Abigail Cline

Current status and future prospects for biologic treatments of psoriasis.

ABSTRACT 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.

Advances in Psoriasis

Abstract Psoriasis treatments range from topical treatments and phototherapy to oral systemic medications and injections. Despite good control of the disease when applying appropriate treatments (according to disease severity, insurance parameters, patient preference, and patients’ ability to adhere), continued advancements will allow even better symptomatic control, reduced adverse effects, and patient satisfaction. This review aims to assess traditional and new psoriasis treatments and how to apply them in clinical practice. A literature review on psoriasis treatments and clinical applications was performed using PubMed. Mild-to-moderate psoriasis treatments include topicals, localized phototherapy, and newer therapies combining two types of topicals, phototherapy with topicals, and easy-to-use foam and spray vehicles. Moderate-to-severe psoriasis therapies include monotherapy or various combinations of generalized phototherapy, oral treatments, and biologic agents, with new oral and biologic agents on the horizon. Dermatologists and primary care providers share roles in screening for associated comorbidities (including cardiovascular disorders, chronic kidney disease, Crohn disease, dyslipidemia, diabetes mellitus/insulin resistance, depression, metabolic syndrome, obesity, and psoriatic arthritis), managing patients’ treatments, and reevaluating treatment needs as new therapies are approved. Continued advancements in psoriasis treatment and improvement in coordinated care will allow better overall care of patients with psoriasis.

Advances in treating psoriasis in the elderly with small molecule inhibitors

ABSTRACT Introduction: Due to the chronic nature of psoriasis, the population of elderly psoriasis patients is increasing. However, many elderly psoriatic patients are not adequately treated because management is challenging as a result of comorbidities, polypharmacy, and progressive impairment of organ systems. Physicians may hesitate to use systemic or biologic agents in elderly psoriasis patients because of an increased risk of adverse events in this patient population. Small molecule medications are emerging as promising options for elderly patients with psoriasis and other inflammatory conditions. Areas covered: Here we review the efficacy, safety and tolerability of small molecule inhibitors apremilast, tofacitinib, ruxolitinib, baricitinib, and peficitinib in the treatment of psoriasis, with focus on their use in the elderly population. Expert opinion: Although small molecule inhibitors demonstrate efficacy in elderly patients with psoriasis, they will require larger head-to-head studies and post-marketing registries to evaluate their effectiveness and safety in specific patient populations. Apremilast, ruxolitinib, and peficitinib are effective agents with favorable side effect profiles; however, physicians should exercise caution when prescribing tofacitinib or baricitinib in elderly populations due to adverse events. The high cost of these drugs in the U.S. is likely to limit their use.

Targeting p19 as a treatment option for psoriasis: an evidence-based review of guselkumab

Further understanding of psoriasis pathogenesis has led to the development of effective biologic medications. Guselkumab (GUS) is a subcutaneously administered monoclonal antibody that targets the p19 cytokine subunit in IL-23 and IL-39 and is US Food and Drug Administration (FDA) approved for the treatment of moderate-to-severe psoriasis in adult patients. This review evaluates the pharmacology, safety and efficacy of GUS in patients with psoriasis. We performed a literature review by searching online databases including PubMed and Google Scholar. In clinical trials, GUS improved diseases including psoriatic arthritis (PsA) and specific areas of disease (scalp, feet, hands and fingernails). In the Phase III trials VOYAGE 1 and 2, more GUS than adalimumab (ADM) patients experienced a ≥90% reduction in Psoriasis Area and Severity Index (PASI) score (PASI90) (VOYAGE 1: 80.2% vs 53.0%; VOYAGE 2: 75.2% vs 54.8%; P<0.001 for both) and Investigator Global Assessment score of 0 or 1 (VOYAGE 1: 84.2% vs 61.7%; VOAYGE 2: 83.5% vs 64.9%; P<0.001 for both) at Week 24. GUS was also successful in treating patients unresponsive to ADM and ustekinumab in the VOYAGE 2 and NAVIGATE trials, respectively. While long-term data are necessary, GUS appears to have a favorable side effect profile with most common adverse effects including nasopharyngitis and upper respiratory tract infections. GUS is a well-tolerated and effective medication for patients with psoriasis. Continued study of GUS and the p19 subunit will help to determine GUS’s ultimate place in therapy.

Future Therapeutics in Psoriasis

In recent years, investigations into psoriasis pathophysiology have expanded the development of immunomodulatory and biological molecules. These advancements have transformed treatment regimens for psoriasis by selectively targeting immune signaling molecules. The aim of this chapter is to review the clinical and research data surrounding these emerging treatments, ranging from those undergoing development to those already in clinical trials. Therapies are organized by method of administration (topicals, orals, and injectables) and then phase of clinical trial. Many of these promising medications are small-molecule inhibitors and biologics, while some draw from traditional mechanisms of actions like steroids and vitamin analogs. It is too soon to know how effective these future agents will be and where they will fit into treatment algorithms. It will remain critical for clinicians to be aware of the limitations, important monitoring, and drug safety when selecting these novel treatments. However, even as the psoriasis treatment armamentarium continues to expand, many psoriasis patients may continue to experience recalcitrant disease.

Management of herpes zoster (shingles) during pregnancy

Abstract An infection with the varicella-zoster virus (VZV) causes both varicella and herpes zoster (HZ). Although rare, the development of HZ does occur during pregnancy. Maternal HZ does not result in increased foetal mortality, and the passage of VZV to the foetus rarely occurs. However, HZ does increase maternal morbidity. Upon infection with HZ, patients typically present with a viral prodrome preceding the appearance of the characteristic zoster rash. HZ is usually diagnosed clinically by the zoster rash, but can also be confirmed by a polymerase chain reaction and an enzyme-linked immunosorbent assay. Pregnant women with an uncomplicated HZ should be treated with oral acyclovir. The major complications of HZ are subacute herpetic neuralgia and post-herpetic neuralgia. Other complications include zoster ophthalmicus, disseminated HZ and secondary bacterial infections. Regarding prophylaxis, the varicella and the zoster vaccines are not recommended for pregnant women, and it is important to advise non-immune pregnant women to avoid an exposure to VZV. Although HZ infection has a minimal effect on the foetus, maternal HZ and its complications cause a significant burden. It is important to focus care on the mother with appropriate treatment and management of complications as they develop.

Aryl Hydrocarbon Receptor Activation: From Coal to Dioxin

For more than 2,000 years, topical coal tar has been used to reduce inflammation in atopic dermatitis (AD) and psoriasis. Although its mechanism of action has been poorly understood, current evidence—including elegant knockout studies— points to aryl hydrocarbons as being responsible for coal tar’s therapeutic effect (1). Coal tar contains a wide range of polycyclic aromatic hydrocarbons (PAHs), which activate aryl hydrocarbon receptors (AHRs) (2). AHRs are cytoplasmic transcription factors that translocate to the nucleus upon ligand recognition, where they bind to xenobiotic response elements (XREs) in the DNA (3). AHRs induce CYP450 enzymes that detoxify PAHs in keratinocytes (4). AHRs are widely expressed in skin, where they are involved in developing and maintaining the skin barrier. AHR activation directly enhances epidermal differentiation by restoring epidermal barrier proteins— such as filaggrin, hoernerin, and involucrin— and by blocking the effects of Th2 cytokines, such as the IL-4/ STAT6 signaling pathway (2). AHRs are crucial in regulating the development of lymphoid cells and the induction of regulatory T cells (5,6). These anti-inflammatory effects of AHR activation have been proposed as a mechanism of coal tar therapy (2). The AHR pathway is a promising pharmacological target for developing a tidier alternative to messy coal tar. Tapinarof is a AHR agonist with clinical efficacy for AD and psoriasis patients, reducing erythema, epidermal thickening, and tissue cytokine levels (7,8,9). Tapinarof reduces IL-17A levels, which is a key player in psoriasis. Moreover, tapinarof also demonstrates efficacy in AD, which is largely driven by Th2 cytokines (8). While AHR activation may be driving tapinarof’s efficacy in psoriasis and AD, tapinarof also has antioxidant properties that may derive from Nrf2 pathway activation (9). NrF2 is a leucine zipper protein that regulates antioxidant proteins which protect against oxidative damage triggered by injury and inflammation. AHR/Nrf2 dual activation is thought to drive the efficacy of coal tar and may also play a role in tapinarof’s mechanism of action (2). Tapinarof is moving onto a phase 3 trial for AD after successfully meeting its primary and secondary efficacy endpoints in a large international, phase 2, dose-ranging study. Tapinarof is also scheduled for a phase 3 study for mild-to-moderate plaque psoriasis after a strong showing in a phase 2 study (10). Tapinarof represents a potential new topical therapy that would be able to treat both psoriasis and atopic dermatitis. Therapeutic use of AHR agonists may be controversial because toxic effects of dioxin (one of which is chloracne) are also mediated by AHR activation (11,12). However, AHR activation itself may not lead to toxic effects as several studies report diverse downstream effects by different exogenous and endogenous ligands. Several prescription medications (e.g., leflunomide, prednisolone, omeprazole) also activate AHRs, although AHR activation is not their primary mechanism of action (13). These compounds are not associated with dioxin-related adverse events. Thus, although endogenous ligands, some marketed compounds, and dioxin share AHR as a target, their effects differ (14). Topical tapinarof appears to have a good safety profile, though folliculitis was observed, perhaps echoing concerns about chloracne. For future AHR agonist development, it is crucial to understand alternative AHR signaling mechanisms and distinct downstream biology. The emerging evidence of a more physiological role of AHR and the therapeutic effect of AHR activation suggest that it might be time to consider AHR agonists as a pharmacological target to treat inflammatory diseases.

Comparing leukapheresis protocols for an AML patient with symptomatic leukostasis

Acute myeloid leukemia (AML) is a malignancy characterized by rapid clonal proliferation of myeloid precursors, which can result in hyperleukocytosis. Leukapheresis can be used to rapidly reduce the white blood cell count (WBC). However, the only FDA cleared device for WBC depletion, the COBE Spectra, will no longer be supported by the manufacturer in 2017, and there are few studies comparing different methods of leukapheresis.

The perceived promise of p19 inhibitors

The search for better-targeted treatments for psoriasis has focused on the interleukin (IL)-23/17 pathway, including the two subunits of IL-23, p40 and p19. The p40 subunit is shared with IL-12, while the p19 subunit is present in IL-23 and not in IL-12. Ustekinumab and briakinumab target p40, while tildrakizumab, guselkumab, and risankizumab target p19. Inhibiting psoriasis by blocking IL-23 with a p19 inhibitor seems to be one of the best ways to treat psoriasis. This approach can be highly effective and, as Blauvelt et al. report in this issue of the BJD, is associated with an adverse-event rate lower than that of etanercept. We think – and we tell our patients – that inhibiting this particular target is a ‘natural’ way to treat psoriasis. The genes for p19 and its receptor are tied to the development of psoriasis. In addition, certain p19 alleles are protective against psoriasis and related inflammatory diseases (such as Crohn disease), thus supporting our comment to patients that inhibiting p19 seems to be ‘nature’s way of preventing psoriasis and other diseases caused by an overactive immune system’. Evidence shows that p19 also plays a role as an endogenous activator of endothelial inflammation. Therefore, p19 inhibition may (we stress may) also reduce cardiovascular comorbidity in patients. This is especially important as psoriasis is an independent risk factor for cardiovascular mortality due to vascular inflammation. The apparent safety of p19 inhibition is remarkable (although this will need to be confirmed by critically important, large, long-term, study results from registries of use in clinical practice). Blauvelt et al. found that during 64 weeks of treatment, tildrakizumab was well tolerated. The adverseevent rate with tildrakizumab was not just lower than with etanercept; tildrakizumab’s adverse-event rate was lower than or comparable to the placebo’s adverse-event rate. Just 20 years ago, we would have been thrilled to have such a treatment, something more potent than methotrexate, yet nearly free of detectable adverse side-effects to the liver, the kidney or, as far as we can tell, even to the immune system. But illustrative of how far psoriasis treatment has come, tildrakizumab represents perhaps only a rather pedestrian development. Its efficacy may be on a par with ustekinumab and adalimumab, but not in the same league as anti-IL-17 blockers or even the other anti-p19 drugs, guselkumab and risankizumab. While the p19 inhibitors all demonstrate clinical improvement in Psoriasis Area and Severity Index (PASI) scores, PASI90 was achieved by 75 3% of patients taking risankizumab and 73% of patients taking guselkumab, compared with 52% of patients taking tildrakizumab. Tildrakizumab appears to be another good psoriasis treatment option, but far from a revolutionary step forward in a market already crowded with biologics. The genuine promise of p19 inhibitors is observed in the sustained duration of clinical response seen after even single doses. Complete clearing is becoming a realistic expectation; 56 3% of patients treated with risankizumab sustained a PASI100 response at week 52. The half-life of tildrakizumab and risankizumab is 20–28 days; guselkumab’s half-life is 12– 19 days. The far longer duration of pharmacological action supports a fundamental role for IL-23 in psoriasis pathogenesis.

Validity and Reliability of a Rosacea Self-Assessment Tool

The lack of validated rosacea assessment tools is a hurdle in assessing rosacea severity. This article discusses a valid and reliable rosacea severity self-assessment tool (RSAT) to measure rosacea severity. To determine test-retest validity, participants completed the self-assessment twice. A blinded physician graded the participants disease severity with the Investigator Global Severity (IGS) score. Pearson correlations were used to assess the relationship between the self-assessment measure and the IGS. Test-retest RSAT measurements were correlated. The RSAT represents a valid and reliable tool. This tool may facilitate determination of rosacea severity in survey research studies.