Anti-tumor Necrosis Factor-α Research Articles

Anti-tumour necrosis factor-α therapy and recurrent or new primary cancers in patients with inflammatory bowel disease, rheumatoid arthritis, or psoriasis and previous cancer in Denmark: a nationwide, population-based cohort study

Safety of anti-tumour necrosis factor-α (TNFα) therapy in people with a history of cancer and with an immune-mediated disease is unknown. We aimed to assess the risk of recurrence of initial cancer or development of a new primary cancer after treatment with anti-TNFα therapy. In this Danish, population-based cohort study we recruited adults (≥18 years) with inflammatory bowel disease (IBD), rheumatoid arthritis, or psoriasis and a primary cancer diagnosed between Jan 1, 1999 and Dec 31, 2016. Patients were recruited from the prospectively recorded Danish National Patient Registry and the Danish Cancer Registry. Participants were matched 1:10 between the treatment group who received anti-TNFα therapy and the control group (no anti-TNFα therapy) and we excluded individuals with a cancer diagnosed before their first anti-TNFα treatment (or before matching date for controls), individuals diagnosed with IBD, rheumatoid arthritis, or psoriasis after anti-TNFα initiation (or respective match date for controls), and individuals who received anti-TNFα with fewer than five matched controls. Using adjusted Cox proportional hazards regression, we estimated the primary outcome of development of recurrent or new primary cancer in patients who received anti-TNFα therapy compared with patients who did not receive this therapy, matched by sex, immune-mediated disease type, cancer type, and time from initial cancer diagnosis to first anti-TNFα registration. Overall, 25 738 patients with immune-mediated disease and a history of cancer were identified. 434 patients who received anti-TNFα therapy after their initial cancer were matched to 4328 patients in the control group. During 18 752 person-years (median 5·6 years [IQR 2·8-7·9]) of follow up, 635 individuals developed recurrent or new primary cancer, 72 of whom had received anti-TNFα therapy and 563 of whom were in the control group. The median time between anti-TNFα treatment and recurrent or new primary cancer diagnosis was 2·8 years (IQR 1·7-5·4). The incidence of recurrent or new primary cancer development was 30·3 cases (95% CI 24·0-38·2) per 1000 person-years in the anti-TNFα treatment group and 34·4 cases (31·7-37·3) per 1000 person-years in the control group, yielding an adjusted hazard ratio of 0·82 (95% CI 0·61-1·11). Use of anti-TNFα therapy was not associated with recurrent or new primary cancer development in patients with previous cancer. Timing of anti-TNFα therapy after an initial cancer diagnosis did not influence recurrent or new primary cancer development. This observation might guide clinical decision making among providers treating immune-mediated diseases with anti-TNFα medications. None.

Tuberculosis Disease in Children and Adolescents on Therapy With Antitumor Necrosis Factor-ɑ Agents: A Collaborative, Multicenter Paediatric Tuberculosis Network European Trials Group (ptbnet) Study.

In adults, anti-tumor necrosis factor-α (TNF-α) therapy is associated with progression of latent tuberculosis (TB) infection (LTBI) to TB disease, but pediatric data are limited. Retrospective multicenter study within the Paediatric Tuberculosis Network European Trials Group, capturing patients <18 years who developed TB disease during anti-TNF-α therapy. Sixty-six tertiary healthcare institutions providing care for children with TB participated. Nineteen cases were identified: Crohn's disease (n = 8; 42%) and juvenile idiopathic arthritis (n = 6; 32%) were the commonest underlying conditions. Immune-based TB screening (tuberculin skin test and/or interferon-γ release assay) was performed in 15 patients before commencing anti-TNF-α therapy but only identified 1 LTBI case; 13 patients were already receiving immunosuppressants at the time of screening. The median interval between starting anti-TNF-α therapy and TB diagnosis was 13.1 (IQR, 7.1-20.3) months. All cases presented with severe disease, predominantly miliary TB (n = 14; 78%). One case was diagnosed postmortem. TB was microbiologically confirmed in 15 cases (79%). The median duration of anti-TB treatment was 50 (IQR, 46-66) weeks. Five of 15 (33%) cases who had completed TB treatment had long-term sequelae. LTBI screening is frequently false-negative in this patient population, likely due to immunosuppressants impairing test performance. Therefore, patients with immune-mediated diseases should be screened for LTBI at the point of diagnosis, before commencing immunosuppressive medication. Children on anti-TNF-α therapy are prone to severe TB disease and significant long-term morbidity. Those observations underscore the need for robust LTBI screening programs in this high-risk patient population, even in low-TB-prevalence settings.

Conferring extracellular matrix affinity enhances local therapeutic efficacy of anti-TNF-\u03b1 antibody in a murine model of rheumatoid arthritis

BackgroundAlthough disease in a majority of rheumatoid arthritis (RA) patients is often initially limited to one or a few joints, currently approved medications including anti-tumor necrosis factor-α antibody (α-TNF) are injected systemically. Given that α-TNF systemic injection typically does not cure RA and involves risk of treatment-related adverse events, one possible approach to enhance therapeutic efficacy and reduce α-TNF systemic exposure is to retain the antibodies in arthritic joints after local administration. The aim of this study was to evaluate the approach of conferring extracellular matrix (ECM) binding affinity to α-TNF antibodies in a RA model.Methodsα-TNF was chemically conjugated with a promiscuous ECM-binding peptide derived from placenta growth factor 2 (PlGF-2123-144). The binding activity of PlGF-2123-144-conjugated α-TNF (PlGF-2123-144-α-TNF) against ECM proteins was assessed by ELISA and by immunostaining on human cartilage specimens. The effect of conjugation on antibody function was assessed as a neutralizing activity against osteoclast differentiation. Retention at the injection site and therapeutic efficacy of PlGF-2123-144-α-TNF were tested in a collagen antibody-induced arthritis (CAIA) model in the mouse.ResultsPlGF-2123-144 peptide conjugation conferred α-TNF with affinity to ECM proteins without impairment of antigen recognition. PlGF-2123-144-α-TNF locally injected at a paw in the CAIA model was retained for at least 96 h at the injection site, whereas unmodified α-TNF was dispersed rapidly after injection. Local treatment with unmodified α-TNF did not suppress the arthritis score relative to isotype controls. By contrast, local administration of PlGF-2123-144-α-TNF suppressed arthritis development almost completely in the treated paw even at a 1000× lower dose.ConclusionThese data demonstrate that retention of α-TNF in arthritic joints can suppress arthritis development and enhance therapeutic efficacy. This simple bioengineering approach of ECM-binding peptide conjugation offers a powerful and clinically translational approach to treat RA.

Sepsis Immunometabolism: From Defining Sepsis to Understanding How Energy Production Affects Immune Response.

Objectives:This review will examine current definitions and trends in sepsis management as well pathophysiologic mechanisms in animal and ex vivo studies that correlate decreased energy production with deranged inflammatory response during the septic process.Data Sources:The latest articles in the literature that focus on the role of immunometabolism and associated mechanisms in sepsis were selected.Study Selection:The most relevant, original articles were included in the review.Data Extraction:All pertinent data for sepsis definitions as well as changes in immunometabolic pathways during the septic process was reviewed and assessed for inclusion in this article.Data Synthesis:Sepsis is a major cause of multiple organ dysfunction. It is the principal cause of death resulting from infection and one of the most expensive conditions treated in the United States. Despite current efforts to accurately define sepsis, novel treatments and highly trained providers, mortality rates for sepsis remain high, prompting a need for further investigation of underlying immunometabolic mechanisms to identify potential treatment targets. The definition of sepsis has shifted and changed in the past few decades due to poorly defined criteria, as well as unclear guidelines for providers with regards to management of severe sepsis and septic shock. The early identification of patients with a systemic inflammatory response that will progress to septic shock is critical since recent traditional therapeutic approaches, such as early goal-directed therapy, IV immunoglobulin, and anti–tumor necrosis factor-α antibodies have failed.Conclusions:There are no effective anti-sepsis drug therapies due to complex inflammatory and metabolic interactions. Further studies regarding the interface between innate immunity and metabolism should be investigated to effectively address septic patient mortality rates.

Targeting inflammatory sites through collagen affinity enhances the therapeutic efficacy of anti-inflammatory antibodies.

Enhancing the therapeutic efficacy of drugs for inflammatory diseases is of high demand. One possible approach is targeting drugs to the extracellular matrix of the inflamed area. Here, we target collagens in the matrix, which are inaccessible in most tissues yet are exposed to the bloodstream in the inflamed area because of vascular hyperpermeability. We conferred collagen affinity to anti-tumor necrosis factor-α (α-TNF) antibody by conjugating a collagen-binding peptide (CBP) derived from the sequence of decorin. CBP-α-TNF accumulated in the inflamed paw of the arthritis model, and arthritis development was significantly suppressed by treatment with CBP-α-TNF compared with the unmodified antibody. Similarly, CBP-anti-transforming growth factor-β (α-TGF-β) accumulated in the inflamed lung of pulmonary fibrosis model and significantly suppressed pulmonary fibrosis compared with the unmodified antibody. Together, collagen affinity enables the anticytokine antibodies to target arthritis and pulmonary fibrosis accompanied by inflammation, demonstrating a clinically translational approach to treat inflammatory diseases.

Diagnosis and Treatment Recommendation and Exploration for Critical and Refractory Adverse Effects Related to Immunocheckpoint Inhibitors

免疫检查点抑制剂（immune checkpoint inhibitors, ICIs）的应用改写了很多恶性肿瘤的治疗策略，成为肿瘤治疗的又一个里程碑。ICIs作用原理可以理解为“刹车理论”，在“松开刹车”后会带来一系列的全身性毒副反应，其中部分可能为危重和难治性，甚至具有潜在致死性。本文对免疫相关不良事件（immune-related adverse effects, irAEs）相关的最新国内外指南及共识中关于3度-4度irAEs的诊治建议进行了汇总，包括欧洲肿瘤内科学会年会（European Society for Medical Oncology, ESMO）、美国国立综合癌症网络（National Comprehensive Cancer Network, NCCN）/美国临床肿瘤学会（American Society of Clinical Oncology, ASCO）、肿瘤免疫治疗学会（Society for Immunotherapy of Cancer, SITC）和中国临床肿瘤学会（Chinese Society of Clinical Oncology, CSCO）指南，并复习了2019年5月20日前公开发表的关于irAEs的个案报告和相关的综述文献后，对以上指南和共识中尚未纳入的3级-4级irAEs的诊治建议进行补充，重点介绍了特异性免疫抑制药物在不同的irAEs中成功应用的情况，包括抗白介素6（interleukin 6, IL-6）阻断、抗CD20单抗、抗肿瘤坏死因子α（tumor necrosis factor-α, TNFα）单抗、抗整合素4单抗、Janus激酶抑制剂、血小板生成素受体激动剂和抗胸腺细胞球蛋白（antithymocyte globulin, ATG）。本文对于类固醇激素在irAEs中超大剂量使用和升级使用及反复使用提出质疑，并强调应同时关注激素继发的感染、肿瘤进展和无法满足ICIs再挑战的等问题。本文提出对于危重和难治性irAEs的“降阶梯治疗”原则，建议应尽早使用细胞因子靶向药物这些特异性免疫抑制药物。免疫治疗时代诸多的irAEs是传统化疗及小分子靶向治疗时代不曾有过的，不断地挑战肿瘤科大夫的知识储备和临床基本技能。因此，建立肿瘤多学科讨论体系对于肿瘤患者的治疗管理极为重要。

Ulcerative intestinal tuberculosis case as a complication of treatment by infliximab for intestinal Behçet's disease

Rationale:Intestinal Behçet's disease (BD) is characterized by intestinal ulcerations and gastrointestinal symptoms. Ulcerative intestinal tuberculosis (TB) is usually with dyspepsia, abdominal pain, vomiting, and weight loss. The 2 diseases exhibit similar clinical manifestations, but the most critical aspects of their clinical courses and required treatments are not at all similar.Patient concerns:We present a case in which a patient with intestinal Behçet's disease developed a de novo ulcerative intestinal TB infection after the start of anti-tumor necrosis factor-α treatment. This was despite histopathologic examination without caseous necrosis granuloma and negative for acid-fast staining and latent TB screen.Diagnoses:Intestinal Behçet's disease and intestinal TB.Interventions:The patient was treated with quadruple antituberculous chemotherapy, comprising rifapentine, isoniazid, ethambutol, and pyrazinamide.Outcomes:At follow-up about 3 months, the therapy of oral antituberculous drugs and thalidomide was continued and the patient's condition had stabilized.Lessons:This case illustrates the importance of closely monitoring patients who are on infliximab for possible onset of TB, even without abdominal symptoms, and with negative screening results for latent TB.

Macular edema associated with non-infectious uveitis: pathophysiology, etiology, prevalence, impact and management challenges.

Macular edema (ME) is the most common sight-threatening complication in uveitis. The diagnostic and therapeutic management of the uveitic macular edema (UME) might be challenging due to the complex diagnostic workup and the difficulties physicians face to find the underlying cause, and due to its usually recurrent nature and the fact that it can be refractory to conventional treatment. Some of the mild cases can be treated with topical steroids, which can be combined with non-steroid anti-inflammatory drugs. However, immunomodulators such as methotrexate, tacrolimus, azathioprine, cyclosporine and mycophenolate mofetil together with anti-tumor necrosis factor-α (anti-TNF alpha) monoclonal antibodies such as adalimumab and infliximab, may be required to control the inflammation and the associated ME in refractory cases, or when an underlying disease is present. This review of the literature will focus mostly on the non-infectious UME.

Infliximab biosimilar CT-P13 is interchangeable with its originator for patients with inflammatory bowel disease in real world practice.

Background/AimsAn interim analysis of post-marketing surveillance of CT-P13, an infliximab biosimilar, was performed to evaluate its safety and efficacy in Japanese patients with inflammatory bowel disease.MethodsPatients were prospectively enrolled between November 2014 and March 2017, after the launch of CT-P13 in Japan, and case report forms of patients followed for at least 4 months were analyzed as of July 2018.ResultsOf 523 patients in the analysis set, 372 remained on CT-P13 therapy, while 54 (20.2%) of 267 patients with Crohn’s disease, and 97 (37.9%) of 256 patients with ulcerative colitis were withdrawn during follow-up. A total of 144 adverse drug reactions (ADRs) were reported in 106 patients (20.3%). Infusion reaction was the most frequent ADR observed in 49 patients (9.4%). Efficacy parameters decreased immediately after the start of treatment in naïve patients to anti-tumor necrosis factor-α antibody. In the patients switched from originator infliximab for nonmedical reasons, the decreased parameters due to proceeded treatment with the originator were maintained in low ranges, and the treatment continuation rate was high with low ADR incidence. In contrast, in patients switched for medical reasons such as adverse event or loss of response, the incidence of ADRs was high. However, the efficacy parameters were improved, and the treatment continuation rate was not significantly different from that of the naïve patient group.ConclusionsIn this interim analysis, CT-P13 was comparable to the originator infliximab with respect to ADRs and efficacy, and is therefore considered to be a cost-efficient interchangeable biosimilar for Japanese patients with inflammatory bowel disease.

Small-Bowel Crohn Disease Treated With Anti-Tumor Necrosis Factor-α Therapy: MR Enterography Score Changes After 1 Year Predict Long-Term Outcomes.

OBJECTIVE. The purpose of this article is to assess the ability of MR enterography (MRE) to predict the evolution of Crohn disease (CD) under anti-tumor necrosis factor-α (anti-TNF) therapy. In particular, we analyzed the effect of achieving a radiologic response (RR) on long-term patient outcomes. MATERIALS AND METHODS. We included patients with small-bowel CD who successfully started receiving anti-TNF (infliximab or adalimumab) therapy and achieved clinical remission between 2008 and 2015. MRE was performed at baseline and close to 1 year after treatment initiation. The degree of CD activity was evaluated on the basis of a per-patient MRE score used at our hospital. Individual scores were calculated and recorded on the day of analysis. The median duration of follow-up after induction therapy was 5 years (interquartile range, 2.5-9.0 years). Cumulative probabilities of not having a loss of response (LOR) were assessed using the Kaplan-Meier method and compared using the log-rank test. RESULTS. Thirty-four patients fulfilled the prerequisites for inclusion in the study. Complete RR was achieved in nine patients (26.5%), partial RR in 13 (38.2%), and either no RR or worsening in 12 (35.3%). For the three aforementioned response groups, the estimated probability of absence of LOR at 5 years was 0.88, 0.69, and 0.25, respectively, and the log-rank test suggested that the risk rates for LOR were different (p = 0.023). Based on Cox regression, an MRE score reduction of less than 50% at close to 1 year after treatment initiation was an independent risk factor for LOR (hazard ratio, 0.257; 95% CI, 0.070-0.953; p = 0.027). CONCLUSION. The MRE response after 1 year is a predictor of the efficacy of anti-TNF treatment.

Therapeutic drug monitoring of infliximab in spondyloarthritis. A review of the literature

Available evidence indicates that a therapeutic drug monitoring strategy leads to major cost savings related to the anti-tumour necrosis factor-α therapy in both inflammatory bowel disease and rheumatoid arthritis (RA) patients, with no negative impact on efficacy. However, although the systematic use of therapeutic drug monitoring could potentially be beneficial and economically acceptable to drug dose optimization, it is not justifiable for all drugs. Infliximab (IFX) is a chimeric monoclonal immunoglobulin G1 targeting tumour necrosis factor. It has been approved for the treatment of immuno-inflammatory diseases, including RA, ankylosing spondylitis, psoriatic arthritis, Crohn's disease and ulcerative colitis. IFX's pharmacokinetics is highly variable and influences clinical response in chronic inflammatory diseases. Clinical response increases with IFX trough concentrations in RA, ankylosing spondylitis, inflammatory bowel disease and psoriatic patients. Target concentrations predictive of good clinical response were proposed in RA, Crohn's disease and ulcerative colitis. The purpose of this article is to review the current literature surrounding IFX serum concentrations and their related parameters with disease activity in patients with spondyloarthritis. Gathering information about the efficacy of IFX in patients with spondyloarthritis and relating IFX serum concentrations to disease activity were the main goals of this study.

Earlier discontinuation of TNF-α inhibitor therapy in female patients with inflammatory bowel disease is related to a greater risk of side effects.

In rheumatoid arthritis and psoriasis female sex has been shown to be associated with discontinuation of anti-tumour necrosis factor-α (TNF-α) therapy. To retrospectively assess the association between sex and TNF-α drug persistence in patients with inflammatory bowel disease (IBD). All IBD patients on anti-TNF-α therapy with a minimum follow-up of 12months in a single tertiary centre were identified. Patient and treatment characteristics and reasons for anti-TNF-α discontinuation were recorded. Overall and cause-specific drug persistence was analysed with Kaplan-Meier followed by Cox proportional hazards regression models. We included 529 patients (49.9% male) with 631 treatment episodes (2280 anti-TNF-α treatment years) and 289 discontinuations of therapy. Female sex (adjusted hazard ratio [aHR] 1.42, 95% confidence interval [CI] 1.16-1.74), greater age at start of therapy per decade (aHR 1.15, 95% CI 1.04-1.27] and dose escalation (aHR 3.74, 95% CI 2.78-5.02) were associated with TNF-α inhibitor discontinuation. Total cohort cause-specific analysis identified female sex to be associated with side effects (aHR 4.05, 95% CI 2.36-6.98) but not to other discontinuation reasons. Adalimumab (aHR 1.70, 95% CI 1.11-2.60) and golimumab (aHR 4.97, 95% CI 2.30-10.74) use and dose-escalation (aHR 7.71, 95% CI 5.28-11.26) were associated with secondary loss of response. Drug persistence of anti-TNF-α therapy is lower in females as compared to males, mainly because of higher rates of side effects in females. Understanding the sex specific differences in effectiveness and safety of anti-TNF-α compounds can aid physicians in clinical decision-making.

Retrospective investigation of tacrolimus combined with an anti-tumor necrosis factorα antibody as remission induction therapy for refractory ulcerative colitis: Efficacy, safety, and relapse rate.

Background and AimCombined therapy with tacrolimus (TAC) and an anti‐tumor necrosis factorα (TNFα) antibody is used to induce remission in ulcerative colitis (UC) patients who have not responded to monotherapy with either drug. We evaluated the efficacy and safety of combined therapy, as well as the relapse rate.MethodsCombined therapy was performed to induce remission in UC patients showing an inadequate response to monotherapy with TAC or an anti‐TNFα antibody. The following items were assessed retrospectively: (i) clinical characteristics, (ii) the remission induction rate, (iii) the relapse rate, and (iv) adverse events.ResultsCombined therapy induced remission in 7 of the 12 patients (58.3%). There were no significant differences in clinical characteristics between the patients with and without the successful induction of remission. However, the number of female patients tended to be higher in the remission group than in the nonremission group. The remission group also showed trends of a lower clinical activity index (Lichtiger index; CAI) on admission and before combined therapy and a lower total dose of prednisolone during hospitalization. The 1‐year relapse rate was 33.3%. Adverse events due to combined therapy included renal impairment (n = 2), tremors (n = 2), influenza (n = 1), and a positive cytomegalovirus antibody test (n = 3). None of these events were serious.ConclusionsCombined therapy was effective in more than half of the patients with refractory UC who had not responded to monotherapy. Our findings suggest that combination therapy may be a new, third option for the treatment of refractory UC.

P038 Persistent inflammatory markers and deregulated immune response in clinical remission Crohn's disease patients treated with infliximab

BACKGROUND: The development of Inflammatory Bowel Diseases (IBD) comprises an imbalance among gut microbiota, genetic susceptibility and exacerbated immune responses, which predispose to chronic inflammation in affected patients, who are usually treated with biological agents such as anti-tumor necrosis factor-α (TNF-α). Despite that, even during clinical remission periods, Crohn’s disease (CD) patients may still present endoscopic disease activity and possibly a residual systemic inflammatory response. Therefore, in this study we aimed to evaluate the responsiveness and immune profile of peripheral blood mononuclear cells (PBMC) of infliximab-treated patients, as well as the relationship between the altered responses and the clinical disease presentation. METHODS: We enrolled 20 healthy controls (HC) and 39 CD patients, which were classified according to the Harvey-Bradshaw Index (HBI) and Simple Endoscopic Score for Crohn’s Disease (SES-CD). All were using anti-TNF-α therapy (infliximab), including 61.5% in combination with Azathioprine. RESULTS: Although 94% of the patients were in clinical remission, 51.3% presented disease mucosal activity. Considering the Montreal classification, 12.8% had colonic disease, while 33.4% had ileal and 53.8% ileocolonic disease. Most the patients developed complications, being 20.5% stenosis and 35.9% structuring disease, while 59% had perianal disease. The immunophenotyping identification of PBMC by flow cytometry showed increased CD14+ and CD14++CD16+ monocytes in CD, indicating a tendency towards an inflammatory response because of the increased CD16 expression, along with augmented NKT and decreased NK cells and B lymphocytes. Considering the population of regulatory lymphocytes, CD patients had increased CD4+CD25+CTLA-4+ and CD4+CD25+FOXP3+ cells, together with augmented expression of CTLA-4 and FOXP3 in CD4+CD25- and CD4+CD25+ lymphocytes, indicating the raising of an important systemic counter regulatory response. Nevertheless, there was an increase in the inflammatory cytokine IL-6 in plasma and when PBMC was restimulated in vitro with bacterial-derived lipopolysaccharide (LPS), CD patients produced more TNF than healthy controls. Indeed, plasma dosage of LPS pointed to increased detection in CD samples, suggesting that these patients still present bacteria translocation to circulation. CONCLUSION(S): Even in clinical remission, CD patients had a relevant systemic inflammatory response together with increased regulatory population, probably elicited in an attempt to achieve immune-regulation after biological therapy. Financial support: Fapesp # 2017/08651-1.

Long-term effect of NUDT15 R139C on hematologic indices in inflammatory bowel disease patients treated with thiopurine.

A missense variant of the nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15) gene (R139C) predisposes Asian patients with inflammatory bowel disease (IBD) to thiopurine-induced leukopenia. This study evaluates the long-term effect of NUDT15 R139C heterozygosity on hematological parameters during thiopurine administration. We enrolled 83 Japanese IBD patients who were on anti-tumor necrosis factor-α agents and had used thiopurine. NUDT15 R139C was genotyped by polymerase chain reaction. We retrospectively reviewed patient clinical charts to collect data on white blood cell (WBC) count, mean corpuscular volume (MCV), hemoglobin, and platelet count during the 24months following thiopurine initiation. The included patients had either Crohn's disease (54; 65.1%) or ulcerative colitis (29; 34.9%). Genotyping of NUDT15 R139C identified 62 patients (74.7%) of genotype C/C and 21 (25.3%) of genotype C/T. The median dose of thiopurine was lower in the C/T group than in the C/C group after starting thiopurine. At 6months, the mean WBC count of the C/T group became significantly lower than that of the C/C group (P = 0.008) and remained lower through the 24months. The C/T group developed grade 2-4 leukopenia by 6months, which persisted through 12-24months. The mean MCV in the C/T group became higher than that of the C/C group after 3months. NUDT15 R139C heterozygosity affected the WBC count and MCV for 24months after thiopurine administration. Our results indicate that careful monitoring of leukopenia and dose adjustment are necessary throughout treatment in IBD patients heterozygous for the NUDT15 R139C.

Recurrent ruptured abdominal aneurysms in polyarteritis nodosa successfully treated with infliximab.

Systemic polyarteritis nodosa (PAN) is a rare form of necrotizing vasculitis in children. Recurrent episodes of abdominal aneurysm ruptures are uncommon and life-threatening condition in children. Failures of response to immunosuppressive medications and radiological intervention also lead to high mortality. Some reports suggested that tumor necrosis factor (TNF) might have role in the inflammation of this disease. After an English-language literature review, this is the first case report in children of recurrent abdominal-ruptured aneurysms with a failure of conventional therapy but successfully treated with anti-TNF-α monoclonal antibody. We herein describe a 9-year-old girl who presented with chronic abdominal pain, hypertension, and massive lower gastrointestinal bleeding. The disease was refractory to conventional treatment, including administration of a corticosteroid, cyclophosphamide, and intravenous immunoglobulin, and recurrent-ruptured aneurysms developed in the gastrointestinal tract. Arterial embolization during angiography resulted in temporary improvement of the gastrointestinal bleeding. Infliximab, a chimeric anti-tumor necrosis factor-α monoclonal antibody, was initiated and resulted in disease remission with resolution of the gastrointestinal bleeding and abdominal pain. Anti-TNF therapy might be another treatment option for refractory disease to prevent ongoing inflammation that could lead to aneurysmal dilatation or even rupture. However, early recognition of refractory disease and aggressive treatment in the early course of the disease are crucial to reduce morbidity and mortality.

Hyaluronan concentration and molecular mass in psoriatic arthritis: biomarkers of disease severity, resistance to treatment, and outcome

Objective: Low molecular mass hyaluronan causes inflammatory processes and can act as a pro-inflammatory cytokine in skin and other sites of activity in psoriatic arthritis (PsA). This study investigated whether the molecular mass distribution of hyaluronan (HA) in skin and the quantity of circulating HA are related to the clinical inflammatory picture in PsA with active disease and to the effect of treatment with anti-tumour necrosis factor-α (anti-TNF-α) adalimumab.Methods: Twenty patients with TNF-α-naïve active polyarticular PsA were included in this prospective clinical trial of treatment with 40 mg s.c. adalimumab according to standard procedure. Clinical activity, patients’ assessments, and skin biopsies were captured at inclusion and at the 12 week follow-up. Ten healthy individuals were recruited for comparison of HA analyses. Histochemistry of skin inflammation, serum HA, and molecular mass of HA were determined.Results: Overall improvements in clinical parameters were observed. Eight of 18 patients reached minimum disease activity after 12 weeks and disease activity was significantly reduced (p < 0.0001). Patients with elevated serum HA values were significantly older, had later onset of arthritis and more deformed joints, still had swollen joints after treatment, and had more circulating inflammatory biomarkers. More severe disease pathology showed a wide spectrum of high-molecular-mass HA accompanied by low mass HA. The treatment appears partly to normalize the HA mass distribution.Conclusion: HA concentration and mass seem to be two possible factors in the inflammatory pathology of PsA acting as biomarkers for disease severity, resistance to treatment, and worse outcome.

Effect of Biological Treatment on Fatigue in Psoriasis: A Systematic Review and Meta-Analysis.

Fatigue is frequent in patients with psoriasis. Though conventional drugs in general have no effect on fatigue, biological agents have demonstrated beneficial effects in several other chronic inflammatory diseases. The objective of the present study was to evaluate the effect of biological drugs on fatigue in patients with psoriasis vulgaris. We conducted a meta-analysis of randomized controlled trials in which anti-interleukin-12/23, anti-interleukin-23, anti-interleukin-17, or anti-tumor necrosis factor-α agents were used for psoriasis vulgaris and fatigue was an outcome measure. A total of eight randomized controlled trials fulfilled criteria for inclusion in the meta-analysis. The studies used two fatigue reporting scales: the Functional Assessment of Chronic Illness Therapy-Fatigue and the Short Form 36 Health Survey Vitality Subscale. Treatment by biological agents in general compared with placebo led to a significant reduction in fatigue, with a standardized mean difference of - 0.40 (95% confidence interval - 0.46 to - 0.34; p < 0.001). Biological drugs used for the treatment of psoriasis vulgaris have a consistently small-to-moderate beneficial effect on fatigue independent of the type of drug.

Early vedolizumab trough levels at induction in inflammatory bowel disease patients with treatment failure during maintenance

Vedolizumab (VDZ) is effective as an induction and maintenance treatment for Crohn's disease and ulcerative colitis, but, as observed with antitumour necrosis factor-α (anti-TNFα) agents, some patients are nonetheless experiencing loss of response. The aim of this study was to investigate the impact of the pharmacokinetics of VDZ during induction on long-term treatment response. This study focused on a single cohort of 103 inflammatory bowel disease patients treated with VDZ. VDZ trough levels (TLs) were measured by enzyme-linked immunosorbent assay (n=536 samples), and thereafter correlated to clinical, biological, endoscopic and serological data. For patients exposed previously to infliximab, antibodies to infliximab were measured at baseline. On the basis of the outcome at the end of follow-up, patients were then categorized into long-term response, optimized and treatment failure groups. During VDZ induction, at week 6, inflammatory bowel disease patients with long-term response had higher TLs compared with patients in the treatment failure group (33 vs. 24 µg/ml, P=0.02). A cut-off TL of 28 µg/ml predicted a sustained response in the follow-up with an area under curve of 0.723 (95% confidence interval=0.567-0.878, P=0.02). Patients with mucosal healing in maintenance had higher TLs at week 6 (41.65 µg/ml) compared with patients with mild (26 µg/ml) or severe endoscopic activity (20.8 µg/ml), P=0.009. Positive perinuclear antineutrophil cytoplasmic antibody serology was associated with lower TLs. Patients previously exposed to anti-TNFα had lower TLs than naive patients (22.5 vs. 36 µg/ml, P=0.03) without any impact of detectable antibodies to infliximab. Finally, the presence of an immunomodulator at induction did not impact on VDZ TLs at induction. We confirmed that a drug exposure-efficacy association was found early on at induction. This study emphasizes that previous exposure to anti-TNFα and positive perinuclear antineutrophil cytoplasmic antibody serology are important factors influencing VDZ TLs at induction.

Clinical and biological predictors of response to standardised paediatric colitis therapy (PROTECT): a multicentre inception cohort study

Lack of evidence-based outcomes data leads to uncertainty in developing treatment regimens in children who are newly diagnosed with ulcerative colitis. We hypothesised that pretreatment clinical, transcriptomic, and microbial factors predict disease course. In this inception cohort study, we recruited paediatric patients aged 4-17 years with newly diagnosed ulcerative colitis from 29 centres in the USA and Canada. Patients initially received standardised mesalazine or corticosteroids, with pre-established criteria for escalation to immunomodulators (ie, thiopurines) or anti-tumor necrosis factor-α (TNFα) therapy. We used RNA sequencing to define rectal gene expression before treatment, and 16S sequencing to characterise rectal and faecal microbiota. The primary outcome was week 52 corticosteroid-free remission with no therapy beyond mesalazine. We assessed factors associated with the primary outcome using logistic regression models of the per-protocol population. This study is registered with ClinicalTrials.gov, number NCT01536535. Between July 10, 2012, and April 21, 2015, of 467 patients recruited, 428 started medical therapy, of whom 400 (93%) were evaluable at 52 weeks and 386 (90%) completed the study period with no protocol violations. 150 (38%) of 400 participants achieved week 52 corticosteroid-free remission, of whom 147 (98%) were taking mesalazine and three (2%) were taking no medication. 74 (19%) of 400 were escalated to immunomodulators alone, 123 (31%) anti-TNFα therapy, and 25 (6%) colectomy. Low baseline clinical severity, high baseline haemoglobin, and week 4 clinical remission were associated with achieving week 52 corticosteroid-free remission (n=386, logistic model area under the curve [AUC] 0·70, 95% CI 0·65-0·75; specificity 77%, 95% CI 71-82). Baseline severity and remission by week 4 were validated in an independent cohort of 274 paediatric patients with newly diagnosed ulcerative colitis. After adjusting for clinical predictors, an antimicrobial peptide gene signature (odds ratio [OR] 0·57, 95% CI 0·39-0·81; p=0·002) and abundance of Ruminococcaceae (OR 1·43, 1·02-2·00; p=0·04), and Sutterella (OR 0·81, 0·65-1·00; p=0·05) were independently associated with week 52 corticosteroid-free remission. Our findings support the utility of initial clinical activity and treatment response by 4 weeks to predict week 52 corticosteroid-free remission with mesalazine alone in children who are newly diagnosed with ulcerative colitis. The development of personalised clinical and biological signatures holds the promise of informing ulcerative colitis therapeutic decisions. US National Institutes of Health.