Clinical Flare Research Articles

Issue Highlights

Issue Highlights

Clinical response rate and flares of hidradenitis suppurativa in the treatment with adalimumab.

Hidradenitis suppurativa/acne inversa (HS) is a chronic, inflammatory, skin disease. adalimumab is the sole approved drug for the treatment of HS, but it only partially controls the symptoms. To evaluate the incidence of flares during 108weeks of therapy and the clinical response to adalimumab. In total, 20 patients with moderate-severe HS treated with adalimumab were included to evaluate the number of flares, mean time interval between flares, lesion count number of patients who reached the Hidradenitis Suppurativa Clinical Response (HiSCR) of ≥50% reduction in inflammatory lesion count, and the International Hidradenitis Suppurativa Severity Score System (IHS4), pain visual analogue scale (VAS) and Dermatology Life Quality Index (DLQI). In total, 90% of patients reported at least 1 flare, and in total 48 flares were counted for the whole group; mean time between flares was 26.9±16.4weeks. Duration between flares was 30.5±16.3 and 12.5±5.7, respectively, in responders and nonresponders. A progressive decline in flares was observed with treatment, while a gradual increase in the number of patients achieving HiSCR was attained during the observational period. Lesion count, IHS4, pain VAS and DLQI decreased throughout the study. In detail, adalimumab showed a higher efficacy on nodules and abscesses than on draining tunnels. The study was limited by its retrospective nature and small number of patients. Adalimumab is an effective and safe treatment for patients with HS despite the high number of flares.

Efficacy of rituximab in difficult-to-manage autoimmune hepatitis: Results from the International Autoimmune Hepatitis Group.

Background & AimsTreatment options remain limited for patients with autoimmune hepatitis (AIH), while there are still concerns over the consequences of long-term corticosteroid use. A few studies have suggested a role for B cell-driven autoimmune liver injury in AIH. This multicentre, international retrospective cohort study from the International Autoimmune Hepatitis Group aims to evaluate the clinical efficacy and safety of rituximab in difficult-to-manage AIH.MethodsClinical data from 22 patients who received rituximab between 2007 and 2017 were collected from centres in the United Kingdom, Germany and Canada. Clinical response was assessed using changes in biochemical and immunological parameters up to 24 months post-rituximab infusion. In addition, we compared the doses of prednisolone used 3 months before and 12 months after treatment, and assessed freedom from AIH flares over the post-treatment period.ResultsTwenty-two patients with type-1 AIH were included, with a median age of 40 years at diagnosis (range 19–79); 15/22 (68%) were female and 18/22 (82%) were Caucasian. The median period from diagnosis to the end of follow-up in these patients was 11 years (range 3–28). Values of alanine aminotransferase, aspartate aminotransferase and albumin improved significantly following rituximab therapy, and were sustained for up to 2 years (all p ≪0.001). Prednisolone doses were significantly reduced by 12 months post-treatment (p = 0.003), with 13/21 (62%) patients having a dose reduction. Over a median post-treatment follow-up period of 6 years (range 1–10), 5 patients developed AIH flares at a median of 22 months post-treatment, giving an estimated 71% freedom from AIH flare at 2 years. Four of these patients received a second course of treatment, of whom 2 had subsequent further flares. No serious adverse events attributable to rituximab were recorded.ConclusionIn patients with difficult-to-manage AIH, rituximab appears to be clinically effective and well tolerated. Rituximab was associated with sustained improvements in serum liver tests, an absence of clinical disease flares, and a reduction in prednisolone dose. Controlled trials are warranted to further evaluate B cell-targeting therapies in patients with AIH.Lay summaryAutoimmune hepatitis is an autoimmune condition of the liver, usually treated with medications that suppress the immune system, such as steroids. However, some patients do not respond to this treatment. We analysed the safety and efficacy of rituximab in patients who were not responding to first- or second-line therapies. Rituximab was safe and improved liver blood tests in 70% of patients over a 2-year follow-up period, while enabling steroid doses to be reduced in two-thirds of patients, which is a very positive clinical outcome.

Predictors of Flares in Infliximab-treated Children With Inflammatory Bowel Disease

AbstractOne third of pediatric IBD patients who initially respond to infliximab (IFX) lose that response over time. This retrospective study, including 62 children treated with IFX from 2004 to 2017, aimed to identify factors associated with clinical flare. Ulcerative colitis, extreme body mass index, and lowest IFX trough levels were associated with clinical flare in the whole population. In Crohn disease patients, perianal disease was pejorative, while location proximal to ligament of Treitz was protective. Underweight patients probably correspond to the most severe cases who are more likely to relapse, with hypoalbuminemia responsible for lower systemic IFX availability. Obesity probably induces higher IFX clearance.

Gelsolin: a new biomarker of disease activity in SLE patients associated with HDL-c.

To identify potential biomarkers of disease activity analysing the proteome of high-density lipoprotein (HDL) particles from SLE patients in clinical remission and when they develop a flare compared with a healthy control group. Quantitative proteomic analyses of purified HDL were performed using Tandem Mass Tag isobaric tag-labelling and nanoLC-Orbitrap (nLC-MS/MS) from nine SLE patients in clinical remission when they developed a flare and from nine healthy controls (9-9-9). We verified the identified proteins by Western blot and ELISA in a cohort of 104 SLE women patients, 46 healthy women and 14 SLE patients when a flare developed. We found 17 proteins with a significant fold-change (>1.1) compared with the control group. In lupus patients experiencing a flare compared with those in remission, we identified four proteins with a significant fold-change (C4, Indian Hedgehog protein, S100A8 and gelsolin). Plasma gelsolin (pGSN) levels were decreased in the 104 SLE patients (176.02(74.9) mcg/l) compared with the control group (217.13(86.7) mcg/l); P=0.005 and when they developed a clinical flare (104.84(41.7) mcg/l); P=0.002). pGSN levels were associated with HDL cholesterol levels (r = 0.316, P<0.001). Antimalarial treated patients showed significant higher levels of pGSN (214.56(88.94) mcg/l regarding 170.35(66.36) mcg/l); P = 0.017. Decreased pGSN are associated with clinical disease activity in SLE patients. Antimalarial treatment and HDL cholesterol are associated with higher levels of pGSN.

Assessment of small bowel mucosal healing by video capsule endoscopy for the prediction of short-term and long-term risk of Crohn's disease flare: a prospective cohort study

The optimal monitoring strategy for predicting disease course in Crohn's disease remains undefined. We aimed to evaluate the accuracy, safety, and tolerability of an intensive monitoring strategy designed to predict the future course of Crohn's disease in patients with quiescent disease. In a prospective observational cohort study, we recruited patients older than 18 years with quiescent (for 3-24 months) Crohn's disease involving the small bowel with confirmed small bowel patency from three tertiary medical centres in Israel. Enrolled patients underwent baseline magnetic resonance enterography (MRE) and patency capsule, clinical or biomarker assessment every 3 months, and video capsule endoscopy (VCE) at baseline and every 6 months for 2 years or until a clinical flare (the primary outcome, defined as an increase in the Crohn's disease activity index score by 70 points or more) or disease worsening necessitating treatment intensification. We assessed the ability of the different Crohn's disease monitoring methods used to predict the occurrence of a flare during the 24-month follow-up period. Of 90 screened patients, 29 were excluded (17 because of non-patent small bowel). Of the 61 patients enrolled between July 3, 2013, and Feb 1, 2015, 17 (28%) had a flare during the 24-month follow-up. No clinicodemographic parameter predicted future flare. A baseline VCE Lewis score of 350 or more identified patients with future flare (area under the curve [AUC] 0·79, 95% CI 0·66-0·88; p<0·0001; hazard ratio 10·7, 3·8-30·3). C-reactive protein at baseline had an AUC of 0·73 (0·6-0·84; p=0·0013) for predicting flare. The AUC of baseline faecal calprotectin for the prediction of flare occurring within 2 years was 0·62 (0·49-0·74; p=0·17), but progressively improved for shorter timespans and reached an AUC of 0·81 (0·76-0·85) for the prediction of flare occurring within 3 months. Of four MRE-based indices, only MRE global score correlated with 2-year flare risk (AUC 0·71, 0·58-0·82; p=0·024). During follow-up, a Lewis score increase of 383 points or more from baseline predicted imminent disease exacerbation within 6 months (AUC 0·79, 0·65-0·89; p=0·011). The safety and tolerability of the 231 VCEs ingested was excellent, with none being retained. In patients with quiescent Crohn's disease involving the small bowel, faecal calprotectin predicts short-term flare risk, whereas VCE predicts both short-term and long-term risk of disease exacerbation. If corroborated by additional studies, protocols incorporating VCE could expand the scope of available methods for monitoring disease activity and predicting outcomes in small bowel Crohn's disease. The Leona M & Harry B Helmsley Charitable Trust.

Consecutive fecal calprotectin measurements for predicting relapse in pediatric Crohn's disease patients.

BACKGROUNDAsymptomatic children with Crohn’s disease (CD) require ongoing monitoring to ensure early recognition of a disease exacerbation.AIMIn a cohort of pediatric CD patients, we aimed to assess the utility of serial fecal calprotectin measurements to detect intestinal inflammatory activity and predict disease relapse.METHODSIn this prospective longitudinal cohort study, children with CD on infliximab therapy in clinical remission were included. Fecal calprotectin levels were assessed at baseline and at subsequent 2-5 visits. Clinical and biochemical disease activity were assessed using the Pediatric Crohn’s Disease Activity Index, C-reactive protein and erythrocyte sedimentation rate at baseline and at visits over the following 18 mo.RESULTS53 children were included and eighteen patients (34%) had a clinical disease relapse during the study. Baseline fecal calprotectin levels were higher in patients that developed symptomatic relapse [median (interquartile range), relapse 723 μg/g (283-1758) vs 244 μg/g (61-627), P = 0.02]. Fecal calprotectin levels > 250 μg/g demonstrated good predictive accuracy of a clinical flare within 3 mo (area under the receiver operator curve was 0.86, 95% confidence limits 0.781 to 0.937).CONCLUSIONRoutine fecal calprotectin testing in children with CD in clinical remission is useful to predict relapse. Levels > 250 μg/g are a good predictor of relapse in the following 3 mo. This information is important to guide monitoring standards used in this population.

Immune Profiling and Precision Medicine in Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disorder with a wide range of clinical symptoms. Enormous progress has been made in the immunological and genetic understanding of SLE. However, the biology of disease heterogeneity in SLE has remained largely unexplored. Human immune profiling studies, helped by recent technological advances especially in single-cell and “omics” analyses, are now shedding light on the cellular and molecular basis of clinical symptoms and disease flares in individual patients. Peripheral blood immunophenotyping analysis with flow cytometry or mass cytometry are identifying responsible cell subsets and markers characteristic of disease heterogeneity. Transcriptome analysis is discovering molecular networks responsible for disease activity, disease subtype and future relapse. In this review, we summarize recent advances in the immune profiling analysis of SLE patients and discuss how they will be used for future precision medicine.

Individualized Dynamics in the Gut Microbiota Precede Crohn's Disease Flares.

Crohn's disease (CD) is a chronic relapsing-remitting gut inflammatory disorder with a heterogeneous unpredictable course. Dysbiosis occurs in CD; however, whether microbial dynamics in quiescent CD are instrumental in increasing the risk of a subsequent flare remains undefined. We analyzed the long-term dynamics of microbial composition in a prospective observational cohort of patients with quiescent CD (45 cases, 217 samples) over 2 years or until clinical flare occurred, aiming to identify whether changes in the microbiome precede and predict clinical relapse. Machine learning was used to prioritize microbial and clinical factors that discriminate between relapsers and nonrelapsers in the quiescent phase. Patients with CD in clinical, biomarker, and mucosal remission showed significantly reduced microbial richness and increased dysbiosis index compared with healthy controls. Of the 45 patients with quiescent CD, 12 (27%) flared during follow-up. Samples in quiescent patients preceding flare showed significantly reduced abundance of Christensenellaceae and S24.7, and increased abundance of Gemellaceae compared with those in remission throughout. A composite flare index was associated with a subsequent flare. Notably, higher individualized microbial instability in the quiescent phase was associated with a higher risk of a subsequent flare (hazard ratio 11.32, 95% confidence interval 3-42, P = 0.0035) using two preflare samples. Importantly, machine learning prioritized the flare index and the intrapersonal instability over clinical factors to best discriminate between relapsers and nonrelapsers. Individualized microbial variations in quiescent CD significantly increase the risk of future exacerbation and may provide a model to guide personalized preemptive therapy intensification.

Serum MMP-9: a novel biomarker for prediction of clinical relapse in patients with quiescent Crohn's disease, a post hoc analysis.

Background:Matrix metalloproteinase-9 (MMP-9) is a novel marker of intestinal inflammation. The aim of this study was to assess if serum MMP-9 levels predict clinical flare in patients with quiescent Crohn’s disease (CD).Methods:This study was a post hoc analysis of a prospective observational study in which quiescent CD patients were included and followed until clinical relapse or the end of a 2-year follow-up period. Serial C-reactive protein (CRP) and fecal calprotectin (FC) levels were measured, and the patients underwent repeated capsule endoscopies (CEs) every 6 months. Small bowel inflammation was quantified by Lewis score (LS) for CE. A baseline magnetic resonance enterography was also performed, and MaRIA score was calculated. Serum MMP-9 levels in baseline blood samples were quantified by ELISA.Results:Out of 58 eligible enrolled patients, 16 had a flare. Higher levels of baseline MMP-9 were found in patients who developed subsequent symptomatic flare compared with patients who did not [median 661 ng/ml, 25–75 interquartile range (IQR; 478.2–1441.3) versus 525.5 ng/ ml (339–662.7), respectively, p = 0.01]. Patients with serum MMP-9 levels of 945 ng/ ml or higher were at increased risk for relapse within 24 months [area under the curve (AUC) of 0.72 [95% confidence interval (CI): 0.56–0.88]; hazard ratio 8.1 (95% CI 3.0–21.9, p < 0.001)]. Serum MMP-9 concentrations showed weak and moderate correlation to baseline LS and FC, respectively (r = 0.31, p = 0.02; r = 0.46, p < 0.001). No correlation was found between serum MMP-9 to CRP and MaRIA score.Conclusions:Serum MMP-9 may be a promising biomarker for prediction of clinical flare in CD patients with quiescent disease.

SNP Analysis as a Potential Predictor of Disease Progression Within the UCLA IBD Biobank

Introduction: Inflammatory bowel diseases (IBD) are a set of complex gastrointestinal disorders affecting roughly 3 million Americans. Therapies directed against key mediators have been relatively successful in treating certain aspects of IBD. However, approximately 40% of patients do not initially respond to anti-TNF therapy and an additional 30% of patients lose response over time. Given the high refractory response rates, a more directed and personalized approach to managing these patients is needed. We set out to develop personalized care pathways for IBD based upon predictive biomarkers using samples collected from over 400 patients enrolled in the IBD biobank. Our initial analysis has focused on single nucleotide polymorphisms (SNPs). The aim of the initial research is to determine if two known IBD susceptibility loci, rs3731257 and rs7134599, are predictors of disease progression. Methods: Cohorts within the IBD biobank were identified based on chart review evaluating for inflammation status and disease progression over a fiver year follow up period. Individual SNP's were analyzed using a TaqMan SNP Genotyping Assay. This assay contains two allele-specific TaqMan probes with distinct fluorescent dyes and a PCR primer pairs to detect the two SNP's. Results: A subset analysis of 190 patients showed 96 patients with UC, 85 patients with CD, and 9 patients with indeterminate diagnosis. Within the UC patients, 29 patients had inflammation on initial endoscopy based on pathology reports, while 41 patients were not inflamed. In those with moderate to severe inflammation on initial colonoscopy, 54% had discordant CRP levels while those with no to mild inflammation on colonoscopy had 87% concordant CRP levels. Of the non-inflammed, 46% had disease progression or a flare on follow up and 19 had available colonic biopsy samples on which to perform SNP analyses (10 non-progressors and 9 progressors). For the SNP rs3731257, there was a trend towards significance in that those with GG nucleotides had an increased risk of developing disease progression or clinical flare (OR 6.45, p= 0.14). For the SNP rs7134599, there was no statistical significance. Conclusion: SNP analysis may represent a tool to predict clinical disease progression in those who present with a non-inflamed initial colonoscopy. We hope to continue efforts in characterizing the UCLA IBD biobank to find additional predictive biomarkers through epigenetic and microbial analysis.

Flares of Disease in Children with Clinically Inactive Juvenile Idiopathic Arthritis Were Not Correlated with Ultrasound Findings.

The validity of our current definitions for clinically inactive disease (CID) in juvenile idiopathic arthritis (JIA) based on physical examination is challenged by the development of advanced musculoskeletal imaging tools. We aimed to prospectively determine the prevalence of abnormal ultrasound (US) findings in children with CID in JIA and their clinical significance. Children aged ≥ 4 years with CID and a history of arthritis from a single tertiary center were approached over 1 year. Standard US of knees, tibiotalar joints, subtalar joints, and wrists were performed at baseline and at a followup visit. US images were scored by 2 pediatric musculoskeletal radiologists. Forty children with CID were enrolled and followed clinically. The median duration of inactive disease was 1 year. The most common International League of Associations for Rheumatology JIA categories were extended oligoarticular JIA (30%) and rheumatoid factor-negative polyarthritis (38%). At baseline, among a total of 289 joints scanned, 24 joints (8%) had at least 1 abnormal finding in 18 (45%) of 40 subjects. When evaluated at the individual joint level against flares identified during followup exams, these baseline US findings had a sensitivity of 15% and a positive predictive value of 12%. The predictive performance of the second US was even less. Our study demonstrates that nearly half of children with CID had abnormal US findings in 1 of 8 commonly affected joints. These findings did not correlate with subsequent clinical flares in up to 2 years of followup.

Trib1 Is Overexpressed in Systemic Lupus Erythematosus, While It Regulates Immunoglobulin Production in Murine B Cells.

Systemic lupus erythematosus (SLE) is a severe and heterogeneous autoimmune disease with a complex genetic etiology, characterized by the production of various pathogenic autoantibodies, which participate in end-organ damages. The majority of human SLE occurs in adults as a polygenic disease, and clinical flares interspersed with silent phases of various lengths characterize the usual evolution of the disease in time. Trying to understand the mechanism of the different phenotypic traits of the disease, and considering the central role of B cells in SLE, we previously performed a detailed wide analysis of gene expression variation in B cells from quiescent SLE patients. This analysis pointed out an overexpression of TRIB1. TRIB1 is a pseudokinase that has been implicated in the development of leukemia and also metabolic disorders. It is hypothesized that Trib1 plays an adapter or scaffold function in signaling pathways, notably in MAPK pathways. Therefore, we planned to understand the functional significance of TRIB1 overexpression in B cells in SLE. We produced a new knock-in model with B-cell-specific overexpression of Trib1. We showed that overexpression of Trib1 specifically in B cells does not impact B cell development nor induce any development of SLE symptoms in the mice. By contrast, Trib1 has a negative regulatory function on the production of immunoglobulins, notably IgG1, but also on the production of autoantibodies in an induced model. We observed a decrease of Erk activation in BCR-stimulated Trib1 overexpressing B cells. Finally, we searched for Trib1 partners in B cells by proteomic analysis in order to explore the regulatory function of Trib1 in B cells. Interestingly, we find an interaction between Trib1 and CD72, a negative regulator of B cells whose deficiency in mice leads to the development of autoimmunity. In conclusion, the overexpression of Trib1 could be one of the molecular pathways implicated in the negative regulation of B cells during SLE.

Preemptive immunosuppressive treatment for asymptomatic serological reactivation may reduce renal flares in patients with lupus nephritis: a cohort study.

Serological activity may precede clinical flares of lupus nephritis (LN) but the management of asymptomatic serological reactivation (ASR) remains undefined. We conducted a retrospective analysis of 138 episodes of ASR, which included 53 episodes in which immunosuppression was increased preemptively and 85 episodes in which treatment was unaltered. Preemptive immunosuppressive treatment comprised increasing the dose of prednisolone to ∼0.5 mg/kg/day, and in patients already on mycophenolate mofetil (MMF) or azathioprine (AZA), increasing the dose to 1.5 g/day and 100 mg/day, respectively. Thirty-four episodes of renal flare occurred during follow-up (88.8 ± 77.3 and 82.8 ± 89.7 months in the preemptive group and controls, respectively), following 5 (9.4%) of preemptively treated ASR and 27 (31.8%) of untreated ASR [hazard ratio 0.3 (confidence interval 0.1-0.7), P = 0.012]. Preemptive treatment was associated with superior survival free of renal relapse (99, 92 and 90% at 6, 12 and 24 month, respectively, compared with 94, 69 and 64% in controls; P = 0.011), whereas survival rate free of extrarenal relapse was similar in the two groups. Preemptively treated patients who did not develop renal flares showed better renal function preservation (estimated glomerular filtration rate slope +0.54 ± 0.43 mL/min/1.73 m2/year, compared with -2.11 ± 0.50 and -1.00 ± 0.33 mL/min/1.73 m2/year, respectively, in controls who did and did not develop subsequent renal flares; P = 0.001 and 0.012, respectively). Preemptive treatment was associated with an increased incidence of gastrointestinal side effects attributed to MMF (P = 0.031), whereas infection rate did not differ between the two groups. A preemptive moderate increase of immunosuppression for ASR in LN patients may reduce renal flares and confer benefit to long-term renal function.

Prolonged azathioprine treatment reduces the need for surgery in early Crohn's disease

Whether an early use of azathioprine (AZA) can alter the natural history of Crohn's disease (CD) remains debated. The aim of this study is to evaluate the impact of AZA on disease progression in a cohort of patients with early CD. This longitudinal cohort study examined patients with early CD defined as disease duration ≤18months and no previous use of disease-modifying agents according to Paris definition. The primary outcome was the proportion of CD-related intestinal surgery. Cox regression analysis was performed to identify potential predictive factors of CD progression. One-hundred and ninety patients with early CD were enrolled in the study. After a median follow-up of 57months (interquartile range, 31.3-76.2), 31 patients underwent abdominal surgeries, 48 patients were hospitalized, and 68 patients experienced clinical flares. The cumulative rate of remaining free of CD-related bowel surgery, hospitalization, and flare at 5years on AZA treatment was 0.65, 0.59, and 0.39, respectively. Three independent predictors of CD-related operations were identified: prior bowel resection (hazard ratio [HR], 9.23; 95% confidence interval [CI] 3.67-23.23), smoker (HR, 4.0; 95% CI 1.38-11.65), and hemoglobin <110g/L at the time of initiation of AZA (HR, 4.36; 95% CI 1.80-10.58). Conversely, AZA treatment duration >36months (HR, 0.04; 95% CI 0.01-0.15) was associated with reduced CD-related operations. Prior bowel resection, smoking, and hemoglobin <110g/L at the time of initiation of AZA were risk factors associated with intestinal surgery in patients with early CD. However, prolonged use (≥36months) of AZA was associated with a more favorable disease course of early CD.

Patients with juvenile idiopathic arthritis in clinical remission with positive power Doppler signal in joint ultrasonography have an increased rate of clinical flare: a prospective study

BackgroundUltrasonography (US) studies carried out on joints of juvenile idiopathic arthritis (JIA) patients in clinical remission demonstrate the presence of subclinical synovitis. The significance of subclinical synovitis and the positive power Doppler (PD) signal on US in JIA in clinical remission is not well understood. The objectives of this study were to assess whether the changes detected by US in patients with JIA in clinical remission can predict disease flare and to evaluate factors associated with flare and joint damage over 30 months of follow-up.MethodsA prospective study was performed with clinical and ultrasound evaluation in 34 joints of JIA patients in clinical remission. Clinical evaluation including physical exam, functional capacity and inflammatory markers was performed at baseline and every six months thereafter, for a total period of 30 months. US evaluation included presence of synovitis, PD signal and erosion at baseline and every 12 months thereafter. Subclinical synovitis was defined when there was synovitis with or without positive PD signal in US joints of patients in clinical remission. Flare was defined as any joint presenting clinical arthritis requiring therapy modification.ResultsWe evaluated a total of 35 patients, 28 (80%) girls, 14 (40%) persistent oligoarticular subtype, 12 (34.3%) oligoarticular extended and 9 (25.7%) polyarticular and 26 (74.3%) in remission on medication. Twenty (57.1%) patients flared. The risk of flare was five times higher in patients with positive PD signal and 14 times higher in patients in remission on medication. Regarding the assessment of joints after 6 months and 12 months of US evaluation, 70/3162 (2.2%) joints and 80/2108 (3.8%) joints flared, respectively. Joints with subclinical synovitis with positive PD signal flared more after 6 and 12 months. Twenty five of 2108 (1.2%) joints showed erosion over time. Joints with subclinical synovitis with or without positive PD signal showed more erosion.ConclusionsPatients in remission on medication with subclinical synovitis with positive PD signal on US have a higher risk of flare, therefore they should be monitored closely during treatment. In the same way, joints with subclinical synovitis with or without positive PD signal should be monitored due to the risk of flare and joint damage.

The proposed role of ultrasound in the management of giant cell arteritis in routine clinical practice.

To develop and explore a protocol for using colour duplex sonography (CDS) in the routine care of GCA. We tested CDS of temporal arteries and axillary arteries (AXs) on consecutive patients with suspected or established GCA, between July 2014 and September 2016. We assessed 293 patients [age 72 (10), female/male 196/97], of whom 118 had clinically confirmed GCA. Seventy-three percent of patients had already received high-dose glucocorticoids (GCs) for 17 (33) days. Among new referrals with <7 days of GC treatment (n = 55), the sensitivity of CDS was 63.3% (95% CI: 44%, 80%), specificity 100% (95% CI: 83%, 100%), positive predictive value 100% and negative predictive value 64.5% (95% CI: 53%, 74%). Sensitivity rose to 81.8% in patients with jaw claudication and high inflammatory markers. During the observation period, the rate of temporal artery biopsies decreased from 72 (42%) to 36 (25%) (P = 0.002). CDS was positive in 21% of 89 follow-up scans in asymptomatic individuals, compared with 37% in patients experiencing clinical flares. Over time, the number of halos reduced; only new or flaring patients showed a halo in four or more sites. The diameter of axillary halos reduced from referral [1.6 (0.4) mm] to follow-up [1.4 (0.2) mm, P = 0.01] or flares [1.4 (0.2) mm, P = 0.02]. CDS provides high positive predictive value for diagnosing GCA and allows for a significant reduction in temporal artery biopsies. We explored the role of CDS in detecting flares and demonstrated a relationship to the extent of the distribution of halos, but not to their size.

Transient Increases of Serum AFP and PIVKA-II Levels After Proton Therapy Do Not Necessarily Indicate Progression of Hepatocellular Carcinoma

Alpha-fetoprotein (AFP) and protein induced by vikamin K antagonist II (PIVKA-II) are useful serum biomarkers to monitor progression of hepatocellular carcinoma (HCC) after proton therapy (PT). Despite the clinical response, however, a transient increase in the biomarkers, so called surge or flare, is frequently observed, which could lead to misinterpretation of tumor progression. In addition, pseudoprogression on diagnostic imaging is also experienced during follow-up. To date, however, few investigators have reported these phenomena after PT, and their mechanisms remain hardly understood. In this study, we investigated changes of AFP and PIVKA-II and pseudoprogression on magnetic resonance imaging (MRI) after PT, and the relationship between this flare phenomenon and clinical response. This study included 60 patients with stage I/II HCC undergoing PT in our institution between September 2013 and March 2016. Patients who were taking warfarin or had a recurrence outside the PT field within 12 months after PT were excluded from analysis. Median serum levels of AFP and PIVKA-II before PT were 13.5 ng/ml (range 1-8,667) and 36 mAU/ml (range 12-35,600), respectively. The delivered dose was 66 GyE in 10 fractions. Serum levels of AFP and PIVKA-II were measured at 1, 3, 6, 9, and 12 months after PT. AFP and PIVKA-II flares were defined as >20% increase in serum levels above 20 ng/ml (AFP) or 40 mAU/ml (PIVKA-II). The size of PT-targeted lesions was measured by MRI. Overall response at 12 months after PT was CR in 55%, PR in 25%, and other in 20%. Among the 60 patients, 4 had a transient rise of AFP, while 23 had a PIVKA-II flare. The median increase rate compared to the level at preceding examinations was 36.5% (range, 30-447%) for AFP and 115% (range, 25-3,740%) for PIVKA-II. The median time to AFP and PIVKA-II flare peaks was 3.5 and 6 months, respectively. AFP and PIVKA-II flares were observed in two consecutive follow-ups in one and 8 patients, respectively. PIVKA-II flares were also observed in inconsecutive follow-ups in 4 patients. Both AFP and PIVKA-II flares were observed in 2 patients. Of them, one patient had simultaneous AFP and PIVKA-II flares at 1 month after PT. Both PIVKA-II flare and pseudoprogression on MRI were observed in 2 patients. Among them, one patient had simultaneous PIVKA-II flare and pseudoprogression at 1 month after PT. No patient had AFP and PIVKA-II flares and pseudoprogression on MRI. Univariate logistic regression analysis showed no relationship between clinical outcome and flares of AFP and PIVKA-II. Increases in AFP and PIVKA-II levels during follow-up after PT should be assessed with caution to avoid misinterpretation of therapeutic outcome. Combination of serum biomarkers of AFP and PIVKA-II and imaging examination is essential to monitor tumor progression after PT.

Role of capsule endoscopy and fecal biomarkers in small-bowel Crohn's disease to assess remission and predict relapse

Capsule endoscopy (CE) is the most sensitive test to diagnose small-bowel Crohn's disease (CD). Conventional parameters poorly assess CD remission, and although fecal biomarkers assess colonic activity, their role in assessing remission is uncertain. We report CE findings in small-bowel CD patients in clinical remission compared with fecal biomarkers and standard clinical tools to determine mucosal remission and predict relapses. Forty-three adult small-bowel CD patients in clinical remission (Crohn's Disease Activity Index [CDAI]<150) were prospectively enrolled at 4 academic centers and followed clinically for 12 months. Baseline CE studies were scored using the Capsule Endoscopy Scoring Index (CESI or Lewis score). Baseline and endpoint fecal biomarkers were assayed. CE findings were normal in 17 patients (40%), mild inflammation in 19 (44%), and moderate to severe inflammation in 7 (16%). Of the 26 patients (60%) with mucosal inflammation on CE, 85% had elevated baseline fecal calprotectin and 77% elevated lactoferrin level. Calprotectin and lactoferrin were normal in all patients without inflammation and elevated in all with moderate to severe inflammation. CESI correlated significantly with calprotectin, lactoferrin, and S100A12 levels but not either CDAI or C-reactive protein. During follow-up, 14% of patients exhibited a clinical flare; all had mucosal inflammation at CE and 83% had elevated baseline calprotectin and lactoferrin levels. In small-bowel CD patients in clinical remission, many had ongoing mucosal inflammation assessed by CE and fecal biomarkers. Only some developed a clinical flare during medium-term follow-up. These findings suggest CE and fecal biomarkers are useful in monitoring small-bowel CD progress.

Serum viral load at the virological relapse predicts subsequent clinical flares in chronic hepatitis B patients off entecavir therapy.

Therapeutic duration of nucleos(t)ide analogues for chronic hepatitis B (CHB) is not indefinite in many parts of the world. Viral reactivation is common off therapy, but the risk of subsequent clinical outcome remains unclear and unpredictable. We aimed to quantify the incidence of and explore the predictors for clinical flare following virological relapse in CHB patients who discontinue entecavir therapy. This multicenter cohort study prospectively monitored 133 CHB patients who were HBeAg-negative and viral DNA-undetectable when discontinuing entecavir after at least 3years on therapy. Following virological relapse (viral DNA >2,000IU/mL) that occurred in 92 patients, the incidences of subsequent clinical flare and persistent (unremittent for 3months) or severe hepatitis (with jaundice or coagulopathy) were determined, and risk factors were explored. Patients did not resume antiviral therapy until occurrence of persistent or severe hepatitis. The cumulative incidence of clinical hepatitis 2years after virological relapse was 61.0% (95% confidence interval [CI], 49.9-72.3%) and that of persistent or severe hepatitis was 53.0% (95% CI, 40.9-66.2%). Serum viral load at the virological relapse was associated with both clinical hepatitis (adjusted hazard ratio [HR], 1.31 per log IU/mL; 95% CI, 1.07-1.60) and persistent or severe hepatitis (adjusted HR, 1.63 per log IU/mL; 95% CI, 1.27-2.10), after adjustment for serum aminotransferase and alfa-fetoprotein levels in the multivariate analysis. Viral DNA >100000IU/mL predicted a nearly inevitable occurrence of clinical flare (P<0.0001). A high viral load at the virological relapse predicts subsequent clinical hepatitis in CHB patients who discontinue entecavir.