Treatment of moderate-to-severe psoriasis in adults: An expert consensus statement using a Delphi method to produce a decision-making algorithm.

BACKGROUND: New highly effective drugs for moderate-to-severe cutaneous psoriasis are regularly marketed, and the hierarchy of treatments thus requires frequent review. OBJECTIVES: A Delphi method was used to enable a structured expert consensus on the use of systemic treatments and phototherapy among adults with moderate-to-severe psoriasis. METHODS: The Delphi method consists in achieving a convergence of opinions among a panel of experts using several rounds of questionnaires with controlled feedback between rounds. A two-part Delphi questionnaire was administered online to French psoriasis experts. In the first part, 180 items related to the prescription of systemic treatments and phototherapy for adult patients with moderate-to-severe psoriasis were grouped into 21 sections covering different lines of treatment and different forms of cutaneous psoriasis. The experts voted on each proposal using an ordinal 7-point Likert scale. The second part comprised 11 open-ended questions about special indications for each therapeutic class. These were converted into 101 questions for subsequent rounds. Consensus was deemed to have been reached if more than 80% of the experts agreed with a given proposal. RESULTS: Three rounds of questionnaires were sequentially sent to 35 participants between November 2021 and March 2022. Thirty-three (94%) completed all three rounds. For plaque psoriasis, only methotrexate was recommended by the experts as first-line systemic treatment (89% of votes). Cyclosporin was advocated in pustular and erythrodermic psoriasis, and acitretin was suggested for hyperkeratotic and palmoplantar psoriasis. In the event of failure of or intolerance to non-biological systemic treatments, guselkumab, risankizumab, ixekizumab or secukinumab were recommended by more than 80% of the experts. Tumor Necrosis Factor (TNF) inhibitors remain useful for patients with cardiovascular risk factors. Special indications were provided for each therapeutic class (methotrexate/narrowband ultraviolet B phototherapy, psoralen/ultraviolet A phototherapy, cyclosporin, acitretin, apremilast, TNF inhibitors, interleukin (IL)-12/23 inhibitors, IL-17(R)A inhibitors, and IL-23 inhibitors). CONCLUSIONS: This expert consensus statement indicate that newly available IL-17 and IL-23 inhibitors may be favored over TNF and IL-12/23 inhibitors as first-line biologics. The Centre of Evidence of the French Society of Dermatology has drawn up a decision-making algorithm to guide clinicians in the therapeutic management of moderate-to-severe psoriasis.

Methods and approaches to estimate B vitamin status in dairy cows: Knowledge, gaps and advances.

Clinical symptoms of B vitamin deficiency are rarely observed in ruminants because these vitamins are synthesized by the rumen microbiota. However, over the last decades, numerous reports of beneficial effects on production and metabolic efficiency of dairy cows have been published supporting that, under some conditions, B vitamin subclinical deficiency is present in these animals. Due to their roles as coenzymes or cofactors in major metabolic pathways, an adequate supply in B vitamins is critical to optimize metabolic efficiency. Nowadays, taking into account the growing interest for the Smart Farming concept, fulfilling ruminant requirements for B vitamins according to their physiological stage under different feeding management cannot be neglected. In dairy cows, B vitamin supply is greatly dependent of the activity of the ruminal microbiota. Indeed, the amount of vitamins reaching the small intestine is dependent of the utilization of the vitamins provided by the diet and their synthesis by the microorganisms present in the rumen. The two major challenges faced to determine B vitamin status of ruminants are the difficulty to estimate B vitamin supply due to the lack of knowledge on factors driving the fate of B vitamins in the digestive tract, especially in the rumen, and the choice and thresholds of biomarkers reflecting adequately the animal status. The present paper aims to present the actual state of knowledge on the methodological approaches used to estimate B vitamin supply and status of ruminant and to point out future research orientations.

Palmoplantar pustulosis and acrodermatitis continua of Hallopeau: demographic and clinical comparative study in a large multicentre cohort.

BACKGROUND: Acral pustular disease within the pustular psoriasis/psoriasis-like spectrum mainly includes palmoplantar pustulosis (PPP) and acrodermatitis continua of Hallopeau (ACH). Scarce data argue for a distinction between these two entities, but no study has compared the clinical and epidemiologic characteristics of ACH and PPP. OBJECTIVES: We aimed to perform a comparative description of the epidemiological and clinical characteristics of PPP and ACH in a multicentre retrospective cohort. METHODS: In this multicentre national retrospective cohort study, we compared the epidemiological characteristics, comorbidities and psoriasis characteristics of patients with PPP and ACH. RESULTS: A total of 234 patients were included: 203 (87%) with PPP, 18 (8%) with ACH and 13 (6%) with both, according to 2017 ERASPEN criteria. As compared with ACH, PPP was associated with female sex, smoking activity and higher median BMI (P = 0.01, P = 0.02 and P = 0.05 respectively). A family background of psoriasis was more frequent in PPP than ACH. Age of onset of palmoplantar disease was similar between PPP and ACH patients, median age 44 and 48 years respectively. Peripheral joint inflammatory involvement was the only rheumatic disease associated with ACH. The association with another psoriasis type was similar in PPP and ACH (57.6% and 61.1% respectively). CONCLUSION: Our study confirms in a large PPP cohort the predominance of females and a high prevalence of smoking and elevated body mass index but also shows an association of these features in PPP as compared with ACH. In addition, it highlights peripheral arthritis as the only arthritis endotype associated with ACH. Increased knowledge of the immunogenetic backgrounds underlying these two entities is warranted to better stratify pustular psoriasis or psoriasis-like entities for precision medicine.

Combined biotin, folic acid, and vitamin B12 supplementation given during the transition period to dairy cows: Part I. Effects on lactation performance, energy and protein metabolism, and hormones.

Biotin (B8), folates (B9), and vitamin B12 (B12) are involved and interrelated in several metabolic reactions related to energy and protein metabolism. We hypothesized that a low supply of one of the latter vitamins during the transition period would impair metabolic status. The purpose of this study was to evaluate the effect of B8 supplementation on the response of lactation performance and selected energy and protein metabolites and hormones to a combined supplementation of B9 and B12 given to periparturient dairy cows, from d -21 to 21 relative to calving. A total of 32 multiparous Holstein cows housed in tie stalls were randomly assigned, according to their previous 305-d milk yield, to 8 incomplete blocks of 4 treatments: (1) a 2-mL weekly i.m. injection of saline (0.9% NaCl; B8-/B9B12-); (2) 20 mg/d of dietary B8 (unprotected from ruminal degradation) and 2-mL weekly i.m. injection of 0.9% NaCl (B8+/B9B12-); (3) 2.6 g/d of dietary B9 (unprotected) and 2-mL weekly i.m. injection of 10 mg of B12 (B8-/B9B12+); and (4) 20 mg/d of dietary B8, 2.6 g/d of dietary B9, and weekly i.m. injection of 10 mg of B12 (B8+/B9B12+) in a 2 × 2 factorial arrangement. Milk yield and dry matter intake were obtained daily and milk components weekly. Blood samples were taken weekly from d -21 to calving and 3 times per week from calving to 21 d following parturition. Prepartum plasma concentrations of glucose, insulin, nonesterified fatty acids (NEFA), ß-hydroxybutyrate (BHB), and adiponectin were unaffected by treatments. Biotin, B9, and B12 supplements increased their respective concentrations in plasma and milk. Cows fed the B8 supplement tended to have lower dry matter intake, but only cows in B8+/B9B12- had greater plasma concentrations of NEFA compared with B8-/B9B12-. Milk and total solid yields were greater by 13.5 and 13.9%, respectively, for B8-/B9B12+ [45.5 (standard error, SE: 1.8) and 5.81 (0.22) kg/d, respectively] compared with B8-/B9B12- [40.1 (1.9) and 5.10 (0.23) kg/d, respectively], but these effects were suppressed when combined with the B8 supplement. Cows in the B8-/B9B12+ group had decreased plasma insulin and tended to have increased NEFA concentrations, but postpartum plasma concentrations of glucose, BHB, leptin, and adiponectin were not affected. These cows also mobilized more body fat reserves, as suggested by a tendency to increased plasma NEFA and more milk total solids compared with B8-/B9B12- cows. However, plasma concentrations of BHB and adiponectin were similar among treatments. This suggests that the B9 and B12 supplements enhanced efficiency of energy metabolism in early lactation cows. Folic acid and B12 supplementation increased postpartum plasma Cys and homocysteine concentrations but did not affect plasma Met concentration, suggesting an upregulation of the transsulfuration pathway. In summary, our results showed that, under the current experimental conditions, increasing B8 supply did not improve responses to the B9 and B12 supplementation.

Combined biotin, folic acid, and vitamin B12 supplementation given during the transition period to dairy cows: Part II. Effects on energy balance and fatty acid composition of colostrum and milk.

Biotin (B8), folate (B9), and vitamin B12 (B12) are involved in several metabolic reactions related to energy metabolism. We hypothesized that a low supply of one of these vitamins during the transition period would impair metabolic status. This study was undertaken to assess the interaction between B8 supplement and a supplementation of B9 and B12 regarding body weight (BW) change, dry matter intake, energy balance, and fatty acid (FA) compositions of colostrum and milk fat from d -21 to 21 relative to calving. Thirty-two multiparous Holstein cows housed in tie stalls were randomly assigned, according to their previous 305-d milk yield, to 8 incomplete blocks in 4 treatments: (1) a 2-mL weekly i.m. injection of saline (0.9% NaCl; B8-/B9B12-); (2) 20 mg/d of dietary B8 (unprotected from ruminal degradation) and 2-mL weekly i.m. injection of 0.9% NaCl (B8+/B9B12-); (3) 2.6 g/d of dietary B9 (unprotected) and 2-mL weekly i.m. injection of 10 mg of B12 (B8-/B9B12+); (4) 20 mg/d of dietary B8, 2.6 g/d of dietary B9, and 2-mL weekly i.m. injection of 10 mg of B12 (B8+/B9B12+) in a 2 × 2 factorial arrangement. Colostrum was sampled at first milking. and milk samples were collected weekly on 2 consecutive milkings and analyzed for FA composition. Body condition score and BW were recorded every week throughout the trial. Within the first 21 d of lactation, B8-/B9B12+ cows had an increased milk yield by 13.5% [45.5 (standard error, SE: 1.8) kg/d] compared with B8-/B9B12- cows [40.1 (SE: 1.9)], whereas B8 supplement had no effect. Even though body condition score was not affected by treatment, B8-/B9B12+ cows had greater BW loss by 24 kg, suggesting higher mobilization of body reserves. Accordingly, milk de novo FA decreased and preformed FA concentration increased in B8-/B9B12+ cows compared with B8-/B9B12- cows. In addition, cows in the B8+/B9B12- group had decreased milk de novo FA and increased preformed FA concentration compared with B8-/B9B12- cows. Treatment had no effect on colostrum preformed FA concentration. Supplemental B8 decreased concentrations of ruminal biohydrogenation intermediates and odd- and branched-chain FA in colostrum and milk fat. Moreover, postpartum dry matter intake for B8+ cows tended to be lower by 1.6 kg/d. These results could indicate ruminal perturbation caused by the B8 supplement, which was not protected from rumen degradation. Under the conditions of the current study, in contrast to B8+/B9B12- cows, B8-/B9B12+ cows produced more milk without increasing dry matter intake, although these cows had greater body fat mobilization in early lactation as suggested by the FA profile and BW loss.

Meta-analysis of apparent ruminal synthesis and postruminal flow of B vitamins in dairy cows.

As milk production has significantly increased over the past decade(s), existing estimates of the B-vitamin needs of the modern dairy cow are currently being reconsidered, as suboptimal B-vitamin supply may affect metabolic efficiency. At the same time, however, "true" (i.e., biologically active forms, excluding nonfunctional analogs) B-vitamin supply also cannot be adequately estimated by dietary intake, as the rumen microbiota has been shown to play a significant role in synthesis and utilization of B vitamins. Given their complex impact on the metabolism of dairy cows, incorporating these key nutrients into the next generation of mathematical models could help to better predict animal production and performance. Therefore, the purpose of this study was to generate hypotheses of regulation in the absence of supplemental B vitamins by creating empirical models, through a meta-analysis, to describe true B-vitamin supply to the cow (postruminal flow, PRF) and apparent ruminal synthesis (ARS). The database used for this meta-analysis consisted of 340 individual cow observations from 15 studies with 16 experiments, where diet and postruminal digesta samples were (post hoc) analyzed for content of B vitamins (B1, B2, B3, B6, B9, B12). Equations of univariate and multivariate linear form were considered. Models describing ARS considered dry matter intake (DMI, kg/d), B-vitamin dietary concentration [mg/kg of dry matter (DM)] and rumen-level variables such as rumen digestible neutral detergent fiber (NDF) and starch (g/kg of DM), total volatile fatty acids (VFA, mM), acetate, propionate, butyrate, and valerate molar proportions (% of VFA), mean pH, and fractional rates of degradation of NDF and starch (%/h). Models describing PRF considered dietary-level driving variables such as DMI, B-vitamin dietary concentration (mg/kg of DM), starch and crude protein (g/kg of DM) and forage NDF (g/kg of DM). Equations developed were required to contain all significant slope parameters and contained no significant collinearity between driving variables. Concordance correlation coefficient was used to evaluate the models on the developmental data set due to data scarcity. Overall, modeling ARS yielded better-performing models compared with modeling PRF, and DMI was included in all prediction equations as a scalar variable. The B-vitamin dietary concentration had a negative effect on the ARS of B1, B2, B3, and B6 but increased the PRF of B2 and B9. The rumen digestible NDF concentration had a negative effect on the ARS of B2, B3, and B6, whereas rumen digestible starch concentration had a negative effect on the ARS of B1 and a positive effect on the ARS of B9. In the best prediction models, the dietary starch increased PRF of B1, B2, and B9 but decreased PRF of B12. The equations developed may be used to better understand the effect of diet and ruminal environment on the true supply of B vitamins to the dairy cow and stimulate the development of better-defined requirements in the future.

French guidelines for the management of oral lichen planus (excluding pharmacological therapy).

INTRODUCTION: Oral lichen is a chronic inflammatory disease for which diagnostic management and follow-up are heterogeneous given the absence of specific guidelines in France. Our objective was to develop French multidisciplinary guidelines for the management of oral lichen. MATERIALS AND METHODS: Working groups from the Groupe d'Etude de la Muqueuse Buccale (GEMUB) formulated a list of research questions and the corresponding recommendations according to the "formal consensus" method for developing practice guidelines. These recommendations were submitted to a group of experts and the degree of agreement for each recommendation was assessed by a scoring group. RESULTS: Twenty-two research questions, divided into 3 themes (nosological classification and initial assessment, induced oral lichenoid lesions, and follow-up) resulted in 22 recommendations. Initial biopsy for histology is recommended in the absence of reticulated lesions. Biopsy for direct immunofluorescence is recommended for ulcerated, erosive, bullous types and for diffuse erythematous gingivitis. Management should include a periodontal and dental check-up, and investigation for extra-oral lesions. Hepatitis C testing is recommended only if risk factors are present. Definitions, triggering factors and the management of "induced oral lichenoid lesions" were clarified. Oral lichen must be monitored by a practitioner familiar with the disease at least once a year, using objective tools. CONCLUSION: This formalised consensus of multidisciplinary experts provides clinical practice guidelines on the management and monitoring of oral lichen.

Response to a glucose tolerance test in early-lactation Holstein cows receiving a supplementation of biotin, folic acid, and vitamin B12.

The aim of the study was to evaluate glucose and insulin metabolism of cows receiving a supplementation of biotin (B8), folic acid (B9), and vitamin B12 (B12) during the transition period. According to a 2 × 2 factorial arrangement, 32 cows were randomly assigned to 9 incomplete blocks according to their previous 305-d milk yield. Within each block, cows were randomly assigned to 1 of the following levels of biotin from -27 to 28 d relative to the parturition: (1) no biotin supplement (B8-) or (2) 20 mg/d of dietary biotin (B8+). Within each level of biotin, the cows received either (1) 2-mL weekly intramuscular injections of saline 0.9% NaCl (B9B12-) or (2) 2.6 g/d of dietary folic acid and 2-mL weekly intramuscular injections of 10 mg of vitamin B12 (B9B12+). An intravenous glucose tolerance test was performed at 25 d in milk. Baseline plasma glucagon, glucose, and nonesterified fatty acid concentrations did not differ among treatments. For B9B12+ cows, baseline plasma insulin concentration and maximal glucose concentration after glucose administration were greater when also combined with biotin compared with no biotin combination, whereas there was no effect in B9B12- cows. There was no treatment effect on time to reach half-maximal glucose and insulin concentrations, glucose positive incremental area under the curve, and glucose and insulin clearance rates. Regarding insulin results, maximal plasma concentration and positive incremental area under the curve were respectively 51 and 74% greater for cows receiving the B8 supplement than for cows who did not. Moreover, plasma nonesterified fatty acid concentration nadir tended to be reached later for B8 cows. Insulin peak was reached earlier for cows in the group B9B12+ than cows in B9B12-, regardless of B8 supplementation. Under the current conditions, our results suggested that cows receiving a B8 supplement had a reduced insulin sensitivity in early lactation. Insulin response was faster for B9B12+ cows, but this was not translated into further improvements following the glucose administration challenge.

Efficacy and safety of TNF blockers and of ustekinumab in palmoplantar pustulosis and in acrodermatitis continua of Hallopeau.

BACKGROUND: Palmoplantar pustulosis (PPP) and acrodermatitis continua of Hallopeau (ACH) are rare variants of psoriasis. Knowledge of the efficacy of biologics is scarce. OBJECTIVES: To evaluate the real-life efficacy of tumour necrosis factor blockers and ustekinumab in PPP and in ACH. METHODS: A multicentre retrospective descriptive study was conducted in 19 dermatology departments, including all patients with PPP or ACH seen from 2014 to 2016 who received one of the studied biologics. The data were collected by a standardized document. Factors associated with complete clearance (CC) were analysed by multivariate analysis, estimating odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Among 92 patients included, 50 received adalimumab, 44 ustekinumab, 36 etanercept and 31 infliximab. Improvement and CC were observed in 83.9% and 20.0% patients receiving infliximab, 75.0% and 38.6% ustekinumab, 57.1% and 20.0% etanercept and 60.4% and 29.2% adalimumab. We found no significant difference in CC rates or duration of treatment among the biological treatments (P = 0.18 and P = 0.10, respectively). On multivariate analysis, CC with etanercept was associated with the ACH form and not smoking [OR = 9.5 (95% CI 1.1-82.7), P = 0.04 and 0.1 (0.01-0.9), P = 0.04]; with ustekinumab, male sex and absence of obesity [6.0 (1.3-28.6), P = 0.02 and 4.7 (1.0-22.7), P = 0.05]; with adalimumab, the ACH form [11.9 (2.7-52.3), P = 0.001]; and with infliximab, obesity [5.6 (1.1-29.4), P = 0.04]. CONCLUSIONS: We found no difference in efficacy between TNF blockers and ustekinumab and among the three different TNF blockers in real life for PPP or ACH, which reveals the heterogeneity of clinical response to biologics in pustular psoriasis as compared with plaque psoriasis.

Tattoo complications in treated and non-treated psoriatic patients.

BACKGROUND: Tattooing is a widespread phenomenon, with an estimated prevalence of 10-30% in Western populations. For psoriasis patients, current recommendations are to avoid having a tattoo if the disease is active and they are receiving immunosuppressive treatments. Although scientific data supporting these recommendations are lacking, dermatologists are often reluctant to advocate tattooing in psoriasis patients. OBJECTIVE: We aimed to evaluate the frequency of tattoo complications in patients with psoriasis and determine whether the occurrence of complications was associated with psoriasis status and treatments received at the time of tattooing. METHODS: We performed a multicentre cross-sectional study. Adults with psoriasis were consecutively included and classified as tattooed or non-tattooed. Prevalence of complications associated with tattoos was then evaluated according to psoriasis onset and treatments. The study was divided into three parts, in which data were collected through a series of questionnaires filled in by the dermatologist. Complications included pruritus, oedema, allergic reaction/eczema, infection/superinfection, granuloma, lichenification, photosensitivity, Koebner phenomenon and psoriasis flare after tattooing. Diagnosis of complications was made retrospectively. RESULTS: We included 2053 psoriatic patients, 20.2% had 894 tattoos. Amongst non-tattooed patients, 15.4% had wished to be tattooed, with psoriasis being stated as a reason for not having a tattoo by 44.0% and 5.7% indicating that they planned to have a tattoo in the future. Local complications, such as oedema, pruritus, allergy and Koebner phenomenon, were reported in tattoos in 6.6%, most frequently in patients with psoriasis requiring treatment at the time of tattooing (P < 0.0001). No severe complications were reported. CONCLUSIONS: The rate of tattoo complications in psoriasis patients was low. Although the risk of complications was highest amongst patients with psoriasis requiring treatment at the time of tattooing, all the complications observed were benign. These results can be helpful for practitioners to give objective information to patients.

Technical note: Extrapolation of hepatic glycogen concentration of the whole organ by performing a liver biopsy.

Glycogen, a complex polysaccharide, is the form of storage of glucose in mammals that can be released rapidly when needed. Recent studies have mainly reported hepatic glycogen concentration for early-lactating cows, when the energy demand is higher than the energy supply from dry matter intake, driving the cow to use the energy stored as hepatic glycogen. Generally, liver samples are obtained through percutaneous needle biopsies in the right lobe of the liver. Our objective was to analyze the variation of glycogen concentration in the livers of Holstein and Jersey cows among different liver locations representing all lobes, to evaluate whether samples obtained by liver biopsies are representative of the whole organ. Liver from 10 culled lactating cows (5 Holstein and 5 Jersey cows) from 30 to 113 mo of age at slaughter were obtained. Each liver was sampled no more than 3 h after death on the following sites: 3 sites in the right lobe (1 to 3), 2 in the diaphragmatic surface of the left lobe (4 and 5), 3 in the visceral surface of the left lobe (6 to 8), 1 in the quadrate lobe (9), and 1 in the caudate lobe (10). Samples were snap frozen in liquid N2 and were then analyzed for glucose concentration after conversion of glycogen to glucose using amyloglucosidase (EC 3.2.1.3). Glycogen results are reported as grams of glucose per 100 g of wet weight of liver (i.e., percent of wet weight of liver). Liver weights averaged 5.1 [standard deviation (SD) 1.2, minimum 3.3, maximum 6.2] kg for Holstein and 6.0 (SD 1.8, minimum 4.7, maximum 8.9) kg for Jersey cows. Holstein cows [1.31, standard error of the mean (SEM) 0.05% of wet weight] had greater liver glycogen concentration than did Jersey cows (0.75, SEM 0.05% of wet weight). No significant difference was noted among the 10 liver locations regarding glycogen concentration and averaged, for both breeds, 1.03% of wet weight (SEM 0.10). These results suggest that, in dairy cows, percutaneous needle liver biopsy in the right lobe is an accurate technique to fairly extrapolate glycogen concentration of the whole organ.

Short communication: Potential prediction of vitamin B12 concentration based on mid-infrared spectral data using Holstein Dairy Herd Improvement milk samples.

The purpose of this study was (1) to predict the quantitative concentration of vitamin B12 in milk using mid-infrared (MIR) spectrometry, and (2) to evaluate the potential of MIR spectra to discriminate different clusters of records based on their B12 concentration. Milk samples were collected from 4,340 Holstein cows between 3 and 592 d in milk and located in 100 herds. Samples were taken using in-line milk meters and divided into 2 aliquots: one for MIR spectrometry and the other for B12 concentration reference analyses by radioassay. Analyses were performed on 311 selected spectral wavelengths. A partial least squares regression model was built to quantify B12 concentration. Discriminant analysis was used to isolate B12 concentration clusters. A B12 concentration threshold was set at 442 ng/dL, because this represents the cutoff value for a 250-mL glass of milk to fulfill 46% of the daily vitamin B12 recommended dietary allowance for individuals 14 yr or older. For each analysis, records coming from two-thirds of herds were used to calibrate prediction equations, and the remaining records (one-third of herds for validation) were used to assess the prediction performance. In the case of discriminant analysis, validation sets were divided into evaluation sets (one-third of herds) to obtain alternate probability cutoffs and in test sets (two-thirds of herds) to validate equations. Spectral and B12 concentration outliers were identified by calculating standardized Mahalanobis distance and with a residual analysis, respectively (n = 3,154). Regarding quantitative B12 concentration, cross-validation and validation coefficients of determination averaged 0.51 and 0.46, respectively, which are relatively low, which would limit the potential use of the developed quantitative equations. In addition, root mean square errors of prediction of cross validation and validation sets averaged 88.9 and 94.7 ng/dL, respectively. Area under the receiver operating characteristic curve of test sets averaged 0.81 based on the 442 ng/dL threshold, which could be considered to represent good accuracy of classification. However, the false discovery rate averaged 36%. In summary, models predicting quantitative B12 concentration had low cross-validation and validation coefficients of determination, limiting their use, but the proposed discriminant models could be used to identify milk samples with naturally high B12.

Cross-sectional study of the effect of diet composition on plasma folate and vitamin B12 concentrations in Holstein cows in the United States and Canada.

The objective of this cross-sectional study was to assess the variability of plasma folate and vitamin B12 concentrations in lactating Holstein cows across the United States and Canada. We also evaluated the effect of diet composition and cow characteristics on folate and vitamin B12 plasma vitamin concentrations. A total of 22 and 24 US and Canadian dairy herds were enrolled, totaling 427 and 476 cows at 10 to 197 days in milk across all US and Canadian herds, respectively. Blood samples were taken to analyze plasma folate and vitamin B12 concentrations, and ingredients of the diet were collected to determine nutrient composition. To reduce the number of interdependent variables in the analysis of the association of diet composition with plasma vitamin concentrations, we conducted a principal component analysis. Plasma folate concentrations were lower for US cows [13.4 ng/mL, 95% confidence interval (CI): 12.7-14.2] than for Canadian cows (14.5 ng/mL, 95% CI: 13.7-15.2), and the opposite was observed for plasma vitamin B12 concentrations (US 206 pg/mL, 95% CI: 192-221; Canada 170 pg/mL, 95% CI: 159-181). The highest plasma concentrations of both vitamins were observed in the Northwest region of the United States (Oregon and Washington). Cows in California had the lowest plasma folate concentrations, and cows in Québec and New York State had the lowest plasma vitamin B12 concentrations. Plasma folate concentrations were higher for multiparous than for primiparous cows and plasma vitamin B12 concentrations progressively increased from parity 1 to 3 and higher. For both studied vitamins, plasma concentrations were lower at 0 to 55 than at 56 to 200 days in milk. Of 3 principal components, the one associated with dietary carbohydrates was significantly correlated with plasma folate and vitamin B12 concentrations. Indeed, plasma folate concentrations decreased with dietary fiber concentrations (i.e., neutral and acid detergent fibers and lignin) and increased with dietary nonfiber carbohydrate concentrations. We obtained the opposite results for plasma vitamin B12 concentrations. Both multivariable models explained 41% (pseudo-R2) of the variation in plasma folate and vitamin B12 concentrations. Information gathered in this study is the first step toward determining sources of variation in plasma folate and vitamin B12 concentrations, as well as the vitamin status of cows.

Symposium review: One-carbon metabolism and methyl donor nutrition in the dairy cow.

The present review focuses on methyl donor metabolism and nutrition in the periparturient and lactating dairy cow. Methyl donors are involved in one-carbon metabolism, which includes the folate and Met cycles. These cycles work in unison to support lipid, nucleotide, and protein synthesis, as well as methylation reactions and the maintenance of redox status. A key feature of one-carbon metabolism is the multi-step conversion of tetrahydrofolate to 5-methyltetrahyrofolate. Homocysteine and 5-methyltetrahyrofolate are utilized by vitamin B12-dependent Met synthase to couple the folate and Met cycles and generate Met. Methionine may also be remethylated from choline-derived betaine under the action of betaine hydroxymethyltransferase. Regardless, Met is converted within the Met cycle to S-adenosylmethionine, which is universally utilized in methyl-group transfer reactions including the synthesis of phosphatidylcholine. Homocysteine may also enter the transsulfuration pathway to generate glutathione or taurine for scavenging of reactive oxygen metabolites. In the transition cow, a high demand exists for compounds with a labile methyl group. Limited methyl group supply may contribute to inadequate hepatic phosphatidylcholine synthesis and hepatic triglyceride export, systemic oxidative stress, and compromised milk production. To minimize the perils associated with methyl donor deficiency, the peripartum cow relies on de novo methylneogenesis from tetrahydrofolate. In addition, dietary supplementation of rumen-protected folic acid, vitamin B12, Met, choline, and betaine are potential nutritional approaches to target one-carbon pools and improve methyl donor balance in transition cows. Such strategies have merit considering research demonstrating their ability to improve milk production efficiency, milk protein synthesis, hepatic health, and immune response. This review aims to summarize the current understanding of folic acid, vitamin B12, Met, choline, and betaine utilization in the dairy cow. Methyl donor co-supplementation, fatty acid feeding strategies that may optimize methyl donor supplementation efficacy, and potential epigenetic mechanisms are also considered.

[Use of rituximab in maintenance treatment of pemphigus: A retrospective series]. / Utilisation en pratique du rituximab en 2nde ligne et au-delà dans le traitement du pemphigus: série rétrospective.

INTRODUCTION: Rituximab (RTX), currently recommended as first-line treatment in moderate to severe pemphigus vulgaris (PV) and superficial pemphigus (PS) along with initial systemic steroids, may also be used as second-line or subsequent treatment, and this therapeutic strategy was investigated in a real-life monocentre retrospective survey. MATERIAL AND METHODS: All patients treated between January 2010 and March 2018 with RTX as second-line or subsequent treatment for moderate to severe PV or PS and followed for at least one year were included. The main objective was to evaluate rates and times of complete clinical remission (CCR) after a first course of RTX. The secondary objectives consisted mainly of treatment safety, and frequency and time to relapse after the initial CCR. RESULTS: The 24 patients selected received on average 2 cycles of RTX (i.e. 24 initial cycles and 24 additional cycles in all) over a mean follow-up period of 45 months. 18/24 (75%) patients achieved initial CCR within a mean 7.7 months. Despite at least one relapse in 13/18 initially responding patients regardless of relapse time, 59% (14/24) and 33% (8/24) were either in CCR and off treatment, or in partial remission, whether treated or untreated, according to the latest patient news, with an overall response rate of 92%. Safety was fair in these fragile patients. DISCUSSION AND CONCLUSION: This survey of the practical use of RTX confirms its interest in moderate to severe pemphigus as a second-line or subsequent treatment, a situation that probably remains relevant even if this molecule is increasingly used as first-line therapy.

Biological treatments for paediatric psoriasis : a retrospective observational study on biological drug survival in daily practice in childhood psoriasis.

BACKGROUND: Three biotherapies - etanercept, adalimumab and ustekinumab - are licensed in childhood psoriasis. The few data available on their efficacy and tolerance are mainly derived from industry trials. However, biological drug survival impacts long-term performance in real-life settings. OBJECTIVE: The objective of this study was to evaluate the survival rates of biological therapies in children with psoriasis in real-life conditions. Secondary objectives were to evaluate the factors associated with the choice of the biological therapy and to report severe adverse events. MATERIALS AND METHODS: This study was an observational retrospective study. Data were extracted from the clinical records of 134 children. Kaplan-Meier estimates were used to analyse drug survival overall and in subgroups of plaque psoriasis, bio-naïve and non-naïve patients. RESULTS: We analysed 184 treatment courses: 70 with etanercept, 68 with adalimumab and 46 with ustekinumab. Factors associated with the choice of first-line biological agent were age at initiation (younger for adalimumab, P < 0.0001), age at onset of psoriasis (younger for adalimumab and etanercept, P = 0.03) and baseline Psoriasis Assessment Severity Index and Physician global assessment (both higher for adalimumab, P < 0.001). Drug survival rates were higher for ustekinumab than for adalimumab and etanercept (P < 0.0001) for all treatment and all psoriasis types, plaque-type psoriasis (P = 0.0003), patients naïve for biological agents (P = 0.0007) and non-naïve patients (P = 0.007). We reported eight serious adverse events (SAEs): severe infections (n = 3), significant weight gain (n = 2), psoriasis flare (n = 1) and malaise (n = 1). Biological therapy was discontinued in three children (one with psoriasis flare and two with weight gain). Only the two cases of weight gain resulted in an unfavourable outcome. CONCLUSIONS: Our real-life comparative study found that ustekinumab had the best drug survival outcome. The profile of SAEs in children was comparable to that in adults. These results will assist dermatologists in the decision-making process when choosing treatment options for children with psoriasis in daily practice.

Glucose and insulin responses to an intravenous glucose tolerance test administered to feed-restricted dairy cows receiving folic acid and vitamin B12 supplements.

The present experiment was conducted to determine whether, during periods of negative energy balance, the increase in glucose availability, despite similar DMI and greater milk production, induced by a combined supplement of folic acid and vitamin B12 was related to effects of insulin on metabolism. Sixteen multiparous Holstein cows averaging 45 days in milk (standard deviation: 3) were assigned to 8 blocks of 2 animals each according to their milk production (45 kg/d; standard deviation: 6) during the week preceding the beginning of the experiment. Within each block, they received weekly intramuscular injections of either saline (CON) or folic acid and vitamin B12 (VIT) during 5 consecutive weeks. During the last week, the cows were fed 75% of their ad libitum intake during 4 d. Blood samples were taken the morning before starting the feed restriction and on the third day of feed restriction. On the fourth day of feed restriction, the daily meal was not served and an intravenous glucose tolerance test was performed. During the 4 wk preceding the feed restriction, milk production and DMI were not affected by treatments. During the feed restriction, the vitamin supplement tended to decrease milk fat concentration and increase milk concentration of lactose. Plasma concentrations of homocysteine, Ile, Leu, Val, and branched-chain AA increased in VIT cows during the restriction but not in CON cows. During the glucose tolerance test, insulin peak height was lower and insulin incremental positive area under the curve tended to be lower for VIT than for CON [83 (95% confidence interval, CI: 64-108) vs. 123 (95% CI: 84-180) µg·180 min/L, respectively]. Free fatty acid nadir was reached earlier for VIT than for CON [34 (95% CI: 26-43) vs. 46 (95% CI: 31-57) min, respectively]. Glucose area under the curve, clearance rate and peak height, insulin time to reach the peak and clearance rate, and free fatty acid nadir did not differ between VIT and CON. The reduction in insulin release during a glucose tolerance test without changes in glucose clearance rate or area under the curve suggests that the vitamin supplement improved insulin sensitivity in feed-restricted lactating dairy cows.

Methotrexate efficacy and tolerance in plaque psoriasis. A prospective real-life multicentre study in France.

BACKGROUND: Methotrexate (MTX) is a major systemic treatment for moderate to severe plaque psoriasis. A randomized trial has recently been published evaluating a single weekly dosage (17.5mg), but few prospective real-life data are available. The main objective of this study was to prospectively evaluate the efficacy of MTX in real-life. The secondary objectives were to evaluate predictive parameters for treatment efficacy and the frequency of adverse events. PATIENTS AND METHODS: A prospective cohort involving consecutive at in 25 centres belonging to GEM RESOPSO included all adults with plaque psoriasis in whom MTX treatment was initiated. The efficacy criterion was achievement of PASI 75 at week (W) 12/16. The impact of demographic data, psoriasis characteristics (duration, topography, rheumatism), dosage (W12/16 dosage, cumulative dose after 4 weeks), and mode of administration (subcutaneous vs. oral, concomitant use of folic acid) on efficacy was evaluated. Intention-to-treat (ITT),per protocol (PP), and multivariate analyses were performed. RESULTS: Two hundred and fifty-six patients (F/M: 105/151; mean age: 45.0 years; rheumatism: 12.6%) with plaque psoriasis were included. 99 patients were not analysed at W12/16 (16 because of inefficacy, 16 because of intolerance, 56 were lost to follow-up or had data missing). PASI 75 was achieved in 98 patients, with efficacy of 38.3% in the ITT analysis and 58.3% in the PP analysis. In the ITT analysis, absence of previous use of cyclosporine (P=0.01) and a cumulative dose of MTX>60mg after 4 weeks (P<0.0001) were associated with higher PASI 75 rates. In the PP analysis, only absence of previous use of cyclosporine (P=0.0009) was associated with a better PASI 75 results. There was no association between PASI 75 and patient characteristics (including body mass index), clinical aspects of psoriasis, route of administration, combination with folic acid, or W12/16 dose. Adverse events were reported by 34.8% of patients. These consisted mainly of digestive disorders (nausea, abdominal pain), asthenia and moderate hepatic cytolysis. The frequency of adverse events was correlated with methotrexate dosage. DISCUSSION: The efficacy of MTX in plaque psoriasis in this real-life study of 256 patients is consistent with the data in the literature, including the recently published randomized trial (41% PASI 75). This rate was unaffected by patient weight, route of administration and combined use of folic acid. Absence of previous use of cyclosporine appears to be associated with better efficacy although there is no clear explanation for this. The initial dosage (high dose in the first month) appears to be associated with superior efficacy for W12/W16.

Synovial nerve fiber density decreases with naturally-occurring osteoarthritis in horses.

OBJECTIVE: To measure the nerve fiber density in synovial membranes from healthy and OA equine joints and to investigate the relationship between synovial innervation and OA severity, synovial vascularity and synovitis. DESIGN: Twenty-five equine metacarpophalangeal joints were collected post-mortem. The joints were dissected and the macroscopic lesions of the articular cartilage were scored. Synovial membrane specimens (n = 50) were harvested, fixed, sectioned and scored histologically. Immunohistochemical staining and immunofluorescence with S-100 protein, that identifies nerve fibers, and ⍺-actin, that stains vascular smooth muscle, were also performed on site-matched specimens and the relationships between these tissues was interrogated. RESULTS: The nerve fiber density was higher in the superficial layer (≤200 µm) of the synovium when compared to the deeper layer in control equine joints (mean difference (95% C.I.): 0.054% (0.018%, 0.11%)). In osteoarthritic joints, synovial innervation decreased in the superficial layer with increasing macroscopic OA score (ß (SEM), 95% C.I.: -0.0061 (0.00021), -0.0011, -0.00017). The blood vessel density was also higher in the superficial layer of the synovium compared to the deep layer in the control (mean difference (95% C.I.): 1.1% (0.36%, 2.3%)) and OA (mean difference (95% C.I.): 0.60% (0.22%, 1.2%)) equine joints. Moreover, considering all synovial specimens, higher nerve fiber density in the deep layer positively correlated with blood vessel density (ß (SEM), 95% C.I.: 0.11 (0.036), 0.035, 0.18). CONCLUSION: The reduction in nerve fiber density with advanced cartilage degeneration suggests that peripheral neuropathy is associated with equine OA. Whether this link is associated with neuropathic pain, requires further investigation.

Distinctive cutaneous and systemic features associated with specific antimyositis antibodies in adults with dermatomyositis: a prospective multicentric study of 117 patients.

BACKGROUND: Identification of myositis-specific autoantibodies (MSAs) for dermatomyositis (DM) could allow the characterization of an antibody-associated clinical phenotype. OBJECTIVE: We sought to define the clinical phenotype of DM and the risk of cancer, interstitial lung disease (ILD) and calcinosis based on MSA. METHODS: A 3.5-year multicentre prospective study of adult DM patients was conducted to determine the clinical phenotype associated with MSAs and the presence of cancer, ILD and calcinosis. RESULTS: MSAs were detected in 47.1% of 117 included patients. Patients with antimelanoma differentiation-associated protein-5 antibodies (13.7%) had significantly more palmar violaceous macules/papules [odds ratio (OR) 9.9], mechanic's hands (OR 8), cutaneous necrosis (OR 3.2), articular involvement (OR 15.2) and a higher risk of ILD (OR 25.3). Patients with antitranscriptional intermediary factor-1 antibodies (11.1%), antinuclear matrix protein-2 antibodies (6.8%) and antiaminoacyl-transfer RNA synthetase (5.1%) had, respectively, significantly more poikiloderma (OR 5.9), calcinosis (OR 9.8) and articular involvement (OR 15.2). Cutaneous necrosis was the only clinical manifestation significantly associated with cancer (OR 3.1). CONCLUSION: Recognition of the adult DM phenotype associated with MSAs would allow more accurate appraisal of the risk of cancer, ILD and calcinosis.