Clinical Use of Super Bioavailable Itraconazole for the Management of Dermatophytosis: Consensus Statement by Dermatologists from India via the Modified Delphi Technique.

INTRODUCTION: Super bioavailable itraconazole (SB ITZ) overcomes the limitations of conventional itraconazole (CITZ) such as inter-individual variability and reduced bioavailability. It has been approved for systemic mycoses in Australia and Europe as 50mg and the United States as 65mg and in India as 50mg, 65mg, 100mg, and 130mg. However, data on the ideal dose and duration of SB ITZ treatment in managing dermatophytosis is insufficient. This consensus discusses the suitability, dosage, duration of treatment, and relevance of using SB ITZ in managing dermatophytosis in different clinical scenarios. METHODS: Sixteen dermatologists, (>15 years of experience in the field and ≥2 years clinical experience with SB ITZ) formed the expert panel. A modified Delphi technique was employed, and a consensus was reached if the concordance in response was >75%. RESULTS: A total of 26 consensus statements were developed. The preferred dose of SB ITZ is 130mg once daily and if not tolerated, 65mg twice daily. The preferred duration for treating naïve dermatophytosis is 4-6 weeks and that for recalcitrant dermatophytosis is 6-8 weeks. Moreover, cure rates for dermatophytosis are a little better with SB ITZ than with CITZ with a similar safety profile as of CITZ. Better patient compliance and efficacy are associated with SB ITZ than with CITZ, even in patients with comorbidities and special needs such as patients with diabetes, extensive lesions, corticosteroid abuse, adolescents, and those on multiple drugs. CONCLUSION: Expert opinions indicate that overall clinical experience with SB ITZ is better than that with CITZ.

Cardiovascular Considerations and Implications for Treatment in Psoriasis: An Updated Review.

Psoriasis, a prevalent chronic inflammatory skin disorder affecting 2-3% of the global population, has transcended its dermatological confines, revealing a profound association with cardiovascular diseases (CVD). This comprehensive review explores the intricate interplay between psoriasis and cardiovascular system, delving into genetic links, immune pathways, and adipose tissue dysfunction beyond conventional CVD risk factors. The pathophysiological connections unveil unique signatures, distinct from other inflammatory skin conditions, in particular psoriasis-specific genetic polymorphisms in IL-23 and TNF-α have consistently been linked to CVD. The review navigates the complex landscape of psoriasis treatments, addressing challenges and future directions in particular relevance to CVDs in psoriasis. Therapeutic interventions, including TNF inhibitors (TNFi), present promise in reducing cardiovascular risks, and methotrexate could constitute a favourable choice. Conversely, the relationship between IL-12/23 inhibitors and cardiovascular risk remains uncertain, while recent evidence indicates that Janus kinase inhibitors may not carry CVD risks. Emerging evidence supports the safety and efficacy of IL-17 and IL-23 inhibitors in patients with CVDs, hinting at evolving therapeutic paradigms. Lifestyle modifications, statins, and emerging therapies offer preventive strategies. Dedicated screening guidelines for CVD risk assessment in psoriasis are however lacking. Further, the impact of different disease phenotypes and treatment hierarchies in cardiovascular outcomes remains elusive, demanding ongoing research at the intersection of dermatology, rheumatology, and cardiology. In conclusion, unraveling the intricate connections between psoriasis and CVD provides a foundation for a holistic approach to patient care. Collaboration between specialties, advancements in screening methodologies, and a nuanced understanding of treatment impacts are essential for comprehensive cardiovascular risk management in individuals with psoriasis.

Psoriasis is a skin condition that not only affects the skin but is also linked to issues in the body's fat tissue, which can lead to inflammation and heart problems. The fat tissue in people with psoriasis contains various immune cells, contributing to obesity and insulin resistance. Research has found a strong connection between inflammation in fat tissues and cardiovascular problems in people with psoriasis. Specific substances released by fat tissue, like leptin, resistin, and adiponectin, can impact inflammation and cardiovascular health. Psoriasis patients often show increased levels of these substances. Treatment for psoriasis may influence cardiovascular health. Some studies suggest that certain medications, like methotrexate or TNF inhibitors, may lower the risk of heart events. However, there are also concerns about potential adverse effects, and further research is needed to fully understand how psoriasis treatments affect cardiovascular outcomes. To manage the cardiovascular risks associated with psoriasis, regular screening for heart-related issues is recommended. Lifestyle changes, such as a healthy diet, stress management, and smoking cessation, are also essential. Additionally, specific medications, like statins and metformin, may be beneficial in controlling cardiovascular risk factors in people with psoriasis. Despite advancements in understanding the relationship between psoriasis and cardiovascular health, there are still challenges. Research is ongoing to develop better screening guidelines and treatment strategies. Collaboration between dermatologists, rheumatologists, and cardiologists is crucial to address the complex nature of this condition and its impact on the heart.

A challenging case of borderline lepromatous leprosy non-responsive to WHO-MDT: exploring approaches beyond WHO-MDT.

Just as we prioritize personalized medicine for various other medical conditions, we should also include a neglected disease like leprosy, ensuring that patients receive the best care possible and improving their quality of life. Our case highlights the importance of instituting an alternate therapeutic regimen in a scenario where there is a lack of clinical response to multidrug therapy, even in the absence of documented drug resistance of the currently available molecular diagnostics. The search for the perfect regimen tailored for each individual leprosy patient should continue. Alternate anti-leprosy therapy is highly useful in cases with confirmed drug resistance or clinically non-responsive cases; however, their misuse should also be strictly avoided to prevent the development of resistance to them.

Assessing the impact of childhood and adolescent chronic plaque psoriasis on parents/caregivers using the Family Dermatology Life Quality Index (FDLQI): A cross-sectional study.

Background Chronic childhood diseases are a burden for paediatric patients and their caregivers. Limited data are available on the effect of paediatric psoriasis on the caregiver's well-being and quality of life. Objective To assess the impact of childhood and adolescent chronic plaque psoriasis on parents/caregivers quality of life. Methods A single-centre cross-sectional study was performed which included 102 children with psoriasis and their caregivers. Clinico-demographic data of children and socio-demographic details of primary caregivers were collected. Out of pocket expenditure for treatment was calculated for all the patients. The quality of life of children was assessed using the Children's Dermatology Life Quality Index (CDLQI) and the caregiver's quality of life was assessed using the Family Dermatology Life Quality Index (FDLQI). Results CDLQI was impaired in 85.29 % of children with a median score of 7. The item 'symptoms' was most commonly affected (87.2%), followed by 'self-conscious' (70.5%) and 'treatment' (65.6%). FDLQI was impaired in 96.1% of caregivers with a median value of 11. The most affected FDLQI items were 'emotional' in 95%, followed by 'time-spent' in 78.4%. Almost 40% of patients had catastrophic health expenditure (CHE) and their FDLQI was significantly higher (p-0.014) compared to caregivers who did not experience catastrophic health expenditure. FDLQI had a positive relationship with the involvement of exposed body sites (p-0.003), CDLQI (p-0.000), treatment expense (p-0.031) and a negative correlation with duration of illness (p-0.04). Conclusion Childhood psoriasis has a negative impact on the quality of life of the children and caregivers highlighting the need for intervention strategies for both.

Cutaneous-immuno-neuro-endocrine (CINE) system: A complex enterprise transforming skin into a super organ.

Skin is now emerging as a complex realm of three chief systems viz. immune system, nervous system, and endocrine system. The cells involved in their intricate crosstalk, namely native skin cells, intra-cutaneous immune cells and cutaneous sensory neurons have diverse origin and distinct functions. However, recent studies have explored their role beyond their pre-defined functional boundaries, such that the cells shun their traditional functions and adopt unconventional roles. For example, the native skin cells, apart from providing for basic structural framework of skin, also perform special immune functions and participate in extensive neuro-endocrine circuitry, which were traditionally designated as functions of cutaneous resident immune cells and sensory neurons respectively. At the cellular level, this unique collaboration is brought out by special molecules called neuromediators including neurotransmitters, neuropeptides, neurotrophins, neurohormones and cytokines/chemokines. While this intricate crosstalk is essential for maintaining cutaneous homeostasis, its disruption is seen in various cutaneous diseases. Recent study models have led to a paradigm shift in our understanding of pathophysiology of many such disorders. In this review, we have described in detail the interaction of immune cells with neurons and native skin cells, role of neuromediators, the endocrine aspect in skin and current understanding of cutaneous neuro-immuno-endocrine loop in one of the commonest skin diseases, psoriasis. An accurate knowledge of this unique crosstalk can prove crucial in understanding the pathophysiology of different skin diseases and allow for generation of targeted therapeutic modalities.

Transmission patterns of C1-INH deficiency hereditary angioedema favors a wild-type male offspring: Our experience at Chandigarh, India.

BACKGROUND: Deficiency of C1-inhibitor (C1-INH) protein, caused by pathogenic variants in the Serpin family G member 1 (SERPING1) gene, is the commonest pathophysiological abnormality (in ∼95 % cases) in patients with hereditary angioedema (HAE). C1-INH protein provides negative control over kallikrein-kinin system (KKS). Although the inheritance of the HAE-C1-INH is autosomal dominant, female predominance has often been observed in patients with HAE. OBJECTIVE: To analyze the risk of transmission of SERPING1 gene variant from father or mother to their offspring. METHODS: Pedigree charts of 42 families with a confirmed diagnosis of HAE-C1-INH and a pathogenic variant in the SERPING1 gene were analysed. Patients with HAE who had had at least one child were included for analyses to assess the risk of transmission from the father or mother to their offspring. RESULTS: Overall, 49 % (189/385) of all offspring inherited the genetic defect. In the subgroup analyses, 54.8 % (90/164) female offspring and 44.8 % (99/221; p < 0.02) male offspring inherited the genetic defect. Inheritance of the genetic defect was significantly lower in male offspring. Fathers with SERPING1 gene variant had a statistically significant skewed transmission of the wild type to the male offspring as compared to the variant (57.8 % wild type vs. 42.1 % variant; p < 0.02), whereas no statistically significant difference was found when a father transmitted the variant to a female offspring. Mothers with SERPING1 gene variant had no statistically significant difference in variant transmission to male or female offsprings. CONCLUSION: Results of the study suggest that the transmission pattern of SERPING1 gene variant favours the transmission of wild-type alleles in males, especially when the father is the carrier; hence, overall, fewer males and more female offspring inherited the variant. This could be because of a selection of wild-type male sperms during spermatogenesis, as the KLK system has been reported to play a crucial role in the regulation of spermatogenesis. Although, a similar pattern was observed in the maternal transmission of the SERPING1 gene variant; the difference was not statistically significant, likely because of a small sample size.

Tofacitinib in dermatology: a potential opportunity for topical applicability through novel drug-delivery systems.

Tofacitinib is a first-generation JAK inhibitor approved by the US FDA for treating rheumatoid arthritis. It exhibits a broad-spectrum inhibitory effect with abilities to block JAK-STAT signalling. The primary objective of this review is to obtain knowledge about cutting-edge methods for effectively treating a variety of skin problems by including tofacitinib into formulations that are based on nanocarriers. The review also highlights clinical trials and offers an update on published clinical patents. Nanocarriers provide superior performance compared to conventional treatments in terms of efficacy, stability, drug bioavailability, target selectivity and sustained drug release. Current review has the potential to make significant contributions to the ongoing discussion involving dermatological treatments and the prospective impact of nanotechnology on transforming healthcare within this field.

Reverse Koebner phenomenon in erythema nodosum leprosum.

BACKGROUND: Erythema nodosum leprosum (ENL) is an immunologically mediated phenomenon complicating the course of leprosy. Reverse Koebner phenomenon is the term used to describe the sparing of previously injured or diseased skin by new skin lesions of the disease. METHODS: A middle-aged woman with a known case of lepromatous leprosy for the past year presented with an eruption of reddish painful nodules over her body. The lesions were found to characteristically spare the sites of previous scars. RESULTS: This sparing phenomenon of previous scar sites has been termed reverse Koebner phenomenon, a site of the body that offers greater resistance than the rest of the body to the onset of the disease, seen in various diseases, but it has never been described in ENL. CONCLUSION: This sparing of scar sites in ENL can be attributed to reverse Koebner phenomenon.

Delay in diagnosis is the most important proximate reason for mortality in hereditary angio-oedema: our experience at Chandigarh, India.

BACKGROUND: Hereditary angio-oedema (HAE) is a rare autosomal dominant disorder characterized clinically by recurrent episodes of nonpruritic subcutaneous and/or submucosal oedema. Laryngeal oedema is the commonest cause of mortality in patients with HAE. Prior to the availability of first-line treatment options for the management of HAE, mortality was as high as 30%. Mortality has significantly declined in countries where first-line treatment options are available and patients can access these therapies. There is a paucity of literature on the outcomes of patients with HAE in developing countries where availability of and access to first-line treatment options are still a challenge. OBJECTIVES: To report our experience on mortality in patients with HAE and to report factors associated with the death of these patients. METHODS: We carried out a record review of all patients diagnosed with HAE between January 1996 and August 2022. Families with HAE who had reported the death of at least one family member/relative from laryngeal oedema were studied in detail. RESULTS: Of the 65 families (170 patients) registered in the clinic, 16 families reported the death of at least one family member/relative from laryngeal oedema (total of 36 deaths). Of these 16 families, 14 reported that 1 or more family members had experienced at least 1 attack of laryngeal oedema. One patient died during follow-up when she was taking long-term prophylaxis with stanozolol and tranexamic acid, while the remaining 35 patients were not diagnosed with HAE at the time of their death. At the time of death of all 36 patients, at least 1 other family member had symptoms suggestive of HAE, but the diagnosis was not established for the family. CONCLUSIONS: To our knowledge, this is the largest single-centre cohort of patients with HAE in India reporting mortality data and factors associated with death in these families. The delay in diagnosis is the most important reason for mortality.

Oral Acitretin Plus Topical Triamcinolone vs Topical Triamcinolone Monotherapy in Patients With Symptomatic Oral Lichen Planus: A Randomized Clinical Trial.

Importance: Symptomatic oral lichen planus (OLP) can be challenging to treat. Objective: To compare the efficacy of oral acitretin plus topical triamcinolone acetonide (TAC), 0.1%, with TAC monotherapy in patients with symptomatic OLP. Design, Setting, and Participants: This monocentric, investigator-initiated, placebo-controlled, investigator- and patient-blinded randomized clinical trial was conducted from December 2018 to June 2020 at the Postgraduate Institute of Medical Education and Research, a tertiary referral center in Chandigarh, India. Sixty-four patients 18 years or older with symptomatic OLP were recruited by consecutive sampling. Data were analyzed from July to December 2020. Intervention: The patients were randomized to receive either a combination of oral acitretin (25-35 mg/d) and TAC (treatment group) or TAC in combination with placebo (placebo group) for 28 weeks, with an additional 8 weeks of treatment-free follow-up after the end of treatment (36 weeks of total study duration). Main Outcomes and Measures: The disease severity and treatment response were assessed using Oral Disease Severity Score (ODSS), Oral Health Impact Profile 14 (OHIP-14), and visual analog scale (VAS). The primary aim was to assess the number of patients achieving ODSS-75 (75% reduction in ODSS compared with baseline) in both groups at 28 weeks and at the end of 36 weeks. Results: Among 64 patients, 31 in the treatment group and 30 in the placebo group completed the study (mean [SD] age, 50.6 [15.2] years vs 49.2 [14.4] years; male-female ratio, 13:19 vs 16:16). Baseline ODSS, visual analog scale, and Oral Health Impact Profile 14 scores were comparable in both groups. In the intention-to-treat analysis, there was a statistically significant higher number of patients achieving 75% or higher reduction in ODSS in the treatment group compared with the placebo group at the end of 28 weeks (28 [88%] vs 15 [47%], a 41 [95% CI, 20-61] percentage point difference between groups; P < .001; Cramér V = 0.47) and 36 weeks (27 [84%] vs 13 [41%], a 43 [95% CI, 23-67] percentage point difference between groups; P < .001; Cramér V = 0.47). Relapses during the posttreatment follow-up of 8 weeks were low among patients in both treatment and placebo groups (1 [3%] vs 2 [6%], a 3 [95% CI, -13 to 7] percentage point difference between groups; P > .99; Cramér V = 0.07). Conclusion and Relevance: In this randomized clinical trial, the combination of oral acitretin and TAC was more effective than TAC monotherapy in patients with symptomatic OLP. Trial Registration: Clinical Trial Registry of India Identifier: CTRI/2018/11/016448.

Genomic characterization of Mycobacterium lepromatosis from ENL patients from India.

BACKGROUND: Leprosy is caused by Mycobacterium leprae and Mycobacterium lepromatosis. Both organisms cannot be cultured in vitro. M. lepromatosis was found to be associated mainly with diffuse lepromatous leprosy and with Lucio's phenomena initially. Later, M. lepromatosis was observed in borderline leprosy cases (BL), lepromatous leprosy cases (LL) and leprosy reactional cases (T1R and ENL). Although many cases are being reported with similar clinical features like Lucio phenomenon in India but M. lepromatosis was not isolated from these cases. The aim of this study was to screen MB patients and patients with type 2 reaction for the presence of M. lepromatosis. METHODOLOGY: We recruited a total of 75 multibacillary leprosy cases (45 MB cases without reaction and 30 type 2 reaction (ENL) cases) from TLM hospitals Purulia (West Bengal), Barabanki (Uttar Pradesh), Shahdara (Delhi) and PGIMER (Chandigarh), India. Punch biopsies of 5 mm were collected in 70% ethanol from all the study subjects. DNA was extracted followed by Hemi-nested PCR targeting 16S rRNA gene specific for M. lepromatosis. Further, PCR products were processed for Sanger sequencing for an absolute confirmation of M. lepromatosis. Whole genome sequencing was done to confirm the presence of M. lepromatosis. RESULT: We observed presence of M. lepromatosis in 4 necrotic ENL patients by heminested PCR. There was 100% 16S rRNA sequence similarity with M. lepromatosis FJ924 in one case, 98.96% in two cases and in one case it was 90.9% similarity by nucleotide BLAST (BLASTn) by using the NCBI website. On the basis of Sanger sequencing, we noted presence of M. lepromatosis in 3 necrotic ENL patients as one sample only gave 90.9% similarity by BLASTn. On the basis of de novo assembly and genome obtained, only one sample S4 with a 2.9 mb genome size was qualified for downstream analysis. Sixteen M. lepromatosis- specific proteins were identified in this case and the closest species was M. lepromatosis strain FJ924 based on whole genome level phylogeny. CONCLUSION: These results provide valuable insights into the prevalence of M. lepromatosis in ENL patients in different regions of India and contribute to our understanding of the genetic characteristics of this pathogen in the context of leprosy.

Mycobacterium Indicus Pranii (MIP) Vaccine: Pharmacology, Indication, Dosing Schedules, Administration, and Side Effects in Clinical Practice.

Mycobacterium indicus pranii (MIP), previously called Mw vaccine, is a one-of-a-kind immunomodulatory vaccine. It was indigenously developed in India for use in leprosy. MIP is heat-killed Mycobacterium w, which is a non-pathogenic atypical mycobacterium belonging to Class IV of Runyon classification. It shares epitopes with Mycobacterium leprae and Mycobacterium tuberculosis, which forms the rationale behind its use in leprosy and tuberculosis. MIP activates both innate and acquired immunity. It induces a Th1 and Th17 immune response along with downregulation of Th2 pathway and activates macrophages and dendritic cells. MIP vaccine is safe with adverse effects such as local site erythema, swelling, and rarely fever and other systemic reactions. Apart from leprosy, MIP has been used in dermatological diseases such as warts and psoriasis. Clinical trials have evaluated the efficacy of MIP in a plenitude of non-dermatological conditions such as category II tuberculosis, Gram-negative sepsis, non-small cell lung cancer, human immunodeficiency virus (HIV), muscle-invasive bladder cancer, and very recently, coronavirus 2019 (COVID-19). In vitro and animal studies have also demonstrated its utility in leishmaniasis, melanoma, and as a vaccine for the prevention of pregnancy. The PubMed database was searched using "Mycobacterium indicus pranii, MIP, Mycobacterium w" as the keyword in title. This comprehensive review provides useful information for healthcare professionals about immunotherapeutic potential of MIP vaccine, its composition, dosing schedule, administration, and side effects besides its efficacy in various indications other than leprosy.

Assessment of Clinical, Histopathological, and Bacteriological Findings in Treated Leprosy Patients with Persistent Skin Lesions: A Retrospective Cohort Study.

Since the introduction of multidrug therapy (MDT), various disabilities/morbidities due to leprosy have been prevented. However, there is a subset of patients in whom the skin lesions do not resolve completely or remain unchanged despite a full course of MDT, which is a great source of anxiety to the patient and their family members. Hence, we tried to ascertain the putative causes and risk factors of persistent skin lesions (PSLs) by analyzing the clinical, histopathological, bacteriological, and drug resistance patterns. This is a retrospective, cohort study wherein 35 patients who had PSLs after completion of MDT were included. The majority of the patients were 18 to 30 years of age, with males predominating. Borderline tuberculoid leprosy was the most common clinical spectrum observed (71.4%). The majority had PSLs distributed predominantly over photo-exposed sites (upper limbs > trunk > face). Eight patients (22.8%) had a history of contact with leprosy patients in their family, and six patients (17.1%) had associated comorbidities. Improvement in histopathological parameters such as a decrease in granuloma fraction was observed in 22 patients (62.8%) with PSLs after release from treatment in comparison with baseline. Four patients (11.4%) were noted to have drug resistance (three to rifampicin and one to dapsone). Thus, our study emphasizes that leprosy patients with PSLs after completion of MDT should undergo histopathological evaluation and drug resistance studies.