Adherence to biologics in patients with psoriasis

Introduction: Psoriasis has a profound impact on patients’ lives, but adherence to topical treatment of psoriasis is still poor. Biologic treatment has revolutionized the management of psoriasis, but adherence to treatment may still be a barrier for some patients.

Areas covered: A PubMed search was conducted in August 2017 using the terms ‘biologics psoriasis adherence’ and ‘biologics psoriasis survival.’ Additional articles were obtained by perusing the references of articles identified in the original PubMed search. Articles that did not specifically mention ‘survival,’ ‘adherence,’ or ‘persistence’ were not included. We review the measures used to assess adherence to biologics for psoriasis and the factors impacting drug survival and adherence rates for biologics in psoriasis.

Expert commentary: Drug survival and adherence rates for biologic therapy is less than ideal but may be modifiable. Means that may improve adherence and drug survival include individualized choice of biologic and providing additional support for patients who are at increased risk for prematurely stopping treatment.     

Systematic overview of neuroanatomical differences in ADHD: Definitive evidence

Objectives: This article seeks to identify neuroanatomical differences in ADHD through an overview of systematic reviews that report encephalic differences compared to a control group in volume, area, activation likelihood or chemical composition.

Methods: We conducted a systematic search using Cochrane guidelines and PRISMA criteria in PubMed, Scopus, Web of Science, Cochrane Database of Systematic Reviews and Database of Abstracts of Reviews of Effects.

Results: Results revealed broad encephalic involvement that includes a functional frontal and cingulate hypoactivation and structural differences in corpus callosum, cerebellum and basal nuclei.

Conclusions: ADHD symptoms might be due to a multi-network unbalanced functioning hypothesis.     

The effect of preexisting anti-carrier immunity on subsequent responses to CRM197 or Qb-VLP conjugate vaccines

Context: Certain antigens, such as haptens (small molecules), short peptides, and carbohydrates (e.g. bacterial polysaccharides) are non- or poorly immunogenic unless conjugated to a carrier molecule that provides a structural scaffold for antigen presentation as well as T cell help required for B-cell activation and maturation. However, the carriers themselves are immunogenic and resulting carrier-specific immune responses may impact the immunogenicity of other conjugate vaccines using the same carrier that are administered subsequently.

Objective: Herein, using two different carriers (cross-reactive material 197, CRM and Qb-VLP), we examined in mice the impact that preexisting anti-carrier antibodies (Ab) had on subsequent immune responses to conjugates with either the same or a different carrier.

Method: For this purpose, we used two nicotine hapten conjugates (NIC7-CRM or NIC-Qb), two IgE peptide conjugates (Y-CRM or Y-Qb), and a pneumococcal polysaccharide conjugate (Prevnar 13^®).

Results: Prior exposure to CRM or Qb-VLP significantly reduced subsequent responses to the conjugated antigen having the homologous carrier, with the exception of Prevnar 13® where anti-polysaccharide responses were similar to those in animals without preexisting anti-carrier Ab.

Conclusion: Collectively, the data suggest that the relative sizes of the antigen and carrier, as well as the conjugation density for a given conjugate impact the extent of anti-carrier suppression. All animals developed anti-carrier responses with repeat vaccination and the differences in Ab titer between groups with and without preexisting anti-carrier responses became less apparent; however, anti-carrier effects were more durable for Ab function.     

Current status and future prospects for biologic treatments of psoriasis

Introduction: Biological agents have transformed psoriasis treatment by selectively targeting immune signaling molecules involved in psoriasis pathogenesis. While biologics offer the most effective treatment of moderate to severe psoriasis, they are not without complications. Some patients treated with biologics have poor clinical responses, form anti-drug antibodies, or develop adverse events. Additionally, there is growing need for head-to-head studies comparing biologic treatment regimens, efficacy, and safety.

Areas covered: Here we review the literature surrounding biologics already in clinical use and those undergoing development and clinical trials. We also investigate the development and approval of small molecules inhibitors and biosimilars used to treat psoriasis.

Expert commentary: As the psoriasis treatment armamentarium continues to expand, it is important to follow the safety profile of these drugs both in clinical trials and in post-marketing registries to ensure their long-term safety. Physicians must be aware of the limitations of existing safety data of a drug and the potential risk for rare adverse events when selecting appropriate treatments and monitoring patient outcomes.     

Psoriatic arthritis: lessons from imaging studies and implications for therapy

Introduction: Modern imaging may aid in the diagnosis, prognosis and monitoring of therapeutic response in psoriatic arthritis (PsA). Detection of osteitis and technical advances like whole body magnetic resonance imaging (MRI) exemplify the value of this technology.

Areas covered: Ultrasound (US) provides a clinic-based tool for evaluating both joint pathologies and extra-articular structures (especially enthesitis) including skin and nail disease. Recent studies have demonstrated subclinical disease in psoriasis without arthritis, as well as in PsA, with implications for diagnosis and treatment classification. Modern imaging can also facilitate decisions on tapering of expensive biologics, though real-world clinical studies are still lacking.

Expert commentary: The increase in novel PsA therapies should increase the utilization of modern imaging, providing both increased validation of imaging biomarkers as well as responsive outcome measures.     

ALK protein expression in pulmonary adenocarcinoma of Tunisian patients

Background. It is now necessary to determine ALK status in order to use targeted therapy. Aim: herein, we assess immunohistochemical profile of ALK protein in a series of Tunisian patients with pulmonary adenocarcinoma.

Materials and Methods. ALK protein expression was studied applying the D5F3 antibody with a fully automated Ventana CDx technique on a series of 19 patients.

Results. Positive ALK expression was found in one case (5.2%) corresponding to a papillary adenocarcinoma which showed a strong granular and homogenous cytoplasmic staining. The patient was a 30-years-old woman.

Conclusion. The frequency of positive ALK expression based on immunohistochemistry in our series was similar to that reported in the world literature.     

A randomized study comparing the pharmacokinetics of the potential biosimilar PF-06438179/GP1111 with Remicade® (infliximab) in healthy subjects (REFLECTIONS B537-01)

Background: To demonstrate pharmacokinetic (PK) similarity of PF-06438179/GP1111, a potential biosimilar to Remicade®, to Remicade® sourced from European Union (infliximab-EU) and United States (infliximab-US), and of infliximab-EU to infliximab-US.

Methods: In this phase I, parallel-group, three-arm trial, healthy adult subjects were randomized to receive a single 10-mg/kg intravenous infusion of PF-06438179/GP1111, infliximab-EU, or infliximab-US. PK, and safety and immunogenicity evaluations were performed over 8 and 12 weeks, respectively. PK similarity was established if the 90% confidence intervals (CIs) of the test-to-reference ratios for PK parameters, C_max, AUC_T, and AUC_inf, were within the 80.00–125.00% pre-specified equivalence window.

Results: Of 151 subjects randomized, 146 received study treatment; 130 were eligible for PK similarity assessment. Serum concentration–time profiles were similar across the three treatments. The 90% CIs for test-to-reference ratios for C_max, AUC_T, and AUC_inf were within 80.00–125.00% for comparison of PF-06438179/GP1111 to infliximab-EU and infliximab-US, and of infliximab-EU to infliximab-US. Similar numbers of subjects across treatment groups experienced adverse events. Anti-drug and neutralizing antibody profiles were largely similar among groups.

Conclusions: This study demonstrated PK similarity of PF-06438179/GP1111 to infliximab-EU and infliximab-US, and of infliximab-EU to infliximab-US. All three products displayed comparable safety and immunogenicity profiles.

Trial registration: CT.gov identifier NCT01844804     

Therapeutic options for cutaneous lupus erythematosus: recent advances and future prospects

Introduction: Treatment and prevention are of critical importance in patients with cutaneous lupus erythematosus (CLE), as the disease can have a devastating effect on patient well-being and quality of life.

Areas Covered: We conducted a selective search of the PubMed database for articles published between December 2010 and November 2015. This review encompasses both non-pharmaceutical (photoprotection, smoking cessation, drug withdrawal, and vitamin D replacement) and pharmaceutical (topicals, antimalarials, immunosuppressives, biologics, etc.) interventions used in the treatment of CLE.

Expert Commentary: Recent work has expanded our understanding of established therapies as well as introduced new treatments for consideration, though existing medications still prove inadequate for a subset of patients. Changes in trial design may help to alleviate this issue.     

CRISPR and personalized Treg therapy: new insights into the treatment of rheumatoid arthritis

Introduction: Rheumatoid arthritis (RA), as one of the most disabling autoimmune diseases, is a common health problem that progressively reduces the life quality of patients. Although various biologics have been introduced for RA, attempts to establish an efficient long-term therapies failed due to the heterogeneity of this disease.

Methods: In the last decade, immunomodulatory approaches such as T cell adoptive therapy have been developed for controlling autoimmunity. Regulatory T cells (Tregs), the major self-tolerance mediator, are crucial for down-regulation of aberrant immune stimulations. Hence, recruiting ex vivo Tregs emerged as a promising therapy for a variety of autoimmune diseases.

Results: The major bottleneck of the Treg adoptive therapy is maintaining the in vivo stability and plasticity of these fascinating cells. Recent progress in genome editing technology clustered regularly interspaced short palindromic repeats (CRISPR) in combination with CRISPR-associated (Cas) 9 system provided a new solution for this bottleneck.

Conclusions: The present paper discusses RA pathogenesis and the potential application of new developments in CRISPR-mediated Treg genome editing in personalized therapy of RA.     

The Orientalisation of North Africa: New hints from the study of autosomal STRs in an Arab population

Background: Recent genomic analyses suggest that the current North African gene pool was mainly influenced by population flow coming from the East that altered the genetic structure of autochthonous Berber populations. Such genetic flow has not been extensively addressed yet using North African populations of Middle-eastern origin as reference.

Aim: To discern the Middle-eastern component in the genetic background of Tunisian Arabs and evaluate the extent of gene flow from the Middle East into North African autochthonous Berber populations.

Subjects and methods: This study has examined 113 Tunisians of well-known Arabian origin from Kairouan region, using 15 autosomal Short Tandem Repeats (STRs) loci.

Results: No deviations from Hardy-Weinberg equilibrium were observed and all loci presented high levels of heterozygosity. Principal coordinate and STRUCTURE analyses were consistent in clustering together North African and Middle Eastern populations, likely reflecting the recent gene flow from the East dating back to the Arab conquest period. This demographic migration and the Arabisation process that submerged the original Berber language and customs seems to have be accompanied by substantial gene flow and genetic admixture.

Conclusion: This study represents an additional step to obtain a comprehensive understanding of the complex demographic history of North African populations.     

Testing times: identifying puberty in an identified skeletal sample

Background: Identifying the onset of puberty in skeletal remains can provide evidence of social changes associated with the onset of adulthood.

Aim: This paper presents the first test of a skeletal method for identifying stages of development associated with the onset of puberty in a skeletal sample of known age and cause of death.

Materials and methods: Skeletal methods for assessing skeletal development associated with changes associated with puberty were recorded in the identified skeletal collection in Coimbra, Portugal. Historical data on the onset of menarche in this country are used to test the method.

Results: As expected, females mature faster than their male counterparts. There is some side asymmetry in development. Menarche was found to have been achieved by an average age of 15.

Conclusions: Asymmetry must be taken into account when dealing with partially preserved skeletons. Age of menarche is consistent, although marginally higher, than the age expected based on historical data for this time and location. Skeletal development in males could not be tested against historical data, due to the lack of counterpart historical data. The ill health known to be present in this prematurely deceased population may have delayed skeletal development and the onset of puberty.     

Update of sarilumb to treat rheumatoid arthritis based on randomized clinical trials: a systematic review

Introduction: Sarilumab is a human monoclonal antibody against Interleukin 6 α (IL-6α) receptor. Compared to tocilizumab, another IL-6 α receptor antibody, sarilumab has a different structure and higher affinity.

Areas covered: In a systematic literature review, we examined all sarilumab randomized clinical trials (RCTs) in rheumatoid arthritis. The 6 reviewed RCTs included patients who were inadequate MTX, DMARD and/or TNFi responders. Sarilumab 150–200 mg every 2 weeks improved RA signs, symptoms, function and decreased radiological progression up to 52 weeks. The most common adverse events were infections and neutropenia, the latter of which will require careful observation in future trials.

Examination of the effect of sero-positivity, disease duration, presence of erosions, use of previous biologic and comparisons to other biologics etc are still needed to complete understanding of this drug’s profile. Long term studies, too, will be needed to assess long term tolerability

Expert commentary: Results support the use of sarilumab to treat RA patients with inadequate response to MTX, other DMARDs and TNFis, although further studies are needed to fully assess its toxicity and understand the specific place of sarilumab in the RA armamentarium.     

Y-Chromosome haplotypes reveal relationships between populations of the Arabian Peninsula,North Africa and South Asia

Background: The United Arab Emirates (UAE) is positioned at the crossroads of human migration out of Africa and through to Asia and Europe.

Aim: To compare the degree of genetic diversity of the Arabian UAE population with populations in other countries from the Middle East, South Asia and North Africa.

Subjects and methods: Twenty-seven Y-STR were analysed in 217 individuals. Y-STR haplotypes from this study were compared to population data stored in YHRD, using MDS and AMOVA.

Results: Two hundred and twelve haplotypes were observed in the 217 individuals studied. Although the reduction in Y-STR loci from 27 to 17 resulted in a decrease in discriminatory power, comparisons of populations were possible. The UAE population clustered closer with other populations of the Middle East. The South Asian and North African populations were separated by Middle Eastern populations in between both clusters.

Conclusion: This is the first study to report the diversity of a population of the Arabian Peninsula using 27 Y-STR. MDS plots show that Middle Eastern populations are positioned in the centre, with African, Asian and European populations around the Arab population cluster. The findings of this study are consistent with this region being at the epicentre of human migration between continents.     

Allergen immunotherapy in allergic rhinitis: current use and future trends

Introduction: Type-1 allergies are among the most chronic common diseases of humans. Allergen immunotherapy (AIT) is the only causative and disease-modifying treatment option besides allergen avoidance. Severe systemic adverse allergic reactions may be induced by every AIT treatment. Different approaches have been used to provide safer AIT preparations to lower or even totally overcome this risk.

Areas covered: A structured literature recherche in Medline and Pubmed under inclusion of national and international guidelines and Cochrane meta-analyses has been performed aiming at reviewing clinical use of such approaches in AIT.

New allergen preparations may include allergoids, recombinant allergens (recA) and modified recombinant allergens (recA) in subcutaneous as well as in mucosal immunotherapies (application e.g. using bronchial, nasal, oral and sublingual application) with sublingual being the established mucosal application route and new ways of application like intralymphatic and epicutaneous immunotherapy.

Expert commentary: Immune-modifying agents like Virus-like particles and CpG-motifs, adjuvants like MPL and aluminum hydroxide are evaluated and found to increase and direct the immunological response toward immunological tolerance.

New forms of allergen extracts can improve safety and efficacy of AIT and may change our way of performing allergen immunotherapy in the future.     

Evaluating mtDNA patterns of genetic isolation using a re-sampling procedure: A case study on Italian populations

Background: A number of studies which have investigated isolation patterns in human populations rely on the analysis of intra- and inter-population genetic statistics of mtDNA polymorphisms. However, this approach makes it difficult to differentiate between the effects of long-term genetic isolation and the random fluctuations of statistics due to reduced sample size.

Aim: To overcome the confounding effect of sample size when detecting signatures of genetic isolation.

Subjects and methods: A re-sampling based procedure was employed to evaluate reduction in intra-population diversity, departure from surrounding genetic background and demographic stationarity in 34 Italian populations subject to isolation factors.

Results: Signatures of genetic isolation were detected for all three statistics in seven populations: Pusteria valley, Sappada, Sauris, Timau settled in the eastern Italian Alps and Cappadocia, Filettino and Vallepietra settled in the Appenines. However, this study was unable to find signals for any of the statistics analysed in 19 populations. Finally, eight populations showing signals of isolation were found for one or two statistics.

Conclusion: The analysis revealed that the use of population genetic statistics combined with re-sampling procedure can help detect signatures of genetic isolation in human populations, even using a single, although highly informative, locus like mtDNA.     

Matrix Metalloproteinase-9 rs17576 Gene Polymorphism and Behçet’s Disease: Is There an Association?

Background: Clinical studies have reported a significant association between matrix metalloproteinases (MMP), particularly (MMP-9), and inflammatory diseases including Behçet’s disease (BD).

Purpose: To study the relationship between MMP-9 rs17576 gene polymorphism and the development of BD, and its relation to disease activity among Egyptian patients.

Methods: A total of 100 BD patients and 100 healthy control volunteers were genotyped for MMP-9 rs17576 polymorphism with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), followed by the confirmation of our results in random subgroups using direct DNA sequencing technique.

Results: The frequency of the GG genotype and G allele was significantly higher in BD patients as compared to the normal controls (p = 0.011, OR 8.61; p = 0.03, OR 1.65, respectively). There was no significant association between the MMP-9 rs17576 polymorphism and the clinical outcomes of BD.

Conclusion: our study suggests a significant association of the MMP-9 rs17576 A/G polymorphism with increased risk of BD development in Egyptian patients.     

Pregnane X Receptor Polymorphisms and Risk of Inflammatory Bowel Disease: A Meta-Analysis

Background: Pregnane X receptor (PXR) gene polymorphisms have been widely studied in terms of the association with inflammatory bowel disease (IBD), with inconsistent results.

Objective: The present meta-analysis was performed to assess the association between PXR gene polymorphisms and the susceptibility of IBD, Crohn’s disease (CD), and ulcerative colitis (UC).

Methods: PubMed, Wanfang, and CNKI databases were searched for eligible studies before November 1, 2016. Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to calculate the various genetic models using either a fixed-effect or a random-effect model. The heterogeneity of the included studies was examined with Cochran Q and I² statistics. Begg’s rank correlation test and Egger’s linear regression test were used to assess the publication bias.

Results: A total of six studies with 4248 cases and 3853 controls were included in this meta-analysis. Three PXR gene polymorphisms were evaluated: rs1523127, rs2276707, and rs6785049. Our analyses of rs1523127, rs2276707, and rs6785049 suggested that PXR gene polymorphism had no obvious influence on the risk of IBD in Caucasians. Subgroup analyses based on disease type showed similar results.

Conclusion: Our meta-analysis revealed that PXR gene polymorphism may not be significantly associated with IBD susceptibility. However, the number of original studies was limited and further studies with large samples are needed to verify the results.

Abbreviations: PXR = pregnane X receptor, IBD = inflammatory bowel disease, CD = Crohn’s disease, UC = ulcerative colitis, ORs = pooled odds ratios, 95% CIs = 95% confidence intervals, NOS = Newcastle–Ottawa scale, HWE = Hardy–Weinberg equilibrium.     

Unusual sleep experiences and dissociation as mediators between sleep quality and proneness to hallucinations in a nonclinical population sample: a preliminary study

Introduction: The purpose of this study was to examine the relationship of sleep quality to proneness to hallucinations and the mediating role of dissociation and unusual sleep experiences in a nonclinical sample.

Methods: One hundred and seventy-seven participants completed a questionnaire on sleep quality, a dissociative experiences scale, an unusual sleep experiences scale and a hallucination proneness scale.

Results: The results showed a significant positive association between quality of sleep and hallucination proneness, dissociation and unusual sleep experiences, and that dissociation and unusual sleep experiences fully mediated between sleep quality and hallucination proneness.

Conclusions: Our study highlights the importance of variables related to sleep quality and unusual sleep experiences and dissociation in understanding hallucinations, and the importance of taking these variables into consideration in designing intervention directed at reducing distress caused by hallucinations.