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A graded challenge with adalimumab could be safe in case of a delayed allergic reaction to golimumab, after a detailed allergological evaluation and the exclusion of allergic sensitization using skin tests. [ABSTRACT FROM AUTHOR]

Abstract A graded challenge with adalimumab could be safe in case of a delayed allergic reaction to golimumab, after a detailed allergological evaluation and the exclusion of allergic sensitization using skin tests.

Idiopathic sclerosing orbital inflammatory syndrome (ISOIS) is a rare, progressive and hard to control disease. There is a deep gap of evidence regarding application of disease-modifying drugs (DMD) regimen as a potentially effective treatment for orbital inflammatory diseases. We aimed to report the results of using DMDs and discuss the concept of applying this modality of treatment in patients with ISOIS. This was a prospective interventional case series conducted in a tertiary university-based hospital. Biopsy proven patients with active ISOIS were included. Systematic criteria were developed to define and measure disease activity and monitor response to treatment. A DMD regimen including an anti-tumor necrosis factor alpha (anti-TNF alpha) agent plus azathioprine and low-dose corticosteroids were used. Comprehensive ophthalmic, orbital and systemic assessments were performed during each visit. Five eligible patients with primary ISOIS were included. Mean age was 34.20 (SD = 13.33, range 19–53) years. Three had unilateral and two had bilateral involvement. Four had diffuse orbital involvement pattern and progressive worsening of visual functions, reduced extraocular motility and proptosis. In one patient the disease was localized to extraocular muscle and lacrimal gland. Disease activity was decreased and stabilized after DMDs regimen in all patients. Mean follow up was 32.80 (SD = 30.80, range: 12–86) months. Biologic DMD (b-DMD) including anti-TNF alpha, corticosteroid and azathioprine were effective in decreasing disease activity and could change course of the disease. This study supports the concept of using b-DMD regimen in treatment of ISOIS. [ABSTRACT FROM AUTHOR]

BackgroundAnkylosing spondylitis (AS) is characterized by back pain which can lead to spinal ankylosis. Anti-tumor necrosis factor (TNF) dramatically alleviates symptoms, but spinal damage can still be progressive even during anti-TNF treatment. Smoking is a one of well-known risk factors for structural damage in AS. However, it has not been confirmed that smoking can affect radiographic progression even during anti-TNF treatment.ObjectiveTo investigate factors associated with radiographic progression during anti-TNF treatment with a focus on smoking status which is known as one of poor prognostic factors for AS.Materials and methodsWe conducted a retrospective cohort study of AS patients who began the first-line anti-TNF treatment between 2001 and 2018 according to availability of smoking data. All enrolled patients were observed until the last visit, the first-line anti-TNF discontinuation, or December 2019. Radiographic damage was assessed using the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS). The mSASSS progression rate (units/year) was calculated using the baseline mSASSS, the final mSASSS during observation period, and the duration between them. Univariable and multivariable logistic regression analyses were performed to identify associated factors of mSASSS progression rate > 1 unit/year.ResultsAmong 459 AS patients, 185 (40.3%) patients were never smokers, 62 (13.5%) were ex-smokers and 212 (46.2%) were current smokers at baseline. Ex- and current smokers had higher mSASSS progression rates than never smokers [never smoker 0.1 (0.0–0.7), ex-smoker 0.6 (0.0–1.5), and current smoker 0.6 (0.0–1.5) units/year, P < 0.001]. In the multivariable logistic analysis, current smoking [adjusted odds ratio (OR) 1.69, 95% CI 1.01–2.82, P = 0.047] and higher baseline mSASSS [adjusted OR 1.03, 95% CI 1.01–1.04, P < 0.001] were associated with a mSASSS progression rate > 1 unit/year.ConclusionCurrent smoking is a modifiable risk factor for radiographic progression in patients with AS on anti-TNF treatment. Quitting smoking should be strongly recommended.

PurposePediatric uveitis is the leading cause of acquired child blindness, due to unremitting inflammation and long-term steroid exposition. Biotherapies with anti-tumor necrosis factor alpha (anti-TNFα) are effective in controlling inflammation for severe pediatric uveitis in recent studies. Major concern of anti-TNFα prescription is the balance between the severity of the disease and side effects of the drug. The aim of the present study is to describe a cohort of children with severe uveitis and to highlight the risk factors for a pejorative development that led to the prescription of anti-TNFα drugs.MethodA retrospective case-control study was carried out on children with uveitis associated with systemic inflammatory disease or idiopathic uveitis, with a minimum follow-up of 5 years. Anti-TNFα-treated patients (case) were studied and compared with patients who were not requiring anti-TNFα (control). Univariate logistic regression analyses were performed to compare both groups and determine the risk factors for anti-TNFα therapy.ResultsSeventy-three cases of pediatric uveitis were included, 13 cases and 60 controls. The risk factors associated with increased odds of anti-TNFα therapy were initial systemic disorder associated with uveitis [OR = 11.22 (1.37–91.85), p = 0.0241), family history of autoimmune diseases [OR = 9.43 (2.27–39.15), p = 0.0020], uveitis diagnosis before the age of 6 [OR = 4.05 (1.16–14.13), p = 0.0284], eye surgery [OR = 26.22 (2.63–261.77), p = 0.0054], ocular complications at the first slit lamp exam [OR = 67.11 (3.78–1191.69), p = 0.0042], low visual acuity at diagnosis (≥0.3 logMAR) [OR = 11.76 (2.91–47.62), p = 0.0005] and especially low binocular acuity at diagnosis (≥0.3 logMAR) [OR = 8.75 (1.93–39.57), p = 0.0048], panuveitis [OR = 9.17 (2.23–37.60), p = 0.0021], having positive ANA [OR = 3.89 (1.07–14.11), p = 0.0391], and positive HLA B27 [OR = 9.43 (2.27–39.16), p = 0.0020].ConclusionThose risk factors could be used to establish a new follow-up and treatment schedule for severe uncontrolled uveitis. This could help to better predict the best time to start anti-TNF therapy.

Crohn's disease is a chronic inflammatory bowel disease that affects various intestinal segments and can involve the perianal region. Although anti-tumor necrosis factor (TNF) agents have revolutionized the management of Crohn's disease and improved the prognosis for patients with perianal Crohn's disease (pCD), their long-term effectiveness is limited: over 60% of patients relapse after one year of maintenance therapy. In recent years, significant advances have been made in the treatment of complex perianal fistulas after anti-TNF failure. Concomitant treatment with antibiotics and immunosuppressants improves the effectiveness of anti-TNF agents. Therapeutic drug monitoring and dose adjustment of anti-TNF therapy (targeting a higher trough level) might also improve treatment response. Novel therapeutic strategies might provide new opportunities for pCD management; for example, ustekinumab might be effective after anti-TNF treatment failure, although more studies are needed. As suggested in recent international guidelines, mesenchymal stem cell injection might be an effective, safe treatment for complex pCD.

Background: Anti-drug antibodies to infliximab (ATI) and adalimumab (ATA) are associated with loss of response to tumor necrosis factor antagonist (anti-TNF) therapy in inflammatory bowel disease (IBD). We evaluated the relationship between patient sex and serum TNF antagonist drug and antibody concentrations in inflammatory bowel disease.Methods: A nationwide multicenter retrospective cohort study was conducted by evaluating patients' charts from July 2018 until September 2021. The effect of patient sex on anti-drug antibodies and serum drug concentration in patients with IBD across seven hospitals was investigated. A subgroup analysis also investigated the effect of anti-TNF combination therapy. Geometric means were calculated, and multiple linear regression was used to estimate the adjusted ratio of geometric means (RoGM) and their 95% confidence intervals (CI).Results: In the total study sample (n = 1093), males receiving infliximab had higher anti-drug antibody concentrations (38.3 vs. 22.3 AU/ml; aRoGM = 1.72, 95% CI: 1.30–2.27, p < 0.001) compared to females. Additionally, infliximab serum drug concentrations among males were lower compared to females (2.6 vs. 4.1 ug/ml; aRoGM = 0.62, 95% CI: 0.44–0.88, p = 0.007). In the subgroup analysis (n = 359), male compared to female patients on combination therapy with infliximab and immunomodulators had similar anti-drug antibody concentrations (30.2 vs. 21.9 AU/ml; aRoGM = 1.38, 95% CI: 0.79–2.40, p = 0.254). There was no difference in the anti-drug antibody and serum drug concentrations among males and females on adalimumab.Conclusion: In patients receiving infliximab, anti-drug antibodies were higher in males than females. Consistent with this, serum drug concentrations were lower in males than females on infliximab. There was no difference in anti-drug antibody and serum drug concentrations among males and females on adalimumab. In addition, no difference in anti-drug antibodies between males and females receiving anti-TNF combination therapy was observed.

Background: Anti-tumor necrosis factor (TNF) agents are increasingly used for rheumatic diseases and inflammatory bowel disease (IBD), but are associated with the development of anti-TNF-induced lupus (ATIL). Nonetheless, few ATIL studies on non-Caucasian IBD patients exist. Here, we investigated the incidence, clinical features, and risk factors of ATIL in Korea. Methods: We retrospectively reviewed the medical records of IBD patients undergoing anti-TNF therapy at our tertiary IBD center between 2008 and 2020. ATIL was diagnosed as a temporal association between symptoms and anti-TNF agents, and the presence of at least one serologic and non-serologic American College of Rheumatology criterion. The risk factors for ATIL occurrence were assessed using multivariate Cox regression analysis. Results: Of 1362 IBD patients treated with anti-TNF agents, 50 (3.7%) ATIL cases were suspected, of which 14 (1.0%) received a definitive diagnosis. Arthritis and mucocutaneous symptoms were observed in 13 and 4 patients, respectively. All ATIL cases were positive for anti-nuclear and anti-dsDNA antibodies. Four patients (30.8%) improved while continuing anti-TNF therapy. At the final follow up, the ATIL group (n = 14) had a lower IBD remission rate (30.8% versus 68.8%, p = 0.019) than the non-ATIL group (n = 36). Ulcerative colitis and longer disease duration were associated with ATIL occurrence, with hazard ratios of 7.017 (p = 0.005) and 1.118 (p = 0.002), respectively. Conclusion: Although rare, ATIL is associated with poor treatment response to IBD in Korean patients. ATIL should be considered if arthritis and mucocutaneous symptoms develop during anti-TNF therapy for IBD. [ABSTRACT FROM AUTHOR]

BackgroundConcomitant use of methotrexate (MTX) improves the clinical efficacy of anti-TNF agents in the treatment of rheumatoid arthritis (RA). We aimed to clarify the cytotoxic effect of MTX on transmembrane TNF (tmTNF)-expressing cells treated with anti-TNF agents.MethodsJurkat T cells stably expressing tmTNF were used for the following experiments. Cytotoxicity induced by an anti-TNF agent (infliximab, adalimumab, or certolizumab pegol) with concomitant MTX were compared with that by MTX alone or by an anti-TNF agent alone using flow cytometry. Apoptosis-induction mediated by reverse signal through tmTNF, complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP) were evaluated. Folic acid and Y-27632, a Rho kinase inhibitor, were used as inhibitors to study intracellular signaling pathway in apoptosis induced by MTX and anti-TNF agents.ResultsApoptosis of tmTNF-expressing cells was significantly increased by the concomitant administration of MTX and an anti-TNF agent, compared with MTX alone or an anti-TNF agent alone. The apoptosis induction by concomitant MTX was most pronounced in infliximab-treatment. Reverse signal transduction, but not CDC or ADCC/ADCP, was responsible for the coordinate effect of MTX and an anti-TNF agent on tmTNF-expressing cells. Folic acid inhibited MTX-mediated apoptosis, while Y-27632 suppressed JNK activation and infliximab-induced apoptosis via revere signal through tmTNF.ConclusionThe apoptotic effect was enhanced by combination of MTX and an anti-TNF agent in tmTNF-expressing cells. The intracellular pathways induced by MTX and anti-TNF agents seem to be independent. These findings might explain at least in part improved the clinical response upon co-therapy of MTX and an anti-TNF agent in RA.

Background: Concomitant use of methotrexate (MTX) improves the clinical efficacy of anti-TNF agents in the treatment of rheumatoid arthritis (RA). We aimed to clarify the cytotoxic effect of MTX on transmembrane TNF (tmTNF)-expressing cells treated with anti-TNF agents. Methods: Jurkat T cells stably expressing tmTNF were used for the following experiments. Cytotoxicity induced by an anti-TNF agent (infliximab, adalimumab, or certolizumab pegol) with concomitant MTX were compared with that by MTX alone or by an anti-TNF agent alone using flow cytometry. Apoptosis-induction mediated by reverse signal through tmTNF, complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP) were evaluated. Folic acid and Y-27632, a Rho kinase inhibitor, were used as inhibitors to study intracellular signaling pathway in apoptosis induced by MTX and anti-TNF agents. Results: Apoptosis of tmTNF-expressing cells was significantly increased by the concomitant administration of MTX and an anti-TNF agent, compared with MTX alone or an anti-TNF agent alone. The apoptosis induction by concomitant MTX was most pronounced in infliximab-treatment. Reverse signal transduction, but not CDC or ADCC/ADCP, was responsible for the coordinate effect of MTX and an anti-TNF agent on tmTNF-expressing cells. Folic acid inhibited MTX-mediated apoptosis, while Y-27632 suppressed JNK activation and infliximab-induced apoptosis via revere signal through tmTNF. Conclusion: The apoptotic effect was enhanced by combination of MTX and an anti-TNF agent in tmTNF-expressing cells. The intracellular pathways induced by MTX and anti-TNF agents seem to be independent. These findings might explain at least in part improved the clinical response upon co-therapy of MTX and an anti-TNF agent in RA. [ABSTRACT FROM AUTHOR]

Crohn's disease is a progressive and disabling inflammatory disease involving the gastrointestinal tract. It usually produces inflammatory lesions in the ileocolonic region, but up to half of patients will also develop complications such as strictures in the long term. Indeed, a proportion of patients have progression of the disease with the development of stricturing lesions because there are no drugs that effectively prevent or reverse established fibrosis, and hence these patients are usually treated with surgery or endoscopic balloon dilation. Fibrotic lesions are always associated with some degree of inflammatory changes, but there is little evidence supporting the use of medical therapy in this context. Here, we discuss the most important findings on the possible use of immunomodulators or biologics in the prevention and treatment of intestinal strictures in Crohn's disease patients. Recent evidence demonstrates that these drugs may also be effective in treating lesions with high levels of collagen deposition, and thus might, at least in some patients, reduce the progression of the disease and bowel damage, and further avoid the need for surgery and a disabling course in the long term. [ABSTRACT FROM AUTHOR]

OBJECTIVE The aim of this study was to explore the long-term risk of infection in patients with Crohn's disease (CD) on infliximab (IFX) therapy. METHODS All CD patients treated with IFX were recruited from January 2008 to December 2015. Their characteristics and infectious events during IFX therapy were prospectively collected, and the risk of infection was evaluated using Cox regression. RESULTS Seventy CD patients receiving IFX were consecutively recruited. During a median of 15 months, 15 patients experienced 17 infectious events which occurred within a median of 21 weeks after the initiation of IFX therapy. Of 17 infectious events, eight were viral infections, six were bacterial infections, and the others were fungal infections. IFX was discontinued in 6 (40.0%) out of 15 cases due to infections. Compared with those without infections, patients with infectious events were more likely of Montreal B1 (inflammatory) behavior, with concomitant use of systemic corticosteroids when infliximab was started but less mucosal healing when infections occurred ( P < 0.05). By Cox hazard ratio (HR) analysis, patients with B1 behavior had a higher risk of developing infections than those with B3 (fistulizing) behavior (HR 4.897, P = 0.010). Successful corticosteroid withdrawal (HR 0.275, P = 0.035) or mucosal healing (HR 0.155, P = 0.002) were associated with a lower risk of infections. CONCLUSIONS Long-term use of IFX in CD patients has a high risk of infections. Failure in mucosal healing and increased concomitant use of systemic corticosteroids are independent risk factors of infections during IFX therapy. [ABSTRACT FROM AUTHOR]

The clinical importance of the thyroid nodules in patients with axial spondyloarthritis (ax-SpA) rests with the need to exclude thyroid malignancy. The aim of this study is to assess the risk of thyroid malignancy in ax-SpA patients receiving anti-TNF therapy. From September 2015 until December 2015, 70 patients diagnosed with ax-SpA were included in the research. Forty of the patients had received anti-TNF therapy, and 30 of the patients were anti-TNF naive. All cases were screened for the presence of nodules in the thyroid gland with ultrasound. Of the patients that received anti-TNF therapy, 15 (37.5%); and of the anti-TNF naive patients, 11 (36.7%) had thyroid nodule(s). Four patients from the anti-TNF group underwent fine needle aspiration biopsy of the nodules, and two of them were diagnosed with papillary thyroid carcinoma. None of the nodules in anti-TNF naive patients required biopsy. When compared to the normal population, the standardized incidence ratio (SIR) was found to be increased in both male (SIR 2.03, 95% CI 1.9 to 18) and female (SIR 2.7, 95% CI 2.6 to 24) cases. It is not yet established whether the development of cancer during the treatment process is the effect of the treatment or if it is a part of the natural course of the disease or if it is coincidental. We saw a mild increase in thyroid malignancies in ax-SpA patients who received anti-TNF therapy. Therefore, we believe that the thyroid gland should also be taken into consideration while screening for malignancy before anti-TNF therapy. [ABSTRACT FROM AUTHOR]

We developed a technique for the measurement of surface plasmon resonance (SPR) to detect interactions of anti-tumor necrosis factor (TNF) agents with transmembrane TNF-α (mTNF-α) on living whole cells. The injection of a suspension of mTNF-α expressing Jurkat cells, used as an analyte, gave a clear binding response to anti-TNF agents, such as etanercept, infliximab and adalimumab, immobilized on sensorchip. The binding response of the analyte cells increased in a concentration-dependent manner and was competitively reduced by adding soluble TNF receptors to the analyte cell suspension. Treatment of analyte cells with free anti-TNF agent before injection reduced the binding response between the analyte cells and immobilized-etanercept on sensorchip, and the inhibitory effect of free anti-TNF agent was concordant with the affinity of anti-TNF agent for soluble TNF-α. These findings indicate that the SPR response arises from specific binding between anti-TNF agent and its target on cell membrane. [ABSTRACT FROM AUTHOR]

Background & Aims Mucosal healing is an independent predictor of sustained clinical remission in patients with ulcerative colitis (UC) treated with infliximab. We investigated whether infliximab concentrations during induction therapy are associated with short-term mucosal healing (STMH) in patients with UC. Methods We performed a retrospective, single-center analysis of data collected from a tertiary referral center from 101 patients with UC who received scheduled induction therapy with infliximab at weeks 0, 2, and 6 and had an endoscopic evaluation at baseline and after induction therapy. STMH was defined as Mayo endoscopic sub-score ≤1, assessed at weeks 10–14, with baseline sub-score ≥2. Infliximab concentrations were evaluated in serum samples collected at weeks 0, 2, 6, and 14 of infliximab therapy by using an enzyme-linked immunosorbent assay we developed. Results Fifty-four patients (53.4%) achieved STMH. Patients with STMH had a higher median infliximab concentration at weeks 2, 6, and 14 than patients without STMH. A receiver operating characteristic (ROC) analysis identified infliximab concentration thresholds of 28.3 (area under the ROC curve [AUROC], 0.638), 15 (AUROC, 0.688), and 2.1 μg/mL (AUROC, 0.781) that associated with STMH at weeks 2, 6, and 14, respectively. Multiple logistic regression analysis identified infliximab concentration ≥15 at week 6 ( P = .025; odds ratio, 4.6; 95% confidence interval, 1.2–17.1) and ≥2.1 μg/mL at week 14 ( P = .004; odds ratio, 5.6; 95% confidence interval, 1.7–18) as independent factors associated with STMH. Conclusions In an analysis of data from real-life clinical practice, we associated infliximab concentrations during the induction therapy with STMH in patients with UC. [ABSTRACT FROM AUTHOR]

Background & Aims There are limited data on the effects of discontinuing infliximab therapy for Crohn’s disease (CD). We investigated the long-term outcome of patients with CD who discontinued infliximab while in clinical remission, and searched for prognostic markers of continued remission after infliximab cessation. Methods We performed a retrospective, single-center study of 100 patients with CD who discontinued infliximab upon achieving clinical remission; 84 patients continued immunomodulator therapy. Clinical and endoscopic data were retrieved from a medical database in Belgium, and patients were followed up through April 2013 (median, 9.7 y; interquartile range, 8–11.5 y). Sustained clinical remission (SCR) was defined as maintenance of disease remission, without escalation in medical therapy or CD-related surgeries, until the end of the follow-up period. We measured trough concentrations of infliximab, antibodies to microbial antigens, and circulating inflammatory markers in serum samples collected before treatment and at the time of infliximab discontinuation. Results At the end of the follow-up period, 52 patients had SCR. Univariate (log-rank) analysis associated SCR with patient age at diagnosis (≥25 y; P = .012) and disease duration (<1 y; P = .017). Among factors evaluated at the time of infliximab discontinuation, infliximab trough concentrations (<6 μg/mL; P = .031), complete mucosal healing ( P = .046), and serum positivity for vascular cell adhesion molecule-1 (>0.67 μg/mL; P = .024) were associated with SCR. In multiple Cox proportional hazards regression analysis, only age at diagnosis of 25 years and older was associated independently with SCR (hazard ratio, 1.83; 95% confidence interval, 1.03–3.25; P = .04). Conclusions In a large, real-life study, 52% of patients with CD who discontinued infliximab upon achieving clinical remission remained in SCR after a median period of approximately 10 years; Most patients remained on immunomodulator therapy. Although patients with CD have variable responses to infliximab, a subgroup achieved long-term remission after infliximab discontinuation. [ABSTRACT FROM AUTHOR]

We performed a prospective study of patients with inflammatory bowel diseases to examine variations in treatment among medical centers. In a prospective cohort study of 1659 patients with Crohn’s disease and 946 patients with ulcerative colitis seen at 7 high-volume referral centers, we collected data on demographics, disease characteristics, and medical and surgical treatments. We used logistic regression to determine differences in treatment among centers, controlling for potential confounders. We found significant variations among centers in the treatment of Crohn’s disease with immunomodulators (odds ratio [OR], 3.34; 95% confidence interval [CI], 2.09–5.32) but not anti–tumor necrosis factor agents (OR, 1.64; 95% CI, 0.97–2.77). There was less variation in the treatment of ulcerative colitis; we found no difference in use of immunomodulators (OR, 1.83; 95% CI, 1.00–3.36) or anti–tumor necrosis factor therapy (OR, 0.81; 95% CI, 0.40–1.65). The development and implementation of evidence-based standards of care for inflammatory bowel disease may help reduce variation and improve outcomes. [ABSTRACT FROM AUTHOR]

Background In recent years several trials have addressed treatment challenges in Crohn's disease. Clinical trials however, represent a very special situation. Aims To perform a cross-sectional survey among gastroenterologists on the current clinical real life therapeutic approach focussing on the use of biologics. Methods A survey including six main questions on clinical management of loss of response, diagnostic evaluation prior to major treatment changes, preference for anti-tumour necrosis factor (TNF) agent, (de-)escalation strategies as well as a basic section regarding personal information was sent by mail to all gastroenterologists in Switzerland ( n = 318). Results In total, 120 questionnaires were analysed (response rate 37.7%). 90% of gastroenterologists in Switzerland use a thiopurine as the first step-up strategy (anti-TNF alone 7.5%, combination 2.5%). To address loss of response, most physicians prefer shortening the interval of anti-TNF administration followed by dose increase, switching the biologic and adding a thiopurine. In case of prolonged remission on combination therapy, the thiopurine is stopped first (52.6%) after a mean treatment duration of 15.7 months (biologic first in 41.4%). Conclusions Everyday clinical practice in Crohn's disease patients appears to be incongruent with clinical data derived from major trials. Studies investigating reasons underlying these discrepancies are of need to optimize and harmonize treatment. [ABSTRACT FROM AUTHOR]

Background: Ankylosing spondylitis (AS) is characterized by back pain which can lead to spinal ankylosis. Anti-tumor necrosis factor (TNF) dramatically alleviates symptoms, but spinal damage can still be progressive even during anti-TNF treatment. Smoking is a one of well-known risk factors for structural damage in AS. However, it has not been confirmed that smoking can affect radiographic progression even during anti-TNF treatment., Objective: To investigate factors associated with radiographic progression during anti-TNF treatment with a focus on smoking status which is known as one of poor prognostic factors for AS., Materials and Methods: We conducted a retrospective cohort study of AS patients who began the first-line anti-TNF treatment between 2001 and 2018 according to availability of smoking data. All enrolled patients were observed until the last visit, the first-line anti-TNF discontinuation, or December 2019. Radiographic damage was assessed using the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS). The mSASSS progression rate (units/year) was calculated using the baseline mSASSS, the final mSASSS during observation period, and the duration between them. Univariable and multivariable logistic regression analyses were performed to identify associated factors of mSASSS progression rate > 1 unit/year., Results: Among 459 AS patients, 185 (40.3%) patients were never smokers, 62 (13.5%) were ex-smokers and 212 (46.2%) were current smokers at baseline. Ex- and current smokers had higher mSASSS progression rates than never smokers [never smoker 0.1 (0.0-0.7), ex-smoker 0.6 (0.0-1.5), and current smoker 0.6 (0.0-1.5) units/year, P < 0.001]. In the multivariable logistic analysis, current smoking [adjusted odds ratio (OR) 1.69, 95% CI 1.01-2.82, P = 0.047] and higher baseline mSASSS [adjusted OR 1.03, 95% CI 1.01-1.04, P < 0.001] were associated with a mSASSS progression rate > 1 unit/year., Conclusion: Current smoking is a modifiable risk factor for radiographic progression in patients with AS on anti-TNF treatment. Quitting smoking should be strongly recommended., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Nam, Koo, Choi, Shin, Lee, Joo and Kim.)

Background & Aims: Patients with Crohn''s disease who become unresponsive to therapy with tumor necrosis factor antagonists are managed initially with either empiric dose escalation or testing-based strategies. The comparative cost effectiveness of these 2 strategies is unknown. We investigated whether a testing-based strategy is more cost effective than an empiric dose-escalation strategy. Methods: A decision analytic model that simulated 2 cohorts of patients with Crohn''s disease compared outcomes for the 2 strategies over a 1-year time period. The incremental cost-effectiveness ratio of the empiric strategy was expressed as cost per quality-adjusted life-year (QALY) gained, compared with the testing-based strategy. We performed 1-way, probabilistic, and prespecified secondary analyses. Results: The testing strategy yielded similar QALYs compared with the empiric strategy (0.801 vs 0.800, respectively) but was less expensive ($31,870 vs $37,266, respectively). In sensitivity analyses, the incremental cost-effectiveness ratio of the empiric strategy ranged from $500,000 to more than $5 million per QALY gained. Similar rates of remission (63% vs 66%) and response (28% vs 26%) were achieved through differential use of available interventions. The testing-based strategy resulted in a higher percentage of surgeries (48% vs 34%) and lower percentage use of high-dose biological therapy (41% vs 54%). Conclusions: A testing-based strategy is a cost-effective alternative to the current strategy of empiric dose escalation for managing patients with Crohn''s disease who have lost responsiveness to infliximab. The basis for this difference is lower cost at similar outcomes. [Copyright &y& Elsevier]

Objectives: Previous short-term trials found etanercept (0.2 or 0.4 mg/kg) to be effective and well tolerated in Japanese children with juvenile idiopathic arthritis (JIA) who were intolerant/resistant to methotrexate. The aim of this study was to evaluate the long-term safety and efficacy of etanercept in Japanese children with JIA. Methods: Patients (4-19 years) who received etanercept in one of three short-term studies continued onto this long-term open-label study. Results: Of the 32 patients enrolled, 18 (56.3%) completed 192 weeks of the study and 14 (43.8%) were discontinued; 7 (21.9%) for patient refusal, 2 (6.3%) for adverse events (AEs), and 5 (15.6%) for lack of efficacy. All patients reported AEs; 31 (96.9%) reported infections and 6 (18.8%) reported serious AEs. Main efficacy assessments included change from baseline in the American College of Rheumatology Pediatric core components, including mean improvements from baseline in the physician global assessment (90.7%), patient/guardian global assessments (54.1%), Childhood Health Assessment Questionnaire (84.6%), and median improvements in C-reactive protein levels (92.7%). No unexpected safety results were reported, and early efficacy responses were sustained in the long term. Conclusions: This study provides further evidence that etanercept is an effective therapeutic option for Japanese children with polyarticular-course JIA. [ABSTRACT FROM AUTHOR]

We assessed the effect of total large-joint arthroplasty combined with anti-tumor necrosis factor (TNF) therapy for rheumatoid arthritis (RA). We studied 45 RA patients (age 57.91 ± 12.74 years, RA duration 13.43 ± 8.28 years) who underwent total arthroplasty (35 knees, 19 hips, 3 elbows, and 1 ankle) between August 2002 and November 2009. All patients received anti-TNF agents (infliximab, 22; etanercept, 33; adalimumab, 3) during the period of the study (that is, they were being treated with the agents when operated on and postoperatively). The disease activity score 28 (DAS28)-erythrocyte sedimentation rate (mean ± standard deviation) in all patients improved significantly from baseline (just before the operation; 4.32 ± 0.99) to 1 year after the operation (3.35 ± 0.93) in contrast with the finding that the mean DAS28-ESR values had remained unchanged from 1 year before the operation to the baseline. Changes in clinical variables in the 58 cases were investigated at baseline, and at 4, 12, and 52 weeks after the operation. The patients were divided by a median split of baseline demographics into 2 groups for further evaluation. Compared with the high-value groups, those with low C-reactive protein and matrix metalloproteinase-3 values showed better results and had lower disease activity. Overall, the DAS28-ESR in both groups had improved 1 year after the operation. In RA patients who are being treated with anti-TNF agents, large-joint arthroplasty may be beneficial, not only for the relief of pain arising from joint destruction, but also for the systemic reduction of RA activity. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a chronic inflammatory systemic disease characterized by symmetric arthritis leading to progressive erosion of cartilage and bone. Psoriatic arthritis and ankylosing spondylitis are also inflammatory arthritides that belong to the spondyloarthritides. Disease.modifying anti-rheumatic drugs and biologic therapies including anti-TNF agents are used in their treatment. The TNF antagonists have shown rapid and sustained therapeutic responses. However, a substantial number of patients fail to respond to anti-TNF agents or experience side effects. Golimumab is a human monoclonal antibody to TNF-a requiring less frequent administration compared with current anti-TNF products. Various trials have shown promising results in terms of efficacy and safety in methotrexate-naive and -resistant patients with RA as well as in patients previously treated with other anti-TNF agents. The efficacy of golimumab has also been demonstrated in patients with psoriatic arthritis and ankylosing spondylitis. INSET: Key issues. [ABSTRACT FROM AUTHOR]

The aim of this study was to comparatively evaluate oxidative status of ankylosing spondylitis (AS) patients receiving anti-tumor necrosis factor (TNF) or non-steroid anti-inflammatory drugs (NSAID). Forty-seven patients with AS and 27 healthy controls were enrolled. Of these, 23 were on anti-TNF (group 1) and 24 on NSAIDs (group 2). Groups 1 and 2 were consisted of matched patients with respect to age, gender, body mass index, disease duration, C-reactive protein, erythrocyte sedimentation rate, total cholesterol, and Bath Ankylosing Spondylitis Disease Activity Index. Mean duration of treatment for patients in group 1 was 12.6 ± 6.8 months. Serum total antioxidative status (TAS) and total oxidative status (TOS) levels were determined using new automated methods. Oxidative stress index (OSI) was calculated. The groups' carotid intima-media thicknesses (IMT-C) were also measured using ultrasonography. Group 1 had the highest TAS and lowest TOS levels. The TOS levels of group 1 was lower than the control, while group 2 being higher than controls. The difference in TOS levels between group 1 and group 2 was statistically significant ( p = 0.040). OSI values were highest in group 2 and lowest in group 1. There was no significant correlation between oxidant/antioxidant parameters and IMT-C for group 1 ( r = −0.30, p = 0.198 for OSI; r = 0.22, p = 0.366 for TAS; r = −0.22, p = 0.361 for TOS). This is the first study to evaluate total oxidative/antioxidative status in patients with AS on anti-TNF agent. These results clearly indicate positive effects of anti-TNF treatment on oxidative status of AS patients. The limited effects of NSAIDs compared with controls may be due to excess impaired oxidative status in the patients in this study. [ABSTRACT FROM AUTHOR]

We report on a case in which a combination of an insulin infusion and plasma exchange were successfully used in the acute management of hyperlipaemic pancreatitis. [ABSTRACT FROM AUTHOR]

Purpose: Pediatric uveitis is the leading cause of acquired child blindness, due to unremitting inflammation and long-term steroid exposition. Biotherapies with anti-tumor necrosis factor alpha (anti-TNFα) are effective in controlling inflammation for severe pediatric uveitis in recent studies. Major concern of anti-TNFα prescription is the balance between the severity of the disease and side effects of the drug. The aim of the present study is to describe a cohort of children with severe uveitis and to highlight the risk factors for a pejorative development that led to the prescription of anti-TNFα drugs., Method: A retrospective case-control study was carried out on children with uveitis associated with systemic inflammatory disease or idiopathic uveitis, with a minimum follow-up of 5 years. Anti-TNFα-treated patients (case) were studied and compared with patients who were not requiring anti-TNFα (control). Univariate logistic regression analyses were performed to compare both groups and determine the risk factors for anti-TNFα therapy., Results: Seventy-three cases of pediatric uveitis were included, 13 cases and 60 controls. The risk factors associated with increased odds of anti-TNFα therapy were initial systemic disorder associated with uveitis [OR = 11.22 (1.37-91.85), p = 0.0241), family history of autoimmune diseases [OR = 9.43 (2.27-39.15), p = 0.0020], uveitis diagnosis before the age of 6 [OR = 4.05 (1.16-14.13), p = 0.0284], eye surgery [OR = 26.22 (2.63-261.77), p = 0.0054], ocular complications at the first slit lamp exam [OR = 67.11 (3.78-1191.69), p = 0.0042], low visual acuity at diagnosis (≥0.3 logMAR) [OR = 11.76 (2.91-47.62), p = 0.0005] and especially low binocular acuity at diagnosis (≥0.3 logMAR) [OR = 8.75 (1.93-39.57), p = 0.0048], panuveitis [OR = 9.17 (2.23-37.60), p = 0.0021], having positive ANA [OR = 3.89 (1.07-14.11), p = 0.0391], and positive HLA B27 [OR = 9.43 (2.27-39.16), p = 0.0020]., Conclusion: Those risk factors could be used to establish a new follow-up and treatment schedule for severe uncontrolled uveitis. This could help to better predict the best time to start anti-TNF therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Osswald, Rameau, Terzic, Sordet, Bourcier and Sauer.)

Crohn's disease is a chronic inflammatory bowel disease that affects various intestinal segments and can involve the perianal region. Although anti-tumor necrosis factor (TNF) agents have revolutionized the management of Crohn's disease and improved the prognosis for patients with perianal Crohn's disease (pCD), their long-term effectiveness is limited: over 60% of patients relapse after one year of maintenance therapy. In recent years, significant advances have been made in the treatment of complex perianal fistulas after anti-TNF failure. Concomitant treatment with antibiotics and immunosuppressants improves the effectiveness of anti-TNF agents. Therapeutic drug monitoring and dose adjustment of anti-TNF therapy (targeting a higher trough level) might also improve treatment response. Novel therapeutic strategies might provide new opportunities for pCD management; for example, ustekinumab might be effective after anti-TNF treatment failure, although more studies are needed. As suggested in recent international guidelines, mesenchymal stem cell injection might be an effective, safe treatment for complex pCD., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors. Published by Elsevier B.V.)

Background: Anti-drug antibodies to infliximab (ATI) and adalimumab (ATA) are associated with loss of response to tumor necrosis factor antagonist (anti-TNF) therapy in inflammatory bowel disease (IBD). We evaluated the relationship between patient sex and serum TNF antagonist drug and antibody concentrations in inflammatory bowel disease. Methods: A nationwide multicenter retrospective cohort study was conducted by evaluating patients' charts from July 2018 until September 2021. The effect of patient sex on anti-drug antibodies and serum drug concentration in patients with IBD across seven hospitals was investigated. A subgroup analysis also investigated the effect of anti-TNF combination therapy. Geometric means were calculated, and multiple linear regression was used to estimate the adjusted ratio of geometric means (RoGM) and their 95% confidence intervals (CI). Results: In the total study sample ( n = 1093), males receiving infliximab had higher anti-drug antibody concentrations (38.3 vs. 22.3 AU/ml; aRoGM = 1.72, 95% CI: 1.30-2.27, p < 0.001) compared to females. Additionally, infliximab serum drug concentrations among males were lower compared to females (2.6 vs. 4.1 ug/ml; aRoGM = 0.62, 95% CI: 0.44-0.88, p = 0.007). In the subgroup analysis ( n = 359), male compared to female patients on combination therapy with infliximab and immunomodulators had similar anti-drug antibody concentrations (30.2 vs. 21.9 AU/ml; aRoGM = 1.38, 95% CI: 0.79-2.40, p = 0.254). There was no difference in the anti-drug antibody and serum drug concentrations among males and females on adalimumab. Conclusion: In patients receiving infliximab, anti-drug antibodies were higher in males than females. Consistent with this, serum drug concentrations were lower in males than females on infliximab. There was no difference in anti-drug antibody and serum drug concentrations among males and females on adalimumab. In addition, no difference in anti-drug antibodies between males and females receiving anti-TNF combination therapy was observed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Shehab, Alasfour, Abdullah, Alhendi, Alhadab, Alfadhli, Ziyab and Battat.)

Higher infliximab trough levels are associated with clinical and endoscopic remission in patients with Crohn's disease (CD). We investigated pharmacodynamic features of infliximab and radiological healing. We performed a substudy of the TAILORIX trial (patients with active luminal CD in Europe, treated with infliximab), analyzing baseline and week 54 magnetic resonance enterography (MRE) data. MREs were scored using the MaRIA score by blinded central readers. Radiologic response and remission were defined, based on MaRIA criteria in all segments, as scores below 11 and 7, respectively. We collected data on infliximab trough levels, biomarkers, and endoscopic findings. Our primary aim was to evaluate pharmacodynamic features associated with radiologic response and remission, based on MRE assessments at baseline and at 54 weeks after initiation of infliximab therapy. We analyzed data from 36 patients (50% female; median age 35.7 years; interquartile age range, 25.6–48.6 years; median disease duration, 1.5 months; interquartile duration range, 0.6–22.4 months). At week 54 of treatment, 36.4% of patients had a radiologic response, 30.3% of patients were in remission, and 71% had endoscopic features of remission. At baseline, there was a correlation between the CD endoscopic index of severity and MaRIA scores (κ = 0.46; P =.008), but we found no correlation at week 54 (κ = 0.06; P =.75). Radiologic remission correlated with infliximab trough level at week 14 (P =.049) when the infliximab trough level cut-off value was set at 7.8 μg/mL (area under the curve, 0.74; 75% sensitivity; 86% specificity; 90% negative predictive value; 57% positive predictive value). Radiologic response correlated with infliximab trough levels at week 14 (P =.048) when the infliximab trough level cut-off value was set at 7.8 μg/mL (area under the curve, 0.73; 70% sensitivity; 90% specificity; 86% negative predictive value; 78% positive predictive value) and with continuous pharmacologic evidence of response (infliximab trough levels above 5.0 μg/mL at all time points) (P =.034). In a substudy of data from the TAILORIX trial of patients with active luminal CD, we identified a relationship between exposure to infliximab and radiologic evidence of outcomes. [ABSTRACT FROM AUTHOR]

Background & Aims Infliximab is a safe and effective therapy for ulcerative colitis (UC). We conducted a multicenter retrospective cohort study that included 7 European countries and Israel to examine whether infliximab discontinuation can be considered for patients who achieve sustained remission. Methods We performed a retrospective cohort study, collecting medical records from 13 tertiary care referral inflammatory bowel disease centers of all patients with UC treated with infliximab (n = 193). We compared the disease course of patients with at least 12 months of clinical remission who discontinued infliximab (n = 111) with that of patients who continued scheduled treatment (controls, n = 82). We examined the incidence rates of relapse, hospitalization and colectomy, the comparative effectiveness of different therapeutic strategies after discontinuation, and assessed the rates of response, remission, and adverse effects after infliximab re-initiation. Statistical analyses used time-to-event methods. Results In the entire cohort, 67 patients (34.7%) relapsed during the follow-up period. The incidence rate of relapse was significantly higher after discontinuation (23.3 per 100 person-years) compared with the control group (7.2 per 100 person-years) in univariable analysis (log-rank P < .001; hazard ratio, 3.41; 95% confidence interval, 1.88–6.20) and multivariable analysis (hazard ratio, 3.70; 95% confidence interval, 2.02–6.77). Rates of hospitalization and colectomy did not differ between groups. Thiopurines appeared to be the best treatment option after infliximab discontinuation (incidence of relapse: 15.0 per 100 person-years for thiopurines, 27.4 per 100 person-years for thiopurines plus aminosalicylates, and 31.2 per 100 person-years for aminosalicylates alone; log-rank P = .032). Response was regained in 77.1% of patients and remission in 51.4% of patients who re-initiated infliximab. However, 17.1% had infusion reactions and 17.1% reported other adverse events. Conclusions In a multinational retrospective cohort study of patients with UC in sustained clinical remission, we associated discontinuation of infliximab with an increased risk of relapse. Treatment re-initiation is effective and safe. [ABSTRACT FROM AUTHOR]

Background & Aims Behçet’s disease is a chronic, relapsing inflammatory disease that can involve the mouth, skin, eyes, genitals, and intestines. Active intestinal Behçet’s disease can be complicated by gastrointestinal (GI) bleeding and perforation. We performed a multicenter, open-label, uncontrolled study to evaluate the efficacy and safety of adalimumab, a fully human monoclonal antibody against tumor necrosis factor α, in patients with intestinal Behçet’s disease who were refractory to corticosteroid and/or immunomodulator therapies. Methods The study was conducted at 12 sites in Japan, from November 2010 through October 2012. Twenty patients were given 160 mg adalimumab at the start of the study and 80 mg 2 weeks later, followed by 40 mg every other week for 52 weeks; for some patients, the dose was increased to 80 mg every other week. A composite efficacy index, combining GI symptom and endoscopic assessments, was used to evaluate efficacy. The primary efficacy end point was the percentage of patients with scores of 1 or lower for GI symptom and endoscopic assessments at week 24. Secondary end points included complete remission and resolution of non-GI Behçet’s-related symptoms. Results Nine patients (45%) had GI symptom and endoscopic assessment scores of 1 or lower at week 24 of treatment, and 12 patients (60%) had these scores by week 52. Four patients (20%) achieved complete remission at weeks 24 and 52. Individual global GI symptom and endoscopic scores improved for most patients at weeks 24 and 52. Two thirds of patients with oral aphthous ulcers, skin symptoms, and genital ulcers, and 88% of patients with erythema nodosum had complete resolution of these conditions at week 52. A total of 9 of 13 patients (69%) taking steroids at baseline were able to taper (n = 1) or completely discontinue steroids (n = 8) during the study. No new safety signals were observed. Conclusions Adalimumab is a potentially effective treatment for intestinal Behçet’s disease in Japanese patients who are refractory to conventional treatments. ClinicalTrials.gov number: NCT01243671 . [ABSTRACT FROM AUTHOR]

Background & Aims Our post hoc analysis assessed the association of early (at weeks 26–30) clinical, endoscopic, biologic, and pharmacokinetic outcomes with corticosteroid-free remission at week 50 (CSFR50); CSFR50 was observed in 55.2% and 65.4% of patients treated with infliximab, alone or in combination with azathioprine, respectively. Methods We analyzed data from 203 patients: 96 received infliximab monotherapy and 107 received combination therapy. Receiver operating characteristic analysis was used to set cut-off points for the week 30 trough serum infliximab concentration (SIC30) and percentage change, from baseline, in the C-reactive protein (CRP) level at week 26, to predict CSFR50. Univariate and multivariate procedures analyzed predictive parameters of CSFR50 (odds ratio [OR] and 95% confidence interval [CI]). Mucosal healing (MH, zero ulcers) and CRP normalization (<8.0 mg/L) also were assessed. Results Trough SIC30 was higher in patients with than without CSFR50. Patients given combination therapy had higher trough SIC30s than those given monotherapy. Median trough SIC30 was significantly higher in patients with than without CSFR50 among those on infliximab monotherapy (2.14 vs 0.80 μg/mL; P = .006), but not for those on combination therapy (3.56 vs 3.54 μg/mL; P =.31). In patients with increased baseline levels of CRP (n = 120), corticosteroid-free remission at week 26 (CSFR26) (OR, 4.09; 95% CI, 1.65–10.11), and trough SIC30s of 3.0 μg/mL or greater (OR, 3.20; 95% CI, 1.38–7.42) were associated significantly with CSFR50. In patients evaluable for MH (n = 123), trough SIC30s of 3.0 μg/mL or greater (OR, 3.34; 95% CI, 1.53–7.28) and CRP normalization (OR, 2.69; 95% CI, 1.10–6.54) were associated significantly with MH at week 26 (MH26). Furthermore, CSFR26 (OR, 4.43; 95% CI, 1.81–10.82) and MH26 (OR, 3.01; 95% CI, 1.33–6.81) were associated significantly with CSFR50. Conclusions Trough SIC30 is associated positively with MH26; CSFR26 and MH26 are independent predictors of CSFR50. Trough SIC30 of 3.0 μg/mL or greater early during maintenance treatment is an important determinant of clinical and endoscopic Crohn’s disease outcomes. ClinicalTrials.gov number, NCT00094458 . [ABSTRACT FROM AUTHOR]

Background & Aims: The IMAgINE 1 study (NCT00409682) evaluated the safety and efficacy of adalimumab double-blind maintenance dosing regimens following open-label induction for pediatric patients with moderate to severe Crohn''s disease (CD). Methods: We studied 192 patients with Pediatric Crohn''s Disease Activity Index (PCDAI) scores >30 for whom conventional treatment was unsuccessful. Patients received open-label induction therapy with subcutaneous adalimumab at weeks 0 and 2 (160 mg and 80 mg, or 80 mg and 40 mg, for body weight ≥40 kg or <40 kg). At week 4, 188 patients were assigned to groups based on achievement of clinical response (defined as decrease in PCDAI ≥15 points from baseline; 155/188 [82.4%]) and prior exposure to infliximab (82/188 [43.6%]). Groups were given double-blind maintenance therapy with adalimumab at high (40 mg or 20 mg for body weight ≥40 kg or <40 kg; n = 93) or low doses (20 mg or 10 mg for body weight ≥40 kg or <40 kg; n = 95) every other week for 48 weeks. Clinical remission (PCDAI ≤10) at week 26 (the primary end point) was compared between groups using the Cochran–Mantel–Haenszel test, adjusting for strata, with nonresponder imputation. Adverse events were monitored to evaluate safety. Results: A total of 152 of 188 patients (80.9%) completed all 26 weeks of the study. At week 26, 63 patients (33.5%) were in clinical remission, with no significant difference between high- and low-dose groups (36/93 [38.7%] vs 27/95 [28.4%]; P = .075). No new safety signals were detected. Conclusions: Adalimumab induced and maintained clinical remission of children with CD, with a safety profile comparable to that of adult patients with CD. More children who received high compared with low dose were in remission at week 26, but the difference between dose groups was not statistically significant. [Copyright &y& Elsevier]