ObjectivesThe PALACE 4 trial evaluated apremilast monotherapy in patients with active PsA who were DMARD-naive.MethodsEligible patients were randomized (1:1:1) to placebo, apremilast 20 mg twice a day or apremilast 30 mg twice a day. At week 16 or 24, placebo patients were rerandomized to apremilast. Double-blind apremilast treatment continued to week 52, with extension up to 4 years. The primary endpoint was the proportion of patients achieving ⩾20% improvement in ACR response criteria (ACR20) at week 16; secondary endpoints included the mean change in the HAQ Disability Index (HAQ-DI) score at week 16.ResultsA total of 527 patients with mean disease duration of 3.4 years and high disease activity were randomized and received treatment. More apremilast patients achieved ACR20 response at week 16 [placebo, 15.9%; 20 mg, 28.0% (P = 0.0062); 30 mg, 30.7% (P = 0.0010)]. The mean HAQ-DI improvements were −0.17 (20 mg; P = 0.0008) and −0.21 (30 mg; P < 0.0001) vs 0.03 (placebo). Both apremilast doses showed significant ACR50 responses vs placebo at week 16 and improvements in secondary efficacy measures (swollen/tender joint counts) and psoriasis assessments, with sustained improvements through week 52. Common adverse events (AEs) over 52 weeks were diarrhoea, nausea, headache and upper respiratory tract infection; most events were mild or moderate. Serious AEs and AEs leading to discontinuation were comparable between groups. Laboratory abnormalities were infrequent and transient.ConclusionsIn DMARD-naive patients, apremilast monotherapy improved PsA signs/symptoms over 52 weeks and was generally well tolerated.Trial registrationClinicalTrials.gov (http://clinicaltrials.gov), NCT01307423.

Single color fluorescence in situ hybridization (FISH) has been utilized on sperm to estimate nondisjunction rates for chromosomes 1, 12, 15, 16, X and Y. Using single-color FISH, one cannot distinguish nonhybridization from nullisomy nor disomy from diploidy. In order to provide an internal control, a multicolor FISH strategy was employed. Satellite probes specific for 13 human chromosomes were used on multiple semen samples from two normal donors. Two or three probes were hybridized simultaneously and scored by two independent observers. Over all experiments, 40,641 sperm were analyzed. The majority of autosomes had no significant difference in aneuploidy between chromosomes or between donors. However, a significant difference was observed for chromosome 18 between donors (χ²₂ = 7.078, 0.025 < P < 0.05). Additionally, no significant difference was found between donors for sex chromosome aneuploidy. The frequency of sex chromosome aneuploidy was similar to that seen in paternally derived 47, XXY and 47, XYY conceptuses. Furthermore, 0.15% of sperm were found to be diploid. Based on the results of this study, as much as 19% of all sperm may be chromosomally abnormal. This method proved to be useful for determining aneuploidy of human chromosomes in sperm and valuable in exploring whether individual differences of nondisjunction exist.

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.

Klinefelter (47,XXY) syndrome occurs in approximately 1:800 male births and accounts for about 10-20% of males attending infertility clinics. Recent studies have shown no obvious phenotypic differences between subjects in which the extra X-chromosome is of paternal or maternal origin; however, a minority of Klinefelter patients are adversely affected clinically and intellectually to an exceptional level, and the underlying basis of this phenotypic variation is not known. We hypothesize that skewed X-inactivation and possibly parental origin of the X-chromosomes is involved. In this study, we determined parental origin and inactivation status of the X-chromosomes in 17 cytogenetically confirmed 47,XXY cases, two 48,XXYY cases and one mosaic 46,XY/47,XXY case. Eight highly polymorphic markers specific to the X-chromosome and the polymorphic human androgen-receptor (HUMARA) methylation assay were used to determine the parental origin and X-inactivation status of the X-chromosomes, respectively. Overall, 17 cases were fully informative, enabling parental origin to be assigned. In 59% of cases, both X-chromosomes were of maternal origin (Xm); in the remaining 41%, one X was of maternal (Xm) and one was of paternal origin (Xp). In 5 of 16 (31%) cases informative at the HUMARA locus, skewed X-inactivation was observed as defined by greater than 80% preferential inactivation involving one of the two X-chromosomes. The two 48,XmXpYY cases both showed preferential paternal X-chromosome (Xp) inactivation. Three 47,XmXmY cases also showed preferential inactivation in one of the two maternal X-chromosomes. These results suggest that skewed X-inactivation in Klinefelter (47,XXY and 48,XXYY) patients may be common and could explain the wide range of mental deficiency and phenotypic abnormalities observed in this disorder. Further studies are warranted to examine the role of X-inactivation and genetic imprinting in Klinefelter patients.

Klinefelter (47,XXY) syndrome occurs in approximately 1:800 male births and accounts for about 10-20% of males attending infertility clinics. Recent studies have shown no obvious phenotypic differences between subjects in which the extra X-chromosome is of paternal or maternal origin; however, a minority of Klinefelter patients are adversely affected clinically and intellectually to an exceptional level, and the underlying basis of this phenotypic variation is not known. We hypothesize that skewed X-inactivation and possibly parental origin of the X-chromosomes is involved. In this study, we determined parental origin and inactivation status of the X-chromosomes in 17 cytogenetically confirmed 47,XXY cases, two 48,XXYY cases and one mosaic 46,XY/47,XXY case. Eight highly polymorphic markers specific to the X-chromosome and the polymorphic human androgen-receptor (HUMARA) methylation assay were used to determine the parental origin and X-inactivation status of the X-chromosomes, respectively. Overall, 17 cases were fully informative, enabling parental origin to be assigned. In 59% of cases, both X-chromosomes were of maternal origin (Xm); in the remaining 41%, one X was of maternal (Xm) and one was of paternal origin (Xp). In 5 of 16 (31%) cases informative at the HUMARA locus, skewed X-inactivation was observed as defined by greater than 80% preferential inactivation involving one of the two X-chromosomes. The two 48,XmXpYY cases both showed preferential paternal X-chromosome (Xp) inactivation. Three 47,XmXmY cases also showed preferential inactivation in one of the two maternal X-chromosomes. These results suggest that skewed X-inactivation in Klinefelter (47,XXY and 48,XXYY) patients may be common and could explain the wide range of mental deficiency and phenotypic abnormalities observed in this disorder. Further studies are warranted to examine the role of X-inactivation and genetic imprinting in Klinefelter patients.