Physio-Cognitive Decline Syndrome as the Phenotype and Treatment Target of Unhealthy Aging.

In this era of unprecedented longevity, healthy aging is an important public health priority. Avoiding or shortening the period of disability or dementia before death is critical to achieving the defining objectives of healthy aging, namely to develop and maintain functional capabilities that enable wellbeing in older age. The first step is to identify people who are at risk and then to implement effective primary interventions. Geriatricians have identified a distinct clinical phenotype of concurrent physical frailty and cognitive impairment, which predicts high risk of incident dementia and disability and is potentially reversible. Differing operational definitions for this phenotype include "cognitive frailty", "motoric cognitive risk syndrome" and the recently proposed "physio-cognitive decline syndrome (PCDS)". PCDS is defined as concurrent mobility impairment no disability (MIND: slow gait or/and weak handgrip) and cognitive impairment no dementia (CIND: ≥1.5 SD below the mean for age-, sex-, and education-matched norms in any cognitive domain but without dementia). By these criteria, PCDS has a prevalence of 10-15% among community-dwelling older persons without dementia or disability, who are at increased risk for incident disability (HR 3.9, 95% CI 3.0-5.1), incident dementia (HR 3.4, 95% CI 2.4-5.0) and all-cause mortality (HR 6.7, 95% CI 1.8-26.1). Moreover, PCDS is associated with characteristic neuroanatomic changes in the cerebellum and hippocampus, and their neurocircuitry, which are distinct from neuroimaging features in normal aging and common dementia syndromes. Basic research and longitudinal clinical studies also implicate a hypothetical muscle-brain axis in the pathoetiology of PCDS. Most important, community-dwelling elders with PCDS who participated in a multidomain intervention had significant improvements in global cognitive function, and especially in the subdomains of naming and concentration. Our proposed operational definition of PCDS successfully identifies an appreciable population of at-risk older people, establishes a distinct phenotype with an apparently unique pathoetiology, and is potentially reversible. We now need further studies to elucidate the pathophysiology of PCDS, to validate neuroimaging features and muscle-secreted microRNA biomarkers, and to evaluate the effectiveness of sustained multidomain interventions.

ABCB1 in dermatology: roles in skin diseases and their treatment.

Adenosine triphosphate-binding cassette subfamily B member 1 (ABCB1), also known as permeability glycoprotein, multidrug-resistant protein 1, or cluster of differentiation 243 (CD243), is a crucial protein for purging foreign substances from cells. The functions of ABCB1 have been investigated extensively for their roles in cancer, stem cells, and drug resistance. Abundant pharmacogenetic studies have been conducted on ABCB1 and its association with treatment responsiveness to various agents, particularly chemotherapeutic and immunomodulatory agents. However, its functions in the skin and implications on dermatotherapeutics are far less reported. In this article, we reviewed the roles of ABCB1 in dermatology. ABCB1 is expressed in the skin and its appendages during drug delivery and transport. It is associated with treatment responsiveness to various agents, including topical steroids, methotrexate, cyclosporine, azathioprine, antihistamines, antifungal agents, colchicine, tacrolimus, ivermectin, tetracycline, retinoid acids, and biologic agents. Moreover, genetic variation in ABCB1 is associated with the pathogenesis of several dermatoses, including psoriasis, atopic dermatitis, melanoma, bullous pemphigoid, Behçet disease, and lichen planus. Further investigation is warranted to elucidate the roles of ABCB1 in dermatology and the possibility of enhancing therapeutic efficacy through ABCB1 manipulation.

Oral disease-modifying antirheumatic drugs and immunosuppressants with antiviral potential, including SARS-CoV-2 infection: a review.

There have been several episodes of viral infection evolving into epidemics in recent decades, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the latest example. Its high infectivity and moderate mortality have resulted in an urgent need to find an effective treatment modality. Although the category of immunosuppressive drugs usually poses a risk of infection due to interference of the immune system, some of them have been found to exert antiviral properties and are already used in daily practice. Recently, hydroxychloroquine and baricitinib have been proposed as potential drugs for SARS-CoV-2. In fact, there are other immunosuppressants known with antiviral activities, including cyclosporine A, hydroxyurea, minocycline, mycophenolic acid, mycophenolate mofetil, leflunomide, tofacitinib, and thalidomide. The inherent antiviral activity could be a treatment choice for patients with coexisting rheumatological disorders and infections. Clinical evidence, their possible mode of actions and spectrum of antiviral activities are included in this review article. LAY SUMMARY: Immunosuppressants often raise the concern of infection risks, especially for patients with underlying immune disorders. However, some disease-modifying antirheumatic drugs (DMARDs) with inherent antiviral activity would be a reasonable choice in the situation of concomitant viral infections and flare up of autoimmune diseases. This review covers DMARDs of treatment potential for SARS-CoV-2 in part I, and antiviral mechanisms plus trial evidence for viruses other than SARS-CoV-2 in part II.

Safety in moderate-to-severe plaque psoriasis patients with latent tuberculosis treated with guselkumab and anti-tuberculosis treatments concomitantly: results from pooled phase 3 VOYAGE 1 & VOYAGE 2 trials.

BACKGROUND: Patients treated with tumour necrosis factor (TNF) inhibitors are at risk of new-onset tuberculosis (TB) or reactivation of latent tuberculosis infection (LTBI). Association between TB/LTBI and interleukin (IL)-23 inhibitors for psoriasis is unclear. Patients with LTBI typically initiate LTBI therapy before receiving biologics. OBJECTIVES: Safety in moderate-to-severe psoriasis patients with LTBI treated with guselkumab (IL-23 inhibitor) and LTBI treatment was evaluated. METHODS: In the VOYAGE 1 & VOYAGE 2 studies, patients screened for LTBI were randomized to guselkumab, placebo, or adalimumab (TNF inhibitor) at baseline. Placebo â†’ guselkumab crossover occurred at week 16 and adalimumab â†’ guselkumab at week 52 (VOYAGE 1), or at week 28 or later (VOYAGE 2). Incidence of active TB, adverse events (AEs), serious AEs (SAEs), and markedly abnormal liver function tests [alanine aminotransferase test (ALT); aspartate aminotransferase test (AST)] were evaluated using pooled data through week 100 in guselkumab-treated patients receiving and not receiving LTBI treatment. RESULTS: At baseline, 130 randomized patients (guselkumab: n = 69; adalimumab: n = 36; placebo: n = 25) tested positive for LTBI and received concomitant LTBI treatments (LTBI+). No active TB was reported among guselkumab-treated patients without LTBI (LTBI-) through week 100. Two cases of active TB occurred in LTBI- patients treated with adalimumab. Through week 16, across all treatment groups, greater proportions of LTBI+ patients reported ALT and AST elevations compared with LTBI- patients. Through week 100, proportions of patients experiencing AEs and SAEs were comparable between LTBI+ and LTBI- patients. CONCLUSIONS: No cases of active TB, including reactivation of LTBI, were reported in patients with or without LTBI treated with guselkumab through up to 2 years. LTBI treatment was effective across all treatment groups in preventing reactivation of LTBI. Long-term treatment with guselkumab was generally well-tolerated through up to 2 years in patients receiving LTBI medications.

Tofacitinib in patients with moderate-to-severe chronic plaque psoriasis: long-term safety and efficacy in an open-label extension study.

BACKGROUND: Tofacitinib is an oral Janus kinase inhibitor. Final safety and efficacy data from an open-label extension study of tofacitinib in psoriasis are reported. OBJECTIVES: To evaluate the long-term safety and durability of efficacy of tofacitinib in adults with moderate-to-severe chronic plaque psoriasis. METHODS: Eligible patients who completed qualifying phase II/III tofacitinib studies received tofacitinib 10 mg twice daily (q12h) until month 3; subsequently, the dose could be adjusted by investigators to either 5 or 10 mg q12h. Adverse events (AEs) are reported up to month 66 and laboratory data up to month 54. Efficacy end points up to month 54 included Physician's Global Assessment of 'clear' or 'almost clear' (PGA response) and 75% improvement in Psoriasis Area and Severity Index (PASI 75). RESULTS: Overall, 2867 patients received tofacitinib, with a median treatment duration of 35·6 months. Adverse events (AEs) and serious AEs were reported in 82·5% and 13·7% of patients, respectively; 13·9% of patients discontinued owing to AEs; and 29 patients died. Incidence rates (patients with event/100 patient-years) were 1·16 for serious infections, 0·67 for malignancies and 0·26 for major adverse cardiovascular events. After initial changes in qualifying studies, most laboratory parameters were generally stable over 54 months. PGA response was achieved by 52-62% of patients and PASI 75 by 56-74% of patients at each study visit through month 54. CONCLUSIONS: In patients with psoriasis, the safety profile of tofacitinib over 66 months was similar to previous reports in phase III studies and efficacy was sustained through 54 months (NCT01163253).

HLA-Cw6 and psoriasis.

Psoriasis is a multifactorial disease with a strong genetic background. HLA-Cw6 is one of the most strongly associated psoriasis susceptibility alleles. It is repeatedly observed to affect disease course, phenotypic features, severity, comorbidities and treatment outcomes. To the best of our knowledge, the roles of HLA-Cw6 in psoriasis have not yet been thoroughly reviewed. The worldwide frequency of the HLA-Cw6 allele varies greatly, with it being generally higher in white people than in Asians. The allele is associated with type I early-onset psoriasis. Stress, obesity and streptococcal pharyngitis are commonly observed in HLA-Cw6-positive patients. Phenotypically, HLA-Cw6 has been found to be associated with guttate psoriasis. In addition, patients carrying the allele are more likely to have arm, leg and trunk involvement, and the Koebner phenomenon. Patients with psoriatic arthritis with HLA-Cw6 more often have early onset and tend to show cutaneous symptoms before musculoskeletal symptoms. HLA-Cw6-positive patients have been shown in several studies to be more responsive to methotrexate and ustekinumab. However, this difference in ustekinumab efficacy was only moderate in a post-hoc analysis of a pivotal phase III study. HLA-Cw6 positivity also tends to be less frequent in high-need patients who fail conventional therapy. Small studies have also investigated the role of HLA-Cw6 in remission of psoriasis during pregnancy, and with the comorbidities of photosensitivity and atherosclerosis. Given the diverse nature of psoriasis pathogenesis, as well as the difference of HLA-Cw6 positivity in different ethnic groups, more studies are needed to confirm the role of HLA-Cw6 in psoriasis.

The role of ß-blockers in dermatological treatment: a review.

Many systemic medications have been used off-label in cutaneous diseases. Use of ß-adrenergic-blocking agents has risen in popularity among dermatologists since the discovery of their efficacy in treating infantile haemangioma. There has also been an increase in the interest of the applications of ß-blockers in other skin disorders. Overall, ß-blockers are effective in treating diseases of vascular origin and promote wound healing. They are relatively safe and inexpensive medications that could be included in the armamentarium against skin diseases.

Efficacy and safety of guselkumab in patients with psoriasis who have an inadequate response to ustekinumab: results of the randomized, double-blind, phase III NAVIGATE trial.

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.

Immunogenicity and safety of concomitant MF59-adjuvanted influenza vaccine and 23-valent pneumococcal polysaccharide vaccine administration in older adults.

BACKGROUND: Concomitant administration of influenza and pneumococcal vaccines facilitates their uptake by older adults; however, data on immunogenicity and safety of concomitant administration of adjuvanted trivalent inactivated influenza vaccine (aIIV3) and 23-valent pneumococcal polysaccharide vaccine (PPSV23) have not been reported. METHODS: Subjects aged ≥65 years (N=224) were randomized 1:1:1:1 to receive MF59-aIIV3 alone, MF59-aIIV3+PPSV23 in contralateral arms, MF59-aIIV3+PPSV23 in the same arm or PPSV23 alone (Clinical Trial Number - NCT02225327). Hemagglutination inhibition assay and multiplex opsonophagocytic killing assay were used to compare immunogenicity after single or concomitant vaccination. RESULTS: All groups met immunogenicity criteria for the influenza vaccine in older adults with similar seroconversion rates and geometric mean fold-increases, irrespective of concomitant vaccinations and injection site. For each pneumococcal serotype, opsonic index (OI) increased markedly after the PPSV23 vaccination, irrespective of the concomitant influenza vaccine. All subjects showed an OI≥8 for serotypes 6B, 18C and 19A post-vaccination, with a suggestion that the ipsilateral concomitant vaccination might be associated with higher OIs for some antigens. Local and systemic adverse events were more common in subjects receiving PPSV23 compared to those receiving aIIV3 alone. CONCLUSIONS: No interference was observed with antibody responses to influenza or pneumococcal antigens when aIIV3 and PPSV23 were administered concomitantly.

Increased risk of glomerulonephritis and chronic kidney disease in relation to the severity of psoriasis, concomitant medication, and comorbidity: a nationwide population-based cohort study.

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.

Cisd2 mediates lifespan: is there an interconnection among Ca²âº homeostasis, autophagy, and lifespan?

CISD2, an evolutionarily conserved novel gene, plays a crucial role in lifespan control and human disease. Mutations in human CISD2 cause type 2 Wolfram syndrome, a rare neurodegenerative and metabolic disorder associated with a shortened lifespan. Significantly, the CISD2 gene is located within a region on human chromosome 4q where a genetic component for human longevity has been mapped through a comparative genome analysis of centenarian siblings. We created Cisd2 knockout (loss-of-function) and transgenic (gain-of-function) mice to study the role of Cisd2 in development and pathophysiology, and demonstrated that Cisd2 expression affects lifespan in mammals. In the Cisd2 knockout mice, Cisd2 deficiency shortens lifespan and drives a panel of premature aging phenotypes. Additionally, an age-dependent decrease of Cisd2 expression has been detected during normal aging in mice. Interestingly, in the Cisd2 transgenic mice, we demonstrated that a persistent level of Cisd2 expression over the different stages of life gives the mice a long-lived phenotype that is linked to an extension in healthy lifespan and a delay in age-associated diseases. At the cellular level, Cisd2 deficiency leads to mitochondrial breakdown and dysfunction accompanied by cell death with autophagic features. Recent studies revealed that Cisd2 may function as an autophagy regulator involved in the Bcl-2 mediated regulation of autophagy. Furthermore, Cisd2 regulates Ca(2+) homeostasis and Ca(2+) has been proposed to have an important regulatory role in autophagy. Finally, it remains to be elucidated if and how the regulation in Ca(2+) homeostasis, autophagy and lifespan are interconnected at the molecular, cellular and organism levels.