A Multi-Disciplinary Approach to Perianal Fistulizing Crohn's Disease.

Perianal fistulizing Crohn's disease represents a severe phenotype associated with significant morbidity. Patients with perianal fistulizing disease are more likely to have a severe disease course and have significant reductions in quality of life. Moreover, these patients are at risk for the development of distal rectal and anal cancers. Given the complexity and severity of this patient group, the management of perianal Crohn's disease must be undertaken by a multidisciplinary team. The gastroenterologist and colorectal surgeon play a critical role in the diagnosis and management of perianal fistulizing disease. An examination under anesthesia provides critical information and is an essential part of the work-up of complex perianal fistulas. The radiologist also plays a central role in characterizing anatomy and assessing response to treatment. Several imaging modalities are available for these patients with magnetic resonance imaging as the imaging modality of choice. Perianal disease developing after ileal pouch-anal anastomosis represents a particularly challenging form of fistulizing disease and requires a multidisciplinary clinical and radiologic approach to differentiate surgical complications from recurrent Crohn's disease.

Is synoptic operative reporting necessary for Crohn's disease surgery? Variability in surgical reports across inflammatory bowel disease referral centres.

AIM: Ileocolic resection (ICR) is the most commonly performed operation in Crohn's disease (CD) patients. The surgical report is a vital tool for accessing information to gauge a patient's long-term prognosis and guide treatment decisions. Dictated narrative reports are the traditional method for surgical documentation but often lack essential information. The objective was to assess the quality of operation note in CD patients undergoing ICR. METHOD: This was a multi-institutional retrospective cohort collaborative study involving four tertiary inflammatory bowel disease referral centres in the USA and Canada. The patients were consecutive CD patients undergoing ICR between 2014 and 2020. There were no interventions. The main outcome measures were the variability and frequency of 28 critical items in the operation note. RESULTS: An analysis of 400 consecutive operation reports in four institutions (n = 100/institution) revealed significant variability in almost all variables. The initial surgical approach and wound protector use were the most consistently or frequently reported across all inflammatory bowel disease centres. The limitation was that this was a retrospective cohort study with inevitable selection bias. CONCLUSIONS: This study highlights the need for synoptic reporting in CD patients undergoing ICR.

An international, multicentre, double-blind, randomized study (DISSCO): effect of diacerein vs celecoxib on symptoms in knee osteoarthritis.

OBJECTIVE: The objective of this study was to investigate whether diacerein has comparable efficacy with celecoxib in pain reduction for treatment in symptomatic knee OA patients. METHODS: This randomized double-blind multicentre non-inferiority trial evaluated diacerein vs celecoxib treatment in patients with Kellgren-Lawrence grade 2-3 and pain scoring ≥4 (10-cm VAS). Patients were randomized to 6 months of treatment with diacerein 50 mg (n = 187) once daily for 1 month and twice daily thereafter, or celecoxib 200 mg (n = 193) once daily. The primary outcome was the change in WOMAC pain score (0-50 cm) at 6 months, and the secondary outcomes were WOMAC sub-scores, VAS pain score, and the OMERACT-OARSI responder rate. RESULTS: In the per protocol population, the adjusted mean change from baseline in the WOMAC pain score was -11.1 ( 0.9) with diacerein (n = 140) and -11.8 (0.9) with celecoxib (n = 148). The intergroup difference was 0.7 (95% CI: -1.8, 3.2; P = 0.597), meeting the non-inferiority margin. Supportive analysis of the intention-to-treat population gave similar results. Other outcomes showed no significant difference between treatment groups. The incidence of treatment-related adverse events was low and balanced between groups, but a greater incidence of diarrhoea occurred with diacerein (10.2% vs 3.7%). Diarrhoea was considered mild-to-moderate in all but one case with complete resolution. CONCLUSIONS: Diacerein was non-inferior to celecoxib in reducing knee OA pain and improving physical function. Diacerein also demonstrated a good safety profile. TRIAL REGISTRATION: A multicentre study on the effect of DIacerein on Structure and Symptoms vs Celecoxib in Osteoarthritis is a National Institutes of Health (NCT02688400) and European Clinical Trial Database (2015-002933-23) registered phase III (Canada) or IV (Europe) study.

Chondroitin sulphate reduces both cartilage volume loss and bone marrow lesions in knee osteoarthritis patients starting as early as 6 months after initiation of therapy: a randomised, double-blind, placebo-controlled pilot study using MRI.

OBJECTIVE: To determine the effect of chondroitin sulphate (CS) treatment on cartilage volume loss, subchondral bone marrow lesions (BML), synovitis and disease symptoms in patients with knee osteoarthritis (OA). METHODS: In this pilot multicentre, randomised, double-blind, controlled trial in primary knee OA, 69 patients with clinical signs of synovitis were randomised to receive CS 800 mg or placebo once daily for 6 months followed by an open-label phase of 6 months in which patients in both groups received CS 800 mg once daily. Cartilage volume and BML were assessed by MRI at baseline and at 6 and 12 months; synovial membrane thickness was assessed at baseline and at 6 months. RESULTS: The CS group showed significantly less cartilage volume loss than the placebo group as early as 6 months for the global knee (p=0.030), lateral compartment (p=0.015) and tibial plateaus (p=0.002), with significance persisting at 12 months. Significantly lower BML scores were found for the CS group at 12 months in the lateral compartment (p=0.035) and the lateral femoral condyle (p=0.044). Disease symptoms were similar between the two groups. CONCLUSION: CS treatment significantly reduced the cartilage volume loss in knee OA starting at 6 months of treatment, and BML at 12 months. These findings suggest a joint structure protective effect of CS and provide new in vivo information on its mode of action in knee OA.

Robust and Gradient Thickness Porous Membranes for In Vitro Modeling of Physiological Barriers.

Porous membranes are fundamental elements for tissue-chip barrier and co-culture models. However, the exaggerated thickness of commonly available membranes may represent a stumbling block impeding a more accurate in vitro modeling. Existing techniques to fabricate membranes such as solvent cast, spin-coating, sputtering and PE-CVD result in uniform thickness films. Here, we developed a robust method to generate ultrathin porous parylene C (UPP) membranes not just with precise thicknesses down to 300 nm, but with variable gradients in thicknesses, while at the same time having porosities up to 25%. We also show surface etching and increased roughness lead to improved cell attachment. Next, we examined the mechanical properties of UPP membranes with varying porosity and thickness and fit our data to previously published models, which can help determine practical upper limits of porosity and lower limits of thickness. Lastly, we validate a straightforward approach allowing the successful integration of the UPP membranes into a prototyped 3D-printed scaffold, demonstrating mechanical robustness and allowing cell adhesion under varying flow conditions. Collectively, our results support the integration and the use of UPP membranes to examine cell-cell interaction in vitro.

Chondroitin sulfate efficacy versus celecoxib on knee osteoarthritis structural changes using magnetic resonance imaging: a 2-year multicentre exploratory study.

BACKGROUND: In osteoarthritis (OA) treatment, although chondroitin sulfate (CS) was found in a number of studies using radiography to have a structure-modifying effect, to date CS use is still under debate. A clinical study using quantitative magnetic resonance imaging (qMRI) is therefore of the utmost importance. Here we report data from a 24-month, randomised, double-blind, double-dummy, controlled, comparative exploratory study of knee OA. The primary endpoint was to determine the effect of CS 1200 mg/day versus celecoxib 200 mg/day on cartilage volume loss (CVL) in the lateral compartment over time as measured by qMRI. Secondary endpoints included assessment of the OA structural changes and signs and symptoms of OA. METHODS: qMRI was performed at baseline and at 12 and 24 months. CVL, bone marrow lesion size, and synovial thickness were evaluated using qMRI. The primary statistical analysis was carried out on the modified intention-to-treat (mITT) population (n = 138) using chi-squared, Fisher's exact, Wilcoxon Mann-Whitney, and Student's t tests and analysis of covariance. Analyses were also conducted on the according-to-protocol (ATP; n = 120) population. RESULTS: In the adjusted mITT analysis, compared with celecoxib treatment, patients treated with CS had a significant reduced CVL at 24 months in the medial compartment (celecoxib -8.1 % ± 4.2, CS -6.3 % ± 3.2; p = 0.018) and medial condyle (-7.7 % ± 4.7, -5.5 % ± 3.9; p = 0.008); no significant effect was seen in the lateral compartment. In the ATP population, CS reduced CVL in the medial compartment at 12 months (celecoxib -5.6 % ± 3.0, CS -4.5 % ± 2.6; p = 0.049) and 24 months (celecoxib -8.4 % ± 4.2, CS -6.6 % ± 3.3; p = 0.021), and in the medial condyle at 24 months (celocoxib -8.1 % ± 4.7, CS -5.7 % ± 4.0; p = 0.010). A trend towards a statistically reduced synovial thickness (celecoxib +17.96 ± 33.73 mm, CS -0.66 ± 22.72 mm; p = 0.076) in the medial suprapatellar bursa was observed in CS patients. Both groups experienced a marked reduction in the incidence of patients with joint swelling/effusion and in symptoms over time. Data showed similar good safety profiles including cardiovascular adverse events for both drugs. CONCLUSION: This study demonstrated, for the first time in a 2-year randomised controlled trial using qMRI, the superiority of CS over celecoxib at reducing CVL in knee OA patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT01354145 . Registered 13 May 2011.

Enantiomer selective glucuronidation of the non-steroidal pure anti-androgen bicalutamide by human liver and kidney: role of the human UDP-glucuronosyltransferase (UGT)1A9 enzyme.

Bicalutamide (Casodex(®) ) is a non-steroidal pure anti-androgen used in the treatment of localized prostate cancer. It is a racemate drug, and its activity resides in the (R)-enantiomer, with little in the (S)-enantiomer. A major metabolic pathway for bicalutamide is glucuronidation catalysed by UDP-glucuronosyltransferase (UGT) enzymes. While (S)bicalutamide is directly glucuronidated, (R)bicalutamide requires hydroxylation prior to glucuronidation. The contribution of human tissues and UGT isoforms in the metabolism of these enantiomers has not been extensively investigated. In this study, both (R) and/or (S)bicalutamide were converted into glucuronide (-G) derivatives after incubation of pure and racemic solutions with microsomal extracts from human liver and kidney. Intestinal microsomes exhibited only low reactivity with these substrates. Km values of liver and kidney samples for (S)bicalutamide glucuronidation were similar, and lower than values obtained with the (R)-enantiomer. Among the 16 human UGTs tested, UGT1A8 and UGT1A9 were able to form both (S) and (R)bicalutamide-G from pure or racemic substrates. UGT2B7 was also able to form (R)bicalutamide-G. Kinetic parameters of the recombinant UGT2B7, UGT1A8 and UGT1A9 enzymes support a predominant role of the UGT1A9 isoform in bicalutamide metabolism. Accordingly, (S)bicalutamide inhibited the ability of human liver and kidney microsomes to glucuronidate the UGT1A9 probe substrate, propofol. In conclusion, the present study provides the first comprehensive analysis of in vitro bicalutamide glucuronidation by human tissues and UGTs and identifies UGT1A9 as a major contributor for (R) and (S) glucuronidation in the human liver and kidney.

Total Knee Replacement as a Knee Osteoarthritis Outcome: Predictors Derived from a 4-Year Long-Term Observation following a Randomized Clinical Trial Using Chondroitin Sulfate.

OBJECTIVE: To predict, using clinical and qMRI data, the incidence of total knee replacement (TKR) during the long-term follow-up of knee osteoarthritis (OA) patients who formerly received chondroitin sulfate (CS) or placebo treatment. DESIGN: A post hoc intention-to-treat analysis to evaluate the incidence of TKR was done on knee OA patients who had participated in a 12-month trial evaluating the impact of CS (800 mg/d) versus placebo for 6 months, followed by a 6-month open-phase in which all patients received CS. Additionally, the clinical and qMRI predictors of TKR were determined. RESULTS: Thirteen TKRs were performed in the population after a 4-year follow-up. More TKRs were performed in the placebo group than in the CS group (69% vs. 31%, P = 0.150, logistic regression). The statistically significant predictors of TKRs were, at baseline, higher WOMAC pain and function scores, presence of bone marrow lesions (BMLs), and higher C-reactive protein levels. Loss of medial cartilage volume and increase in WOMAC pain and function at one-year were also predictors of TKR. Multivariate analyses revealed that baseline presence of BML and higher WOMAC pain score were independent predictors. Time to occurrence of the TKR also favored the CS group versus placebo (log-rank, P = 0.094). CONCLUSION: Symptoms such as knee pain and function, presence of BML, and cartilage volume loss predict the long-term occurrence of a "hard" outcome such as TKR.

An open-label pilot study evaluating by magnetic resonance imaging the potential for a disease-modifying effect of celecoxib compared to a modelized historical control cohort in the treatment of knee osteoarthritis.

OBJECTIVES: The aim of the study was to evaluate by quantitative magnetic resonance imaging the effect of celecoxib 200 mg daily on cartilage volume loss over 12 months in knee osteoarthritis. METHODS: The primary outcome of this study was to evaluate cartilage volume loss in the medial compartment of the knee (femoral condyle and tibial plateau) assessed by quantitative magnetic resonance imaging on subjects receiving continuous treatment with celecoxib 200 mg daily for 12 months compared with a modelized historical control cohort, as expressed by the percentage loss from baseline. Safety of the medication was also assessed. Comparison of the observed volume loss to the expected loss was evaluated by a multivariate linear regression model based on a historical cohort. RESULTS: For the primary outcome, the 95% confidence intervals for the mean observed celecoxib cohort joint medial compartment cartilage volume loss (6.81% [6.01; 7.60]) and mean predicted loss (modelized historical cohort) (5.65% [5.10; 6.19]) overlap, indicating no significant difference and hence no effect of celecoxib on the medial compartment cartilage volume loss. Similar findings were demonstrated for the lateral compartment cartilage loss. The safety data reported several minor adverse events similar to those typically seen in a 1-year clinical trial. CONCLUSIONS: Although celecoxib was demonstrated to be safe for knee osteoarthritis at a 200 mg daily dose, it did not provide a protective effect on knee cartilage loss. Cohort modelization is an efficient and unbiased way to provide a comparator group for the assessment of novel treatments when classic head-to-head randomized controlled trials are not feasible.

Intraarticular corticosteroids, supervised physiotherapy, or a combination of the two in the treatment of adhesive capsulitis of the shoulder: a placebo-controlled trial.

OBJECTIVE: To compare the efficacy of a single intraarticular corticosteroid injection, a supervised physiotherapy program, a combination of the two, and placebo in the treatment of adhesive capsulitis of the shoulder. METHODS: Ninety-three subjects with adhesive capsulitis of <1 year's duration were randomized to 1 of 4 treatment groups: group 1, corticosteroid injection (triamcinolone hexacetonide 40 mg) performed under fluoroscopic guidance followed by 12 sessions of supervised physiotherapy; group 2, corticosteroid injection alone; group 3, saline injection followed by supervised physiotherapy; or group 4, saline injection alone (placebo group). All subjects were taught a simple home exercise program. Subjects were reassessed after 6 weeks, 3 months, 6 months, and 1 year. The primary outcome measure was improvement in the Shoulder Pain and Disability Index (SPADI) score. RESULTS: At 6 weeks, the total SPADI scores had improved significantly more in groups 1 and 2 compared with groups 3 and 4 (P = 0.0004). The total range of active and passive motion increased in all groups, with group 1 having significantly greater improvement than the other 3 groups. At 3 months, groups 1 and 2 still showed significantly greater improvement in SPADI scores than group 4. There was no difference between groups 3 and 4 at any of the followup assessments except for greater improvement in the range of shoulder flexion in group 3 at 3 months. At 12 months, all groups had improved to a similar degree with respect to all outcome measures. CONCLUSION: A single intraarticular injection of corticosteroid administered under fluoroscopy combined with a simple home exercise program is effective in improving shoulder pain and disability in patients with adhesive capsulitis. Adding supervised physiotherapy provides faster improvement in shoulder range of motion. When used alone, supervised physiotherapy is of limited efficacy in the management of adhesive capsulitis.