Background-Autoinflammatory diseases manifest inflammation without evidence of infection, high-titer autoantibodies, or autoreactive T cells. We report a disorder caused by mutations of IL1RN, which encodes the interleukin-1-receptor antagonist, with prominent involvement of skin

ObjectiveEvaluate apremilast efficacy across various psoriatic arthritis (PsA) manifestations beginning at week 2 in biological-naïve patients with PsA.MethodsPatients were randomised (1:1) to apremilast 30 mg twice daily or placebo. At week 16, patients whose swollen and tender joint counts had not improved by ≥10% were eligible for early escape. At week 24, all patients received apremilast through week 52.ResultsAmong 219 randomised patients (apremilast: n=110; placebo: n=109), a significantly greater American College of Rheumatology 20 response at week 16 (primary outcome) was observed with apremilast versus placebo (38.2% (42/110) vs 20.2% (22/109); P=0.004); response rates at week 2 (first assessment) were 16.4% (18/110) versus 6.4% (7/109) (P=0.025). Improvements in other efficacy outcomes, including 28-joint count Disease Activity Score (DAS-28) using C reactive protein (CRP), swollen joint count, Health Assessment Questionnaire-Disability Index (HAQ-DI), enthesitis and morning stiffness severity, were observed with apremilast at week 2. At week 16, apremilast significantly reduced PsA disease activity versus placebo, with changes in DAS-28 (CRP) (P<0.0001), HAQ-DI (P=0.023) and Gladman Enthesitis Index (P=0.001). Improvements were maintained with continued treatment through week 52. Over 52 weeks, apremilast’s safety profile was consistent with prior phase 3 studies in psoriasis and PsA. During weeks 0–24, the incidence of protocol-defined diarrhoea was 11.0% (apremilast) and 8.3% (placebo); serious adverse event rates were 2.8% (apremilast) and 4.6% (placebo).ConclusionsIn biological-naïve patients with PsA, onset of effect with apremilast was observed at week 2 and continued through week 52. The safety profile was consistent with previous reports.Trial registration numberNCT01925768; Results.

Laminopathies are a group of genetic disorders caused by LMNA mutations; they include muscular dystrophies, lipodystrophies and progeroid syndromes. We identified a novel heterozygous LMNA mutation, L59R, in a patient with the general appearance of mandibuloacral dysplasia and progeroid features. Examination of the nuclei of dermal fibroblasts revealed the irregular morphology characteristic of LMNA mutant cells. The nuclear morphological abnormalities of LMNA mutant lymphoblastoid cell lines were less prominent compared to those of primary fibroblasts. Since it has been reported that progeroid features are associated with increased extracellular matrix in dermal tissues, we compared a subset of these components in fibroblast cultures from LMNA mutants with those of control fibroblasts. There was no evidence of intracellular accumulation or altered mobility of collagen chains, or altered conversion of procollagen to collagen, suggesting that skin fibroblastmediated matrix production may not play a significant role in the pathogenesis of this particular laminopathy.

BackgroundACTIVE is the first apremilast (APR) trial to evaluate time to onset of efficacy beginning at Wk 2 in biologic-naïve psoriatic arthritis (PsA) patients (pts) who may have had exposure to 1 prior conventional DMARD.ObjectivesReport the study results through Wk 52.MethodsPts were randomized (1:1) to APR 30 mg BID or placebo (PBO). Pts were eligible for early escape (investigator discretion) at Wk 16. At Wk 24, all pts entered active treatment with APR. The primary endpoint was ACR20 response at Wk 16. Other assessments included changes in DAS-28 (CRP), SJC, TJC, HAQ-DI, morning stiffness duration/severity, and enthesitis, as measured by the Gladman Enthesitis Index (GEI; 0=no enthesitis, 6=all 6 sites active). Along with collection of safety data, tolerability adverse events (AEs) of diarrhea were further characterized.Results219 pts were randomized (APR: n=110; PBO: n=109); overall, 160/180 (88.9%) pts receiving APR completed Wk 52. Separation in the proportion of ACR20 responders to APR vs PBO was noted at Wk 2 (16.4% vs 6.4%; P=0.0252), the first post-baseline (BL) visit. Early onset of response to APR was observed across clinical assessments, with improvements in DAS-28 (CRP), SJC, HAQ-DI, enthesitis, and morning stiffness severity (Table). At Wk 16, significant ACR20 response rates were observed with APR vs PBO (38.2% vs 20.2%; P<0.005), with similar rates for the subset of pts with use of 1 prior non-biologic DMARD (39.2% vs 20.5%; P<0.05), which comprises 69% of study pts. Significant reductions in PsA disease activity/manifestations vs PBO were also demonstrated by changes in DAS-28 (CRP) (P<0.0001), SJC, and HAQ-DI (P=0.0229), and improvements in morning stiffness severity and GEI score (P=0.0014). With continued APR exposure, the Wk 52 ACR20/ACR50/ACR70 response rates were 63.3%/32.4%/14.0%, and percent change in SJC was −74.5%. Among APR pts with BL enthesitis, 62.8% reached a GEI score of 0. Overall incidence of AEs in the PBO-controlled period was generally similar between APR and PBO. The most commonly reported AEs (≥5% of pts) with APR vs PBO were nasopharyngitis (8.3% vs 6.4%), nausea (8.3% vs 1.8%), headache (7.3% vs 3.7%), hypertension (6.4% vs 6.4%), and diarrhea (pt or investigator reported) (14.7% vs 11.0%); using a protocol-defined characterization of diarrhea (≥2 watery/liquid stools/day), overall incidence was lower for APR and PBO (11.0% and 8.3%). Serious AEs were lower with APR vs PBO (2.8% vs 4.6%). No opportunistic infections, reactivations of TB, or cases of marked depression were seen. In general, no increase was seen in AE incidence/severity with longer-term exposure to APR.ConclusionsIn biologic-naïve pts treated with APR, onset of effect was observed starting at Wk 2 across PsA manifestations, including morning stiffness severity and enthesitis, with sustained improvements through Wk 52. AEs were consistent with those reported for other APR phase 3 PsA and psoriasis studies.Disclosure of InterestP. Nash Grant/research support from: Celgene Corporation, K. Ohson Grant/resea...

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