Inflammatory bowel diseases (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), are complex chronic inflammatory conditions of the gastrointestinal tract that are driven by perturbed cytokine pathways. Anti-tumor necrosis factor-α (TNF) antibodies are mainstay therapies for IBD. However, up to 40% of patients are nonresponsive to anti-TNF agents, which makes the identification of alternative therapeutic targets a priority. Here we show that, relative to healthy controls, inflamed intestinal tissues from patients with IBD express high amounts of the cytokine oncostatin M (OSM) and its receptor (OSMR), which correlate closely with histopathological disease severity. The OSMR is expressed in nonhematopoietic, nonepithelial intestinal stromal cells, which respond to OSM by producing various proinflammatory molecules, including interleukin (IL)-6, the leukocyte adhesion factor ICAM1, and chemokines that attract neutrophils, monocytes, and T cells. In an animal model of anti-TNF-resistant intestinal inflammation, genetic deletion or pharmacological blockade of OSM significantly attenuates colitis. Furthermore, according to an analysis of more than 200 patients with IBD, including two cohorts from phase 3 clinical trials of infliximab and golimumab, high pretreatment expression of OSM is strongly associated with failure of anti-TNF therapy. OSM is thus a potential biomarker and therapeutic target for IBD, and has particular relevance for anti-TNF-resistant patients.

Oncostatin M drives intestinal inflammation and predicts response to tumor necrosis factor-neutralizing therapy in patients with inflammatory bowel disease

To evaluate the possibility that switching from reference biologic medicines to biosimilars could lead to altered clinical outcomes, including enhanced immunogenicity, compromised safety, or diminished efficacy for patients, a systematic literature review was conducted of all switching studies between related biologics (including biosimilars). A systematic search was conducted using the Medline® and Embase® databases up to 30 June 2017 employing specific medical subject heading terms. Additionally, the snowball method and a hand search were also applied. Publications were considered if they contained efficacy or safety information related to a switch from a reference medicine to a biosimilar. Non-English, non-human studies, editorials, notes, and short surveys were excluded. Primary data were available from 90 studies that enrolled 14,225 unique individuals. They included protein medicines used in supportive care as well as those used as therapeutic agents. The medicines contained seven different molecular entities that were used to treat 14 diseases. The great majority of the publications did not report differences in immunogenicity, safety, or efficacy. The nature and intensity of safety signals reported after switching from reference medicines to biosimilars were the same as those already known from continued use of the reference medicines alone. Three large multiple switch studies with different biosimilars did not show differences in efficacy or safety after multiple switches between reference medicine and biosimilar. Two publications reported a loss of efficacy or increased dropout rates. While use of each biologic must be assessed individually, these results provide reassurance to healthcare professionals and the public that the risk of immunogenicity-related safety concerns or diminished efficacy is unchanged after switching from a reference biologic to a biosimilar medicine.

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Switching Reference Medicines to Biosimilars: A Systematic Literature Review of Clinical Outcomes

Emerging role of vitamin D in autoimmune diseases: An update on evidence and therapeutic implications.

Objective: To describe clinical and imaging responses in neurosarcoidosis to infliximab, a monoclonal antibody against tumor necrosis factor–α. Methods: Investigators at 6 US centers retrospectively identified patients with CNS sarcoidosis treated with infliximab, including only patients with definite or probable neurosarcoidosis following rigorous exclusion of other causes. Results: Of 66 patients with CNS sarcoidosis (27 definite, 39 probable) treated with infliximab for a median of 1.5 years, the mean age was 47.5 years at infliximab initiation (SD 11.7, range 24–71 years); 56.1% were female; 62.1% were white, 37.0% African American, and 3% Hispanic. Sarcoidosis was isolated to the CNS in 19.7%. Using infliximab doses ranging from 3 to 7 mg/kg every 4–8 weeks, MRI evidence of a favorable treatment response was observed in 82.1% of patients with imaging follow-up (n = 56), with complete remission of active disease in 51.8% and partial MRI improvement in 30.1%; MRI worsened in 1 patient (1.8%). There was clinical improvement in 77.3% of patients, with complete neurologic recovery in 28.8%, partial improvement in 48.5%, clinical stability in 18.2%, worsening in 3%, and 1 lost to follow-up. In 16 patients in remission when infliximab was discontinued, the disease recurred in 9 (56%), typically in the same neuroanatomic location. Conclusions: Most patients with CNS sarcoidosis treated with infliximab exhibit favorable imaging and clinical treatment responses, including some previously refractory to other immunosuppressive treatments. Classification of evidence: This study provides Class IV evidence that for patients with CNS sarcoidosis infliximab is associated with favorable imaging and clinical responses.

Infliximab for the treatment of CNS sarcoidosis: A multi-institutional series

Objectives An increased risk of tuberculosis (TB) has been reported in patients treated with TNF-α antagonists, an issue that has been highlighted in a WHO black box warning. This review aimed to assess the risk of TB in patients undergoing TNF-α antagonists treatment. Methods A systematic literature search for randomised controlled trials (RCTs) was performed in MEDLINE, Embase and Cochrane library and studies selected for inclusion according to predefined criteria. ORs with 95% CIs were calculated using the random-effect model. Subgroup analyses considered the effects of drug type, disease and TB endemicity. The quality of evidence was assessed using the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach. Results 29 RCTs involving 11 879 patients were included (14 for infliximab, 9 for adalimumab, 2 for golimumab, 1 for etanercept and 3 for certolizumab pegol). Of 7912 patients allocated to TNF-α antagonists, 45 (0.57%) developed TB, while only 3 cases occurred in 3967 patients allocated to control groups, resulting in an OR of 1.94 (95% CI 1.10 to 3.44, p=0.02). Subgroup analyses indicated that patients of rheumatoid arthritis (RA) had a higher increased risk of TB when treated with TNF-α antagonists (OR 2.29 (1.09 to 4.78), p=0.03). The level of the evidence was recommended as ‘low’ by the GRADE system. Conclusions Findings from our meta-analysis indicate that the risk of TB may be significantly increased in patients treated with TNF-α antagonists. However, further studies are needed to reveal the biological mechanism of the increased TB risk caused by TNF-α antagonists treatment.

https://bmjopen.bmj.com/content/bmjopen/7/3/e012567.full.pdf

Risk of tuberculosis in patients treated with TNF-α antagonists: a systematic review and meta-analysis of randomised controlled trials

Introduction: TNF-α is a pro-inflammatory cytokine known to a have a key role in the pathogenesis of chronic immune-mediated diseases. TNF-α inhibitors can be administered either as monotherapy or in combination with other anti-inflammatory or disease-modifying anti-rheumatic drugs (DMARDs) to treat chronic immune-mediated diseases.Areas covered: Patients receiving TNF-α inhibitors are at high risk of infections. Based on our experience, in this paper, we discuss the risk of infections associated with the administration of TNF-α inhibitors and the strategies for mitigating against the development of these serious adverse events.Expert opinion: Infliximab more so than etanercept appears to be responsible for the increased risk of infections. Re-activation of latent tuberculosis (LTB) infection and the overall risk of opportunistic infections should be considered before beginning TNF-α inhibitor therapy. A careful medical history, Mantoux test and chest-x-ray should always be performed before prescribing TN...

Infection risk associated with anti-TNF-α agents: a review

Introduction: TNF-α inhibitors have demonstrated efficacy both as monotherapy and in combination with disease-modifying antirheumatic drugs (DMARDs) in the treatment of chronic inflammatory immune-mediated diseases such as rheumatoid arthritis, Crohn’s disease, ankylosing spondylitis, psoriasis and/or psoriatic arthritis, and may be administered off-label to treat disseminated granuloma annulare systemic lupus erythematosus and systemic sclerosis. There are several TNF-α inhibitors available for clinical use including infliximab, adalimumab, golimumab, certolizumab pegol and etanercept.Areas covered: infliximab and adalimumab can induce the development of anti-infliximab (anti-IFX) and anti-adalimumab (anti-ADA) monoclonal antibodies (mAbs). In this review, we discuss the impact of anti-IFX and anti-ADA mAbs upon efficacy and safety of these biological agents.Expert opinion: IgG/IgE neutralizing antibodies against infliximab and adalimumab decrease the possibility of achieving a minimal disease activity s...

Immunogenicity of infliximab and adalimumab: what is its role in hypersensitivity and modulation of therapeutic efficacy and safety?

TNF-α inhibitors have demonstrated efficacy both as monotherapy and in combination with disease-modifying anti-rheumatic drugs (DMARDs) in the treatment of chronic inflammatory immune-mediated diseases such as rheumatoid arthritis, Crohn’s disease, ulcerative colitis, ankylosing spondylitis (AS), psoriasis (Ps) and/or psoriatic arthritis (PsA) and may be administered off-label to treat disseminated granuloma annulare, systemic lupus erythematosus and systemic sclerosis. There are several TNF-α inhibitors available for clinical use including infliximab, adalimumab, golimumab, certolizumab pegol and etanercept. In this article, we discuss the efficacy and safety of etanercept in the treatment of spondyloarthritis and juvenile idiopathic arthritis (JIA). Etanercept is effective in the treatment of PsA, AS, JIA and uveitis. Independent predictors of achieving a sustained clinical improvement or MDA in children with JIA include shorter disease duration, no concurrent oral corticosteroid use, history of...

Update upon efficacy and safety of etanercept for the treatment of spondyloarthritis and juvenile idiopathic arthritis

Introduction: TNF-α inhibitors have demonstrated efficacy both as monotherapy and in combination with disease-modifying anti-rheumatic drugs (DMARDs) in the treatment of chronic inflammatory immune-mediated diseases. Etanercept is a decoy receptor” for TNF-α and it is composed of two p75 TNF-α receptors fused to human IgG1.Areas covered: We discuss the potential role of pharmacogenetics in predicting the response to etanercept in patients with Ps and PsA.Expert opinion: Pharmacogenetics represents the new frontier for the discovery of potential genetic markers of biological response to TNF-α inhibitors. Clinical studies showed that TNF-α −308 G/G, +489 GG and the +489 GA, TNF-α −857C (rs1799724), TNFRSF1B 676T (rs1061622), TNFAIP3 G SNP (rs610604), FcγRIIIA-V158F, HLA-C*06, IL-17 A (rs2275913 and rs10484879), IL-17F (rs763780) and IL17RA (rs4819554) SNPs favor the response to etanercept. However, most of these studies are often small and not sufficiently powered to detect an effect and markers ten...

Impact of pharmacogenomics upon the therapeutic response to etanercept in psoriasis and psoriatic arthritis

Cilostazol is a selective inhibitor of phosphodiesterase-III with antiplatelet, antithrombotic and vasodilating properties. The aim of our study was to evaluate the effect of the drug on vasculopathy and Raynaud’s phenomenon (RP), in a series of patients with systemic sclerosis (SSc), before and after cilostazol treatment. Twenty-one consecutive SSc patients with moderate or severe RP were enrolled in an open-label study. Cilostazol was administered at the dose of 100 mg twice a day, for 12 months. Evaluations included: daily RP attack diary documenting the frequency and duration of RP episodes, Health Assessment Questionnaire-Disability Index, scleroderma visual analogue scales (VAS), flow-mediated dilation and immunological status, including endothelin 1 and interleukin 6 plasma levels. Thirteen patients completed the study. RP duration and daily number episodes recorded over a 3-week period significantly decreased after cilostazol treatment (p = 0.0049 and p = 0.0067, respectively). VAS score indicated a significant amelioration of the patients’ perception of RP (p = 0.0117), and both baseline and post-ischemic brachial artery diameters were significantly increased after cilostazol treatment, as compared with basal values (p = 0.0119 and p = 0.0076, respectively). None of the patients developed digital ulcers during the study. A significant clinical improvement of RP was recorded in SSc patients undergoing cilostazol treatment. Study results indicate a potential role of cilostazol as oral maintenance therapy in SSc patients with RP.

Elena Penza

Papers

Infection risk associated with anti-TNF-α agents: a review

Immunogenicity of infliximab and adalimumab: what is its role in hypersensitivity and modulation of therapeutic efficacy and safety?

Update upon efficacy and safety of etanercept for the treatment of spondyloarthritis and juvenile idiopathic arthritis

Impact of pharmacogenomics upon the therapeutic response to etanercept in psoriasis and psoriatic arthritis

Efficacy of cilostazol for the treatment of Raynaud’s phenomenon in systemic sclerosis patients