Summary
Background
Guselkumab, an anti‐interleukin‐23 monoclonal antibody, has demonstrated significant efficacy in phase III psoriasis trials.
Objectives
To evaluate the efficacy and safety of ...guselkumab in patients with moderate‐to‐severe plaque psoriasis who had an inadequate response to ustekinumab.
Methods
In this phase III, randomized, double‐blind study, 871 patients received open‐label ustekinumab (45 mg or 90 mg) at weeks 0 and 4. At week 16, 268 patients with an inadequate response to ustekinumab Investigator's Global Assessment (IGA) ≥ 2 were randomized (double‐blind) to guselkumab 100 mg or to continue ustekinumab; 585 of 871 patients (67%) with IGA 0/1 at week 16 continued open‐label ustekinumab. The primary end point was the number of visits at which randomized patients achieved IGA 0/1 and at least a two‐grade improvement (from week 16) from week 28 to week 40. Improvement ≥ 90% or 100% in Psoriasis Area and Severity Index (PASI 90/100) and Dermatology Life Quality Index (DLQI) of 0/1 were also assessed.
Results
The mean number of visits at which patients achieved IGA 0/1 and at least a two‐grade improvemen (week 28–40) was significantly greater in the guselkumab group vs. the randomized ustekinumab group (1·5 vs. 0·7; P < 0·001); greater proportions of patients in the guselkumab group achieved IGA 0/1 and at least a two‐grade improvement at week 28 (31·1% vs. 14·3%; P = 0·001) and week 52 (36·3% vs. 17·3%; P < 0·001). Greater proportions of patients treated with guselkumab achieved PASI 90, PASI 100 and DLQI 0/1 at week 52. After week 16, 64·4% of patients in the guselkumab group and 55·6% in the ustekinumab group had at least one adverse event (AE); infections were the most frequent AE type. Overall, 6·7% (n = 9) of patients in the guselkumab group had at least one serious AE compared with 4·5% (n = 6) for the ustekinumab group.
Conclusions
Patients treated with ustekinumab who did not achieve an IGA of 0/1 by week 16 derived significant benefit from switching to guselkumab.
What's already known about this topic?
Interleukin (IL)‐23/IL‐17 is the major pathway that drives the chronic inflammation underlying the pathophysiology of psoriasis.
Ustekinumab is a monoclonal antibody targeting IL‐12 and IL‐23 and is currently approved for patients with plaque psoriasis.
Guselkumab is a novel anti‐IL‐23 monoclonal antibody and has demonstrated high efficacy in patients with plaque psoriasis in two recent phase III trials.
What does this study add?
Guselkumab demonstrated greater efficacy compared with ustekinumab among patients who failed to achieve an Investigator's Global Assessment score of 0 or 1 with ustekinumab therapy.
The types of adverse events (AEs) with guselkumab and ustekinumab were similar, with infections being the most common.
A slightly higher incidence of AEs was reported in the guselkumab group, primarily driven by AEs of back pain, psoriatic arthropathy and mild injection site reactions.
Linked Comment: Albrecht and Gerdes. Br J Dermatol 2018; 178:20.
Plain language summary available online
Summary
Background
Ustekinumab, an interleukin (IL)‐12 and IL‐23 blocker, has emerged as a new therapeutic option for patients with psoriasis. It is generally well tolerated but safety data on the ...use of ustekinumab in patients with viral hepatitis are limited.
Objective
To assess the safety profile of ustekinumab in the treatment of patients with psoriasis who have concomitant hepatitis B or hepatitis C.
Methods
This study included 18 patients with concurrent psoriasis and hepatitis B virus (HBV) infection (14 patients) or hepatitis C virus (HCV) infection (four patients) who were treated with at least two ustekinumab injections. Viral loads were measured at baseline and each time before the administration of ustekinumab. Relevant clinical data were recorded.
Results
Among 11 patients positive for hepatitis B surface antigen (HBsAg), two out of the seven (29%) patients who did not receive antiviral prophylaxis exhibited HBV reactivation during ustekinumab treatment. No viral reactivation was observed in the three occult HBV‐infected patients (HBsAg‐negative/hepatitis B core antibody‐positive patients). One patient with HCV, liver cirrhosis and treated hepatocellular carcinoma (HCC) experienced HCV reactivation and recurrent HCC during the ustekinumab treatment. No significant increase in aminotransferase levels was observed in any patient.
Conclusions
Antiviral prophylaxis appears to minimize the risk of viral reactivation in patients with concurrent psoriasis and HBV infection. Without effective anti‐viral prophylaxis, the risk/benefit of ustekinumab treatment should be carefully assessed in patients with psoriasis and HBV or HCV infection and/or HCC. Close monitoring for HBV and HCV viral load is recommended, particularly for patients with high‐risk factors. Serum aminotransferase determination may not be useful for early detection of viral reactivation.
What's already known about this topic?
Interleukin (IL)‐12 plays a central role in mounting an immune response directed towards the elimination of pathogens.
Ustekinumab, an IL‐12/23 blocker may theoretically carry the risk of hepatitis B (HBV) and hepatitis C virus (HCV) reactivation with its use.
What does this study add?
Ustekinumab appears to be well tolerated in patients with concurrent psoriasis and HBV infection under antiviral prophylaxis.
The risk of HCV reactivation during ustekinumab treatment does exist and appropriate vigilance should be exercised, especially in specific high‐risk patient groups.
DNA methylation is a defining feature of mammalian cellular identity and is essential for normal development. Most cell types, except germ cells and pre-implantation embryos, display relatively ...stable DNA methylation patterns, with 70-80% of all CpGs being methylated. Despite recent advances, we still have a limited understanding of when, where and how many CpGs participate in genomic regulation. Here we report the in-depth analysis of 42 whole-genome bisulphite sequencing data sets across 30 diverse human cell and tissue types. We observe dynamic regulation for only 21.8% of autosomal CpGs within a normal developmental context, most of which are distal to transcription start sites. These dynamic CpGs co-localize with gene regulatory elements, particularly enhancers and transcription-factor-binding sites, which allow identification of key lineage-specific regulators. In addition, differentially methylated regions (DMRs) often contain single nucleotide polymorphisms associated with cell-type-related diseases as determined by genome-wide association studies. The results also highlight the general inefficiency of whole-genome bisulphite sequencing, as 70-80% of the sequencing reads across these data sets provided little or no relevant information about CpG methylation. To demonstrate further the utility of our DMR set, we use it to classify unknown samples and identify representative signature regions that recapitulate major DNA methylation dynamics. In summary, although in theory every CpG can change its methylation state, our results suggest that only a fraction does so as part of coordinated regulatory programs. Therefore, our selected DMRs can serve as a starting point to guide new, more effective reduced representation approaches to capture the most informative fraction of CpGs, as well as further pinpoint putative regulatory elements.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary
Background
Ustekinumab, an interleukin‐12/23 inhibitor, is effective in the treatment of psoriasis. A recent Italian study showed more favourable response to ustekinumab in patients with ...positive human leucocyte antigen (HLA)‐Cw6. Nonetheless, there are differences in genetic susceptibility to psoriasis between races, and no studies have specifically assessed the candidate genetic markers in predicting therapy outcome in Chinese patients with psoriasis treated with ustekinumab.
Objectives
To determine whether HLA gene polymorphisms can predict the response to ustekinumab in Chinese patients with psoriasis.
Methods
Sixty‐six patients with psoriasis treated with ustekinumab were included in the study, and the effectiveness of ustekinumab therapy was evaluated at weeks 0, 16 and 28 by Psoriasis Area and Severity Index (PASI).
Results
More HLA‐Cw6‐positive patients achieved a PASI 75 response at week 4 compared with HLA‐Cw6‐negative patients (38% vs. 9%, P = 0·019). Similarly, at week 16, patients carrying the HLA‐Cw6 allele showed a higher likelihood of achieving PASI 50, 75 and 90 than Cw6‐negative patients, although this was not statistically significant. At week 28, a significantly higher percentage of HLA‐Cw6‐positive patients maintained PASI 90 response compared with Cw6‐negative patients (63% vs. 26%, P = 0·035). Further analysis of other HLA allele polymorphisms did not show significant associations with therapeutic response to ustekinumab.
Conclusions
This pharmacogenetic study provides preliminary data indicating that positive HLA‐Cw6 is associated with a good response to ustekinumab treatment in Chinese patients with psoriasis.
What's already known about this topic?
Biological therapies have revolutionized the treatment of psoriasis. Variability in genes involved in the immunological pathways of biological therapy may account for the different treatment outcomes.
Human leucocyte antigen (HLA)‐Cw6 is the major psoriasis susceptibility gene and has a strong association with clinical psoriasis phenotypes.
Studies investigating potential predictors for response to biologics are limited, particularly in Asian populations.
What does this study add?
Our study showed that HLA‐Cw6‐positive patients have a faster response and maintain a longer treatment response to ustekinumab than HLA‐Cw6‐negative patients.
HLA‐Cw6 can be a pragmatic predictor for the response to ustekinumab not only in white patients but also in Chinese patients with psoriasis.
These results will help dermatologists in guiding therapeutic decisions.
Summary Background Ustekinumab is a monoclonal antibody that targets interleukin (IL)‐12/23 p40 to treat psoriasis. The IL‐12 pathway is also important in regulating immunity to Mycobacterium ...tuberculosis.
Objectives To evaluate the safety of isoniazid (INH) prophylaxis for newly identified latent tuberculosis infection (LTBI) in ustekinumab‐treated patients with psoriasis.
Methods Safety data from 3177 psoriasis patients evaluated across five phase III trials of ustekinumab (45 or 90 mg) conducted in North America, Europe and Asia were analysed. LTBI was diagnosed based on positive tuberculin skin test or QuantiFERON®‐TB test (Cellestis, Carnegie, Vic., Australia) without evidence of active tuberculosis.
Results At baseline, 101/2898 (3·5%) non‐Asian and 66/279 (23·7%) Asian patients were newly identified with LTBI, and all were treated with INH. Through week 12, among patients who received INH, rates of adverse events (AEs) representative of INH toxicity were generally comparable between control and ustekinumab‐treated patients, as well as between ustekinumab dose groups. Markedly abnormal alanine transaminase values occurred with comparable incidences between control and ustekinumab‐treated patients. The rate of study agent discontinuation due to INH toxicity was low (5/167, 3·0%) and comparable between control and ustekinumab groups through week 12. The rate of INH‐related AEs did not increase disproportionately through week 28. No cases of active tuberculosis were reported in patients who received concomitant INH starting at baseline.
Conclusions Across five trials of ustekinumab‐treated patients with psoriasis, no cases of LTBI reactivation were observed in patients receiving concomitant INH prophylaxis for LTBI. INH prophylaxis was generally well tolerated by these patients with psoriasis.
See also the Commentary by Shear
This paper explores the connection between the H
3
BO
3
flux concentration and the co-existence of Eu
2+
and Eu
3+
dopants within CaMgSi
2
O
6
crystals (diopside). The samples were synthesised using ...a solid-state synthesis method under varying atmospheric conditions, including oxidative (air), neutral (N
2
), and reductive (H
2
/N
2
mixture) environments. Additionally, some materials underwent chemical modification by partially substituting Si
4+
with Al
3+
ions acting as charge compensation defects stabilizing Eu
3+
luminescence. Depending on the specific synthesis conditions, the materials predominantly displayed either the orange-red luminescence of Eu
3+
(under oxidising conditions) or the blue luminescence of Eu
2+
; however, the comprehensive results confirmed the co-existence of Eu
3+
/Eu
2+
luminescence in both cases. This work shows that varying flux concentrations added during synthesis significantly affect the relative strength of Eu
2+
and Eu
3+
emissions in a manner dependent on the synthesis atmosphere. The emission of Eu
2+
increases with a higher flux concentration in materials synthesised under oxidative and neutral atmospheres independent of the chemical modification. In contrast, for materials obtained under a reductive atmosphere, the changes in the Eu
3+
emission intensity depended on the presence or absence of Al
3+
ions namely the increase of flux increased the Eu
3+
intensity in the case of unmodified materials and decreased in the Al-modified ones. All observed effects were qualitatively explained considering the double role of the flux in the studied system, which besides facilitating the diffusion of chemical species during synthesis acts as a charge compensating agent by creating B′
Si
centres stabilizing Eu
3+
emission.
The reduction of lanthanides (Ln
3+
) incorporated into alkali earth sites in a matrix,
, requires the creation of electron donating defects,
e.g.
, and elimination of charge compensation defects,
e.g.
V′′
Me
, from the vicinity of the
.
Background
Vitamin D has antineoplastic effects, but the synthesis of vitamin D requires ultraviolet radiation, a known risk factor for melanoma.
Objective
To investigate the correlations between ...serum vitamin D levels and risk and prognosis of melanoma.
Methods
A systematic review and meta‐analysis were conducted. Online databases were searched on 31 Oct 2018.
Results
Twenty‐five studies with a total of 11166 patients with melanoma were included. There was no significant difference in serum vitamin D levels between patients with melanoma and controls standardized mean difference (SMD), −0.185; 95% confidence interval (CI), −0.533 to 0.162. However, the prevalence of vitamin D deficiency was significantly higher in patients with melanoma than that in controls (odds ratio, 2.115; 95% CI, 1.151–3.885). In terms of prognosis, serum vitamin D levels were significantly higher in melanoma patients with lower Breslow thickness (≦1 vs. >1 mm: SMD, 0.243; 95% CI, 0.160–0.327). Moreover, melanoma patients with lower vitamin D levels had a significantly higher mortality rate (hazard ratio, 1.558; 95% CI, 1.258–1.931).
Conclusions
Vitamin D deficiency is associated with higher Breslow thickness and mortality in melanoma patients.
Summary
Background
Aspirin increases the risk of gastrointestinal bleeding.
Aim
To investigate the risk of lower gastrointestinal bleeding (LGIB) in aspirin users.
Methods
Low‐dose (75‐325 mg daily) ...aspirin users and controls matched by age, gender and enrollment time in a 1:5 ratio were selected from 1 million randomly sampled subjects in the National Health Insurance Research Database of Taiwan. Cox proportional hazard regression models were developed to evaluate the predictors of LGIB with adjustments for age, gender, comorbidities including coronary artery disease, ischaemic stroke, diabetes, hypertension, chronic kidney disease, liver cirrhosis, chronic obstructive pulmonary disease, dyslipidemia, uncomplicated peptic ulcer disease, history of peptic ulcer bleeding, and concomitant use of clopidogrel, ticlopidine, warfarin, nonsteroidal anti‐inflammatory drugs (NSAIDs), cyclooxygenase‐2 inhibitors, steroids, proton pump inhibitors (PPIs), histamine‐2 receptor antagonists (H2RAs), nitrates, alendronate, selective serotonin reuptake inhibitors (SSRIs) and calcium channel blockers.
Results
A total of 53 805 aspirin users and 269 025 controls were included. Aspirin group had a higher incidence of LGIB within 1 year than control group (0.20% vs 0.06%, P<.0001). Aspirin (hazard ratio HR: 2.75, 95% confidence interval CI: 2.06‐3.65), NSAIDs (HR: 8.61, 95% CI: 3.28‐22.58), steroids (HR: 10.50, 95% CI: 1.98‐55.57), SSRIs (HR: 11.71, 95% CI: 1.40‐97.94), PPIs (HR: 8.47, 95% CI: 2.26‐31.71), and H2RAs (HR: 10.83, 95% CI: 2.98‐39.33) were significantly associated with LGIB.
Conclusions
The risk of LGIB was higher in low‐dose aspirin users than in aspirin nonusers in this nationwide cohort. Low‐dose aspirin, NSAIDs, steroids, SSRIs, PPIs and H2RAs were independent risk factors for LGIB.
Linked ContentThis article is linked to Taha and Chen et al papers. To view these articles visit https://doi.org/10.1111/apt.14114 and https://doi.org/10.1111/apt.14138.
Summary
Background
Few studies have examined the association between psoriasis and glomerulonephritis (GN) as well as chronic kidney disease (CKD).
Objectives
To determine the risk of CKD in patients ...with psoriasis and evaluate the impact of the severity of psoriasis, comorbidities and concomitant drugs on the risk of GN and CKD in patients with psoriasis.
Methods
We identified 4344 patients with psoriasis for the study cohort and randomly selected 13 032 subjects as a control cohort. Each subject was individually followed for up for 5 years to identify those who subsequently developed GN and CKD.
Results
After adjustment for traditional CKD risk factors, psoriasis was found to be independently associated with an increased risk of CKD during the follow‐up period hazard ratio (HR) 1·28; 95% confidence interval (CI) 1·14–1·44. The increased incidence of GN in patients with psoriasis (HR 1·50, 95% CI 1·24–1·81) may contribute to the positive association between psoriasis and CKD. Patients with mild and severe psoriasis had an increased risk of CKD and GN compared with the control cohort; the risk increased with severity. Patients with psoriasis and arthritis exhibited a higher risk of CKD than patients without arthritis (HR 1·62 vs. 1·26). Among drugs, nonsteroidal anti‐inflammatory drugs (NSAIDs) have the strongest association with CKD in patients with psoriasis (adjusted odds ratio 1·69, 95% CI 1·14–2·49).
Conclusions
Psoriasis was associated with a higher risk of developing CKD and GN. High severity, psoriatic arthritis involvement and concomitant NSAIDs use further increased the risk of CKD in patients with psoriasis.
What's already known about this topic?
There is an increased risk of multiple comorbidities in patients with psoriasis.
What does this study add?
Both mild and severe psoriasis presented an increased risk of chronic kidney disease (CKD) and glomerulonephritis, independent of traditional risk factors for CKD.
The development of CKD in patients with psoriasis was multifaceted. High severity, psoriatic arthritis involvement and concomitant nonsteroidal anti‐inflammatory drug use further increased the risk of CKD in patients with psoriasis.
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