Filgotinib (GLPG0634/GS-6034), an oral JAK1 selective inhibitor, is effective in combination with methotrexate (MTX) in patients with active rheumatoid arthritis and insufficient response to MTX: results from a randomised, dose-finding study (DARWIN 1).

OBJECTIVES: To evaluate the efficacy and safety of different doses and regimens of filgotinib, an oral Janus kinase 1 inhibitor, as add-on treatment to methotrexate (MTX) in patients with active rheumatoid arthritis (RA) and inadequate response to MTX. METHODS: In this 24-week phase IIb study, patients with moderate-to-severe active RA receiving a stable dose of MTX were randomised (1:1:1:1:1:1:1) to receive placebo or 50, 100 or 200 mg filgotinib, administered once daily or twice daily. Primary end point was the percentage of patients achieving a week 12 American College of Rheumatology (ACR)20 response. RESULTS: Overall, 594 patients were randomised and treated. At week 12, significantly more patients receiving filgotinib 100 mg once daily or 200 mg daily (both regimens) achieved an ACR20 response versus placebo. For other key end points at week 12 (ACR50, ACR-N, Disease Activity Score based on 28 joints and C reactive protein value, Clinical Disease Activity Index, Simplified Disease Activity Index and Health Assessment Questionnaire-Disability Index), differences in favour of 100  or 200 mg filgotinib daily were seen versus placebo; responses were maintained or improved through to week 24. Rapid onset of action and dose-dependent responses were observed for most efficacy end points and were associated with an increased haemoglobin concentration. No significant differences between once-daily and twice-daily regimens were seen. Treatment-emergent adverse event rates were similar in placebo and filgotinib groups. Serious infections occurred in one and five patients in the placebo and filgotinib groups, respectively. No tuberculosis or opportunistic infections were reported. CONCLUSIONS: Filgotinib as add-on to MTX improved the signs and symptoms of active RA over 24 weeks and was associated with a rapid onset of action. Filgotinib was generally well tolerated. TRIAL REGISTRATION NUMBER: NCT01888874.

Filgotinib (GLPG0634/GS-6034), an oral selective JAK1 inhibitor, is effective as monotherapy in patients with active rheumatoid arthritis: results from a randomised, dose-finding study (DARWIN 2).

OBJECTIVES: To evaluate the efficacy and safety of different doses of filgotinib, an oral Janus kinase 1 inhibitor, as monotherapy in patients with active rheumatoid arthritis (RA) and previous inadequate response to methotrexate (MTX). METHODS: In this 24-week phase IIb study, patients with moderately to severely active RA were randomised (1:1:1:1) to receive 50, 100 or 200 mg filgotinib once daily, or placebo, after a ≥4-week washout from MTX. The primary end point was the percentage of patients achieving an American College of Rheumatology (ACR)20 response at week 12. RESULTS: Overall, 283 patients were randomised and treated. At week 12, significantly more patients receiving filgotinib at any dose achieved ACR20 responses versus placebo (≥65% vs 29%, p<0.001). For other key end points at week 12 (ACR50, ACR70, ACR-N, Disease Activity Score based on 28 joints and C reactive protein, Clinical Disease Activity Index, Simplified Disease Activity Index and Health Assessment Questionnaire-Disability Index) significant differences from baseline in favour of filgotinib 100 and 200 mg versus placebo were seen; responses were maintained or improved through week 24. Rapid onset of action was observed for most efficacy end points. Dose-dependent increases in haemoglobin were observed. The percentage of patients with treatment-emergent adverse events (TEAE) was similar in the placebo and filgotinib groups (∼40%). Eight patients on filgotinib and one on placebo had a serious TEAE, and four patients, all of whom received filgotinib, experienced a serious infection. No tuberculosis or opportunistic infections were reported. CONCLUSIONS: Over 24 weeks, filgotinib as monotherapy was efficacious in treating the signs and symptoms of active RA, with a rapid onset of action. Filgotinib was generally well tolerated. TRIAL REGISTRATION NUMBER: NCT01894516.

[Prevalence, severity, and predictors of bronchopulmonary dysplasia in a cohort of very preterm infants]. / Prévalence, gravité et facteurs prédictifs de la dysplasie bronchopulmonaire dans une cohorte ultramarine de grands prématurés.

OBJECTIVES: The aim of this retrospective cohort study was to determine the prevalence and severity of BPD and its predictors in a regional cohort of very preterm (VP) infants in Reunion Island. METHODS: All autochthonous VP infants, live-born before the 33rd week of gestation (WG) between 1st January 2008 and 31st December 2009, were eligible for the study. Only VP infants surviving at least 28 days, for whom the parameters were known from birth, were included in the case-control study of predictors of moderate to severe BPD (BPDmo/s). RESULTS: In VP infants less than 33 WG, the rate of overall BPD (3 grades of severity) was 30.7%. Among those who survived 28 days or more, the rate of BPDmo/s was 13.1% (95%CI: 10.2-15.9%). In VP infants less than 32 WG that survived at 36 WG, the prevalence of BPDmo/s was 18.2% (95% CI: 14.2-22.1%). In a fixed-effect logistic model, adjusted for gestational age, postnatal growth, and the mode of ventilation at 24h, 4 key factors were predictive of BDPmo/s: small for gestational age, surfactant, delayed energy intake, and late-onset neonatal infection. In a mixed-effect logistic model adjusted for these same cofactors, the site was associated with BPDmo/s, in line with a center-effect. CONCLUSION: The prevalence of BPDmo/s in the mixed-race population of Reunion Island is consistent with those observed in Europe but were site-specific. In our setting, predictors of individual BPDmo/s are similar to those already identified.

[Brain tuberculoma in a 10-year-old child: the diagnosis is in the belly]. / Tuberculome cérébral chez une enfant de 10 ans diagnostiqué par biopsie d'une adénopathie abdominale.

We report the case of a 10-year-old child from Reunion Island who was hospitalized because of headaches and partial convulsive fits. The brain MRI showed several conglomerated right frontal lesions suggestive of a tumor process. This girl, vaccinated with BCG, had familial risk factors for tuberculosis and a 20-mm tuberculin intradermo-reaction. Given the palpation of an abdominal mass, a thoracoabdominal scan was done, which revealed the presence of mesenteric adenopathies. Their biopsy confirmed the diagnosis of tuberculosis without having to perform neurosurgery. A 2-month quadritherapy and a 10-month dual therapy against tuberculosis led to the disappearance of brain damage and mesenteric adenopathies, with focal epilepsy the only sequela. The tuberculosis incidence in Reunion Island (8/100,000) is comparable with the French average, but the island is surrounded by high-endemic countries. Tuberculomas were responsible for one-third of expanding intracranial lesions in Europe in 1933, and their incidence remains high in developing countries. Even though extrapulmonary or disseminated tuberculosis has become rare in children in industrialized countries, this diagnosis must be kept in mind, in spite of vaccination. In accordance with international guidelines, this case report shows the importance of a systematic extensive check-up (cervical, thoracic and abdominopelvic) when brain tuberculosis is suspected in order to find more accessible tuberculosis lesions and to avoid the side effects of a brain biopsy.

Successful treatment of moderate to severe plaque psoriasis with the PEGylated Fab' certolizumab pegol: results of a phase II randomized, placebo-controlled trial with a re-treatment extension.

BACKGROUND: Certolizumab pegol (CZP) is a PEGylated antitumour necrosis factor agent. OBJECTIVES: To evaluate the efficacy and safety of CZP in patients with plaque psoriasis. METHODS: In a randomized, placebo-controlled, double-blind study, 176 patients with moderate to severe psoriasis received placebo or CZP 400 mg at week 0 followed by placebo or CZP (200 or 400 mg) every other week until week 10. Co-primary endpoints were ≥ 75% improvement from baseline in Psoriasis Area and Severity Index (PASI 75) and a Physician's Global Assessment (PGA) of clear-almost clear at week 12. A re-treatment extension study was conducted in 71 CZP PASI 75 responders who relapsed during a 12- to 24-week observation period without treatment. RESULTS: PASI 75 was achieved by 44/59 (75%), 48/58 (83%) and 4/59 (7%) patients in the CZP 200 mg, CZP 400 mg and placebo groups, respectively (P < 0·001 for both treatment arms vs. placebo). A PGA score of clear-almost clear was achieved by 53%, 72% and 2%, respectively (P < 0·001 for both treatment arms vs. placebo). In the re-treatment study median PASI scores were similar at week 12 in the first treatment and re-treatment periods for both CZP groups. Serious adverse events occurred in 3%, 5% and 2% of CZP 200 mg, CZP 400 mg and placebo patients, respectively. CONCLUSIONS: Treatment with CZP significantly improved psoriasis at week 12. Similar efficacy was observed at week 12 in patients receiving re-treatment for loss of response after drug withdrawal.

Comparison of the effects of cetirizine and ebastine on the skin response to histamine iontophoresis monitored with laser Doppler flowmetry.

BACKGROUND: The administration of histamine with iontophoresis is an alternative method to skin prick tests or intradermal injections. Skin reactions obtained with this method can be recorded with laser Doppler flowmetry (LDF) and previous studies with this method have shown histamine-induced laser Doppler changes in the wheal area. OBJECTIVE: In order to compare the influence of two H1 receptor antagonists (cetirizine 10 mg vs. ebastine 10 mg) on the skin vascular responses to histamine introduced by iontophoresis, we designed a double-blind, randomized, two-period crossover trial in which 18 volunteers were randomized. METHODS: Before and 2, 5 and 7 h after drug administration, iontophoresis (30 s, 1.4 mA/cm2) of histamine 10% was performed and followed by (1) monitoring of skin vascular responses with LDF at the administration site and at 1 cm from it, and (2) wheal and flare area measurements. RESULTS: 2, 5 and 7 h after intake of the antihistaminic drug, there were significant differences between both drugs. Concerning LDF recordings, we noted at the histamine administration site an increase in perfusion unit (PU) values which is an effect known to be in proportion to the degree of inhibition of wheal reaction, and at 1 cm distal to the histamine administration site, there was a decrease in PU values. These changes were more marked under cetirizine. A greater suppressive effect of cetirizine on the wheal and flare reaction was consistently observed at all time points during the study, demonstrating its superior efficacy. CONCLUSION: We conclude that (1) cetirizine demonstrated a stronger antihistaminic effect compared to ebastine at all time points; (2) iontophoresis appears to be an appropriate method to study specific microvascular changes at the delivery site of histamine and hence to detect the earliest changes occurring at the site of agonist-antagonist competition in the skin.

Scoring of atopic dermatitis by SCORAD using a training atlas by investigators from different disciplines. ETAC Study Group. Early Treatment of the Atopic Child.

The ETAC (Early Treatment of the Atopic Child) study, a multi-national double-blind placebo-controlled randomized trials, has been in progress since 1994. Fifty-six centers in Europe and Canada participate in this study. A total of 817 children with atopic dermatitis [AD] were recruited. The severity of AD was scored using the SCORAD (objective criteria). Ninety-eight investigators (mostly pediatricians) were trained by three members of the European Task Force on Atopic Dermatitis [ETFAD] to standardize their objective SCORAD scoring (system developed by the ETFAD). The experts selected photographs and prepared a training atlas. The percentages of photographs assessed by the 98 non-expert investigators below, within and above the range of evaluations by the three experts were calculated. Taking over and underscoring together, edema/papulation was the easiest intensity item to score (82% within the range by the experts). The global symptom score, as well as lichenification, edema/papulation, oozing and excoriation registered by physicians with dermatological experience were not statistically significantly different from those by other. Erythema was statistically significantly better scored by those with dermatological experience. The results of the Euclidean Distance method showed that the item excoriations gave the largest distance. Erythema and excoriations were scored better by dermatologically experienced physicians (t-test, p = 0.042 and p = 0.063 respectively), but lichenification was better scored by non-dermatologically experienced physicians (p = 0.013). The extent of surface area involved in the disease was calculated on 3 sets of photographs. Most evaluations by the 98 nonexpert investigators were within the range of the experts. Dermatologically experienced physicians scored significantly better than the others (t-test, p = 0.006). This training program is useful for standardizing the scoring in AD and indicates that SCORAD can be used by investigators from different disciplines.

[Clinical formulations of amphotericin B]. / Formulations galéniques d'amphotéricine B.

The clinical use of amphotericin B is impaired by its poor water solubility and by the severity of its side effects. Several amphotericin B formulations have already been prepared in an attempt to overcome these disadvantages. The following methods have been proposed to solubilize amphotericin B in water: the complexation of amphotericin B with metallic ions, sodium tetraborate or gamma cyclodextrin or the synthesis of semi-synthetic derivatives. Another approach was to use a carrier (liposomes, lipoproteins, emulsions or surfactants) to target amphotericin B. This paper summarizes and criticizes these formulations.

Comparison of nephrotoxicities of different polyoxyethyleneglycol formulations of amphotericin B in rats.

The aim of the present study was to assess whether amphotericin B (AmB)-Myrj 59, AmB-polyoxyethyleneglycol 24 cholesterol (PC), and AmB-Synperonic A50 (SA50) were less nephrotoxic than AmB-deoxycholate (DC). Rats were treated with the different AmB formulations (10 mg/kg of body weight) intraperitoneally or with the surfactants alone. A group of control rats receiving the vehicle was also examined. After 6 days of daily intraperitoneal injections of AmB-DC, decreased body weight and glomerular filtration rate as well as increased degree of diuresis, uremia, microalbuminuria, and N-acetyl-beta-D-glucosaminidase excretion in urine were noted. Urinary excretion of potassium and sodium was also decreased in AmB-DC-treated rats. Most of these effects were more pronounced with AmB-PC and AmB-SA50. In contrast, AmB-Myrj 59 was less nephrotoxic than AmB-DC. Indeed, after 6 days of treatment with AmB-Myrj 59, the natriuria, kaliuria, albuminuria, and glomerular filtration rates were unchanged compared with those of controls. Moreover, the body weight loss and uremia increase of the rats treated by AmB-Myrj 59 were less than those of the rats treated with the commercial preparation. Among the surfactants, only PC was toxic for the rats. The intrinsic toxicity of PC and the higher systemic exposure to AmB could contribute to increased toxicities of AmB-PC and AmB-SA50, respectively. AmB-Myrj 59 was less nephrotoxic than AmB-DC at equivalent areas under the plasma concentration-time curves. These preliminary results suggest that this formulation could be a good alternative to the commercial product.

The influence of Myrj 59 on the solubility, toxicity and activity of amphotericin B.

The effect of Myrj 59 (a polyoxyethyleneglycol derivative of stearic acid) on amphotericin B (Am B) solubility, toxicity and activity has been investigated. We showed that Myrj 59 could solubilize the antibiotic. Moreover, it also decreased and abolished the haemolytic activity of the drug by increasing the resistance of the red blood cells and impairing the interaction of Am B with the cellular membrane cholesterol, but it did not modify the in-vitro antifungal activity of the drug. On the other hand, Myrj 59 did not decrease the acute in-vivo toxicity of the drug (LD50 and nephrotoxicity). In a previous study we have shown that a polyoxyethleneglycol derivative of cholesterol could solubilize Am B and was able to decrease the in-vitro and in-vivo toxicity of the antibiotic without altering its in-vitro antifungal activity. The results of the present study suggest that the cholesterol moiety of the surfactant is not necessary to decrease the in-vitro lytic activity of the drug but could play a role in the reduction of the in-vivo toxicity.