Therapeutic agents for Hailey-Hailey disease: A narrative review.

Hailey-Hailey disease (HHD) is an autosomal dominant genetic disorder of keratinocyte adhesion. It occurs due to mutations in ATP2C1, a gene on chromosome 3q21-24 which encodes human secretory pathway Ca2+/Mn2+ ATPase isoform 1, a calcium pump on the Golgi apparatus membrane. Recently, there has been a focus on certain pro-inflammatory cytokines such as IL-6 and IL-8 which play a role in HHD. Various triggers include excessive heat, menstruation, pregnancy, sweating, friction, exposure to sunlight and superficial infections. The therapy of the disorder is better understood by the varied pathogenetic steps and we aimed to comprehensively search for the various medical therapies used in HHD and align them with the existing knowledge on the pathogenesis and delineate them according to their major mode of action.

Th1 and Th2 cytokine expression in hyperkeratotic chronic hand eczema and the role of Tofacitinib a oral JAK inhibitor.

Tissue cytokines in chronic hand eczema (CHE) can predict targeted therapy with novel drugs including JAK inhibitors. Our primary objective was to assess the tissue expression of cytokines of Th1 and Th2 cell lines in CHE patients and to study the efficacy of oral tofacitinib. We recruited patients presenting with recalcitrant CHE. Lesional and non-lesional tissue samples were assessed for Th1(IFN-γ, TNF-α) and Th2 related cytokines (IL-4, IL-13, IL-2,) using real time PCR. Tofacitinib 5 mg twice daily was initiated with 4 weekly assessment and we also noted relapses post therapy.Of 21 refractory hyperkeratotic CHE patients, cytokine analysis was performed in 11 patients which showed upregulation of IL-4 [n = 5/11, 1.87-fold increase], TNF-α (n = 5/11, 5.13-fold) and IFN-γ (n = 6/11, 1.98-fold) as compared to uninvolved skin. All patients (100%) had used topical corticosteroids (TCS) and 4/21 (19%) had failed methotrexate and 2/21 (9.5%) had failed acitretin. Tofacitinib 5 mg twice daily was given in 15/21 patients. The mean time to achieve hand eczema severity index 90 (HECSI 90) was 4 weeks (mean duration of treatment:5.8 months, n = 12). Side effects were observed in 4/12 (33.3%) patients and relapse was noted in 3/12 (25%) patients after a mean duration of 7 months after discontinuation of tofacitinib. Tofacitinib (pan-JAK inhibitor) showed an excellent response in refractory CHE patients with predominant tissue Th1/Th2 cells related cytokine expression.

A Pilot Real-World Study of Ultrasonography Findings of Hidradenitis Suppurativa in Indian Patients and Its Diagnostic and Therapeutic Implications.

Introduction Hidradenitis suppurativa (HS) is a multifactorial chronic inflammatory follicular disorder affecting apocrine gland-bearing areas of the body. We conducted an observational study to assess the ultrasonography (USG) findings in suspected HS patients at a tertiary care center in North India over 6 months. Aim The aim of this article was to study the USG findings in HS and correlate clinical and USG findings and scoring systems in HS with stage wise treatments. Materials and Methods All patients with a clinical suspicion of HS underwent an USG examination after clinical examination with a probe of 18 Hz frequency. Hurley's staging of patients was used to stage clinically, and the HS-SOS scoring and Doppler changes were assessed on USG. The treatment was revised in case of a change in the USG grading of severity. Results A total of 23 patients suspected of HS underwent USG evaluation, of which 12 (52%) were male and 9 (48%) were females, with the mean age being 25.3 years (range: 14-40 years). Based on the HS clinical grading, eleven patients (47.8%) were Hurley's stage I, six patients (26%) were stage II, and six patients (26%) were stage III. USG demonstrated that three patients had been misdiagnosed and had folliculitis (8.6%) and Crohn's disease (4.3%). Out of the remaining twenty patients with USG features of HS, based on HS SOS grading, three patients (15%) were grade I, seven (35%) were grade II, and ten (50%) were grade III. Of these, nineteen patients (95%) had axillary involvement, which was bilateral in 84% of cases. The other region affected was the groin in five patients (26.3%), while two had inframammary involvement (10.5%). On further characterization of the type of lesion, nodules (41; 40.6%) were the most common type of lesion by sinuses and thickened hair follicles in 31 (30.6%) patients. Based on USG findings, the management of 26% of patients was changed from medical to surgical intervention. Conclusion USG and Doppler are noninvasive bedside tools for the examination of HS, which helps to rule out differentials and delineate the extent and depth of the disease better by picking up subclinical lesions and help in determining disease activity by Doppler, which in turn helps in planning appropriate medical and surgical management of patients. It also identifies radiological parameters that help identify patients who could fail medical management.

Implications of drug resistance in leprosy: disease course, reactions and the use of novel drugs.

Leprosy remains a significant neglected tropical disease despite the goal of elimination having been achieved in various endemic nations over the past two decades. Reactional episodes complicate the disease course, resulting in deformities and disability. The main aim of treatment is to kill Mycobacterium leprae and decrease the bacterial load, which could help prevent further bacilli transmission. A major concern in breaking the chain of transmission and possibly for recurrent reactions is the role of drug-resistant bacilli. Though some data is available on the background prevalence of drug resistance in leprosy, there is a paucity of studies that look for resistance specifically in leprosy reactions. Administration of long-term steroids or immunosuppressants for chronic and recurrent responses in the presence of drug resistance has the twin effect of perpetuating the multiplication of resistant bacilli and encouraging the dissemination of leprosy. The increasing trend of prescribing second-line drugs for leprosy or type 2 reactions without prior assessment of drug resistance can potentially precipitate a severe public health problem as this can promote the development of resistance to second-line drugs as well. A comprehensive multicenter study, including drug resistance surveillance testing in cases of reactions, is necessary, along with the current measures to stop the spread of leprosy. Here, we have detailed the history of drug resistance in leprosy, given pointers on when to suspect drug resistance, described the role of resistance in reactions, methods of resistance testing, and the management of resistant cases with second-line therapy.

Analyzing the clinical efficacy and safety of levocetirizine based on its receptor occupancy, intraclass comparison and role in the treatment of CSU: an AROG consensus statement.

INTRODUCTION: Chronic spontaneous urticaria (CSU) is characterized by urticaria persisting for more than 6 weeks. Antihistamines, notably sgAH (second generation antihistamines) are the first line of treatment for CSU. AREAS COVERED: This consensus aimed to review the existing research on receptor occupancy of antihistamines, including levocetirizine, and translate its implications in the treatment of CSU. The consensus deliberations were under the banner of the Antihistamine Receptor Occupancy Group (AROG) from India, an expert panel of 12 dermatologists with a mix of institutional and practitioner backgrounds. This group analyzed the existing translational research on the receptor occupancy of levocetirizine to establish the clinical efficacy and safety of levocetirizine in the treatment of CSU using the grading of recommendations assessment, development, and evaluation (GRADE) method vis-a-vis the varied SGAH. EXPERT OPINION: SGAH constitute the first step in the therapeutic ladder for managing CSU. Levocetirizine has high bioavailability, high affinity and occupancy of the H1 receptor, rapid onset of action, limited distribution and minimal hepatic metabolism. It exhibits significant anti-inflammatory effects at clinically relevant concentrations. The marked receptor occupancy translates to enhanced efficacy as compared to similarly dosed SGAH with the lower cost making it an appropriate drug for chronic use. Receptor occupancy should be the basis of intra-class head-to-head trials in CSU.

An Algorithmic Approach Towards Diagnosis of Patients with Hereditary Reticulate Pigmentary Disorders- A narrative review.

Hereditary reticulate pigmentary disorders include a group of genetic disorders with net-like pigmentation as their predominant presentation. Many of these hereditary reticulate pigmentary disorders have a wide array of cutaneous presentations with overlapping features. Furthermore, some of these disorders also have systemic manifestations. The overlapping features often add confusion and cause delay in the diagnosis. Based on the literature search, we propose an easy-to-follow concise diagnostic algorithm for the same. This would aid in ordering a definite genetic test. A thorough data search was done using data base PubMed using the following keywords. It included "'inherit*' OR 'genetic'" AND "reticulate AND pigment*"'. Thereafter, an individual disease search was done using keywords 'Dowling-Degos disease', 'Dyschromatosis Hereditaria Symmetrica', 'Acropigmentation of Kitamura', 'Dyschromatosis Universalis Hereditaria', 'Naegeli-Franceschetti-Jadasssohn syndrome', 'X-linked reticulate pigmentary disorder' and 'Dyskeratosis congenita'. The search included case reports, series, observational studies, narrative and systematic reviews, clinical trials. Acquired pigmentary disorders were excluded. A total of 1994 articles were retrieved. Finally, 625 articles were included for the review. The articles were narrative review articles (40), case series (23), observational studies (44), and case reports (518). An easy-to-follow clinical diagnostic algorithm based on age of onset, distribution, and other parameters would definitely aid in reaching a provisional diagnosis. And further this approach will help in the genetic workup of a case of hereditary reticulate pigmentary disorder.

Case Report: Recurrent Type 2 Leprosy Reaction Associated with Multiple Nerve Function Impairments Refractory to Steroids: A Therapeutic Challenge.

Nerve function impairment (NFI) in leprosy results in serious deformities of the face, hands, and feet and contributes significantly to the stigma associated with the disease. Most literature on NFI focuses on either type 1 reaction-associated NFI, or the silent neuropathy, whereas NFI associated with type 2 reaction (T2R) is less well researched. The latter, however, can be more refractory to conventional treatment, not solely owing to its recurrent nature. We present a therapeutically challenging case of a 31-year-old male with borderline lepromatous leprosy with recurrent T2R associated with recurrent and progressive sensorimotor NFI, largely unresponsive to oral steroids and multibacillary, multidrug therapy.

Clinico-mycological and therapeutic updates on cutaneous dermatophytic infections in the era of Trichophyton indotineae.

Trichophyton indotineae has emerged as a novel dermatophyte species resulting in treatment recalcitrant skin infections. While the earliest reports came from India, T. indotineae has now spread to many parts of the world and is rapidly becoming a global health concern. Accurate identification of T. indotineae requires elaborate mycological investigations which is beyond the domain of routine microbiology testing. Extensive, non-inflammatory and atypical presentations are commonly seen with this novel species. T. indotineae shows an alarmingly high rate of mutations in the squalene epoxidase gene leading to lowered in vitro susceptibility to terbinafine. This has also translated into a lowered clinical response and requirement of a higher dose and much longer durations of treatment with the drug. Although the species remains largely susceptible to itraconazole, prolonged treatment durations are required to achieve cure with itraconazole. Fluconazole and griseofulvin do not have satisfactory in vitro or clinical activity. Apart from requirement of prolonged treatment durations, relapse postsuccessful treatment is a distressing and yet unexplained consequence of this "species-shift." Use of third generation azoles and combinations of systemic antifungals is unwarranted as both have not demonstrated clear superiority over itraconazole given alone, and the former is an important class of drugs for invasive mycoses.

Case Report: Mixed Airborne Contact Dermatitis-Chronic Actinic Dermatitis Pattern of Parthenium Dermatitis with Response to Tofacitinib Therapy.

Parthenium hysterophorus is the commonest cause of plant dermatitis in India. It classically causes airborne contact dermatitis (ABCD), characterized by pruritic, eczematous, and lichenified lesions involving predominantly the face and flexural areas. Over time, however, a transition to chronic actinic dermatitis (CAD) pattern, with prominent involvement of sun-exposed sites, may occur. Management involves strict protective measures and topical and oral corticosteroids or immunomodulatory agents but often leads to only limited success. We report a patient with a chronic and extensive mixed ABCD-CAD pattern of parthenium dermatitis recalcitrant to conventional treatment, with rapid resolution after initiation of treatment with tofacitinib.

Tofacitinib: A Treatment Option for Recalcitrant Polymorphic Light Eruption and Its Mechanistic Rationale.

Background: Polymorphous light eruption is largely characterized by a delayed-type (type IV) hypersensitivity reaction to 1 or more undefined endogenous ultraviolet-induced skin antigens. Objectives: To evaluate the efficacy of tofacitinib in refractory cases of polymorphous light eruption. Methods: Seven patients who had failed multiple systemic treatments or relapsed within 2 weeks of existing systemic agents with concomitant photoprotection were offered tofacitinib after written consent. Results: Initiation of tofacitinib led to a marked reduction of itching (mean ± SD 3.1 ± 1.12 days) followed by clinical resolution (mean ± SD 2.6 ± 1.1 weeks). The duration of therapy ranged from 1 to 3 months (mean ± SD 2 ± 0.63 months), and 4 of 7 patients had a recurrence in 5.5 weeks and were again initiated on tofacitinib with a prompt response. Conclusion: Tofacitinib inhibits Janus kinase (JAK)1 and JAK3 thus it can abrogate the effects of the predominant cytokine milieu of polymorphic light eruption (PMLE) and thus reduce the expression of aberrant inflammatory T lymphocyte expression in PMLE.

A Real-World Study of Steroid-Free Monotherapy with Tofacitinib in Severe and Therapy-Recalcitrant Alopecia Areata, Alopecia Totalis, and Alopecia Universalis Cases: A Retrospective Analysis.

Background: Alopecia areata (AA) presents with noncicatricial alopecia and has multifactorial etiology. Janus Kinase inhibitors (JAKibs) with potential efficacy and favorable side-effect profile are the first class of drugs to receive FDA approval in AA. Objectives: Our primary objective was to assess the complete response rates to tofacitinib monotherapy in severe and recalcitrant AA, alopecia totalis (AT), and alopecia universalis (AU) patients using the latest percentage change in Severity of alopecia tool (SALT) score. We also aimed to analyze the various systemic agents used by these patients prior to the use of tofacitinib. Materials and Methods: Institutional records of 17 patients with severe or refractory AA, AT, and AU treated with tofacitinib monotherapy were analyzed, retrospectively. The response to tofacitinib therapy was determined after calculating percentage change in SALT score. End of treatment was defined as the dose which resulted in a significant response (complete/near complete response was ≥75% hair regrowth from baseline as determined by SALT score). Results: Majority of patients had severe AA (SALT ≥ 50) (n = 9/17, 52.94%), while five patients had AT and three had AU. All patients had received either systemic glucocorticoids (GCS), which included oral mini pulse (OMP) (n = 8), intravenous pulse steroids (n = 4), and daily oral GCS (n = 6) or immunosuppressive agents (ISAs) which included cyclosporine (n = 14) followed by methotrexate (n = 6) and azathioprine (n = 6). Mean SALT score prior to starting tofacitinib was 74.23. Mean dose of tofacitinib used was 13.23 mg (10-15 mg) and mean duration of treatment was 9.23 months. Latest percentage change of SALT score ranged from 70.58% to 100%, with an average of 91.47%. Most patients showed complete/near complete response (13/17, 76.47%). Conclusion: Tofacitinib was found to be safe and effective in severe/refractory AA, AU, and AT patients recalcitrant to other treatment modalities in our study. Further studies are needed to assess the effect of these targeted drugs on JAK-STAT expression or tissue cytokines involved in the pathogenesis of AA using immunohistochemistry.

IADVL SIG Recalcitrant Dermatophytosis Position Statement on Super Bioavailable Itraconazole.

Itraconazole (ITZ) has been the mainstay of oral antifungal treatment for the current epidemic of recalcitrant dermatophytosis (RD) in India. Recently, a newer formulation of ITZ, super bioavailable itraconazole (SUBA-ITZ), is made available in the market by many pharmaceutical companies. It is important for dermatologists to understand the pharmacokinetic properties of SUBA-ITZ vis-a-vis conventional pellet formulation to use it effectively and safely. Indian Association of Dermatologists, Venereologists and Leprologists (IADVL) has established a special interest group for recalcitrant dermatophytosis (SIG-RD) to strengthen research, continuing medical education, and industry collaboration on the subject. This position statement on SUBA-ITZ by SIG-RD is an attempt to address current pieces of evidence and the position of this new formulation in the management of RD.