Australian consensus: Treatment goals for moderate to severe psoriasis in the era of targeted therapies - Considerations for paediatric patients.

BACKGROUND: Treatment goals have been established in Australia to facilitate the management of adults with moderate to severe psoriasis. The Australasian College of Dermatologists sought to determine if and how these adult treatment goals could be modified to accommodate the needs of paediatric and adolescent patients. METHODS: A modified Delphi approach was used. Comprehensive literature review and guideline evaluation resulted in the development of statements and other questions to establish current clinical practices. Two rounds of anonymous voting were undertaken, with a collaborative meeting held in between to discuss areas of discordance. Overall, consensus was defined as achievement of ≥75% agreement in the range 7-9 on a 9-point scale (1 strongly disagree; 9 strongly agree). RESULTS: Consensus was achieved on 23/29 statements in round 1 and 17/18 statements in round 2. There was a high level of concordance with treatment criteria in the adult setting. The limitations of applying assessment tools developed for use in adult patients to the paediatric setting were highlighted. Treatment targets in the paediatric setting should include objective metrics for disease severity and psychological impact on the patients and their family, and be based on validated, age-appropriate tools. CONCLUSION: While the assessment, classification and management of moderate to severe psoriasis in paediatric patients aligns with metrics established for adults, it is vital that nuances in the transition from childhood to adolescence be taken into account. Future research should focus on psoriasis severity assessment scales specific to the paediatric setting.

Therapeutic and Phytochemical Properties of Thymoquinone Derived from Nigella Sativa.

BACKGROUND: Nigella sativa (N. sativa), commonly known as black seed or black cumin, belongs to the family Ranunculaceae. It contains several phytoconstituents, thymoquinone (TQ), thymol, thymohydroquinone, carvacrol, and dithymoquinone. TQ is the main phytoconstituent present in N. sativa that is used as an herbal compound, and it is widely used as an antihypertensive, liver tonic, diuretic, digestive, anti-diarrheal, appetite stimulant, analgesic, and antibacterial agent, and in skin disorders. OBJECTIVE: The study focused on collecting data on the therapeutic or pharmacological activities of TQ present in N. sativa seed. METHODS: Antidiabetic, anticancer, immunomodulator, analgesic, antimicrobial, antiinflammatory, hepato-protective, renal protective, and antioxidant properties of TQ have been studied by various scientists. CONCLUSION: TQ seems to have a variety of consequences on how infected cells behave at the cellular level.

Pharmacophore Variants of the Macrocyclic Peptide Triazole Inactivator of HIV-1 Env.

Previously we established a family of macrocyclic peptide triazoles (cPTs) that inactivate the Env protein complex of HIV-1, and identified the pharmacophore that engages Env's receptor binding pocket. Here, we examined the hypothesis that the side chains of both components of the triazole Pro - Trp segment of cPT pharmacophore work in tandem to make intimate contacts with two proximal subsites of the overall CD4 binding site of gp120 to stabilize binding and function. Variations of the triazole Pro R group, which previously had been significantly optimized, led to identification of a variant MG-II-20 that contains a pyrazole substitution. MG-II-20 has improved functional properties over previously examined variants, with Kd for gp120 in the nM range. In contrast, new variants of the Trp indole side chain, with either methyl- or bromo- components appended, had disruptive effects on gp120 binding, reflecting the sensitivity of function to changes in this component of the encounter complex. Plausible in silico models of cPT:gp120 complex structures were obtained that are consistent with the overall hypothesisof occupancy by the triazole Pro and Trp side chains, respectively, into the ß20/21 and Phe43 sub-cavities. The overall results strengthen the definition of the cPT-Env inactivator binding site and provide a new lead composition (MG-II-20) as well as structure-function findings to guide future HIV-1 Env inactivator design.

A Delphi consensus on the nomenclature and diagnosis of lichen planus pigmentosus and related entities.

BACKGROUND: Although well known in clinical practice, research in lichen planus pigmentosus and related dermal pigmentary diseases is restricted due to lack of consensus on nomenclature and disease definition. AIMS AND OBJECTIVES: Delphi exercise to define and categorise acquired dermal pigmentary diseases. METHODS: Core areas were identified including disease definition, etiopathogenesis, risk factors, clinical features, diagnostic methods, treatment modalities and outcome measures. The Delphi exercise was conducted in three rounds. RESULTS: Sixteen researchers representing 12 different universities across India and Australia agreed to be part of this Delphi exercise. At the end of three rounds, a consensus of >80% was reached on usage of the umbrella term 'acquired dermal macular hyperpigmentation'. It was agreed that there were minimal differences, if any, among the disorders previously defined as ashy dermatosis, erythema dyschromicum perstans, Riehl's melanosis and pigmented contact dermatitis. It was also agreed that lichen planus pigmentosus, erythema dyschromicum perstans and ashy dermatosis did not differ significantly apart from the sites of involvement, as historically described in the literature. Exposure to hair colours, sunlight and cosmetics was associated with these disorders in a significant proportion of patients. Participants agreed that both histopathology and dermatoscopy could diagnose dermal pigmentation characteristic of acquired dermal macular hyperpigmentation but could not differentiate the individual entities of ashy dermatosis, erythema dyschromicum perstans, Riehl's melanosis, lichen planus pigmentosus and pigmented contact dermatitis. LIMITATIONS: A wider consensus involving representatives from East Asian, European and Latin American countries is required. CONCLUSION: Acquired dermal macular hyperpigmentation could be an appropriate conglomerate terminology for acquired dermatoses characterised by idiopathic or multifactorial non-inflammatory macular dermal hyperpigmentation.

Cost-Utility Analysis of Rituximab vs Mycophenolate Mofetil for the Treatment of Pemphigus Vulgaris.

Importance: There is an increasing body of literature that supports the use of rituximab as a first-line steroid-sparing agent in pemphigus vulgaris. However, the cost of rituximab is substantial compared with conventional agents, and there are limited health economic data to justify its use. Objective: To evaluate the cost-effectiveness of rituximab biosimilars relative to mycophenolate mofetil as a first-line steroid-sparing agent for moderate to severe pemphigus vulgaris. Design, Setting, and Participants: A cost-utility analysis over a 24-month time horizon was conducted from the perspective of the Australian health care sector using a modeled cohort of treatment-naive adult patients with moderate to severe pemphigus vulgaris. A Markov cohort model was constructed to simulate disease progression following first-line treatment with rituximab biosimilars or mycophenolate mofetil. The simulated cohort transitioned between controlled disease, uncontrolled disease, and death. Efficacy and utility data were obtained from available published literature. Cost data were primarily obtained from published government data. One-way and probabilistic sensitivity analyses were performed to assess uncertainty. Primary outcomes were the changes in cost and quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER) over the 24 months. Interventions: Rituximab biosimilars and mycophenolate mofetil. Results: The simulated cohort of treatment-naive patients had a mean age of 50.8 years, a female-to-male ratio of 1.24, and moderate to severe disease as classified by the Harman criteria. First-line rituximab biosimilars were associated with a cost reduction of AU$639 and an improvement of 0.07 QALYs compared with mycophenolate mofetil, resulting in an ICER of -AU$8818/QALY. Rituximab biosimilars were therefore more effective and less costly compared with mycophenolate mofetil. Sensitivity analyses demonstrated that rituximab biosimilars remained cost-effective across a range of values for cost, utility, and transition probability input parameters and willingness-to-pay thresholds. Conclusions and Relevance: In this cost-utility analysis, rituximab biosimilars were cost-effective compared with mycophenolate mofetil for moderate to severe pemphigus vulgaris. Further investigation into its cost-effectiveness over a longer time horizon is necessary, but the favorable results of this study suggest that the high acquisition costs of rituximab biosimilars may be offset by its effectiveness and provide economic evidence in support of its listing on the Pharmaceutical Benefits Scheme for pemphigus vulgaris.

Australian experience and practical approach to the 308-nm excimer light therapy in dermatology.

The monochromatic excimer light therapy (308-nm excimer laser and lamp) is used to treat focal dermatoses with inflammation or hypopigmentation. In Australia, despite excimer light therapy being a proven effective treatment for many cutaneous conditions, barriers such as access and affordability provide considerable limitations to patients. This study aims to retrospectively evaluate the different applications of excimer light therapy in treating dermatologic conditions within the Australian setting and provide practical information for its use.

Patient factors associated with dermatology outpatient non-attendance: An analysis of racial and ethnic diversity.

Non-attendance to dermatology outpatient appointments is a risk factor for poorer patient outcomes. The culturally and linguistically diverse (CALD) communities in Australia have been identified as at risk of poorer health outcomes, but there is a paucity of data assessing patient factors that may increase outpatient non-attendance. To investigate this, we performed a retrospective cross-sectional study of dermatology appointments from patients attending a tertiary, referral public hospital located in one of Australia's most racially and ethnically diverse communities. Patients within the 18-45 years age bracket were 61% more likely not to attend when compared with older age groups. Those born in Oceania, Middle East Asia, and surprisingly Australia were more likely to miss an appointment, whilst those born in East and Southeast Asia were more likely to attend. Those who spoke Arabic at home were more likely not to attend, whilst those who spoke Vietnamese at home were more likely to attend. This study sheds further light on health disparities in non-attendance and emphasizes the importance of not collectively amalgamating all groups of the CALD community.

Autologous Non-Cultured Epidermal Cellular Grafting in the Surgical Treatment of Stable Vitiligo: The Skin Hospital Protocol.

Autologous non-cultured epidermal cellular grafting is the treatment of choice for patients with stable refractory vitiligo. Recently, studies have shown cost-effective alternatives for this procedure, superseding previous techniques that required large research facilities or expensive pre-packaged kits. We provide modifications to current techniques, including the use of individual Petri dishes to allow for processing larger skin grafts, hyfrecation instead of conventional manual dermabrasion of the recipient site to reduce scar formation as well as better margin delineation, and an intravenous giving set with a filter for improved filtration of the mixed cell population. These modifications facilitated sufficient skin repigmentation in a cost-effective outpatient setting.

Repigmentation in vitiligo using janus kinase (JAK) inhibitors with phototherapy: systematic review and Meta-analysis.

INTRODUCTION: Vitiligo is an autoimmune disorder characterized by progressive loss of melanocytes, leading to cutaneous depigmentation. Vitiligo has significant psychosocial impacts on patients and is challenging to manage with limited treatment options. Recent studies have suggested promising results for JAK1/3 inhibitors including tofacitinib and ruxolitinib. OBJECTIVE: To determine the expected response of vitiligo to JAK inhibitor therapy and factors which influence response rates. METHODS: A systematic review and meta-analysis was performed according to PRISMA guidelines. Good response was defined as repigmentation >50% or a 'good' or 'excellent' outcome as described by authors. Partial response was defined as some repigmentation <50%. RESULTS: From the 9 eligible studies, individual patient data from 45 cases were pooled. Good response was achieved in 57.8%, partial response in 22.2%, and none or minimal response in 20% of cases. When subgrouped according to site, facial vitiligo had the highest good response rate (70%), compared to extremities (27.3%) and torso/non-sun exposed areas (13.6%). Concurrent phototherapy was significant associated with higher rates of good overall response (p < .001) and good facial response (p < .001). CONCLUSIONS: There is promising low-quality evidence regarding the effectiveness of JAK inhibitors in vitiligo. Concurrent UVB phototherapy appears to improve efficacy of JAK inhibitors for vitiligo.

Melasma.

BACKGROUND: Melasma is a common disorder of hyperpigmentation of the skin, characterised by brown pigmentation primarily on the face. Given its frequent facial involvement, it has a significant impact on the quality of life of patients. Management can often be quite difficult, requiring extensive treatment periods and multiple modalities for ongoing maintenance. OBJECTIVE: The aim of this article is to provide evidence-based clinical updates to clinicians, specifically general practitioners, to assist with their everyday practice and effective assessment and treatment of melasma. DISCUSSION: Therapeutic modalities are chosen on the basis of disease presentation, patient preference, treatment periods and side-effect profiles of treatment agents; often a combination of therapies is required.

Management of chronic hand and foot eczema. An Australia/New Zealand Clinical narrative.

Chronic hand/foot eczemas are common, but treatment is often challenging, with widespread dissatisfaction over current available options. Detailed history is important, particularly with regard to potential exposure to irritants and allergens. Patch testing should be regarded as a standard investigation. Individual treatment outcomes and targets, including systemic therapy, should be discussed early with patients, restoring function being the primary goal, with clearing the skin a secondary outcome. Each new treatment, where appropriate, should be considered additive or overlapping to any previous therapy. Management extends beyond mere pharmacological or physical treatment, and requires an encompassing approach including removal or avoidance of causative factors, behavioural changes and social support. To date, there is little evidence to guide sequences or combinations of therapies. Moderately symptomatic patients (e.g. DLQI ≥ 10) should be started on a potent/super-potent topical corticosteroid applied once or twice per day for 4 weeks, with tapering to twice weekly application. If response is inadequate, consider phototherapy, and then a 12-week trial of a retinoid (alitretinoin or acitretin). Second line systemic treatments include methotrexate, ciclosporin and azathioprine. For patients presenting with severe symptomatic disease (DLQI ≥ 15), consider predniso(lo)ne 0.5-1.0 mg/kg/day (or ciclosporin 3 - 5 mg/kg/day) for 4-6 weeks with tapering, and then treating as for moderate disease as above. In non-responders, botulinum toxin and/or iontophoresis, if associated with hyperhidrosis, may sometimes help. Some patients only respond to long-term systemic corticosteroids. The data on sequencing of newer agents, such as dupilumab or JAK inhibitors, are immature.

Compliance to treatment guidelines and survival in women undergoing interval debulking surgery for advanced epithelial ovarian cancer.

BACKGROUND: One of the primary treatment strategies for advanced epithelial ovarian cancers includes neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) and adjuvant chemotherapy. Compliance to treatment is important to possibly improve outcomes. AIM: To audit treatment compliance and its effect on overall survival (OS) and disease free survival (DFS) in women undergoing IDS. METHODS AND RESULTS: Women diagnosed with advanced epithelial ovarian cancer undergoing IDS were included. Details of compliance to chemotherapy and surgery as per standard guidelines were assessed, and correlation with survival was studied. Reasons for protocol deviation at various levels were documented and analysed. A total of 182 patients were included. The total number of deviations was 134 with deviation at any level being 89 (48.9%) and at all levels 5%. Both patient- and treatment-related factors contributed towards deviation. Deviation or noncompliance towards treatment resulted in a significantly reduced 5-year OS (34.4% vs 58.2%; P = .001) compared with compliant patients, which retained its significance on multivariate analysis (P = .024) as well. CONCLUSION: Deviation from treatment guidelines resulted in a significantly lower 5-year OS compared with those who remained treatment compliant. Both patient- and treatment-related factors contributed towards noncompliance and hence towards lower survival.

Does preoperative CA-125 cutoff value and percent reduction in CA-125 levels correlate with surgical and survival outcome after neoadjuvant chemotherapy in patients with advanced-stage ovarian cancer? - Our experience from a tertiary cancer institute.

AIM: The aim of the study is to evaluate percent fall in CA-125 levels after neoadjuvant chemotherapy (NAC) and preoperative CA-125 value to predict surgical and survival outcomes in women with advanced-stage epithelial ovarian cancer (EOC). METHODS: A retrospective review of 406 women receiving NAC for advanced-stage EOC from January 2012 to July 2015 was conducted. Data were collected for demography, radiographic profile, CA-125 levels before and after NAC, chemotherapy, and surgicopathological information. Percent fall in CA-125 was categorized into two groups: <95% (R < 95) and >95% (R > 95) fall from prechemotherapy to preoperative levels. Similarly, women were also categorized using preoperative CA-125 levels of <100 and >100 U/ml. A subset of women from January 2012 to December 2013 was followed to June 2015 for evidence of any recurrence to determine survival outcomes. RESULTS: About 56% women had R > 95 and 44% had R < 95. As compared to R < 95, R > 95 group was more likely to have complete cytoreduction (P = 0.00). Furthermore, women with R > 95 had significant better progression-free survival (PFS) as compared to women with R < 95 (P = 0.009) but no difference in overall survival (OS) (P = 0.28). Women with preoperative CA-125 <100 had significant higher number of complete cytoreduction (55% vs. 40%; P = 0.00) and were associated with both PFS (P = 0.007) and OS benefit (P = 0.02). CONCLUSION: Our data showed that >95% fall in CA-125 and an absolute preoperative CA-125 value of <100 U/ml is associated with better surgical and survival outcome in women with advanced EOC. These data are important in patient counseling and treatment planning.

The efficacy and safety of tacrolimus as mono- and adjunctive therapy for vitiligo: A systematic review of randomised clinical trials.

There is currently no definitive treatment for vitiligo; various modalities include immune modulators phototherapy and skin camouflage. We investigated the efficacy and safety of topical tacrolimus either as monotherapy or combined therapy in the treatment of vitiligo. Electronic systematic search of the literature was carried out using four major databases. Randomised clinical trials (RCTs) that reported the use of topical tacrolimus in the treatment of human vitiligo have been included in a systematic review and meta-analysis. Meta-analysis was conducted via RevMan, and risk of bias was assessed through the Cochrane quality assessment tool. The protocol was published through PROSPERO (CRD42018112430). A total of 19 studies including 814 patients were included in our systematic review. The random-effects-model meta-analysis of two studies revealed that the tacrolimus and narrowband ultraviolet B (NB-UVB) combination therapy rates is better than NB-UVB alone in inducing >75% repigmentation [RR 1.34 (95% CI: 01.05-1.71), P = 0.02]. Tacrolimus and steroids had similar potency in acheiving >75% repigmentation [RR 1.02 (95% CI: 0.19-5.51), P = 0.98]. Meta-analysis of two studies revealed that the fractional laser and tacrolimus combination therapy is no better than tacrolimus alone in causing >75% repigmentation [RR 2.11 (95% CI: 0.87-5.09), P = 0.10]. Further investigating tacrolimus as mono- or adjuvant therapy for vitiligo is highly recommended. Combining tacrolimus to other treatment options such as steroids, phototherapy and laser may be superior to using tacrolimus alone.