Guselkumab, a Novel Monoclonal Antibody Inhibitor of the p19 Subunit of IL-23, for Psoriatic Arthritis and Plaque Psoriasis: A Review of Its Mechanism, Use, and Clinical Effectiveness.

Psoriatic arthritis and plaque psoriasis are autoimmune conditions affecting multiple organs, including the skin. The pathophysiology and etiology of these conditions are not fully understood; however, numerous factors are believed to play a critical role, including genetics and environmental risk factors. Furthermore, research suggests the IL-23/IL-17 pathway partially mediates these diseases. Once the IL-23 receptor is bound and activated, two subunits, p19, and p40, act through different signaling pathways. Ultimately, inflammation is produced through the effector molecule, IL-17, other cytokines, and tumor necrosis factor (TNF). Traditionally, these chronic conditions have been treated with TNF-α inhibitors and methotrexate, a dihydrofolate reductase inhibitor. Although successful in inhibiting the immune system, these drugs can have many adverse effects due to their broad targets. In recent years, more targeted therapy has become popular. Guselkumab is a monoclonal antibody that inhibits the p19 subunit of IL-23. It has been FDA-approved to treat both plaque psoriasis and psoriatic arthritis. Clinical trials showing guselkumab's efficacy have been promising, even showing improvement in symptoms of plaque psoriasis patients resistant to adalimumab, a TNF-α inhibitor. Guselkumab has also been shown to be well tolerated with a similar safety profile as other biologics inhibiting the immune system. In addition to its efficacy in treating plaque psoriasis and psoriatic arthritis, the mechanism of action offers a targeted approach that may minimize the broad immunosuppressive effects often associated with traditional therapies, providing a potential advantage in the long-term management of these autoimmune conditions.

Erenumab for headaches in idiopathic intracranial hypertension: A prospective open-label evaluation.

OBJECTIVE: To determine the effectiveness of erenumab in treating headaches in idiopathic intracranial hypertension (IIH) in whom papilledema had resolved. BACKGROUND: Disability in IIH is predominantly driven by debilitating headaches with no evidence for the use of preventative therapies. Headache therapy in IIH is an urgent unmet need. METHODS: A prospective, open-label study in the United Kingdom was conducted. Adult females with confirmed diagnosis of IIH now in ocular remission (papilledema resolved) with chronic headaches (≥15 days a month) and failure of ≥3 preventative medications received erenumab 4-weekly (assessments were 3-monthly). The primary end point was change in monthly moderate/severe headache days (MmsHD) from baseline (30-day pretreatment period) compared to 12 months. RESULTS: Fifty-five patients, mean (SD) age 35.3 (9) years and mean duration of headaches 10.4 (8.4) years with 3.7 (0.9) preventative treatment failures, were enrolled. Mean baseline MmsHD was 16.1 (4.7) and total monthly headache days (MHD) was (29) 2.3. MmsHD reduced substantially at 12 months by mean (SD) [95% CI] 10.8 (4.0) [9.5, 11.9], p < 0.001 and MHD reduced by 13.0 (9.5) [10.2, 15.7], p < 0.001. Crystal clear days (days without any head pain) increased by 13.1 (9.5) [9.6, 15.3], p < 0.001, headache severity (scale 0-10) fell by 1.3 (1.7) [0.9, 1.9], p < 0.001, and monthly analgesic days reduced by 4.3 (9.2) [1.6, 6.9], p = 0.002. All these measures had improved significantly by 3 months, with a consistent significant response to 12 months. Headache impact test-6 score and quality of life Short Form-36 Health Survey significantly improved at 12 months. Sensitivity analysis revealed similar results for patients with and without a prior migraine diagnosis (28/55 (52%) patients) or those with or without medication overuse (27/55 (48%) patients). CONCLUSIONS: This study provides evidence for the effectiveness of erenumab to treat headaches in IIH patients with resolution of papilledema. It provides mechanistic insights suggesting that calcitonin gene-related peptide is likely a modulator driving headache and a useful therapeutic target.

Calcitonin gene related peptide monoclonal antibody treats headache in patients with active idiopathic intracranial hypertension.

BACKGROUND: Headache is the dominant factor for quality of life related disability in idiopathic intracranial hypertension (IIH) and typically has migraine-like characteristics. There are currently no evidence-based therapeutics for headache in IIH, and consequently this is an important unmet clinical need. CASE SERIES: We report a series of seven patients in whom headaches were the presenting feature of IIH and the headaches had migraine-like characteristics, as is typical in many IIH patients. Papilloedema settled (ocular remission) but headaches continued. These headaches responded markedly to erenumab, a monoclonal antibody targeted against the calcitonin gene related peptide (CGRP) receptor. Of note, there was a recurrence of raised ICP, as evidenced by a return of the papilloedema, however the headaches did not recur whilst treated with erenumab. CONCLUSIONS: Those with prior IIH who have their headaches successfully treated with CGRP therapy, should remain under close ocular surveillance (particularly when weight gain is evident) as papilloedema can re-occur in the absence of headache. These cases may suggest that CGRP could be a mechanistic driver for headache in patients with active IIH.

Fe-S cluster biogenesis by the bacterial Suf pathway.

Biogenesis of iron-sulfur (FeS) clusters in an essential process in living organisms due to the critical role of FeS cluster proteins in myriad cell functions. During biogenesis of FeS clusters, multi-protein complexes are used to drive the mobilization and protection of reactive sulfur and iron intermediates, regulate assembly of various FeS clusters on an ATPase-dependent, multi-protein scaffold, and target nascent clusters to their downstream protein targets. The evolutionarily ancient sulfur formation (Suf) pathway for FeS cluster assembly is found in bacteria and archaea. In Escherichia coli, the Suf pathway functions as an emergency pathway under conditions of iron limitation or oxidative stress. In other pathogenic bacteria, such as Mycobacterium tuberculosis and Enterococcus faecalis, the Suf pathway is the sole source for FeS clusters and therefore is a potential target for the development of novel antibacterial compounds. Here we summarize the considerable progress that has been made in characterizing the first step of mobilization and protection of reactive sulfur carried out by the SufS-SufE or SufS-SufU complex, FeS cluster assembly on SufBC2D scaffold complexes, and the downstream trafficking of nascent FeS clusters to A-type carrier (ATC) proteins. Cell Biology of Metals III edited by Roland Lill and Mick Petris.

No compelling evidence that more physically attractive young adult women have higher estradiol or progesterone.

Putative associations between sex hormones and attractive physical characteristics in women are central to many theories of human physical attractiveness and mate choice. Although such theories have become very influential, evidence that physically attractive and unattractive women have different hormonal profiles is equivocal. Consequently, we investigated hypothesized relationships between salivary estradiol and progesterone and two aspects of women's physical attractiveness that are commonly assumed to be correlated with levels of these hormones: facial attractiveness (N = 249) and waist-to-hip ratio (N = 247). Our analyses revealed no compelling evidence that women with more attractive faces or lower (i.e., more attractive) waist-to-hip ratios had higher levels of estradiol or progesterone. One analysis did suggest that women with more attractive waist-to-hip ratios had significantly higher progesterone, but the relationship was weak and the relationship not significant in other analyses. These results do not support the influential hypothesis that between-women differences in physical attractiveness are related to estradiol and/or progesterone.

General sexual desire, but not desire for uncommitted sexual relationships, tracks changes in women's hormonal status.

Several recent longitudinal studies have investigated the hormonal correlates of both young adult women's general sexual desire and, more specifically, their desire for uncommitted sexual relationships. Findings across these studies have been mixed, potentially because each study tested only small samples of women (Ns = 43, 33, and 14). Here we report results from a much larger (N = 375) longitudinal study of hormonal correlates of young adult women's general sexual desire and their desire for uncommitted sexual relationships. Our analyses suggest that within-woman changes in general sexual desire are negatively related to progesterone, but are not related to testosterone or cortisol. We observed some positive relationships for estradiol, but these were generally only significant for solitary sexual desire. By contrast with our results for general sexual desire, analyses showed no evidence that changes in women's desire for uncommitted sexual relationships are related to their hormonal status. Together, these results suggest that changes in hormonal status contribute to changes in women's general sexual desire, but do not influence women's desire for uncommitted sexual relationships.

A longitudinal analysis of women's salivary testosterone and intrasexual competitiveness.

Research on within-subject changes in women's intrasexual competitiveness has generally focused on possible relationships between women's intrasexual competitiveness and estimates of their fertility. While this approach is useful for testing hypotheses about the adaptive function of changes in women's intrasexual competitiveness, it offers little insight into the proximate mechanisms through which such changes might occur. To investigate this issue, we carried out a longitudinal study of the hormonal correlates of changes in intrasexual competitiveness in a large sample of heterosexual women (N=136). Each woman provided saliva samples and completed an intrasexual competitiveness questionnaire in five weekly test sessions. Multilevel modeling of these data revealed a significant, positive within-subject effect of testosterone on intrasexual competitiveness, indicating that women reported greater intrasexual competitiveness when testosterone was high. By contrast, there were no significant effects of estradiol, progesterone, estradiol-to-progesterone ratio, or cortisol and no significant effects of any hormones on reported relationship jealousy. This is the first study to demonstrate correlated changes in measured testosterone levels and women's reported intrasexual competitiveness, implicating testosterone in the regulation of women's intrasexual competitiveness.

Facial coloration tracks changes in women's estradiol.

Red facial coloration is an important social cue in many primate species, including humans. In such species, the vasodilatory effects of estradiol may cause red facial coloration to change systematically during females' ovarian cycle. Although increased red facial coloration during estrus has been observed in female mandrills (Mandrillus sphinx) and rhesus macaques (Macaca mulatta), evidence linking primate facial color changes directly to changes in measured estradiol is lacking. Addressing this issue, we used a longitudinal design to demonstrate that red facial coloration tracks within-subject changes in women's estradiol, but not within-subject changes in women's progesterone or estradiol-to-progesterone ratio. Moreover, the relationship between estradiol and facial redness was observed in two independent samples of women (N = 50 and N = 65). Our results suggest that changes in facial coloration may provide cues of women's fertility and present the first evidence for a direct link between estradiol and female facial redness in a primate species.

The reward value of infant facial cuteness tracks within-subject changes in women's salivary testosterone.

"Baby schema" refers to infant characteristics, such as facial cues, that positively influence cuteness perceptions and trigger caregiving and protective behaviors in adults. Current models of hormonal regulation of parenting behaviors address how hormones may modulate protective behaviors and nurturance, but not how hormones may modulate responses to infant cuteness. To explore this issue, we investigated possible relationships between the reward value of infant facial cuteness and within-woman changes in testosterone, estradiol, and progesterone levels. Multilevel modeling of these data showed that infant cuteness was more rewarding when women's salivary testosterone levels were high. Moreover, this within-woman effect of testosterone was independent of the possible effects of estradiol and progesterone and was not simply a consequence of changes in women's cuteness perceptions. These results suggest that testosterone may modulate differential responses to infant facial cuteness, potentially revealing a new route through which testosterone shapes selective allocation of parental resources.

Women's hormone levels modulate the motivational salience of facial attractiveness and sexual dimorphism.

The physical attractiveness of faces is positively correlated with both behavioral and neural measures of their motivational salience. Although previous work suggests that hormone levels modulate women's perceptions of others' facial attractiveness, studies have not yet investigated whether hormone levels also modulate the motivational salience of facial characteristics. To address this issue, we investigated the relationships between within-subject changes in women's salivary hormone levels (estradiol, progesterone, testosterone, and estradiol-to-progesterone ratio) and within-subject changes in the motivational salience of attractiveness and sexual dimorphism in male and female faces. The motivational salience of physically attractive faces in general and feminine female faces, but not masculine male faces, was greater in test sessions where women had high testosterone levels. Additionally, the reward value of sexually dimorphic faces in general and attractive female faces, but not attractive male faces, was greater in test sessions where women had high estradiol-to-progesterone ratios. These results provide the first evidence that the motivational salience of facial attractiveness and sexual dimorphism is modulated by within-woman changes in hormone levels.

Changes in salivary estradiol predict changes in women's preferences for vocal masculinity.

Although many studies have reported that women's preferences for masculine physical characteristics in men change systematically during the menstrual cycle, the hormonal mechanisms underpinning these changes are currently poorly understood. Previous studies investigating the relationships between measured hormone levels and women's masculinity preferences tested only judgments of men's facial attractiveness. Results of these studies suggested that preferences for masculine characteristics in men's faces were related to either women's estradiol or testosterone levels. To investigate the hormonal correlates of within-woman variation in masculinity preferences further, here we measured 62 women's salivary estradiol, progesterone, and testosterone levels and their preferences for masculine characteristics in men's voices in five weekly test sessions. Multilevel modeling of these data showed that changes in salivary estradiol were the best predictor of changes in women's preferences for vocal masculinity. These results complement other recent research implicating estradiol in women's mate preferences, attention to courtship signals, sexual motivation, and sexual strategies, and are the first to link women's voice preferences directly to measured hormone levels.