Infliximab Treatment Research Articles

Emergence of new manifestations during infliximab treatment in Behçet's syndrome.

Infliximab (IFX) is increasingly being used for the treatment of severe manifestations of Behçet's syndrome (BS). However, emergence of new manifestations has also been occasionally reported during IFX treatment. We aimed to assess the frequency of new manifestations in our BS patients treated with IFX. A chart review was conducted to identify all BS patients treated with IFX in our clinic between 2004 and 2020. Demographic data, indications for IFX initiation, concomitant treatments and outcomes were recorded. A new manifestation was defined as the emergence of a new organ involvement or mucocutaneous manifestation developing for the first time during IFX treatment or within 12 weeks after the last infusion of IFX. Among our 282 patients who used IFX, 19 (7%) patients had developed a total of 23 new manifestations during a mean follow-up of 20.0 (15.3) months. Patients with vascular involvement were more likely to develop a new manifestation (12/19, 63%). Initial manifestations that required IFX were in remission at the time of new manifestation in 14/19 patients. IFX treatment was intensified (n = 6) and/or glucocorticoids, immunosuppressives or colchicine was added to IFX (n = 21). IFX was switched to another agent for the remaining manifestations (n = 8). These treatment modifications led to remission in 17/19 patients. New manifestations developed during IFX treatment in 7% of our patients with BS. They could be managed by intensifying IFX treatment or adding other agents in the majority of these manifestations.

Learning Longitudinal Patterns and Subtypes of Pediatric Crohn Disease Treated With Infliximab via Trajectory Cluster Analysis.

The objective of this study is to identify subgroups of pediatric Crohn disease (CD) who had differential responses to the infliximab treatment through trajectory cluster analysis of disease activity using data from electronic health records. We conducted a retrospective study of 295 pediatric patients with CD who had been treated with infliximab for a minimum of one year at the Center for Inflammatory Bowel Disease at The Children's Hospital of Philadelphia between January 2010 and December 2017. The evolution of disease was described, and subgroups of patients were identified using trajectory analysis of longitudinal data of C-reactive protein (CRP). We compared patient characteristics, biomarker for disease activity, and long-term surgical outcomes across subgroups. Cox regression models were used to evaluate the added value of the subgroup classification to baseline phenotype and location in prediction of long-term surgical outcomes. We identified three subgroups of patients with differential relapse-and-remission profiles (n = 33, 65 and 197 from subgroup 1 to 3), which represented patients with a higher risk of infliximab non-response, with infliximab response but with occasional disease flares, and patients with long-term response. Patients with the best treatment response had a significantly lower frequency of complicated disease phenotypes (P = 0.01), including perianal involvement (P = 0.05), lower baseline CRP (P < 0.01) and calprotectin (P = 0.01), and lowest risk of IBD-related gastrointestinal surgery within 10 years of starting treatment (P < 0.01). Readily available longitudinal data from electronic health records can be leveraged to provide deeper characterization of treatment response in pediatric CD.

Infliximab for Anoperineal Lesions in Crohn's Disease: Remission Appears to be Based on Rapid Combination Therapy at High Doses

Abstract Study Aim The aim of the present study was to compare in real life the characteristics of treatment with infliximab according to the presence or absence of anoperineal involvement in Crohn's disease. Methods We performed a single-center, prospective, non-interventional study, on patients with Crohn's disease in remission who had been treated with infliximab for at least 1 year. Patients with poor treatment compliance, on antibiotics, or those with a stoma were excluded. Results We included 52 patients in this study: 34 with anoperineal lesions with or without luminal lesions, and 18 with luminal lesions only. Patients with anoperineal lesions were more likely to have undergone surgery (70.6% versus 38.9%, p = 0.027), had a shorter median time to infliximab treatment initiation (0.5 versus 5.5 years, p = 0.005), a higher mean dose of infliximab (6.6 versus 5.1 mg/kg, p = 0.015), and were more likely to receive combination treatments including infliximab (52.9% versus 11.1%, p = 0.008) than patients with luminal involvement only. Conclusions In our study, infliximab treatment was initiated more quickly, at higher doses, and more in combination therapy for anoperineal Crohn's disease than for luminal damage alone. Additional studies are required to confirm this finding and to assess the tolerance of this treatment throughout patient management.

P020 Proton Pump Inhibitor Therapy: Providing "Acid" Outcomes in Patients With Inflammatory Bowel Disease Under Infliximab Treatment.

A recent meta-analysis has suggested that proton pump inhibitor (PPI) therapy is associated with lower clinical remission rates and a higher number of hospitalizations in patients with inflammatory bowel disease (IBD) under infliximab therapy. We aimed to assess if these differences kept their significance when adjusted for other possible confounders. Cohort study of consecutive patients with Crohn's disease (CD) and Ulcerative Colitis (UC) under infliximab therapy. A minimum follow-up of 54 weeks after introduction of infliximab treatment was required. The analyzed outcomes were deep remission at week 54 and the need of IBD-related hospitalization, corticosteroid treatment or abdominal surgery under infliximab treatment. Collected possible confounders were age, gender, smoking habits, perianal disease, extra-intestinal manifestations, familiar history of IBD and concomitant use of immunomodulators. Our final sample included 104 patients, 56 (53.8%) of them females, with a mean age of 38.2±13.1 years. From these, 77 (74.0%) had CD and 27 (26.0%) had UC. PPI therapy was described in 21 (20.2%) of the patients under infliximab treatment. On univariate analysis, PPI users were found to have significantly lower rates of deep remission at week 54 (7.7 vs 28.3%; p = 0.034) and higher IBD-related hospitalization rates (47.6 vs 21.7%; p = 0.034). No differences were found regarding the need of corticosteroid therapy (4.8 vs 10.8%; p = 0.398) or abdominal surgery (33.7 vs 21.7; p = 0.201). When adjusted for the collected confounders by multivariate analysis, while not significantly influencing deep remission at week 54 (OR = 0.16; 95%CI = 0.02-1.63; p = 0.121), concomitant PPI therapy was a significant independent risk factor for IBD-related hospitalization (OR = 3.22; 95%CI = 1.11-9.34; p = 0.04). Despite not conducting to significantly different deep remission rates, concomitant PPI therapy was associated with a three-fold increase in hospitalization rates in IBD patients under infliximab treatment, even when adjusted for classical risk factors for adverse outcomes in IBD. These findings emphasize the importance of restricting PPI treatment to those with a clear clinical indication, especially in this set of patients.

Abstract 13032: Endothelial Cell Response to Intravenous Immunoglobulin, Infliximab and Atorvastatin Treatment During the Acute Phase of Kawasaki Disease

Introduction: Damage to coronary arteries (CA) during the acute phase of Kawasaki disease (KD) is linked to inflammatory cell infiltration, myofibroblast generation (EndMT: endothelial-mesenchymal transition), and endothelial cell (EC) dysfunction. To promote EC health, we performed a Phase I/IIa clinical trial (6-week course) of atorvastatin in patients with acute KD and coronary artery Z score &gt; 2.5. We demonstrated that atorvastatin was safe and well-tolerated. However, its effect on EC in KD has not been systematically studied. Hypothesis: Treatment with atorvastatin added to intravenous immunoglobulin (IVIG) and infliximab (IFX) promotes EC health in acute KD patients. Methods: We performed RNAseq on human umbilical vein ECs (HUVECs) incubated with pooled sera from KD patients (pre-treatment or subacute illness day 17-25) treated with IVIG and IFX with or without atorvastatin added to their initial treatment. Results: Differentially expressed genes (DEGs) from HUVECs incubated with sera pooled from 5 KD patients collected pre- and post-treatment (IVIG + IFX) that were suppressed by treatment included IL-8 , CCL2 and ICAM1 , molecules in the TNFα and IL1β pathways that have key roles in recruitment of inflammatory cells to EC. Subacute sera pooled from 5 patients treated with IVIG + IFX + atorvastatin induced expression of NOS3 , KLF2 and KLF4 , molecules that promote EC homeostasis and angiogenesis, and suppressed expression of TGFB2 and Dickkopf WNT signaling pathway inhibitor 1 ( DKK1 ), molecules in the TGFβ and WNT signaling pathways. These results were validated by RT-PCR on HUVECs incubated with independent individual sera from patients treated with/without atorvastatin. Conclusions: HUVECs incubated with pre- or post-treatment sera from KD patients showed upregulation of IL1 and TNFα pathway genes that were dramatically suppressed after treatment with IVIG and IFX. Incubation of HUVECs with post-treatment sera from patients who also received atorvastatin showed reduced expression of DKK1 and TGFB2 , suggesting reduced EndMT, and increased NOS3 and KLF4 , key mediators of EC homeostasis. These results suggest that atorvastatin improves EC health and may block KD-induced myofibroblast proliferation in the CA wall.

Efficacy and safety of vedolizumab and infliximab treatment for immune-mediated diarrhea and colitis in patients with cancer: a two-center observational study

BackgroundCurrent treatment guidelines for immune-mediated diarrhea and colitis (IMDC) recommend steroids as first-line therapy, followed by selective immunosuppressive therapy (SIT) (infliximab or vedolizumab) for refractory cases. We aimed to compare...

Safety Prediction of Infants Born to Mothers with Crohn's Disease Treated with Biological Agents in the Late Gestation Period.

Objectives: Knowledge gaps exist in the use of biologics for pregnant patients with Crohn's disease (CD), especially the usage of ustekinumab (UST) and infliximab (IFX) infusion during the late gestation period. In this case series, we investigated perinatal and neonatal outcomes and pharmacokinetics of these biologics in pregnant CD patients. Methods: Pregnant CD patients under treatment with IFX or UST during January 2017 to December 2019 were monitored. Growth and development of their babies were followed up to six months. Drug concentrations were measured in maternal peripheral and cord blood at delivery and infants' blood at six months of age. Results: Four cases were kept IFX treatment until late gestation (median last dose: 31.2 weeks). One case received UST until 23 weeks of gestation. All cases were in clinical remission but moderately undernourished. Babies were delivered by cesarean section at full term without any complications or congenital abnormalities. No growth or developmental defects and no susceptibility to infections were observed by six months. However, two babies whose mothers received IFX after 30 weeks of gestation were detected IFX in their blood at six months of age (0.94 and 0.24 pg/ml). Concentrations of UST in maternal and cord blood were 267.7 and 756.5 ng/ml, respectively. UST was not detected in the infant at six months of age. Conclusions: Administration of UST or IFX to pregnant patients with CD is safe, particularly IFX to be given in the late gestation period. Understanding of the pharmacokinetics of biologics in maternal-infant interactions may improve the management of pregnant CD patients.

Influence of Vitamin D3 Supplementation on Infliximab Effectiveness in Chinese Patients With Crohn's Disease: A Retrospective Cohort Study.

Background: It remains uncertain whether vitamin D3 (vitD3) supplementation is beneficial for remission of Crohn's disease (CD). The influence of vitD3 supplementation on Infliximab (IFX) effectiveness was analyzed in Chinese CD patients.Methods: In this retrospective cohort study, moderate-to-severe CD patients, who were bio-naïve and prescribed with IFX treatment for at least 54 weeks, were recorded from January 2014 to December 2019. VitD3 supplementation was defined as patients additionally took oral vitD3 (125 IU/d) within 3 days after the first infusion and persisted in the whole follow-up period. Disease activity was assessed using Harvey-Bradshaw Index (HBI). Serum cytokine profiles (IL-2, IL-4, IL-6, IL-10, TNF-α, and IFN-γ) were quantitatively analyzed in a subset of all patients at baseline and 54-week after intervention.Results: Among 73 enrolled patients, 37 took vitD3 regularly (D3-patients), the others (non-D3-patients) did not. At 54-week, the mean 25-hydroxyvitaminD level increased in D3-patients (20.33 vs. 15.07 ng/mL, P < 0.001). The clinical remission rate was higher in D3-patients compared to non-D3-patients (83.8 vs. 61.6%, P = 0.030). The decrease of HBI from baseline to 54-week was more in D3-patients than non-D3-patients (7.41 ± 3.0 vs. 6.28 ± 2.75, P = 0.023). Furthermore, vitD3 supplementation was independently related to the increase of remission rate at 54-week in D3-patients (β = −1.667, P = 0.015). The benefit of vitD3 supplementation was significant only in patients with deficient vitD3 (all P < 0.05), but not in non-deficient vitD3. A total of nine patients (four non-D3-patients and five D3-patients) were selected to determine serum cytokine profiles after 54-week IFX treatment. In non-D3-patients, the decreases of TNF-α and IL-6 at 54-week were more obvious than at baseline (P = 0.032, 0.022, respectively). In D3-patients, however, only IL-10 increased at 54-week compared with its baseline value (P = 0.037).Conclusions: VitD3 supplementation could improve IFX effectiveness in CD patients, especially for patients with vitD3 deficiency. This beneficial effect of vitD3 supplementation probably arose from the up-regulation of IL-10.Trial Registration: NCT04606017.

Risk Factors of Cytomegalovirus Reactivation in Ulcerative Colitis Patients: A Meta-Analysis.

Cytomegalovirus (CMV) infection is associated with exacerbation of disease activity in patients with ulcerative colitis (UC). However, the risk factors for CMV reactivation in this population remain debatable. This meta-analysis was performed to identify the risk factors for CMV reactivation in UC patients. PubMed, Cochrane Library, EMBASE, Web of Science, and China National Knowledge Infrastructure were searched from the inception of these databases to 31 August 2021, with the aim of identifying studies that investigated the risk factors of CMV reactivation in UC patients. A quality assessment of the included studies was performed with the Newcastle-Ottawa Scale. The publication bias was assessed respectively via a funnel plot and Egger’s regression asymmetry test. The robustness and reliability of each outcome were evaluated by sensitivity analysis. Twenty studies were included in the final meta-analysis, comprising a total of 2099 patients with UC. A significantly higher risk of CMV reactivation was observed in patients with severe UC (OR = 1.465, 95% CI: 1.107 to 1.939, p = 0.008), pancolitis (OR = 2.108, 95% CI: 1.586 to 2.800, p = 0.0001), older age of UC onset (MD = 6.212, 95% CI: 2.552 to 9.971, p = 0.001), as well as use of glucocorticoids (OR = 4.175, 95% CI: 3.076 to 5.666, p = 0.001), immunosuppressants (OR = 1.795, 95% CI: 1.289 to 2.501, p = 0.001), and azathioprine (OR = 1.444, 95% CI: 1.012 to 2.061, p = 0.043). However, infliximab treatment was observed not to increase the occurrence of CMV reactivation in patients who suffered from UC. In contrast, 5-aminosalicylic acid (OR = 0.674, 95% CI: 0.492 to 0.924, p = 0.014) was associated with a lower risk of CMV reactivation. Patients with UC should be closely monitored for risk factors of CMV reactivation in order to provide timely diagnosis and antiviral treatment.

P24 Ankylosing spondylitis &amp; uveitis - challenges in management

Case report - IntroductionAnkylosing spondylitis is a chronic inflammatory condition involving spine, chest and sacroiliac joints. It can be associated with extra spinal manifestations which include uveitis and enthesitis, as well as other features of an inflammatory spondyloarthropathy including psoriasis and inflammatory bowel disease. It is characterised by the presence of inflammatory back pain, limited range of spinal movement, sacroiliitis on imaging, excess spinal bone formation and a high prevalence of HLA-B27. The main aims of treatment are to improve symptoms and retain function as well as to prevent disease complications.Case report - Case descriptionA 49-year-old male diagnosed with ankylosing spondylitis at the age of 23 (HLA-B27 positive, classical radiographic features on plain radiographs and MRI), with background of meningitis and subsequent epilepsy (not on treatment since the age of 13), severe hip osteoarthritis and osteoporosis. He has peripheral elbow and knee synovitis. At the age of 27 he developed sight-threatening bilateral recurrent anterior uveitis complicated by cystoid macular oedema (causing central vision loss). Initial management included anti-inflammatories and steroids. He progressed to biologics but developed a rash on adalimumab. He was switched to infliximab in 2010. In 2015 it was switched due to reduced response to golimumab which was non-beneficial. Subsequently he was switched to etanercept but after 3 months it was discontinued due to eye flare. The patient’s therapy was switched to certolizumab, which was non-beneficial for spine and discontinued. In 2016, infliximab was retried as the patient thought it worked best. Unfortunately, in 2018 patient developed Infliximab antibodies and treatment was changed to secukinumab. After 9 months this was stopped owing to ongoing active eye and spine disease. Adalimumab was re-tried; however, it was discontinued as it was showing no benefit. In 2020 Eeanercept (Benepali) was re-tried; however, only for 4 months because of severe flare of joint and eye disease. Tofacitinib was commenced but was non-beneficial and hence it was discontinued. Currently he continues on ixekizumab, oral prednisolone and also receives steroid eye and joint injections. On commencing biologics he was on methotrexate; however, the patient stopped. He was switched to mycophenolate mofetil which he remained on for 10 years. It was switched to methotrexate to try and control peripheral inflammatory joint disease better (re-tried for the second time) which the patient has recently discontinued as he felt it was non-beneficial.Case report - DiscussionThe case is very challenging. The patient’s disease continues to flare despite changing therapies. He continues to get flares in his back disease, eye disease and peripheral synovitis. His latest BASDI was 5.1 and VAS was 9/10. Measurements: intermalleolar distance 15cm, modified Schober’s 4cm, right lateral flexion 3.8cm and left lateral flexion 11cm. His latest MRI of whole spine and SI joints (in 2020) showed signs of previously active seronegative spondyloarthropathy with established cervical and thoracic ankyloses as well as bilateral sacroiliac joint ankylosis. There is a need for repeated steroid injections to the knees as well as the eyes. He continues on oral prednisolone which was first started in 2006. This is associated with multiple side effects, i.e., osteoporosis. The patient has already completed 8 years of bisphosphonate therapy. He is under regular review with the osteoporosis clinic. His bone density scan showed worsening bone mineral density and bisphosphonates had to be restarted. The patient adjusted medications depending on his symptoms. Recently he also discontinued methotrexate as he felt it was of no benefit to him at all. We are very limited at present to find combined medications to manage both the patient’s inflammatory back disease and inflammatory eye disease.Case report - Key learning pointsThis patient was diagnosed with ankylosing spondylitis 26 years ago. To date he has tried 5 different anti-TNF agents (two of which have also been re-tried at a different time point). This failed to control his disease as he continued to experience flares in either inflammatory back or eye disease. The biologic classes were also changed – he has tried one IL-17A agent as well as a JAK-I. Unfortunately, they both failed to control his disease. He currently continues on a second IL-17A; however, he still requires steroid eye and joint injections as well as systemic steroids. Throughout the years he has tried different DMARDs – most recently methotrexate. Unfortunately, the patient decided to discontinue it as he felt it was of no benefit to him. All of the above indicates that there is still a need to find a collaborative treatment option that will control the patient’s inflammatory back disease, inflammatory eye disease and peripheral synovitis. The aim would be, if possible, to decrease the steroid dose as well (currently on prednisolone 15mg daily) in order to prevent the steroid-associated side effects.

Perianal disease onset age is associated with distinct disease features and need for intestinal resection in perianal Crohn\u2019s disease: a ten-year hospital-based observational study in China

Background and aimsThe significance of different ages of perianal disease (PD) onset in patients with perianal Crohn’s disease (PCD) remains unknown. We aimed to investigate the impact of paediatric-onset PD (POP) and adult-onset PD (AOP) on the Crohn’s disease (CD) course in a Chinese cohort.MethodsThe medical records of diagnosed PCD patients from 2008 to 2018 were reviewed retrospectively. The cumulative incidence and predictors of intestinal resection were calculated using the Kaplan–Meier and logistic regression analysis.ResultsComplex perianal fistulas (71.7% vs 50.0%, p = 0.011) and infliximab (IFX) treatment (33.3% vs 22.0%, p = 0.044) were more common among the POP patients (age < 18 years old, n = 84). A younger PD onset age (15.1 ± 2.9 vs 30.2 ± 10.5 years, p < 0.001) and shorter PCD diagnostic delay (12 vs 24 months, p = 0.033) was found in the POP cohort. AOP patients (age ≥ 18 years old, n = 209) had a higher rate of current smoking (12.9% vs 4.8%, p = 0.040), stricturing behaviour (42.1% vs 27.4%, p = 0.024) and intestinal resection (21.1% vs 4.8%, p = 0.001). The cumulative probability of intestinal resection in AOP patients was higher than that in POP patients (p = 0.007). In multivariable analysis, AOP (OR: 4.939, 95% CI 1.538–15.855, p = 0.007), stricturing behaviour (OR: 1.810, 95% CI 1.008–3.251, p = 0.047) and rectal inflammation (OR: 3.166, 95% CI 1.119–8.959, p = 0.030) were predictive factors for CD-related intestinal resection in all PCD patients. AOP patients with complex perianal fistula (OR: 2.257, 95% CI 1.041–4.891, p = 0.039) and POP patients with rectal inflammation (OR: 3.166, 95% CI 1.119–8.959, p = 0.030) were more likely to suffer intestinal resection. The IFX administration significantly decreased the rate of intestinal resection in AOP patients (r = − 0.900, p = 0.037).ConclusionsThe AOP patients have more complicated luminal disease and higher rate of intestinal resection than COP patients. The perianal diseases onset-age can provide clinical treatment guidance for individual management of CD patients.

Subclinical cardiac organ damage in patients with moderate to severe psoriasis treated with infliximab

Abstract Background Psoriasis is an immune mediated disease that has been associated with elevated risk of cardiovascular (CV) disease. Comorbidities, psoriasis treatment and presence of subclinical cardiac organ damage can modulate CV risk in psoriasis. Purpose To assess the prevalence and covariables of subclinical cardiac organ damage in patients with moderate-to-severe psoriasis on infliximab treatment. Methods Echocardiography was performed in 53 psoriasis patients (age 47±15 years, 30% women) and 99 control subjects (age 47±11 years, 28% women). Subclinical cardiac organ damage was defined as presence of left ventricular (LV) hypertrophy, concentric LV geometry and/or dilated left atrium. Psoriasis area and severity index (PASI) was used to assess the severity of psoriasis. Hypertension was defined as use of antihypertensive medication/history of hypertension and/or elevated ambulatory blood pressure ≥130/80 mmHg. Results Hypertension was the most common comorbidity, present in 66% of patients and 61% of control subjects (p=0.54). Smoking was more prevalent in psoriasis patients than controls (37% vs 17%, p=0.005), while other CV risk factors and antihypertensive treatment did not differ between groups. Subclinical cardiac organ damage was less prevalent in psoriasis patients than controls (51% vs. 73%, p=0.007, Figure). In the total study cohort, having psoriasis was associated with lower prevalence of subclinical cardiac organ damage independent of hypertension, smoking, age and sex (odds ratio [OR] 0.30, 95% confidence interval [CI] 0.13–0.72, p=0.007) in logistic regression analysis. Among psoriasis patients, hypertension was associated with a near seven-fold increased risk of cardiac organ damage (OR 6.88 [95% CI 1.32–35.98], p=0.022) independent of age, sex and body mass index. PASI at start of treatment or current PASI was not associated with presence of subclinical cardiac organ damage. Conclusion Psoriasis patients on infliximab treatment had less subclinical cardiac organ damage compared with controls, suggesting that inhibition of CV inflammation may attenuate cardiac organ damage in psoriasis. Hypertension was the strongest covariable for subclinical cardiac organ damage in psoriasis patients. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): This work was supported by the Western and South-Eastern Regional Health Authorities of Norway and Hjertefondet, University of Bergen.

Psoriasis severity and the risk of left ventricular remodelling in psoriasis patients treated with infliximab

Abstract Background Psoriasis is an immune mediated skin disorder with a great variation in disease severity. Chronic inflammation predisposes to subclinical cardiac damage like left ventricular (LV) remodelling. However, the association of psoriasis severity with LV remodelling is not known. Purpose To assess LV remodelling in patients with moderate to severe psoriasis treated with infliximab. Methods Psoriasis severity was assessed by the Psoriasis Area Severity Index (PASI) before initiation of treatment with the tumour necrosis factor α inhibitor infliximab in 53 patients (age 47±15 years, 30% women, body mass index (BMI) 29.2±5.5 kg/m2). Echocardiography was preformed after a mean follow-up of 4.9±3.8 years and compared to 99 control subjects (age 47±11 years, 28% women, BMI 29.9±3.9 kg/m2). LV remodelling was assessed from LV relative wall thickness and LV mass index by echocardiography. Results Both psoriasis patients and controls had high prevalence of hypertension (66% vs. 61%, p=0.54) and obesity (34% vs. 33% p=0.94). Psoriasis patients were more likely to be smokers than controls (37% vs. 17%, p=0.005), but other cardiovascular risk factors were similarly distributed. Psoriasis patients had higher LV relative wall thickness (0.38±0.09 vs. 0.34±0.07, p=0.001), but lower LV mass index (36.1±9.6 g/m2.7 vs. 40.3±9.8 g/m2.7, p=0.014), compared to controls. Having psoriasis remained associated with higher LV relative wall thickness (β 0.25, p=0.002) and lower LV mass index (β-0.20, p=0.02) in multivariable analyses after adjustment for age, sex, smoking, hypertension and BMI. In psoriasis patients mean PASI decreased from 16.1±11.5 to 0.8±0.8 during infliximab treatment, p&amp;lt;0.001. Higher PASI at start of treatment was associated with a higher LV relative wall thickness at follow-up (Table), but not with higher LV mass index in univariable analyses. After adjusting for sex, age and hypertension, higher PASI at start of treatment (β 0.36, p=0.006) still predicted greater LV relative wall thickness at follow-up in psoriasis patients (Table). Conclusion Higher psoriasis severity before infliximab treatment predicted presence of adverse LV remodelling after 4.9 years treatment despite nearly complete clinical remission. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): This work was supported by the Western and South-Eastern Regional Health Authorities of Norway and Hjertefondet, University of Bergen.

Development of pulmonary sarcoidosis in Crohn\u2019s disease patient under infliximab biosimilar treatment after long-term original infliximab treatment: a case report and literature review

BackgroundInflammatory bowel disease (IBD) is chronic inflammation of the gastrointestinal tract, although its etiology has largely been unclear. Tumor necrosis factor inhibitors (TNF-I) are effective for the treatment. Recently, biosimilars of TNF-I, such as CT-P13, have been developed and are thought to possess equal efficacy and safety to the original TNF-I. Sarcoidosis is also a systemic granulomatous disease of unknown etiology. In steroid-resistant cases of sarcoidosis, TNF-I have been reported effective for achieving resolution. However, the progression of sarcoidosis due to the TNF-I also has been reported. We herein report a case of pulmonary sarcoidosis with a Crohn’s disease (CD) patient developed after a long period administration (15 years) of TNF-I.Case presentationsA 37-year-old woman with CD who had been diagnosed at 22 years old had been treated with the TNF-I (original infliximab; O-IFX and infliximab biosimilar; IFX-BS). Fifteen years after starting the TNF-I, she developed a fever and right chest pain. Chest computed tomography (CT) revealed clustered small nodules in both lungs and multiple enlarged hilar lymph nodes. Infectious diseases including tuberculosis were negative. Bronchoscopic examination was performed and the biopsy specimens were obtained. A pathological examination demonstrated noncaseating granulomatous lesions and no malignant findings. TNF-I were discontinued because of the possibility of TNF-I-related sarcoidosis. After having discontinued for four months, her symptoms and the lesions had disappeared completely. Fortunately, despite the discontinuation of TNF-I, she has maintained remission.ConclusionsTo our knowledge, this is the first case in which sarcoidosis developed after switching from O-IFX to IFX-BS. To clarify the characteristics of the cases with development of sarcoidosis during administration of TNF-I, we searched PubMed and identified 106 cases. When developing an unexplained fever, asthenia, uveitis and skin lesions in patients with TNF-I treatment, sarcoidosis should be suspected. Once the diagnosis of sarcoidosis due to TNF-I was made, the discontinuation of TNF-I and administration of steroid therapy should be executed promptly. When re-starting TNF-I, another TNF-I should be used for disease control. Clinicians should be aware of the possibility of sarcoidosis in patients under anti-TNF therapy.

Impact of Infliximab Biosimilar CT-P13 Dose and Infusion Interval on Real-World Drug Survival and Effectiveness in Patients with Ankylosing Spondylitis.

CT-P13 is an infliximab biosimilar approved for indications including ankylosing spondylitis (AS); the approved maintenance regimen is 5 mg/kg infused every 6–8 weeks. In clinical practice, modifications to infliximab dose and/or infusion interval can be beneficial to the patient. For CT-P13, real-world data on dose and/or interval adjustment are lacking. This analysis investigated the impact of such treatment pattern changes on effectiveness and drug survival up to five years for adult (≥18 years old) patients with AS in the Korean, real-world, retrospective rheumatoid arthritis and ankylosing spondylitis (RAAS) study. Overall, 337 patients with AS were identified: 219 who initiated infliximab treatment with CT-P13 (‘naïve’) and 118 who switched from reference infliximab to CT-P13 (‘switched’). Overall, 18/235 (7.7%), 110/224 (49.1%), and 101/186 (54.3%) evaluable patients had dose, infusion interval, or combined treatment pattern changes, respectively. More naïve (61.0%) versus switched (42.6%) patients had treatment pattern changes. Overall, Bath Ankylosing Spondylitis Disease Activity Index scores decreased from baseline to week 54, then remained stable; improvements were greater for patients with than without treatment pattern changes. Drug survival did not differ significantly between patients with or without treatment pattern changes. Findings suggest that adjusting dose and/or infusion interval can improve clinical outcomes for CT-P13-treated patients with AS.

Effects of long-term infliximab and tocilizumab treatment on anxiety-like behavior and cognitive function in naive rats.

Circulating cytokines have been proposed to be implicated in the development of mood disorders and cognitive impairment. This study aims to examine the effect of chronic treatment with infliximab, a tumor necrosis factor-alpha (TNF-alpha) inhibitor, and tocilizumab, an antibody against interleukin-6 (IL-6) receptor on anxiety-like behavior and cognitive function. Twenty-eight male, Wistar rats were randomly allocated into negative control, vehicle, infliximab and tocilizumab groups. After 8weeks of intraperitoneal drug administration, rats performed the elevated-plus maze, the elevated-zero maze, the olfactory social memory and the passive avoidance tests. Brain sections at the level of the hippocampus, the amygdala and the prefrontal cortex were histologically examined. Finally, hippocampal and amygdaloid brain-derived neurotrophic factor (BDNF) expression was determined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Infliximab group exhibited a significantly higher number of entries and time spent into the open arms of the mazes, showing a lower level of anxiety. In the olfactory social memory test, tocilizumab significantly increased the ratio of interaction. Both infliximab- and tocilizumab-treated animals had a significantly lower latency time in the passive avoidance test that suggests an improved memory. Histological examination revealed similar morphology and neuronal density between groups. BDNF expression levels were significantly increased in the groups receiving anti-cytokine treatment. Our findings suggest that long-term peripheral TNF-alpha and IL-6 inhibition improves anxiety and cognitive function in rats and leads to an increased BDNF expression in the brain.

Infliximab and Tocilizumab Reduce Anxiety-Like Behaviour and Improve Cognitive Performance in a Juvenile Collagen-Induced Arthritis Rat Model.

Anxiety disorders and cognitive decline are highly prevalent in rheumatic diseases, including Juvenile Idiopathic Arthritis (JIA). In this study, we investigated the effect of long-term treatment with infliximab and tocilizumab on anxiety-like behaviour and cognitive performance in a juvenile collagen-induced arthritis (CIA) rat model. Forty-nine rats with established moderate arthritis were randomly allocated into 7 equal groups: negative control, vehicle, methotrexate, infliximab, tocilizumab, methotrexate + infliximab and methotrexate + tocilizumab groups. Behavioural tests were performed to evaluate anxiety-like behaviour and cognitive function. Neuropathological changes were investigated by histological examination at the level of the hippocampus, the amygdala and the prefrontal cortex. Also, the expression of Brain-Derived Neurotrophic Factor (BDNF), a biomarker associated with neuronal survival and plasticity, was determined in the hippocampus and the amygdala by RT-qPCR. We found that both infliximab and tocilizumab reduced anxiety-like behaviour in the elevated-plus and elevated-zero maze tests. Tocilizumab, also, improved cognitive function in the olfactory social memory and passive avoidance tests. Anti-cytokine treatment reversed the histopathological changes in the brain induced by CIA. BDNF expression was higher in all treatment groups and especially those receiving monoclonal antibodies combined with methotrexate. Our data provide evidence that chronic infliximab and tocilizumab treatment reduces anxiety-like behaviour, improves cognitive function, reverses neuropathological changes and increases central BDNF expression in a juvenile arthritis rat model. These findings may be translated to humans to address behavioural comorbidities associated with JIA.

Real-world safety and efficacy of CT-P13, an infliximab biosimilar, in Japanese rheumatoid arthritis patients naïve to or switched from biologics.

The aim of this post-marketing surveillance (PMS) study is to evaluate the real-world safety and efficacy of CT-P13, the first biosimilar of infliximab (IFX). Japanese patients with rheumatoid arthritis were prospectively registered from November 2014 and followed up for 1 year. Of 794 patients in the analysis set, 318 patients naïve to biological disease-modifying antirheumatic drugs (bDMARDs) showed an immediate decrease in Disease Activity Score in 28 joints with C-reactive protein (DAS28-CRP) and increased remission rate (DAS28-CRP < 2.6). In patients who switched from IFX to CT-P13 for non-medical reasons (n = 374), the low DAS28-CRP due to previous IFX treatment decreased further with continued CT-P13 therapy. As in naïve patients, patients who switched from other bDMARDs, mainly for medical reasons (n = 102), responded similarly to CT-P13. CT-P13 in this PMS and IFX in a previous PMS had similar adverse reaction profiles, although the incidence rate in naïve patients in this current PMS was lower due to earlier initiation of CT-P13 therapy. CT-P13 showed excellent effectiveness as first-line therapy, no clinical difficulties in switching from IFX, and clinical improvement in patients who failed other bDMARDs. CT-P13 could be a cost-effective alternative to IFX in the treatment of rheumatoid arthritis.

Infliximab therapy in parenchymal neuro-Behçet's disease: A single-center experience.

Parenchymal neuro-Behçet's disease involvement is the most serious complication of Behçet's disease, and no sufficient data on its treatment exists. This study aims to investigate the efficacy and safety of infliximab treatment in neuro-Behçet's disease patients with parenchymal involvement. Patients who were diagnosed with Behçet's disease with parenchymal neurological involvement and underwent infliximab treatment for at least 12months were included in the study. Demographic, clinical, and radiological data of the patients were accessed through the electronic database of our hospital. This study comprises 19 patients who were diagnosed with neuro-Behçet's disease and used infliximab: 12 male and 7 female patients. The mean age of the patients was 36.5±11.7years, and the diagnostic age was 26.3±10.8years. The duration of treatment with infliximab was 32.3months (minimum 11, max 79). In the 19 patients receiving infliximab treatment, 11 (58%) patients achieved remission (complete disappearance of neurological symptoms) and 7 (37%) patients achieved disease stability (no new neurological findings); steroid treatments were discontinued for these 18 patients. In addition, only 5 patients were concomitantly taking immunosuppressive drugs with the infliximab. Infliximab was discontinued after the development of a new parenchymal attack in the 9th month of infliximab treatment. In conclusion, parenchymal neurological involvement in Behçet's disease is an important cause of disability, and no sufficient data exists in literature on its treatment. The results of our study suggest that infliximab treatment was effective and safe in neuro-Behçet's disease parenchymal involvement for preventing long-term neurological attacks and discontinuing corticosteroid treatment.

The Selective 5-HT1A Agonist SR57746A Protects Intestinal Epithelial Cells and Enteric Glia Cells and Promotes Mucosal Recovery in Experimental Colitis.

Neurotrophic growth factors can stabilize the intestinal barrier by preventing the apoptosis of enteric glial cells (EGCs) and enterocytes. We reasoned that a selective 5-HT1A receptor agonist may have neuroprotective properties in the gut and that topical application of SR57746A might be an effective treatment strategy in inflammatory bowel disease (IBD). The therapeutic potential of 5-HT1A receptor agonist SR57746A in IBD was evaluated in vitro (nontransformed NCM460 colonic epithelial cells, SW480 colorectal carcinoma cells) and in vivo (murine dextran sulfate sodium [DSS] colitis and CD4-T-cell transfer colitis). In vitro, we analyzed the effect of SR57746A on apoptosis in intestinal epithelial cells (IECs) and EGCs, and upon proliferation, migration, and intracellular signaling in IECs. In vivo, the effect of topical application of SR57746 on disease activity and on histological and endoscopic findings was compared with intraperitoneal infliximab and placebo, respectively. The SR57746A activates PI3-K/AKT- and ERK-signaling in IECs. Depending on ERK- and AKT activation, SR57746A potently prevents apoptosis of IECs without inducing proliferation or migration in these cells. Moreover, SR57746A prevented apoptosis in EGCs in vitro. Topical SR57746A treatment significantly reduced mucosal injury in 2 experimental murine colitis models and was as effective as intraperitoneal infliximab treatment. Treatment with SR57746A prevents inflammatory cell damage and apoptosis in IECs and EGCs, similar to the neurotrophic effects of EGCs on IECs. Topical treatment with SR57746A could be a candidate for clinical evaluation in the treatment of IBD.