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A 26-year-old woman under immunosuppression with infliximab due to Crohn’s disease was referred to the gynaecology emergency room with dispersed and coalescing vesicular lesions on the vulvar region extending to the right lower limb involving S2–S3 dermatome, associated with severe pain. Clinical history, physical examination and serological testing was consistent with herpes zoster infection. The patient was treated with valaciclovir for 14 days and cefradine for 7 days (due to the possibility of secondary bacterial infection). Significant symptomatic improvement was noted after 1 week. The 1-year follow-up was unremarkable. According to our knowledge and review of the literature, this is one of the few cases reported of vulvar herpes zoster, especially related to infliximab.

Introduction and aims: The incidence of paediatric inflammatory bowel disease has increased in recent decades. The aim of the present study was to evaluate the role of proactive and serial monitoring of tumour necrosis factor (TNF) inhibitor levels to maintain clinical remission and mucosal healing in the follow-up of paediatric patients with Crohn disease (CD).Method: Prospective study that included all patients diagnosed with CD and treated with adali-mumab or infliximab between May 2015 and November 2020 who underwent serial and proactive monitoring of TNF inhibitor levels.Results: The study included 30 patients, 21 male (70%). The mean age at diagnosis was 11.3 years (SD, 2.0), the mean age at initiation of TNF inhibitors was 12.6 years (SD, 1.9) with a mean duration of follow-up of 27.1 +/- 9.1 months. Clinical remission was defined as a weighted Pediatric Crohn's Disease Activity Index (wPCDAI) of less than 12.5 and mucosal healing as a Mucosal Inflammation Non-invasive Index (MINI) of less than 8. During the follow-up, patients were in clinical remission in 87.1% of the visits, presented with mild disease in 11.4% and with moderate disease in 1.5%, and mucosal healing was assumed in 83% of the visits. The rates of clinical remission and mucosal healing at 1, 2, and 3 years of follow-up were 83.3%, 95.8%, 92.8%, and 86.7%, 87.5% and 85.7%, respectively. Conclusions: Proactive and serial monitoring of serum TNF inhibitor levels may make it possible for patients to maintain clinical remission and mucosal healing in the maintenance phase, with individualised optimization of the required dosage and minimization of secondary loss of response.(c) 2022 Asociacion Espanola de Pediatria. Published by Elsevier Espana, S.L.U. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Induction of remission in biologic-experienced individuals with moderate to severe Crohn’s disease (CD) can be a challenge. We hereby present a case of CD with secondary non-response to infliximab. Adding methotrexate and switching to ustekinumab plus methotrexate did not stop the inflammatory process. Therefore, combination therapy with two classes of biologics consisting of ustekinumab and adalimumab plus methotrexate was initiated. He achieved clinical remission in 4 weeks and remained on triple therapy for 6 months which was subsequently tailored to adalimumab/methotrexate combination therapy due to insurance restriction on ustekinumab. He remained in remission for the duration of follow-up, 14 months after initiation of triple therapy and 8 months after switching to methotrexate/adalimumab biologic monotherapy. Triple therapy with anti-TNF, IL-12/23 inhibitor and methotrexate could potentially be an option for induction of remission in biologic-experienced individuals with good initial clinical response to anti-TNF agents.

International audience; Paradoxical reaction (PR) and immune reconstitution inflammatory syndrome (IRIS) are common complications of tuberculosis treatment. Corticosteroids are first-line treatment for severe PR or IRIS, particularly neurological. We report four cases of severe PR or IRIS during tuberculosis treatment who required TNF-α antagonists, and identified 20 additional cases through literature review. They were 14 women and 10 men, with a median age of 36 years (interquartile range, 28-52). Twelve were immunocompromised before tuberculosis: untreated HIV infection (n=6), or immunosuppressive treatment (TNF-α antagonists, n=5; tacrolimus, n=1). Tuberculosis was mostly neuromeningeal (n=15), pulmonary (n=10), lymph node (n=6), and miliary (n=6), multi-susceptible in 23 cases. PR or IRIS started after a median time of 6 weeks (IQR, 4-9) following anti-tuberculosis treatment start, and consisted primarily of tuberculomas (n=11), cerebral vasculitis (n=8), and lymphadenitis (n=6). First-line treatment of PR or IRIS was high-dose corticosteroids in 23 cases. TNF-α antagonists were used as salvage treatment in all cases, with infliximab (n=17), thalidomide (n=6), and adalimumab (n=3). All patients improved, but 6 had neurological sequelae, and 4 had TNF-α antagonist-related severe adverse events. TNF-α antagonists are safe and effective as salvage or corticosteroid-sparing therapeutic for severe PR or IRIS during tuberculosis treatment.

Pediatric ulcerative colitis is likely to be more severe than adult ulcerative colitis. Failure to thrive should be considered during therapy. A 10-year-old boy was diagnosed with ulcerative colitis based on his clinical presentation and colonoscopy and biopsy results. The administration of 5-aminosalicylic acid and prednisolone resulted in remission ; however, the symptoms reappeared after the discontinuation of prednisolone. Then, infliximab was administered ; however, the patient was resistant to it and appeared to be dependent on prednisolone. Vedolizumab, a monoclonal antibody against α4β7 integrin, was administered, which resulted in rapid remission. A steady decrease in prednisolone followed, and remission was maintained even after prednisolone discontinuation. Vedolizumab may be effective in pediatric patients with moderate-to-severe refractory ulcerative colitis. Vedolizumab prevents lymphocytes from binding to MAdCAM-1, which is selectively expressed in the gastrointestinal submucosa, leading to the mitigation of the systemic side effects of immunosuppression, such as infections. In Japan, vedolizumab use is not yet approved for use in children, but its effectiveness and safety in children is expected to be investigated in the future.

A 43-year-old Japanese woman with rheumatoid arthritis treated by infliximab and methotrexate for 11 years was admitted for proteinuria and purpura. A kidney biopsy revealed endothelial damage-dominant nephritis with IgA deposition. Infliximab and methotrexate were discontinued, and tocilizumab was started; however, proteinuria persisted. Therefore, tocilizumab was discontinued, and oral prednisolone and methylprednisolone pulse therapy were administered. After 6 months, urinary protein was less than 0.1 g/day, and purpura subsided. To our knowledge, this is the first case of endothelial damage-dominant nephritis related to IgA vasculitis involving the skin and kidney after long-term use of infliximab and methotrexate.

Although biological agents have revolutionized the management of inflammatory bowel diseases (IBDs), a significant proportion of patients show primary non-response or develop secondary loss of response. Therapeutic drug monitoring (TDM) is advocated to maintain the efficacy of biologic agents. Reactive TDM can rationalize the management of primary non-response and secondary loss of response and has shown to be more cost-effective compared with empiric dose escalation. Proactive TDM is shown to increase clinical remission and the durability of the response to a biologic agent. However, the efficacy of proactive and reactive TDM has been questioned in recent studies and meta-analyses. Hence, we need a different approach to TDM, which addresses inflammatory burden, the individual patient, and disease factors. Bayesian approaches, which use population pharmacokinetic models, enable clinicians to make better use of TDM for dose adjustment. With rapid improvement in computer technology, these Bayesian model-based software packages are now available for clinical use. Bayesian dashboard systems allow clinicians to apply model-based dosing to understand an individual's pharmacokinetics and achieve a target serum drug concentration. The model is updated using previously measured drug concentrations and relevant patient factors, such as body weight, C-reactive protein, and serum albumin concentration, to maintain effective drug concentrations in the serum. Initial studies have found utility for the Bayesian approach in induction and maintenance, in adult and pediatric patients, in clinical trials, and in real-life situations for patients with IBD treated with infliximab. This needs confirmation in larger studies. This article reviews the Bayesian approach to therapeutic drug monitoring in IBD.

Background Biologicals, such as anti-tumor necrosis factor (anti-TNF), reduce cardiovascular disease (CVD) in patients with inflammatory rheumatic diseases. Impaired renal function is a known predictor of CVD and elevated in ankylosing spondylitis (AS). Objective To assess the effect of anti-TNF on renal function in patients with AS and whether anti-TNF use is safe in AS patients with pre-existing risk factors for renal decline. Method Biological-naïve consecutive AS patients treated with etanercept or adalimumab were prospectively followed from 2005 to 2014. Renal function was determined by calculation of the estimated glomerular filtration rate (eGFR), estimated with the abbreviated modification of diet in renal disease (MDRD) formula. The effect of anti-TNF on eGFR was analyzed using mixed model analysis. Results 211 AS patients were followed for a median of 156 (36–286) weeks. Overall mixed model analyses showed a significant decrease of eGFR over time (β = − 0.040, p = 0.000), although this association did not remain significant after adjustment for responding to anti-TNF, alcohol use, disease duration, body mass index (BMI), C-reactive protein (CRP), and disease activity (β = − 0.018, p = 0.094). However, patients with pre-existing risk factors for renal decline did have a significant change in eGFR over time (β = − 0.029, p = 0.006). Conclusions We found a significant change in eGFR over time, although this small decrease was not clinically relevant. This study further demonstrates that anti-TNF does not affect renal function in AS patients with and without existing risk factors for renal decline, which means that use of anti-TNF is safe concerning renal function in patients with AS. Key Points• Previous studies showed that biologicals, such as anti-tumor necrosis factor (anti-TNF), reduce cardiovascular disease (CVD) in patients with inflammatory rheumatic diseases, such as ankylosing spondylitis (AS).• Impaired renal function is a known predictor of CVD, and also a known concern for many AS patients.• Use of anti-TNF is safe with regard to renal function in patients with AS.• The effect of anti-TNF on CVD in AS patients does not seem to be mediated by changes in renal function.

In response to the COVID-19 pandemic, the CDC issued guidance advising patients and providers to adopt social distancing practices such as home-based infusions (H-BI).We performed a mixed methods evaluation to summarize perceptions, concerns, and experiences with H-BI among all inflammatory bowel disease patients 18-90 years of age who transitioned to home-based infliximab or vedolizumab infusions between March to July 2020 at a tertiary care center. Semi-structured interviews were conducted and analyzed using an iterative, inductive thematic approach. Baseline characteristics and outcome on safety, COVID-19 transmission, delays in infusions, and H-BI persistence were collected.Of the 57 participants who transitioned to H-BI, 20 (33%) responded. Four major categories and six major themes related to expectations, experience, perceived safety, and logistical factors were identified. Initial perceptions were mixed, however these resolved. One patient developed COVID-19, one patient experienced an adverse event, 12 (21%) patients experienced an infusion delay, and 6 (11%) patients transitioned from H-BI.Despite mixed initial perceptions, respondents had a positive experience with most respondents planning to continue H-BI after the pandemic resolves. Several real-world actionable barriers were identified related to scheduling, communication between stakeholders, and nursing quality. No major safety concerns were identified.

After market exclusivity ends for biologic drugs, biosimilars-follow-on versions made by other manufacturers-can compete with lower prices. Biosimilars have modestly reduced prescription drug spending for US payers, but it is unclear whether patients have directly experienced any savings. In this study we assessed whether availability of biosimilar infliximab was associated with lower out-of-pocket (OOP) costs, using claims from a national data set of commercially insured patients from 2014 to 2018. We used two-part models, adjusting for patient demographics, clinical characteristics, insurance plan type, and calendar month. Compared with the reference biologic, there was no difference in the percentage of biosimilar claims with OOP costs (30.1% vs. 30.8%; adjusted odds ratio (aOR) 0.98, 95% confidence interval (CI), 0.84-1.15, P = 0.84) or the average nonzero OOP cost (median $378 vs. $538, adjusted mean ratio (aMR) 0.97, 95% CI, 0.80-1.18, P = 0.77). The percentage of claims with OOP costs was lower after biosimilar competition (30.7% vs. 35.0%, aOR 0.96, 95% CI, 0.94-0.99, P = 0.003), but average nonzero costs increased (median $534 vs. $520, aMR 1.04, 95% CI, 1.01-1.07, P = 0.004). Thus, early biosimilar infliximab competition did not improve affordability for patients. Policymakers need to better assure that competition in the biosimilar market translates to lower costs for patients using these medications.

Ultrasound is valuable in tight control algorithms for Crohn's disease (CD). However, the correlation between ultrasonographic response and anti-tumor necrosis factor (TNF) drug levels remains unknown. Elucidating this correlation would be helpful in optimizing the use of anti-TNF drugs. Thus, the authors aimed to investigate this correlation.Between June 2020 and June 2021, all patients with CD who completed anti-TNF induction therapy were retrospectively included. Ultrasound was performed at week 0 and week 14, and proactive therapeutic drug monitoring of anti-TNF drugs was performed at week 14. The receiver operating characteristic (ROC) curve was used in the correlation analysis.Ninety-two patients (60 treated with infliximab and 32 with adalimumab) were included. At week 14, an ultrasonographic response was detected in 43 patients. Patients with ultrasonographic response had significantly higher median drug levels (5.9 mcg/mL for infliximab; 18.2 mcg/mL for adalimumab) than those without (0.9 mcg/mL for infliximab, P0.001; 4.8 mcg/mL for adalimumab, P0.001). The ROC curve showed a significant correlation between ultrasonographic response and anti-TNF drug levels (area under the curve = 0.79 for infliximab, P0.001; area under the curve = 0.86 for adalimumab, P0.001). The optimal cut-off values for infliximab and adalimumab correlated with ultrasonographic response were 5.0 and 10.5 mcg/mL, respectively. An incremental increase was observed in ultrasonographic response with higher anti-TNF drug levels.Higher anti-TNF drug levels are associated with an increased likelihood of ultrasonographic response in patients with CD.

Anti-tumor necrosis factor (anti-TNF) monoclonal antibody, infliximab, is the primary therapeutic modality for patients with Crohn's disease (CD) and ulcerative colitis (UC), refractory to conventional therapy. Biosimilars of infliximab have been shown to have equivalent efficacy to originator infliximab. We compared the safety and efficacy of infliximab biosimilar with the originator in Indian patients with inflammatory bowel disease (IBD).Patients with IBD treated with either originator or biosimilar infliximab from January 2005 to October 2020 were included in this retrospective analysis. The safety and efficacy of originator or biosimilar infliximab in inducing and maintaining clinical remission at weeks 14 and 52 for CD and UC were evaluated. Disease activity was estimated at baseline, after induction therapy, after 1 year of treatment, and during 12 months of follow-up.In all, 137 patients (82 CD; 55 UC) were included, of whom 102 were on originator, and 35 patients received biosimilar. In biosimilar group, clinical response and remission rates at weeks 14 and 52 were 84.2%, 58% and 68.4%, 52.6% in CD and 81.2%, 56.2% and 68.7%, 62.5% in UC patients, respectively. Among patients who were on originator, clinical response and remission rates at weeks 14 and 52 were 79.4%, 46% and 57.1%, 43% in CD and 72%, 64.1% and 66.7%, 56.4% in UC patients, respectively. Thirty-three (24.1%) patients experienced adverse events; eighteen developed tuberculosis (TB), of whom 17 received originator and one patient received biosimilar.Infliximab biosimilar is comparable to originator infliximab in terms of safety profile and its efficacy in inducing and maintaining remission in patients with IBD.

Background Infliximab (IFX) has been shown to be effective rescue therapy for hospitalized ulcerative colitis patients failing intravenous (IV) corticosteroids (CS). There is little evidence, however, describing its use in similar hospitalized Crohn's Disease (CD) patients. Study question To determine if IFX is an effective rescue therapy for IV CS resistant CD patients. Study design A retrospective study of inpatients with CD who received IFX as rescue therapy at 2 tertiary care hospitals from January 1, 2006, to December 31, 2016. Records were reviewed for demographics, disease activity, preadmission and inpatient treatment, surgical rates, and 30- and 90-day readmission rates. Measures and Outcomes: Efficacy of IFX as rescue therapy was defined by discharge without surgery and readmission rates. Only patients failing IV CS before IFX were included in the final analysis. Results Forty patients received IFX, of which 17 had failed IV CS. Four patients were receiving outpatient IFX therapy, but still received IV CS during hospitalization before IFX. The mean duration of IV CS therapy before IFX was 6.9 days. Of the 15 patients (88%) who responded to rescue IFX, the median hospital stay following IFX was 3 days (range 3-18 days). Readmission rates were 29% and 47% at 30 and 90 days respectively, without further surgeries noted. Conclusions In our series of hospitalized CD patients failing IV CS, those treated with IFX had low rates of urgent surgery and a generally rapid response to treatment, supporting IFX as an effective rescue therapy. By only including those with prior failure of IV CS, we have likely excluded patients for whom IFX was given in the hospital for reasons other than severe disease. Our results suggest that individuals with severe acute CD flare can be treated with early introduction of IFX, avoiding prolonged CS use, and hospitalization.

Infliximab is an anti-tumour necrosis factor agent used in the treatment of inflammatory bowel disease (IBD), which includes Crohn's disease and ulcerative colitis. While the use of infliximab is well established in the treatment of IBD, there are now four recently FDA-approved infliximab biosimilars that are increasingly used due to their cost-benefit for patients, institutions and payors. In addition, shortening the length of infliximab infusions from 120 min (standard infusion) to 60 min or less (rapid infusion) has been shown to safely provide further cost-benefit while also improving patient convenience. The safety of rapid infusions has been well-established for the infliximab reference product, however, there are limited data available regarding the safety of rapid infusions for infliximab biosimilars. The purpose of this study was to compare the incidence and severity of infusion reactions among patients with IBD receiving rapid infusion of infliximab reference product compared with infliximab biosimilar.This was a retrospective analysis of electronic health record data of patients with a diagnosis of IBD receiving an infliximab reference product or infliximab biosimilar infusion between December 2020 and December 2021. Patient-level variables included demographics, immunomodulator use, IBD-related hospitalization and infliximab trough concentration and antibody levels. Infusion-related variables of interest included total number of infusions, drug, dose, dosing interval, infusion time and use of pre-medications. Infusion-related reactions were defined as safety concerns documented by the administering nurse (anaphylaxis, shortness of breath, hypotension, swelling, rash, pruritus, hives, flushing, chest pain, muscle pain, joint pain, fevers, chills, headache or hypertension) or administration of emergency medications. Fisher's exact test was used to compare reaction rates.A total of 188 patients met inclusion criteria for analysis, and a total of 1124 infusions were administered during the study period. There were no statistically significant differences among any of the pre-specified outcomes. There were no differences in the incidence of infusion reactions among rapid infusion (60 min) infliximab and infliximab biosimilars (p = 0.863). Additionally, there were no differences in the incidence of infusion reactions among standard infusion (120 min) infliximab and infliximab biosimilars (p = 0.993). Finally, there were no differences among the rate of infusion reactions between rapid infusion of infliximab biosimilars and standard infusion of infliximab biosimilars (p = 0.536). Eight patients experienced safety issues, with three patients requiring emergency medications (1.6% of 188 patients).Rapid infusions of infliximab biosimilars were not associated with an increase in the incidence of infusion reactions compared with: rapid infusion of infliximab reference product, standard infusion of infliximab biosimilars, or standard infusion of infliximab reference product. This should reassure clinicians that rapid infusions of infliximab biosimilars are safe in clinical practice.

Ustekinumab (UST), an antibody against the p40 subunit of interleukin-12/23, has been proven to be effective in patients with Crohn's disease (CD). However, large, long-term comparative studies of UST against anti--tumor necrosis factor (TNF) agents are lacking. We compared the effectiveness of anti-TNF agents and UST in CD patients without prior use of biologics.We used a large nationwide anonymized Japanese database containing administrative medical claims data and various related patient data. In a propensity score-matched cohort with similar clinical characteristics, 2-year effectiveness was compared between patients treated with infliximab or adalimumab (anti-TNF group) and those treated with UST (UST group). Primary outcomes were cumulative rates of hospitalization, surgery, and persistence.Among 53 540 CD patients, 7047 were extracted for eligibility, of which 5665 were treated with an anti-TNF agent and 1382 with UST. After propensity score matching, the cumulative hospitalization rates were comparable between anti-TNF and UST groups (P = 0.85; 25.3% vs 26.5% at 1 year, 33.8% vs 39.8% at 2 years). The cumulative surgery rates were also comparable between these groups (P = 0.46; 5.5% vs 5.1% at 1 year, 8.3% vs 8.4% at 2 years). The persistence rate at 1 year was higher in UST group (90.8% vs 92.5%), and that at 2 years was higher in anti-TNF group (81.2% and 74.6%); however, there was no significant difference in the cumulative persistence rate (P = 0.55).Anti-TNF agents and UST appear to have comparable effectiveness for CD patients without prior use of biologics.

Measuring of serum infliximab (IFX) induction concentrations might reduce primary non-response rates in inflammatory bowel diseases (IBD), but optimal target concentrations are unclear. We investigated whether IFX induction concentrations predict short-term endoscopic response at week 12 or treatment persistence at week 52.Sixty-nine IBD patients (Crohn's disease, n=24; ulcerative colitis, n=45) received standard IFX induction of 5 mg/kg bodyweight at weeks 0, 2, and 6. Responders continued maintenance therapy and underwent follow-up until week 52 or treatment discontinuation. We measured IFX concentrations at weeks 2, 6, and 12, and evaluated treatment response around week 12 with endoscopy or with clinical scores and fecal calprotectin. Using the receiver operating characteristic analysis, we determined optimal IFX concentration thresholds associated with treatment response. We further compared IFX induction concentrations between patients persisting on IFX at week 52 and patients discontinuing treatment due to insufficient response.Responders (74%, 51 out of 69 patients) had significantly higher median IFX concentrations than non-responders at weeks 6 (25.06 vs. 19.68 µg/ml; P = 0.04) and 12 (18.03 vs. 10.02 µg/ml; P = 0.03), but not at week 2 (33.12 vs. 34.20 µg/ml; P = 0.97). Optimal IFX concentration thresholds for induction response were 21.33 and 5.13 µg/ml at weeks 6 and 12, respectively. Fifty-three patients continued IFX maintenance therapy until week 52. Induction concentrations failed to predict persistence on IFX therapy at week 52.Higher IFX induction concentrations predict endoscopic short-term response. However, induction concentrations failed to predict long-term persistence on IFX treatment.

Biologic therapy resulted in a significant positive impact on the management of inflammatory bowel disease (IBD) however data on the efficacy and side effects of these therapies in the elderly is scant.To evaluate retrospectively the drug sustainability, effectiveness, and safety of the biologic therapies in the elderly IBD population.Consecutive elderly (≥ 60 years old) IBD patients, treated with biologics [infliximab (IFX), adalimumab (ADAL), vedolizumab (VDZ), ustekinumab (UST)] followed at the McGill University Inflammatory Bowel Diseases Center were included between January 2000 and 2020. Efficacy was measured by clinical scores at 3, 6-9 and 12-18 mo after initiation of the biologic therapy. Patients completing induction therapy were included. Adverse events (AEs) or serious AE were collected during and within three months of stopping of the biologic therapy.We identified a total of 147 elderly patients with IBD treated with biologicals during the study period, including 109 with Crohn's disease and 38 with ulcerative colitis. Patients received the following biologicals: IFX (28.5%), ADAL (38.7%), VDZ (15.6%), UST (17%). The mean duration of biologic treatment was 157.5 (SD = 148) wk. Parallel steroid therapy was given in 34% at baseline, 19% at 3 mo, 16.3% at 6-9 mo and 6.5% at 12-18 mo. The remission rates at 3, 6-9 and 12-18 mo were not significantly different among biological therapies. Kaplan-Meyer analysis did not show statistical difference for drug sustainability (Current biologics were not different regarding drug sustainability, effectiveness, and safety in the elderly IBD population. Therefore, we are not able to suggest a preferred sequencing order among biologicals.

Introduction: Patients with chronic inflammatory rheumatic diseases (CIRD) who receive intravenous therapy requiring hospitalization are likely to be more affected than those with receiving oral therapy during COVID-19 pandemic. We aimed to investigate the effect of the COVID-19 pandemic on adherence to treatment in patients with CIRD receiving intravenous treatments. Methods: We evaluated patients with CIRD who were treated with intravenous immunosuppressive therapy such as rituximab (RTX), cyclophosphamide (CTX), infliximab (IFX), tocilizumab (TCZ) and abatacept (ABA) in our inpatient rheumatology clinic. The patientsʼ medical treatment compliance and clinical follow-up were evaluated. Treatment discontinuation was decided according to postponement of at least one dose and discontinuation of CIRD treatments. Demographics and clinical characteristics were compared between treatment-incompliant (TI) and treatment-compliant (TC) groups. Results: A total of 181 CIRD patients were enrolled. Rheumatoid arthritis was the most common disease requiring intravenous immunosuppressive treatment followed by axial spondyloarthritis and Behçet’s disease. Joint involvement was the most common followed by lung and kidney involvements. Rituximab was the most widely used intravenous immunosuppressive treatment for the CIRD. 34% patients have postponed at least one dose of their intravenous CIRD treatment and 25% discontinued. Fear of COVID-19 and SARS-CoV-2 positivity were the most common reasons. The TI group had a longer disease duration and a higher frequency of inflammatory arthritis than the TC group (p=0.013 and p=0.044, respectively). Conclusions: Fear of COVID-19 and SARS-CoV-2 positivity seemed to be the major reasons for discontinuing/postponing intravenous treatments in CIRD patients. Patients with long disease duration and less systemic involvement may be more prone to discontinuing their treatments.

Inflammatory labyrinthitis is defined as a fluctuant vestibulo-cochlear syndrome associated with an impairment of the blood-labyrinthine barrier (BLB) on delayed FLAIR MRI sequences. Systemic and intratympanic corticosteroids are the gold standard treatment but their effect is frequently insufficient. The objective is here to determine whether infliximab could be of value in the treatment of bilateral inflammatory labyrinthitis. A retrospective monocentric study was conducted between January 2013 and December 2021. All patients included in the study were affected with a bilateral vestibulo-cochlear syndrome associated with bilateral blood-labyrinthine barrier impairment. Patients were administered infliximab at the dose of 5 mg/kg every 6 weeks for 6 months. Audiometry, MRI with delayed FLAIR sequences on the labyrinth, and corticosteroid doses still required were assessed both before and after treatment with infliximab was completed. Pure-tone average (PTA) was the primary outcome. The secondary outcomes were the speech recognition threshold (SRT), the Dizziness Handicap Inventory (DHI) score, and the corticosteroid (CS) dose. A total of nine patients including five men and four women were enrolled in the study. Thirteen ears were analyzed. After a 6-month period of treatment, the mean PTA (54 ± 24 db versus 66 ± 22 db; p = 0.027), SRT (54 ± 37 db versus 66 ± 32 db; p = 0.041) and DHI score (27 ± 15 versus 9 ± 2; p = 0.032) significantly improved. After the 6-month treatment period, the mean CS dose decreased from 38 ± 33 to 6 ± 5 mg/day (p = 0.003). We conclude that infliximab substantially improves the vestibulo-cochlear function in patients with bilateral inflammatory labyrinthitis and could be of value in corticosteroid-dependent cases.

Therapeutic drug monitoring (TDM) is a useful tool for optimising the use of anti-TNFα inhibitors in patients with inflammatory bowel diseases (IBDs). Recently, point-of-care methods for the quantification of drug levels and anti-drug antibodies (ADAs) have been developed to overcome the limitations of conventional enzyme-linked immunoabsorbent assays (ELISAs). Here, we evaluated the performance, interchangeability, and agreement between an automated ELISA-based immunoassay (CHORUS Promonitor) and the lateral flow assay (RIDA®QUICK) for the quantification of infliximab (IFX, n = 65) and adalimumab (ADM, n = 58) plasma levels in IBD patients. Thirty-two samples for IFX and twenty-three samples for ADM that tested positively for the presence of ADAs were also used. Overall, data analysis showed a good agreement of ADM trough concentrations (R2 = 0.75) between the two assays as well as for ADA measurement (K > 0.8). However, IFX levels highlighted a weak correlation (R2 = 0.58) between the two kits, with the RIDA®QUICK assay overestimating IFX plasma values by 30% when compared to the CHORUS Promonitor kit. Results from this study show that the two assays are not quantitatively and qualitatively interchangeable due to substantial discrepancies in some results. Accordingly, the same assay should be used for the longitudinal follow-up of IBD patients.

Therapeutic drug monitoring (TDM) of anti-TNF-α is an important tool in clinical practice for inflammatory diseases. In this study, we have evaluated the performance of several assays for drug and antidrug antibodies (ADA) measurement in the serum. 50 sera from patients treated with infliximab (IFX) and 49 sera from patients treated with adalimumab (ADAL) were monitored with four immunoassays. We have compared Promonitor, i-Track10®, and ez-track1 assays to our gold standard Lisa Tracker® ELISA using Cohen’s kappa, Passing-Bablok, and Bland–Altman analysis. The qualitative analysis evaluated by Cohen’s kappa values found for IFX measurements an “almost perfect” concordance for Promonitor, “moderate” for i-Track10® and “substantial” for ez-Track1. For ADAL, kappa values were “moderate” for all tested methods. For anti-IFX, kappa values were “almost perfect” for Promonitor, “fair” for i-Track10®, and “substantial” for ez-Track1. For anti-ADAL, kappa values were “almost perfect” for all three assays. For quantitative analysis of drug measurements, Pearson’s r values were all above 0.9 and Lin’s concordance coefficients of all immunoassays were around 0.80. Performances of the four evaluated immunoassays were acceptable for TDM based on our laboratory experience. Nevertheless, concordance between the four methods for IFX measurement was not perfect and we recommend the use of the same assay for the follow-up of a given patient. The performances of the four immunoassays evaluated were similar and are acceptable for TDM based on our laboratory experience.

Crohn’s disease (CD) is a chronic inflammation of the digestive tract that significantly impairs patients’ quality of life and well-being. Anti-TNF biologicals revolutionised the treatment of CD, yet many patients do not adequately respond to such therapy. Previous studies have demonstrated a pro-inflammatory pattern in the composition of CD patients’ immunoglobulin G (IgG) N-glycome compared to healthy individuals. Here, we utilised the high-throughput UHPLC method for N-glycan analysis to explore the longitudinal effect of the anti-TNF drugs infliximab and adalimumab on N-glycome composition of total serum IgG in 198 patients, as well as the predictive potential of IgG N-glycans at baseline to detect primary non-responders to anti-TNF therapy in 1315 patients. We discovered a significant decrease in IgG agalactosylation and an increase in monogalactosylation, digalactosylation and sialylation during the 14 weeks of anti-TNF treatment, regardless of therapy response, all of which suggested a diminished inflammatory environment in CD patients treated with anti-TNF therapy. Furthermore, we observed that IgG N-glycome might contain certain information regarding the anti-TNF therapy outcome before initiating the treatment. However, it is impossible to predict future primary non-responders to anti-TNF therapy based solely on IgG N-glycome composition at baseline.

Background: Inflammatory bowel diseases (IBDs), including ulcerative colitis (UC) and Crohn’s disease (CD), are chronic and disabling diseases that affect patient health-related quality of life (HRQoL). IBD patients are frequently exposed to high levels of stress and psychological distress. Biological drugs have been proven to reduce inflammation, hospitalization, and most of the complications that characterize IBDs; their potential contribution to patients’ HRQoL remains to be explored. Aim: To evaluate and compare any change in the HRQoL and markers of inflammation in IBD patients undergoing biological drugs (infliximab or vedolizumab). Material and Methods: A prospective observational study was conducted on a cohort of IBD patients, aged >18 years, who were prescribed with infliximab or vedolizumab. Demographic and disease-related data at baseline were collected. Standard hematological and clinical biochemistry parameters, including C-reactive protein (CRP), white blood cells count (WBC), erythrocytes sedimentation rate (ESR), and α1 and α2 globulins were measured after a 12-h fast at baseline (T0), after 6 weeks (T1), and at 14 weeks (T2) of biological treatment. Steroid use, disease activity as measured by the Harvey–Bradshaw index (HBI) and partial Mayo score (pMS) for the CD and UC, respectively, were also recorded at each timepoint. The Short Form 36 Health Survey (SF-36), Functional Assessment of Chronic Illness Therapy (FACIT-F), and Work Productivity and Activity Impairment–General Health Questionnaire (WPAI:GH) were administered to each patient at baseline, T1, and T2 to address the study aims. Results: Fifty eligible consecutive patients (52% with CD and 48% with UC) were included in the study. Twenty-two patients received infliximab and twenty-eight received vedolizumab. We noted a significant reduction in the CRP, WBC, α1, and α2 globulins from T0 to T2 (p = 0.046, p = 0.002, p = 0.008, and p = 0.002, respectively). Participants showed a significant decrease in steroid administration during the observation period. A significant reduction in the HBI of CD patients at all three timepoints and a similarly significant decrease in the pMS of UC patients from baseline to T1 were recorded. Statistically significant changes were observed in all questionnaires during follow-up as well as an overall improvement in the HRQoL. The interdependence analysis carried out between the biomarkers and the scores of the individual subscales showed a significant correlation between the variation (Δ) of the CRP, Hb, MCH, and MCV with physical and emotional dimensions of the SF-36 and FACIT-F tools; work productivity loss expressed by some of the WPAI:GH items negatively correlated with the ΔWBC and positively with the ΔMCV, ΔMCH, and Δ α1 globulins. A sub-analysis according to the type of treatment showed that patients receiving infliximab experienced a more pronounced improvement in their HRQoL (according to both SF-36 and FACIT-F) compared with patients receiving vedolizumab. Conclusions: Both infliximab and vedolizumab played an important role in contributing to the improvement of the HRQoL in IBD patients by also reducing inflammation and, consequently, steroid use in patients with an active disease. HRQoL, being one of the treatment goals, should also be assessed when taking charge of IBD patients to assess their clinical response and remission. The specific correlation between the biomarkers of inflammation and life’s spheres, as well as their possible role as clinical markers of HRQoL, should be further investigated.

Background. Infliximab (IFX) biosimilar was the first biosimilar approved in Jordan in 2014, with limited evidence of its safety and effectiveness from the Middle East and North Africa (MENA) region. Thus, this study aimed to evaluate the safety and effectiveness of IFX biosimilar in active rheumatoid arthritis (RA) patients over 34 weeks by investigating (1) the adverse events (AEs), serious adverse events (SAEs), and therapy discontinuation and (2) the score changes of the 28-Joint Disease Activity Score (DAS28) and the Health Assessment Questionnaire Disability Index (HAQ-DI). Methods. This multicenter prospective cohort study collected clinical parameters within hospital settings every four weeks. The numbers and percentages of observed AEs and SAEs were informed. The DAS28 utilizing Erythrocyte Sedimentation Rate (ESR), HAQ-DI, and ESR were reported at baseline and 14th and 30th weeks; thus, they were reported as means (SD). Results. A total of 22 RA patients were enrolled and initiated IFX biosimilar, of which nine (41.0%) discontinued the study, but their data were analyzed up to the point of withdrawal. A total of 35 AEs were reported in 14 patients, including two (5.7%) SAEs. None of the participants discontinued treatment due to AEs. The mean (SD) score of DAS28-ESR significantly decreased from 6.55 (1.16) at baseline to 4.59 (1.45) at week 14 ( p < 0.0001 ) and to 4.77 (1.09) at week 30 ( p < 0.0001 ). Similarly, the mean (SD) HAQ-DI score significantly decreased from 0.95 (0.74) at baseline to 0.48 (0.62) at week 14 ( p = 0.008 ) and to 0.71 (0.78) at week 30 ( p = 0.483 ). The mean (SD) value of ESR decreased from 58.75 (26.94) at baseline to 47.92 (33.89) at week 14 ( p = 0.082 ) and to 39.83 (17.38) at week 30 ( p = 0.005 ). Conclusion. IFX biosimilar demonstrated safety and effectiveness in managing RA patients bringing real-world clinical support for biosimilars’ role in rheumatology.

Immunosuppressive therapy is standard for the treatment of inflammatory diseases and for minimizing rejection in transplant patients. However, immunosuppressant drugs are associated with an increased risk of certain cancers. In particular, melanoma is an immunogenic tumor and as such, is strongly influenced by the immune system. We performed this literature review to summarize the effects of commonly used immunomodulating agents on melanoma development, recurrence and progression. We outline the mechanism of action of each drug and discuss the available evidence on its influence on melanoma. Based on existing literature, we recommend avoiding the following agents in patients with a history of invasive melanoma: cyclosporine, sirolimus, natalizumab, IL-6 inhibitors, cyclophosphamide, methotrexate and the tumor necrosis factor-alpha inhibitors infliximab and etanercept. If there are no viable alternative agents, we recommend for these patients to see a dermatologist every 6 months for a thorough skin examination.

To evaluate the efficacy of standard and optimized infliximab induction dosing in attaining corticosteroid (CS) free clinical remission at week 52 and the effect that post-induction trough levels have on long-term outcome.Inflammatory bowel disease (IBD) patients ≤18 years commenced on infliximab between August 1, 2016, and August 1, 2018, from Vancouver, Canada, and Glasgow, Scotland, were included. The Glasgow cohort followed standard induction while the Vancouver cohort undertook induction optimization based on clinical, biomarker, and proactive infliximab trough levels. Baseline characteristics and laboratory values were documented.In total, 140 children were included [median age 14.1 years (interquartile range (IQR) 12.0-16.0)]; 54% male. CS-free clinical remission at week 52 was higher in the optimized group compared to the standard cohort [65/78 (83%) vs. 32/62 (52%), P0.001]. Combined CS-free clinical and biomarker remission (CRP5 mg/L) was also higher in the optimized compared to the standard cohort [65/78 (83%) vs 25/62 (40%), P0.001]. The median post-induction trough level was higher in children who were in CS-free clinical remission at week 52 [3.6 mg/L (1.5-7.1)] vs. those who were not [2.0 mg/L (0.8-4.1), P = 0.04]. The odds of attaining a therapeutic post-induction trough level were almost 4-fold higher in the optimized group than the standard cohort (OR 3.97, 95% CI: 1.89-8.68, P0.001).Standard infliximab induction resulted in less favorable long-term outcomes for pediatric IBD patients. Optimizing induction using clinical, biomarker, and proactive trough levels resulted in higher post-induction trough levels and a greater odds of attaining long-term clinical remission.

© 2022 The Authors. Liver International published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited., Background & aims: No multi-national prospective study of drug-induced liver injury (DILI) has originated in Europe. The design of a prospective European DILI registry, clinical features and short-term outcomes of the cases and controls is reported. Methods: Patients with suspected DILI were prospectively enrolled in the United Kingdom, Spain, Germany, Switzerland, Portugal and Iceland, 2016-2021. DILI cases or non-DILI acute liver injury controls following causality assessment were enrolled. Results: Of 446 adjudicated patients, 246 DILI patients and 100 had acute liver injury due to other aetiologies, mostly autoimmune hepatitis (n = 42) and viral hepatitis (n = 34). DILI patients (mean age 56 years), 57% women, 60% with jaundice and 3.6% had pre-existing liver disease. DILI cases and non-DILI acute liver injury controls had similar demographics, clinical features and outcomes. A single agent was implicated in 199 (81%) DILI cases. Amoxicillin-clavulanate, flucloxacillin, atorvastatin, nivolumab/ipilimumab, infliximab and nitrofurantoin were the most commonly implicated drugs. Multiple conventional medications were implicated in 37 (15%) and 18 cases were caused by herbal and dietary supplements. The most common single causative drug classes were antibacterials (40%) and antineoplastic/immunomodulating agents (27%). Overall, 13 (5.3%) had drug-induced autoimmune-like hepatitis due to nitrofurantoin, methyldopa, infliximab, methylprednisolone and minocycline. Only six (2.4%) DILI patients died (50% had liver-related death), and another six received liver transplantation. Conclusions: In this first multi-national European prospective DILI Registry study, antibacterials were the most commonly implicated medications, whereas antineoplastic and immunomodulating agents accounted for higher proportion of DILI than previously described. This European initiative provides an important opportunity to advance the study on DILI., Set up of the Prospective European Drug-Induced Liver Injury Registry (Pro-Euro-DILI Registry) was supported by an award to RJA and GPA from the EASL Registry Research Grants Programme. JIG and GPA are supported by National Institute of Health Research Nottingham Digestive Diseases Biomedical Research Unit and Nottingham Biomedical Research Centre [BRC-1215-20003]. RJA and MIL receive support from AEMPS. IAA holds a Sara Borrell contract (CD20/00083) funded by ISCiii. CIBERehd is funded by ISCiii. This article is based upon work from COST Action “CA17112 - Prospective European Drug-Induced Liver Injury Network” supported by COST (European Cooperation in Science and Technology). www.cost.eu. All authors of this manuscript are members of COST Action CA17112. The Pro-Euro-DILI is a part of the Transbioline Consortium. The TransBioLine project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 821283. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA.

Despite growing awareness of the nocebo effect, few studies have evaluated the nocebo effect using combined assessment of patient-reported outcome measures (PROMs), clinical indices, and objective biomarkers in inflammatory bowel disease (IBD) patients switching from originator to biosimilar medicines.This study aimed to compare these outcomes across switch and non-switch cohorts to evaluate the nocebo effect in patients with IBD.Parallel cohorts of IBD patients who (1) switched from originator to biosimilar (CT-P13) infliximab and (2) continued biosimilar (CT-P13) infliximab were evaluated over 32 weeks. Clinical disease activity, objective biomarkers and PROMs were assessed at baseline, and weeks 16 and 32 across both cohorts. The PROM of interest was patient-perceived disease activity evaluated using a 0-100 visual analogue scale (VAS) per the IBD-Control Questionnaire.Of 81 patients, 47 switched from originator to biosimilar (CT-P13) infliximab. A negative change from baseline patient-reported disease control was observed across the switch cohort compared with the non-switch cohort at week 16 (mean VAS - 8.21 vs. 1.26; p = 0.03), but not at week 32 (mean VAS - 1.21 vs. 1.38; p = 0.58). Corresponding clinical and objective biomarker assessments over these timepoints were comparable across both cohorts.This study demonstrated a temporary yet discernible nocebo effect in the first 16 weeks following non-medical switching that was not sustained at week 32. Negative patient perceptions may be overcome by a patient-inclusive approach to non-medical switching in conjunction with close clinical follow-up and disease monitoring.

Background: Anti-tumor necrosis factor-α (TNF-α) is a life-changing treatment leading to quality-of-life improvement. Nonetheless, this treatment is associated with a high risk of infection, especially tuberculosis. Objective: Our study aimed to determine the frequency of active tuberculosis in our patients with chronic rheumatic disease and treated with TNF-α. Methods: We conducted a retrospective study including patients with Rheumatoid Arthritis and Spondylarthritis diagnosed according to ACR/EULAR 2009 criteria and ASAS 2010, respectively, and treated with biological agents for at least 6 months. We collected data regarding tuberculosis screening and the occurrence of active tuberculosis during follow-up. Results: 82 patients were included (37 men and 45 women). The mean age was 42 ± 3.4 years. At inclusion, no patient had a medical history of tuberculosis. The diagnosis of latent tuberculosis infection was established in 17 patients (20.7%). Prophylactic treatment was prescribed in all these cases for three months. Two cases (2.4%) of active tuberculosis occurred under biologic (infliximab). It was two severe forms of tuberculosis. The first case had miliary tuberculosis associated with hepatic and peritoneal involvement. The second one had pleural tuberculosis. These two patients received anti-tuberculosis therapy, and the biological treatment was interrupted. Given the high disease activity, the anti-TNF-α was restarted after 3 and 4 months. There was no recurrence of tuberculosis after 7 years of follow-up. Conclusion: The use of TNF-α blockers is associated with a risk of disseminated forms of tuberculosis. Tuberculosis screening, which is recommended before the biological onset, is also necessary under this treatment. Restarting the anti-TNF-α after appropriate treatment of tuberculosis seemed to be safe.

This cross-cohort study aimed to (1) determine a network-based molecular signature that predicts the likelihood of inadequate response to the tumor necrosis factor-ɑ inhibitor (TNFi) therapy, infliximab, in ulcerative colitis (UC) patients, and (2) address biomarker irreproducibility across different cohort studies. Whole-transcriptome microarray data were derived from biopsies of affected colon tissue from 2 cohorts of infliximab-treated UC patients (training N = 24 and validation N = 22). Response was defined as endoscopic and histologic healing at 4-6 weeks and 8 weeks, respectively. From the training cohort, genes with RNA expression that significantly correlated with clinical response outcomes were mapped onto the Human Interactome network map of protein-protein interactions to identify a largest connected component (LCC) of proteins indicative of infliximab response status in UC. Expression levels of transcripts within the LCC were fed into a probabilistic neural network model to generate a classifier that predicts inadequate response to infliximab. A classifier predictive of inadequate response to infliximab was generated and tested in a cross-cohort, blinded fashion; the AUC was 0.83 and inadequate response was predicted with a 100% positive predictive value and 64% sensitivity. Genes separately identified from the 2 cohorts that correlated with response to infliximab appeared distinct but mapped onto the same network region of the Human Interactome, reflecting a common underlying biology of response among UC patients. Cross-cohort validation of a classifier predictive of infliximab response status in UC patients indicates that a molecular signature of non-response to TNFi therapies is present in patients' baseline gene expression data. The goal is to develop a diagnostic test that predicts which patients will have an inadequate response to targeted therapies and define new targets and pathways for therapeutic development.

Cronkhite-Canada syndrome (CCS) is a non-hereditary disorder characterized by non-neoplastic gastrointestinal polyposis and ectodermal changes. While corticosteroids are considered effective, some cases are refractory. A 48-year-old woman presented with diarrhea, anorexia, and epigastralgia lasting for 3 months. She suffered from alopecia and nail dystrophy. Gastrointestinal endoscopy with histological examination confirmed non-neoplastic polyposis from the stomach to the rectum, confirming the diagnosis of CCS. Linked color imaging (LCI) with magnified endoscopy revealed a ribbon-like proliferation of capillaries surrounding the pits in the colonic mucosa. Histologically, the polyps had dilated glands, edematous stroma with inflammatory cell infiltrates and increased capillaries just beneath the epithelium. Immunohistochemical examination confirmed the expression of vascular endothelial growth factor (VEGF), mainly in the superficial epithelial and crypt cells. Steroid therapy was ineffective, and concomitant infliximab therapy provided symptomatic relief. Although symptoms rapidly improved with combination therapy, capillary hyperplasia and slight inflammation persisted in the colon mucosa after polyp resolution. Withdrawal of steroid treatment resulted in flare-ups of symptoms and polyps. Repeated magnified observations at LCI during post-relapse retreatment clearly captured the resolution process of both neovascularization and inflammation. Once the capillary hyperplasia and inflammation subsided, the steroid could be tapered off without relapse. To our knowledge, this is the first report describing the involvement of VEGF-induced angiogenesis and LCI findings in CCS; LCI observations are useful not only in the active phase of CCS, but also in determining subtle capillary hyperplasia and residual inflammation in remission, which may be an indicator of continued treatment.

Recently, the European Respiratory Society (ERS) developed new international guidelines for the treatment of sarcoidosis. This manuscript attempts to distill the ERS Sarcoidosis Treatment Guidelines to a manageable format that can be easily used by practitioners.The ERS Sarcoidosis Treatment Guidelines addressed the treatment of pulmonary, skin, cardiac, neurologic, and sarcoidosis-associated fatigue. Therapeutic drug dosing and treatment algorithms for these conditions were also addressed. Glucocorticoids were the initial recommended treatment for these conditions except for sarcoidosis-associated fatigue where a pulmonary exercise program or a neurostimulant was initially suggested. Because of the risk of glucocorticoid side-effects, the Guidelines recommended early consideration of glucocorticoid-sparing therapy including certain antimetabolites and two specific tumor necrosis alpha antagonists: infliximab and adalimumab.The ERS Sarcoidosis Treatment Guidelines used a rigorous GRADE (Grading of Recommendations, Assessment, Development and Evaluations) methodology to update treatment recommendations for this condition. This manuscript summarizes the Guideline findings in practical terms for clinicians. Suggested algorithms and treatment dosing recommendations are provided.

Infliximab is a mouse/human chimeric IgG1 monoclonal antibody which recognizes the proinflammatory cytokine, tumor necrosis factor α (TNFα), and inhibits receptor interactions, thereby decreasing inflammation and autoimmune response in patients. This monoclonal antibody has been successfully used to treat rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis. However, the high treatment cost limits patient access to this biotherapy. One alternative to this problem is the use of biosimilars. In this work, we describe the stable expression and physicochemical characterization of an anti-TNFα antibody. While infliximab is produced in recombinant murine SP2/0 cells, our anti-TNFα IgG antibody was expressed in recombinant murine NS0 myeloma cells. The best anti-TNFα antibody-expressing clone was selected from three clone candidates based on the stability of IgG expression levels, specific productivity as well as TNFα-binding activity compared to commercial infliximab. Our results indicate that the selected cell clone, culture medium, and fermentation mode allowed for the production of an anti-TNFα antibody with similar characteristics to the reference commercially available product. An optimization of the selected culture medium by metabolomics may increase the volumetric productivity of the process to satisfy the demand for this product. Further experiments should be performed to evaluate the biological properties of this anti-TNFα antibody. KEY POINTS: • An anti-TNFα antibody was produced in NS0 cells using perfusion culture. • A proprietary chemically defined culture medium was used to replace commercially available protein-free medium. • The purified anti-TNFα antibody was comparable to the reference marketed product.

Limited data are currently available regarding anti-tumor necrosis factor (TNF) use and outcomes in very early onset inflammatory bowel disease (VEOIBD) patients. We aimed to assess the long-term outcomes and time to progression to anti-TNF treatment in VEOIBD patients.We retrospectively reviewed IBD patients diagnosed under 6 years of age, between January 2005 and December 2019, from the British-Columbia (BC) Pediatric IBD database. Demographic data, disease characteristics, disease location and severity were documented. Data on anti-TNF treatment at initiation and during follow up including type of biologic, dosing, and response were collected. Kaplan-Meier curves were used to assess the number of years to progression to anti-TNF treatment and the parameters influencing commencement.Eighty-nine patients with VEOIBD were diagnosed during the study period. Median age at diagnosis was 3.8 years [interquartile range (IQR) 2.6-5.1], 45.3% had Crohn disease (CD) and 62.8% were males. Median duration of follow up was 6.39 years (IQR 3.71-10.55). Anti-TNF treatment was started on 39.5% of patients and 7.0% underwent surgery. Rapid progression to biologic treatment was associated with Perianal fistulizing disease or stricturing disease in CD patients ( P = 0.026, P = 0.033, respectively), and disease severity ( P = 0.017) in ulcerative colitis(UC) patients. The median dose of infliximab at 1 year was 10 mg/kg (IQR 7.5-11) and a median dose interval of 4.5 weeks (IQR 4-6). Clinical remission was reported in 61.8% of patients on their first biologic agent.The response rate was higher than previously reported and might be due to higher infliximab dosing with shorter infusion intervals than standard dosing.

Background Budesonide remains the backbone therapy for microscopic colitis [MC]; however, relapses are frequent, and some patients are intolerant or dependent. Anti-TNF therapy is increasingly used to treat these patients, but available evidence is still limited. The aim of this study was to evaluate the effectiveness and safety of anti-TNF therapy in MC patients failing budesonide. Methods In a multicentre retrospective cohort study, budesonide-refractory, -dependent, or -intolerant MC patients treated with anti-TNF agents were included. Clinical remission was defined as fewer than three bowel movements per day, and clinical response was defined as an improvement in stool frequency of at least 50%. Results Fourteen patients were included. Median age was 58.5 years, median disease duration was 25 months, and median follow-up was 29.5 months. Seven patients were treated with infliximab [IFX], and seven with adalimumab. Clinical remission without steroids at 12 weeks was reached in 5/14 [35.7%] patients; all of these received IFX. Clinical response at 12 and 52 weeks, was obtained in 9/14 [64.3%] and 7/14 [50%] patients, respectively. Five patients switched to another anti-TNF agent. When considering both first- and second-line anti-TNF therapies, 7 [50%] patients were in clinical remission at Week 52. Mild to moderate adverse events were reported in six ptients. Two patients were treated with vedolizumab, of whom one had clinical response; one patient treated with ustekinumab had no response. Conclusions This is the first multicentre cohort study showing that half of patients treated with anti-TNF therapy for MC achieved clinical remission in case of budesonide failure.

In recent years, many antibody drugs that play an important role in the pharmacotherapy of several diseases have been developed. Antibody drugs exhibit immunogenicity in vivo leading to the development of antibodies against the antibody drug (anti-drug antibody). Nonetheless, other factors also affect the pharmacokinetics of antibody drugs. Recently, therapeutic drug monitoring (TDM) of infliximab was introduced for personalized medicine. However, the usefulness of TDM in antibody therapy remains unclear. In addition to intervention studies, real-world data analysis is important. Unlike small-molecule drugs, antibody drugs do not have a uniform molecular weight; therefore, using the conventional analysis methods, it is impossible to determine the true pharmacokinetic outcomes of these agents. To analyze structural changes of antibody drugs in the body, new technologies are necessary. In the future, along with the development of new drugs, the establishment of novel analytical methods is essential to facilitate the promotion of personalized medicine.

Since the expiry of the patents on originator anti-TNF agents in Europe, France has authorized the sale of biosimilars. The penetration rate of anti-TNF agents and their biosimilars, and the cost savings driven by the introduction of biosimilars appears to vary widely. This study aimed to describe the market share of anti-TNFs and their biosimilars, and the cost savings generated by the introduction of biosimilars in French hospitals 5 years ago.The pharmaceutical component of the French national uniform hospital discharge data set database (PMSI) was used to study sales of infliximab, etanercept and adalimumab originators and biosimilars, and to estimate cost savings generated by the introduction of biosimilars onto the market, using the historical tariffs of the originators.The penetration rate of anti-TNF biosimilars in France in 76% for infliximab, 74% for etanercept and 77% for adalimumab. In 2020, Inflectra® (41%) was the Remicade® biosimilar with the highest sales volume, while Erelzi® (57%) and Amgevita® (64%) were the most widely sold biosimilars of Enbrel® and Humira® respectively. In terms of cost savings since the launch of biosimilars, overall, for all biosimilars taken together, over the 5-year period, a total of 824 million Euro was saved, in relation to the historical tariffs of the originators.This study shows firstly that the penetration rate of anti-TNF biosimilars in France 5 years after their launch is close to 80%. Secondly, we show that the cost savings generated by the use of biosimilars to anti-TNF agents exceed 820 million Euro over 5 years.

Interleukin-8 (CXCL8) produced in the tumor microenvironment correlates with poor response to checkpoint inhibitors and is known to chemoattract and activate immunosuppressive myeloid leukocytes. In human cancer, IL8 mRNA levels correlate with IL1B and TNF transcripts. Both cytokines induced IL-8 functional expression from a broad variety of human cancer cell lines, primary colon carcinoma organoids, and fresh human tumor explants. Although IL8 is absent from the mouse genome, a similar murine axis in which TNFα and IL-1β upregulate CXCL1 and CXCL2 in tumor cells was revealed. Furthermore, intratumoral injection of TNFα and IL-1β induced IL-8 release from human malignant cells xenografted in immunodeficient mice. In all these cases, the clinically used TNFα blockers infliximab and etanercept or the IL-1β inhibitor anakinra was able to interfere with this pathogenic cytokine loop. Finally, in paired plasma samples of patients with cancer undergoing TNFα blockade with infliximab in a clinical trial, reductions of circulating IL-8 were substantiated.Significance:IL-8 attracts immunosuppressive protumor myeloid cells to the tumor microenvironment, and IL-8 levels correlate with poor response to checkpoint inhibitors. TNFα and IL-1β are identified as major inducers of IL-8 expression on malignant cells across cancer types and models in a manner that is druggable with clinically available neutralizing agents.This article is highlighted in the In This Issue feature, p. 2007

The aim of this study was to analyze the therapeutic results of rheumatoid arthritis (RA) therapy with different biologic disease-modifying antirheumatic drugs (bDMARDs) and the first Janus-activated kinase (JAK) inhibitor in real-life clinical settings. This is a prospective, observational, longitudinal study at the largest rheumatology clinic in Bulgaria conducted during the period 2012-2020. One hundred seventy-four patients were followed up for a period of one year. Patients naïve to biological therapy were consecutively assigned on the available at the time bDMARDs (infliximab, etanercept, adalimumab, rituximab, golimumab, cetrolizumab, tocilizumab) or tofacitinib. We evaluated the disease activity score (DAS28-CRP), Health assessment questionnaires (HAQ) and short form 36 (SF-36) were applied at the initiation of biological therapy, after 6, and 12 months of follow-up. We analyze the changes in the two major subgroups of SF36-physical (MCS) and mental health (PCS). The age and gender distribution were similar between the groups on bDMARDs and tsDMARD. All observed indicators for disease control and QoL improve after the initiation of the biological or JAK inhibitor therapy. We also analyze the effect of therapies on DAS28-CRP, HAQ, SF-36 (PCS, MCS). Dispersion analysis for the effect of therapy measured through DAS28 between 1st and 3rd measurement shows a statically significant difference in between the average effect of therapies (p = 0.005). According to the average change in DAS28 between the first and third measurement the most effective is the golimumab (Median difference = 2.745), followed by rituximab (median = 2.305) and etanercept (median = 2.070). According to the average change in HAQ between first and third the most effective is tofacitinib (median 0.563), followed rituximab and infliximab (median 0.500 for both). Less effective in term of HAQ changes between the first and third measurement appears to be etanercept (median difference 0.250). All differences are statistically significant (p 0.05). Regarding the changes in the QoL measured with SF-36 MCS and PCS there is no statistically significant differences in the average effect of different therapeutic agents. Tofacitinib is non-inferior in comparison to bDMARDs and improve both-disease activity and QoL in patients with RA.

Observational studies are often considered unreliable for evaluating relative treatment effectiveness, but it has been suggested that following target trial protocols could reduce bias. Using observational data from patients with rheumatoid arthritis (RA) in the Swedish Rheumatology Quality Register (SRQ), between 2006 and 2020, we emulated the protocol of the Swedish Farmacotherapy trial (SWEFOT) and compared the results. SWEFOT was a pragmatic trial nested in SRQ, between 2002 and 2005, where methotrexate (MTX) insufficient responders were randomized to receive additional infliximab or sulfasalazine (SSZ) + hydroxychloroquine (HCQ). Patients with RA initiating infliximab (N = 313) or SSZ + HCQ (N = 196) after MTX were identified in SRQ and the Prescribed Drugs Register, mimicking the SWEFOT eligibility criteria. The primary outcome was the proportion of European Alliance of Associations for Rheumatology (EULAR) good responders at 9 months, classifying patients who discontinued treatment as "nonresponders." Through sensitivity analyses, we assessed the impact of relaxing eligibility criteria. The observed proportions reaching EULAR good response were close to those reported in SWEFOT: 39% (vs. 39% in SWEFOT) for infliximab and 28% (vs. 25%) for SSZ + HCQ. The crude observed response ratio was 1.39 (95% confidence interval (CI) 1.04-1.86), increasing to 1.48 (95% CI 0.98-2.24) after confounding adjustment, compared to 1.59 (95% CI 1.10-2.30) in SWEFOT. Results remained close to SWEFOT when relaxing eligibility criteria until allowing prior disease-modifying anti-rheumatic drug (DMARD) use which reduced the observed difference between treatments. By applying a prespecified trial emulation protocol to observational clinical registry data, we could replicate the results of SWEFOT, favoring infliximab over SSZ + HCQ combination therapy at 9 months.

This study explores the potential of gene polymorphisms in the canonical and noncanonical NF-kB signaling pathway as a prediction biomarker of anti-tumor necrosis factor (TNF)α response in Crohn's patients.A total of 109 Greek patients with Crohn's disease (CD) were recruited, and the genotype of TLR2 rs3804099, LTA rs909253, TLR4 rs5030728, and MAP3K14/NIK rs7222094 single nucleotide polymorphisms was investigated for association with response to anti-TNFα therapy. Patient's response to therapy was based on the Crohn's Disease Activity Index, depicting the maximum response within 24 months after initiation of treatment.Seventy-three patients (66.7%) were classified as responders while 36 as nonresponders (33.3%). Comparing allelic frequencies between responders and nonresponders, the presence of TLR2 rs3804099 T allele was associated with nonresponse (P = 0.003), even after stratification by anti-TNFα drugs (infliximab: P = 0.032, adalimumab: P = 0.026). No other association was identified for the rest of the polymorphisms under study. Haplotype analysis further enhanced the association of rs3804099 T allele with loss of response, even though the results were NS (P = 0.073).Our results suggest that polymorphisms in the canonical NF-kB pathway genes could potentially act as a predictive biomarker of anti-TNFα response in CD.

ObjectivesTo define the instruments for the Assessment of SpondyloArthritis international Society–Outcomes Measures in Rheumatology (ASAS-OMERACT) core domain set for axial spondyloarthritis (axSpA).MethodsAn international working group representing key stakeholders selected the core outcome instruments following a predefined process: (1) identifying candidate instruments using a systematic literature review; (2) reducing the list of candidate instruments by the working group, (3) assessing the instruments’ psychometric properties following OMERACT filter 2.2, (4) selection of the core instruments by the working group and (5) voting and endorsement by ASAS.ResultsThe updated core set for axSpA includes seven instruments for the domains that are mandatory for all trials: Ankylosing Spondylitis Disease Activity Score and Numerical Rate Scale (NRS) patient global assessment of disease activity, NRS total back pain, average NRS of duration and severity of morning stiffness, NRS fatigue, Bath Ankylosing Spondylitis Function Index and ASAS Health Index. There are 9 additional instruments considered mandatory for disease-modifying antirheumatic drugs (DMARDs) trials: MRI activity Spondyloarthritis Research Consortium of Canada (SPARCC) sacroiliac joints and SPARCC spine, uveitis, inflammatory bowel disease and psoriasis assessed as recommended by ASAS, 44 swollen joint count, Maastricht Ankylosing Spondylitis Enthesitis Score, dactylitis count and modified Stoke Ankylosing Spondylitis Spinal Score. The imaging outcomes are considered mandatory to be included in at least one trial for a drug tested for properties of DMARD. Furthermore, 11 additional instruments were also endorsed by ASAS, which can be used in axSpA trials on top of the core instruments.ConclusionsThe selection of the instruments for the ASAS-OMERACT core domain set completes the update of the core outcome set for axSpA, which should be used in all trials.

Obesity is variably associated with treatment response in biologic-treated patients with inflammatory bowel diseases (IBD). We evaluated the association between obesity and risk of hospitalization, surgery, or serious infections in patients with IBD in new users of biologic agents in a large, multicenter, electronic health record (EHR)-based cohort (CA-IBD).We created an EHR-based cohort of adult patients with IBD who were new users of biologic agents (tumor necrosis factor [TNF-α] antagonists, ustekinumab, and vedolizumab) between January 1, 2010, and June 30, 2017, from 5 health systems in California. Patients were classified as those with normal body mass index (BMI), overweight, or obese based on the World Health Organization classification. We compared the risk of all-cause hospitalization, IBD-related surgery, or serious infections among patients with obesity vs those overweight vs those with normal BMI, using Cox proportional hazard analyses, adjusting for baseline demographic, disease, and treatment characteristics.Of 3,038 biologic-treated patients with IBD (69% with Crohn's disease and 76% on TNF-α antagonists), 28.2% (n = 858) were overweight, and 13.7% (n = 416) were obese. On a follow-up after biologic initiation, obesity was not associated with an increased risk of hospitalization (adjusted hazard ratio [aHR] vs normal BMI, 0.90; [95% confidence interval, 0.72-1.13]); IBD-related surgery (aHR, 0.62 [0.31-1.22]); or serious infection (aHR, 1.11 [0.73-1.71]). Similar results were observed on stratified analysis by disease phenotype (Crohn's disease vs ulcerative colitis) and index biologic therapy (TNF-α antagonists vs non-TNF-α antagonists).In a multicenter, EHR-based cohort of biologic-treated patients with IBD, obesity was not associated with hospitalization, surgery, or serious infections. Further studies examining the effect of visceral obesity on patient-reported and endoscopic outcomes are needed.

Background: Immune checkpoint inhibitors (ICIs) cause inflammatory immune-related adverse events (irAEs), which are often effectively managed with steroids. Less is known about the best management of irAEs refractory to steroid treatment. Objective: We aimed to assess the efficacy of second-line medications used to treat gastrointestinal (GI) irAEs. Methods: This study was a single-center, retrospective medical record review of patients who received steroids for an ICI GI irAE and at least one dose of infliximab, vedolizumab, or adalimumab for irAE treatment from March 25, 2011 to September 20, 2019, approved by Yale University’s Institutional Review Board. Our primary objective was to assess the efficacy of second-line treatment, measured by the change in the Common Terminology Criteria for Adverse Events Version 5.0 grading system. Results: A total of 39 patients met inclusion criteria. Treatment for steroid-refractory GI irAEs demonstrated a high response rate, with irAE resolution seen in 89.7% of patients. Patients who were specifically initiated on infliximab within 14 days of starting steroids had a higher percent resolution seen in 94.4% of patients. The average time to response, defined as the average days from second-line therapy to reported symptom resolution, was 17 days. Conclusion and relevance: Steroid-refractory GI irAEs can be managed effectively in most patients with immunosuppressive therapy, such as infliximab. Furthermore, initiating second-line immunosuppressive therapy within 14 days of steroid failure resulted in a higher rate of symptom resolution.

Patients with multisystem inflammatory syndrome in children (MIS-C) can develop clinical features resembling Kawasaki disease (KD). A full picture of MIS-C in East Asia which has higher incidence of KD than other regions remains unclear. We report on a 15-year-old Japanese boy with refractory MIS-C who was successfully treated with infliximab. A Japanese boy who was diagnosed with coronavirus disease 2019 (COVID-19) before a month developed MIS-C with fulfilling six principal symptoms of KD. Laboratory data showed extreme hyperferritinemia (11,404 ng/mL), besides lymphopenia and thrombocytopenia. The patient was refractory to initial therapy with intravenous immunoglobulin (IVIG; 2 g/kg), aspirin, and prednisolone. He was therefore administered a second IVIG (2 g/kg) and infliximab (5 mg/kg) on days 7 and 8 from the onset of fever, respectively, which resulted in an improvement of clinical symptoms. Only four Japanese cases with MIS-C were reported and all of them were responsive to IVIG. The hyperferritinemia in this case was distinctive from previously reported MIS-C cases in Japan and other cohorts and may be associated with refractoriness to IVIG therapy. Marked elevation of circulating ferritin levels is known to be induced by tumor necrosis factor-α, which plays a key role in the pathogenesis of both KD and MIS-C. Thus, for MIS-C patients with hyperferritinemia, early intervention with adjunctive infliximab may induce a more rapid resolution of inflammation and improve outcome. Because MIS-C may be heterogeneous with respect to immunopathology, genetic background, clinical phenotypes and response to therapies, optimized treatment strategies according to immunopathogenesis are required.

Subcutaneous infliximab recently received approval for the treatment of various immune-mediated inflammatory diseases in Europe, following pivotal clinical trials in patients with rheumatoid arthritis and inflammatory bowel disease. Subcutaneous infliximab demonstrated an improved pharmacokinetic profile compared with intravenous infliximab: the more stable exposure and increased systemic drug concentrations mean it has been cited as a biobetter. Alongside the pharmacokinetic advantages, potential benefits for efficacy, immunogenicity, and health-related quality-of-life outcomes have been suggested with subcutaneous infliximab. During the coronavirus disease 2019 pandemic, the benefits of subcutaneous over intravenous therapies became apparent: switching from intravenous to subcutaneous infliximab reduced the hospital visit-related healthcare resource burden and potential viral transmission. Clinical advantages observed in pivotal trials are also being seen in the real world. Accumulating experience from four European countries (the UK, Spain, France, and Germany) in patients with rheumatic diseases and inflammatory bowel disease supports clinical trial findings that subcutaneous infliximab is well tolerated, increases serum drug concentrations, and offers maintained or improved efficacy outcomes for patients switching from intravenous infliximab. Initial evidence is emerging with subcutaneous infliximab treatment after intravenous infliximab failure. High patient satisfaction and pharmacoeconomic benefits have also been reported with subcutaneous infliximab. Treatments aligned with patient preferences for the flexibility and convenience of at-home subcutaneous administration could boost adherence and treatment outcomes. Altogether, findings suggest that switching from intravenous to subcutaneous infliximab could be advantageous, and healthcare professionals should be prepared to discuss supporting data as part of shared decision making during patient consultations.The tumor necrosis factor inhibitor infliximab is one treatment option that may be appropriate for patients with immune-mediated inflammatory diseases. Patients may prefer tumor necrosis factor inhibitors administered via the subcutaneous (SC) or intravenous (IV) route, with preferences influencing treatment satisfaction and outcomes. In 2019, CT-P13 SC became the first SC infliximab product to receive regulatory approval in Europe, based on pivotal clinical studies that compared SC infliximab to IV infliximab in patients with rheumatoid arthritis and inflammatory bowel disease. Subcutaneous infliximab is now approved in Europe for the treatment of adults with rheumatoid arthritis, Crohn’s disease, ulcerative colitis, ankylosing spondylitis, psoriatic arthritis, and psoriasis. Patients began to switch from IV to SC infliximab outside clinical trials in March 2020, during the coronavirus disease 2019 pandemic. Switching from IV to SC infliximab allowed patients to self-administer treatment at home rather than attend hospital for infusions, reducing potential hospital-acquired infections and lessening the strain on healthcare systems during the pandemic. Clinical trial evidence and growing real-world experience demonstrate that SC infliximab offers clinical advantages in terms of an improved pharmacokinetic profile and potential efficacy, immunogenicity, and health-related quality-of-life benefits compared with IV infliximab. Patients have also reported increased satisfaction with SC infliximab after switching from IV infliximab. Together with the long-standing flexibility and convenience benefits of SC administration, the clinical advantages of SC infliximab make it a valid therapeutic option for rheumatoid arthritis and inflammatory bowel disease. This warrants discussion with appropriate patients as part of shared treatment decision making.

Burn injury remains a serious cause of morbidity and mortality worldwide. Severity of burns is determined by the percentage of burned area compared to the body surface area, age of patient, and by the depth of skin and soft tissue involvement; these factors determine management as well as prospective outcomes. The pathophysiology of partial- to full-thickness burn conversion remains poorly understood and is associated with a worse overall prognosis. Recent studies have demonstrated that an altered inflammatory response may play a significant role in this conversion and therefore a reduction in early inflammation is crucial to ultimately decreasing burn severity and morbidity. We hypothesize that the application of a microcapillary gelatin-alginate hydrogel loaded with anti-TNF-α (infliximab) monoclonal antibodies to a partial-thickness burn will reduce inflammation within partially burned skin and prevent further progression to a full-thickness burn.Assembly of the microfluidic hydrogels is achieved by embedding microfibers within a hydrogel scaffold composed of a gelatin-alginate blend, which is then soaked in a solution containing anti-TNF-α antibodies for drug loading. 12 young (2-4 months) and 12 old (16 months) mice were given partial thickness burns. The treatment cohort received the anti-TNF-α infused hydrogel with an occlusive dressing and the control cohort only received an occlusive dressing. Mice were euthanized at post-burn day 3 and skin samples were taken. Burn depth was evaluated using Vimentin immunostaining.All mice in the treatment cohort demonstrated decreased conversion of burn from partial to full thickness injury (old = p0.01, young = p0.001) as compared to the control group. Old mice had greater depth of burn than young mice (p0.001). There were greater eosinophils in the treatment cohort for both young and old mice, but it did not reach statistical significance.The application of a novel microcapillary gelatin-alginate hydrogel infused with anti-TNF-α antibody to partial thickness burns in mice showed reduction in partial to full thickness burn secondary progression as compared to controls using this murine model; this promising finding might help decrease the high morbidity and mortality associated with burn injuries.