Acute brucella melitensis M16 infection model in mice treated with tumor necrosis factor-alpha inhibitors

Introduction: There is limited data in the literature about brucellosis related to an intracellular pathogen and anti-tumor necrosis factor alpha (anti-TNFα) medication. The aim of this study was to evaluate acute Brucella infections in mice receiving anti-TNFα drug treatment. Methodology: Anti-TNFα drugs were injected in mice on the first and fifth days of the study, after which the mice were infected with B. melitensis M16 strain. Mice were sacrificed on the fourteenth day after infection. Bacterial loads in the liver and spleen were defined, and histopathological changes were evaluated. Results: Neither the liver nor the spleen showed an increased bacterial load in all anti-TNFα drug groups when compared to a non-treated, infected group. The most significant histopathological findings were neutrophil infiltrations in the red pulp of the spleen and apoptotic cells with hepatocellular pleomorphism in the liver. There was no significant difference among the groups in terms of previously reported histopathological findings, such as extramedullary hematopoiesis and granuloma formation. Conclusions: There were no differences in hepatic and splenic bacterial load and granuloma formation, which indicate worsening of the acute Brucella infection in mice; in other words, anti-TNFα treatment did not exacerbate the acute Brucella spp. infection in mice. © 2015 Kutlu et al

Tumor Necrosis Factor Alpha Antagonists and Occurrence of Autoantibodies in Inflammatory Bowel Disease Patients: A Single Center Experience

Background & Aims: Appearance of auto antibodies have been described during anti-tumor necrosis factor (TNF) alpha therapy; however, their prevalence and clinical relevance are still unclear. We investigated prevalence of autoantibodies in inflammatory bowel diseases (IBD) patients on anti-TNFα treatment and occurrence of clinical symptoms. Methods: Titers of ANA, anti-dsDNA, SMA, AMA, LKM were evaluated from blood samples in patients receiving anti-TNFα inhibitor (adalimumab, infliximab). Results: Among 39 patients treated with anti-TNFα therapy, twenty of them developed ANA, mostly induced by infliximab. 55% ANA positive patients developed peripheral polyarthralgias with no need for intervention. No patients with positive autoantibodies developed a drug-induced lupus. The incidence of dsDNA, SMA and AMA was low and was not associated with autoimmune disease. Conclusions: Immune response induced by anti-TNFα is restricted to ANA, with lower prevalence of dsDNA antibodies, SMA and AMA. Further studies are needed to clarify the role of autoantibodies during anti-TNFα therapy

Antioxidative potential of a combined therapy of anti TNFα and Zn acetate in experimental colitis.

AIM: To evaluate whether combination therapy with anti-tumour necrosis factor α (TNFα) antibody and Zn acetate is beneficial in dextran sodium sulphate (DSS) colitis. METHODS: Colitis was induced in CD1-Swiss mice with 5% DSS for 7 d. The experimental mice were then randomised into the following subgroups: standard diet + DSS treated (induced colitis group); standard diet + DSS + subcutaneous 25 μg anti-TNFα treated group; Zn acetate treated group + DSS + subcutaneous 25 μg anti-TNFα; standard diet + DSS + subcutaneous 6.25 μg anti-TNFα treated group and Zn acetate treated group + DSS + subcutaneous 6.25 μg anti-TNFα. Each group of mice was matched with a similar group of sham control animals. Macroscopic and histological features were scored blindly. Homogenates of the colonic mucosa were assessed for myeloperoxidase activity as a biochemical marker of inflammation and DNA adducts (8OH-dG) as a measure of oxidative damage. RESULTS: DSS produced submucosal erosions, ulcers, inflammatory cell infiltration and cryptic abscesses which were reduced in both groups of mice receiving either anti-TNFα alone or combined with zinc. The effect was more pronounced in the latter group (vs Zn diet, P < 0.02). Myeloperoxidase activity (vs controls, P < 0.02) and DNA adducts, greatly elevated in the DSS fed colitis group (vs controls, P < 0.05), were significantly reduced in the treated groups, with a more remarkable effect in the group receiving combined therapy (vs standard diet, P < 0.04). CONCLUSION: DSS induces colonic inflammation which is modulated by the administration of anti-TNFα. Combining anti-TNFα with Zn acetate offers marginal benefit in colitis severity

Onset of lupus like syndrome in patients with spondyloarthritis treated with anti-TNF-α

<p>Abstract</p> <p>Background</p> <p>The anti-TNFα therapy has been since its approval by the FDA, along with nonsteroidal antiinflammatory drugs (NSAIDs), one of the most important therapies for control of spondyloarthritis (SpA). The onset of Lupus Like Syndrome (LLS) has been described in patients with rheumatoid arthritis (RA) treated with anti-TNFα therapy but there is little literature on the occurrence of this entity in patients with SpA.</p> <p>Methods</p> <p>We studied 57 patients with SpA who received more than 1 year of anti-TNFα therapy (infliximab, adalimumab or etanercept). Patients were analyzed for the development of LLS, in addition to measuring ANA levels ≥ 1:160 and Anti-dsDNA (measured by IIF).</p> <p>Results</p> <p>In total, 7.01% of patients treated with anti-TNFα had titers of ANA ≥ 1:160, whereas 3.5% of patients had serum levels of dsDNA. However, only one patient (1.75%; n = 1) experienced clinical symptoms of LLS; this was a female patient with a history of psoriatic arthritis.</p> <p>Conclusions</p> <p>The presence of LLS secondary to anti-TNFα therapy in patients with SpA is observed less frequently compared with patients with RA. LLS was only detected in a patient with a history of psoriasis since youth, who developed psoriatic arthritis after 27 years of age and had received anti-TNFα therapy for > 2 years. This may be because LLS is an entity clearly associated with innate immunity, with little central role of B and T cells.</p

Biologic Therapy for HLA-B27-associated Ocular Disorders

The treatment of articular and extra-articular manifestations associated with HLA-B27 has undergone dramatic changes over the past two decades, mainly as a consequence of the introduction of biologic agents and in particular anti-tumor necrosis factor α (anti-TNFα) agents. Uveitis is known to be the most frequent extra-articular feature in HLA-B27-associated spondyloarthritides. Topical corticosteroids and cycloplegic agents remain the cornerstones of treatment. However, biologic therapy may be effective in the management of refractory or recurrent forms of uveitis. This review gives an update on the management of HLA-B27-associated ocular disorders with biologics, including anti-TNFα agents and non-anti-TNFα biologic modifier drugs. There is an emerging role for newer biologics targeting interleukin-12/23 and interleukin-17 for the treatment of spondyloarthritides but data on their efficacy on anterior uveitis are sparse

Polygenetic risk scores do not add predictive power to clinical models for response to anti-TNFα therapy in inflammatory bowel disease

BACKGROUND: Anti-tumour necrosis factor alpha (TNFα) therapy is widely used in the management of Crohn’s disease (CD) and ulcerative colitis (UC). However, up to a third of patients do not respond to induction therapy and another third of patients lose response over time. To aid patient stratification, polygenetic risk scores have been identified as predictors of response to anti-TNFα therapy. We aimed to replicate the association between polygenetic risk scores and response to anti-TNFα therapy in an independent cohort of patients, to establish its clinical validity. MATERIALS AND METHODS: Primary non-response, primary response, durable response and loss of response to anti-TNFα therapy was retrospectively assessed for each patient using stringent definitions. Genome wide genotyping was performed and previously described polygenetic risk scores for primary non-response and durable response were calculated. We compared polygenetic risk scores between patients with primary response and primary non-response, and between patients with durable response and loss of response, using separate analyses for CD and UC. RESULTS: Out of 334 patients with CD, 15 (4%) patients met criteria for primary non-response, 221 (66%) for primary response, 115 (34%) for durable response and 35 (10%) for loss of response. Out of 112 patients with UC, 12 (11%) met criteria for primary non-response, 68 (61%) for primary response, 19 (17%) for durable response and 20 (18%) for loss of response. No significant differences in polygenetic risk scores were found between primary non-responders and primary responders, and between durable responders and loss of responders. CONCLUSIONS: We could not replicate the previously reported association between polygenetic risk scores and response to anti-TNFα therapy in an independent cohort of patients with CD or UC. Currently, there is insufficient evidence to use polygenetic risk scores to predict response to anti-TNFα therapy in patients with IBD

The phenotype of circulating follicular-helper T cells in patients with rheumatoid arthritis defines CD200 as a potential therapeutic target

Rheumatoid arthritis (RA) is a systemic autoimmune disease primarily affecting synovial joints in which the development of autoantibodies represents a failure of normal tolerance mechanisms, suggesting a role for follicular helper T cells (TFH) in the genesis of autoimmunity. To determine whether quantitative or qualitative abnormalities in the circulating TFH cell population exist, we analysed by flow cytometry the number and profile of these cells in 35 patients with RA and 15 matched controls. Results were correlated with patient characteristics, including the presence of autoantibodies, disease activity, and treatment with biologic agents. Circulating TFH cells from patients with RA show significantly increased expression of the immunoglobulin superfamily receptor CD200, with highest levels seen in seropositive patients (P=0.0045) and patients treated with anti-TNFα agents (P=0.0008). This occurs in the absence of any change in TFH numbers or overt bias towards Th1, Th2, or Th17 phenotypes. CD200 levels did not correlate with DAS28 scores (P=0.887). Although the number of circulating TFH cells is not altered in the blood of patients with RA, the TFH cells have a distinct phenotype. These differences associate TFH cells with the pathogenesis of RA and support the relevance of the CD200/CD200R signalling pathway as a potential therapeutic target

Treatment patterns and intensification within 5 year of follow-up of the first-line anti-TNFα used for the treatment of IBD : Results from the VERNE study

Altres ajuts: Takeda Farmacéutica España S.A.Background: Anti-TNFα represent one of the main treatment approaches for the management of inflammatory bowel diseases (IBD). Therefore,the evaluation of their treatment patterns over time provides valuable insights about the clinical value of therapies and associated costs. Aims: To assess the treatment patterns with the first anti-TNFα in IBD. Methods: Retrospective, observational study. Results: 310 IBD patients were analyzed along a 5-year follow-up period. 56.2% of Crohn's disease (CD) patients started with adalimumab (ADA), while 43.8% started with infliximab (IFX). 12.9% of ulcerative colitis (UC) patients initiated with ADA, while 87.1% initiated with IFX. Treatment intensification was required in 28.9% of CD and 37.1% of UC patients. Median time to treatment intensification was shorter in UC than in CD (5.3 vs. 14.3 months; p = 0.028). Treatment discontinuation due to reasons other than remission were observed in 40.7% of CD and 40.5% of UC patients, although, in UC patients there was a trend to lower discontinuation rates with IFX (36.6%) than with ADA (66.7%). Loss of response accounted for approximately one-third of discontinuations, in both CD and UC. Conclusions: Around one-third of IBD biologic-naive patients treated with an anti-TNFα required treatment intensification (earlier in UC) and around 40% discontinued the anti-TNFα due to inappropriate disease control

Complex regulation of neutrophil-derived MMP-9 secretion in central nervous system tuberculosis.

BACKGROUND: Central nervous system tuberculosis (CNS-TB) may be fatal even with treatment. Neutrophils are the key mediators of TB immunopathology, and raised CSF matrix metalloproteinase-9 (MMP-9) which correlates to neutrophil count in CNS-TB is associated with neurological deficit and death. The mechanisms by which neutrophils drive TB-associated CNS matrix destruction are not clearly defined. METHODS: Human brain biopsies with histologically proven CNS-TB were stained for neutrophils, neutrophil elastase, and MMP-9. Neutrophil MMP-9 secretion and gene expression were analyzed using Luminex and real-time PCR. Type IV collagen degradation was evaluated using confocal microscopy and quantitative fluorescent assays. Intracellular signaling pathways were investigated by immunoblotting and chemical inhibitors. RESULTS: MMP-9-expressing neutrophils were present in tuberculous granulomas in CNS-TB and neutrophil-derived MMP-9 secretion was upregulated by Mycobacterium tuberculosis (M.tb). Concurrent direct stimulation by M.tb and activation via monocyte-dependent networks had an additive effect on neutrophil MMP-9 secretion. Destruction of type IV collagen, a key component of the blood-brain barrier, was inhibited by neutralizing neutrophil MMP-9. Monocyte-neutrophil networks driving MMP-9 secretion in TB were regulated by MAP-kinase and Akt-PI3 kinase pathways and the transcription factor NF-kB. TNFα neutralization suppressed MMP-9 secretion to baseline while dexamethasone did not. CONCLUSIONS: Multiple signaling paths regulate neutrophil-derived MMP-9 secretion, which is increased in CNS-TB. These paths may be better targets for host-directed therapies than steroids currently used in CNS-TB

Optimal management of Cogan’s syndrome: a multidisciplinary approach

Cogan's syndrome (CS) is a rare disorder characterized by nonsyphilitic interstitial keratitis (IK) and audio-vestibular symptoms. CS affects mainly young Caucasian adults, mostly during their first three decades of age, and may develop into typical and atypical variants. Typical CS manifests primarily with IK and hearing loss, whereas atypical CS usually presents with inflammatory ocular manifestations in association with audio-vestibular symptoms but mostly different Ménière-like symptoms and, more frequently, with systemic inflammation (70%), of which vasculitis is the pathogenic mechanism. CS is considered as an autoimmune- or immune-mediated disease supported mainly by the beneficial response to corticosteroids. Using well-developed assays, antibodies to inner ear antigens, anti-Hsp70, and antineutrophil cytoplasmic antibodies were found to be associated with CS. Corticosteroids represent the first line of treatment, and multiple immunosuppressive drugs have been tried with variable degrees of success. Tumor necrosis factor-alpha blockers and other biological agents are a recent novel therapeutic option in CS. Cochlear implantation is a valuable rescue surgical strategy in cases with severe sensorineural hearing loss unresponsive to intensive and/or innovative immunosuppressive regimens