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Idiopathic retroperitoneal fibrosis (IRF) is a rare condition characterized by the development of a peri-aortic and peri-iliac tissue showing chronic inflammatory infiltrates and pronounced fibrosis. Ureteral entrapment with consequent obstructive uropathy is one of the most common complications which can lead to acute renal failure and, in the long term, to varying degrees of chronic kidney disease. Common symptoms at onset include lower back, abdominal or flank pain. Pain is frequently referred to the hip, to the groin and to the lateral regions of the leg, often with nocturnal exacerbations and not responding to position changes. The disease is commonly associated with signs of systemic inflammatory response (malaise, fever, and anorexia and weight loss). Glucocorticoids are considered the cornerstone of the therapy. The use of other immunosuppressive agents, including cyclophosphamide, azathioprine, methotrexate, mycophenolate mofetil and biological agents such as rituximab, tocilizumab and infliximab have been reported as a valuable option mostly in case reports, cases series and small studies. These agents allowed to reduce cumulative dose of glucocorticoids and their adverse effects. Combined therapy is preferable for all patients who suffer from significant glucocorticoid- related toxicity or in cases where glucocorticoids alone are insufficient to treat the condition. |
The objective of this study was to describe the efficacy and safety of infliximab (IFX) reintroduction in Crohn's disease (CD) after stopping for loss of response or intolerance.
We conducted a prospective multicenter observational cohort study including adult patients with clinically (CD Activity Index >150) and objectively active luminal CD in whom IFX was reintroduced after at least 6 months of discontinuation. The reasons for the initial discontinuation could be a secondary loss of response or IFX intolerance. The reintroduction schedule included 3 IFX infusions at weeks 0, 4, and 8, after a systematic premedication. The primary end point was the efficacy of IFX retreatment at week 26 defined by a CD Activity Index of <150 in the absence of IFX discontinuation or use of corticosteroids, surgery, or other biologic.
At week 26, 24 patients (35%) among the 69 analyzed reached the primary end point. No significant difference was observed between rates of clinical remission at week 26 in patients with prior LOR (n = 48) and those with IFX intolerance (n = 21) (35% and 33%, P = 0.87, respectively). Thirty-two acute infusion reactions were recorded in 27 patients, leading to withdrawal of IFX in 20 patients. No pharmacokinetic characteristic at baseline but detection of positive anti-drug antibodies at week 4 was predictive of IFX failure or infusion reaction at week 26.
In this first prospective cohort study, IFX retreatment was safe and effective in one-third of the patients with CD, regardless the reason of prior discontinuation. Early detection of anti-drug antibodies can predict subsequent IFX reintroduction failure and infusion reactions. |
Obesity is variably associated with treatment response in biologic-treated patients with inflammatory bowel diseases (IBD). We evaluated the association between obesity and risk of hospitalization, surgery, or serious infections in patients with IBD in new users of biologic agents in a large, multicenter, electronic health record (EHR)-based cohort (CA-IBD).
We created an EHR-based cohort of adult patients with IBD who were new users of biologic agents (tumor necrosis factor [TNF-α] antagonists, ustekinumab, and vedolizumab) between January 1, 2010, and June 30, 2017, from 5 health systems in California. Patients were classified as those with normal body mass index (BMI), overweight, or obese based on the World Health Organization classification. We compared the risk of all-cause hospitalization, IBD-related surgery, or serious infections among patients with obesity vs those overweight vs those with normal BMI, using Cox proportional hazard analyses, adjusting for baseline demographic, disease, and treatment characteristics.
Of 3,038 biologic-treated patients with IBD (69% with Crohn's disease and 76% on TNF-α antagonists), 28.2% (n = 858) were overweight, and 13.7% (n = 416) were obese. On a follow-up after biologic initiation, obesity was not associated with an increased risk of hospitalization (adjusted hazard ratio [aHR] vs normal BMI, 0.90; [95% confidence interval, 0.72-1.13]); IBD-related surgery (aHR, 0.62 [0.31-1.22]); or serious infection (aHR, 1.11 [0.73-1.71]). Similar results were observed on stratified analysis by disease phenotype (Crohn's disease vs ulcerative colitis) and index biologic therapy (TNF-α antagonists vs non-TNF-α antagonists).
In a multicenter, EHR-based cohort of biologic-treated patients with IBD, obesity was not associated with hospitalization, surgery, or serious infections. Further studies examining the effect of visceral obesity on patient-reported and endoscopic outcomes are needed. |
Secondary structural and functional abnormalities of the neurovascular unit are important pathological mechanisms following traumatic brain injury (TBI). The neurovascular unit maintains blood-brain barrier and vascular integrity through interactions among glial cells, pericytes and endothelial cells. Trauma-induced neuroinflammation and oxidative stress may act as initiating factors for pathological damage after TBI, which in turn impairs cerebral microcirculatory function. Studies have shown that the tumor necrosis factor α (TNF-α)/nuclear factor-κB (NF-κB) pathway regulates inflammation and oxidative damage, but its role in pericyte-mediated cerebral microcirculation are currently unknown. Herein, we assessed TNF-α/NF-κB signaling and inducible nitric oxide synthase (iNOS), and the effects of the TNF-α inhibitor infliximab after TBI. Whether pericyte damage is dependent on the TNF-α/NF-κB/iNOS axis was also evaluated to explore the mechanisms underlying disturbances in the microcirculation after TBI. Microglia are activated after TBI to promote inflammatory factors and free radical release, and upregulate NF-κB and iNOS expression. After lipopolysaccharide treatment, the activity of TNF-α/NF-κB/iNOS in BV2 cells was also upregulated. Inhibition of TNF-α using infliximab reduced NF-κB phosphorylation and nuclear translocation and downregulated iNOS expression, which attenuated the inflammation and oxidative damage. Meanwhile, inhibition of TNF-α reversed pericyte marker loss, and improved pericyte function and microcirculation perfusion after TBI. In conclusion, our study suggests that microglia released TNF-α after TBI, which promoted neuroinflammation and oxidative stress by activating downstream NF-κB/iNOS signals, and this led to pericyte-mediated disturbance of the cerebral microcirculation. |
Pyoderma gangrenosum (PG) is an inflammatory dermatosis characterized by the rapid progression of a painful, necrolytic ulcer with an irregular and undermined border. The prevalence of PG in patients with Crohn's disease (CD) has been estimated to be 0.7%. Here, we report a case that presented various painful skin lesions, including erythema, vesicles, plaques, and ulcers, one week before the fourth infliximab infusion for CD. PG was diagnosed and the lesions subsided after a 390-mg ustekinumab infusion for one month. It suggests that different lesions of PG may occur concomitantly in CD patients, and the therapy should be re-evaluated on time. |
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The use of biologic therapy for antibiotic-refractory pouchitis is controversial, due to few studies on the subject and lack of convincing results.
To study the efficacy of biologic therapy for refractory pouchitis.
In this retrospective study, patient records at the Medical and Surgical departments in our hospital during an eleven-year period were scrutinized. 25 patients treated with biologics for refractory pouchitis were identified.
The majority of these patients (
This retrospective study suggests that biologic therapy may be effective for both idiopathic and Crohn's-like refractory pouchitis. Naïve patients seem to respond more successfully than not naïve patients. In cases without response on first-line treatment should second-line treatment be considered. Due to the high risk of adverse reactions Infliximab should be avoided to not naïve patients. |
Biologic medications are novel therapeutics in the treatment of Autoimmune Inner Ear Disease (AIED), an etiology of Sensorineural Hearing Loss (SNHL). The goal of this study is to review the currently available literature on the efficacy of biologic medications on autoimmune-mediated hearing loss and associated symptomology among patients with AIED.
A systematic review of Pubmed, Scopus, Cochrane, and Web of Science databases was conducted to identify studies investigating the impact of biologic medications on hearing outcomes. Bias assessment was independently conducted by three authors and studies were stratified based on risk of bias.
Of 174 unique abstracts screened, 12 articles met inclusion criteria for formal review. One randomized control trial, seven prospective cohort studies, and four retrospective cohort studies were included. Seven biologic medications, Etanercept, Infliximab, Adalimumab, Golimumab, Rituximab, Anakinra, and Canakinumab, were identified targeting three unique molecular targets, TNF-α, CD20, and IL-1.
The effects of biologic medications in treating SNHL was highly variable without clear efficacy of a drug or drug category, likely due to rarity of disease, multifactorial etiologies of AIED, and cohort heterogeneity. However, several medications alleviate symptoms associated with AIED, such as vertigo and tinnitus. While biologic medications may be promising therapeutics in AIED patients, the evidence is currently inconclusive. Large-scale randomized control trials and prospective cohort reviews are required to establish the efficacy of biologic medications in treating hearing loss. |
Biologicals, such as anti-tumor necrosis factor (anti-TNF), reduce cardiovascular disease (CVD) in patients with inflammatory rheumatic diseases. Impaired renal function is a known predictor of CVD and elevated in ankylosing spondylitis (AS).
To assess the effect of anti-TNF on renal function in patients with AS and whether anti-TNF use is safe in AS patients with pre-existing risk factors for renal decline.
Biological-naïve consecutive AS patients treated with etanercept or adalimumab were prospectively followed from 2005 to 2014. Renal function was determined by calculation of the estimated glomerular filtration rate (eGFR), estimated with the abbreviated modification of diet in renal disease (MDRD) formula. The effect of anti-TNF on eGFR was analyzed using mixed model analysis.
211 AS patients were followed for a median of 156 (36-286) weeks. Overall mixed model analyses showed a significant decrease of eGFR over time (β = - 0.040, p = 0.000), although this association did not remain significant after adjustment for responding to anti-TNF, alcohol use, disease duration, body mass index (BMI), C-reactive protein (CRP), and disease activity (β = - 0.018, p = 0.094). However, patients with pre-existing risk factors for renal decline did have a significant change in eGFR over time (β = - 0.029, p = 0.006).
We found a significant change in eGFR over time, although this small decrease was not clinically relevant. This study further demonstrates that anti-TNF does not affect renal function in AS patients with and without existing risk factors for renal decline, which means that use of anti-TNF is safe concerning renal function in patients with AS. Key Points • Previous studies showed that biologicals, such as anti-tumor necrosis factor (anti-TNF), reduce cardiovascular disease (CVD) in patients with inflammatory rheumatic diseases, such as ankylosing spondylitis (AS). • Impaired renal function is a known predictor of CVD, and also a known concern for many AS patients. • Use of anti-TNF is safe with regard to renal function in patients with AS. • The effect of anti-TNF on CVD in AS patients does not seem to be mediated by changes in renal function. |
Despite growing awareness of the nocebo effect, few studies have evaluated the nocebo effect using combined assessment of patient-reported outcome measures (PROMs), clinical indices, and objective biomarkers in inflammatory bowel disease (IBD) patients switching from originator to biosimilar medicines.
This study aimed to compare these outcomes across switch and non-switch cohorts to evaluate the nocebo effect in patients with IBD.
Parallel cohorts of IBD patients who (1) switched from originator to biosimilar (CT-P13) infliximab and (2) continued biosimilar (CT-P13) infliximab were evaluated over 32 weeks. Clinical disease activity, objective biomarkers and PROMs were assessed at baseline, and weeks 16 and 32 across both cohorts. The PROM of interest was patient-perceived disease activity evaluated using a 0-100 visual analogue scale (VAS) per the IBD-Control Questionnaire.
Of 81 patients, 47 switched from originator to biosimilar (CT-P13) infliximab. A negative change from baseline patient-reported disease control was observed across the switch cohort compared with the non-switch cohort at week 16 (mean VAS - 8.21 vs. 1.26; p = 0.03), but not at week 32 (mean VAS - 1.21 vs. 1.38; p = 0.58). Corresponding clinical and objective biomarker assessments over these timepoints were comparable across both cohorts.
This study demonstrated a temporary yet discernible nocebo effect in the first 16 weeks following non-medical switching that was not sustained at week 32. Negative patient perceptions may be overcome by a patient-inclusive approach to non-medical switching in conjunction with close clinical follow-up and disease monitoring. |
Inflammatory bowel disease (IBD) is of high medical and socioeconomic relevance. Moderate and severe disease courses often require treatment with biologics. The aim of this study was to evaluate machine learning (ML)-based methods for the prediction of biologic therapy in IBD patients using a large prescription database.
The present retrospective cohort study utilized a longitudinal prescription database (LRx). Patients with at least one prescription for an intestinal anti-inflammatory agent from a gastroenterologist between January 2015 and July 2021 were included. Patients who had received an initial biologic therapy prescription (infliximab, adalimumab, golimumab, vedolizumab, or ustekinumab) were categorized as the "biologic group". The potential predictors included in the machine learning-based models were age, sex, and the 100 most frequently prescribed drugs within 12 months prior to the index date. Six machine learning-based methods were used for the prediction of biologic therapy.
A total of 122,089 patients were included in this study. Of these, 15,824 (13.0%) received at least one prescription for a biologic drug. The Light Gradient Boosting Machine had the best performance (accuracy = 74%) and was able to correctly identify 78.5% of the biologics patients and 72.6% of the non-biologics patients in the testing dataset. The most important variable was prednisolone, followed by lower age, mesalazine, budesonide, and ferric iron.
In summary, this study reveals the advantages of ML-based models in predicting biologic therapy in IBD patients based on pre-treatment and demographic variables. There is a need for further studies in this regard that take into account individual patient characteristics, i.e., genetics and gut microbiota, to adequately address the challenges of finding optimal treatment strategies for patients with IBD. |
Immunosuppressants and biologicals are widely used therapeutics for various chronic inflammatory diseases (CID). To gain more detailed insight into their downstream effects, we examined their impact on serum immunoglobulin G (IgG) glycosylation. We analyzed IgG subclass-specific fragment crystallizable (Fc) N-glycosylation in patients suffering from various CID using the LC-MS approach. Firstly, we compared IgG Fc N-glycosylation between 128 CID patients and 204 healthy controls. Our results replicated previously observed CID-related decrease in IgG Fc galactosylation (adjusted |
Muscle injuries are common in humans and are often associated with irrecoverable damage and disability. Upon muscle injury, TNF-α signaling pathways modulate the healing process and are predominantly associated with tissue degradation. In this study we assumed that TNF-α inhibition could reduce the TNF-α-associated tissue degradation after muscle injury.
Therefore, the left soleus muscle of 42 male Wistar rats was injured using a standardized open muscle injury model. All rats were treated immediately after injury either with infliximab (single i.p. injection; 10 mg/kg b.w.) or saline solution i.p. Final measurements were conducted at day one, four, and 14 post injury. The muscle force, the muscle cell proliferation, the muscle cell coverage as well as the myofiber diameter served as read out parameters of our experiment.
Systemic application of infliximab could significantly reduce the TNF-α levels in the injured muscle at day four upon trauma compared to saline treated animals. The ratio of muscle weight to body weight was increased and the twitch muscle force showed a significant rise 14 days after trauma and TNF-α inhibition. Quantification of myofiber diameter in the penumbra zone showed a significant difference between both groups at day one and four after injury, indicated by muscle hypertrophy in the infliximab group. Planimetric analysis of the injured muscle at day 14 revealed increased muscle tissue fraction in the infliximab group compared to the control animals. Muscle cell proliferation did not differ between both groups.
These data provide evidence that the TNF-α blockade positively regulates the restauration of skeletal muscles upon injury. |
Adalimumab (ADA) and infliximab (IFX) are the cornerstones of the treatment of Crohn's disease (CD). It remains controversial whether there is a difference in the effectiveness and safety between IFX and ADA for CD.
To perform a meta-analysis to compare the effectiveness and safety of ADA and IFX in CD.
PubMed, Embase, Cochrane Library, and Web of Science databases were searched. Cohort studies were considered for inclusion. The primary outcomes were induction of response and remission, maintenance of response and remission, and secondary loss of response. Adverse events were secondary outcomes.
Fourteen cohort studies were included. There was no apparent difference between the two agents in the induction response [odds ratio (OR): 1.27, 95% confidence interval (CI): 0.93-1.74,
ADA and IFX have similar clinical benefits for anti-tumor necrosis factor-α naïve or non-naïve CD patients. Overall adverse events rate is higher in patients in the IFX group. |
Infliximab trough level (ITL) severely affects therapeutic outcomes of Crohn's disease (CD) patients under infliximab (IFX). Recently, frontier research has focused on identifying ITL based on different therapeutic targets. Although previous studies have elaborated clinical value of ITL monitoring on short-term outcomes in CD patients during therapy, studies contraposing the predictive value of ITL on long-term endoscopic outcomes in CD patients are still scarce domestically and overseas.
To explore the predictive value of ITL in combination with inflammatory biomarkers on long-term endoscopic outcomes in CD with clinical remission during IFX maintenance therapy.
CD patients with endoscopic remission under long-term IFX maintenance therapy in the First Affiliated Hospital of Zhejiang Chinese Medicine University from January 2012 to December 2020 were collected. ITL and inflammatory biomarkers were continuously monitored during the therapy. The Step I study was conducted from weeks 14 to 54 of IFX treatment. The Step II study was conducted from weeks 54 to 108 of IFX treatment. Endoscopic outcomes were defined as endoscopic activity (Crohn's disease endoscopic index of severity score > 2 points or Rutgeerts score > i1) and endoscopic remission (Crohn's disease endoscopic index of severity score ≤ 2 points or Rutgeerts ≤ i1). Endoscopic relapse free survival was defined as endoscopic remission at the beginning of the study stage and maintaining endoscopic remission during the study stage.
At week 14, low ITL [odds ratio (OR) = 0.666, 95% confidence interval (CI): 0.514-0.862,
Combination of ITL, CRP, and FCP contribute to long-term endoscopic prognosis monitoring. During IFX maintenance treatment, low ITL, high CRP level, and high FCP level were independent risk factors of CD patients with clinical remission in adverse endoscopy outcomes within 1-year follow-up. |
Tumor necrosis factor-alpha inhibitors, including infliximab and adalimumab, are effective medical treatments for perianal fistulising Crohn's disease (CD), but not all patients achieve fistula healing.
To determine the correlation between perianal fistula healing and closure with infliximab and adalimumab trough levels.
In this multicentre retrospective study conducted across four tertiary inflammatory bowel disease centres in Australia, we identified CD patients with perianal fistulae on maintenance infliximab or adalimumab who had a trough level within twelve weeks of clinical assessment. Data collected included demographics, serum infliximab and adalimumab trough levels (mg/L) within 12 wk before or after their most recent clinical assessment and concomitant medical or surgical therapy. The primary outcome was fistula healing, defined as cessation in fistula drainage. The secondary outcome was fistula closure, defined as healing and closure of all external fistula openings. Differences between patients who did or did not achieve fistula healing were compared using the chi-square test,
One hundred and fourteen patients (66 infliximab, 48 adalimumab) were included. Forty-eight (72.7%) patients on maintenance infliximab achieved fistula healing and 18 (27.3%) achieved fistula closure. Thirty-seven (77%) patients on maintenance adalimumab achieved fistula healing and 17 (35.4%) achieved fistula closure. Patients who achieved fistula healing had significantly higher infliximab and adalimumab trough levels than patients who did not [infliximab: 6.4 (3.8-9.5)
Higher maintenance infliximab and adalimumab trough levels are associated with perianal fistula healing in CD. |
Oral traumatic ulcers (OTU) are common in dental routine, and the control of proinflammatory cytokines, such as the tumor necrosis factor-alpha (TNF-α), may interfere with OTU repair. Our aim was to evaluate the role of TNF-α in the healing process of OTU in rats. Wistar male rats were divided into six groups: a control-group (treated with 0.1 mL/kg of saline) and five groups treated with anti-TNF-α infliximab (INF) at 1, 3, 5, 7, and 10 mg/kg immediately before OTU production. The animals were weighed (day 0) and euthanized on days 1, 3, 7, 14 and 21 after ulceration. The ulcers were clinically measured, and the mucosa samples were histologically (scores 0-4), histochemically (collagen assay (pircrosirius)), histomorphometrically (cell counting), and immunohistochemically (TNF-α, α-smooth-muscle-actin (α-SMA), monocyte-chemoattractive-protein-1 (MCP-1), interleukin-8 (IL-8), and fibroblast-growth-factor (FGF)) analyzed. The Evans blue assay was used to measure the vascular permeability. ANOVA-1-2-way/Bonferroni, Kruskal-Wallis/Dunn, and correlation analyses were performed (GraphPad Prism 5.0, p < 0.05). High doses of INF reduced the OTU area (p = 0.043), body mass loss (p = 0.023), vascular permeability (p < 0.001), and reduced delayed histologic scores (p < 0.05), polymorphonuclear (p < 0.001) and mononuclear (p < 0.001) cells, blood vessel counting (p = 0.006), and total (p < 0.001), type-I (p = 0.018), and type-III (p < 0.001) collagen. INF treatment reduced TNF-α immunostaining and delayed MPC-1, FGF, and α-SMA expression, with little/none influence in IL-8 immunostaining. TNF-α blockage by INF reduced acute inflammation in OTU but delayed cell migration and wound healing. |
Large gaps exist in understanding the symptomatic and functional impact of sarcoidosis, a rare multisystem granulomatous disease affecting fewer than 200,000 individuals in the United States. Smartphones could be used for prospective research, especially for rare diseases where organizing large cohorts can be challenging, given their near ubiquitous ownership and ability to track objective and subjective data with increasingly sophisticated technology.
We aimed to investigate whether smartphones could assess the quality of life (QoL) and physical activity of a large cohort of individuals with sarcoidosis.
We developed a mobile app (Sarcoidosis App) for a prospective, cross-sectional study on individuals with sarcoidosis. The Sarcoidosis App was made available on both Apple and Android smartphones. Individuals with sarcoidosis were recruited, consented, and enrolled entirely within the app. Surveys on sarcoidosis history, medical history, and medications were administered. Patients completed modules from the Sarcoidosis Assessment Tool, a validated patient-reported outcomes assessment of physical activity, fatigue, pain, skin symptoms, sleep, and lungs symptoms. Physical activity measured by smartphones was tracked as available.
From April 2018 to May 2020, the App was downloaded 2558 times, and 629 individuals enrolled (404, 64.2% female; mean age 51 years; 513, 81.6% White; 86, 13.7% Black). Two-thirds of participants had a college or graduate degree, and more than half of them reported an income greater than US $60,000. Both QoL related to physical activity (P<.001, ρ=0.250) and fatigue (P<.01, ρ=-0.203) correlated with actual smartphone-tracked physical activity. Overall, 19.0% (98/517) of participants missed at least 1 week of school or work in an observed month owing to sarcoidosis, and 44.4% (279/629) reported that finances "greatly" or "severely" affected by sarcoidosis. Furthermore, 71.2% (437/614) of participants reported taking medications for sarcoidosis, with the most common being prednisone, methotrexate, hydroxychloroquine, and infliximab. Moreover, 46.4% (244/526) reported medication side effects, most commonly due to prednisone.
We demonstrate that smartphones can prospectively recruit, consent, and study physical activity, QoL, and medication usage in a large sarcoidosis cohort, using both passively collected objective data and qualitative surveys that did not require any in-person encounters. Our study's limitations include the study population being weighted toward more educated and wealthier individuals, suggesting that recruitment was not representative of the full spectrum of patients with sarcoidosis in the United States. Our study provides a model for future smartphone-enabled clinical research for rare diseases and highlights key technical challenges that future research teams interested in smartphone-based research for rare diseases should anticipate. |
We aimed to evaluate US treatment patterns and, more specifically, switch patterns among patients with psoriasis (PsO) who initiated treatment with targeted therapy (TT) and subsequently switched to another therapy.
This retrospective study used IBM
A total of 11,526 patients with PsO were included; mean [standard deviation (SD)] age and Charlson Comorbidity Index score were 48.3 (12.8) years and 0.9 (1.43), respectively. During the follow-up, 69.2% of the patients were treated with NTT. Median time to first NTT, for those who received NTT, was 205 days (longest: adalimumab, 252 days). Among patients who switched to NTT after initiating treatment with TT, 52.6% reinitiated treatment with TT (least common: apremilast, 45.6%), with a median time to reinitiation of 106 days (longest: other biologics, 136 days). For all patients on NTT, the probability of reinitiating any TT was 60.7% at 24 months.
PsO treatment is often cyclical in nature. Patients frequently experience drug holidays or transition back to TT after using NTT. The consideration of real-world treatment patterns in future economic models may provide new insights into the clinical effectiveness and value of PsO treatments.
Psoriasis is a chronic inflammatory skin disease that affects 3.0% of adults or an estimated 7.56 million Americans. The most common type of psoriasis is called plaque psoriasis because of its appearance with red patches and silvery scales on the skin. A major concern of medical providers is that not all patients continue their treatment as prescribed. Many patients discontinue, switch, and often restart treatment. To develop effective psoriasis treatment plans for shared decision-making among medical providers and patients, it is important to look at how treatments are used in the real world. This can be done by conducting studies using insurance claims data from healthcare insurance providers. In this study, we evaluated treatment patterns and, more specifically, patterns in changes of treatment in US patients who began their psoriasis treatment with a targeted therapy (biologics or apremilast) and then changed to another therapy. We found that patients often took drug holidays (days with no treatment) and returned back to using a targeted therapy after using a non-targeted therapy (e.g., other oral therapy, topical treatment, phototherapy, or no treatment). Findings from this real-world study may support future studies on the clinical effectiveness and value of current and future treatments for psoriasis—especially within these targeted to non-targeted transitions. |
The aim of this study was to evaluate the cost effectiveness of tofacitinib versus other treatment options currently available in Colombia in naïve to biologics (first-line) and exposed to biologics (second-line) patients with moderate to severe active ulcerative colitis (UC).
A Markov model was constructed with 8-week cycles, simulating a cohort of patients in a 5-year time horizon. The health states included remission, treatment response, active UC, and colectomy. The transition probabilities for the induction and maintenance phase were obtained from a network meta-analysis, and effectiveness was measured using quality-adjusted life-years (QALYs). Unit costs were derived from official national sources.
For first line, the incremental cost-effectiveness ratio (ICER) per QALY was $883 for tofacitinib and $3619 for infliximab, compared with adalimumab. Sensitivity analysis showed that tofacitinib is cost effective in 45% of the iterations, adalimumab in 5%, and infliximab in 50%. Meanwhile, the ICER of adalimumab was $14,927 compared with tofacitinib in second-line treatment. In the sensitivity analysis, tofacitinib was cost effective in 64% of the iterations, followed by adalimumab in 36%. Infliximab and golimumab were not included due to data limitations in the network meta-analysis of second-line treatment.
The analysis suggests that in Colombia, treatment with tofacitinib for patients with moderate-to-severe UC is a cost-effective option in both lines compared with other treatment options. |
Inflammatory bowel disease (IBD) guidelines recommend tumor necrosis factor-α inhibitors (TNFis) for patients who have not responded to conventional therapy, and vedolizumab in case of inadequate response to conventional therapy and/or TNFis. Recent studies have shown that vedolizumab may also be effective in the earlier treatment lines. Therefore, we conducted cost-effectiveness analyses to determine the optimal treatment sequence in patients with IBD.
A Markov model with a 10-year time horizon compared the cost-effectiveness of different biologic treatment sequences in patients with moderate to severe ulcerative colitis (UC) and Crohn's disease (CD) from the UK and French perspectives. Subcutaneous formulations of infliximab, vedolizumab, and adalimumab were evaluated. Comparative effectiveness was based on a network meta-analysis of clinical trials and real-world evidence. Costs included pharmacotherapy, surgery, adverse events, and disease management.
The results indicated that treatment sequences starting with infliximab were less costly and more effective than those starting with vedolizumab for patients with UC in the United Kingdom and France, and patients with just CD in France. For patients with CD in the United Kingdom, treatment sequences starting with infliximab resulted in better health outcomes with incremental cost-effectiveness ratios (ICERs) near the threshold.
Based on the ICERs, treatment sequences starting with infliximab are the dominant option for patients with UC in the United Kingdom, and patients with UC and CD in France. In UK patients with CD, ICERs were near the assumed "willingness to pay" threshold. These results reinforce the UK's National Institute for Health and Care Excellence recommendations for using infliximab prior to using vedolizumab in biologics-naïve patients.
A Markov model compared the cost-effectiveness of biologic treatment sequences in patients with moderate to severe inflammatory bowel diseases from a European perspective. The results indicated that treatment sequences starting with infliximab are the dominant option than those starting with vedolizumab. |
To assess the efficacy and safety of infliximab versus placebo in the treatment of patients with juvenile-onset spondyloarthritis (JoSpA).
Phase III, randomized, double-blind, placebo-controlled trial of 12 weeks that included patients ≤ 18 years old with JoSpA not responding to nonsteroidal anti-inflammatory drugs, sulfasalazine, or methotrexate. Patients were randomly assigned 1:1 to the infusion of infliximab 5mg/kg or placebo; completers entered then an open-label extension (OLE) period of 42 weeks. The primary endpoint was the number of active joints. Secondary outcomes included the assessment of disease activity, tender entheses, spinal mobility, serum C-reactive protein (CRP), the Bath Ankylosing Spondylitis Disease Activity and Functional Index, and the Childhood Health Assessment Questionnaire (CHAQ).
We randomized 12 patients to infliximab and 14 to placebo. No significant differences were found between groups at baseline. At week 12, the mean number of active joints was 1.4 (SD 2.4) in the infliximab group and 4.1 (SD 3.0) in the placebo group (p = 0.0002). A repeated-measures mixed model analysis that included all endpoints in the study demonstrated sustained favourable outcomes of infliximab for active joints, tender joints, swollen joints, and tender enthesis counts, as well as for CHAQ and CRP (p < 0.01). Adverse events were more frequent in the infliximab group, including infections and infusion reactions, but none of them was serious.
Infliximab is efficacious for patients with JoSpA with an inadequate response to conventional treatment. No serious adverse events with the use of infliximab were observed. |
Introduction Incorporation of a plant-based diet was effective in both induction and short-term relapse prevention in Crohn's disease. Ten-year long-term relapse-free rates in Crohn's disease are around 10% to 23%. Objective We investigated whether infliximab and plant-based diet as first-line therapy enhance the long-term relapse-free rate in patients with Crohn's disease. Methods This single-group, prospective study was performed in tertiary hospitals in Japan. Remission was induced in 24 consecutive newly diagnosed adult patients with Crohn's disease during hospitalization via 3 standard infliximab infusions together with a plant-based diet. Patients were instructed to continue the diet after discharge. Scheduled maintenance infliximab infusion was not used. The primary endpoint was relapse, which was defined as the appearance of symptoms resulting in the alteration of therapeutic modality. The secondary endpoints were C-reactive protein level, plant-based diet score, and surgery. Results The median follow-up period was 8.6 years. Thirteen cases were relapse-free. The relapse-free rate evaluated by Kaplan-Meier survival analysis at 1, 2, 3, and 4 years was 79%, 66%, 57%, and 52%, respectively. There was no further reduction afterward up to 10 years. The relapse-free rate with normal C-reactive protein levels at 1 to 2 and 3 to 10 years was 57% and 52%, respectively. The plant-based diet score at 20 months and 5 years was significantly higher relative to baseline ( |
Clinical data on the efficacy and safety of non-medical switch between adalimumab(ADA) biosimilars are limited.
The aim of this study was to evaluate medium-term clinical efficacy, drug sustainability and safety comparing non-medical switches from the originator to biosimilar ADA, and between ADA biosimilars.
276 consecutive patients on maintenance ADA therapy (n = 205 Crohn's disease, n = 71 ulcerative colitis) were included. Data on clinical efficacy, biomarkers and adverse events were collected at four time points: 8-12 weeks prior switch, at baseline/switch, 8-12 weeks and 20-24 weeks after switch. Drug survival was evaluated after a median 40(IQR:35-42) weeks follow-up.
A total 174 patients underwent a non-medical switch from the originator to a biosimilar, and 102 patients had a biosimilar-to-biosimilar switch. No significant difference was found in clinical remission rates at any time point in patients switching from originator to biosimilar(87.3%/88.5%/86.5%/85.7%) or biosimilar to biosimilar(74.5%/78.4%/85.3%/79.8%). Mean C-reactive protein levels remained unchanged in both cohorts(p = 0.856 and p = 0.525). Drug survival was similar between the two cohorts with a probability of 91.6%(SE: 2.2) and 87.0%(SE:3.4) to stay on drug after 40 weeks(log-rank:0.96; p = 0.327). Five cases of injection related adverse events were reported.
Clinical benefit was sustained following non-medical switch from originator to biosimilar, or between biosimilars in adalimumab treated IBD patients. |
Monitoring plasma levels of Infliximab plays an important role in optimising treatment in patients with inflammatory bowel disease (IBD). The aim of the following study has been to determine the predictive potential of monitoring infliximab plasma levels for sustained clinical response and evaluate its usefulness to improve treatment efficacy and symptom control, in patients with IBD.
This single-centre retrospective study (2017-2019) included patients diagnosed with IBD treated with infliximab. Serum levels and the occurrence of drug-associated immunogenicity were analysed at Week 8 post-induction and 6, 12 and 24 months. Clinical parameters and inflammatory markers were recorded such as subjective global assessment (SGA), C-reactive protein (CRP) and faecal calprotectin (FC). Factors associated with early discontinuation and dose intensification of infliximab were determined.
Multivariate analysis determined that IFX concentrations>7μg/mL at week 8, and at 6 months, are associated with inflammatory remission (p=0.046, 0.045). IFX>7μg/mL at 12 months predicted remission at 18 months of treatment (p=0.006). IFX values>3μg/mL at 12 months are associated with stable SGA at 18 months (p=0.001). Such values at 18 months are associated with stable SGA at 24 months (p=0.044).
The predictive potential of monitoring IFX plasma levels as a strategy to evaluate sustained long-term clinical response was confirmed. Our results highlight the importance of its introduction into routine clinical practice to enable early identification of non-responders, treatment optimisation, relapse prevention and improve long-term therapy maintenance. |
Registry-based observational prospective study aimed at describing the use of biologic drugs in pediatric-onset scleritis. Data were collected at baseline, at 3-, 6-, 12-month follow-up and at last assessment. Scleral inflammation was graded according to Sen classification. Five patients (9 eyes) treated with adalimumab, infliximab, abatacept and secukinumab were included. All patients were previously treated with conventional immunosuppressors and glucocorticoids. Median biologic treatment duration was 28 (IQR = 118) months. At 6-months, scleritis resolved in all eyes. At 12-months, complete disease control was observed in 7/9 eyes (77.8%). The number of relapses 12 months before and after treatment initiation was 17 and 2, respectively. Mean BCVA was 0.83 (range 0.3-1.0) at baseline and 1.0 for all eyes after 12 months. Glucocorticoids had been withdrawn in 4/5 patients.In conclusion, biological agents proved to be effective in pediatric-onset scleritis, allowing a noticeable steroid-sparing effect and preserving visual function and bulbar integrity. |
There is insufficient evidence on the clinical effectiveness and safety of infliximab (IFX) treatment of Takayasu arteritis (TA) in infants.
We evaluated the therapeutic effectiveness and safety of IFX in a retrospective case series of 10 infantile TA patients. Observations included assessment of clinical symptoms, laboratory testing, and vascular imaging.
Fever was the presenting symptom for 8 of 10 infants with TA. During acute episodes, leucocyte and inflammatory indices were significantly increased. Vascular imaging showed the most commonly involved arteries to be carotid arteries, abdominal aortas, and coronary arteries (9 cases, 90%). Two weeks after initiating IFX treatment, leukocyte and platelet counts decreased and hemoglobin levels increased. There were statistically significant clinical improvements 6 weeks after starting treatment compared with before treatment (p < 0.05). Inflammatory indices decreased 2 weeks after starting IFX treatment compared with before treatment (p < 0.05). Vascular lesions began to recover within 1.5-3 months of initiating IFX therapy, and involved vessels significantly recovered within 13 months. Some arteries remained stenotic, with intimal thickening and uneven lumen wall thicknesses. The only adverse event was a treatment-responsive allergic reaction during IFX infusion in one infant.
Fever was the main manifestation of illness and was often accompanied by significantly increased inflammatory indices. IFX treatment was apparently effective and reduced or eliminated need for glucocorticoids. IFX had a reasonably good safety profile. |
We report on the incidental finding of Kaposi sarcoma of the colon in the setting of refractory ulcerative colitis treatment. The patient was under long-term immunosuppression with infliximab, vedolizumab, and prednisolone. Serologic analysis excluded human immunodeficiency virus (HIV) infection.
Wir berichten über den Zufallsbefund eines Kaposi-Sarkoms des Kolons bei schwerer therapierefraktärer Colitis ulcerosa. Die Patientin war zuvor lange immunsuppressiv mit Infliximab, Vedolizumab und Prednisolon behandelt worden. Serologische Untersuchungen schlossen eine HIV(„human immunodeficiency virus“)-Infektion aus. |
Dermatomyositis is an autoimmune disease mainly characterized by muscle and skin involvement. Its association with cancer is known but the term «paraneoplastic» remains debated. We report here the case of a 71-year-old woman with a new diagnosis of dermatomyositis with, at the same time, the discovery of a lung adenocarcinoma. Lung cancer was treated with pembrolizumab, an immune checkpoint inhibitor directed against the "Programmed cell Death protein 1" (PD-1) receptor. Three weeks later, the patient presented a severe flare of dermatomyositis. Administration of intravenous corticosteroids and infliximab were ineffective. Intravenous immunoglobulins were then administered, followed by subcutaneous methotrexate, with a progressive positive evolution. Flares of pre-existing autoimmune diseases are observed under immune check point inhibitors, even when the evolution of the cancer is favourable. These immune-related adverse events are often «mild to moderate» and severe immune related side effects are not more frequent when the patient has a pre-existing autoimmune disease. Treatment can be maintained in the majority of cases. However, as demonstrated in this clinical case, although immune checkpoint inhibitors are not contraindicated in autoimmune diseases, the presence of myositis requires special attention given the potential severity of flares.
: La dermatomyosite est une maladie auto-immune principalement caractérisée par une atteinte musculaire et cutanée. Son association avec le cancer est connue, mais le terme «paranéoplasique» reste débattu. Nous rapportons ici le cas d’une patiente de 71 ans avec un nouveau diagnostic de dermatomyosite et, au même moment, la découverte d’un adénocarcinome pulmonaire. La néoplasie pulmonaire a été traitée par pembrolizumab, un inhibiteur des points de contrôle immunitaire dirigé contre le récepteur «Programmed cell Death protein 1» (PD-1). Trois semaines plus tard, la patiente présentera une poussée sévère de dermatomyosite, ne répondant pas à la corticothérapie intraveineuse ni à l’infliximab. Des immunoglobulines intraveineuses sont alors administrées, suivies de méthotrexate sous-cutané, avec une évolution progressivement positive. On observe des poussées de maladies auto-immunes préexistantes sous inhibiteurs de points de contrôle immunitaire, même quand l’évolution néoplasique est favorable. Ces effets secondaires immuno-induits sont souvent «légers à modérés» et on n’observe pas plus de manifestations indésirables «sévères» lorsque le patient présente une maladie auto-immune pré-existante. Le traitement peut être maintenu dans la majorité des cas. Toutefois, comme démontré dans ce cas clinique, bien que les inhibiteurs de points de contrôle immunitaire ne soient pas contre-indiqués en cas de maladie auto-immune, la présence d’une myosite nécessite une attention particulière vu la gravité potentielle des poussées. |
Rheumatic immune-related adverse events (irAE) such as (poly)arthritis in patients undergoing immune checkpoint inhibitor (ICI) treatment pose a major clinical challenge. ICI therapy improves CD8
Peripheral CD8 obtained from ICI-treated patients with and without arthritis irAEs and from AA patients with and without a history of malignancy were stimulated in media containing
CD8 from patients with irAE showed significantly lower frequency and expression of cell-surface molecule characteristic for activation, effector-functions, homing, exhaustion and apoptosis and reduced release of cytotoxic and proinflammatory immune mediators compared with CD8 from ICI patients who did not develop irAE. This was accompanied by a higher glycolytic rate and ATP production. Gene-expression analysis of pre-ICI-treated CD8 revealed several differentially expressed transcripts in patients who later developed arthritis irAEs. In vitro tofacitinib or infliximab treatment did not significantly change the immune-metabolic profile nor the capacity to release cytolytic mediators that inhibit the growth of the human lung cancer cell line H838.
Our study shows that CD8 from ICI-treated patients who develop a musculoskeletal irAE has a distinct immune-effector and metabolic profile from those that remain irAE free. This specific irAE profile overlaps with the one observed in CD8 from AA patients and may prove useful for novel therapeutic strategies to manage ICI-induced irAEs. |
There is a need to better understand the positioning of biologic therapies for long-term outcomes in biologic-naïve Crohn's disease (CD). We assessed the comparative effectiveness of infliximab and ustekinumab among induction responders for 1-year outcomes.
This post hoc analysis included data from 220 biologic-naïve CD participants with response to induction therapy from 2 clinical trial programs. Participants achieving 1-year clinical remission (CR) (Crohn's disease activity index <150), corticosteroid-free CR, normalization of fecal calprotectin (FC), endoscopic response (Simple Endoscopic Score for CD decrease ≥50% from baseline), and endoscopic remission (ER) (Simple Endoscopic Score for CD <3) were compared. Multivariate logistic regression evaluated the likelihood of achieving the outcomes adjusted for confounders. Propensity score matching created a cohort with similar distribution of baseline covariates.
One-year CR and corticosteroid-free CR rates were similar between infliximab-treated and ustekinumab-treated patients (CR, 66 of 110 [60.0%] vs 63 of 110 [57.3%]; adjusted odds ratio [aOR], 1.15; 95% CI, 0.67-1.98; P = .681; corticosteroid-free CR, 11 of 28 (39.3%) vs 27 of 51 [52.9%]; aOR, 0.58; 95% CI, 0.23-1.47; P = .251). Compared with ustekinumab-treated patients, infliximab-treated participants were more likely to achieve 1-year endoscopic response (43 of 92 [46.7%] vs 6 of 30 [20.0%], aOR, 3.59; 95% CI, 1.34-9.66; P = .011) and ER (31 of 92 [33.7%] vs 4 of 30 [13.3%]; aOR, 3.35; 95% CI, 1.07-10.49; P = .038). Among patients with FC ≥250 mg/kg at baseline, normalization (<250 mg/kg) at 1-year was similar between groups. Similar results were observed within the propensity matched population for all analyses.
Treatment with infliximab and ustekinumab among induction responders achieved 1-year CR with similar efficacy, but infliximab may confer greater benefit for endoscopic outcomes. Findings should be interpreted with caution as our analyses were unpowered.
In this post hoc analysis of biologic-naïve CD patients, treatment with infliximab and ustekinumab among induction responders achieved 1-year clinical remission with similar efficacy, but infliximab may confer greater benefit for endoscopic outcomes. |
A 45-year-old man with a 10-year history of biopsy-proven, steroid-dependent sclerosing mesenteritis failed/was intolerant to tamoxifen, azathioprine, colchicine, cyclophosphamide, and methotrexate. He developed osteoporosis, diabetes, and bilateral cataracts. He responded to infliximab but was diagnosed with mesenteric large B-cell lymphoma 6 months after treatment initiation. He achieved remission from lymphoma after chemotherapy, but the sclerosing mesenteritis remained poorly controlled. He was treated with ustekinumab (520 mg intravenously followed by 90 mg subcutaneously every 8 weeks), leading to complete steroid-free remission. He remains symptom and cancer-free 24 months after starting ustekinumab. |
Immune checkpoint inhibitors (ICIs) have improved cancer outcomes. However, immune-related adverse effects are common. The aim was to investigate the incidence of diarrhea and colitis of ICIs alone and in combination with chemotherapy or tyrosine kinase inhibitors (TKIs), histopathological findings, and management.
Two separate studies, including meta-analyses, were performed. Key inclusion criteria were for Study I) phase I-IV trials, and data on diarrhea and/or colitis; for Study II) studies describing histopathologic and endoscopic findings and/or biologic treatment for ICI-induced colitis.
The incidence of anti-PD-1/PD-L1 antibody-induced diarrhea and colitis was 10% and 2%, respectively, with no clinically relevant differences between the compounds. The CTLA-4 inhibitor, ipilimumab, induced diarrhea and colitis in 33% and 7% of patients, respectively, whereas the incidence of diarrhea and colitis following ipilimumab combined with nivolumab was 21%-37% and 4%-8%, depending on regimen. The incidence of all-grade diarrhea following ICIs combined with chemotherapy or TKIs was high (17%-56%), whereas only 0.5% of patients developed severe (≥grade 3) colitis. The main patterns of histopathologic presentation after PD-1/CTLA-4 inhibitor mono- or combination therapy were acute and chronic active colitis and microscopic colitis-like. Infliximab and vedolizumab were equally effective against ICI-induced colitis.
Expanding treatment options include combinations of ICIs and chemotherapy/TKI with a high incidence of diarrhea and a low incidence of colitis; thus, a potential risk of overtreatment with corticosteroids exists. We suggest a more tailored approach, particularly for the management of low-grade diarrhea. Prospective clinical trials are needed to refine management. |
Real-life data on the efficacy of ustekinumab as first-line therapy for the treatment of luminal Crohn's disease (CD) compared with anti-tumor necrosis factor (anti-TNF) agents are lacking. We compared the clinical response rates at 3 months in 2 cohorts of biologic-naïve patients treated by ustekinumab and anti-TNF agents.
Biologic-naïve patients starting either ustekinumab or an anti-TNF agent for luminal CD between 2016 and 2019 in 2 tertiary centers were retrospectively included. The primary endpoint was clinical response at 3 months, defined as a Harvey-Bradshaw Index <4 or a 3-point drop in the score without steroids, need for CD-related surgery, or treatment discontinuation owing to failure or intolerance. Patients treated with ustekinumab were matched to patients receiving anti-TNF agents by a propensity score algorithm.
We included 156 patients starting anti-TNF agents (95 adalimumab and 61 infliximab) and 50 ustekinumab. After matching, clinical response rates at 3 months were 64% and 86% in the ustekinumab and anti-TNF groups, respectively (P = .01). At 12 months, in multivariate analysis adjusted for disease duration, location, concomitant immunosuppressant and steroids, and symptoms, clinical remission was independently associated with the biological therapy received (odds ratio, 2.6 for anti-TNF agent vs ustekinumab; P = .02). With a median follow-up duration of 40 (interquartile range, 23-52) months, no difference was observed in terms of time to drug withdrawal (P = .29) or safety.
This retrospective real-world data suggest that an anti-TNF agent as a first-line biological therapy is associated with higher rates of response at 3 months than ustekinumab in patients with CD.
We conducted a retrospective real-world study to compare the efficacy of biologics in Crohn’s disease. Our data suggest that an anti-tumor necrosis factor agent as a first-line biological therapy is associated with higher rates of response at 3 months than ustekinumab in Crohn’s disease. |
Ulcerative colitis (UC) classically presents with abdominal pain, hematochezia, or diarrhea. However, it can present atypically in pediatric and pregnant patients, posing a diagnostic challenge. A healthy, 16-year-old primigravida presented at 18 weeks and six days of gestation with sudden-onset altered mental status and severe anemia. Hematochezia began about 12 hours after admission. She underwent extensive workup, leading to an endoscopic and histopathologic diagnosis of UC, and achieved prenatal remission with high-dose steroids and infliximab. Her pregnancy, however, was complicated by severe preeclampsia, and her child's post-delivery course was medically complex from an unrelated etiology. Pregnancy-onset inflammatory bowel disease (IBD) in the pediatric population is an uncommon but important consideration. Early diagnosis, treatment, and counseling are vital to achieve results comparable to those of patients without IBD. |
Clinically overt granulomatous involvement of the nervous system (i.e. neurosarcoidosis) can be seen in up to 10% of patients with sarcoidosis. Establishing a diagnosis of neurosarcoidosis is often challenging due to the heterogeneity of clinical presentations that are sometimes nonspecific, and inaccessibility of tissue confirmation. Recommended treatments are based on expert opinions that are derived from clinical experience and limited data from retrospective studies, as data from randomized controlled studies are limited.
In this article, we comprehensively review all available literature on epidemiology, clinical presentations, diagnosis, treatment, and outcomes of neurosarcoidosis. We also offer our opinions on diagnostic approach and treatment strategy.
Given the invasive nature and the limited sensitivity of biopsy of the nervous system, diagnosis of neurosarcoidosis is usually made when ancillary tests (such as magnetic resonance imaging and cerebrospinal fluid analysis) are compatible, and alternative diagnoses are reasonably excluded in patients with established extraneural sarcoidosis. Several factors must be taken into consideration to formulate the initial treatment strategy, including the extent of the disease, severity, functional impairment, comorbidities, and patient's preference. In addition, treatment regimen of neurosarcoidosis should be formulated with an emphasis on long-term strategy. |
There are numerous biological therapies and small molecules licensed for luminal Crohn's disease (CD), but these are often studied in placebo-controlled trials, meaning relative efficacy is uncertain. We examined this in a network meta-analysis.
We searched the literature to 1 July 2022, judging efficacy according to induction of clinical remission, clinical response and maintenance of clinical remission, and according to previous exposure or non-exposure to biologics. We used a random effects model and reported data as pooled relative risks (RRs) with 95% CIs, ranking drugs according to p-score.
We identified 25 induction of remission trials (8720 patients). Based on failure to achieve clinical remission, infliximab 5 mg/kg ranked first versus placebo (RR=0.67, 95% CI 0.56 to 0.79, p-score 0.95), with risankizumab 600 mg second and upadacitinib 45 mg once daily third. However, risankizumab 600 mg ranked first for clinical remission in biologic-naïve (RR=0.66, 95% CI 0.52 to 0.85, p-score 0.78) and in biologic-exposed patients (RR=0.74, 95% CI 0.67 to 0.82, p-score 0.92). In 15 maintenance of remission trials (4016 patients), based on relapse of disease activity, upadacitinib 30 mg once daily ranked first (RR=0.61, 95% CI 0.52 to 0.72, p-score 0.93) with adalimumab 40 mg weekly second, and infliximab 10 mg/kg 8-weekly third. Adalimumab 40 mg weekly ranked first in biologic-naïve patients (RR=0.59, 95% CI 0.48 to 0.73, p-score 0.86), and vedolizumab 108 mg 2-weekly first in biologic-exposed (RR=0.70, 95% CI 0.57 to 0.86, p-score 0.82).
In a network meta-analysis, infliximab 5 mg/kg ranked first for induction of clinical remission in all patients with luminal CD, but risankizumab 600 mg was first in biologic-naïve and biologic-exposed patients. Upadacitinib 30 mg once daily ranked first for maintenance of remission. |
Restorative proctocolectomy with IPAA is the procedure of choice when colectomy is needed for medically refractory ulcerative colitis. Pouchitis is one of the most common complications among patients who have undergone IPAA and represents a spectrum of disease varying in both phenotype and clinical course.
This study aimed to assist clinicians and surgeons in the treatment of both acute and chronic pouchitis, including newer therapies and future directions.
Diagnosis is made by endoscopy of the pouch with biopsy because other conditions may produce similar symptoms such as increased stool frequency, abdominal cramps, and urgency. Pouchitis is classified by duration (acute versus chronic), disease pattern (infrequent, relapsing, and continuous), and response to antibiotics (responsive, dependent, and refractory). The Pouchitis Disease Activity Index may be used to measure disease activity. The management of pouchitis is guided by the disease phenotype. Acute episodes are treated with an initial 2-week course of antibiotics (typically ciprofloxacin or metronidazole), although patients with relapsing or chronic pouchitis may require long-term antibiotic treatment or the cycling of different antibiotics. Certain probiotics may also be used for maintenance therapy in those with chronic symptoms. For patients with chronic antibiotic refractory pouchitis, oral budesonide, immunosuppressive agents (azathioprine), or biologic therapy (infliximab, adalimumab, vedolizumab, and ustekinumab) may be required for both induction and maintenance with close monitoring for potential side effects. In rare cases, diverting ileostomy or pouch excision may be required.
Pouchitis represents a spectrum of disease phenotypes, ranging from acute antibiotic responsive pouchitis to chronic antibiotic refractory pouchitis. The management of pouchitis is primarily directed by the disease phenotype. |
Few Saudi studies have examined adverse drug reactions (ADRs) in patients with rheumatoid arthritis (RA) receiving intravenous (IV) originator biologics. Therefore, this study aimed to evaluate the prevalence, types, and predictors of ADRs following long-term IV originator biologic use in patients with RA.
This retrospective, single-center study included adult patients with RA who received IV originator biologics between 2015 and 2020. Medical records were reviewed and data regarding ADRs were collected and evaluated for causality using the Naranjo scale. Binary logistic regression analysis was performed to identify the odds for and factors associated with developing ADRs for each biologic.
A total of 129 patients (87.6% women) with a mean (standard deviation) age of 54 (13) years were included in this study. A total of 1963 doses of tocilizumab (38.76%), rituximab (38.76%), abatacept (13.95%), and infliximab (8.53%), were administered during the study period. ADRs with a Naranjo score ≥ 1 were experienced by 103 (78%) patients, with an average of 2.2 events per patient. Infection (26.6%) and skin and mucous membrane disorders (14.18%) were the most commonly reported ADRs. Abatacept was associated with a significantly higher risk of multiple ADRs than the other biologics (adjusted odds ratio: 3.145, 95% confidence interval 1.004-9.854, p = 0.049).
There was a high prevalence of ADRs among patients with RA receiving biologics. Abatacept was associated with a greater risk of multiple ADRs than other biologics. Infection was the most common ADR. Future multicenter longitudinal studies are warranted. |
Crohn's disease (CD) is characterized by excessive protease activity and extracellular matrix (ECM) remodeling. To date, 30-50% of patients experience non-response to anti-TNF-α treatment. This study aimed to assess whether serological biomarkers of ECM turnover could monitor or predict response to infliximab (IFX) induction therapy in patients with and without a surgical history.
Serum biomarkers of type I (C1M), III (C3M), IV (C4M), and VI (C6Ma3) collagen degradation, type III (PRO-C3) and VI (PRO-C6) collagen formation, basement membrane turnover (PRO-C4), and T-cell activity (C4G), were measured at baseline and week 14, in 63 patients with CD undergoing IFX induction therapy. Patients were stratified according to surgical history.
C4M was elevated at baseline in responders with a surgical history (
Baseline levels of a serological biomarker for type IV collagen degradation associated with response to IFX induction therapy, and biomarkers of type III and VI collagen formation may be used to monitor response at the end of induction therapy in patients with a surgical history. Biomarker ratios of type IV collagen turnover demonstrated promising results in monitoring treatment response in patients without a surgical history. |
There is limited information regarding disease-modifying antirheumatic drug (DMARD)-dependent risks of overall, incident, and recurrent herpes zoster (HZ) during first-line biologic DMARD (bDMARD) or targeted synthetic DMARD (tsDMARD) treatment among patients with seropositive rheumatoid arthritis (RA) in terms of HZ risk.
A total of 11,720 patients with seropositive RA who were prescribed bDMARD or tofacitinib between January 2011 and January 2019 from the Korean Health Insurance Review & Assessment Service database were studied. A multivariate Cox proportional hazards regression model was adopted to evaluate the adjusted hazard ratio (aHR) with 95% confidence interval (CI) for the risk of HZ dependent on the choice of first-line bDMARDs or tsDMARD, including etanercept, infliximab, adalimumab, golimumab, tocilizumab, rituximab, tofacitinib, and abatacept.
During the 34,702 person-years of follow-up, 1686 cases (14.4%) of HZ were identified, including 1372 (11.7%) incident and 314 (2.7%) recurrent HZs. Compared with that of the abatacept group, tofacitinib increased the overall risk (aHR, 2.46; 95% CI, 1.61-3.76; P<0.001), incidence (aHR, 1.99; 95% CI, 1.18-3.37; P=0.011), and recurrence (aHR, 3.69; 95% CI, 1.77-7.69; P<0.001) of HZ. Infliximab (aHR, 1.36; 95% CI, 1.06-1.74; P=0.017) and adalimumab (aHR, 1.29; 95% CI, 1.02-1.64; P=0.032) also increased the overall HZ risk. Moreover, a history of HZ was found to be an independent risk factor for HZ (aHR, 1.54; 95% CI, 1.33-1.78; P<0.001).
HZ risk is significantly increased in RA patients with a history of HZ after the initiation of bDMARDs or tsDMARD. The risk of incident and recurrent HZ was higher after tofacitinib treatment in patients with RA than that after treatment with bDMARDs. Individualized characteristics and history of HZ should be considered when selecting bDMARDs or tsDMARD for RA patients considering HZ risks. |
Antitumour necrosis factor (TNF) drugs impair serological responses following SARS-CoV-2 vaccination. We sought to assess if a third dose of a messenger RNA (mRNA)-based vaccine substantially boosted anti-SARS-CoV-2 antibody responses and protective immunity in infliximab-treated patients with IBD.
Third dose vaccine induced anti-SARS-CoV-2 spike (anti-S) receptor-binding domain (RBD) antibody responses, breakthrough SARS-CoV-2 infection, reinfection and persistent oropharyngeal carriage in patients with IBD treated with infliximab were compared with a reference cohort treated with vedolizumab from the impaCt of bioLogic therApy on saRs-cov-2 Infection and immuniTY (CLARITY) IBD study.
Geometric mean (SD) anti-S RBD antibody concentrations increased in both groups following a third dose of an mRNA-based vaccine. However, concentrations were lower in patients treated with infliximab than vedolizumab, irrespective of whether their first two primary vaccine doses were ChAdOx1 nCoV-19 (1856 U/mL (5.2) vs 10 728 U/mL (3.1), p<0.0001) or BNT162b2 vaccines (2164 U/mL (4.1) vs 15 116 U/mL (3.4), p<0.0001). However, no differences in anti-S RBD antibody concentrations were seen following third and fourth doses of an mRNA-based vaccine, irrespective of the combination of primary vaccinations received. Post-third dose, anti-S RBD antibody half-life estimates were shorter in infliximab-treated than vedolizumab-treated patients (37.0 days (95% CI 35.6 to 38.6) vs 52.0 days (95% CI 49.0 to 55.4), p<0.0001).Compared with vedolizumab-treated, infliximab-treated patients were more likely to experience SARS-CoV-2 breakthrough infection (HR 2.23 (95% CI 1.46 to 3.38), p=0.00018) and reinfection (HR 2.10 (95% CI 1.31 to 3.35), p=0.0019), but this effect was uncoupled from third vaccine dose anti-S RBD antibody concentrations. Reinfection occurred predominantly during the Omicron wave and was predicted by SARS-CoV-2 antinucleocapsid concentrations after the initial infection. We did not observe persistent oropharyngeal carriage of SARS-CoV-2. Hospitalisations and deaths were uncommon in both groups.
Following a third dose of an mRNA-based vaccine, infliximab was associated with attenuated serological responses and more SARS-CoV-2 breakthrough infection and reinfection which were not predicted by the magnitude of anti-S RBD responses, indicative of vaccine escape by the Omicron variant.
ISRCTN45176516. |
No multi-national prospective study of drug-induced liver injury (DILI) has originated in Europe. The design of a prospective European DILI registry, clinical features and short-term outcomes of the cases and controls is reported.
Patients with suspected DILI were prospectively enrolled in the United Kingdom, Spain, Germany, Switzerland, Portugal and Iceland, 2016-2021. DILI cases or non-DILI acute liver injury controls following causality assessment were enrolled.
Of 446 adjudicated patients, 246 DILI patients and 100 had acute liver injury due to other aetiologies, mostly autoimmune hepatitis (n = 42) and viral hepatitis (n = 34). DILI patients (mean age 56 years), 57% women, 60% with jaundice and 3.6% had pre-existing liver disease. DILI cases and non-DILI acute liver injury controls had similar demographics, clinical features and outcomes. A single agent was implicated in 199 (81%) DILI cases. Amoxicillin-clavulanate, flucloxacillin, atorvastatin, nivolumab/ipilimumab, infliximab and nitrofurantoin were the most commonly implicated drugs. Multiple conventional medications were implicated in 37 (15%) and 18 cases were caused by herbal and dietary supplements. The most common single causative drug classes were antibacterials (40%) and antineoplastic/immunomodulating agents (27%). Overall, 13 (5.3%) had drug-induced autoimmune-like hepatitis due to nitrofurantoin, methyldopa, infliximab, methylprednisolone and minocycline. Only six (2.4%) DILI patients died (50% had liver-related death), and another six received liver transplantation.
In this first multi-national European prospective DILI Registry study, antibacterials were the most commonly implicated medications, whereas antineoplastic and immunomodulating agents accounted for higher proportion of DILI than previously described. This European initiative provides an important opportunity to advance the study on DILI. |
Kawasaki disease (KD) is an acute and febrile systemic vasculitis that occurs during childhood. Infliximab (IFX) is a chimeric monoclonal antibody that binds to tumor necrosis factor-α. Although IFX therapy is a useful option for refractory KD, vaccine-associated infections may develop after therapy. In Japan, IFX therapy is recommended after a duration of at least 3 months after live vaccinations or at least 6 months after Bacillus Calmette-Guérin (BCG) in children with KD. However, the appropriate duration between live vaccinations and IFX therapy is unclear.
We investigated children who developed KD within 3 months after live vaccinations or within 6 months after BCG. Clinical characteristics, side effects of therapies and efficacy of live vaccinations were retrospectively investigated.
Forty-eight patients developed KD within 3 months of live vaccinations or within 6 months after BCG. Eight patients underwent IFX therapy. There were no apparent vaccine-associated infections. The patients who underwent IFX acquired protective IgG antibody titers in the 5 of 6 live vaccines.
Safe and appropriate duration between live vaccinations and IFX therapy for KD patients could be shorter in the future, although more studies are warranted to establish the safe duration. |
Endoscopic-post-operative-recurrence [ePOR] in Crohn's disease [CD] after ileocecal resection [ICR] is a major concern. We aimed to evaluate the effectiveness of early prophylaxis with biologics and to compare anti-tumour necrosis factor [anti-TNF] therapy to vedolizumab [VDZ] and ustekinumab [UST] in a real-world setting.
A retrospective multicentre study of CD-adults after curative ICR on early prophylaxis was undertaken. ePOR was defined as a Rutgeerts score [RS] ≥ i2 or colonic-segmental-SES-CD ≥ 6. Multivariable logistic regression was used to evaluate risk factors, and inverse probability treatment weighting [IPTW] was applied to compare the effectiveness between agents.
The study included 297 patients (53.9% males, age at diagnosis 24 years [19-32], age at ICR 34 years [26-43], 18.5% smokers, 27.6% biologic-naïve, 65.7% anti-TNF experienced, 28.6% two or more biologics and 17.2% previous surgery). Overall, 224, 39 and 34 patients received anti-TNF, VDZ or UST, respectively. Patients treated with VDZ and UST were more biologic experienced with higher rates of previous surgery. ePOR rates within 1 year were 41.8%. ePOR rates by treatment groups were: anti-TNF 40.2%, VDZ 33% and UST 61.8%. Risk factors for ePOR at 1 year were: past-infliximab (adjusted odds ratio [adj.OR] = 1.73 [95% confidence interval, CI: 1.01-2.97]), past-adalimumab [adj.OR = 2.32 [95% CI: 1.35-4.01] and surgical aspects. After IPTW, the risk of ePOR within 1 year of VDZ vs anti-TNF or UST vs anti-TNF was comparable (OR = 0.55 [95% CI: 0.25-1.19], OR = 1.86 [95% CI: 0.79-4.38]), respectively.
Prevention of ePOR within 1 year after surgery was successful in ~60% of patients. Patients treated with VDZ or UST consisted of a more refractory group. After controlling for confounders, no differences in ePOR risk were seen between anti-TNF prophylaxis and other groups. |
Vaccination has been effective in preventing COVID-19 infections and related mortality. However, waning immunity after two-dose vaccination prompted health authorities to recommend a third dose of COVID-19 vaccine to boost immunity. The aim of our study was to assess willingness to receive a third (booster) dose among patients with inflammatory bowel disease (IBD).
A cross-sectional study was performed at an IBD tertiary care center. Patients were recruited at the infusion room from 1 January 2022 to 31 March 2022. The primary outcome was the prevalence of a third (booster) dose of the BNT162b2 vaccine in infliximab- or vedolizumab-treated patients with IBD. The secondary outcome evaluated whether the prevalence of a third (booster) dose of the BNT162b2 vaccine differed based on type of COVID-19 vaccine, gender, age, type of biologic therapy, and citizenship.
In total, 499 patients with IBD were included in this study. The median age was 34.5 years, and 60% had ulcerative colitis (UC). Among the study participants, 302 (60.5%) patients were vaccinated with BNT162b2, and 197 (39.5%) were vaccinated with ChAdOx1 nCoV-19. Of the total number of participants, 400 (80.2%) were receiving infliximab, and 99 (19.8%) were receiving vedolizumab. Overall, 290 (58.1%) of the included patients were willing to receive the third (booster) dose. Patients vaccinated with BNT162b2 were more likely to be willing to receive a booster dose compared to patients vaccinated with ChAdOx1 nCoV-19 (201 (66.5%) vs. 103 (52.0%),
The percentage of patients with IBD willing to receive or having already received a third (booster) dose of BNT162b2 vaccine was lower compared to the general population. In addition, patients who received two doses of BNT162b2 vaccines were more likely to be willing to receive a third (booster) dose compared to patients who received ChAdOx1 nCoV-19. Patients treated with infliximab were more likely to be willing to receive a third (booster) dose of COVID-19 vaccine. |
The advent of monoclonal antibodies (mAbs) has revolutionized the management of many immune-mediated diseases such as inflammatory bowel disease (IBD). Infliximab and adalimumab were the first mAbs approved for the management of IBD, and are still commonly prescribed for the treatment of both Crohn's disease (CD) and ulcerative colitis (UC). Although mAbs have demonstrated high effectiveness rates in the management of IBD, some patients fail to respond adequately to mAbs, resulting in disease progression and the flare-up of symptoms.
The objective was to explore the predictors of treatment failure among IBD patients on infliximab (INF) and adalimumab (ADA)-as demonstrated via colonoscopy with a simple endoscopic score (SES-CD) of ≥1 for CD and a Mayo score of ≥2 for UC-and compare the rates of treatment failure among patients on those two mAbs.
This was a prospective cohort study among IBD patients aged 18 years and above who had not had any exposure to mAbs before. Those patients were followed after the initiation of biologic treatment with either INF or ADA until they were switched to another treatment due to failure of these mAbs in preventing the disease progression. Univariate and multiple logistic regressions were conducted to examine the predictors and rates of treatment failure.
A total of 146 IBD patients (118 patients on INF and 28 on ADA) met the inclusion criteria and were included in the analysis. The mean age of the patients was 31 years, and most of them were males (59%) with CD (75%). About 27% and 26% of the patients had penetrating and non-stricturing-non-penetrating CD behavior, respectively. Patients with UC had significantly higher odds of treatment failure compared to their counterparts with CD (OR = 2.58, 95% CI [1.06-6.26],
Infliximab was shown to be more effective in the management of IBD, with lower incidence rates of treatment failure in comparison to adalimumab. |
Previous studies have consistently revealed that both local and systemic inflammations are the key to the onset and progression of osteoarthritis (OA). Thus, anti-inflammatory biologic agents could potentially attenuate the progression of OA. We conducted this meta-analysis to examine the efficacy and safety of ant-inflammatory biologic agents among OA patients.
Five databases were searched for randomized controlled trials (RCTs) comparing biologics with placebo or each other in OA patients. Data of pain, physical function, stiffness, and adverse events (AEs) were extracted for a conventional and a Bayesian network meta-analysis.
15 studies with data for 1566 patients were analyzed. In the conventional meta-analysis, etanercept (SMD -0.47; 95% CI -0.89, -0.05) and infliximab (SMD -2.04; CI -2.56, -1.52) were superior to placebo for knee pain. In the network meta-analysis, infliximab was superior to all the other biologic agents in improving pain (vs. hyaluronic acid (SMD -22.95; CI -34.21, -10.43), vs. adalimumab (SMD -21.71; CI -32.65, -11.00), vs. anakinra (SMD -24.63; CI -38.79, -10.05), vs. canakinumab (SMD -32.83; CI -44.45, -20.68), vs. etanercept (SMD -18.40; CI -29.93, -5.73), vs. lutikizumab (SMD -25.11; CI -36.47, -14.78), vs. naproxen (SMD -30.16; CI -41.78, -17.38), vs. tocilizumab (SMD -24.02; CI -35.63, -11.86) and vs. placebo (SMD -25.88; CI -34.87, -16.60)). No significant differences were observed between biologics and placebo regarding physical function, stiffness, and risk of AEs.
The findings suggest that infliximab may relieve pain more than other biological agents in OA patients. No significant differences were observed between biologics and placebo regarding physical function, stiffness, and risk of AEs. The results must be interpreted cautiously; therefore, further randomized controlled trials are warranted. |
Psoriasis is an autoimmune disease in which the disturbed dependencies between lymphocytes, dendritic cells, keratinocytes and neutrophils play the most important role. One of them is the overproduction of neutrophil extracellular traps (NETs). The release of NETs can be induced by pathogens, as well as antibodies and immune complexes, cytokines and chemokines, including TNFα. The first step of the NET creation is the activation of peptidyl arginine deiminase 4 (PAD-4). PAD-4 seems to be responsible for citrullination of histones and chromatin decondensation, but the data on PAD-4 in NETs is inconclusive. Thus, the current study aimed to determine PAD-4 and TNFα levels in the serum of psoriatic patients by ELISA and observe the response of these factors to systemic (anti-17a, anti-TNFα and methotrexate) therapies. Increased levels of both PAD-4 and its main stimulus factor TNFα in pre-treatment patients have been reported along with the concentrations of proteins correlated with disease severity (PASI, BSA). Before treatment, the irregularities in the case of anti-nuclear antibodies level (ANA) were also observed. All of the applied therapies led to a decrease in PAD-4 and TNFα levels after 12 weeks. The most significant changes, both in protein concentrations as well as in scale scores, were noted with anti-TNFα therapy (adalimumab and infliximab). This phenomenon may be associated with the inhibition of TNFα production at different stages of psoriasis development, including NET creation. The obtained data suggest the participation of PAD-4 in the activation of neutrophils to produce NETs in psoriasis, which may create opportunities for modern therapies with PAD inhibitors. However, further exploration of gene and protein expression in psoriatic skin is needed. |
In cases of sepsis, the immune system responds with an uncontrolled release of proinflammatory cytokines and reactive oxygen species. The lungs, kidneys, and liver are among the early impacted organs during sepsis and are a direct cause of mortality. The aim of this study was to compare the effects of infliximab (IFX) and celecoxib (CLX) on septic rats that went through a cecal ligation and puncture (CLP) surgery to induce sepsis. This study included four groups: sham, CLP (untreated), and CLP-treated with CLX or IFX. The administration of "low dose" CLX or IFX was performed after 2 h following the induction of sepsis. Twenty-four hours following the induction of sepsis, the rats were sacrificed and blood samples were collected to evaluate kidney, liver, and lung injuries. MDA and NOx content, in addition to SOD activity and GSH levels, were evaluated in the tissue homogenates of each group. Tissue samples were also investigated histopathologically. In a separate experiment, the same groups were employed to evaluate the survival of septic rats in a 7-day observation period. The results of this study showed that treatment with either CLX or IFX ameliorated the three organs' damage compared to septic-untreated rats, decreased oxidative stress, enhanced the antioxidant defense, and reduced serum cytokines. As a result, a higher survival rate resulted: 62.5% and 37.5% after the administration of CLX and IFX, respectively, compared to 0% in the CLP group after 7 days. No significant differences were observed between the two agents in all measured parameters. Histopathological examination confirmed the observed results. In conclusion, CLX and IFX ameliorated lung, kidney, and liver injuries associated with sepsis through anti-inflammatory and antioxidant actions, which correlated to the increase in survival observed with both of them. |
Ulcerative colitis (US) is a chronic disease of unknown etiology. It is incurable and its clinical course is intermittent, characterized by periods of remission and relapse. The prevalence and incidence of the disease has been increasing worldwide. The update presented herein includes the participation of healthcare professionals, decision-makers, and a representative of the patients, all of whom declared their conflicts of interest. Answerable clinical questions were formulated, and the outcomes were graded. The information search was conducted on the Medline/PubMed, Embase, Epistemonikos, and LILACS databases, and covered grey literature sources, as well. The search was updated on November 30, 2020, with no restrictions regarding date or language. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) classification system was implemented to establish the strength of the recommendation and quality of evidence. A formal consensus was developed, based on the RAND/UCLA methodology and the document was peer reviewed. The short version of the Clinical Practice Guidelines for the Treatment of Ulcerative Colitis in the Adult Population is presented herein, together with the supporting evidence and respective recommendations. In mild-to-moderate UC, budesonide MMX is an option when treatment with 5-ASA fails, and before using systemic steroids. In moderate-to-severe UC, infliximab, adalimumab, vedolizumab, ustekinumab, and tofacitinib can be used as first-line therapy. If there is anti-TNF therapy failure, ustekinumab and tofacitinib provide the best results. In patients with antibiotic-refractory pouchitis, anti-TNFs are the treatment of choice. |
Bipolar disorder (BD) is characterized by a pro-inflammatory biotype, and is a major cause of cardiovascular disease (CVD), consequently causing elevated rates of morbidity and mortality among individuals with BD.
The present study is based on a 12-week clinical trial assessing the antidepressant effects of adjunctive infliximab treatment in BD. Generalized estimating equation (GEE) models were used to evaluate CVD risk in people with BD following adjunctive infliximab treatment at baseline and week 12. Participants (baseline: n = 40; endpoint: 33) were randomized for an infliximab-treatment or placebo group. CVD-risk was calculated using Framingham risk scores (FRS), mean arterial blood pressure (MAP) and total cholesterol (TC).
There was no main effect of treatment on FRS in infliximab-treated participants compared to controls (p = 0.408). Similarly, there were no significant differences in MAP between the infliximab-treated and control group (p = 0.796). The effect of treatment on TC was not significant (p = 0.130), however, an evaluation across time suggested the main effect of the group was significant at week 0 (p = 0.01), but not week 12 (p = 0.219).
Cardiovascular disease was not an outcome of the original clinical trial, and our participant group did not have a high CVD-risk at baseline.
There were no significant treatment effects of infliximab on FRS, MAP and TC. The current study highlights the complexity of immune-system targets that influence CVD in psychiatric populations. Future studies should include a large scale, combinatorial omnibus biomarker approach to evaluate the immune and vascular link in BD. |
Primary nonresponse to infliximab in patients with ulcerative colitis (UC) is common. However, there are currently no effective biomarkers for this prediction. This study aimed to identify potential predictors for precision anti-tumor necrosis factor-alpha treatment in patients with UC. Four GPL570 datasets (GSE14580, GSE12251, GSE23597, and GSE16879) were included in this study. Sixty-nine differentially expressed genes (DEGs) were identified, while 67 were up-regulated and two were down-regulated by comparing the gene expression in response samples with the nonresponse samples. Gene Ontology analysis showed that DEGs were mostly enriched in neutrophil-mediated immunity, neutrophil activation, neutrophil activation involved in the immune response, neutrophil degranulation, and leukocyte migration. Kyoto Encyclopaedia of Genes and Genomes analysis indicated that these DEGs were mostly enriched in cytokine-cytokine receptor interactions and interleukin (IL)-17 signalling pathways. After protein-protein interaction network analysis, verification by test set, and confirmation of clinical UC samples, S100 calcium-binding protein A8 (S100A8), S100A9, triggering receptor expressed on myeloid cells 1 (TREM1), toll-like receptor 2 (TLR2), IL1B, and formyl peptide receptor 1 (FPR1) were identified as the hub genes. We found that the immune cell composition in the intestinal tissues of UC patients with primary nonresponse included naïve CD4+ T cells, memory resting CD4+ T cells, resting natural killer cells, resting dendritic cells, activating dendritic cells, eosinophils, and neutrophils. Among these, neutrophils showed the most significant differences. In addition, all six potential predictors were significantly associated with the neutrophil count. Our study identified six potential biomarkers, namely S100A8, S100A9, TREM1, TLR2, IL1B, and FPR1, and one type of immune cell, neutrophils, between UC patients with response and primary nonresponse to infliximab. We speculated that changes in the expression of these six potential biomarkers combined with changes in the activity or local quantity of neutrophils might help predict primary nonresponse to infliximab in patients with UC. |
In response to the COVID-19 pandemic, the CDC issued guidance advising patients and providers to adopt social distancing practices such as home-based infusions (H-BI).
We performed a mixed methods evaluation to summarize perceptions, concerns, and experiences with H-BI among all inflammatory bowel disease patients 18-90 years of age who transitioned to home-based infliximab or vedolizumab infusions between March to July 2020 at a tertiary care center. Semi-structured interviews were conducted and analyzed using an iterative, inductive thematic approach. Baseline characteristics and outcome on safety, COVID-19 transmission, delays in infusions, and H-BI persistence were collected.
Of the 57 participants who transitioned to H-BI, 20 (33%) responded. Four major categories and six major themes related to expectations, experience, perceived safety, and logistical factors were identified. Initial perceptions were mixed, however these resolved. One patient developed COVID-19, one patient experienced an adverse event, 12 (21%) patients experienced an infusion delay, and 6 (11%) patients transitioned from H-BI.
Despite mixed initial perceptions, respondents had a positive experience with most respondents planning to continue H-BI after the pandemic resolves. Several real-world actionable barriers were identified related to scheduling, communication between stakeholders, and nursing quality. No major safety concerns were identified. |
Kawasaki disease (KD) is a medium and small vessel vasculitis which usually has a good response to immunoglobulin therapy (IVIG). We present a case of incomplete KD with IVIG resistance associated with an unusual combination of vesicular guttate-psoriasiform rash, hypertension and late onset small joint arthritis.
A four-month-old male infant from Sri Lanka presented with high fever, conjunctival redness, pedal oedema and skin rash. He was found to have hypertension since admission with a high white cell count and high inflammatory markers. There was poor response to intravenous antibiotics and subsequent 2D echocardiogram revealed coronary artery aneurysms suggestive of KD. In the third week of illness he developed a vesiculo-papular rash involving face, trunk and limbs - which on biopsy revealed features of guttate psoriasis. Fever spikes continued and the coronary arteries showed progressive dilatation despite timely intravenous immunoglobulin administered on day 6 and methylprednisolone administered on day 10-13. Therapeutic response by means of reduction of fever was seen only after initiation of intravenous infliximab on day 28 of illness for which the fever responded within 24 hours. He developed a small joint arthritis of hands and feet on day 40 of illness which responded only after initiating methotrexate therapy. The hypertension persisted for 4 months after the onset of the illness before complete resolution.
This case report depicts an unusual presentation of KD with a vesicular guttate-psoriasiform eruption, hypertension and late onset small joint arthritis. It highlights that clinicians should be aware of the fact that KD could present with such atypical manifestations and could develop unusual complications. |
Cronkhite-Canada syndrome (CCS) is a non-hereditary disorder characterized by non-neoplastic gastrointestinal polyposis and ectodermal changes. While corticosteroids are considered effective, some cases are refractory. A 48-year-old woman presented with diarrhea, anorexia, and epigastralgia lasting for 3 months. She suffered from alopecia and nail dystrophy. Gastrointestinal endoscopy with histological examination confirmed non-neoplastic polyposis from the stomach to the rectum, confirming the diagnosis of CCS. Linked color imaging (LCI) with magnified endoscopy revealed a ribbon-like proliferation of capillaries surrounding the pits in the colonic mucosa. Histologically, the polyps had dilated glands, edematous stroma with inflammatory cell infiltrates and increased capillaries just beneath the epithelium. Immunohistochemical examination confirmed the expression of vascular endothelial growth factor (VEGF), mainly in the superficial epithelial and crypt cells. Steroid therapy was ineffective, and concomitant infliximab therapy provided symptomatic relief. Although symptoms rapidly improved with combination therapy, capillary hyperplasia and slight inflammation persisted in the colon mucosa after polyp resolution. Withdrawal of steroid treatment resulted in flare-ups of symptoms and polyps. Repeated magnified observations at LCI during post-relapse retreatment clearly captured the resolution process of both neovascularization and inflammation. Once the capillary hyperplasia and inflammation subsided, the steroid could be tapered off without relapse. To our knowledge, this is the first report describing the involvement of VEGF-induced angiogenesis and LCI findings in CCS; LCI observations are useful not only in the active phase of CCS, but also in determining subtle capillary hyperplasia and residual inflammation in remission, which may be an indicator of continued treatment. |
Background Damage to the coronary arteries during the acute phase of Kawasaki disease (KD) is linked to inflammatory cell infiltration, myointimal proliferation, and endothelial cell (EC) dysfunction. To understand the response of ECs to KD treatment, we studied the genome-wide transcriptional changes in cultured ECs incubated with KD sera before and after treatment with or without atorvastatin. Methods and Results RNA sequencing of human umbilical vein ECs incubated with pooled sera from patients with acute KD before or after treatment with intravenous immunoglobulin and infliximab revealed differentially expressed genes in interleukin-1, tumor necrosis factor-α, and inflammatory cell recruitment pathways. Subacute sera pooled from patients treated with intravenous immunoglobulin, infliximab, and atorvastatin uniquely induced expression of |
Few data exist regarding the immunogenicity of the third dose of BNT162b2 relative to the second dose in patients with inflammatory bowel disease (IBD) on different immunosuppressive therapies. We investigated the immunogenicity of BNT162b2 vaccine booster dose in patients with IBD on infliximab combination therapy.
This is a prospective single-center observational study conducted from January 1, 2022 to February 28, 2022. Patients were recruited at the time of attendance at the infusion center. Eligibility criteria included patients with a confirmed diagnosis of IBD who are receiving infliximab with azathioprine or 6-mercaptopurine. Patients who received two doses of BNT162b2 vaccine (second dose group) were compared to patients who had received three doses of BNT162b2 vaccine [third dose (booster) group]. Patients were excluded if they were infected or had symptoms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) previously since the start of the pandemic or received other vaccines than the BNT162b2. Our primary outcome was the concentrations of SARS-CoV-2 antibodies Immunoglobulin G (IgG) and neutralizing antibodies 40-45 weeks from the first dose of BNT162b2 vaccine in patients with IBD receiving infliximab combination therapy. Medians with interquartile range (IQR) were calculated.
In total, 162 patients with IBD and receiving infliximab combination therapy were recruited, and the number of patients in both the second dose group and third dose (booster) group was 81. Mean age was 35 years old in both groups. Median (IQR) SARS-CoV-2 IgG levels were significantly lower after the second dose [125 BAU/ml (43, 192)] compared to patients who received the third booster dose [207 BAU/ml (181, 234)] (
Most patients with IBD on infliximab combination therapy had positive SARS-CoV-2 IgG and neutralizing antibody concentrations 40-45 weeks post BNT162b2 vaccination. However, SARS-CoV-2 IgG and neutralizing antibody concentrations were lower in patients who received two doses only compared to patients who received a third dose. A longer follow-up study is needed to evaluate decay in antibodies over time. |
An association between tumor necrosis factor (TNF)-α inhibitors and hypoglycemia has been detected in a few case reports and small case series; however, no relevant pharmacovigilance data have been published yet.
The objective of this study was to detect and characterize relevant safety signals between hypoglycemia and TNF-α inhibitor use.
Indication-focused disproportionality analysis was conducted to detect increased reporting of TNF-α-associated hypoglycemia compared with all other reports with the same indication during the same time period. Reporting odds ratios (RORs) with 95% confidence intervals (CIs) were calculated to determine disproportionality. To reduce potential confounding factors, adjusted RORs were further calculated by logistic regression to control for age, sex, diabetes status, and concomitant drugs that potentially affect blood glucose levels.
In all, 1086 adverse drug reactions related to TNF-α inhibitors were reported as 'hypoglycemia'. There were no disproportionality signals of hypoglycemia in TNF-α inhibitor users with indication of inflammatory bowel disease. When TNF-α inhibitors were considered as a class, disproportion for hypoglycemia only emerged in indication of psoriasis (n = 267, ROR 1.20, 95% CI 1.02-1.41). In further analyses of specific TNF-α inhibitor type, significant RORs for hypoglycemia were found in indication of rheumatic disease, including adalimumab in ankylosing spondylitis (n = 37, ROR 1.97, 95% CI 1.28-3.04), psoriasis (n = 160, ROR 1.64, 95% CI 1.37-1.97), and rheumatoid arthritis (n = 230, ROR 1.35, 95% CI 1.16-1.56) and infliximab in psoriasis (n = 18, ROR 2.14, 95% CI 1.33-3.42). After adjusting for confounding factors, only the signals of adalimumab were stable.
Our study identified some potential pharmacovigilance signals between hypoglycemia and TNF-α inhibitors, which warrants further validation. |
Mucosal healing (MH) is currently the gold standard in Crohn's disease (CD) management. Noninvasive assessment of MH in CD patients is increasingly a concern of clinicians.
This retrospective study included 106 patients with confirmed CD who were divided into a training cohort (n = 73) and a testing cohort (n = 33). Patient demographics were evaluated to establish a clinical model. Radiomics features were extracted from computed tomography enterography (CTE) images. A radiomics signature was constructed, and a radiomics score (Rad-score) was calculated by using the radiomics signature-based formula. A clinical radiomics nomogram was then built by incorporating the Rad-score and significant clinical features. The diagnostic performance of the three models was evaluated using receiver operating characteristic (ROC) curve analysis.
Of the 106 patients with CD, 37 exhibited MH after 26 weeks of infliximab (IFX) treatment. The area under the ROC curve (AUC) of the clinical radiomics nomogram for distinguishing MH from non-MH, which was based on the disease duration and Rad-score, was 0.880 (95% confidence interval [CI]: 0.809-0.943) in the training cohort and 0.877 (95% CI: 0.745-0.983) in the testing cohort. Decision curve analysis (DCA) confirmed the clinical utility of the clinical radiomics nomogram.
This is a preliminary study suggesting that this CTE-based radiomics model has potential value for predicting MH in CD patients. A nomogram constructed by combining radiomics signatures and clinical features can help clinicians select appropriate therapeutic strategies for CD patients.
• The disease duration (odds ratio (OR) = 0.969, 95% confidence interval (CI) = 0.943-0.995, p = 0.021) was an independent predictor of MH in the clinical model. • The AUC of the radiomics model constructed by the five radiomics features was 0.846 (95% CI: 0.759-0.921) in the training cohort and 0.817 (95% CI: 0.665-0.945) in the testing cohort for differentiating MH from non-MH. • The AUC of the clinical radiomics nomogram was 0.880 (95% CI: 0.809-0.943) in the training cohort and 0.877 (95% CI: 0.745-0.983) in the testing cohort for distinguishing MH from non-MH. |
This study explores the potential of gene polymorphisms in the canonical and noncanonical NF-kB signaling pathway as a prediction biomarker of anti-tumor necrosis factor (TNF)α response in Crohn's patients.
A total of 109 Greek patients with Crohn's disease (CD) were recruited, and the genotype of TLR2 rs3804099, LTA rs909253, TLR4 rs5030728, and MAP3K14/NIK rs7222094 single nucleotide polymorphisms was investigated for association with response to anti-TNFα therapy. Patient's response to therapy was based on the Crohn's Disease Activity Index, depicting the maximum response within 24 months after initiation of treatment.
Seventy-three patients (66.7%) were classified as responders while 36 as nonresponders (33.3%). Comparing allelic frequencies between responders and nonresponders, the presence of TLR2 rs3804099 T allele was associated with nonresponse (P = 0.003), even after stratification by anti-TNFα drugs (infliximab: P = 0.032, adalimumab: P = 0.026). No other association was identified for the rest of the polymorphisms under study. Haplotype analysis further enhanced the association of rs3804099 T allele with loss of response, even though the results were NS (P = 0.073).
Our results suggest that polymorphisms in the canonical NF-kB pathway genes could potentially act as a predictive biomarker of anti-TNFα response in CD. |
Ankylosing spondylitis (AS) is a common immune-related systemic chronic inflammatory osteoarthropathy. Previous studies have proven that biologic agents, including IL-17A inhibitors (IL17Ai), TNF-
PubMed, Scopus, Embase, CNKI, and the Cochrane Library were systematically searched. A frequentist framework network meta-analysis with a random-effects model was performed. Ranking effects were calculated by surface under the cumulative ranking analysis (SUCRA) and cluster-rank analysis.
IL17AFi reported both the highest ASAS40 (SUCRA = 91.4%) and ASAS20 (SUCRA = 92.5%) response, while IL6i and IL23i reported the lowest responses (SUCRA = 6.6% and 19.9%, respectively). With the exceptions of IL6i (RR 0.60, 95% CI (0.22 to 1.67) for ASAS40 and 1.36 (0.71 to 2.58) for ASAS20) and IL23i (0.98 (0.68 to 1.40) for ASAS40 and 0.91 (0.70 to 1.19) for ASAS20), all biological drugs demonstrated statistically superior ASAS responses than placebo. TNFiFMA performed best in the suppression of disease activity (SUCRA = 77.4%, SMD 2.35, and 95% CI (1.11 to 3.59)) and functional improvement (SUCRA = 68.8%, SMD 1.67, and 95% CI (0.59 to 2.74)). There were no significant differences in tolerability or safety between biologic drugs and placebo.
The novel IL-17 A/F dual variable domain inhibitor, bimekizumab, may be an ideal future treatment choice for AS, while IL-23 and IL-6 inhibitors demonstrate little potential in the treatment of AS. For patients with rapid disease progression and severe functional limitation, TNF- |
Infliximab is a chimeric monoclonal antibody against tumour necrosis factor (TNF)-α, with a wide variety of uses. Monoclonal antibody therapies specifically targeting TNF-α, have emerged as a novel treatment option for patients with refractory sarcoidosis, with infliximab being the most widely used. This is not true of other TNF-α inhibitors, for example etanercept, which have a different mechanism of action, and are not effective in sarcoidosis. It is well documented that infliximab therapy can result in the production of autoantibodies, however clinical symptoms or disease is rare. In this report, we describe a 37-year-old male with a history of sarcoidosis requiring infliximab therapy, who presented during the course of his treatment with the onset of new migratory joint pain, increasing fatigue and positive serum autoantibodies, heralding the development of infliximab-induced lupus. |
Depression is a chronic and prevalent neuropsychiatric disorder; clinical symptoms include excessive sad mood, anhedonia, increased anxiety, disturbed sleep, and cognitive deficits. The exact etiopathogenesis of depression is not well understood. Studies have suggested that tumor necrosis factor-alpha (TNF-α) and interleukins (ILs) perform vital roles in the pathogenesis and treatment of depression. Increasing evidence suggests the upregulation of TNF-α and ILs expression in patients with depression. Therefore, biologics like TNF inhibitors (etanercept, infliximab, adalimumab) and IL inhibitors (ustekinumab) have become key compounds in the treatment of depression. Interestingly, treatment with an antidepressant has been found to decrease the TNF-α level and improve depression-like behaviors in several preclinical and clinical studies. In the current article, we have reviewed the recent findings linking TNF-α and the pathogenesis of depression proving TNF-α inhibitors as potential new therapeutic agents. Animal models and clinical studies further support that TNF-α inhibitors are effective in ameliorating depression-like behaviors. Moreover, studies showed that peripheral injection of TNF-α exhibits depressive symptoms. These symptoms have been improved by treatment with TNF-α inhibitors. Hence suggesting TNF-α inhibitors as potential new antidepressants for the management of depressive disorder. |
Despite introduction of biological disease modifying anti-rheumatic drugs (DMARDs) for Rheumatoid arthritis (RA) treatment, therapeutic strategies do not always lead to disease control and remission. Hence, a more efficient patient stratification and monitoring biomarkers and tools are needed to enable a more personalized medicine. We used a whole blood based functional flow cytometry assay to characterize immune cells from RA patients (treated or not), healthy donors and psoriatic arthritis (PsA) patients according to their responses to LPS and/or anti-TNFα (infliximab, IFX). Activation marker expression was measured using a 10-color flow cytometry panel following a no-wash protocol. Naïve-to-treatment RA patients had a stronger inflammatory profile in comparison to healthy donors at basal level. Higher expression of activation markers (CD69 and/or CD11b) on NK, B cells and granulocytes and lower expression of the adhesion molecule CD62L were measured on monocytes, granulocytes and B cells. After LPS, naïve RA patients' cells were less capable of regulating CD69, CD11b, CD16 or CD62L showing impaired activation capabilities. Upon LPS and IFX co-incubation, hierarchical clustering analysis showed different profiles between cohorts. We believe that this whole blood-based approach should further be assessed for RA patient characterization as it provides new perspectives for stratification and/or monitoring. |
There is no consensus on the management of immune checkpoint inhibitor (ICI) for treating cancer in patients with pre-existing inflammatory bowel disease (IBD). The Groupe d'Étude Thérapeutique des Affections Inflammatoires du tube Digestif (GETAID) aimed to provide recommendations on this topic.
A dedicated working group performed a comprehensive expert-based review of the literature, generated clinical key question and shaped recommendations that were further voted for approval by the educational and scientific committees of the GETAID. Using consensus methods, treatment modalities were defined by vote.
Majority of patients with IBD in clinical remission can be treated with ICI after cancer diagnosis. The rate of relapse or immune-related diarrhoea or colitis upon ICI treatment is up to 39.8% and is maximal with ICI combination therapy compared to monotherapies. When starting ICI in a patient with IBD, it is recommended to assess disease activity and pursue ongoing maintenance therapy. In case of relapse or immune-related diarrhoea or colitis upon ICI treatment, treatment depends on grading of diarrhoea or colitis and may include corticosteroid therapy, infliximab and/or vedolizumab.
In the present publication, we provided recommendations, which may assist gastroenterologists, haematologists, and oncologists for a better management of patients with pre-existing IBD before and during cancer treatment with ICI. |
Recently, the European Respiratory Society (ERS) developed new international guidelines for the treatment of sarcoidosis. This manuscript attempts to distill the ERS Sarcoidosis Treatment Guidelines to a manageable format that can be easily used by practitioners.
The ERS Sarcoidosis Treatment Guidelines addressed the treatment of pulmonary, skin, cardiac, neurologic, and sarcoidosis-associated fatigue. Therapeutic drug dosing and treatment algorithms for these conditions were also addressed. Glucocorticoids were the initial recommended treatment for these conditions except for sarcoidosis-associated fatigue where a pulmonary exercise program or a neurostimulant was initially suggested. Because of the risk of glucocorticoid side-effects, the Guidelines recommended early consideration of glucocorticoid-sparing therapy including certain antimetabolites and two specific tumor necrosis alpha antagonists: infliximab and adalimumab.
The ERS Sarcoidosis Treatment Guidelines used a rigorous GRADE (Grading of Recommendations, Assessment, Development and Evaluations) methodology to update treatment recommendations for this condition. This manuscript summarizes the Guideline findings in practical terms for clinicians. Suggested algorithms and treatment dosing recommendations are provided. |
Infliximab is a mouse/human chimeric IgG1 monoclonal antibody which recognizes the proinflammatory cytokine, tumor necrosis factor α (TNFα), and inhibits receptor interactions, thereby decreasing inflammation and autoimmune response in patients. This monoclonal antibody has been successfully used to treat rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis. However, the high treatment cost limits patient access to this biotherapy. One alternative to this problem is the use of biosimilars. In this work, we describe the stable expression and physicochemical characterization of an anti-TNFα antibody. While infliximab is produced in recombinant murine SP2/0 cells, our anti-TNFα IgG antibody was expressed in recombinant murine NS0 myeloma cells. The best anti-TNFα antibody-expressing clone was selected from three clone candidates based on the stability of IgG expression levels, specific productivity as well as TNFα-binding activity compared to commercial infliximab. Our results indicate that the selected cell clone, culture medium, and fermentation mode allowed for the production of an anti-TNFα antibody with similar characteristics to the reference commercially available product. An optimization of the selected culture medium by metabolomics may increase the volumetric productivity of the process to satisfy the demand for this product. Further experiments should be performed to evaluate the biological properties of this anti-TNFα antibody. KEY POINTS: • An anti-TNFα antibody was produced in NS0 cells using perfusion culture. • A proprietary chemically defined culture medium was used to replace commercially available protein-free medium. • The purified anti-TNFα antibody was comparable to the reference marketed product. |
Project NORTH compared real-world clinical and economic outcomes in Swedish patients with inflammatory bowel disease (IBD) who switched from originator infliximab to its biosimilar.
Data from electronic medical records and Swedish national registries were linked. Switchers (patients switching from originator infliximab to its biosimilar between 1 April 2014, and 31 December 2017) and non-switchers (patients who received originator infliximab and did not switch to a biosimilar by 31 December 2017) were followed up until 31 October 2019.
Baseline concomitant medication use, disease duration, and inflammatory markers were lower among switchers than non-switchers. At 6 months, the proportion of patients with stable disease was higher among switchers than non-switchers (71/109 [65%] vs 54/107 [50%];
No substantial differences in clinical outcomes or healthcare resource utilization were observed between switchers and non-switchers. Several analyses indicate that non-switchers might have more poorly controlled/severe disease than switchers at baseline. Overall, numerous difficulties might arise when executing a high-quality, real-world study, including possible selection bias for patients with better disease control for NMS, limiting the generalizability of the results. |
The treatment for Kawasaki disease (KD) patients refractory to intravenous immunoglobulin (IVIG) therapy is still controversial, and the efficacy of plasma exchange (PE) and infliximab (IFX) therapy for infantile KD is unknown.
A total of 22 infantile KD patients refractory to initial and additional IVIG, who received either PE or IFX as third-line therapy from October 2008 to February 2020 were examined retrospectively. The patients' sex, age, days of first IVIG, days of PE or IFX therapy, laboratory data preceding PE or IFX therapy, coronary artery lesions (CALs), and adverse effects were investigated.
Thirteen patients received PE and nine patients received IFX as the third-line therapy. For the median age at onset, the median days of first IVIG and PE or IFX, and pre-PE or IFX therapy blood test results, there were no significant between-group differences. At admission, and before and after the third-line therapy, there were also no significant differences in occurrence of CALs. The frequency of serious adverse events was significantly higher in the PE group than in the IFX group.
Although there were no significant differences in patient background, blood test results, or frequency of CALs, the frequency of adverse events was significantly higher in the PE group. With the trend of expansion of IFX therapy for KD patients refractory to IVIG, the role of PE as the additional therapy may become more limited. |
Immune-related adverse events (irAEs) often require treatment with high-dose systemic steroids (SS) and other immunosuppressive agents (ISAs). NCCN Guidelines recommend prophylactic antibiotics for Pneumocystis jirovecii pneumonia (PJP) for patients receiving prolonged SS/ISAs. However, there is a paucity of evidence regarding the incidence of opportunistic infections (OIs) and non-OIs and the role of prophylactic antibiotics in patients on SS/ISAs for irAEs.
A retrospective analysis was conducted of patients treated using immune checkpoint inhibitor (ICI) therapy at 5 MedStar Health hospitals from January 2011 to April 2018. OIs were defined per the Infectious Diseases Society of America guidelines for the prevention and treatment of OIs in patients with HIV. The study cohort included patients who received ≥20 mg daily of a prednisone equivalent for ≥4 weeks to manage irAEs.
The study cohort identified 112 (15%) of 758 total patients treated using ICIs. Baseline characteristics included the following: median age was 64 years, 74% (n=82) of patients were White, 89% (n=100) had an ECOG performance status ≤1, 61% (n=68) had melanoma, 19% (n=21) had non-small cell lung cancer, 45% (n=50) were treated using an anti-PD-(L)1 ICI, and 33% (n=37) were treated using an anti-PD-1/anti-CTLA-4 combination. The median starting SS dose was 100 mg of a prednisone equivalent, and 25% of patients required additional ISAs, with infliximab (n=15) and mycophenolate mofetil (n=9) being the most common. We found that 20% (n=22) of patients developed any infection, including 7% (n=8) with OIs (oral candidiasis [n=4], nondisseminated varicella zoster infection [n=2], PJP [n=1], and Listeria monocytogenes endophthalmitis [n=1]) and 13% (n=14) with non-OIs (most common: Clostridium difficile and pneumonia [n=5 each]). PJP prophylaxis with sulfamethoxazole/trimethoprim was given to 13% (n=14) patients, of whom 43% (n=6) developed OIs/non-OIs.
Our study highlights the fundamental issues for patients on ICI therapy who require SS/ISAs for irAEs: the degree of immunosuppression and the relative risk of OI. We noted a low incidence of OIs overall and breakthrough infections despite PJP prophylaxis. We question whether PJP prophylaxis is efficacious or necessary. Prospective trials are required to answer these questions. |
Ulcerative colitis is a chronic and progressive inflammatory disorder. The regulator of the G-protein signaling (RGS) is involved in the pathogenesis of several immune system disorders. RGS16, a member of the RGS protein superfamily, has been shown to play critical roles in several immune system-related diseases. However, the roles of RGS16 in ulcerative colitis remain to be elucidated.
We analyzed the expression of RGS16 in peripheral blood mononuclear cells (PBMCs) and inflamed mucosa of ulcerative colitis patients using quantitative reverse transcription-PCR, western blotting and immunohistochemistry. We performed Spearman's correlation to analyze the correlation between RGS16 expression and the ulcerative colitis endoscopic index of severity (UCEIS), Mayo index, erythrocyte sedimentation rate (ESR) and serum tumor necrosis factor alpha (TNF-a) and IL-17A levels. Further, PBMCs were stimulated with inflammatory cytokines in vitro .
RGS16 expression significantly increased in the colonic mucosa and PBMCs from patients with ulcerative colitis and significantly correlated with the Mayo index, UCEIS, ESR and serum TNF-α and IL-17A levels. TNF-α upregulated RGS16 expression in PBMCs in a dose- and time-dependent manner via the nuclear factor kappa beta (NF-kB) signaling pathway. Moreover, anti-TNF treatment with infliximab significantly decreased RGS16 expression in PBMCs and intestinal mucosa of patients with ulcerative colitis.
Our study revealed a novel mechanism by which RGS16 expression in ulcerative colitis is positively correlated with disease activity. Thus, RGS16 might serve as a potential therapeutic marker for the treatment of ulcerative colitis. |
To provide data on the use of infliximab biosimilars (IFX-BioS) in children with inflammatory bowel disease (IBD).
A multicenter, observational, retrospective study was performed among the cohort of the Sicilian Network for IBD. All consecutive IBD children who had at least completed the induction with IFX-BioS from its introduction in Sicily to January 2021 were enrolled. Clinical remission at weeks 14 and 52, treatment persistence, and adverse events were the study outcomes.
Eighty-seven patients [Crohn's disease (CD): 57.5% and ulcerative colitis (UC): 42.5%] were included: 75 (86.2%) were antitumor necrosis factor-α (anti-TNF-α) agent naïve, while three (3.45%) were switched from the originator to IFX-BioS. Twenty (23%) patients were multiply switched from the biosimilar CT-P13 to SB2 or GP1111 or vice versa. The median follow-up time was 15 months. Clinical remission was achieved by 55.2 and 65.5% of patients at weeks 14 and 52, respectively, with no differences between CD and UC. Dose escalation was needed in 8.0 and 35.7% of patients during induction and maintenance, respectively. Nine adverse events occurred (incidence rate: 6.13/100 person-year). Treatment persistence was 90.8% at 1 year and 75.7% at 2 years (patients on IFX-BioS at 2 years, n = 28). The risk of treatment discontinuation was higher in patients with extraintestinal manifestations ( P = 0.018) and in those who were nonnaïve to anti-TNF-α ( P = 0.027).
This is the largest cohort of pediatric IBD patients treated with IFX-BioS. Real-life data show that IFX-BioS is efficacious in IBD children, with high percentages of treatment persistence and a low incidence of nonserious adverse events. |
To describe the management and outcome of two extremely rare and painful cases of Mooren's ulcer, an idiopathic peripheral autoimmune-associated ulcerative corneal disease.
Case report with literature review on the management of ocular inflammation in Mooren's ulcer.
A 47-year-old female and a 76-year-old female presented with progressive bilateral Mooren's ulcer that were refractory to conventional immunosuppressive therapy. Following treatment with infliximab, an anti-tumor necrosis factor alpha, a significant improvement in disease progression was observed, with no corneal thinning or perforation at follow-ups.
This case report highlights how infliximab can be effective in cases with Mooren's ulcer refractory to conventional therapies. |
Patients with inflammatory bowel disease (IBD) requiring infliximab frequently spend hours to attend treatment. Through quality improvement (QI) methodology, we aimed to shorten the time spent in the biologics infusion center using the accelerated infusion protocol and describe patient outcomes, safety, and associated cost savings.
From September 2018 through December 2019, eligible IBD patients receiving infliximab were recruited. We implemented interventions including the accelerated infusion protocol, and modifying collection location of infliximab. Statistical process control charts were created. Patients' clinical outcome and cost savings data were analyzed using descriptive statistics and Pearson's chi-square.
During the study period, a total of 60 patients with IBD receiving infliximab were recruited. A total of 315 infusions were administered-152 were under accelerated infusion protocol and 163 under standard protocol. The mean infliximab infusion time was reduced by 47%, from 2.4 h (142 ± 14 min) to 1.2 h (75 ± 10 min) (142 min
Our QI project shortened the infliximab infusion time and total time spent in the infusion center, without compromising patient safety. Estimated cost savings were substantial. The protocol helps reduce work productivity loss. |
Limited data are currently available regarding anti-tumor necrosis factor (TNF) use and outcomes in very early onset inflammatory bowel disease (VEOIBD) patients. We aimed to assess the long-term outcomes and time to progression to anti-TNF treatment in VEOIBD patients.
We retrospectively reviewed IBD patients diagnosed under 6 years of age, between January 2005 and December 2019, from the British-Columbia (BC) Pediatric IBD database. Demographic data, disease characteristics, disease location and severity were documented. Data on anti-TNF treatment at initiation and during follow up including type of biologic, dosing, and response were collected. Kaplan-Meier curves were used to assess the number of years to progression to anti-TNF treatment and the parameters influencing commencement.
Eighty-nine patients with VEOIBD were diagnosed during the study period. Median age at diagnosis was 3.8 years [interquartile range (IQR) 2.6-5.1], 45.3% had Crohn disease (CD) and 62.8% were males. Median duration of follow up was 6.39 years (IQR 3.71-10.55). Anti-TNF treatment was started on 39.5% of patients and 7.0% underwent surgery. Rapid progression to biologic treatment was associated with Perianal fistulizing disease or stricturing disease in CD patients ( P = 0.026, P = 0.033, respectively), and disease severity ( P = 0.017) in ulcerative colitis(UC) patients. The median dose of infliximab at 1 year was 10 mg/kg (IQR 7.5-11) and a median dose interval of 4.5 weeks (IQR 4-6). Clinical remission was reported in 61.8% of patients on their first biologic agent.
The response rate was higher than previously reported and might be due to higher infliximab dosing with shorter infusion intervals than standard dosing. |
To explore the effect and mechanism of pirfenidone in inhibiting pulmonary fibrosis in connective tissue disease-associated interstitial lung disease (CTD-ILD).
From 2018 to 2020, 50 CTD-ILD patients were enrolled in the clinical study. Based on whether pirfenidone was used during treatment, patients were enrolled into the pirfenidone group and the control group. Pulmonary function tests were compared before and after treatment. Enzyme-linked immunosorbent assay (ELISA) was performed to detect the expression of tumor necrosis factor-α (TNF-α), signal transducer and activator of transcription 3 (STAT3), and Krebs Von den Lungen-6 (KL-6) in venous blood before and after treatment. Rat type II (RLE-6TN) lung epithelial cells were cultivated for
In the clinical study, the pulmonary function indices including forced expiratory volume in one second (FEV1), forced vital capacity (FVC), FEV1/FVC, peak expiratory flow (PEF) and partial pressure (PaO
Pirfenidone improved pulmonary function 1 and decreased TNF-α, STAT3, and KL-6 expression in CTD-ILD patients. Moreover, pirfenidone inhibits cell fibrosis through the TNF-α/STAT3/Mucin 1(MUC1) pathway. |
Pulmonary manifestation (PM) of inflammatory bowel disease (IBD) in children is a rare condition. The exact pathogenesis is still unclear, but several explanatory concepts were postulated and several case reports in children were published. We performed a systematic Medline search between April 1976 and April 2022. Different pathophysiological concepts were identified, including the shared embryological origin, "miss-homing" of intestinal based neutrophils and T lymphocytes, inflammatory triggering via certain molecules (tripeptide proline-glycine-proline, interleukin 25), genetic factors and alterations in the microbiome. Most pediatric IBD patients with PM are asymptomatic, but can show alterations in pulmonary function tests and breathing tests. In children, the pulmonary parenchyma is more affected than the airways, leading histologically mainly to organizing pneumonia. Medication-associated lung injury has to be considered in pulmonary symptomatic pediatric IBD patients treated with certain agents (i.e., mesalamine, sulfasalazine or infliximab). Furthermore, the risk of pulmonary embolism is generally increased in pediatric IBD patients. The initial treatment of PM is based on corticosteroids, either inhaled for the larger airways or systemic for smaller airways and parenchymal disease. In summary, this review article summarizes the current knowledge about PM in pediatric IBD patients, focusing on pathophysiological and clinical aspects. |
To investigate the clinical response to infliximab in ocular inflammation patients who develop anti-infliximab antibodies (AIA) vs. those patients who do not develop AIA.
A retrospective review was performed of patients treated with infliximab for noninfectious uveitis (NIU) or scleritis. Clinical response was determined as a composite clinical endpoint and classified as complete, partial, or absent. Nine of 32 infliximab-treated patients (28%) were found to develop AIA. Among the AIA-positive patients, clinical response was complete in 7 patients (78%) and partial in 2 patients (22%). Among the AIA-negative patients, clinical response was complete in 15 patients (65%), partial in 6 patients (26%) and absent in 2 patients (9%). Serum infliximab levels tended to decrease with appearance of AIA but rarely became undetectable.
In this pilot study, AIA-positive patients did not have diminished clinical response to infliximab when compared with AIA-negative patients. There was a high rate of complete clinical response to infliximab in this group of NIU and scleritis patients. Approximately a quarter of patients developed AIA. AIA-positive patients did not have diminished rates of clinical response when compared with AIA-negative patients. This suggests that routine AIA monitoring may not be clinically useful, although validation of this finding in larger cohorts is necessary. |
Juvenile idiopathic arthritis (JIA) is one of the most common pediatric inflammatory rheumatic diseases (PiRDs). Uncontrolled disease activity is associated with decreased quality of life and chronic morbidity. Biologic disease-modifying antirheumatic drugs (bDMARDs) and Janus kinase inhibitors (JAKi) have considerably improved clinical outcomes. For optimized patient care, understanding the efficacy-safety profile of biologics in subgroups of JIA is crucial. This systematic review based on published randomized controlled trials (RCTs) aims to assess efficacy and safety data for bDMARDs and JAKi with various JIA subgroups after 3 months of treatment.
Data for American College of Rheumatology (ACR) pediatric (Pedi) 30, 50, and/or 70 responses after 3 months of treatment were selected from RCTs investigating bDMARDs or JAKi in JIA according to predefined inclusion/exclusion criteria. Treatment and control arms were compared by calculating risk ratios (RRs) with 95% confidence intervals (CIs), and proportions of overall, serious adverse events (AEs) and infections were analyzed. Forest plots were generated to summarize efficacy and safety endpoints across studies, JIA subgroups, and type of biologics.
Twenty-eight out of 41 PiRD RCTs investigated bDMARD or JAKi treatments in JIA. 9 parallel RCTs reported ACR Pedi 30, 50, and/or 70 responses 3 months after treatment initiation. All treatment arms showed improved ACR Pedi responses over controls. RRs ranged from 1.05 to 3.73 in ACR Pedi 30, from 1.20 to 7.90 in ACR Pedi 50, and from 1.19 to 8.73 in ACR Pedi 70. An enhanced effect for ACR Pedi 70 was observed with infliximab combined with methotrexate in PJIA vs. methotrexate monotherapy. A slightly higher risk of gastrointestinal AEs and infections was observed with treatment arms compared to placebo or methotrexate monotherapy.
Investigated bDMARDs and JAKi showed superior treatment responses compared to controls after 3 months of treatment, which were more pronounced in ACR Pedi 50 and 70 than in ACR Pedi 30. Higher susceptibility to infections associated with bDMARDs or JAKi vs. control arms must be weighed against efficacious treatment of the underlying disease and prevention of disease-related damage. Additional RCTs are warranted to further inform development and utilization of biologics in JIA. |
Based on extrapolation of similar clinical outcomes in rheumatoid arthritis to the originator infliximab (IFX) in randomized clinical trials, the first biosimilar antibody CT-P13 was approved for the treatment of psoriasis. To evaluate the safety, efficacy, and drug survival of CT-P13 for psoriasis in real-world clinical practice, prospective post-marketing surveillance was conducted in 165 Japanese psoriasis patients. During a 1-year follow-up period, adverse drug reactions (ADRs) occurred in 29 patients (17.6%). Infusion reaction was the most frequent ADR (6.7%), and mild pneumonia was reported as the only case of infection. Serious ADRs were reported in two patients (1.2%): acute cholecystitis and interstitial pneumonia. The interstitial pneumonia developed after a single infusion of CT-P13 and the patient died of respiratory failure. In naive patients to biologic therapy (n = 44), the Psoriasis Area Severity Index (PASI) decreased rapidly after the start of CT-P13 treatment, and response rate achieving an absolute PASI score <1 was 55% at 30 weeks. The response rate was high (78%) in patients with psoriatic arthritis, and 40% and 20% in those in plaque psoriasis and pustular psoriasis, respectively. Of patients switched from IFX to CT-P13 mainly for nonmedical reasons (n = 105), 57% had already reached PASI <1 by pretreatment with IFX and CT-P13 maintained this status. The incidence of ADRs in this patient group was low and the drug survival rate was as high as 74%, even at 1 year, which was significantly higher than that in the naïve patient group (47%). Patients switched from other biologics for medical reasons (n = 16) responded similarly to biologic-naïve patients, but drug survival was lower (24%). In conclusion, CT-P13 showed excellent effectiveness as a first-line therapy, no clinical difficulties in switching from IFX, and usefulness in patients who failed other biologics. CT-P13 could be a cost-effective alternative to IFX for the treatment of psoriasis. |
Budesonide remains the backbone therapy for microscopic colitis [MC]; however, relapses are frequent, and some patients are intolerant or dependent. Anti-TNF therapy is increasingly used to treat these patients, but available evidence is still limited. The aim of this study was to evaluate the effectiveness and safety of anti-TNF therapy in MC patients failing budesonide.
In a multicentre retrospective cohort study, budesonide-refractory, -dependent, or -intolerant MC patients treated with anti-TNF agents were included. Clinical remission was defined as fewer than three bowel movements per day, and clinical response was defined as an improvement in stool frequency of at least 50%.
Fourteen patients were included. Median age was 58.5 years, median disease duration was 25 months, and median follow-up was 29.5 months. Seven patients were treated with infliximab [IFX], and seven with adalimumab. Clinical remission without steroids at 12 weeks was reached in 5/14 [35.7%] patients; all of these received IFX. Clinical response at 12 and 52 weeks, was obtained in 9/14 [64.3%] and 7/14 [50%] patients, respectively. Five patients switched to another anti-TNF agent. When considering both first- and second-line anti-TNF therapies, 7 [50%] patients were in clinical remission at Week 52. Mild to moderate adverse events were reported in six ptients. Two patients were treated with vedolizumab, of whom one had clinical response; one patient treated with ustekinumab had no response.
This is the first multicentre cohort study showing that half of patients treated with anti-TNF therapy for MC achieved clinical remission in case of budesonide failure. |
Metastasic Crohn disease (MCD) is the most uncommon cutaneous manifestation of Crohn disease. The actual incidence is not clear. There are fewer than 200 cases described in the literature. We report a case of 21 years-old girl that came to our emergency care with large exudative ulcers in the inguinal folds, the vulva, the perianal region and the popliteal fossae. Histopathological examination of the ulcers revealed a non-caseating granulomatous inflammation with abundant multinucleated giant cells and intense lymphocytic infiltrate. Colonoscopy, contrast study of the small bowel and video capsule endoscopy were carried out without evidence of digestive disease. High potency topical steroids (betamethasone 0,5mg/gr twice daily) and 300mg intravenous Infliximab were initiated as the initial line therapy and the ulcers began to heal. We report this case to highlight the presence of cutaneous ulcers without intestinal disease in a young non-pediatric woman as the unique manifestation of the disease. |
Hidradenitis suppurativa (HS) is a chronic inflammatory often recalcitrant to treatment. There is a lack of an updated systematic data review for infliximab use in HS. We conducted a systematic review and meta-analysis of literature on infliximab in HS. This study was performed following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and was pre-registered on PROSPERO (CRD42021283596). In 9/2021, MEDLINE and EMBASE were systematically searched for articles on infliximab in HS. Non-English, duplicate, and studies with <5 HS patients were excluded. Study quality was assessed utilizing Cochrane Risk of Bias for prospective trials and Newcastle-Ottawa Scale for cohort studies. Random effects meta-analytical model, Cochran's Q statistic, and I squared index were performed. Nineteen articles (314 patients) met inclusion criteria (six prospective, 13 retrospective studies). All patients with HS severity data available (n = 299) had moderate-to-severe disease. Outcome measures used for meta-analysis of the pooled response rate were largely based on clinician reported outcomes (16 studies). One utilized both clinician and patient assessment. Two utilized patient-reported response alone. The pooled response rate of HS patients to infliximab was 83% (95% CI, 0.71-0.91). The most common adverse events (AEs) included non-serious infections (13.2%) and infusion reaction (2.9%). The rate of serious AEs was 2.9%. Study limitations include the small number of prospective studies and heterogeneity between studies. Overall, infliximab is an effective treatment for moderate-to-severe HS. Efficacy of infliximab in HS should be compared to other biologics in larger, randomized controlled trials. |
With an increasing number of therapeutic options available for the management of ulcerative colitis (UC), the variability in treatment and prescribing patterns is not well known. While recent guidelines have provided updates on how these therapeutic options should be used, patterns of long-term use of these drugs over the past 2 decades remain unclear.
We analyzed a retrospective, nationwide cohort of more than 1.7 million prescriptions for trends in prescribing behaviors and to evaluate practices suggested in guidelines relating to ordering biologics, step-up therapy, and combination therapy. The primary outcome was 30-day steroid-free remission and secondary outcomes included hospitalization, cost, and additional steroid usage. A pipeline was created to identify cohorts of patients under active UC medical management grouped by prescribing strategies to evaluate comparative outcomes between strategies. Cox proportional hazards and multivariate regression models were utilized to assess postexposure outcomes and adjust for confounders.
Among 6 major drug categories, we noted major baseline differences in patient characteristics at first exposure corresponding to disease activity. We noted earlier use of biologics in patient trajectories (762 days earlier relative to UC diagnosis, 2018 vs 2008; P < .001) and greater overall use of biologics over time (2.53× more in 2018 vs 2008; P < .00001) . Among biologic-naive patients, adalimumab was associated with slightly lower rates of remission compared with infliximab or vedolizumab (odds ratio, 0.92; P < .005). Comparisons of patients with early biologic initiation to patients who transitioned to biologics from 5-aminosalicylic acid suggest lower steroid consumption for early biologic initiation (-761 mg prednisone; P < .001). Combination thiopurine-biologic therapy was associated with higher odds of remission compared with biologic monotherapy (odds ratio, 1.36; P = .01).
As biologic drugs have become increasingly available for UC management, they have increasingly been used at earlier stages of disease management. Large-scale analyses of prescribing behaviors provide evidence supporting early use of biologics compared with step-up therapy and use of thiopurine and biologic combination therapy.
Population-scale analysis reveals patterns in prescribing trends for ulcerative colitis management. Findings include (1) earlier use of biologics in patient trajectories, (2) associations of step-up therapy with higher corticosteroid exposure, and (3) association of combination therapy with positive patient outcomes. |
Cyclosporine is a rescue treatment alternative to avoid colectomy in corticosteroid refractory acute severe ulcerative colitis. In this study, we aimed to evaluate the long-term efficacy and safety of cyclosporine therapy in acute severe ulcerative colitis patients.
Acute severe ulcerative colitis (basal Lichtiger score > 10) patients who did not respond to 40 mg intravenous methylpredniso- lone therapy after 3-5 days were included in the study. The presence of clinical response and remission was assessed at 1st week, 1st, 6th, and 12th month according to the Lichtiger index.
In this study, 40 patients, whose steroid refractory acute severe ulcerative colitis and basal Lichtiger score > 10 points were enrolled. The median disease duration was 49.3 months (2-204). All patients received cyclosporine for 132 ± 78 days (7-270). Clinical response was obtained on seventh day in 82.5%. The clinical response rates of the first and sixth months were 72.5% and 62.5%, respectively. A total of 17/40 (42.5%) patients underwent colectomy within 1 year. In the patients who underwent colectomy, the basal LS (14.2 ± 1.9 vs 12.3 ± 1.7) (P = .002) was higher and the basal hemoglobin value (11.8 ± 2.3 vs 10.1 ± 1.5) (P = .037) was lower than those who did not undergo colectomy.
Our findings suggest that cyclosporine treatment may be successfully and safely used in steroid refractory acute severe ulcerative colitis patients. Cyclosporine is a drug that has recently started to come up again with the introduction of new maintenance treatments. Especially in patients who develop a loss of response to infliximab therapy, or where infliximab therapy is contraindicated, or who have azathioprine intolerance, or are unresponsive. |
In recent years, many antibody drugs that play an important role in the pharmacotherapy of several diseases have been developed. Antibody drugs exhibit immunogenicity in vivo leading to the development of antibodies against the antibody drug (anti-drug antibody). Nonetheless, other factors also affect the pharmacokinetics of antibody drugs. Recently, therapeutic drug monitoring (TDM) of infliximab was introduced for personalized medicine. However, the usefulness of TDM in antibody therapy remains unclear. In addition to intervention studies, real-world data analysis is important. Unlike small-molecule drugs, antibody drugs do not have a uniform molecular weight; therefore, using the conventional analysis methods, it is impossible to determine the true pharmacokinetic outcomes of these agents. To analyze structural changes of antibody drugs in the body, new technologies are necessary. In the future, along with the development of new drugs, the establishment of novel analytical methods is essential to facilitate the promotion of personalized medicine. |
A 20-year-old woman with Crohn's disease receiving infliximab therapy presented to the emergency department with lower extremity swelling secondary to compression of the common iliac vein. On magnetic resonance imaging, an enlarging pelvic mass was identified. The pathology of the mass was consistent with myelolipoma. We believe this is the first case of myelolipoma in a patient on immunosuppression with infliximab. |
Uveitis is the most frequent extra-articular manifestation of juvenile idiopathic arthritis (JIA). Our study is aimed to evaluate the possible difference in arthritis course depending on uveitis presence in patients with JIA, treated with biologics.
From our database of patients with JIA treated with biologics, we extracted patients to whom the first agent was administrated with or without MTX. The exclusion criteria included treatment with current systemic corticosteroids, infliximab, rituximab, observation period <3 years, and no missing data. After selection, 175 patients were eligible for analysis. We evaluated clinically significant flare with joint involvement (which required change of biologic or non-biologic DMARD) and time to flare. We compared two groups: (i) patients with uveitis (
There was no difference in gender distribution and achievement of arthritis remission between groups. Patients in the non-uveitis group predominantly received etanercept (64.3%). In the uveitis group, the most prescribed biologic agent was adalimumab (71.9%). The presence of uveitis increased the risk of JIA flare, OR = 3.8 (95% CI: 1.7; 8.7), and the cumulative probability of joint flare, RR = 4.5 (95% CI: 1.7; 12.1),
The presence of uveitis proved to be a risk factor in JIA flare. Methotrexate can decrease the cumulative flare probability. Further trials are required. |
For infants exposed in utero to anti-tumour necrosis factor-α [TNF] medications, it is advised that live-attenuated vaccinations be postponed until the drug is cleared, but little is known about time to clearance. To minimize delays before live-attenuated vaccination can be given, we aimed to develop a pharmacokinetic model to predict time-to-clearance in infants exposed during pregnancy.
We prospectively followed in utero infliximab/adalimumab-exposed infants of mothers with inflammatory bowel disease across four countries between 2011 and 2018. Infants with a detectable anti-TNF umbilical-cord level and at least one other blood sample during the first year of life were included.
Overall, 107 infants were enrolled, including 166 blood samples from 71 infliximab-exposed infants and 77 samples from 36 adalimumab-exposed infants. Anti-TNF was detectable in 23% [n = 25] of infants at 6 months. At 12 months, adalimumab was not detected but 4% [n = 3] had detectable infliximab. A Bayesian forecasting method was developed using a one-compartment pharmacokinetic model. Model validation showed that the predicted clearing time was in accordance with the measured observations. A clinician-friendly online calculator was developed for calculating full anti-TNF clearing time: https://xiaozhu.shinyapps.io/antiTNFcalculator2/.
Almost one-quarter of infants born to mothers receiving anti-TNF during pregnancy have detectable anti-TNF at 6 months. To limit the time to live-attenuated vaccination in infants of mothers receiving anti-TNF during pregnancy, the results of a cord drug level at birth and a second sample ≥ 1 month thereafter can be used to estimate the time for full anti-TNF clearance in these children. |
This study aimed to evaluate the pharmacokinetics (PK), safety, and immunogenicity of the infliximab biosimilar CMAB008 compared to the reference product (Remicade) in healthy Chinese male subjects to provide the basis for the similarity evaluation of the 2 drugs. In this phase I randomized, double-blind, parallel-controlled, single-dose study, a total of 90 subjects were randomized 1:1 to receive CMAB008 or infliximab reference product with single intravenous injections (5 mg/kg). Blood samples were collected at designed time points for PK and immunogenicity assessment. If the 90%CI of the geometric mean ratio of area under the plasma concentration-time curve from 0 to the time of the last observation, maximum observed plasma concentration, area under the plasma concentration-time curve from 0 to infinity was completely within the range of 80% to 125%, the PK bioequivalence was established. Other PK parameters including time to maximum plasma concentration |
Immunoglobulin A vasculitis (IgAV) is the most common childhood vasculitis affecting small vessels. No clear recommendations are available for severe pediatric cases, and until now, anti-TNF agents have had a limited role in IgAV management. In this report, we describe a pediatric case of severe IgAV, successfully treated with combined therapy including the anti-TNF, infliximab. |
Background and context An increasing number of drugs and blood products need to be delivered by intravenous infusion. In the Canterbury region of New Zealand, these have historically been delivered at a hospital site; however, some infusions could be delivered in a community setting without compromising patient safety. Assessment of problem The Canterbury health system has a key strategic objective of delivering care close to patients' homes. In 2018, Canterbury district health board (DHB) put out a tender for a community infusion service that would deliver blood products and other intravenous drugs with appropriate medical oversight. Strategies for improvement Following an interview and selection process, a fee-for-service contract was developed with a group of general practices with partial common ownership. It was nurse-led with medical oversight available. In July 2018, a Community Infusion Service (CIS) was started in two urban sites in Canterbury. It later expanded to two more sites, one urban and one rural. Results From July 2018 to May 2021, over 3000 infusions and blood transfusions were delivered by the CIS across seven infusion types (blood; immunoglobulin; infliximab; natalizumab; pamidronate; toculizumab; zoledronic acid). Both general practice and hospital services referred patients to the CIS. No major incidents were reported. Patients reported satisfaction with the service. Lessons Infusions and blood products can be delivered safely nearer to patients' homes in primary care in a New Zealand setting. Medical input was rarely required; however, the transition was resource-intensive; it required both overall process and criteria negotiations, as well as individual patient discussions. In its initial stages, the CIS did not have adequate clinical governance and operational support, which affected the speed and scale of its development. |
Interleukin-8 (CXCL8) produced in the tumor microenvironment correlates with poor response to checkpoint inhibitors and is known to chemoattract and activate immunosuppressive myeloid leukocytes. In human cancer, IL8 mRNA levels correlate with IL1B and TNF transcripts. Both cytokines induced IL-8 functional expression from a broad variety of human cancer cell lines, primary colon carcinoma organoids, and fresh human tumor explants. Although IL8 is absent from the mouse genome, a similar murine axis in which TNFα and IL-1β upregulate CXCL1 and CXCL2 in tumor cells was revealed. Furthermore, intratumoral injection of TNFα and IL-1β induced IL-8 release from human malignant cells xenografted in immunodeficient mice. In all these cases, the clinically used TNFα blockers infliximab and etanercept or the IL-1β inhibitor anakinra was able to interfere with this pathogenic cytokine loop. Finally, in paired plasma samples of patients with cancer undergoing TNFα blockade with infliximab in a clinical trial, reductions of circulating IL-8 were substantiated.
IL-8 attracts immunosuppressive protumor myeloid cells to the tumor microenvironment, and IL-8 levels correlate with poor response to checkpoint inhibitors. TNFα and IL-1β are identified as major inducers of IL-8 expression on malignant cells across cancer types and models in a manner that is druggable with clinically available neutralizing agents. This article is highlighted in the In This Issue feature, p. 2007. |
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During illness, adaptations of the hypothalamic-pituitary-thyroid axis reduce energy expenditure, protein catabolism and modulate immune responses to promote survival. Lower serum free triiodothyronine-to-thyroxine (fT3/fT4) ratio has been linked to non-response to treatment in a range of diseases, including in biologic-treated patients with inflammatory bowel disease.
To assess whether baseline serum fT3/fT4 ratio predicted primary non-response (PNR) and non-remission to infliximab and adalimumab in patients with Crohn's disease METHODS: Thyroid function tests were undertaken in stored serum from biologic-naïve adult patients with active luminal Crohn's disease immediately prior to treatment with infliximab (427 originator; 122 biosimilar) or adalimumab (448) in the Personalised Anti-TNF Therapy in Crohn's Disease study (PANTS).
Baseline median [IQR] fT3/fT4 ratios were lower in women than men (0.30 [0.27-0.34] vs 0.32 [0.28-0.36], p < 0.001), in patients with more severe inflammatory disease, and in patients receiving corticosteroids (0.28 [0.25-0.33] vs. 0.32 [0.29-0.36], p < 0.001). Multivariable logistic regression analysis demonstrated that fT3/fT4 ratio was independently associated with PNR at week 14 (odds ratio [OR] 0.51, 95% confidence interval [CI] 0.31-0.85, p = 0.009), but not non-remission or changes in faecal calprotectin concentrations at week 54. The optimal threshold to determine PNR was 0.31 (area under the curve 0.57 [95% CI 0.54-0.61], sensitivity 0.62 [95% CI 0.41-0.74], and specificity 0.53 [95% CI 0.42-0.73]).
Lower baseline serum fT3/fT4 ratio was associated with female sex, corticosteroid use and disease activity. It predicted PNR to anti-TNF treatment at week 14, but not non-remission at week 54. |
Despite an effective vaccine, hepatitis B remains a major global health problem due to its significant morbidity and mortality. Vaccination in immunosuppressed patients such as those treated for an inflammatory bowel disease (IBD) can be less effective. This case describes an uncommon original diagnosis of an acute hepatitis B infection occurring in a vaccinated but immunocompromised IBD patient under long-term infliximab treatment. A low anti-HBs titer and the presence of HBsAg escape mutations are possible hypotheses to explain this unexpected infection.
A 28-year-old Caucasian male, regularly followed-up for a Crohn's disease treated by infliximab, was regularly screened for sexually transmissible infections because of at-risk behaviors. Despite a correct immunization scheme against hepatitis B virus (HBV), an active HBV infection was diagnosed during one of those screenings. Retrospective testing of a sample collected 6 months earlier was in favor of an evolution from an acute hepatitis B toward a chronic hepatitis B. The patient has always had a low anti-HBs antibody levels (near the threshold of 10 IU/L) possibly explaining his infection. In addition, HBV sequencing revealed a genotype A2 HBV strain, carrying the sD144A substitution on the S protein, known as a potential immune escape variant. Dual therapy combining tenofovir disoproxil fumarate and emtricitabine, active against HBV but also efficient as an HIV pre-exposure prophylaxis, was initiated. Ten months after treatment initiation, all surrogate biochemical and virological endpoints for HBV functional cure were achieved. Treatment and periodical monitoring are being maintained.
Emphasis should be placed on HBV screening, vaccination and regular monitoring of patients under long-term immunosuppressive therapy, particularly those with at-risk behaviors. |
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Nearly one-third of patients with inflammatory bowel disease (IBD) do not achieve remission despite our best therapies. When this happens, it is critical to understand the reason for treatment failure. Once nonresponse is confirmed, these patients should be referred to an IBD centre for multidisciplinary care. This review will discuss the remaining treatment options, including escalation of biologics to unlicensed doses, combination biologics, nonvalidated therapies and surgical options. It will additionally provide updates in the management of acute severe ulcerative colitis (ASUC).
There is an increasing interest in combination biologics to treat refractory IBD, although data supporting its safety and effectiveness are limited. The use of hyperbaric oxygen, mesenchymal stem cell therapy and dietary interventions also show early promise in this area. Studies have additionally focused on personalized therapy to identify aggressive phenotypes and predict treatment response in these challenging patients. In ASUC, infliximab and cyclosporine remain mainstays of treatment, and tofacitinib shows promise as a salvage therapy.
Refractory IBD is common, yet large knowledge gaps remain. Recent and ongoing studies have focused on medical, surgical and dietary approaches with mixed success. Larger prospective studies are desperately needed to address this complex issue. |
Over the last decade, there has been rapid expansion of the therapeutic armamentarium, and evolution of treatment strategies, for the management of inflammatory bowel diseases (IBDs). Consequently, there is an increasing need for head-to-head or comparative efficacy trials to inform optimal positioning of therapies, and pragmatic trials comparing treatment strategies to inform treatment approach. In this review, we will discuss the current status and future of comparative efficacy clinical trials in IBD.
Pivotal phase IIIB superiority clinical trials have demonstrated superiority of vedolizumab over adalimumab for achieving clinical remission in patients with moderate-to-severe ulcerative colitis (VARSITY) and failed to demonstrate superiority of ustekinumab over adalimumab in patients with moderate-to-severe Crohn's disease (SEAVUE). Noninferiority clinical trials of biosimilars have confirmed absence of meaningful differences in safety and efficacy of biosimilar infliximab over originator infliximab, as initial therapy or switching stable patients during maintenance. Network meta-analyses, indirect treatment comparison using patient-level data from placebo-controlled trials and real-world observational studies have inform comparative effectiveness and safety of different therapies for management of IBD.
Head-to-head clinical trials are critically important to advance the field of IBD. Comparative efficacy trials are slow and expensive to conduct, may not be broadly generalizable, and are not powered for safety events or other relevant outcomes. Alternative approaches to comparative effectiveness such as network meta-analysis and well designed real-world observational studies are able to bridge gaps in clinical practice. |
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