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The propensity for some monoclonal antibodies (mAbs) to aggregate at physiological and manufacturing pH values can prevent their use as therapeutic molecules or delay time to market. Consequently, developability assessments are essential to select optimum candidates, or inform on mitigation strategies to avoid potential late-stage failures. These studies are typically performed in a range of buffer solutions because factors such as pH can dramatically alter the aggregation propensity of the test mAbs (up to 100-fold in extreme cases). A computational method capable of robustly predicting the aggregation propensity at the pH values of common storage buffers would have substantial value. Here, we describe a mAb aggregation prediction tool (MAPT) that builds on our previously published isotype-dependent, charge-based model of aggregation. We show that the addition of a homology model-derived hydrophobicity descriptor to our electrostatic aggregation model enabled the generation of a robust mAb developability indicator. To contextualize our aggregation scoring system, we analyzed 97 clinical-stage therapeutic mAbs. To further validate our approach, we focused on six mAbs (infliximab, tocilizumab, rituximab, CNTO607, MEDI1912 and MEDI1912_STT) which have been reported to cover a large range of aggregation propensities. The different aggregation propensities of the case study molecules at neutral and slightly acidic pH were correctly predicted, verifying the utility of our computational method.
Successful uptake of biosimilars in rheumatology is limited by lack of real-world evidence regarding effectiveness of biosimilar-to-biosimilar switching. We investigated infliximab biosimilars CT-P13-to-GP1111 switching among patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (AxSpA). Observational cohort study from the DANBIO registry. Patients were classified as originator-naïve or originator-experienced. Retention rates of 1-year GP1111 treatment were explored (Kaplan-Meier). We identified baseline factors (at the time of switch) associated with withdrawal of GP1111 (multivariable Cox-regression analyses with HRs including originator treatment history). Changes in subjective and objective measures of disease activity 4 months before and after the switch were assessed in individual patients. Of 1605 patients (685 RA, 314 PsA and 606 AxSpA, median disease duration was 9 years, 37% in Clinical Disease Activity Index/Ankylosing Spondylitis Disease Activity Score remission), 1171 were originator-naïve. Retention rates at 1-year were 83% (95% CI: 81% to 85%) and 92% (95% CI: 90% to 95%) for the originator-naïve and originator-experienced, respectively. GP1111 retention rates were higher in originator-experienced compared to originator-naïve with RA (HR=0.4 (95% CI: 0.2 to 0.7)) and PsA (HR=0.2 (95% CI: 0.1 to 0.8)), but not significantly for AxSpA: HR=0.6 (95% CI: 0.3 to 1.2). Lower disease activity was associated with higher retention. Changes in disease activity preswitch and postswitch were close to zero. This real-world observational study of more than 1600 patients with inflammatory arthritis showed high 1-year retention following a nationwide infliximab biosimilar-to-biosimilar switch. Retention was higher in originator-experienced and in patients with low disease activity, suggesting outcomes to be affected by patient-related rather than drug-related factors.
A 77-year-old patient with ulcerative colitis (UC) was transferred to our department because of worsening bloody diarrhea and abdominal pain, which was consistent with a UC flare. Two days after admission, she complained of cough and high fever. The polymerase chain reaction (PCR) test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was positive, and a computed tomography showed pneumonia in the left lobe, consistent with coronavirus disease 2019 (COVID-19) pneumonia. However, frequent bloody diarrhea and abdominal pain due to the UC flare persisted; therefore, an additional immunosuppressive agent needed to be considered. We initiated infliximab biosimilar (IFX-BS), and her abdominal symptoms improved. However, they deteriorated after the second IFX-BS infusion. After confirming that the patient was negative for SARS-CoV-2 by PCR, we administered a combination of azathioprine and IFX-BS. The combination treatment improved her intestinal symptoms without worsening COVID-19 pneumonia. She has remained in remission for over a year since her discharge.
Recent studies have emphasized the early use of infliximab (IFX) in pediatric patients with inflammatory bowel disease. Standard dosing of 5 mg/kg/dose may not be sufficient to achieve optimal clinical outcomes. The aim of our study was to compare short-term outcomes with standard dosing of IFX to higher, nonstandard dosing of IFX for induction therapy. Retrospective study of 162 pediatric patients receiving either standard (5-6 mg/kg, n = 90) or nonstandard (>6 mg/kg, n = 72) dosing of IFX during induction was performed. Patient demographics, clinical outcomes, and laboratory data were collected. Need for dose escalation during the first 6 months, combination therapy with immunomodulators, and steroid-free progression were investigated. Clinical remission rates between the 2 groups were significantly different, with patients receiving nonstandard dosing demonstrating higher rates (58% vs 78%; p = 0.012). Use of combination therapy with immunomodulators was significantly different between standard and nonstandard groups (80% vs 48%; p < 0.001). Numeric trend in need for IFX dose escalation in the first 6 months was seen between standard and nonstandard groups (54% vs 39%, respectively; p = 0.087). Post-induction IFX trough concentrations, rates of antibody development, drug discontinuation, and infusion reaction were similar. Nonstandard induction dosing of IFX was associated with higher rates of clinical remission, despite similar rates of serum IFX trough concentrations. There was a numeric trend towards the standard group requiring dose escalation within the first 6 months of therapy. Patients given nonstandard dosing may achieve superior clinical outcomes compared with those on standard dosing.
Patients with various cancers benefit from immune checkpoint inhibitors. However, immune checkpoint inhibitor-induced adverse events have also been reported, such as colitis. Prednisolone is the first-line treatment for immune-related adverse events, but second-line therapy for patients refractory to steroids has not been established. Furthermore, the inflammatory cytokine expression pattern in the intestinal mucosa of patients with steroid-refractory immune-related colitis remains unclear. We present the case of a 48-year-old man diagnosed with immune-related colitis and pancreatitis induced by pembrolizumab for advanced lung cancer. First, we administered 50 mg/day of prednisolone, and the patient's abdominal symptoms improved. However, the pancreatic enzyme levels did not return to normal. Furthermore, the patient's diarrhea worsened and hematochezia appeared at a 40 mg/day prednisolone dose. A mucosal cytokine analysis identified a low interleukin-10 messenger RNA level, which has been associated with a poor response to prednisolone. Thus, we administered 5 mg/kg of infliximab; the patient's diarrhea and hematochezia immediately improved, and the pancreatic enzyme levels returned to normal. Infliximab was administered three times every 2 weeks. After, the patient's colitis and pancreatitis did not recur. To our knowledge, this is the first report demonstrating the effectiveness of infliximab for immune-related colitis and pancreatitis.
Acute severe ulcerative colitis is a rapidly progressive severe form of colitis that can occur in 20-30% patients with ulcerative colitis. Early recognition, hospitalization at centers with experience and expertise and multidisciplinary treatment is the cornerstone of appropriate management of this condition. After excluding infections and other differentials, patients should be started on parenteral corticosteroids to control inflammation. ASUC patients are at high risk for thromboembolic complications and hence DVT prophylaxis is ideally started as soon as possible in the emergency room and continued throughout hospitalization. Objective criteria should be applied to assess improvement and identify patients who are unlikely to improve without second line/rescue therapy as early as 72 hours on steroid therapy. Infliximab and cyclosporine are the most used options for second line therapy and should be administered under direction by gastroenterologists. Disease progression despite aggressive treatment or non-response to second line therapy, complications such as megacolon, perforation, hemorrhage can occur requiring colectomy as a salvage option in those patients.
As the third year of the SARS-CoV-2 pandemic approaches, COVID-19 continues to cause substantial morbidity and mortality due to waning vaccine efficacy and the emergence of new, highly contagious subvariants and better therapies are urgently needed. Hospitalized patients who develop hypoxia due to SARS-CoV-2 infection are typically treated with an antiviral agent, remdesivir, as well as an immunomodulator, dexamethasone, but mortality rates for severe COVID-19 remain unacceptably high. Mounting evidence suggests a second immunomodulator added to the standard of care may benefit some hospitalized patients; however, the optimal treatment remains controversial. On 2 June 2022, the United States National Institutes of Health reported results from a large, randomized placebo-controlled clinical trial known as ACTIV-1. The study found a mortality benefit and substantially improved clinical status for adults hospitalized with COVID-19 who were treated with infliximab, a chimeric monoclonal antibody that binds to and inhibits TNF-α, and is widely used to treat a variety of autoimmune conditions, including rheumatoid arthritis, Crohn's disease, and ulcerative colitis. This manuscript reviews what is known about infliximab as an immunomodulator for patients with COVID-19 and explores how this agent may be used in the future to address the SARS-CoV-2 pandemic.
Infliximab (INF) is intravenously used for the clinical treatment of rheumatoid arthritis. However, it can cause serious side effects, which are mainly associated with systemic exposure and high doses. Here, we developed a modified hydrophobic ion-pairing complexes (INF HIPC) through the sequential introduction of bovine lactoferrin (BLF) and hyaluronic acid (HA) with opposite charges into the INF solution. INF and BLF were found to be not only integrally responsible for the structural integrity of HIPC but also were determined to have respective biological activities by binding human tumor necrosis factor-alpha (hTNF-α) or promoting the proliferation of osteoblasts. The INF HIPC had good stability, high drug-loading efficiency, and long-term retention effects. Whether via knee joint injection or intravenous injection, INF HIPC resulted in lower hTNF-α levels and less cartilage destruction than INFs in the transgenic mouse model. At the same time, INF HIPC could reduce toxicity based on body weight changes in transgenic mice. Our findings provide a simple and promising avenue to develop advanced delivery systems for other antibodies and macromolecules.
Inflammatory bowel disease (IBD) is a condition that affects most of the digestive tract. There is no report of fertility reduction in medically managed IBD women compared with the general population. On the other hand, active IBD can lead to significantly decreased fertility. Over the previous 2 decades, anti-tumor necrosis factor (anti-TNF) has been an effective treatment for managing patients with IBD, increasing the use of infliximab and adalimumab in clinical practice. However, it is unclear which biologics are better for pregnant women with IBD. We conducted a systematic review and meta-analysis for the risk of adverse pregnancy outcomes following treatment with infliximab and adalimumab in women with IBD. Bibliographic databases were retrieved from their inception to July 2022. The results were adverse pregnancy outcomes, including congenital malformations and spontaneous abortion. A total of 8 studies included 527 pregnant women with IBD. Of these, 343 received infliximab, and 184 received adalimumab therapy. Compared to adalimumab, adverse pregnancy outcomes were not increased in infliximab therapy including congenital malformations and spontaneous abortion. Infliximab and adalimumab therapy did not show the difference of risk in adverse pregnancy outcomes in women with IBD. http://www.crd.york.ac.uk/PROSPERO , identifier: CRD 42,021,277,869.
Published data on the safety of biologics other than tumor necrosis factor (TNF) inhibitors during pregnancy are limited. The aim was to detect pharmacovigilance signals for fetal and neonatal adverse drug reactions (ADRs) to biologics taken by pregnant women with autoimmune diseases. We performed a disproportionality analysis of the World Health Organization's VigiBase In the main analysis, the RORs were particularly high for musculoskeletal malformations with anakinra (7.18 [3.50-14.73]), canakinumab (19.54 [12.82-29.79]), and abatacept (5.09 [2.77-9.33]), and for immune system disorders with canakinumab (347.88 [217.9-555.50]) and rituximab (9.27 [2.95-29.15]). After the exclusion of reports with steroids, the ROR was significant for neonatal infections with belimumab (28.49 [5.75-141.25]). We identified possible associations with some adverse fetal and neonatal outcomes, suggesting that vigilance is required when prescribing certain biologics during pregnancy.
There is increasing evidence that proactive monitoring is useful in improving the control of inflammatory bowel disease, although it remains controversial. The aim of this study was to evaluate the efficacy of proactive TDM based on the Bayesian approach to optimise the IFX dose compared with the standard of care dosing in patients with IBD. Retrospective observational cohort of inflammatory bowel disease patients>18 years. Patients were classified into two groups according to the strategy used to optimise the dose of IFX: a standard therapy group (ST-group) with clinically based dose adjustment and therapeutic drug monitoring group (TDM-group), with estimation of pharmacokinetic parameters calculated by Bayesian prediction. A total of 153 patients were included. Of these, 75 were in the TDM-group. Clinical response at week 52 was evaluated in 114 patients. The proportion of patients who achieved clinical remission was higher in the TDM than in the ST-group (80.7% vs 61.4%, respectively, p=0.023). A total of 28 patients (24.6%) met the parameters for the composite variable 'poor clinical outcome' at week 52. The proportion of patients who reached this outcome was lower in the TDM-group than in the ST-group (12.3% vs 36.8%, respectively, p=0.002). Proactive therapeutic drug monitoring using Bayesian approach is associated with higher secondary response and fewer long-term complications.
The aim of our study was to describe the distinct features of inflammatory bowel disease (IBD) in juvenile idiopathic arthritis (JIA) patients and to identify risk factors for its development. Data from the German biologics in paediatric rheumatology registry (Biologika in der Kinderrheumatologie (BiKeR)) collected between 2001 to 2021 were analysed retrospectively. In 5009 JIA patients, 28 developed confirmed IBD before the age of 18 years: 23 (82.1%) with Crohn's disease (CD), 4 (14.3%) with ulcerative colitis (UC) and 1 (3.6%) with IBD-unclassified. The incident rate of IBD during 20 years of observation was 0.56% (0.46% for CD, 0.08% for UC, 0.02% for IBD-U), of whom 20.3% were HLA-B27 positive, 25% had enthesitis-related arthritis and 14.3% psoriatic arthritis. Within 90 days before IBD diagnosis, 82.1% (n=23) received treatment with etanercept (ETA), 39.3% (n=11) NSAID, 17.9% (n=5) systemic corticosteroids, 8 (28.6%) methotrexate (MTX), 14.3% (n=4) sulfasalazine, 10.7% (n=3) leflunomide, and 3.6% (n=1) adalimumab and infliximab, respectively. The incidence of IBD was lower in patients treated with MTX, but higher in patients treated with ETA except if ETA was combined with MTX. Also in patients on leflunomide or sulfasalazine, the IBD incidence was higher. In our JIA cohort, an increased IBD incidence is observed compared to the general population, and the ratio of CD to UC is markedly higher hinting at a distinct phenotype of IBD. Pre-treatment with MTX seems to be protective. Treatment with ETA does not prevent IBD development and JIA patients treated with leflunomide and sulfasalazine may be at an increased risk for IBD development.An infographic is available for this article at: http://links.lww.com/MPG/C985.
Excessive immunosuppression after kidney transplantation (KT) is often encountered in patients undergoing therapy for anti-rejection or autoimmune disease that requires further treatment using immunosuppressive medications (IMs), including biologic agents. We report a novel case wherein a kidney transplant recipient developed severe acute allograft injury and hemorrhagic cystitis at 4.5 years after KT due to adenovirus nephritis after treatment with infliximab for Crohn's disease. The diagnosis was made based on adenovirus immunohistochemistry staining and urine polymerase chain reaction tests. The patient was successfully treated by reducing IMs and administration of immunoglobulin even though allograft function was eventually partially recovered. When new immunosuppressive agents, particularly biologic agents, are initiated for other diseases in addition to maintenance IMs, the following points need to be regarded: (1) pay attention to opportunistic infections even in the late phase of KT, and (2) maintain communication with other specialists who prescribe biologics to ensure appropriate administration of IMs.
To study the association between infliximab trough level (IFX-TL) prior to maintenance treatment and disease outcome in children with Crohn's disease (CD). A retrospective analysis was performed on 35 children with CD who received induction therapy with infliximab (IFX) and the measurement of IFX-TL before maintenance treatment from August 2018 to November 2021. Clinical data and laboratory markers at baseline and before maintenance treatment were collected, and the association between outcome and IFX-TL was analyzed. The clinical remission group, endoscopic remission group, and combined remission group had a significantly higher IFX-TL level than the corresponding non-remission groups ( Among children with CD receiving infliximab induction therapy, the children achieving clinical and endoscopic remission before maintenance treatment tend to have a higher level of IFX-TL. IFX-TL has a certain predictive value for clinical remission.
The implementation of biologic therapy has improved the treatment and clinical course of patients with inflammatory bowel disease since the initial approval of infliximab for Crohn's disease in 1998. However, the efficacy and safety profiles of currently available therapies are still less than optimal in several ways, highlighting the need for novel therapeutic targets. Several new drug classes (Janus kinase inhibitors, anti-integrins, sphingosine-1-phosphate receptor modulators, anti-interleukin-23 antibodies, and stem cell therapies) are currently being studied in Crohn's disease and ulcerative colitis with promising results. This article reviews the current literature and provides an updated overview of the emerging therapies.
Anti-tumor necrosis factor (TNF) antibodies play a major role in treating inflammatory bowel disease (IBD), both in adult and pediatric patients. While there is a large number of studies on efficacy and safety of infliximab in treating children and adolescents with ulcerative colitis (UC), data on adalimumab (ADA) are scarce. Here, we review published case reports, cohort and real-time data, as well as the first randomized trial, ENVISION I, using ADA for treating pediatric UC. Available evidence confirms good efficacy in inducing and maintaining remission in children and adolescents with UC, with even higher response rates compared to adult UC. ENVISION I showed that in UC patients responding to ADA induction therapy, almost half of the patients remained in remission after 52 weeks of therapy on high-dosing ADA (weekly administration). As already well experienced with other biologics, dosing schemes are different between pediatric and adult patients, with children often requiring higher dosing. Further data are required to better understand how to optimize ADA therapy. The present and still-growing evidence places subcutaneous (sc.) anti-TNF-medication as alternative first-line therapy also for pediatric UC. This is also reflected by the preference for sc. medication of adolescent patients allowing less frequent and autonomous drug administration.
Infliximab, a chimeric monoclonal antibody against anti-tumor necrosis factor-α (TNF-α), has revolutionized the management of inflammatory bowel disease. However, a recent nested case-control study showed that anti-TNF-α therapy exposure in patients with autoimmune diseases is associated with an increased risk of inflammatory central nervous system (CNS) events. A 27-year-old man diagnosed with Crohn's disease at 17 years of age was referred to our clinic for suffering with Wernicke's aphasia and the right-hand weakness over two weeks. Nine years of treatment for Crohn's disease with infliximab anti-TNF-α therapy was well tolerated. An initial MRI revealed diffuse leptomeningeal enhancement along the bilateral cerebral sulci without any parenchymal abnormalities. Cerebrospinal fluid (CSF) and serum N-methyl-D-aspartate receptor (NMDAR) antibody testing yielded positive results. Anti-NMDAR encephalitis was diagnosed, and the patient was treated with rituximab. A follow-up brain MRI showed new multiple cerebral lesions in the left insular cortex and subcortical white matter of the left frontal and temporal gyri. Approximately 8 months after symptom onset, the CSF and serum NMDAR antibody converted to negative. Twelve months later, the patient fully recovered from anti-NMDAR encephalitis without any neurological deficits and is currently being treated with the anti-interleukin 12/23 agent ustekinumab for Crohn's disease. This is the first report of not only a patient with infliximab-associated anti-NMDAR encephalitis in Crohn's disease but also of an inflammatory non-demyelinating CNS event during long-term suppression of TNF-α. Our case highlights the need for clinicians to recognize the possibility of a paradoxical autoimmune response occurring with novel biological therapies.
The era of biological therapy has revolutionized in the management of autoimmune rheumatic diseases. There have been conflicting results about the incidence of infections related to these drugs. The purpose of this study was to compare the spectrum and severity of infection between patients on biological disease-modifying antirheumatic drugs (bDMARDs) versus conventional disease-modifying antirheumatic drugs (cDMARDs). This hospital-based prospective observational study was conducted in a tertiary care hospital, and a total 200 patients were enrolled in this study. Patients on either bDMARDs or cDMARDs for at least six weeks presenting with evidence of infection were included. Patients with known immunodeficiency states, multiple comorbidities, and patients on prednisolone >7.5 mg were excluded. Data was expressed as percentage and mean ± SD. Kolmogorov-Smirnov analysis was performed for checking linearity of the data, and analysis of variance (ANOVA) followed by Tukey's HSD test were used to test the significance of difference between more than two parameters in parametric data. Rheumatoid arthritis in 58 patients (29%) were the commonest ones presenting with infections, followed by systemic lupus erythematosus in 37 patients (18.5%). 135 patients (67.5%) were on cDMARDs and 65 patients (32.5%) on bDMARDs. Respiratory tract infection in 47 (34.8%) patients was found to be the commonest infection due to cDMARDs. Incidence of infection was higher with biologics, and types of infection in patients receiving infliximab and etanercept were significantly different from that of cDMARDs. Patients receiving etanercept had higher risk of infections and re-infections, but they were milder compared to cDMARDs. A significantly higher frequency of re-infection was found in patients who had not received vaccination. This study emphasizes that TNF-α inhibitors are significantly associated with higher risk of infections. Patients on etanercept have significantly higher but milder infections as compared to cDMARDs. Vaccination plays a pivotal role in prevention of re-infections.
This study aimed to develop a pH-responsive folic acid-grafted organic/inorganic hybrid nanocomposite system for site-selective oral delivery of therapeutic antibodies. A folic acid-grafted aminoclay (FA-AC) was prepared
Tumor necrosis factor-alpha inhibitor therapy for inflammatory bowel disease may be associated with paradoxical cutaneous adverse events, most commonly psoriasiform eruptions. We present the case of a pediatric female patient with Crohn's disease who developed multiple concurrent cutaneous eruptions while on infliximab treatment, including morphea, psoriasiform dermatitis, and genital lichen sclerosus. Although refractory to skin-directed treatments, all three conditions resolved upon discontinuation of infliximab, supporting their development as a paradoxical reaction to infliximab therapy.
Evaluation of costs and short-term cost-effectiveness of infliximab plus methotrexate (IFX + MTX); triple therapy of hydroxychloquine, sulphasalazine, and methotrexate (TRIPLE); or methotrexate monotherapy (MTX) in patients with new-onset polyarticular juvenile idiopathic arthritis (JIA). In a prospective multicenter study (ACUTE-JIA), costs and health outcomes of 60 randomized patients with new-onset disease-modifying anti-rheumatic drug (DMARD)-naïve polyarticular JIA were analyzed during the first year. A mapping algorithm was used to obtain utility values from Child Health Assessment Questionnaire (CHAQ). Wallace criteriae were used to assess clinically inactive disease (CID). Linear regression with non-parametric bootstrapping was used to adjust imbalances at baseline. Using prices for IFX biosimilar, adjusted annual mean (SD) costs of treatment (€) were 21,164 (4158), 12,136 (5286), and 18,300 (8635) on IFX + MTX, TRIPLE, and MTX, respectively. Incremental cost-effectiveness ratio (ICER) for IFX + MTX as compared with TRIPLE or MTX were 3442 € or 678 € per additional month spent in CID. Mean (SD) quality-adjusted life years (QALYs) for IFX + MTX, TRIPLE and MTX were 0.755 (0.065), 0.725 (0.062), and 0.686 (0.124). ICER for IFX + MTX vs TRIPLE was 294,433 €, and for IFX + MTX vs MTX 31,435 € per QALY gained. In short-term, biosimilar IFX + MTX can be considered cost-effective when compared with MTX alone. TRIPLE was cost-effective when compared with MTX and showed cost advantage when compared with IFX + MTX. Cost per time spent in CID showed similar results than ICER evaluations. This trial was primarily registered with the Ethical Board of Helsinki District University Hospital ( https://www.hus.fi ), clinical trial number 211864, and later with ClinicalTrials.gov, number NCT01015547.
The early outcomes of ulcerative colitis (UC) after rescue therapy with cyclosporine A (CyA) are well known. Published data on the safety of this treatment in perioperative use and data on the long-term prognosis are scarce and are investigated here. All UC patients treated with CyA in Tampere University Hospital between 2009 and 2018 were reviewed from patient records. A total of 182 patients were included with the median follow-up of 3.8 (range 0-13) years. Of all patients, 139 (76%) responded to CyA. A quarter of the responders achieved long-term remission and used thiopurines as maintenance therapy at the end of follow-up. Altogether 83 (46%) needed further enhancement of treatment with corticosteroids (Cs) and 57 (31%) with biologicals or small molecules. Of the nonresponders 27 (55%) were treated surgically within admission to index flare. Infliximab was used as a third-line rescue therapy for 16 patients of whom four benefitted. The overall colectomy rate in this series was 45%. When compared to Cs alone CyA did not increase the risk for severe postoperative complications in patients treated for severe treatment-refractory UC. In conclusion, despite the good initial response to CyA, a large proportion of patients relapsed during long-term follow-up and the colectomy rates remain high. Other therapy attempts after failure of CyA merely postpone surgery in many. We therefore recommend informing patients about the possibility of surgery prior to the initiation of rescue therapy.
Immunomodulators, particularly the thiopurines and to a lesser extent methotrexate, were standard of care for inflammatory bowel diseases, including Crohn's disease and ulcerative colitis, for >40 years. While there has been a renaissance in available therapies with the advent of biologics and small molecules, an impetus remains for the ongoing use of thiopurines and methotrexate. This is particularly true for the maintenance of remission and when used in combination therapy with infliximab to suppress anti-biologic antibodies. This article summarizes the data behind immunomodulator use in Crohn's disease, focusing on the beneficial role these drugs still have while acknowledging their clinical limitations.
TNF-alpha inhibitors have revolutionized the therapeutic care in chronic inflammatory diseases. Several biosimilar products were commercialized at their patent expiry, substantially decreasing the cost of treatment. This longitudinal descriptive study aimed at assessing infliximab, etanercept and adalimumab biosimilar penetration rates using data of the French National Health Data System. A total of 207,118 new or prevalent users from the date of first biosimilar commercialization in France (respectively January 2015, May 2016 and October 2018) were included in the study and followed until September 30, 2021. Biosimilars represented respectively 78%, 46% and 53% of the overall initiations, and 94%, 66% and 60% last year's initiations. A total of 46%, 19% and 17% of originator product prevalent users switched for a biosimilar during the follow-up. Biosimilar penetration rate was much higher for infliximab than for its counterparts, due to its hospital delivery modality. Biosimilar initiation and originator-to-biosimilar switch tended to be observed more in rheumatology than in the other specialties. Biosimilar use was mostly consistent across patient socio-demographic characteristics. Biosimilar initiation rate increased rapidly from their market arrival and originator-to-biosimilar switch rate remained moderate, highlighting the need and usefulness of political action and biosimilar use tracking.
We aimed to predict response to biologics in inflammatory bowel disease (IBD) using computerized image analysis of probe confocal laser endomicroscopy (pCLE) in vivo and assess the binding of fluorescent-labeled biologics ex vivo. Additionally, we investigated genes predictive of anti-tumor necrosis factor (TNF) response. Twenty-nine patients (15 with Crohn's disease [CD], 14 with ulcerative colitis [UC]) underwent colonoscopy with pCLE before and 12 to 14 weeks after starting anti-TNF or anti-integrin α4β7 therapy. Biopsies were taken for fluorescein isothiocyanate-labeled infliximab and vedolizumab staining and gene expression analysis. Computer-aided quantitative image analysis of pCLE was performed. Differentially expressed genes predictive of response were determined and validated in a public cohort. In vivo, vessel tortuosity, crypt morphology, and fluorescein leakage predicted response in UC (area under the receiver-operating characteristic curve [AUROC], 0.93; accuracy 85%, positive predictive value [PPV] 89%; negative predictive value [NPV] 75%) and CD (AUROC, 0.79; accuracy 80%; PPV 75%; NPV 83%) patients. Ex vivo, increased binding of labeled biologic at baseline predicted response in UC (UC) (AUROC, 83%; accuracy 77%; PPV 89%; NPV 50%) but not in Crohn's disease (AUROC 58%). A total of 325 differentially expressed genes distinguished responders from nonresponders, 86 of which fell within the most enriched pathways. A panel including ACTN1, CXCL6, LAMA4, EMILIN1, CRIP2, CXCL13, and MAPKAPK2 showed good prediction of anti-TNF response (AUROC >0.7). Higher mucosal binding of the drug target is associated with response to therapy in UC. In vivo, mucosal and microvascular changes detected by pCLE are associated with response to biologics in inflammatory bowel disease. Anti-TNF-responsive UC patients have a less inflamed and fibrotic state pretreatment. Chemotactic pathways involving CXCL6 or CXCL13 may be novel targets for therapy in nonresponders.
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.
Acute severe ulcerative colitis (ASUC) is a life-threatening medical emergency with considerable morbidity (30% to 40%). Patients with ASUC require hospitalization for prompt medical treatment, and colectomy is considered if medical therapy fails. Corticosteroids remain the primary initial therapy, although one-third of patients do not respond to treatment. Clinical data have indicated that cyclosporine, tacrolimus, and infliximab can be used to treat patients with ASUC who do not respond to intravenous corticosteroids. The effectiveness and safety of sequential therapy have recently been reported; however, the data are not convincing. Importantly, timely decision-making with rescue therapy or surgical treatment is critical to manage ASUC without compromising the health or safety of the patients. In addition, risk stratification and the use of predictive clinical parameters have improved the clinical outcome.of ASUC. Multidisciplinary teams that include inflammatory bowel disease experts, colorectal surgeons, and other medical staff contribute to the better management of patients with ASUC. In this review, we introduce current evidence and present a clinical approach to manage ASUC.
Loss-of-response and adverse events (AE) to biologics have been linked to HLA-DQA105 allele. However, the clinical factors or biologic used may influence treatment duration. Our objective was to evaluate the influence of clinical and therapeutic factors, along with HLA, in biological treatment discontinuation. A retrospective study of consecutive IBD patients treated with biologics between 2007 and 2011 was performed. Main outcome was treatment discontinuation due to primary non-response (PNR), secondary loss of response (SLR) or AE. HLA-DQA1 genotyping was done in all patients. Regression analyses were used to assess risk factors of treatment discontinuation. One hundred fifty patients (61% male) with 312 biologic treatments were included. 147 (47%) were discontinued with a cumulative probability of 30%, 41% and 56% at 1, 2 and 5 years. The use of infliximab (p=0.006) and articular manifestations (p<0.05) were associated with treatment discontinuation. Considering cause of withdrawal, Ulcerative Colitis (UC) had a higher proportion of PNR (HR=4.99; 95% CI=1.71-14.63; p=0.003), SLR was higher if biologics had been indicated due to disease flare (HR=2.32; 95% CI=1.05-5.09; p=0.037) while AE were greater with infliximab (HR=2.46; 95% CI=1.48-4.08; p<0.001) or spondylitis (HR=2.46; 95% CI=1.78-6.89; p<0.001). According to the biological drug, HLA-DQA105 with adalimumab showed more SLR in cases with Crohn's disease (HR=3.49; 95% CI=1.39-8,78; p=0.008) or without concomitant immunomodulator (HR=2.8; 95% CI=1.1-6.93; p=0.026). HLA-DQ A1*05 was relevant in SLR of IBD patients treated with adalimumab without immunosupression. In patients treated with other biologics, clinical factors were more important for treatment interruption, mainly extensive UC or extraintestinal manifestations and having indicated the biologic for flare.
Anticancer immune-checkpoint inhibitors (ICI) can cause immune-related adverse events (irAEs), including interstitial pneumonitis, which is managed chiefly with systemic corticosteroids. When corticosteroids fail, second-line immunosuppressive therapy is indicated. Our objective was to evaluate the prevalence and outcomes of ICI-induced pneumonitis requiring second-line immunosuppressive therapy (IS). We collected data form the REISAMIC pharmacovigilance registry and the multidisciplinary immunological toxicity board at Gustave Roussy (France). No response to steroids was called steroid-refractory pneumonitis and relapse after an initial response was defined as steroid-resistant pneumonitis. Of the 1187 patients screened from the REISAMIC register, 48 (4%) patients had pneumonitis treated with corticosteroids. Five of them (10%) had corticosteroid refractory/resistant disease but only 2 were treated with immunosuppressive therapy. Four additional patients requiring immunosuppressive therapy identified via the immunological toxicity board were included. Immunosuppressive therapy were cyclophosphamide (n=4 pts), infliximab (n=1 pt), intravenous immunoglobulins (n=1 pt). Five of these six patients had corticosteroid-refractory disease and one had corticosteroid-resistant pneumonitis. Five patients had severe pneumonitis (Common Terminology Criteria for Adverse Events grade ≥3) at initial pneumonitis diagnosis. Two months mortality rate in patients treated with IS was 67% (4/6). Among the patients treated with IS, the two patients alive at 5 months were treated with cyclophosphamide. Patients with ICI-pneumonitis treated by steroids received IS in 10% of cases. High mortality at 67% of patients was observed in ICI-pneumonitis after steroid failure. Cyclophosphamide could be a treatment option for pneumonitis after corticosteroid failure that requires further investigations.
Crohn's disease (CD) is a chronic gastrointestinal granulomatous disease. When CD is complicated by abscess formation, the most quality of life of patients were seriously affected, especially those with intestinal fistula, intestinal stenosis or severe disease activity. We present a case of a 20-year-old male with CD associated with intestinal fistula and psoas muscle abscess formation, who was successfully managed by drugs and nutrition without surgery. Surgery is undoubtedly the most effective treatment for CD with abscesses/fistulas. Whereas, for patients sensitive to drug therapy, abscess puncture and drainage could be considered as alternative to surgery, at this time enteral nutrition, antibiotics and immunosuppressants is particularly critical. We suggest that CD patients complicated with abscess formation in clinical, if the infection can be controlled before operation, and the abscess site is convenient for puncture and drainage, who could consider to choose comprehensive treatment like enteral nutrition, antibiotics, continuous local irrigation of the abscess cavity via the catheter and immunosuppressive agents.
To update the evidence on efficacy of DMARDs (disease-modifying antirheumatic drugs) and inform the taskforce of the 2022 update of the European Alliance of Associations for Rheumatology (EULAR) recommendations for management of rheumatoid arthritis (RA). This systematic literature review (SLR) investigated the efficacy of conventional synthetic (cs), biological (b), biosimilar and targeted synthetic (ts)DMARDs in patients with RA. Medline, EMBASE, Cochrane CENTRAL and Web of Science were used to identify all relevant articles published since the previous update in 2019 to 14 January 2022. Of 8969 search results, 169 articles were selected for detailed review and 47 were finally included. Trials investigated the efficacy of csDMARDs, bDMARDs and tsDMARDs, DMARD switching, tapering and trials investigating different treatment strategies. The compounds investigated were csDMARDs (methotrexate (MTX), leflunomide, sulfasalazine, hydroxychloroquine), bDMARDs (abatacept, adalimumab, certolizumab-pegol, denosumab, etanercept, infliximab, levilimab, olokizumab, opineracept, rituximab, sarilumab, tocilizumab) and tsDMARDs (baricitinib, filgotinib, tofacitinib, upadacitinib). The efficacy of csDMARDs+ short-term glucocorticoids in early RA was confirmed and similar to bDMARD+MTX combination therapy. Interleukin-6 pathway inhibition was effective in trials on olokizumab and levilimab. Janus kinase inhibitor (JAKi) was efficacious in different patient populations. After insufficient response to JAKi, patients could respond to TNFi treatment. Tapering of DMARDs was feasible for a proportion of patients, who were able to taper therapy while remaining in low disease activity or remission. The results of this SLR, together with one SLR on safety of DMARD and one on glucocorticoids, informed the taskforce of the 2022 update of the EULAR recommendations for pharmacological management of RA.
This study aimed to evaluate the role of microRNAs (miRNA) as biomarkers of treatment response in rheumatoid arthritis (RA) patients through a systematic review of the literature. The MEDLINE and Embase databases were searched for studies including RA-diagnosed patients treated with disease-modifying antirheumatic drugs (DMARDs) that identify miRNAs as response predictors. Review inclusion criteria were met by 10 studies. The main outcome of the study was the response to treatment, defined according to EULAR criteria. A total of 839 RA patients and 67 healthy donors were included in the selected studies. RA patients presented seropositivity for the rheumatoid factor of 74.7% and anti-citrullinated C-peptide antibodies of 63.6%. After revision, 15 miRNAs were described as treatment response biomarkers for methotrexate, anti-tumour necrosis factor (TNF), and rituximab. Among treatments, methotrexate presented the highest number of predictor miRNAs: miR-16, miR-22, miR-132, miR-146a and miR-155. The most polyvalent miRNAs were miR-146a, predicting response to methotrexate and anti-TNF, and miR-125b, which predicts response to infliximab and rituximab. Our data support the role of miRNAs as biomarkers of treatment response in RA and point to DMARDs modifying the miRNAs expression. Nevertheless, further studies are needed since a meta-analysis that allows definitive conclusions is not possible due to the lack of studies in this field.
To provide an update of the EULAR rheumatoid arthritis (RA) management recommendations addressing the most recent developments in the field. An international task force was formed and solicited three systematic literature research activities on safety and efficacy of disease-modifying antirheumatic drugs (DMARDs) and glucocorticoids (GCs). The new evidence was discussed in light of the last update from 2019. A predefined voting process was applied to each overarching principle and recommendation. Levels of evidence and strengths of recommendation were assigned to and participants finally voted on the level of agreement with each item. The task force agreed on 5 overarching principles and 11 recommendations concerning use of conventional synthetic (cs) DMARDs (methotrexate (MTX), leflunomide, sulfasalazine); GCs; biological (b) DMARDs (tumour necrosis factor inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab including biosimilars), abatacept, rituximab, tocilizumab, sarilumab and targeted synthetic (ts) DMARDs, namely the Janus kinase inhibitors tofacitinib, baricitinib, filgotinib, upadacitinib. Guidance on monotherapy, combination therapy, treatment strategies (treat-to-target) and tapering in sustained clinical remission is provided. Safety aspects, including risk of major cardiovascular events (MACEs) and malignancies, costs and sequencing of b/tsDMARDs were all considered. Initially, MTX plus GCs is recommended and on insufficient response to this therapy within 3-6 months, treatment should be based on stratification according to risk factors; With poor prognostic factors (presence of autoantibodies, high disease activity, early erosions or failure of two csDMARDs), any bDMARD should be added to the csDMARD; after careful consideration of risks of MACEs, malignancies and/or thromboembolic events tsDMARDs may also be considered in this phase. If the first bDMARD (or tsDMARD) fails, any other bDMARD (from another or the same class) or tsDMARD (considering risks) is recommended. With sustained remission, DMARDs may be tapered but should not be stopped. Levels of evidence and levels of agreement were high for most recommendations. These updated EULAR recommendations provide consensus on RA management including safety, effectiveness and cost.
There is limited evidence on within-country discrepancies in biosimilar uptake. This study analyzes differences in timing and diffusion of biosimilar uptake across Portuguese NHS hospitals and explores possible determinants. We analyzed publicly accessible consumption data of originator biologic and biosimilar drugs for adalimumab, etanercept, infliximab, rituximab, and trastuzumab, by hospital and month for the years 2015-2021 ( Academic hospitals were characterized by a quicker uptake of adalimumab and infliximab biosimilars but lower shares for other drugs. A higher total consumption of biologics was related to a lower share of biosimilar uptake. A stronger participation in randomized controlled trials was linked to higher biosimilar shares and quicker uptake, except for rituximab. If all NHS hospitals had biosimilar shares equal to the highest ones, potential annual savings could reach 13.9 million euros. The findings suggest a need for capacity-building on biosimilar prescribing, including for doctors of academic hospitals and those working in settings where high biosimilar use would be expected.
To report a case of frosted branch angiitis presenting in a pediatric patient with unremarkable laboratory work-up apart from SARS-CoV-2 IgG antibodies. Less than four weeks after a SARS-CoV-2 infection, a 10 year-old female presented to the emergency department with severe headache and intermittent fevers. During her hospital admission, the ophthalmology service was consulted for blurry vision. Subsequent eye examination revealed frosted branch angiitis. The patient initially received intravenous corticosteroids but was escalated to plasmapheresis to achieve resolution of her symptoms. Outpatient maintenance therapy consisted of an oral Prednisone taper and Infliximab infusion. This case represents a unique ocular manifestation of COVID-19, as recent SARS-CoV-2 was the sole identifiable cause of the patient's frosted branch angiitis. Additionally, this patient required plasmapheresis to control disease progression.
A 46-year-old man with myelodysplastic syndrome/myeloproliferative neoplasm-unclassifiable underwent myeloablative bone marrow transplantation from an HLA-DR-1-antigen-mismatched related donor while receiving tacrolimus and mycophenolate mofetil (MMF) for graft-versus-host disease (GVHD) prophylaxis. However, grade III acute GVHD of the gut occurred on day 20 and was treated with prednisolone (PSL) and oral beclomethasone dipropionate while continuing MMF. Subsequently, he presented with progressive epigastric pain. Endoscopy demonstrated multiple stomach and duodenal deep ulcers. The ulcers were suspected to be GVHD; thus, the PSL dose was increased and infliximab was administered; however, the ulcers exacerbated, resulting in repeated perforations and hemorrhagic shock. Furthemore, MMF was suspected as the cause of refractory ulcers and was discontinued on day 156, which resolved the ulcers after 6 months. MMF-induced gastrointestinal (GI) injury resembles anti-inflammatory drug-related ulcers and upper and lower GI tract GVHD, respectively. MMF-induced GI injury has been reportedly resolved after discontinuing or reducing the MMF dose. Several reports suggested that refractory upper GI ulcers and rectal sparing colitis were associated with MMF toxicities rather than GVHD in hematopoietic stem cell transplantations. Physicians should be aware that MMF can induce severe GI injury.
This is a case implying a serious infectious complication risk during intensive severe ulcerative colitis treatment. A 26-year-old man developed diarrhea and bloody stool who was diagnosed with ulcerative colitis in 2018. He was managed with 5-aminosalicylic acid, but intolerance reaction resulted in discontinuation of treatment. He relapsed with severe abdominal pain and bloody stools in February 2019. He was referred to our department for intensive therapy. He had been treated with steroids, tacrolimus, granulocyte and monocyte apheresis, infliximab or tofacitinib, which temporarily improved his clinical symptoms. However, his medical condition could not be controlled. Hand-assisted laparoscopic subtotal colectomy was then performed in October 2019. He developed intermittent fever on postoperative day 3. Enhanced computed tomography (CT) revealed multiple deep vein thromboses and pulmonary embolism. Antibiotics and anticoagulation therapy were initiated, but postoperative day 13 CT showed multiple pulmonary cavities containing fluids and air, which were diagnosed as pulmonary abscess. His intermittent fever was over 38.0°C. Severe cough and hemoptysis lasted 3 weeks, the clinical symptoms and laboratory data then gradually improved after the fourth week.
A woman in her 30s was diagnosed with ulcerative colitis (UC) 4 years ago and treated with tacrolimus, azathioprine, and prednisolone 5mg (PSL). Skin ulcers appeared on the right lower leg during the course of treatment, diagnosed as pyoderma gangrenosum (PG). The patient initially improved with an increased PSL and infliximab dose, but then developed multiple skin ulcers and folliculitis throughout her body. She was transferred to our hospital for PG exacerbation treatment. She developed fever after transfer and contrast-enhanced computed tomography showed multiple abscesses in the lungs and kidneys. PSL was decreased and infliximab was discontinued. Antibiotic therapy and granulocyte/monocyte apheresis (GMA) were started. Fever persisted even after antibiotic treatment, and her general condition did not improve. A right renal abscess puncture was performed. Pus was sterile. A sterile abscess associated with PG was suspected. The PSL dose was increased to 1mg/kg and infliximab restarted. Thereafter, the patient's general condition improved, and both lung and renal abscesses contracted. Skin ulcer epithelialization was also observed. Abdominal symptoms were mild during the course of the disease, and colonoscopy showed only a localized ulcerative lesion in the rectum. The patient was later transferred to the department of dermatology at our hospital for PG treatment. Aseptic abscesses are caused by neutrophil infiltration without infection and have been reported to be associated with neutrophilic dermatosis and inflammatory bowel disease. UC-associated aseptic abscess is rare. This is only the sixth case in Japan. Aseptic abscesses can occur in various sites, including subcutaneous and deep organs, but this is the first kidney abscess case. In previous reports, PSL, infliximab, colchicine, and infliximab+GMA were used for aseptic abscesses associated with UC. They all showed abscess reduction. Aseptic abscesses associated with PG should be considered if abscess lesions occur during the course of UC, and a treatment strategy including enhanced immunosuppression should be considered.
Budd-Chiari syndrome (BCS) is considered a rare but serious complication of Behçet's disease (BD). This study was performed to define the prevalence, clinical and biological features, treatment, and clinical course of BSC associated with BD in a Moroccan population. We retrospectively analyzed the medical records of 1578 patients fulfilling the international diagnostic criteria for BD, including those with BSC. Eighteen male and 3 female patients, with a mean age of 36 ± 8.6 years. The inferior vena cava was involved in 81% (n = 17) of cases. All forms of BCS were noted: the chronic form in 52.4% (n = 11), the subacute form in 38% (n = 8), and the fulminant form (2 cases). Ascites was the main clinical sign and was present in 62% of patients (n = 13). Other venous thromboses (superior vena cava and lower limbs) were associated with BSC in 52.4% of patients (n = 11). Arterial involvement was noted in 28.6% (n = 6). Cardiac manifestations were present in 19% (n = 4) of the patients. All the patients received anticoagulants associated with corticosteroids. Immunosuppressants were used in 95% (n = 20). One patient received infliximab. Severe complications were noted in 38% (n = 8) of patients (digestive bleeding, confusion, infections and liver failure). Four patients have died during the study period. BCS in patients with BD is not uncommon and can be life threatening. It is frequently associated with other vascular manifestations that can be difficult to treat, particularly in the presence of pulmonary artery aneurysms. Prognosis improved with the use of immunosuppressants. Biologics can be promising in the early stages.
This study aimed to investigate the effect of infliximab on orthodontic tooth movement in rats. Sixty male Sprague-Dawley rats were randomly divided into two groups: saline group and infliximab group. The two groups of rats received weekly intraperitoneally injection of saline or infliximab (5 mg/kg), respectively. After four weeks of injection, five rats in each group were euthanized and orthodontic appliances were placed in the other twenty-five rats each. On days 1, 3, 7, 14 and 21, five rats from each group were euthanised. Maxillae of all the rats were collected and examined by micro-computed tomography, haematoxylin and eosin staining, tartrate-resistant acid phosphatase staining, and immunohistochemical staining of tumour necrosis factor (TNF)-α, receptor activator of nuclear factor κB ligand (RANKL), receptor activator of nuclear factor κB (RANK), and osteoprotegerin (OPG). All data were analysed with Mann-Whitney test. Infliximab inhibited orthodontic tooth movement and decreased osteoclastogenesis on the compression side during orthodontic tooth movement. The elevated TNF-α level, induced by orthodontic force, was decreased by infliximab. Furthermore, infliximab reduced the expression of RANKL and RANK, while increased the expression of OPG on the compression side. Infliximab inhibits orthodontic tooth movement by reducing levels of TNF-α, RANKL, and RANK, while increasing level of OPG, and decreasing osteoclastogenesis on the compression side of periodontium.
Immune checkpoint inhibitors are widely used in various cancers as a standard treatment. However, while various immune-related adverse events related to immune checkpoint inhibitors have been reported, there are few reports of lower urinary tract symptoms. The patient was a 60-year-old man with primary lung cancer who was receiving long-term nivolumab therapy. He was referred to our department due to the sudden onset of glans penile pain and micturition pain. We suspected non-bacterial cystitis as an immune-related adverse event caused by nivolumab and were able to treat it by administering prednisolone. While his symptoms and findings on cystoscopy recurred during prednisolone therapy, we were able to treat him again by administering an additional dose of infliximab. A few reports have described cases of immune checkpoint inhibitor-induced cystitis for which prednisolone was effective. This report is the first to describe cystitis as a steroid-resistant immune-related adverse event.
Tumor necrosis factor (TNF) inhibitors have been used in the treatment of cardiac sarcoidosis, infliximab being the most commonly used. We have previously reported a case of effective treatment of cardiac sarcoidosis using adalimumab. To describe our experience of using adalimumab in the treatment of cardiac sarcoidosis. We conducted a retrospective study to evaluate patients with cardiac sarcoidosis who received adalimumab treatment at the University of Illinois Health between 2011 and 2022. The outcome was evaluated by assessing safety, tolerability, and ability to taper systemic corticosteroids therapy following initiation of adalimumab. Seven patients met the inclusion criteria. Clinical responses to adalimumab were universally positive. Corticosteroid therapy was discontinued in five patients and the dose was reduced in two patients. Furthermore, adalimumab was well tolerated, and no adverse events were reported. Adalimumab was safe and well-tolerated in seven patients with cardiac sarcoidosis seen at our medical center and exhibited corticosteroid-sparing effects. Our observation further warrants large prospective studies to evaluate the safety and efficacy of adalimumab in the treatment of cardiac sarcoidosis.
In 2020, the European Medicines Agency approved infliximab subcutaneous (SC) for the treatment of inflammatory bowel disease. This new mode of infliximab administration will reduce outpatient visits and costs of intravenous (IV) administration. This article describes a budget impact analysis of introducing infliximab SC to the Big-5 European (E5) market (Germany, France, Italy, Spain and UK) for 5 years, from the healthcare payer's perspective. A prevalence-based budget impact model was developed to examine the financial impact of infliximab SC. "World with" versus "world without" infliximab SC scenarios were compared, including the potential administration costs of IV administration. Introducing infliximab SC in patients with Crohn's disease (CD) for 5 years resulted in cost savings of €42.0 million in the UK, €59.4 million in Germany, and €46.4 million in France and Italy, but increased budget expenditure in Spain by €3.8 million. For ulcerative colitis (UC), cost savings of €42.7 million in the UK, €44.9 million in Germany, €44.3 million in France, and €53.0 million in Italy occurred, but with no savings in Spain for 5 years. Cost-savings per patient was calculated by diving the net budget saving by number of treatment eligible patients. Maximum and minimum saving per patient per year ranged between €38.25 and €575.74 in CD, both from Germany, and €105.06 (France) and €647.25 (Germany) in UC. Healthcare payers in the UK, Germany, France, and Italy, but not in Spain, will make budget savings by using infliximab SC for the treatment of inflammatory bowel disease.
Acute generalized exanthematous pustulosis (AGEP) is a rare dermatological manifestation of the adverse drug reaction that occurs for a varied duration after the receipt of certain drugs. It manifests as an acute onset of generalized exanthematous pustular reaction with an edematous base. It has a characteristic clinical presentation and rapid resolution soon after the removal of the offending drug. The unique histological finding is that of single-cell necrosis of keratinocytes with edema of papillary dermis accompanied by components of vasculitis and/or exocytosis of eosinophils. Management consists of moist antiseptic dressings, topical steroids, infliximab, the use of systemic steroids if needed, and avoiding antibiotics as much as possible. Here, we present a case of AGEP in a setting of usages of antibiotics like vancomycin, cefepime, and ceftriaxone in a patient with cutaneous lymphoma that resolved after withdrawal of the offending antibiotics.
Different classes of medication have been reported in the literature to be associated with an increased risk of gastrointestinal perforation. However, little is known about the risk of drug-induced perforated appendicitis. We analyzed the Food and Drug Administration Adverse Event Reporting System (FAERS), a large national database of reported adverse events associated with post-market FDA-approved medications from January 2011 to October 2021. Patients of any age group with appendiceal perforation were included. Duplicated reports and other anatomical areas of gastrointestinal tract perforation outside the appendix were excluded. During the study period, 474 event cases met inclusion criteria, of which 284 were females. Most reports of perforation occurred in patients 40-49 years ( Findings from the FAERS database highlight the risk of appendiceal perforation in the context of different classes of drugs. Larger pharmacovigilance studies are needed to confirm these observations.
Perianal fistulising Crohn's disease (pfCD) is a disabling phenotype of Crohn's disease (CD) with suboptimal outcomes. We assessed neutrophil extracellular traps (NETs) in perianal fistulas and implicated their roles in pfCD healing. Patients with complex pfCD who developed preplaced seton drainage were recruited during the verified maintenance of remission in CD. Fistula tracts were sampled during definitive surgery plus seton removal. Patient demographics, CD classification, medication strategy, and healing of pfCD were recorded. RNA sequencing was applied for transcriptomic profile analysis. NETs components, including myeloperoxidase (MPO), neutrophil elastase (NE), and citrullinated histone H3 (CitH3), were identified using immunofluorescence. Serum infliximab (IFX), anti-IFX antibodies, and tissue levels of IFX, adalimumab (ADA), MPO and CitH3 were determined using enzyme-linked immunosorbent assays. Peptidyl arginine deiminase IV (PAD4), tumour necrosis factor (TNF)-α, and NE were detected using immunohistochemistry. Gene expression levels of PAD family members were assessed with qPCR. Twenty-one patients were included, 15 of whom adopted IFX as maintenance treatment. RNA-seq revealed difference in neutrophil associated pathways between unhealed and healed fistulas. NETs components (MPO/NE/CitH3) were detectable in the fistulas and were parallel with the PAD4 levels. Eleven of 21 (52%) patients experienced complete healing of the pfCD 108 weeks post-operatively. Fistula NETs were significantly increased in patients with unhealed pfCD. Increased NETs were associated with abundant TNF-α production and the absence of IFX in fistulas. NETs exist in pfCD fistulas, which are associated with unhealed post-operative fistulas in pfCD, suggesting their prognostic roles in pfCD.
Loss of response to infliximab or adalimumab in ulcerative colitis occurs frequently, and dose escalation may aid in regaining clinical benefit. This study aimed to systematically assess the annual loss of response and dose escalation rates for infliximab and adalimumab in ulcerative colitis. A systematic search was conducted from August 1999 to July 2021 for studies reporting loss of response and dose escalation during infliximab and/or adalimumab use in ulcerative colitis patients with primary response. Annual loss of response, dose escalation rates, and clinical benefit after dose escalation were calculated. Subgroup analyses were performed for studies with 1-year follow-up or less. We included 50 unique studies assessing loss of response (infliximab, n = 24; adalimumab, n = 21) or dose escalation (infliximab, n = 21; adalimumab, n = 16). The pooled annual loss of response for infliximab was 10.1% (95% confidence interval [CI], 7.1-14.3) and 13.6% (95% CI, 9.3-19.9) for studies with 1-year follow-up. The pooled annual loss of response for adalimumab was 13.4% (95% CI, 8.2-21.8) and 23.3% (95% CI, 15.4-35.1) for studies with 1-year follow-up. Annual pooled dose escalation rates were 13.8% (95% CI, 8.7-21.7) for infliximab and 21.3% (95% CI, 14.4-31.3) for adalimumab, regaining clinical benefit in 72.4% and 52.3%, respectively. Annual loss of response was 10% for infliximab and 13% for adalimumab, with higher rates during the first year. Annual dose escalation rates were 14% (infliximab) and 21% (adalimumab), with clinical benefit in 72% and 52%, respectively. Uniform definitions are needed to facilitate more robust evaluations. Annual loss of response in ulcerative colitis was 10% for infliximab and 13% for adalimumab, with higher rates during the first year. Annual dose escalation was higher than loss of response, with clinical benefit for 72% (infliximab) and 52% (adalimumab).
Although short-term clinical trials have demonstrated that switching from infliximab (INF) bio-originator to its biosimilar is safe with no significant loss of efficacy, there are limited real-world data comparing their patterns of use and adherence. Using 2015-2018 IBM Marketscan data, we established 4 cohorts of patients with at least one administration or pharmacy claim for INF bio-originator or biosimilar in 2017, including INF naïve biosimilar users, INF prevalent biosimilar users, INF naïve bio-originator users, and INF prevalent bio-originator users, defined according to their prior use of INF from 2015 to their first INF administration in 2017. The proportion of days covered (PDC) was calculated for patients with at least 6, 12, or 18 months of follow-up time. Factors associated with optimal adherence (PDC > 80%) were evaluated using log-binomial models. We identified 96 INF naïve biosimilar users, 223 INF prevalent biosimilar users, 2,149 INF naïve bio-originator users, and 10,970 INF prevalent bio-originator users. At the end of 18 months of follow-up, 64% of INF prevalent bio-originators, 48% of INF naïve biosimilars, 41% of INF naïve bio-originators, and 36% of INF prevalent biosimilars had optimal adherence. Depression, previous hospitalization, and greater use of prior biologics were negatively associated with adherence, whereas IBD diagnoses (referent to RA) and age 55-64 (referent to < 35) were positively associated with high adherence. INF prevalent users had higher adherence in our analyses than INF naïve users. However, further studies with larger sample size are needed to evaluate INF biosimilar users' adherence.
Dosing of tumour necrosis factor-α inhibitors (TNFis) is not personalized causing interindividual variation in serum drug levels; however, dose optimization is not widely implemented. We hypothesized that some patients are overdosed; thus, drug prescription could be reduced by therapeutic drug monitoring (TDM). Independent of disease activity, 239 adults treated for rheumatoid arthritis (n = 99), psoriatic arthritis 15 (n = 48), or spondyloarthritis (n = 92) were recruited for a 48-week prospective, randomized open-label trial. Standard care alone or plus TDM was applied in chronic arthritis patients treated with infliximab (IFX), (n = 81), etanercept (ETN) (n = 79), or adalimumab (ADA) (n = 79). Serum TNFi trough levels assessed at inclusion and every 4 months determined patients within/outside predefined therapeutic intervals, supporting change in prescription or drug switch. The primary endpoint was reduced drug prescription. Compared to standard care, TDM reduced prescribed IFX [-12% (95% confidence interval -20, -3); p = 0.001] and ETN (-15% (-29, 1); p = 0.01], and prolonged the interdosing intervals of ETN [+235% (38, 432); p = 0.02] and ADA [+28% (6, 51); p = 0.04]. Time to drug switch was accelerated (χ2 = 6.03, p = 0.01). No group differences in adverse events, disease activity, or self-reported outcomes were shown, indicating equally sustained remission. TDM reduced prescription of IFX, ETN, and ADA and identified patients benefiting from accelerated drug switch, thereby minimizing treatment failure, risk of toxicity, and unnecessary adverse events.
Biologic drugs have greatly improved treatment outcomes of inflammatory joint diseases, but a substantial proportion of patients either do not respond to treatment or lose response over time. Drug immunogenicity, manifested as the formation of anti-drug antibodies (ADAb), constitute a significant clinical problem. Anti-drug antibodies influence the pharmacokinetics of the drug, are associated with reduced clinical efficacy, and an increased risk of adverse events such as infusion reactions. The prevalence of ADAb differs among drugs and diseases, and the detection of ADAb also depends on the assay format. Most data exist for the tumor necrosis factor-alpha inhibitors infliximab and adalimumab, with a frequency of ADAb that ranges from 10 to 60% across studies. Measurement of ADAb and serum drug concentrations, therapeutic drug monitoring, has been suggested as a strategy to optimize therapy with biologic drugs. Although the recent randomized clinical Norwegian Drug Monitoring (NOR-DRUM) trials show promise towards a personalized medicine prescribing approach by therapeutic drug monitoring, several challenges remain. A plethora of assay formats, with widely differing properties, is currently used for measuring ADAb. Comparing results between different assays and laboratories is difficult, which complicates the development of cut-offs necessary for guidelines and the implementation of ADAb measurements in clinical practice. With the possible exception of infliximab, limited data on clinical relevance and cost effectiveness exist to support therapeutic drug monitoring as a routine clinical strategy to monitor biologic drugs in inflammatory joint diseases. The aim of this review is to provide an overview of the characteristics and prevalence of ADAb, predisposing factors to ADAb formation, commonly used assessment methods, clinical consequences of ADAb, and the potential implications of ADAb assessments for everyday treatment of inflammatory joint diseases.
Immune check-point inhibitors-induced colitis (ICPIs-induced colitis) is one of the immune-related side effects. Steroids and Infliximab are commonly used to treat it. The patients of our report were treated by Vedolizumab. The two patients went to the doctor with bloody stools and were treated by Sintilimab and Camrelizumab, respectively, for their malignant tumors. They were diagnosed as ICPIs-induced colitis based on endoscopic and histologic examination. The original immunotherapy was ceased while the anti-inflammatory therapy was introduced. The patients' colitis symptoms disappeared after the treatment and no recurrence was found during the follow-up period. The unique feature about the case reports is that Vedolizumab combined with short-term corticosteroids had achieved good therapeutic effects. For the symptoms of bloody diarrhea after the ICPIs treatment of cancer, the possibility of ICPIs-induced colitis should be considered. Vedolizumab combined with short-term corticosteroids may be appropriate for the treatment.
Tumor necrosis factor (TNF) inhibitors improved clinical outcomes for patients with psoriasis but are limited by their high cost. There are several biosimilar options approved for the treatment of psoriasis which provides a lower-cost alternative and the potential to increase treatment availability for both biologically naïve and bioexperienced patients. Numerous phase III randomized controlled trials (RCTs) have investigated the effects of switching from biologics to biosimilars; biosimilars had comparable safety and efficacy to their reference products. Real-world evidence may provide complementary information on the expected performance of biosimilars. In this literature review, we analyzed data from real-world studies on switching from biologics for psoriasis to their biosimilars. Effectiveness and safety profiles were comparable when switching from biologics to biosimilars of adalimumab, etanercept, and infliximab. These studies are limited by their sample sizes, duration of follow-up, and single-arm designs without control groups. Based on available real-world evidence, patients may safely and effectively undergo switching to biosimilar therapies for the treatment of psoriasis.
Corticosteroids are a mainstay of the treatment of moderately severe relapses of ulcerative colitis, yet almost 50% of patients do not respond fully to these and risk prolonged steroid use and side effects. There is a lack of clarity about the definitions of steroid resistance, the optimum choice of treatment, and patient and health-care professional treatment preferences. The overall aim of this research was to understand how steroid-resistant ulcerative colitis is managed in adult secondary care and how current practice compares with patient and health-care professional preferences. A mixed-methods study, including an online survey, qualitative interviews and discrete choice experiments. NHS inflammatory bowel disease services in the UK. Adults with ulcerative colitis and health-care professionals treating inflammatory bowel disease. We carried out a survey of health-care professionals ( The survey and the discrete choice experiments with patients and health-care professionals are limited by their relatively small sample sizes. The qualitative studies are subject to selection bias. The timing of the different substudies, both before and during the COVID-19 pandemic, is a potential limitation. We have identified factors influencing treatment decisions for steroid-resistant ulcerative colitis and the characteristics to consider when choosing treatments to evaluate in future randomised controlled trials. The findings may be used to improve discussions between patients and health-care professionals when they review treatment options for steroid-resistant ulcerative colitis. This research highlights the need for consensus work to establish an agreed definition of steroid resistance in ulcerative colitis and a greater understanding of the optimal use of tofacitinib and surgery for this patient group. A randomised controlled trial comparing infliximab with tofacitinib is also recommended. This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Steroids are one of the main treatments for ulcerative colitis; however, steroids work well for only about 50% of people who take them. There are many other treatments that can be given when steroids do not work, but evidence is limited about how these treatments are best used. To carry out better research about the best treatment options and to improve clinical practice in the future, this study aimed to find out how adults with steroid-resistant ulcerative colitis are managed in hospital and why patients and health-care professionals prefer different treatments. The study combined various methods of research, including an online survey of health-care professionals (
Acute pancreatitis (AP), a complex inflammatory disease of the pancreas, is associated with increased morbidity and mortality. Currently, no specific therapies are approved for its treatment, and management is primarily based on supportive care. Despite enhanced understanding of AP pathogenesis, patients remain at significant risk owing to a lack of targeted drug treatments. Therefore, there is an urgent need for effective pharmacological therapeutic measures which may inhibit the early systemic inflammation, thereby preventing subsequent organ failure. This narrative review summarizes the available treatment options for AP and highlights the potential drug classes and pharmacologic therapies including those under clinical development. Although, several therapies targeting different aspects of AP pathogenesis have been investigated, some therapies with promising preclinical activity have been rendered ineffective in clinical trials. Other novel drug classes or molecules including dabigatran (anticoagulant), ulinastatin (protease inhibitor), infliximab (monoclonal antibody), spautin-A41 (autophagy inhibitor), and CM4620-Injectible Emulsion (calcium channel inhibitor) await further clinical assessment. Alternative treatment options using stem cells and nanoparticles are also being explored and may hold promise for AP therapy. However, challenges for exploring targeted treatment approaches include disease complexity, timing of therapeutic intervention, and establishing appropriate clinical endpoints. Understanding the role of specific biomarkers may help in identifying appropriate targets for drug discovery and facilitate determining relevant clinical study endpoints to monitor disease severity and progression, thereby aiding in design of more precise therapies with improved clinical outcomes.
Ulcerative colitis often leads to gastrointestinal bleeding and venous thromboembolism (VTE). At present, there is no clear conclusion about anticoagulant therapy for these patients. Treatment for ulcerative colitis usually includes 5-aminosalicylic acid, corticosteroid, and biologics. Acute ulcerative colitis, usually caused by infection, is usually severe and can be life-threatening. We report the development of VTE in a patient with severe acute ulcerative colitis who experienced gastrointestinal bleeding following hormonal therapy. The patient's indicators suggested that his blood was hypercoagulable and that his prognosis was poor. Patients with ulcerative colitis are prone to form VTE. The use of corticosteroids during treatment increases the risk of thrombus. Anticoagulation strategy for patients with ulcerative colitis after gastrointestinal bleeding is a problem that needs to be discussed.
Many patients with inflammatory bowel disease (IBD) are treated with anti-tumor necrosis factor (TNF) therapies, of which infliximab (IFX) is most commonly used. Loss of response (LOR) to anti-TNF therapy due to immunogenic failure accounts for 20% of subsequent medical intervention and is defined, using a drug sensitive assay, as low or undetectable concentration of drug with high titers of anti-drug antibodies (ADAb). We performed a systematic review to investigate the use of a drug tolerant assay during both induction and maintenance to monitor patients treated with anti-TNFs. After the search on PubMed, 90 publications were reviewed. Most ADAb detection methods are drug sensitive, cannot detect ADAb in the presence of drug, and therefore cannot be used close to drug administration, when the drug concentration is too high. To overcome this major limitation, several drug-tolerant techniques have been developed and will be discussed in this review. Using drug-tolerant assays ADAb against infliximab (IFX) or adalimumab (ADM) can be detected during induction and predict primary non-response or LOR. Drug sensitive assays do not allow detection of ADAb during the induction phase as IFX or ADM concentration is typically high.
The prevention of joint deformity is among the most important treatment goals of psoriatic arthritis. Some biologics disease-modifying antirheumatic drugs (bDMARDs) have been demonstrated to be effective for both the skin and joints, as well as for slowing radiographic progression. However, there has been a lack of direct comparisons of bDMARDs. To evaluate the comparative effects of bDMARDs in preventing radiographic progression in psoriatic arthritis, we conducted a systematic review and network meta-analysis. On March 7 2022, a search for relevant randomized trials was conducted on MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials. Our outcomes included radiographic non-progression, a mean change in the total radiographic score, and adverse events leading to discontinuation (DAE) at week 24. We included 11 trials on 10 bDMARDs, involving 4010 participants. Most bDMARDs were more effective than placebos in achieving radiographic non-progression, including adalimumab (odds ratio (OR) 4.7, 95% confidence interval (CI) 2.66-8.29), etanercept (OR 4.19, 95% CI 1.65-10.61), certolizumab pegol (OR 2.83, 95% CI 1.55-5.2), secukinumab 300 mg (OR 2.63, CI 1.62-4.27), infliximab (OR 2.54, CI 1.13-5.69), ixekizumab (OR 2.22, 95% CI 1.06-4.65), golimumab (OR 2.21, 95% CI 1.24-3.93), and abatacept (OR 1.54, 95% CI 1.03-2.28). A significant reduction in the total radiographic score was found in infliximab (standardized mean difference (SMD) -0.59, 95% CI -0.87, -0.3), etanercept (SMD -0.51, 95% CI -0.78, -0.23), adalimumab (SMD -0.45, 95% CI -0.64, -0.26), ixekizumab (SMD -0.37, 95% CI -0.62, -0.12), secukinumab 300 mg (SMD -0.33, 95% CI -0.50, -0.15), golimumab (SMD -0.33, 95% CI -0.58, -0.09), secukinumab 150 mg (SMD -0.25, 95% CI -0.43, -0.07), certolizumab pegol (SMD -0.23, 95% CI -0.44, -0.03), and ustekinumab (SMD -0.19, 95% CI -0.35, -0.33). No significant differences in DAE were detected between bDMARDs. In conclusion, anti-tumor necrosis factor agents (adalimumab, infliximab, and etanercept) may be preferred for treating psoriatic arthritis for their superiority in preventing radiographic progression.
Ulcerative colitis (UC) is part of the inflammatory bowels diseases, and moderate to severe UC patients can be treated with anti-tumour necrosis α monoclonal antibodies, including infliximab (IFX). Even though treatment of UC patients by IFX has been in place for over a decade, many gaps in modelling of IFX PK in this population remain. This is even more true for acute severe UC (ASUC) patients for which early prediction of IFX pharmacokinetic (PK) could highly improve treatment outcome. Thus, this review aims to compile and analyse published population PK models of IFX in UC and ASUC patients, and to assess the current knowledge on disease activity impact on IFX PK. For this, a semi-systematic literature search was conducted, from which 26 publications including a population PK model analysis of UC patients receiving IFX therapy were selected. Amongst those, only four developed a model specifically for UC patients, and only three populations included severe UC patients. Investigations of disease activity impact on PK were reported in only 4 of the 14 models selected. In addition, the lack of reported model codes and assessment of predictive performance make the use of published models in a clinical setting challenging. Thus, more comprehensive investigation of PK in UC and ASUC is needed as well as more adequate reports on developed models and their evaluation in order to apply them in a clinical setting.
CT-P13 is the first subcutaneous infliximab molecule approved for the management of inflammatory bowel disease (IBD). Compared to intravenous therapy, SC infliximab offers a range of practical, micro- and macroeconomic advantages. Data from the rheumatological literature suggest that subcutaneous CT-P13 may lead to superior disease outcomes in comparison to intravenous infliximab. Existing studies in IBD have focussed on pharmacokinetic comparisons and are inadequately powered to evaluate efficacy and safety differences between the two modes of administration. However, emerging clinical trial and real-world data support comparable clinical, biochemical, endoscopic and safety outcomes between subcutaneous and intravenous infliximab in both luminal Crohn's disease and ulcerative colitis. Across the available data, subcutaneous CT-P13 provides relative pharmacokinetic stability and higher trough drug levels when compared to intravenous administration. The clinical impact of this observation on immunogenicity and treatment persistence is yet to be determined. Trough levels between the two methods of administration should not be compared in isolation as any subcutaneous advantage must be considered in the context of comparable total drug exposure and the theoretical disadvantage of lower peak concentrations compared to intravenous therapy. Furthermore, target drug levels for subcutaneous CT-P13 associated with remission are not known. In this review, we present the available literature surrounding the pharmacokinetics of subcutaneous CT-P13 in the context of therapeutic drug monitoring and highlight the potential significance of these observations on the clinical management of patients with IBD.
Drug persistence reflects an agent's efficacy and safety in routine practice. This study was undertaken to compare the 2-year persistence rates of three biologic disease-modifying antirheumatic drugs (bDMARDs) used to treat rheumatoid arthritis (RA) and to describe their efficacy and safety profiles. This retrospective, observational, single-center study included RA patients who had received at least one intravenous dose of infliximab, abatacept, and/or tocilizumab. Two-year drug persistence was estimated using the Kaplan-Meier method. Efficacy profiles were assessed as changes of Disease-Activity Score-28 (DAS28)-based EULAR-criteria responses. The infliximab, abatacept, and tocilizumab groups included 40, 72, and 93 patients, respectively. Their respective 2-year persistence rates were similar: 55.0%, 45.8%, and 62.4%. Tocilizumab recipients benefited from greater improvement than those given infliximab ( Even if this retrospective work includes different biases (lack of data, recruitment bias, etc.), it highlights that the 2-year persistence rates for infliximab, abatacept, and tocilizumab in daily practice did not differ significantly, thereby confirming the long-term efficacies of these three bDMARDs. However, tocilizumab was associated with more significant DAS28 improvement at 2 years than infliximab and abatacept.
This was a retrospective cohort study aimed at identifying parameters measured at diagnosis of pediatric IBD to predict subsequent biologic therapy, as an equivalent to an unfavorable clinical course. Identification of predictors of poor outcomes is an important issue in current ECCO guidelines on pIBD. The study population consisted of 119 children with Crohn's disease and 112 with ulcerative colitis, diagnosed and monitored for at least 1 year from 2009-2019. The population was divided into the study groups separately: 39 children with CD and 14 with UC who received biologics before the age of 18 y compared to 80 with CD and 98 with UC who did not. The combined analysis of 53 biologic therapy recipients vs. 178 non-recipients with IBD was also conducted. Logistic regression tests (OR, RR) and sensitivity, specificity, PPV, and NPV were used. Factors significantly correlated with subsequent biologic therapy were perianal disease, complicated disease behavior, high PCDAI (CD), fatigue, hypoalbuminemia, high PUCAI (UC) and fever, fatigue, hypoalbuminemia, hypoproteinemia, and elevated CRP (IBD). Marginally significant factors were ileocecal disease, elevated serum IgA, anemia, and L4a-L4b coexistence. Apart from parameters already accepted as POPO (B2/3, perianal disease), interesting observations are the significance of IgA, L4a-L4b in CD, and hypoalbuminemia in UC.
This study aims to measure the concentration of cytokines produced during the inflammation process to investigate if there are any differences in response to treatment of pediatric Crohn's disease and to determine if the initial tumor necrosis factor-alpha (TNF-α) level affected the trough concentration of infliximab (IFX). This study included 30 pediatric patients with moderate-to-severe Crohn's disease. At the time of diagnosis, blood samples were collected for the measurement of cytokines (IL-6, TNF-α, IL-17A, and IL-10). Blood samples were extracted from patients who had begun IFX treatment to measure the IFX trough concentration immediately before the fourth dose administration. All cytokines (TNF-α, IL-6, IL-10, and IL-17A) were significantly higher in patients who did not achieve clinical or biochemical remission than in those who did ( Measuring cytokines at the time of diagnosis can be used to predict the treatment response. Measuring the initial TNF-α concentration may help to predict the treatment response to IFX. When the initial TNF-α concentration is greater than 27.6 pg/mL, a higher dose of IFX may be more appropriate than routinely administering 5 mg/kg of IFX to maintain the therapeutic concentration.
Over the past two years, the entire medical community has taken up the fight against the new coronavirus infection. At the initial encounter with COVID-19, it seemed that this virus mainly affects the respiratory system. Still, with long-term observation, it turned out that the consequences of this disease can be much more severe and associated with lung damage and thromboembolic complications, and be a trigger for autoimmune diseases. According to the literature, after suffering COVID-19, some patients debuted systemic lupus erythematosus, hemolytic anemia, thrombocytopenia, developed GuillainBarr syndrome, vasculitis, and multiple sclerosis, and a case of autoimmune hepatitis (AIH) was described in foreign literature. AIH is a fairly rare disease, the prevalence of which in Europe is 1618 cases per 100 thousand inhabitants, affecting mainly women. It is known that chemicals and drugs (minocycline, diclofenac, methyldopa, infliximab, etanercept), viruses (HAV, HEV, EBV, HCV, CMV), environmental factors can serve as triggers of the autoimmune process in the liver. This article presents two clinical cases of AIH that developed after suffering a new coronavirus infection, which we consider as the initial provoking factor of autoimmune inflammation. Given the rarity of AIH, the description of new triggers is of clinical interest. It may be useful for doctors of different specialties since they faced drug-induced liver damage against the background of antiviral and immunobiological therapy. In the domestic literature, there have not yet been any publications devoted to the debut of AIH in adults after coronavirus infection. В течение последних 2 лет все медицинское сообщество встало на борьбу с новой коронавирусной инфекцией. При первичном столкновении с COVID-19 казалось, что этот вирус поражает преимущественно респираторную систему, но при длительном наблюдении выяснилось, что последствия этой болезни могут быть куда более тяжелыми, сопряженными с поражением легких и тромбоэмболическими осложнениями, а также являться пусковым механизмом для аутоиммунных заболеваний. Согласно литературным данным после перенесенного COVID-19 у некоторых пациентов дебютировали системная красная волчанка, гемолитическая анемия, тромбоцитопения, развивались синдром ГийенаБарре, васкулиты и рассеянный склероз, также в зарубежной литературе описан случай аутоиммунного гепатита (АИГ), который является достаточно редким заболеванием, распространенность которого в Европе составляет 1618 случаев на 100 тыс. жителей, поражает преимущественно женщин. Известно, что в качестве триггеров аутоиммунного процесса в печени могут послужить химические вещества и лекарства (миноциклин, диклофенак, метилдопа, инфликсимаб, этанерцепт), вирусы (HAV, HEV, EBV, HCV, CMV), факторы внешней среды. В данной статье представлены два клинических примера АИГ, развившегося после перенесенной новой коронавирусной инфекции, которая рассматривается нами в качестве первоначального провоцирующего фактора аутоиммунного воспаления. Учитывая редкость АИГ, описание новых триггеров вызывает клинический интерес, может оказаться полезным для врачей разных специальностей, так как ранее в основном сталкивались с лекарственно-индуцированным поражением печени на фоне противовирусной и иммунобиологической терапии. В отечественной литературе пока не встречалось публикаций, посвященных дебюту АИГ у взрослых после коронавирусной инфекции.
Intestinal stricture and obstruction are rare complications of ulcerative colitis (UC). Currently, there are only a few studies on the treatment of UC with intestinal stenosis, however there are no reports on the treatment of UC with benign intestinal stenosis with ustekinumab (UST). A 22-year-old woman was admitted to our hospital due to a 3-year history of recurrent bloody mucous in stool with intermittent abdominal pain and distension developed in the past month. She was steroid-dependent and had developed a secondary loss of response to infliximab. She was diagnosed with UC combined with incomplete intestinal obstruction due to stenosis. The stricture had a mixed pattern with both inflammatory and fibrotic components, with the former covering a larger section of the intestine. The patient was given UST for 56 weeks. The patient's symptoms subsided after treatment with UST. The ulcers healed, and the stenosis was reduced. UST is effective against UC with benign intestinal stenosis. It is thought that UST inhibits the production of transforming growth factor-β and interleukin-17, leading to the suppression of myofibroblast proliferation, ultimately alleviating intestinal stenosis.
The aim of this study was to assess how 6-thioguanine nucleotide (6-TGN) levels and use of oral methotrexate relate to the pharmacokinetics of biologics. This was a prospective cohort study including patients with inflammatory bowel diseases on maintenance doses of infliximab, vedolizumab, or ustekinumab on monotherapy or combination with a thiopurine or oral methotrexate. We collected 6-TGN concentrations, biomarker levels, and clinical and endoscopic disease activity. The primary outcomes were infliximab, vedolizumab, and ustekinumab concentrations as well as anti-drug antibodies (ADAs). A total of 369 patients were recruited (113 infliximab, 133 vedolizumab, and 123 ustekinumab). Patients with 6-TGN levels ≥146 pmol per 8 × 10 Achieving higher 6-TGN levels or the use of methotrexate improved the pharmacokinetics of infliximab. Conversely, these data do not support the use of combination therapy to augment pharmacokinetics with vedolizumab or ustekinumab.
Psoriasis is a chronic, immune-mediated inflammatory disease for which no definitive cure exists and patients difficult to treat with moderate to severe psoriasis often require life-long therapy. In general, the use of any biologic agent as monotherapy allows a long-term efficacy, however survival response may progressively decrease over time. We report real-world long lasting response data in psoriatic patients on treatment with anti-TNFα evaluating those on the same anti-TNFα agent (infliximab, etanercept, adalimumab) from January 2011 and December 2013 to December 31, 2021 as monotherapy. On 210 treated patients, 69 were found to maintain the same anti-TNFα agent. The median survival rate for etanercept, infliximab and adalimumab was 10, 9.6, and 9.5 years respectively and the efficacy rate was similar (mean PASI96). Our results demonstrate that anti-TNFα agents are a long-term effective and safe therapeutic option for a satisfying proportion (33%) of patients with moderate-to-severe chronic plaque psoriasis. Further long-term real life studies are needed to better understand which are the causes of drug failure or persistent response and why these may occur at different time intervals in patients on the same drug.
The pathogenesis of severe COVID-19 is due, in part, to dysregulation of the human immune system in response to SARS-CoV-2 infection. Immune cells infected with SARS-CoV-2 can trigger a hyperinflammatory response of both the adaptive and innate immune system that has been associated with severe disease, hospitalization, and death, and better treatment options are urgently needed. A mainstay of therapy for COVID-19 involves an antiviral agent, remdesivir, in combination with a systemic corticosteroid, dexamethasone. The addition of a second immunomodulator, such as an interleukin-6 inhibitor or a Janus kinase inhibitor, has been associated with clinical benefit in a subset of patients with moderate-to-severe disease, but their use remains controversial. This manuscript reviews what is known about the approach to treatment of severe COVID-19 and examines how immunomodulators such as infliximab and abatacept may alter clinical management and COVID-19 research in the years ahead based on the results of randomized, controlled trials.
Axial spondyloarthritis, often known as ankylosing spondylitis (AS), is an inflammatory condition that mostly affects the axial skeleton. Axial spondyloarthritis is further subdivided into non-radiographic and radiographic AS. For radiographic axial spondyloarthritis, the male-to-female ratio is two to one, while for non-radiographic axial spondyloarthritis, it is one to one, often manifesting in the third decade of life. Effective treatment for AS includes non-steroidal anti-inflammatory medications (NSAIDs) and TNF blockers. All articular symptoms of AS have been seen to improve significantly when treated with TNF inhibitors such as Etanercept, Adalimumab, Infliximab, Certolizumab, and Golimumab. Upadacitinib, has proven to be significantly efficacious in the management of active non-radiographic axial spondyloarthritis (nr-axSpA), with MRI-based or blood tests displaying objective evidence of inflammation, an increased C-reactive protein, and an unsatisfactory response to Non-steroidal anti-inflammatory drug (NSAIDs). the lack of oral therapy options, and the stigma associated with surgical intervention makes it crucial to offer an unambiguous treatment choice, especially in light of the disease's strong heredity. Thus, Upadacitinib's usage in the treatment of nr-axSpA and its clinical trial is a significant step toward the availability of an internationally-approved medicine for the treatment of nr-axSpA.
To assess treatment patterns and initial and maintenance dosing of biologics over 3 years in pediatric patients with ulcerative colitis (UC) or Crohn's disease (CD), utilizing data from the ImproveCareNow registry. Pediatric patients diagnosed with UC or CD and aged 2-17 years were included in the study. Descriptive statistics were employed to summarize baseline demographics. The proportion of patients on medication for UC or CD were analyzed at the baseline visit, 1-year, and 3-year time points (Cohort 1). Biologic maintenance dosage was calculated only for patients who had data for dose and weight at all-time points (Cohort 2). In Cohort 1 (UC = 1784; CD = 4720), baseline treatment in UC included corticosteroid, 5-ASA, and 6-MP/AZA; at 1-year and 3-year time points, treatment with 5-ASA and corticosteroid decreased, whereas 6-MP/AZA and anti-TNFs increased. In CD, baseline treatment included corticosteroid, anti-TNF, 6-MP/AZA, and methotrexate; use of corticosteroids decreased, whereas the use of methotrexate and anti-TNFs increased over 3 years. In Cohort 2 (UC = 350; CD = 1537), at first maintenance dose, UC patients on infliximab received a mean dose of 10.5 mg/kg/8 wk, adalimumab (weight < 40 kg and ≥40 kg) 1.3 mg/kg/2 wk and 0.8 mg/kg/2 wk, and vedolizumab 6.9 mg/kg/8 wks. At the first maintenance dose, CD patients on infliximab received a mean dose of 8.1 mg/kg/8 wk, adalimumab (weight < 40 kg) 1.1 mg/kg/2 wk, adalimumab (weight ≥ 40 kg) 0.8 mg/kg/2 wk, and vedolizumab 10.5 mg/kg/8 wks. The use of corticosteroids was common at the initial visit in patients. Anti-TNFs remain the most used class of biologics, however, reported doses in our study were substantially higher than the standard dosing guidelines.
The clinical symptoms of an immune checkpoint inhibitor (ICI)-induced colitis are similar to those of ulcerative colitis. ICI-induced colitis, like ulcerative colitis, may be complicated by other colitis, such as
The FDA approved adalimumab, an anti-tumor necrosis factor alpha agent, for the treatment of moderate to severe pediatric ulcerative colitis (UC) in February 2021. There are no real-world publications, however, on adalimumab as the first-line biologic in pediatric UC, a form of chronic inflammatory bowel disease (IBD). A retrospective review was conducted to characterize the clinical courses of nine patients with moderate to severe pediatric UC who received adalimumab as their first biologic and had documented drug monitoring trough levels. Seven of the nine patients, or 78%, were switched from adalimumab to another therapy due to continued symptoms or steroid-dependence at an average of 5 months from initiation. Six of these seven patients, or 86%, had adalimumab drug trough levels in the consensus therapeutic range. Three patients were successfully switched to infliximab. Both the Crohn's disease-based dosing and the new FDA-approved pediatric UC dosing of adalimumab were ineffective in inducing remission in the majority of patients in our case series. This study indicates that further real-world observations are needed to optimize and position adalimumab in the treatment paradigm of moderate to severe pediatric UC.
The treatment guidelines for acute Kawasaki disease (KD) have been revised several times. Moreover, the criterion used to define coronary artery abnormalities (CAAs) has changed from the coronary artery's internal diameter to the Z-score. Treatment for KD and methods for evaluating CAAs vary between hospitals, so we investigated the actual status of acute KD treatment and development of CAAs under the 2012 Japanese treatment guidelines for acute KD. The 24th Japanese Nationwide Survey on Kawasaki Disease yielded 2618 patients who developed KD in the Kinki area in 2016. We sent a secondary questionnaire to each participating hospital and used the resulting data to investigate the frequency of CAAs according to Z-score, treatment by KD treatment stage, and predictors of CAAs. The response rate was 80.0%. The data for 1426 patients without major data deficiencies were examined. The frequency of CAAs was 3.0% when based on coronary artery internal diameters and 8.8% when based on Z-scores. Intravenous immunoglobulins combined with corticosteroids were administered as an initial treatment in 12.8% of cases and as a second-line treatment in 16.8% of cases. Corticosteroids, cyclosporine A, infliximab, and plasma exchange were used at similar frequencies for third-line treatment. A pretreatment maximum coronary artery Z-score of ≥1.9 and age <1 year were associated with significantly higher incidences of CAAs. Using the Z-score resulted in a threefold increase in the number of patients diagnosed with CAAs. A pretreatment maximum coronary artery Z-score of ≥1.9 and age <1 year are useful predictors of CAAs.
Uveitis is a major manifestation of Behçet disease (BD) and potentially has a high morbidity. This article reviews recently published data on BD uveitis. A set of classification criteria and a diagnostic algorithm have been developed for BD uveitis. Recent reports have confirmed male predominance and posterior segment inflammation in the majority of BD uveitis patients. A high uveitis attack severity score, fluorescein angiographic leakage at the posterior pole, and disruption of outer retinal layers on optical coherence tomography (OCT) predict poor visual outcome. OCT-angiography studies have suggested subclinical changes of retinal capillaries in patients with or without ocular involvement. In a randomized controlled trial, interferon-α was superior to cyclosporine. Favorable outcomes were reported with earlier initiation, optimization, and withdrawal of infliximab after remission. Adalimumab as first-line was superior to conventional therapy. Classification criteria will be used to select a homogeneous group of patients for research and the diagnostic algorithm may help ophthalmologists predict the probability of BD uveitis based on ocular findings. Fluorescein angiography and OCT are the routine imaging modalities. Clinical relevance of OCT-angiography is unclear. Interferon-α, infliximab, and adalimumab have proven superior efficacy compared to conventional therapy.
Behcet's disease is a systemic autoimmune disorder occasionally associated with otological manifestations, including sensorineural hearing loss. We are reporting a case of Behcet's disease, which was complicated by sensorineural hearing loss and managed successfully with anti-TNF agent Infliximab.
The introduction of biological treatments has revolutionized the management of moderate-to-severe psoriasis. Multiple clinical trials have established the efficacy of biological agents in the treatment of moderate-to-severe psoriasis. Nevertheless, there are no clear indications for optimal monitoring intervals during treatment. Collect and analyze laboratory evaluation data from patients receiving biological therapy to provide a better understanding of the need for laboratory investigations before and during treatment with biological agents, and to analyze adverse events and other factors. Retrospective cohort SETTINGS: Tertiary care center in Riyadh, Saudi Arabia. Data were collected from the electronic medical records of patients attending the dermatology, rheumatology, and gastroenterology clinics from June 2014 to June 2019. The laboratory parameters of patients who have received one of the TNF-alpha inhibitors (adalimumab, etanercept, or infliximab) were collected starting at baseline and up to at least one year from treatment initiation. The time points at which patients developed significantly abnormal laboratory results during treatment with one of the TNF-alpha inhibitors. 250 patients RESULTS: Most patients were treated with adalimumab (38.4%); a similar proportion (38%) with infliximab, whereas only 23.6% were treated with etanercept. The majority of the significant abnormal laboratory results occurred at baseline, 3-6 and 9-12 months. Most abnormalities were among patients using infliximab, followed by etanercept, and then adalimumab. The median number of laboratory abnormalities for dermatology patients was significantly lower than that for gastroenterology patients ( Because dermatology patients showed a lower median number of laboratory abnormalities than patients treated by other specialties in our study, we believe that dermatology patients require less frequent laboratory monitoring. Therefore, we recommend laboratory evaluation at baseline, after 3-6 months, 1 year from the beginning of treatment, and annually thereafter for patients using TNF-alpha inhibitor agents. However, more frequent testing might be warranted according to patient comorbidities, concomitant medications, and physician judgment. Single center and retrospective design. None.
Anti-tumour necrosis factor (anti-TNF) therapies are the most commonly used biologics for inflammatory bowel disease (IBD), but for patients with a comorbidity, newer agents may be a more appropriate treatment choice. To investigate the impact of comorbidities in patients with IBD, on first-line biologic prescribing habits of IBD-specialist healthcare practitioners in the UK. IBD-specialist physicians and nurses were asked to answer an online survey, considering different prescribing scenarios in ulcerative colitis (UC) and Crohn's disease (CD). Respondents could indicate a preference for anti-TNFs or newer biologics, both in the absence and presence of 10 common comorbidities. A total of 120 IBD-specialist healthcare professionals (HCPs) completed the survey. In the absence of comorbidities, anti-TNFs were favoured; infliximab was the preferred first-line biologic in both UC and CD (43% and 37% of respondents, respectively). On introducing comorbidities, the largest shift in prescribing behaviour was for vedolizumab, with preference increasing by 27% and 21%, compared with infliximab, which fell by 14% and 9% in UC and CD, respectively. Chronic/recurring infection (46%), congestive heart failure (≤44%) and malignancies (≤43%) were the most commonly selected comorbidities for vedolizumab treatment. Clinicians adapt their biologic prescribing habits in patients with IBD with comorbidities, considering known contraindications and precautions. A preference for vedolizumab is evident in many cases, however, for several comorbid scenarios, including demyelinating disorders, chronic obstructive pulmonary disease and malignancy, anti-TNFs are prescribed despite known risks. It is important that continual re-evaluation of the IBD treatment landscape is undertaken by HCPs, in alignment with recommendations in published guidelines.
Immune checkpoint inhibitors (ICIs) are a new class of cancer pharmacotherapy consisting of antibodies that block inhibitory immune regulators such as cytotoxic T lymphocyte antigen 4, programmed cell death 1 and programmed death-ligand 1. Checkpoint blockade by ICIs reactivates a tumor-specific T cell response. Immune-related adverse events can occur in various organs including skin, liver, and gastrointestinal tract. Mild to severe colitis is the most common side effect with some experiencing rapid progression to more serious complications including bowel perforation and even death. Prompt diagnosis and management of ICI-induced colitis is crucial for optimal outcome. Unfortunately, its clinical, endoscopic and histopathologic presentations are non-specific and overlap with those of colitis caused by other etiologies, such as infection, medication, graft-
Crohn's disease (CD) is a relapsing and progressive condition characterized by diarrhea, abdominal pain, weight loss, and hematochezia that results in serious complications such as perforations, fistulas, and abscesses. Various medications, interventions, and surgical treatments have been used to treat CD. The Korean guidelines for CD management were distributed in 2012 and revised in 2017 by the Inflammatory Bowel Disease (IBD) Research Group of the Korean Association for the Study of Intestinal Diseases. Substantial progress in mucosal immunologic research has elucidated the pathophysiology of IBD, leading to development of biological agents for treatment of CD. The first developed biologic agent, tumor necrosis factor-α agents, were shown to be efficacious in CD, heralding a new era in management of CD. Subsequently, vedolizumab, a monoclonal antibody against integrin α4β7, and ustekinumab, a human monoclonal antibody that inhibits the common p40 subunit of interleukin-12 and interleukin-23, were both approved for clinical use and are efficacious and safe for both induction and maintenance of remission in moderate-to-severe CD patients. Moreover, a recent study showed the non-inferiority of CT-P13, an infliximab biosimilar, compared with infliximab in CD patients. The third Korean guidelines for CD management provide updated information regarding treatment of moderate-to-severe CD patients with biologic agents.
Psoriatic arthritis (PsA) is a heterogeneous chronic musculoskeletal disease, affecting up to 30% of people with psoriasis. Research into PsA pathogenesis has led to the development of targeted therapies, including Tumor Necrosis Factor inhibitors (TNF-i). Good response is only achieved by ~60% of patients leading to 'trial and error' drug management approaches, adverse reactions and increasing healthcare costs. Robust and well-validated biomarker identification, and subsequent development of sensitive and specific assays, would facilitate the implementation of a stratified approach into clinical care. This review will summarise potential genetic biomarkers for TNF-i (adalimumab, etanercept and infliximab) response that have been reported to date. It will also comment upon the importance of managing clinical confounders when understanding drug response prediction. Variants in multiple gene regions including TNF-A, FCGR2A, TNFAIP3, TNFR1/TNFR1A/TNFRSF1A, TRAIL-R1/TNFRSF10A, FCGR3A have been reported to correlate with TNF-i response at various levels of statistical significance in patients with PsA. However, results were often from heterogenous and underpowered cohorts and none are currently implemented into clinical practice. External validation of genetic biomarkers in large, well-documented cohorts is required, and assessment of the predictive value of combining multiple genetic biomarkers with clinical measures is essential to clinically embed pharmacogenomics into PsA drug management.
Hidradenitis suppurativa (HS) is a chronic inflammatory condition of the apocrine glands primarily affecting the axillae, perineum, and inframammary regions. It is characterized by painful, inflamed cutaneous lesions causing nodules, sinus tracts, and abscesses. Cervicofacial HS is an atypical presentation of HS in the head and neck region and is scarcely reported in the literature. We present a 34-year-old male who developed a large facial swelling overlying the left inferior mandibular border. Management included surgical incision and drainage, antibiotic therapy, followed by infliximab (Remicade). The purpose of this case report was to highlight the presentation, pathophysiology, interdisciplinary approach to treatment and follow-up of patients with cervicofacial HS, and finally, review the cervicofacial HS literature.
Cerebrovascular disease is rarely reported in neurosarcoidosis and constitutes one of its least well-described forms, though recognition for it has grown in the last decade with recent studies estimating a higher frequency of occurrence than previously known. Patients with ischemic stroke were included if the mechanism was directly attributable to sarcoidosis of the CNS. Patients were excluded if an alternative stroke etiology was of equal or higher likelihood than CNS sarcoidosis. Neurologic disease was the initial presenting manifestation of sarcoidosis in 8/11 (72.7%), and ischemic stroke was an inaugural manifestation of sarcoidosis in 4/11 (36.4%). Small vessel disease was the predominant ischemia subtype (10/11, 90.9%) with pontine perforating vessels (6/11, 54.5%) and lenticulostriate arteries (3/11, 27.3%) being the vasculature most often affected. Vessels with a more rostral supratentorial distribution were uncommonly affected. Common neuroinflammatory accompaniments included leptomeningitis (10/11, 90.9%) and cranial nerve disease (3/11, 27.3%). Recurrent strokes occurred in 8/11 (72.7%), and recurrent neuroinflammation occurred in 7/11 (63.6%). Antiplatelet drugs were used in 6/11 (54.5%) patients. Most (10/11, 90.9%) required at least two lines of immunosuppression to achieve inflammatory disease remission in this context; infliximab was the most successfully employed immunosuppressant (7/8 treatment courses, 87.5%). Recurrent strokes occurred in 8/11 (72.7%) patients, and a second inflammatory attack occurred in 7/11 (63.6%) patients. The presenting median modified Rankin Scale score of 4.0 improved to 2.0 over a median period of follow-up of 52.0 months. Ischemic strokes in neurosarcoidosis occur in a caudal-to-rostral distribution, tend to affect small caliber blood vessels that lack collateral blood flow, and typically associate with inflammatory leptomeningeal disease. The risk for relapse in the forms of stroke or neuroinflammation are high in this neurosarcoidosis phenotype.
The optimal treatment strategy for cardiac sarcoidosis has not been standardized. We examined the effectiveness of three prednisone-tapering treatment regimens for cardiac sarcoidosis. We retrospectively reviewed prednisone-tapering treatment regimens for cardiac sarcoidosis that contained prednisone alone (P), prednisone plus methotrexate (P-M), and prednisone plus infliximab containing regimens (P-I). We defined the success of each regimen as the ability to lower the daily prednisone dose to 7.5 mg or less for 6 or more months without developing an adverse cardiac event. We also examined the lowest effective daily prednisone dose achieved without developing an adverse cardiac event. We identified 61 treatment regimens in 33 cardiac sarcoidosis patients that were analyzed. The success rate of prednisone-tapering regimens was significantly different P: 8/30, 27%; P-M: 3/23, 13%; P-I: 6/8, 75%., p = 0.04. The lowest effective daily prednisone dose for the regimens was also significantly different: P: 14.1 ± 10.1 mg; P-M: 16.9 ± 9.4 mg; infliximab: 7.8 ± 4.9 mg, (p = 0.03); by both measures the success was greatest with the P-I regimen. For the treatment of cardiac sarcoidosis, prednisone-tapering regimens containing infliximab are superior to those containing prednisone alone or prednisone plus methotrexate in terms of reaching 7.5 mg/day of prednisone for more than 6 months and achieving the lowest effective prednisone.
Recently, the extraintestinal manifestations of Crohn's disease (CD) have attracted more and more attention, among which interstitial lung disease (ILD) is a rare extraintestinal manifestation. Clinical presentation is polymorphic and pathogenesis remains unclear. The purpose of this article is to elaborate on these rare extraintestinal manifestations of CD, and the importance of short-term chest computed tomography (CT) for differential diagnosis is emphasized. A 27-year-old male patient, who is a student, presented with chief complaints of "loose stools for 4 months, intermittent low-grade fever for 1 month". The next day, he developed a high fever with a body temperature of 39.8°C. A chest CT scan revealed multiple patellar ground glass shadows which suggested ILD. In the time of Corona virus disease (COVID-19), novel coronavirus pneumonia was first suspected according to the patient's history and symptoms, but laboratory examinations did not confirm. Colonoscopy showed multiple ulcers between the sigmoid colon to the terminal ileum, and pathology found epithelioid granuloma in submucosa. Moreover, a total gastrointestinal CT angiography showed that segmental leaping thickening of the bowel. Based on the above results, we ultimately made a diagnosis of CD. After using systemic steroid therapy, his fever was quickly relieved, and a follow-up chest CT showed that multiple patellar ground glass shadows were almost completely absorbed. Then, infliximab was used, and a repeat colonoscopy showed that intestinal ulcers were significantly improved. ILD is a rare extraintestinal manifestation of CD and reveals the excellent response to systemic steroid therapy. Manifestations of pulmonary disease associated with IBD are polymorphic; therefore; clinicians should be more vigilant regarding IBD-related ILD, especially when infectious causes have been excluded in the time of COVID-19. For those with ILD related to IBD, a short-term follow-up CT would be crucial.
Infliximab has been recommended by the American Society of Clinical Oncology (ASCO) guidelines for the treatment of steroid-refractory immune checkpoint inhibitor-related pneumonia (CIP), but clinical evidence remains insufficient. In order to improve the level of diagnosis and treatment and rational use of infliximab in the treatment of CIP, a successful case is reported and the relevant literature is reviewed. We report a 67-year-old male patient with small cell lung cancer (SCLC) who was admitted to hospital with rapidly worsening dyspnea and bilateral interstitial lung following PD-1 inhibitor (tislelizumab) combined with chemotherapy and radiation therapy. According to the comprehensive judgment of the patient's medical history, clinical symptoms, imaging manifestations, laboratory tests, exclusion of infection, heart failure and treatment response, the diagnosis of grade 4 CIP was made. The patient's condition did not improve after high-dose glucocorticoid and immunoglobulin therapy. After infliximab was added, the clinical manifestations and imaging were significantly improved, oxygenation index also gradually return to normal, then the patient was discharged smoothly. This report suggests that infliximab should be considered when high-dose glucocorticoids combined with immunoglobulin are ineffective for severe CIP. At the same time, this case indicates that inflammatory factors, especially tumor necrosis factor (TNF-α), may be prospective in predicting the efficacy of infliximab in the treatment of steroid-refractory CIP.
Recent trials support the clinical efficacy and safety of subcutaneous infliximab (IFX) or vedolizumab (VDZ) for Inflammatory Bowel Disease (IBD). We evaluated the uptake and rationale for choosing to switch from intravenous infusions to subcutaneous injections. Retrospective analysis of all adult patients receiving standard dosing IFX or VDZ maintenance therapy to investigate uptake of subcutaneous injections and the rationale for switching to subcutaneous injections. Of 232 eligible patients (total = 258: IFX = 190, VDZ = 68, and no longer eligible = 26), 58% of patients on IFX and 59% of patients on VDZ chose to switch to subcutaneous treatment. Age, sex, diagnosis, drug, line of treatment, and duration of treatment were not predictors for willingness to switch. Questionnaire responses ( Switch uptake rates were 58%, with 90% of patients eligible to switch. Switch decision was influenced by time savings for patients but not by other patient-related factors.
Inflammation is the main cause of corneal and retinal damage in an ocular alkali burn (OAB). The aim of this study was to investigate the effect of tauroursodeoxycholic acid (TUDCA) on ocular inflammation in a mouse model of an OAB. An OAB was induced in C57BL/6j mouse corneas by using 1 M NaOH. TUDCA (400 mg/kg) or PBS was injected intraperitoneally (IP) once a day for 3 days prior to establishing the OAB model. A single injection of Infliximab (6.25 mg/kg) was administered IP immediately after the OAB. The TUDCA suppressed the infiltration of the CD45-positive cells and decreased the mRNA and protein levels of the upregulated TNF-α and IL-1β in the cornea and retina of the OAB. Furthermore, the TUDCA treatment inhibited the retinal glial activation after an OAB. The TUDCA treatment not only ameliorated CNV and promoted corneal re-epithelization but also attenuated the RGC apoptosis and preserved the retinal structure after the OAB. Finally, the TUDCA reduced the expression of the endoplasmic reticulum (ER) stress molecules, IRE1, GRP78 and CHOP, in the retinal tissues of the OAB mice. The present study demonstrated that the TUDCA inhibits ocular inflammation and protects the cornea and retina from injury in an OAB mouse model. These results provide a potential therapeutic intervention for the treatment of an OAB.
Anti-TNF biologics have been shown to markedly improve the quality of life for patients with Crohn's disease (CD), yet one-third of patients fail to benefit from this treatment. Patients with CD develop a characteristic wrapping of visceral adipose tissue (VAT) in the inflamed intestinal area, termed creeping fat, and it is known that adipose tissue expansion influences the efficacy of anti-TNF drugs. We questioned whether anti-TNF therapies impact the creeping fat in CD, which might affect the outcome of the disease. Adipose tissue biopsies were obtained from a cohort of 14 patients with CD that received anti-TNF drugs and from 29 non-anti-TNF-treated patients (control group) matched by sex, age, and body mass index undergoing surgical interventions for symptomatic complications. We found that anti-TNF therapies restored adipose tissue morphology and suppressed immune cell infiltration in the creeping fat. Additionally, anti-TNF treatments appeared to markedly improve the pro-inflammatory phenotype of adipose-tissue macrophages and adipose-tissue-derived stem cells. Our study provides evidence that anti-TNF medications influence immune cells and progenitor cells in the creeping of patients with CD, suppressing inflammation. We propose that perilesional VAT should be considered when administering anti-TNF therapy in patients with CD.
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.
This analysis evaluates the association between baseline patient-reported symptom (PRS) severity in Crohn's disease (CD), including abdominal pain, stool frequency, general well-being, and achievement of clinical and endoscopic outcomes. We compared baseline PRS to baseline endoscopic scores for the prediction of endoscopic remission (ER). This post hoc analysis of 2 clinical trials of infliximab in CD included 601 patients and evaluated baseline PRS variables (abdominal pain, stool frequency, and general well-being) as measured by the Crohn's disease activity index and their association with 6-month clinical remission (CR) (Crohn's Disease Activity Index<150), corticosteroid-free CR, and week 26/54 ER (absence of mucosal ulceration). Logistic regression models assessed the relationships between PRS and outcomes of interest. Receiver operating characteristic curve analyses compared the sensitivity and specificity of the different baseline PRS compared with baseline endoscopic scores for achievement of ER at weeks 26 and 54. No difference was found comparing patients with higher baseline PRS to those with lower PRS in achieving 6-month CR, 6-month corticosteroid-free CR, or week 26/54 ER. Modified multiplier of the SES-CD (MM-SES-CD) at baseline demonstrated a significant ability to predict week 54 ER (area under the curve, 0.71; 95% CI 0.65-0.78; P=0.017). Baseline PRS in CD is not prognostic of clinical or endoscopic response. In contrast, active endoscopic disease as measured by the MM-SES-CD, more accurately predicts endoscopic outcomes. Endoscopic scores such as the MM-SES-CD may be considered for selection criteria and as a primary outcome of interest in CD trials, with PRS as a co-primary or secondary endpoint.
Although reports of gastrointestinal perforation after immune-related adverse events (irAE) enteritis are rare, the anti- vascular endothelial growth factor (VEGF) effect of bevacizumab may be involved in gastrointestinal perforation. We report a rare case of gastrointestinal perforation in a patient with hepatocellular carcinoma treated with atezolizumab/bevacizumab combination therapy and infliximab before steroid use. A 72-year-old man, who received seven courses of atezolizumab/bevacizumab for hepatocellular carcinoma due to hepatitis B, was admitted to our department with idiopathic abdominal pain and diarrhea (grade 2 [G2]). Computed tomography (CT) and colonoscopy confirmed edema in the gastrointestinal tract. Perforation of the jejunum was observed in a CT performed on the third day and an emergency operation was performed. Intraoperative findings showed severe edema of the jejunum and leakage of feces into the abdominal cavity. The patient was diagnosed with irAE enteritis comprehensively with severe wall thickening on CT and colonoscopy, negative stool culture, and pathological findings of CD8-positive cells. Infliximab was administered before initiating steroids, to prevent reperforation. The enteritis improved by the 22nd day; however, CT performed on the 35th day of illness showed relapse of gastrointestinal wall thickening and G2 diarrhea symptoms; therefore, prednisolone (PSL) 60 mg/day was started on the 36th day of illness. After introducing PSL, enteritis did not reoccur, and the patient was discharged on the 63rd day of illness after admission. There are no reports of gastrointestinal perforation by atezolizumab/bevacizumab for hepatocellular carcinoma, and prior administration of infliximab. We therefore report the clinical course and management.
Pneumocystis jirovecii pneumonia (PJP) is a very rare, potentially life-threatening pulmonary fungal infection that occurs in immunocompromised individuals including patients with inflammatory bowel disease (IBD). Our aim was to describe immunosuppressive treatment exposure as well as the outcome in IBD patients with PJP. PJP cases were retrospectively collected through the COllaborative Network For Exceptionally Rare case reports of the European Crohn's and Colitis Organization. Clinical data were provided through a case report form. 18 PJP episodes were reported in 17 IBD patients (10 ulcerative colitis and 7 Crohn's disease). The median age on PJP diagnosis was 55 years (IQR, 40-68 years). Two PJP (11.1%) occurred in patients on triple immunosuppression, 10 patients (55.6%) had double immunosuppressive treatment, 4 patients (22.2%) had monotherapy and 2 PJP occurred in absence of immunosuppressive treatment (one in a human immunodeficiency virus patient and one in a patient with a history of autologous stem cell transplantation). Immunosuppressive therapies included steroids (n=12), thiopurines (n=10), infliximab (n=4), ciclosporin (n=2), methotrexate (n=1) and tacrolimus (n=1). None of the patients diagnosed with PJP had received prophylaxis. All patients were treated by trimethoprim/sulfamethoxazole or atovaquone and an ICU stay was required in 7 cases. Two patients (aged 71 and 32 years) died, and one patient had a recurrent episode 16 months after initial treatment. Evolution was favourable for the others. This case series reporting potentially fatal PJP highlights the need for adjusted prophylactic therapy in patients with IBD on immunosuppressive therapy.
Ankylosing spondylitis (AS), a type of chronic spondyloarthritis, significantly increases patients' risk of cervical spine fracture. We describe the anesthetic management of a 32-year-old male with AS who was scheduled to have bilateral mandibular third molar extractions under general anesthesia. To minimize the potential for cervical spine damage, a laryngeal mask airway was used for airway management while the patient's head was held firmly during surgery. Additionally, he developed a postoperative surgical infection that was attributed to his continued immunotherapy with infliximab. In patients with AS, postoperative infection control as well as cervical spine protection throughout the perioperative period is important.
Patient-reported outcome (PRO) data have assumed increasing importance in the care of patients with rheumatoid arthritis (RA), yet physician-derived disease activity measures, such as Clinical Disease Activity Index (CDAI), remain the most accepted metrics to assess disease activity. The possibility that newer longitudinal PRO data might be used as a proxy for the CDAI has not been evaluated. Using data from a large pragmatic trial, we evaluated patients with RA initiating golimumab intravenous or infliximab. The classification target was low disease activity (LDA) (CDAI ≤10) at the first visit between months 3 and 12. Data were randomly partitioned into training (80%) and test (20%) data sets. Multiple machine learning (ML) methods (eg, random forests, gradient boosting, support vector machines) were used to classify CDAI disease activity category, conduct feature selection, and assess feature importance. Model performance evaluated cross-validated error, comparing different ML approaches using both training and test data. A total of 494 patients were analyzed, and 36.4% achieved LDA. The most important classification features included several Patient-Reported Outcomes Measurement Information System measures (social participation, pain interference, pain intensity, and physical function), patient global, and baseline CDAI. Among all ML methods, random forests performed best. Overall model accuracy and positive predictive values for all ML methods were approximately 80%. ML methods coupled with longitudinal PRO data appear useful and can achieve reasonable accuracy in classifying LDA among patients starting a new biologic. This approach has promise for real-world evidence generation in the common circumstance when physician-derived disease activity data are not available yet PRO measures are.
Generalized pustular psoriasis (GPP) is a rare severe variant of psoriasis that is characterized by the abrupt widespread onset of small pustules accompanied by systemic manifestations of inflammation. It can arise in patients with a history of psoriasis as well as in those without, sometimes due to medication initiation or withdrawal, pregnancy, or infection. Generalized pustular psoriasis is thought to be driven primarily by innate immunity and unrestrained IL-36 cytokine activity. Recent genetic analyses have identified 3 genetic mutations that are associated with GPP-IL36RN, CARD14, and AP1S3-though these mutations only account for a minority of cases. There are many cutaneous pustular diseases that must be ruled out in the evaluation of a patient with suspected GPP, especially acute generalized exanthematous pustulosis (AGEP), and histologic analysis is the cornerstone of diagnosis. Although the quality of evidence to generate treatment recommendations for GPP is limited, management often includes utilization of systemic agents and/or biologics, usually with adjunctive topical treatment. Accumulating evidence suggests that biologic agents, especially infliximab, may be considered as first-line treatment of GPP, especially in severe acute cases, due to their abrupt onset of action and favorable side-effect profiles compared with oral systemic agents.
Medicare patients in the United States may face high out-of-pocket (OOP) costs for specialty inflammatory bowel disease (IBD) medications. We conducted a study of Medicare OOP costs for specialty IBD medications between 2020 and 2022 and compared them to incomes of typical Medicare beneficiaries. In 2022, median OOP costs ranged from 6.4% to 59.2% of annual income for a Medicare patient with approximately median income. Inflation-adjusted OOP costs for most medications increased between 2020 and 2022 though decreased for infliximab and its biosimilars. OOP costs may limit many Medicare beneficiaries' access to specialty IBD medications.
Infliximab is an effective drug for the treatment of Crohn's disease. As a rare and unique adverse effect of infliximab, hypertension should be paid enough attention in clinical work. At present, there is no relevant case report. We report a case of a 38-year-old man with Crohn's disease who had no history of hypertension and developed hypertension symptoms during infliximab treatment. The patient was treated with 5 mg/kg infliximab on August 27, 2020. From August 27, 2020 to October 20, 2020, the patient underwent 3 treatment sessions. After each injection of infliximab, the patient's blood pressure became elevated, accompanied by dizziness and symmetrical numbness of both lower limbs. Amlodipine benazepril tablets were given orally to control blood pressure. Under close monitoring, 5 mg/kg infliximab was used again. After 10 min of infusion, blood pressure rose to 160/118 mmHg. Infusion was discontinued immediately, after which blood pressure decreased to normal. Adrenal computed tomography did not indicate adrenal hyperplasia or space occupying lesions, and the detection of hypertension related indicators in standing and supine position was abnormal. Since follow up, the patient has stopped using infliximab and has had no hypertension-related symptoms, even without antihypertensives. Measured blood pressure was within the normal range. Hypertension, as one of the rare adverse reactions of infliximab in the treatment of Crohn's disease, should be paid enough attention.
Therapeutic drug monitoring (TDM) is effective in optimizing the efficacy of infliximab in patients with inflammatory bowel disease (IBD). An affordable way of monitoring is in high demand. This study evaluated the analytical and clinical performances of the newly available Remsima monitor kits and compared them with the established enzyme-linked immunosorbent assay kits. The trough level of infliximab in patients with IBD treated with an infliximab originator (Remicade) or biosimilar compounds (Remsima and Remaloce) was measured using a Remsima® Monitor Drug Level (Remsima) kit at the Samsung Medical Center, Seoul, Korea. Twenty-six plasma samples were collected immediately before the infusion of infliximab from 18 patients with IBD (Remicade, n = 8; Remsima, n = 6; and Remaloce, n = 4). The intra-assay intraclass correlation coefficient (ICC) of the RIDA and Remsima kits was 0.951 (95% CI = 0.908-0.976) and 0.990 (95% CI = 0.981-0.995). The inter-assay ICC of infliximab trough level between the RIDA and Remsima kits was very high (R = 0.971; 95% CI = 0.935-0.987), and the mean difference between the kits was 1.458 (95% limits of agreement = -3.302 to 6.219). The intra- and inter-assay reliabilities of all types of infliximab did not show significant differences. Qualitative stratification revealed substantial similarities between the kits (weighted kappa = 0.798). This study indicated that the Remsima kit was reproducible and highly correlated with the RIDA kit.
The use of biologics in paediatric-onset inflammatory bowel disease (PIBD) is rapidly changing. To identify the incidence and prevalence of biologic use within Scottish PIBD services, and to describe patient demographics and outcomes for those patients who required escalation of therapy beyond anti-tumour necrosis factor alpha (anti-TNFα) agents METHODS: We captured a nationwide cohort of prospectively identified patients less than 18 years of age with PIBD (A1 phenotype; diagnosed <17 years of age) within paediatric services over a 4.5-year period (1 January 2015-30 June 2019). All patients who received infliximab, adalimumab, vedolizumab or ustekinumab during the study period and/or received their first dose of these biologics were audited retrospectively. Scotland-wide PIBD-prevalence cases increased from 554 to 644 over the study period. A total of 495 incident new-start biological therapies were commenced on 403 PIBD patients: 295 infliximab (60%), 161 adalimumab (32%), 24 vedolizumab (5%) and 15 ustekunumab (3%). The proportion of new-start biologics changed with infliximab initiation rates decreasing (87%-54%) while adalimumab (13%-31%), vedolizumab (0%-9%) and ustekinumab (0%-6%) all increased. The incidence rate (first dose of new biologic not including biosimilar switch) increased from 6.9% to 8.1% over the study period and point prevalence rates (any biologic use) increased from 20.2% to 43.5% - an average annual percentage increase of 20%. Biosimilar penetration of new-start anti-TNFα agents increased from 3% to 91%. Demographics and outcomes of those patients receiving vedolizumab and ustekinumab were similar. Complete accrual of Scottish nationwide biologic usage within paediatric services demonstrates a rapidly changing, inexorably increasing PIBD biologics landscape.
The early prediction of intravenous corticosteroid (IVCS) resistance in acute severe ulcerative colitis (ASUC) patients remains an unresolved challenge. This study aims to construct and validate a model that accurately predicts IVCS resistance. A retrospective cohort was established, with consecutive inclusion of patients who met the diagnosis criteria of ASUC and received IVCS during index hospitalization in Peking Union Medical College Hospital between March 2012 and January 2020. The primary outcome was IVCS resistance. Classification models, including logistic regression and machine learning-based models, were constructed. External validation was conducted in an independent cohort from Shengjing Hospital of China Medical University. A total of 129 patients were included in the derivation cohort. During index hospitalization, 102 (79.1%) patients responded to IVCS and 27 (20.9%) failed; 18 (14.0%) patients underwent colectomy in 3 months; 6 received cyclosporin as rescue therapy, and 2 eventually escalated to colectomy; 5 succeeded with infliximab as rescue therapy. The Ulcerative Colitis Endoscopic Index of Severity (UCEIS) and C-reactive protein (CRP) level at Day 3 are independent predictors of IVCS resistance. The areas under the receiver-operating characteristic curves (AUROCs) of the logistic regression, decision tree, random forest, and extreme-gradient boosting models were 0.873 (95% confidence interval [CI], 0.704-1.000), 0.648 (95% CI, 0.463-0.833), 0.650 (95% CI, 0.441-0.859), and 0.604 (95% CI, 0.416-0.792), respectively. The logistic regression model achieved the highest AUROC value of 0.703 (95% CI, 0.473-0.934) in the external validation. In patients with ASUC, UCEIS and CRP levels at Day 3 of IVCS treatment appeared to allow the prompt prediction of likely IVCS resistance. We found no evidence of better performance of machine learning-based models in IVCS resistance prediction in ASUC. A nomogram based on the logistic regression model might aid in the management of ASUC patients.
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