Patterns and determinants of response to novel therapies in juvenile and adult-onset polyarthritis.

Biologic and targeted synthetic DMARDs (b/tsDMARDs) have revolutionized the management of multiple rheumatic inflammatory conditions. Among these, polyarticular JIA (pJIA) and RA display similarities in terms of disease pathophysiology and response pattern to b/tsDMARDs. Indeed, the therapeutic efficacy of novel targeted drugs is variable among individual patients, in both RA and pJIA. The mechanisms and determinants of this heterogeneous response are diverse and complex, such that the development of true 'precision'-medicine strategies has proven highly challenging. In this review, we will discuss pathophysiological, patient-specific, drug-specific and environmental factors contributing to individual therapeutic response in pJIA in comparison with what is known in RA. Although some biomarkers have been identified that stratify with respect to the likelihood of either therapeutic response or non-response, few have proved useful in clinical practice so far, likely due to the complexity of treatment-response mechanisms. Consequently, we propose a pragmatic, patient-centred and clinically based approach, i.e. personalized instead of biomarker-based precision medicine in JIA.

A Good Response to Nonsteroidal Antiinflammatory Drugs Does Not Discriminate Patients With Longstanding Axial Spondyloarthritis From Controls With Chronic Back Pain.

OBJECTIVE: To compare the response to nonsteroidal antiinflammatory drugs (NSAIDs) in patients with longstanding axial spondyloarthritis (axSpA) and controls with back pain (nonspondyloarthritis [non-SpA]). METHODS: Consecutive outpatients with chronic back pain (axSpA or non-SpA), were prospectively recruited. Any previous NSAIDs were withdrawn 2 days before study start (baseline). Back pain was assessed using a numerical rating scale (NRS; range 0-10) starting at 2 hours after baseline and several times thereafter up to 4 weeks. "Any response" to NSAIDs was defined as improvement of back pain on the NRS > 2 units, and "good response" as improvement > 50%, compared to baseline. RESULTS: Among 233 patients included, 68 had axSpA (29.2%) and 165 had non-SpA back pain (70.8%). The mean age was 42.7 (SD 10.7) vs 49.3 (SD 11.1) years, symptom duration 15.1 (SD 11.1) years vs 14.6 (SD 11.9) years, and pain score 5.9 (SD 2.3) vs 6.3 (SD 2.0), respectively. Overall, of patients with axSpA or non-SpA back pain, 30.9% vs 29.1% of patients showed any response and 23.5% vs 16.4% of patients showed a good response after 4 weeks, respectively (P value not significant). No differences were found in the rapidity of response or between subgroups of patients based on demographics, including different stages of axSpA. CONCLUSION: No major differences in the response to NSAIDs were found between patients with axSpA and those with non-SpA with longstanding chronic back pain. The item in the Assessment of SpondyloArthritis international Society classification criteria on "response to NSAIDs" needs more study.

Ovarian Cancer Diagnosis and Prognosis Based on Cell-Free DNA Methylation.

Background: Ovarian cancer stands as the deadliest malignant tumor within the female reproductive tract. As a result of the absence of effective diagnostic and monitoring markers, 75% of ovarian cancer cases are diagnosed at a late stage, leading to a mere 50% survival rate within five years. The advancement of molecular biology is essential for accurate diagnosis and treatment of ovarian cancer. Methods: A review of several randomized clinical trials, focusing on the ovarian cancer, was undertaken. The advancement of molecular biology and diagnostic methods related to accurate diagnosis and treatment of ovarian cancer were examined. Results: Liquid biopsy is an innovative method of detecting malignant tumors that has gained increasing attention over the past few years. Cell-free DNA assay-based liquid biopsies show potential in delineating tumor status heterogeneity and tracking tumor recurrence. DNA methylation influences a multitude of biological functions and diseases, especially during the initial phases of cancer. The cell-free DNA methylation profiling system has emerged as a sensitive and non-invasive technique for identifying and detecting the biological origins of cancer. It holds promise as a biomarker, enabling early screening, recurrence monitoring, and prognostic evaluation of cancer. Conclusions: This review evaluates recent advancements and challenges associated with cell-free DNA methylation analysis for the diagnosis, prognosis monitoring, and assessment of therapeutic responses in the management of ovarian cancers, aiming to offer guidance for precise diagnosis and treatment of this disease.

Ovarian cancer stands as the deadliest malignant tumor within the female reproductive tract. As a result of the absence of effective diagnostic and monitoring markers, 75% of ovarian cancer cases are diagnosed at a late stage, leading to a mere 50% survival rate within five years. Nearly 80% of advanced stages have a poor prognosis or recurrence within five years. Ovarian cancer is linked to a grim long-term prognosis attributable to its elevated mortality and recurrence rates. The advancement of molecular biology and diagnostic methods is essential for accurate diagnosis and treatment of ovarian cancer. Liquid biopsy is an innovative method of detecting malignant tumors that has gained increasing attention over the past few years. Cell-free DNA assay-based liquid biopsies show potential in delineating tumor status heterogeneity and tracking tumor recurrence. DNA methylation represents a prevalent epigenetic modification. DNA methylation influences a multitude of biological functions and diseases, especially during the initial phases of cancer. The cell-free DNA methylation profiling system has emerged as a sensitive and non-invasive technique for identifying and detecting the biological origins of cancer. This review assesses recent progress and obstacles linked to cell-free DNA methylation analysis for diagnosing, prognostic monitoring, and evaluating therapeutic responses in managing ovarian cancers.

A circulating, disease-specific, mechanism-linked biomarker for ATTR polyneuropathy diagnosis and response to therapy prediction.

The transthyretin (TTR) amyloidoses (ATTR) are progressive, degenerative diseases resulting from dissociation of the TTR tetramer to monomers, which subsequently misfold and aggregate, forming a spectrum of aggregate structures including oligomers and amyloid fibrils. To determine whether circulating nonnative TTR (NNTTR) levels correlate with the clinical status of patients with V30M TTR familial amyloid polyneuropathy (FAP), we quantified plasma NNTTR using a newly developed sandwich enzyme-linked immunosorbent assay. The assay detected significant plasma levels of NNTTR in most presymptomatic V30M TTR carriers and in all FAP patients. NNTTR was not detected in age-matched control plasmas or in subjects with other peripheral neuropathies, suggesting NNTTR can be useful in diagnosing FAP. NNTTR levels were substantially reduced in patients receiving approved FAP disease-modifying therapies (e.g., the TTR stabilizer tafamidis, 20 mg once daily). This NNTTR decrease was seen in both the responders (average reduction 56.4 ± 4.2%; n = 49) and nonresponders (average reduction of 63.3 ± 4.8%; n = 32) at 12 mo posttreatment. Notably, high pretreatment NNTTR levels were associated with a significantly lower likelihood of clinical response to tafamidis. Our data suggest that NNTTR is a disease driver whose reduction is sufficient to ameliorate FAP so long as pretreatment NNTTR levels are below a critical clinical threshold.

Exposure to Secondhand Smoke Extract Increases Cisplatin Resistance in Head and Neck Cancer Cells.

Chemotherapy and radiotherapy resistance are major obstacles in the long-term efficacy of head and neck squamous cell carcinoma (HNSCC) treatment. Secondhand smoke (SHS) exposure is common and has been proposed as an independent predictor of HNSCC recurrence and disease-free survival. However, the underlying mechanisms responsible for these negative patient outcomes are unknown. To assess the effects of SHS exposure on cisplatin efficacy in cancer cells, three distinct HNSCC cell lines were exposed to sidestream (SS) smoke, the main component of SHS, at concentrations mimicking the nicotine level seen in passive smokers' saliva and treated with cisplatin (0.01-100 µM) for 48 h. Compared to cisplatin treatment alone, cancer cells exposed to both cisplatin and SS smoke extract showed significantly lower cisplatin-induced cell death and higher cell viability, IC50, and indefinite survival capacity. However, SS smoke extract exposure alone did not change cancer cell viability, cell death, or cell proliferation compared to unexposed control cancer cells. Mechanistically, exposure to SS smoke extract significantly reduced the expression of cisplatin influx transporter CTR1, and increased the expression of multidrug-resistant proteins ABCG2 and ATP7A. Our study is the first to document that exposure to SHS can increase cisplatin resistance by altering the expression of several proteins involved in multidrug resistance, thus increasing the cells' capability to evade cisplatin-induced cell death. These findings emphasize the urgent need for clinicians to consider the potential role of SHS on treatment outcomes and to advise cancer patients and caregivers on the potential benefits of avoiding SHS exposure.

Clinical utility of intraductal carcinoma of the prostate in treatment selection for metastatic hormone-sensitive prostate cancer.

BACKGROUND: In recent years, the usefulness of androgen receptor axis-targeted agents (ARATs) such as abiraterone, enzalutamide, and apalutamide for the upfront treatment of metastatic hormone-sensitive prostate cancer (mHSPC) has been demonstrated. However, it remains unclear which patients would truly benefit from these treatments. Furthermore, intraductal carcinoma of the prostate (IDC-P) is a known poor prognostic factor in patients with prostate cancer. We investigated the association between the presence of IDC-P and response to therapy in patients with mHSPC. METHODS: This retrospective analysis included 318 patients with mHSPC who received treatment at Nagoya University and its 12 affiliated institutions between 2014 and 2021. Their biopsy specimens were evaluated for the presence of IDC-P. The patients were classified according to their first-line treatment into the ARAT (n = 100, receiving a combination of androgen-deprivation therapy [ADT] and ARAT) or conventional therapy (n = 218, receiving ADT with or without standard antiandrogen agents) group. We compared the overall survival (OS) and second progression-free survival (PFS2) between the ARAT and conventional groups according to the presence of IDC-P to evaluate whether presence of IDC-P predicts the response to each treatment. PFS2 was defined as the period from mHSPC diagnosis to disease progression on second-line treatment or death. Propensity score matching with one-to-one nearest-neighbor matching was used to minimize the potential effects of selection bias and confounding factors. The clinicopathological variables of the patients were well-balanced after propensity score matching. RESULTS: Most patients in the ARAT (79%) and conventional therapy (71%) groups were ICD-P positive. In the propensity score-matched cohort, the OS and PFS2 of IDC-P-positive patients were significantly longer in the ARAT group than in the conventional group (OS: hazard ratio [HR], 0.36; p = 0.047; PFS2: HR, 0.30; p < 0.001). In contrast, no difference in OS and PFS2 was observed between the ARAT and conventional groups in IDC-P-negative patients (OS: HR, 1.09; p = 0.920; PFS2: HR, 0.40; p = 0.264). CONCLUSIONS: The findings highlight a high prevalence of IDC-P among patients with mHSPC and suggest that IDC-P positivity may be a reliable indicator that ARAT should be implemented as first-line treatment.

Donor-Derived Cell-Free DNA (dd-cfDNA) in Kidney Transplant Recipients With Indication Biopsy-Results of a Prospective Single-Center Trial.

Donor-derived cell-free DNA (dd-cfDNA) identifies allograft injury and discriminates active rejection from no rejection. In this prospective study, 106 kidney transplant recipients with 108 clinically indicated biopsies were enrolled at Heidelberg University Hospital between November 2020 and December 2022 to validate the clinical value of dd-cfDNA in a cohort of German patients. dd-cfDNA was quantified at biopsy and correlated to histopathology. Additionally, dd-cfDNA was determined on days 7, 30, and 90 post-biopsy and analyzed for potential use to monitor response to anti-rejection treatment. dd-cfDNA levels were with a median (IQR) % of 2.00 (0.48-3.20) highest in patients with ABMR, followed by 0.92 (0.19-11.25) in patients with TCMR, 0.44 (0.20-1.10) in patients with borderline changes and 0.20 (0.11-0.53) in patients with no signs of rejection. The AUC for dd-cfDNA to discriminate any type of rejection including borderline changes from no rejection was at 0.72 (95% CI 0.62-0.83). In patients receiving anti-rejection treatment, dd-cfDNA levels significantly decreased during the 7, 30, and 90 days follow-up compared to levels at the time of biopsy (p = 0.006, p = 0.002, and p < 0.001, respectively). In conclusion, dd-cfDNA significantly discriminates active rejection from no rejection. Decreasing dd-cfDNA following anti-rejection treatment may indicate response to therapy. Clinical Trial Registration: https://drks.de/search/de/trial/DRKS00023604, identifier DRKS00023604.

Can ß-catenin, Tenascin and Fascin be potential biomarkers for personalized therapy in Gastric carcinoma?

Gastric carcinoma (GC) is one of the most prevalent cancers worldwide and the fourth leading cause of cancer-related death. Studying the molecular profile of GC is essential for developing targeted therapies. ß-catenin, Tenascin, and Fascin expression are among the molecular abnormalities that are claimed to cause GC progression and chemoresistance. Therefore, they could be used as potential therapeutic targets. This study aimed to evaluate ß-catenin, Tenascin, and Fascin expression and their possible roles as prognostic and predictive biomarkers in GC using immunohistochemistry. This retrospective study included 84 GC cases. Tissue microarrays were constructed, followed by ß-catenin, Tenascin, and Fascin immunostaining. Their expression was assessed and compared with clinicopathological parameters and survival data. The study results revealed that ß-catenin nucleocytoplasmic expression, positive Tenascin, and Fascin expressions were detected in 86.9%, 70%, and 59.5% of cases, respectively. Their expression was significantly associated with poor prognostic parameters, such as deeper tumor invasion, lymph node metastasis, advanced pathological stage, vascular invasion, positive omental nodules, poor response to chemotherapy, and short overall survival. Hence, nucleocytoplasmic ß-catenin expression together with Tenascin and Fascin positivity can be potential prognostic and predictive markers, and they can be used as therapeutic targets for GC.

Gut Microbiota, Metabolome, and Body Composition Signatures of Response to Therapy in Patients with Advanced Melanoma.

Despite the recent breakthroughs in targeted and immunotherapy for melanoma, the overall survival rate remains low. In recent years, considerable attention has been paid to the gut microbiota and other modifiable patient factors (e.g., diet and body composition), though their role in influencing therapeutic responses has yet to be defined. Here, we characterized a cohort of 31 patients with unresectable IIIC-IV-stage cutaneous melanoma prior to initiation of targeted or first-line immunotherapy via the following methods: (i) fecal microbiome and metabolome via 16S rRNA amplicon sequencing and gas chromatography/mass spectrometry, respectively, and (ii) anthropometry, body composition, nutritional status, physical activity, biochemical parameters, and immunoprofiling. According to our data, patients subsequently classified as responders were obese (i.e., with high body mass index and high levels of total, visceral, subcutaneous, and intramuscular adipose tissue), non-sarcopenic, and enriched in certain fecal taxa (e.g., Phascolarctobacterium) and metabolites (e.g., anethole), which were potentially endowed with immunostimulatory and oncoprotective activities. On the other hand, non-response was associated with increased proportions of Streptococcus, Actinomyces, Veillonella, Dorea, Fusobacterium, higher neutrophil levels (and a higher neutrophil-to-lymphocyte ratio), and higher fecal levels of butyric acid and its esters, which also correlated with decreased survival. This exploratory study provides an integrated list of potential early prognostic biomarkers that could improve the clinical management of patients with advanced melanoma, in particular by guiding the design of adjuvant therapeutic strategies to improve treatment response and support long-term health improvement.

Maintenance of Remission With Tofacitinib Therapy in Patients With Ulcerative Colitis.

BACKGROUND & AIMS: Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). The efficacy and safety of tofacitinib in patients with moderate to severe UC, up to 1 year, have been reported. We investigated maintenance of efficacy in patients in remission after 52 weeks of maintenance treatment in the pivotal phase 3 study (OCTAVE Sustain); these patients received open-label, long-term treatment with tofacitinib 5 mg twice daily. METHODS: Patients with moderate to severe UC who completed a 52-week, phase 3 maintenance study (OCTAVE Sustain) were eligible to enroll into the ongoing, phase 3, multicenter, open-label, long-term extension (OCTAVE Open). We analyzed data from 142 patients who were in remission following tofacitinib treatment in OCTAVE Sustain who received tofacitinib 5 mg twice daily during OCTAVE Open. We assessed efficacy (including remission [based on total Mayo score], endoscopic improvement, clinical response, and partial Mayo score up to month 36 of OCTAVE Open) and safety data. RESULTS: After 12 months of tofacitinib 5 mg twice daily in OCTAVE Open, 68.3% of patients were in remission, 73.9% had endoscopic improvement, and 77.5% had a clinical response. At month 36, 50.4%, of the patients were in remission, 55.3% had endoscopic improvement, and 56.0% had a clinical response. The safety profile of tofacitinib 5 mg twice daily revealed no new safety risks associated with long-term exposure up to 36 months. CONCLUSIONS: Efficacy endpoints were maintained for up to 36 months, regardless of prior tofacitinib dose, including patients who reduced from tofacitinib 10 mg to 5 mg twice daily upon OCTAVE Open entry. No new safety risks were identified. ClinicalTrials.gov: OCTAVE Sustain (NCT01458574); OCTAVE Open (NCT01470612).

Clinical Utility of KidneyIntelX in Early Stages of Diabetic Kidney Disease in the CANVAS Trial.

INTRODUCTION: KidneyIntelX is a composite risk score, incorporating biomarkers and clinical variables for predicting progression of diabetic kidney disease (DKD). The utility of this score in the context of sodium glucose co-transporter 2 inhibitors and how changes in the risk score associate with future kidney outcomes are unknown. METHODS: We measured soluble tumor necrosis factor receptor (TNFR)-1, soluble TNFR-2, and kidney injury molecule 1 on banked samples from CANagliflozin cardioVascular Assessment Study (CANVAS) trial participants with baseline DKD (estimated glomerular filtration rate [eGFR] 30-59 mL/min/1.73 m2 or urine albumin-to-creatinine ratio [UACR] ≥30 mg/g) and generated KidneyIntelX risk scores at baseline and years 1, 3, and 6. We assessed the association of baseline and changes in KidneyIntelX with subsequent DKD progression (composite outcome of an eGFR decline of ≥5 mL/min/year [using the 6-week eGFR as the baseline in the canagliflozin group], ≥40% sustained decline in the eGFR, or kidney failure). RESULTS: We included 1,325 CANVAS participants with concurrent DKD and available baseline plasma samples (mean eGFR 65 mL/min/1.73 m2 and median UACR 56 mg/g). During a mean follow-up of 5.6 years, 131 participants (9.9%) experienced the composite kidney outcome. Using risk cutoffs from prior validation studies, KidneyIntelX stratified patients to low- (42%), intermediate- (44%), and high-risk (15%) strata with cumulative incidence for the outcome of 3%, 11%, and 26% (risk ratio 8.4; 95% confidence interval [CI]: 5.0, 14.2) for the high-risk versus low-risk groups. The differences in eGFR slopes for canagliflozin versus placebo were 0.66, 1.52, and 2.16 mL/min/1.73 m2 in low, intermediate, and high KidneyIntelX risk strata, respectively. KidneyIntelX risk scores declined by 5.4% (95% CI: -6.9, -3.9) in the canagliflozin arm at year 1 versus an increase of 6.3% (95% CI: 3.8, 8.7) in the placebo arm (p < 0.001). Changes in the KidneyIntelX score at year 1 were associated with future risk of the composite outcome (odds ratio per 10 unit decrease 0.80; 95% CI: 0.77, 0.83; p < 0.001) after accounting for the treatment arm, without evidence of effect modification by the baseline KidneyIntelX risk stratum or by the treatment arm. CONCLUSIONS: KidneyIntelX successfully risk-stratified a large multinational external cohort for progression of DKD, and greater numerical differences in the eGFR slope for canagliflozin versus placebo were observed in those with higher baseline KidneyIntelX scores. Canagliflozin treatment reduced KidneyIntelX risk scores over time and changes in the KidneyIntelX score from baseline to 1 year associated with future risk of DKD progression, independent of the baseline risk score and treatment arm.

Thyroglobulin and thyroglobulin antibodies: assay-dependent management consequences in patients with differentiated thyroid carcinoma.

OBJECTIVES: International guidelines recommend fixed cut-off values for thyroglobulin (Tg). These cut-offs do not take potential assay differences into account. This study aimed to evaluate if different assays for Tg and Tg antibodies (TgAb) affect management guidance for differentiated thyroid cancer (DTC) patients. METHODS: In 793 samples derived from 413 patients with DTC, Tg and TgAb were simultaneously measured with two immunometric assays: Immulite 2000XPi and Kryptor compact plus. In addition, a qualitative measurement for TgAb interference (recovery test) was performed on the Kryptor compact plus platform. The extent to which different assays lead to different classifications of response to therapy was evaluated when applying the current cut-offs for Tg. RESULTS: Mean Tg concentrations were 37.4% lower with Kryptor as compared with Immulite. Applying guideline based cut-off values for Tg, 33 (4.7%) samples had a Tg-on concentration ≥1.0 µg/L with Immulite and <1.0 µg/L with Kryptor. Of the samples tested as TgAb+ with at least one assay (n=125), 68 (54.4%) samples showed discrepancy in TgAb status. Differences between Immulite and Kryptor measurements resulted in a change in the response to therapy classification in 94 (12.0%) measurements derived from 67 (16.2%) individual patients. CONCLUSIONS: A substantial portion of DTC patients were classified differently dependent on which Tg and TgAb assays are used, when applying the cut-off values as defined in clinical guidelines. Such differences can significantly affect clinical management. In the context of large between-method variation, the recommended Tg cut-offs in guidelines should be used with wisdom rather than as fixed cut-offs.

Improved Pressure Equalization Ratio Following Mannitol Administration in Patients With Severe TBI: A Preliminary Study of a Potential Bedside Marker for Response to Therapy.

BACKGROUND: Performing a cerebrospinal fluid (CSF) drainage challenge can be used to measure the pressure equalization (PE) ratio, which describes the extent to which CSF drainage can equalize pressure to the height of the external ventricular drain and may serve as a correlate of cerebral edema. We sought to assess whether treatment with mannitol improves PE ratio in patients with severe traumatic brain injury (TBI) with elevated intracranial pressure (ICP). METHODS: We studied consecutive patients with TBI and brain edema on computed tomography scan and an external ventricular drain (EVD), admitted to the neurointensive care unit. PE ratio, defined as ICP prior to CSF drainage minus ICP after CSF drainage divided by ICP prior to CSF drainage minus EVD height, was measured as previously described. Patients were treated with mannitol for raised ICP based on clinical indication and PE ratio measured before and after mannitol administration. RESULTS: We studied 20 patients with severe TBI with raised ICP. Mean ICP prior to mannitol treatment was 29 ± 7 mm Hg. PE ratio rose substantially after mannitol treatment (0.62 ± 0.24 vs. 0.29 ± 0.20, p < 0.0001), indicating an improved ability to drain CSF and equalize ICP with the preset height of the EVD. The combination of mannitol and CSF drainage led to an improved reduction in ICP compared with that seen before mannitol therapy (11 ± 2 mm Hg vs. 6 ± 2 mm Hg, p < 0.01), and led to a decrease in ICP below the 20 mm Hg threshold in 77% of cases. CONCLUSIONS: Treatment with mannitol leads to a substantial improvement in PE ratio that reflects the ability to achieve a greater decrease in ICP when CSF drainage is performed after mannitol administration. This preliminary study raises the possibility that PE ratio may be useful to follow response to therapy in patients with cerebral edema and raised ICP. Further studies to determine whether PE ratio may serve as an easily obtained and clinically useful surrogate marker for the extent of brain edema are warranted.

[Current view on the issue of insufficient effectiveness of anti-VEGF therapy for age-related macular degeneration]. / Sovremennyi vzglyad na problemu nedostatochnoi effektivnosti antiangiogennoi terapii vozrastnoi makulyarnoi degeneratsii.

Due to the significant medical and social importance of neovascular (wet) age-related macular degeneration (wAMD), increasing the effectiveness of anti-VEGF therapy used to treat this disease is one of the high-priority problems in modern retinology. This article focuses on pathobiological aspects and clinical manifestations of incomplete responses to anti-VEGF therapy of wAMD, considers the proposed ways to improve the terminology and classification of responses to therapy, as well as the assessment of its correctness and effectiveness of the treatment. It also discusses the available ways to optimize anti-VEGF therapy and define the criteria of its termination in cases when the treatment proves to be futile.

Persistent Diarrhea in Patients With Crohn's Disease After Mucosal Healing Is Associated With Lower Diversity of the Intestinal Microbiome and Increased Dysbiosis.

BACKGROUND & AIMS: In patients with inflammatory bowel diseases (IBDs), symptoms do not always associate with the severity of endoscopic inflammation and can persist after mucosal healing. We investigated whether symptoms in patients with successfully treated IBD are related to the composition of the intestinal microbiome. METHODS: We analyzed 590 tissue biopsy specimens from 215 patients with IBD and 48 healthy individuals (controls). We obtained mucosal biopsy specimens from 2 colon sites (ascending and rectosigmoid) and from the terminal ileum along with clinical data. Bacterial DNA was extracted from the biopsy specimens and the V4 region of 16s ribosomal RNA sequenced by Miseq and processed using the QIIME v1.9 pipeline. RESULTS: Mucosal biopsy specimens from patients with Crohn's disease (CD) who achieved mucosal healing (Mayo scores of 0-1 or segmental endoscopic severity CD scores of 0-5) had lower Chao1 diversity than biopsy specimens from patients with ulcerative colitis (UC) or unclassified IBD (IBD-U), or controls. After endoscopic evidence of improvement in patients with UC or IBD-U, diversity of the tissue-associated microbiota did not differ significantly from that of controls. Colon biopsy specimens from patients with CD had lower microbial diversity, before and after healing (segmental endoscopic severity CD scores, 0-2), than colon biopsy specimens from controls (P < .002). In patients with CD who achieved mucosal healing, residual clinical activity (CD activity index scores >150; P = .03) and persistent diarrhea were associated with reduced microbial diversity (P = .01). Continued diarrhea was associated with a trend toward dysbiosis, based on the microbial dysbiosis index (P = .059). In patients with UC or IBD-U with moderate to severe inflammation, increasing severity of diarrhea was associated with reduced microbial diversity (P = .03). CONCLUSIONS: In an analysis of biopsy specimens from patients with IBD and controls, we found that despite endoscopic evidence of improvement or remission, α-diversity of the tissue-associated intestinal microbiome remained lower in patients with CD than in controls. This observation, along with the reduced Chao1 diversity and greater dysbiosis in intestinal microbiota of patients with residual symptoms of IBD, indicates that microbiome composition could be associated with persistent diarrhea.

Baseline Clearance of Infliximab Is Associated With Requirement for Colectomy in Patients With Acute Severe Ulcerative Colitis.

BACKGROUND & AIMS: Hospitalized patients with acute severe ulcerative colitis (ASUC) often require surgery. Although the tumor necrosis factor antagonist infliximab is an effective salvage therapy to prevent colectomy in patients with ASUC, optimal dosing is unclear. Calculated infliximab clearance has been associated with important outcomes in patients with ulcerative colitis, but its utility in patients with ASUC has not been established. We assessed the relationship between calculated the baseline infliximab clearance before infliximab salvage therapy and the requirement for colectomy in patients hospitalized for ASUC. METHODS: We obtained data from hospitalized patients with ASUC who initiated infliximab therapy. We then calculated the baseline infliximab drug clearance in these patients based on an existing formula. The primary aim was to compare clearance between patients who required colectomy 6 months later and patients who did not require colectomy. Receiver operating characteristic curve analyses evaluated clearance thresholds for colectomy. Multivariable logistic regression analysis evaluated factors associated with colectomy. RESULTS: In 39 patients with ASUC, the median baseline calculated clearance was higher in patients requiring colectomy at 6 months than in patients without colectomy (0.733 vs 0.569 L/d; P = .005). An infliximab clearance threshold of 0.627 L/d identified patients who required colectomy with 80.0% sensitivity and 82.8% specificity (area under the curve, 0.80). A higher proportion of patients with infliximab clearance of 0.627 L/d or more underwent colectomy within 6 months (61.5%) than patients with lower infliximab clearance values (7.7%) (P = .001). Multivariable analysis identified baseline infliximab clearance as the only factor associated with colectomy. The infliximab dose in the hospital was higher in patients who required colectomy. Results were similar at 30 days and 1 year. CONCLUSIONS: In patients hospitalized with ASUC, higher values of calculated infliximab clearance before infliximab administration is associated with higher rates of colectomy. Although patients who required colectomies received higher doses, data on infliximab concentrations are lacking. Infliximab pharmacokinetic models are needed for patients with ASUC to allow comparative trials on clearance-based vs standard dosing.

Low Rates of Retesting for Eradication of Helicobacter pylori Infection After Treatment in the Veterans Health Administration.

BACKGROUND & AIMS: Expert consensus mandates retesting for eradication of Helicobacter pylori infection after treatment, but it is not clear how many patients are actually retested. We evaluated factors associated with retesting for H pylori in a large, nationwide cohort. METHODS: We performed a retrospective cohort study of patients with H pylori infection (detected by urea breath test, stool antigen, or pathology) who were prescribed an eradication regimen from January 1, 1994 through December 31, 2018 within the Veterans Health Administration (VHA). We collected data on demographic features, smoking history, socioeconomic status, facility poverty level and academic status, and provider specialties and professions. The primary outcome was retesting for eradication. Statistical analyses included mixed-effects logistic regression. RESULTS: Of 27,185 patients prescribed an H pylori eradication regimen, 6486 patients (23.9%) were retested. Among 7623 patients for whom we could identify the provider who ordered the test, 2663 patients (34.9%) received the order from a gastroenterological provider. Female sex (odds ratio, 1.22; 95% CI, 1.08-1.38; P = .002) and history of smoking (odds ratio, 1.24; 95% CI, 1.15-1.33; P < .001) were patient factors associated with retesting. There was an interaction between method of initial diagnosis of H pylori infection and provider who ordered the initial test (P < .001). There was significant variation in rates of retesting among VHA facilities (P < .001). CONCLUSIONS: In an analysis of data from a VHA cohort of patients with H pylori infection, we found low rates of retesting after eradication treatment. There is significant variation in rates of retesting among VHA facilities. H pylori testing is ordered by nongastroenterology specialists two-thirds of the time. Confirming eradication of H pylori is mandatory and widespread quality assurance protocols are needed.

Development and Validation of a Clinical Decision Support Tool That Incorporates Pharmacokinetic Data to Predict Endoscopic Healing in Patients Treated With Infliximab.

BACKGROUND & AIMS: Infliximab is an effective treatment for moderate to severe ulcerative colitis (UC). Little is known about patient-related factors that might be used to predict endoscopic healing with infliximab therapy. METHODS: We analyzed data from 484 patients included in the randomized trials of the effects of infliximab therapy for patients with UC (Active Ulcerative Colitis Trials [ACT]-1 and ACT-2). We used a 2-compartment population pharmacokinetic model to calculate baseline infliximab clearance. Two multivariable regression models were derived and validated for their ability to identify patients with endoscopic healing (Mayo endoscopic score, ≤1) at weeks 8 and 30, using only baseline variables. We developed a clinical decision support tool (CDST) and calculator to determine the probability of endoscopic healing in patients starting infliximab. RESULTS: Higher baseline infliximab clearance, stool frequency, and rectal bleeding scores were associated negatively with endoscopic healing at week 8. In the validation set, a CDST score of 9 points or fewer identified patients without endoscopic healing at week 8 with 82% sensitivity (95% CI, 76%-88%), whereas a CDST score of 16 points or more identified patients with endoscopic healing at week 8 with 87% specificity (95% CI, 81%-94%). Higher baseline infliximab clearance, stool frequency score, white blood cell count, and lower body weight were associated negatively with endoscopic healing at week 30. In the validation set, CDST scores of 17 points or fewer identified patients without endoscopic healing at week 30 with 90% sensitivity (95% CI, 85%-95%), whereas scores greater than 22 points identified patients with endoscopic healing at week 30 with 80% specificity (95% CI, 73%-87%). External validation models had a modest predictive value, with an area under of the curve of 0.67 (95% CI, 0.61-0.74). Patient-level probabilities of endoscopic healing at weeks 8 or 30 can be calculated online (www.premedibd.com). CONCLUSIONS: Using data from 2 clinical trials of patients receiving infliximab therapy for UC, we developed and validated the CDST, which uses data on infliximab clearance and baseline patient and disease measures to identify patients most likely to have endoscopic healing. This tool will facilitate therapy decision making and precision medicine.

Combination Therapy Does Not Improve Rate of Clinical or Endoscopic Remission in Patients with Inflammatory Bowel Diseases Treated With Vedolizumab or Ustekinumab.

BACKGROUND & AIMS: Patients with Crohn's disease (CD) or ulcerative colitis (UC) often receive combination therapy with an immunomodulator and tumor necrosis factor antagonists, especially infliximab. However, the benefits of combination therapy with vedolizumab and ustekinumab are unclear. METHODS: We performed a retrospective study of patients with CD or UC initiating vedolizumab or ustekinumab therapy at Massachusetts General Hospital (USA), Alberta Health Sciences (Canada), or Nancy University Hospital (France) with at least 1 year of follow up. The primary outcome was clinical remission or response at week 14, based on the Harvey Bradshaw index for CD or simple clinical colitis index or partial Mayo score for UC. We separately examined week 30 and week 54 clinical outcomes, endoscopic response, and durability of therapy using multivariable regression models and adjusting for relevant confounders. RESULTS: Our study included 549 patients (263 with UC, 286 with CD) receiving maintenance therapy with vedolizumab and 363 patients (4 with UC, 359 with CD) receiving maintenance therapy with ustekinumab with 1 year of follow up. The mean disease duration was 13-15 years. One-hundred thirty-one patients receiving vedolizumab (23.9%; 78 receiving thiopurine, 53 receiving methotrexate) and 120 patients receiving ustekinumab (33.1%, 57 receiving thiopurine, 63 receiving methotrexate) were receiving combination therapy. For vedolizumab, there was no difference in clinical response or remission with combination therapy vs monotherapy at week 14 (68.2% vs 74.1%; P = .22), week 30 (74.3% vs 75.6%; P = .78) or week 54 (78.3% vs 72.9%, P = .33). For ustekinumab, there was no difference in clinical response or remission with combination therapy vs monotherapy at week 14 (54.6% vs 65.8%; P = .08), week 30 (71.6% vs 77.4%; P = .33) or week 54 (62.1% vs 67.0%; P = .52). There were similar proportions of patients remaining on treatment or with endoscopic response at 1 year among patients receiving combination or monotherapy with vedolizumab or ustekinumab. CONCLUSIONS: In patients with CD or UC initiating ustekinumab or vedolizumab therapy, combination therapy with immunomodulators did not increase rates of clinical remission or response, endoscopic remission, or persistence of therapy at 1 year.

Infliximab Exposure Associates With Radiologic Evidence of Healing in Patients With Crohn's Disease.

BACKGROUND & AIMS: Higher infliximab trough levels are associated with clinical and endoscopic remission in patients with Crohn's disease (CD). We investigated pharmacodynamic features of infliximab and radiological healing. METHODS: We performed a substudy of the TAILORIX trial (patients with active luminal CD in Europe, treated with infliximab), analyzing baseline and week 54 magnetic resonance enterography (MRE) data. MREs were scored using the MaRIA score by blinded central readers. Radiologic response and remission were defined, based on MaRIA criteria in all segments, as scores below 11 and 7, respectively. We collected data on infliximab trough levels, biomarkers, and endoscopic findings. Our primary aim was to evaluate pharmacodynamic features associated with radiologic response and remission, based on MRE assessments at baseline and at 54 weeks after initiation of infliximab therapy. RESULTS: We analyzed data from 36 patients (50% female; median age 35.7 years; interquartile age range, 25.6-48.6 years; median disease duration, 1.5 months; interquartile duration range, 0.6-22.4 months). At week 54 of treatment, 36.4% of patients had a radiologic response, 30.3% of patients were in remission, and 71% had endoscopic features of remission. At baseline, there was a correlation between the CD endoscopic index of severity and MaRIA scores (κ = 0.46; P = .008), but we found no correlation at week 54 (κ = 0.06; P = .75). Radiologic remission correlated with infliximab trough level at week 14 (P = .049) when the infliximab trough level cut-off value was set at 7.8 µg/mL (area under the curve, 0.74; 75% sensitivity; 86% specificity; 90% negative predictive value; 57% positive predictive value). Radiologic response correlated with infliximab trough levels at week 14 (P = .048) when the infliximab trough level cut-off value was set at 7.8 µg/mL (area under the curve, 0.73; 70% sensitivity; 90% specificity; 86% negative predictive value; 78% positive predictive value) and with continuous pharmacologic evidence of response (infliximab trough levels above 5.0 µg/mL at all time points) (P = .034). CONCLUSIONS: In a substudy of data from the TAILORIX trial of patients with active luminal CD, we identified a relationship between exposure to infliximab and radiologic evidence of outcomes.