Derlin-1, as a Potential Early Predictive Biomarker for Nonresponse to Infliximab Treatment in Rheumatoid Arthritis, Is Related to Autophagy

BackgroundThe goal of this study was to identify potential predictive biomarkers for the therapeutic effect of infliximab (IFX) in Rheumatoid arthritis (RA) and explore the potential molecular mechanism of nonresponse to IFX treatment to achieve individualized treatment of RA.MethodsDifferential gene expression between IFX responders and nonresponders in the GSE58795 and GSE78068 datasets was identified. Coexpression analysis was used to identify the modules associated with nonresponse to IFX therapy for RA, and enrichment analysis was conducted on module genes. Least absolute shrink and selection operator (LASSO) regression was used to develop a gene signature for predicting the therapeutic effect of IFX in RA, and the area under the receiver operating characteristic curve (AUC) was used to evaluate the predictive value of the signature. Correlation analysis and single-sample gene set enrichment analysis (ssGSEA) were used to explore the potential role of the hub genes. Experimental validation was conducted in synovial tissue and RA fibroblast-like synoviocytes (RA-FLSs).ResultsA total of 46 common genes were obtained among the two datasets. The yellow-green module was identified as the key module associated with nonresponse to IFX therapy for RA. We identified a 25-gene signature in GSE78068, and the AUC for the signature was 0.831 in the internal validation set and 0.924 in the GSE58795 dataset(external validation set). Derlin-1 (DERL1) was identified as the hub gene and demonstrated to be involved in the immune response and autophagy regulation. DERL1 expression was increased in RA synovial tissue compared with OA synovial tissue, and DERL1-siRNA partially inhibited autophagosome formation in RA-FLSs.ConclusionThe 25-gene signature may have potential predictive value for the therapeutic effect of IFX in RA at the beginning of IFX treatment, and autophagy may be involved in nonresponse to IFX treatment. In particular, DERL1 may be associated with the regulation of autophagy.

Clinical Observations on Infliximab Treatment of Infantile Onset Takayasu Arteritis

Background: To study short-term clinical effectiveness and safety of infliximab (IFX) treatment of infants with Takayasu arteritis (TA). Methods: We investigated the therapeutic effectiveness of IFX in 10 infantile TA in a retrospective case series. Evaluation included assessment of clinical symptoms, laboratory testing, and vascular imaging. Results: Fever was the presenting symptom for 8 of 10 infants with TA. In the acute episode, leucocyte and inflammatory indices increased significantly. Vascular imaging showed that the most commonly-involved arteries were carotid arteries, abdominal aortas, and coronary arteries (9 cases, 90%). Two weeks after IFX treatment, leukocyte and platelet counts decreased, and hemoglobin levels increased. There were significant clinical differences 6 weeks after treatment compared with before treatment (p<0.05). Inflammatory indices decreased significantly 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 the involved vessels significantly recovered within 13 months. Some arteries remained stenotic, intimal thickening and uneven lumen wall thickness. Conclusions: TA is rare in infancy. Fever may be the main manifestation of illness, often accompanied by significantly increased inflammatory indices. Early use of IFX appears to be effective, significantly decreasing inflammatory markers and improving clinical features, leading to partial remission of vascular lesions and sustain remissions for some infants. Use of IFX reduced or eliminated need for glucocorticoids. IFX has a reasonable safety profile and does not appear to affect normal growth and development of infants with TA.

Alterations in Kynurenine and NAD+ Salvage Pathways during the Successful Treatment of Inflammatory Bowel Disease Suggest HCAR3 and NNMT as Potential Drug Targets

A meta-analysis of publicly available transcriptomic datasets was performed to identify metabolic pathways profoundly implicated in the progression and treatment of inflammatory bowel disease (IBD). The analysis revealed that genes involved in tryptophan (Trp) metabolism are upregulated in Crohn’s disease (CD) and ulcerative colitis (UC) and return to baseline after successful treatment with infliximab. Microarray and mRNAseq profiles from multiple experiments confirmed that enzymes responsible for Trp degradation via the kynurenine pathway (IDO1, KYNU, IL4I1, KMO, and TDO2), receptor of Trp metabolites (HCAR3), and enzymes catalyzing NAD+ turnover (NAMPT, NNMT, PARP9, CD38) were synchronously coregulated in IBD, but not in intestinal malignancies. The modeling of Trp metabolite fluxes in IBD indicated that changes in gene expression shifted intestinal Trp metabolism from the synthesis of 5-hydroxytryptamine (5HT, serotonin) towards the kynurenine pathway. Based on pathway modeling, this manifested in a decline in mucosal Trp and elevated kynurenine (Kyn) levels, and fueled the production of downstream metabolites, including quinolinate, a substrate for de novo NAD+ synthesis. Interestingly, IBD-dependent alterations in Trp metabolites were normalized in infliximab responders, but not in non-responders. Transcriptomic reconstruction of the NAD+ pathway revealed an increased salvage biosynthesis and utilization of NAD+ in IBD, which normalized in patients successfully treated with infliximab. Treatment-related changes in NAD+ levels correlated with shifts in nicotinamide N-methyltransferase (NNMT) expression. This enzyme helps to maintain a high level of NAD+-dependent proinflammatory signaling by removing excess inhibitory nicotinamide (Nam) from the system. Our analysis highlights the prevalent deregulation of kynurenine and NAD+ biosynthetic pathways in IBD and gives new impetus for conducting an in-depth examination of uncovered phenomena in clinical studies.

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

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

Correlation Between Vascular Inflammation Markers, Diastolic Dysfunction and Cardiovascular Risk in Patients with Takayasu Arteritis

Background: Takayasu Arteritis (TAK) increases vascular stiffness and arterial resistance. Hypertension and atherosclerosis lead to similar changes. We investigated possible differences in cardiovascular remodeling between these diseases and whether the differences are correlated with immune cell expression. Methods: Patients with active TAK arteritis were compared with age- and sex-matched hypertensive and atherosclerotic patients. In a subpopulation of TAK patients, Treg/Th17 cells were measured before (T0) and after 18 months (T18) of infliximab treatment. Echocardiogram, supraaortic Doppler ultrasound, and lymphocytogram were performed in all patients. Histological and immunohistochemical evaluation of the vessel wall was performed to compare the in vivo results. Results: TAK patients have increased aortic valve dysfunction and diastolic dysfunction. These data have been associated with uric acid levels. A significant increase in aortic stiffness was also noted and associated with peripheral T lymphocyte levels. CD3+CD4+ cell infiltrates were detected in the vessel wall samples of these patients. They had a lower mean percentage of Tregs at T0 than controls, but levels increased significantly at T18. Opposite results were found in Th17 cells. Finally, TAK patients were found to have an increased risk of atherosclerotic cardiovascular disease (ASCVD). Conclusion: Our data suggest that different pathogenic mechanisms of vessel damage, including atherosclerosis, underlie TAK patients compared with control subjects. The increased risk of ASCVD in TAK patients correlates directly with the degree of inflammatory cell infiltration in the vessel wall. Infliximab restores the normal frequency of Tregs/Th17 in TAK patients and allows a possible reduction of steroids and immunosuppressants.

Combination of Serological Biomarkers and Clinical Features To Predict Mucosal Healing in Crohn’s Disease: A Multicenter Cohort Study

Background Mucosal healing (MH) has become the treatment goal of patients with Crohn’s disease (CD). This study aims to develop a noninvasive and reliable clinical tool for individual evaluation of mucosal healing in patients with Crohn’s disease. Results The following variables were independently associated with the MH and were subsequently included into the prediction model: PLR (platelet to lymphocyte ratio), CAR (C-reactive protein to albumin ratio), ESR (erythrocyte sedimentation rate), HBI (Harvey-Bradshaw Index) score and infliximab treatment. A primary model and a simple model were established, respectively. The primary model performed better than the simple one in C-index (87.5% vs 83.0 %, p=0.004). There was no statistical significance between these two models in sensitivity (70.43% vs 62.61%, p=0.467), specificity (87.12% vs 80.69%, p=0.448), PPV (72.97% vs 61.54%, p=0.292), NPV (85.65% vs 81.39%, p=0.614), and accuracy (81.61% vs 74.71%, p=0.303). The primary model had good calibration and high levels of explained variation and discrimination in validation cohort. Conclusions This model can be used to predict MH in post-treatment CD patients. It can also be used as an indication of endoscopic surveillance to evaluate mucosal healing in patients with CD after treatment.

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

BackgroundCurrent treatment guidelines for immune-mediated diarrhea and colitis (IMDC) recommend steroids as first-line therapy, followed by selective immunosuppressive therapy (SIT) (infliximab or vedolizumab) for refractory cases. We aimed to compare the efficacy of these two SITs and their impact on cancer outcomes.MethodsWe performed a two-center, retrospective observational cohort study of patients with IMDC who received SITs following steroids from 2016 to 2020. Patients’ demographic, clinical, and overall survival data were collected and analyzed.ResultsA total of 184 patients (62 vedolizumab, 94 infliximab, 28 combined sequentially) were included. The efficacy of achieving clinical remission of IMDC was similar (89% vs 88%, p=0.79) between the two groups. Compared with the infliximab group, the vedolizumab group had a shorter steroid exposure (35 vs 50 days, p<0.001), fewer hospitalizations (16% vs 28%, p=0.005), and a shorter hospital stay (median 10.5 vs 13.5 days, p=0.043), but a longer time to clinical response (17.5 vs 13 days, p=0.012). Longer durations of immune checkpoint inhibitors treatment (OR 1.01, p=0.004) and steroid use (OR 1.02, p=0.043), and infliximab use alone (OR 2.51, p=0.039) were associated with higher IMDC recurrence. Furthermore, ≥3 doses of SIT (p=0.011), and fewer steroid tapering attempts (p=0.012) were associated with favorable overall survival.ConclusionsTreatment with vedolizumab as compared with infliximab for IMDC led to comparable IMDC response rates, shorter duration of steroid use, fewer hospitalizations, and lower IMDC recurrence, though with slightly longer time to IMDC response. Higher number of SIT doses was associated with better survival outcome, while more steroid exposure resulted in worse patient outcomes.

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

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