Safety of selective IL‐23p19 inhibitors for the treatment of psoriasis

Psoriasis is a chronic disease that requires long‐term treatment. Consequently, understanding the safety and tolerability of any potential treatment over time is critical to effective prescribing. The biologic agents currently available for the treatment of psoriasis target a number of different inflammatory cytokines involved in psoriasis disease pathogenesis. The monoclonal antibodies tildrakizumab, guselkumab and risankizumab target the p19 subunit that is specific to interleukin (IL)‐23. This article reviews published data on the safety of these IL‐23p19 inhibitors in patients with psoriasis compared with other currently available biologic therapies. Data from randomized, placebo‐ and active‐controlled phase 3 clinical trials show tildrakizumab, guselkumab and risankizumab to have a favourable risk–benefit profile in patients with moderate to severe psoriasis. No significant safety concerns have been observed for any of these IL‐23p19 inhibitors in the data published to date. The most commonly reported adverse events (AEs) associated with these agents in phase 3 studies were upper respiratory tract infections. No increase was seen in rates of serious infections, malignancies or major adverse cardiovascular events, with no signals suggestive of an elevated risk of opportunistic infections, active tuberculosis or reactivation of latent tuberculosis infection, mucocutaneous Candida infections, triggering or worsening of inflammatory bowel disease, demyelinating disorders or suicidal ideation. Selectively targeting IL‐23p19 may help avoid AEs that have been associated with biologic agents with other mechanisms of action. Data from long‐term extension studies and patient registries will further establish the safety profile of IL‐23p19 inhibitors for the treatment of moderate to severe psoriasis in routine practice.     

Alcoholic-like drinking in simian social groups

We have developed two protocols for inducing sustained, high-dose, alcohol-reinforced, oral alcohol drinking among some members of Macaca nemestrina social groups. Both protocols initially co-present alcohol and the entire daily food supply in a 2-h daily drinking session, with a later return to continuous availability of food. One protocol presents unflavored aqueous alcohol to partially food-deprived subjects; the other compares the drinking of flavored alcohol solutions with the drinking of equally palatable isocaloric non-alcohol solutions when monkeys are not deprived of food. Daily high-dose drinking developed in both protocols, with biomedical changes similar to those of early human alcoholism. Daily drinking to blood alcohol concentrations above 100 mg/dl was sustained in some animals after return to baseline food conditions, and this may have been related to social rank within the groups. Alcohol reinforced drinking of the flavored solutions. Although food deprivation initially produced heavier drinking, drinking with the two protocols was equivalent after return to baseline feeding conditions. These procedures open new opportunities for examining combined social and genetic influences on alcoholic-like drinking.     

Overview of contemporary families.

Perceptions and definitions of the term family have always been varied and complex. Hence, an overview of contemporary families is presented here from several perspectives. First, families as they have been perceived by nursing and social science theorists are reviewed. Demographic changes in the family over the last two decades are then presented, followed by an examination of issues faced by families as they change over time. Finally, families as they exist within varying cultural and social contexts are discussed. Emphasis is placed on the need for health care providers to be flexible in defining and working with individual patients and their families.     

Peripheral mononuclear leucocyte beta adrenoceptors and non-specific bronchial responsiveness to methacholine in young and elderly normal subjects and asthmatic patients.

BACKGROUND--As beta adrenoceptor dysfunction occurs in both the normal elderly subject and in young asthmatic patients, the hypothesis was examined that age related beta adrenoceptor changes are important in the pathogenesis of late onset asthma in old age. METHODS--Subjects were non-smokers who comprised 17 young normal subjects of mean (SE) age 29.4 (1.3) years, 17 elderly normal subjects of 67.2 (1.3) years, seven young asthmatic patients of 31.0 (2.8) years, and 17 elderly asthmatic patients of 68.5 (1.4) years. All asthmatic patients withheld inhalers for 12 hours and oral treatment for 24 hours before each study day. Subjects underwent an inhaled methacholine challenge (Newcastle dosimeter method) on two nonconsecutive days. The slope of the flow at 50% of the vital capacity (FEF50) dose-response curve was derived from the percentage fall in FEE50 divided by methacholine dose (sFEF50). Beta-adrenoceptor density (Bmax) and affinity (%KH) were determined with (125I)iodocyanopindolol as the radioligand in membranes prepared from mononuclear leucocytes. RESULTS--Log sFEF50 was shown to be reproducible (repeatability coefficient 0.41) on the two study days and was inversely related to %KH but not to Bmax. Multiple regression analysis (all 58 subjects, overall R2 = 0.57) revealed an inverse relation between log sFEF50 and %KH, and between log sFEF50 and Bmax. The inverse relation between log sFEF50 and %KH was preserved whereas that between log sFEF50 and Bmax was lost when young asthmatic subjects or when all asthmatic subjects were excluded from multiple regression analysis. CONCLUSIONS--The beta adrenoceptor dysfunction observed in late onset asthma may be similar to that seen during ageing. Thus late onset asthma may represent the extreme of a spectrum of age associated beta adrenoceptor dysfunction.     

Antisocial personality disorder, HIV risk behavior and retention in methadone maintenance therapy

In a sample of 55 consecutive methadone maintenance admissions to our clinic, 42% were diagnosed with antisocial personality disorder (ASPD) using the National Institute of Mental Health Diagnostic Interview Schedule NIMH DIS. Individuals with ASPD exhibited greater risk for HIV infection as defined by more sexual contacts, needle use and equipment sharing. Data at 1 year follow-up were obtained on this group of patients. The objective was to compare the ASPD and non-ASPD groups with regards to demographics, drug abuse history, outcome and retention in treatment. There were no significant differences between the groups on any demographic or treatment outcome variables. Survival analysis indicated that there were no group differences in treatment retention. In conclusion, although there were no differences in treatment outcome between ASPD and non-ASPD groups it is possible that ASPD patients who drop out of treatment will be at higher risk for contracting and spreading HIV within the IV drug using population. These data also suggest that in this population the diagnosis of ASPD using primarily behavioral traits as measured in the NIMH-DIS-III, has little utility in predicting treatment outcome.     

Human immunodeficiency virus-associated Hodgkin's disease. Clinicopathologic studies of 24 cases and preponderance of mixed cellularity type characterized by the occurrence of fibrohistiocytoid stromal cells

Hodgkin's disease (HD) was diagnosed in 24 patients who were either seropositive for human immunodeficiency virus (HIV) (21) or members of a high-risk group (three), but had not developed acquired immune deficiency syndrome (AIDS). Clinical presentation of the disease was characterized by constitutional symptoms in all, especially fever (23/24) and disseminated disease (22/24) at diagnosis. Mediastinal adenopathy was rare. Bone marrow involvement was particularly frequent (12/24), and a positive bone marrow biopsy preceded lymph node biopsy in 5 of the 12. Histopathologic features of these tumors included an increased number of nonlymphoid stromal cells, i.e., histiocytic and/or fibroblastoid. In some tumors these fibrohistiocytoid stromal cells were arranged in bundles, but distinct nodule with birefringent collagen band formation was not observed. Twenty-two patients were treated, most with combination chemotherapy; one was untreated; one, unknown. Sixteen, including the one untreated, died with disease at 3 to 25 months; one died of an unrelated cause; four were alive at 3 to 24 months; three were lost to follow-up. Frequent bone marrow involvement at presentation suggests the usefulness of the bone marrow biopsy for diagnosis in subjects at risk, especially when they present with spiking fever of unknown origin. Contrary to most previous series, virtually all of our cases were of mixed cellularity type, characterized by increased fibrohistiocytoid stromal cells in place of depleting lymphocytes. The classic nodular sclerosing feature with birefringent collagen band formation was not observed. In conclusion, HIV-associated HD was characterized by advanced stage with fever at presentation, preponderance of mixed cellularity histologic type with increased fibrohistiocytoid stromal cells, and poor outcome. Hodgkin's disease in AIDS patients presents an intriguing biological model to study the role of stromal histiocytes in immunodeficient patients.