

BackgroundSo far, inconsistent results have been reported regarding the effect of tumor necrosis factor-alpha (TNF-α) blocking therapy on radiographic progression in ankylosing spondylitis (AS).ObjectivesTo prospectively investigate spinal radiographic progression up...

SAT0354 Nsaid Use in Patients with Ankylosing Spondylitis Treated with and without Tnf-Alpha Blocking Therapy during 2-Year Follow-Up in Daily Clinical Practice

BackgroundNon-steroidal anti-inflammatory drugs (NSAIDs) are regarded as the cornerstone of conventional therapy in ankylosing spondylitis (AS). TNF-α blocking therapy is available for AS patients who have insufficient response to conventional...

Clinical studies on bone-related outcome and the effect of TNF-α blocking therapy in ankylosing spondylitis

To provide an overview of clinical trials and observational studies investigating the effect of tumor necrosis factor-alpha (TNF-α) blocking therapy on bone formation and bone loss in patients with ankylosing spondylitis (AS). The effect of TNF-α blocking therapy on excessive bone formation or osteoproliferation remains inconclusive. Radiographic assessment of spinal osteoproliferation is complicated by the overall slow rate of progression and the high variability between individual AS patients. Multiple studies demonstrated that TNF-α blocking therapy results in a significant increase in bone mineral density (BMD) at the lumbar spine and hip. Based on bone turnover marker (BTM) analysis, this can mainly be explained by an increase in mineralization and decrease in bone resorption. Both osteoproliferation (e.g. syndesmophytes and ankylosis of vertebrae) and excessive bone loss resulting in osteoporosis and vertebral fractures are frequently present in AS. Previous studies showed that BMD increases during TNF-α blocking therapy. Long-term follow-up in a large cohort of patients is needed to investigate whether TNF-α blockers can consolidate or stop spinal osteoproliferation and prevent vertebral fractures. Future studies should focus on the effect of these agents on bone-related outcome in AS patients with early vs. advanced disease.

THU0265 Early change in bone resorption predicts discontinuation of tumor necrosis factor-alpha blocking therapy in patients with ankylosing spondylitis

BackgroundIn ankylosing spondylitis (AS), objective measurements evaluating the effect of tumor necrosis factor-alpha (TNF-α) blocking therapy are lacking.ObjectivesTo investigate the predictive value of bone turnover markers (BTM) in relation to...