Strategies for using topical corticosteroids in children and adults with eczema.

BACKGROUND: Eczema is a common skin condition. Although topical corticosteroids have been a first-line treatment for eczema for decades, there are uncertainties over their optimal use. OBJECTIVES: To establish the effectiveness and safety of different ways of using topical corticosteroids for treating eczema. SEARCH METHODS: We searched databases to January 2021 (Cochrane Skin Specialised Register; CENTRAL; MEDLINE; Embase; GREAT) and five clinical trials registers. We checked bibliographies from included trials to identify further trials. SELECTION CRITERIA: Randomised controlled trials in adults and children with eczema that compared at least two strategies of topical corticosteroid use. We excluded placebo comparisons, other than for trials that evaluated proactive versus reactive treatment. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods, with GRADE certainty of evidence for key findings. Primary outcomes were changes in clinician-reported signs and relevant local adverse events. Secondary outcomes were patient-reported symptoms and relevant systemic adverse events. For local adverse events, we prioritised abnormal skin thinning as a key area of concern for healthcare professionals and patients. MAIN RESULTS: We included 104 trials (8443 participants). Most trials were conducted in high-income countries (81/104), most likely in outpatient or other hospital settings. We judged only one trial to be low risk of bias across all domains. Fifty-five trials had high risk of bias in at least one domain, mostly due to lack of blinding or missing outcome data. Stronger-potency versus weaker-potency topical corticosteroids Sixty-three trials compared different potencies of topical corticosteroids: 12 moderate versus mild, 22 potent versus mild, 25 potent versus moderate, and 6 very potent versus potent. Trials were usually in children with moderate or severe eczema, where specified, lasting one to five weeks. The most reported outcome was Investigator Global Assessment (IGA) of clinician-reported signs of eczema. We pooled four trials that compared moderate- versus mild-potency topical corticosteroids (420 participants). Moderate-potency topical corticosteroids probably result in more participants achieving treatment success, defined as cleared or marked improvement on IGA (52% versus 34%; odds ratio (OR) 2.07, 95% confidence interval (CI) 1.41 to 3.04; moderate-certainty evidence). We pooled nine trials that compared potent versus mild-potency topical corticosteroids (392 participants). Potent topical corticosteroids probably result in a large increase in number achieving treatment success (70% versus 39%; OR 3.71, 95% CI 2.04 to 6.72; moderate-certainty evidence). We pooled 15 trials that compared potent versus moderate-potency topical corticosteroids (1053 participants). There was insufficient evidence of a benefit of potent topical corticosteroids compared to moderate topical corticosteroids (OR 1.33, 95% CI 0.93 to 1.89; moderate-certainty evidence). We pooled three trials that compared very potent versus potent topical corticosteroids (216 participants). The evidence is uncertain with a wide confidence interval (OR 0.53, 95% CI 0.13 to 2.09; low-certainty evidence). Twice daily or more versus once daily application We pooled 15 of 25 trials in this comparison (1821 participants, all reported IGA). The trials usually assessed adults and children with moderate or severe eczema, where specified, using potent topical corticosteroids, lasting two to six weeks. Applying potent topical corticosteroids only once a day probably does not decrease the number achieving treatment success compared to twice daily application (OR 0.97, 95% CI 0.68 to 1.38; 15 trials, 1821 participants; moderate-certainty evidence). Local adverse events Within the trials that tested 'treating eczema flare-up' strategies, we identified only 26 cases of abnormal skin thinning from 2266 participants (1% across 22 trials). Most cases were from the use of higher-potency topical corticosteroids (16 with very potent, 6 with potent, 2 with moderate and 2 with mild). We assessed this evidence as low certainty, except for very potent versus potent topical corticosteroids, which was very low-certainty evidence.  Longer versus shorter-term duration of application for induction of remission No trials were identified. Twice weekly application (weekend, or 'proactive therapy') to prevent relapse (flare-ups) versus no topical corticosteroids/reactive application Nine trials assessed this comparison, generally lasting 16 to 20 weeks. We pooled seven trials that compared weekend (proactive) topical corticosteroids therapy versus no topical corticosteroids (1179 participants, children and adults with a range of eczema severities, though mainly moderate or severe). Weekend (proactive) therapy probably results in a large decrease in likelihood of a relapse from 58% to 25% (risk ratio (RR) 0.43, 95% CI 0.32 to 0.57; 7 trials, 1149 participants; moderate-certainty evidence). Local adverse events We did not identify any cases of abnormal skin thinning in seven trials that assessed skin thinning (1050 participants) at the end of treatment. We assessed this evidence as low certainty. Other comparisons  Other comparisons included newer versus older preparations of topical corticosteroids (15 trials), cream versus ointment (7 trials), topical corticosteroids with wet wrap versus no wet wrap (6 trials), number of days per week applied (4 trials), different concentrations of the same topical corticosteroids (2 trials), time of day applied (2 trials), topical corticosteroids alternating with topical calcineurin inhibitors versus topical corticosteroids alone (1 trial), application to wet versus dry skin (1 trial) and application before versus after emollient (1 trial). No trials compared branded versus generic topical corticosteroids and time between application of emollient and topical corticosteroids. AUTHORS' CONCLUSIONS: Potent and moderate topical corticosteroids are probably more effective than mild topical corticosteroids, primarily in moderate or severe eczema; however, there is uncertain evidence to support any advantage of very potent over potent topical corticosteroids. Effectiveness is similar between once daily and twice daily (or more) frequent use of potent topical corticosteroids to treat eczema flare-ups, and topical corticosteroids weekend (proactive) therapy is probably better than no topical corticosteroids/reactive use to prevent eczema relapse (flare-ups). Adverse events were not well reported and came largely from low- or very low-certainty, short-term trials. In trials that reported abnormal skin thinning, frequency was low overall and increased with increasing potency. We found no trials on the optimum duration of treatment of a flare, branded versus generic topical corticosteroids, and time to leave between application of topical corticosteroids and emollient. There is a need for longer-term trials, in people with mild eczema.

MIC and Upper Limit of Wild-Type Distribution for 13 Antifungal Agents against a Trichophyton mentagrophytes-Trichophyton interdigitale Complex of Indian Origin.

Dermatophytosis due to the Trichophyton mentagrophytes-Trichophyton interdigitale complex is being increasingly reported across India. Reports of therapeutic failure have surfaced recently, but there are no clinical break points (CBP) or epidemiological cutoffs (ECVs) available to guide the treatment of dermatophytosis. In this study, a total of 498 isolates of the T. mentagrophytes-interdigitale complex were collected from six medical centers over a period of five years (2014 to 2018). Antifungal susceptibility testing of the isolates was carried out for itraconazole, fluconazole, ketoconazole, voriconazole, luliconazole, sertaconazole, miconazole, clotrimazole, terbinafine, amorolfine, naftifine, ciclopirox olamine, and griseofulvin. The MICs (in mg/liter) comprising >95% of the modeled populations were as follows: 0.06 for miconazole, luliconazole, and amorolfine; 0.25 for voriconazole; 0.5 for itraconazole, ketoconazole, and ciclopirox olamine; 1 for clotrimazole and sertaconazole; 8 for terbinafine; 16 for naftifine; 32 for fluconazole; and 64 for griseofulvin. A high percentage of isolates above the upper limit of the wild-type MIC (UL-WT) were observed for miconazole (29%), luliconazole (13.9%), terbinafine (11.4%), naftifine (5.2%), and voriconazole (4.8%), while they were low for itraconazole (0.2%). Since the MICs of itraconazole were low against the T. mentagrophytes-interdigitale complex, this could be considered the choice of first-line treatment. The F397L mutation in the squalene epoxidase (SE) gene was observed in 77.1% of isolates with a terbinafine MIC of ≥1 mg/liter, but no mutation was detected in isolates with a terbinafine MIC of <1 mg/liter. In the absence of CBPs, evaluation of the UL-WT may be beneficial for managing dermatophytosis and monitoring the emergence of isolates with reduced susceptibility.

Alarming India-wide phenomenon of antifungal resistance in dermatophytes: A multicentre study.

BACKGROUND: An alarming increase in recalcitrant dermatophytosis has been witnessed in India over the past decade. Drug resistance may play a major role in this scenario. OBJECTIVES: The aim of the present study was to determine the prevalence of in vitro resistance to terbinafine, itraconazole and voriconazole in dermatophytes, and to identify underlying mutations in the fungal squalene epoxidase (SQLE) gene. PATIENTS/METHODS: We analysed skin samples from 402 patients originating from eight locations in India. Fungi were identified by microbiological and molecular methods, tested for antifungal susceptibility (terbinafine, itraconazole, voriconazole), and investigated for missense mutations in SQLE. RESULTS: Trichophyton (T.) mentagrophytes internal transcribed spacer (ITS) Type VIII was found in 314 (78%) samples. Eighteen (5%) samples harboured species identified up to the T interdigitale/mentagrophytes complex, and T rubrum was detected in 19 (5%) samples. 71% of isolates were resistant to terbinafine. The amino acid substitution Phe397Leu in the squalene epoxidase of resistant T mentagrophytes was highly prevalent (91%). Two novel substitutions in resistant Trichophyton strains, Ser395Pro and Ser443Pro, were discovered. The substitution Ala448Thr was found in terbinafine-sensitive and terbinafine-resistant isolates but was associated with increased MICs of itraconazole and voriconazole. CONCLUSIONS: The high frequencies of terbinafine resistance in dermatophytes are worrisome and demand monitoring and further research. Squalene epoxidase substitutions between Leu393 and Ser443 could serve as markers of resistance in the future.

The current Indian epidemic of superficial dermatophytosis due to Trichophyton mentagrophytes-A molecular study.

The disease burden of chronic-relapsing and therapy-refractory superficial dermatophytosis dramatically increased in India within the past 5-6 years. In order to evaluate the prevalence of this trend, 201 skin scrapings were collected from patients from all parts of India and were tested for dermatophytes using both fungal culture and a PCR-ELISA directly performed with native skin scrapings. Fungal culture material was identified by genomic Sanger sequencing of the internal transcribed spacer (ITS) region and the translation elongation factor (TEF)-1α gene. In total, 149 (74.13%) out of the 201 samples showed a dermatophyte-positive culture result. Out of this, 138 (92.62%) samples were identified as Trichophyton (T.) mentagrophytes and 11 (7.38%) as Trichophyton rubrum. The PCR-ELISA revealed similar results: 162 out of 201 (80.56%) samples were dermatophyte-positive showing 151 (93.21%) T mentagrophytes- and 11 (6.79%) T rubrum-positive samples. In this study, we show for the first time a dramatic Indian-wide switch from T rubrum to T mentagrophytes. Additionally, sequencing revealed a solely occurring T mentagrophytes "Indian ITS genotype" that might be disseminated Indian-wide due to the widespread abuse of topical clobetasol and other steroid molecules mixed with antifungal and antibacterial agents.

Cutaneous Dysbiosis and Dermatophytosis: The Unexplored Link.

The skin, besides being the largest interface between the body and the external environment, also forms an ecological niche which is populated by almost a trillion microorganisms. These, collectively known as the cutaneous microbiome, form a dynamic yet well-controlled system that resists invasion by pathogenic microorganisms, functioning as the so-called 'microbiological barrier', modulating the body's immune response, indirectly playing a crucial role in the pathogenesis of several inflammatory diseases. The composition and complexity of the microbiome are yet to be fully understood. The term 'dysbiosis' originally was coined in 1908 for a change in the gut microbiome. The potential role of 'cutaneous dysbiosis' in human dermatophytic infections, especially in the backdrop of the current epidemic of chronic, recurrent and treatment-resistant dermatophytosis, is understandably a topic of interest. The purpose of this review was to assess all studies using culture-independent methods for analysing the skin microbiome in various dermatophyte infections. The PubMed and Google Scholar databases were searched using the terms 'microbiome', 'dysbiosis', 'dermatophytes', 'dermatophytosis' and 'tinea'. All studies involving the use of standard sequencing methods for the study of the microbiome in various dermatophytoses were included. A total of four studies assessing the local skin microbiome associated with dermatophytic infections were found-one for tinea capitis, one for onychomycosis (in both psoriatic and nonpsoriatic nails) and two studying patients of tinea pedis. The studies determined the microbiological patterns in patients and compared them with healthy individuals using sequencing methods. Significant differences in the species diversity and counts of the various microorganisms between patient and control groups were demonstrated in all. However, cross-sectional design and the absence of pre- and post-treatment data along with a limited sample size were the major limitations in all of them. No data regarding other forms of tinea, most importantly, tinea cruris, corporis, faciei, etc. were found. The existing studies demonstrate a change in the microbiome or dysbiosis associated with cases of dermatophytosis, but are inadequate to determine a causal association. The changes may also be wholly or partly attributed to the effect of the infection. Further longitudinal studies from different regions of the world, also involving other forms of dermatophytosis, are required to provide a clearer insight and a more representative picture.

Antifungal stewardship: What we need to know.

Antimicrobial stewardship refers to a well-coordinated program which promotes the scientific and rational use of antimicrobials, reduces the chances of drug resistance and improves patient outcomes. A comprehensive English language literature search was done across multiple databases (PubMed, EMBASE, MEDLINE and Cochrane) for the period 1990-2022, revealing a large volume of reports of growing resistance to established antifungal therapies, against a backdrop of irrational and unscientific prescriptions. As a result of this, antifungal stewardship, a new kid on the block, has recently garnered attention. This review article is an attempt to summarise the basic concept of stewardship programs, highlighting the dire need to implement the same in the present situation of antifungal resistance and treatment failure.

Proposal for a Severity Score (DeASI, Dermatophytosis Area and Severity Index) for the Evaluation of Dermatophyte Infections - A Delphi Consensus Study.

Background: There has been a significant increase in the incidence of recurrent, resistant, and extensive dermatophyte infections worldwide recently. This menace has spurred the need for more well-designed randomized controlled trials to optimize the treatment of dermatophyte skin infections. One of the limitations in designing such studies is the limited availability of standard and validated score, to measure the severity of dermatophyte infections. Aims: To create a severity score for the evaluation of dermatophyte infections. Materials and Methods: A Delphi consensus model was used to frame a severity scoring tool for superficial dermatophyte skin infections. Fourteen experts participated in the first round and twelve experts participated in the second round. Results: Based on the expert consensus, a final scoring system proposed was: Final Severity Score (FSS) = Sum total of Body Surface Area (BSA) in hand units for each patch multiplied by the sum of the scores for pruritis (P), lichenification (L), and actively raised borders (A) for each patch (FSS = BSA in hand units × (P + E + L + A) of patch 1 + BSA in hand units × (P + E + A) of patch 2 …etc.). For measuring hand units more accurately fractional values of 0.25 can be used (0.25 corresponding to an approximate 1/4th of a hand unit). A score of +1 will be added in case of the following - 1) Close contact/family member affected, 2) History of at least one recurrence in the previous 6 months after a course of oral antifungals, 3) History of immunosuppression (on immunosuppressive medication or having underlying immunosuppressive disease). The scores will be valid only if the patient has not used any treatment topical or systemic, for at least 2 weeks before enrolment. Conclusion: The proposed Dermatophytosis Area and Severity Index (DeASI) score will help the physicians and researchers standardize the treatment protocol for dermatophytosis, henceforth, assessing the response to therapy. This will also help to standardize the parameters of effectiveness while designing any clinical trial.

Effectiveness and safety of 0.5% timolol solution in the treatment of pyogenic granuloma: A randomized, double-blind and placebo-controlled study.

Introduction Pyogenic granulomas are benign vascular lesions of the skin and mucosa which are often a source of concern because of their recurrent bleeding even with minimal trauma. Current treatment for pyogenic granuloma is ablative; no medical therapy is standardized to date. Timolol, due to its vasoconstrictive effect, vascular growth factor inhibition and apoptosis promotion properties, is a potential therapeutic option. Objectives: To assess the effectiveness and safety of topical timolol in the treatment of pyogenic granulomas. Methods A two-centre, double-blind and placebo-controlled trial (Registration CTRI/2019/04/018581) was conducted. Patients of either sex were recruited with pyogenic granuloma lesions of less than eight weeks duration. Topical treatment with 0.5% timolol or matching glycerin placebo was continued for six weeks. Changes in color, size, bleeding tendency, physicians' and patients' global assessments and adverse events were assessed. Results Forty subjects were randomized between the two groups which were comparable in age, sex, duration of illness and baseline lesion size.Significant improvement was noted with timolol, with color change from first follow-up onwards and lesion size reduction from second follow-up onward. Patients' assessment of bleeding tendency also showed imrovement from the second visit onward. Between-group comparison showed significant difference with respect to percentage reduction in size (timolol 40.9%, placebo 3.4%; P = 0.002). Rescue treatment (electrosurgery) was required in five patients on placebo and in one in the timolol group (P = 0.182). Complete resolution occurred in 2 (10%) patients with timolol and in no patients on placebo (P = 0.231). Limitations: We observed effects of treatment for only six weeks. Conclusion Topical timolol may be a treatment option for early pyogenic granulomas but complete resolution is unlikely in six weeks. Studies of longer duration are required to assess resolution and recurrence rates.

The unprecedented epidemic-like scenario of dermatophytosis in India: II. Diagnostic methods and taxonomical aspects.

Trichophyton (T.) mentagrophytes now accounts for an overwhelming majority of clinical cases in India, a new "Indian genotype" (T. mentagrophytes ITS genotype VIII) having been isolated from skin samples obtained from cases across a wide geographical distribution in this country. The conventional diagnostic methods, like fungal culture, are, however, inadequate for diagnosing this agent. Thus, molecular methods of diagnosis are necessary for proper characterization of the causative agent. The shift in the predominant agent of dermatophytosis from T. rubrum to T. mentagrophytes, within a relatively short span of time, is without historic parallel. The apparent ease of transmission of a zoophilic fungus among human hosts can also be explained by means of mycological phenomena, like anthropization.

The unprecedented epidemic-like scenario of dermatophytosis in India: I. Epidemiology, risk factors and clinical features.

Dermatophytosis has attained unprecedented dimensions in recent years in India. Its clinical presentation is now multifarious, often with atypical morphology, severe forms and unusually extensive disease in all age groups. We hesitate to call it an epidemic owing to the lack of population-based prevalence surveys. In this part of the review, we discuss the epidemiology and clinical features of this contemporary problem. While the epidemiology is marked by a stark increase in the number of chronic, relapsing and recurrent cases, the clinical distribution is marked by a disproportionate rise in the number of cases with tinea corporis and cruris, cases presenting with the involvement of extensive areas, and tinea faciei.

The unprecedented epidemic-like scenario of dermatophytosis in India: III. Antifungal resistance and treatment options.

One of the canonical features of the current outbreak of dermatophytosis in India is its unresponsiveness to treatment in majority of cases. Though there appears to be discordance between in vivo and in vitro resistance, demonstration of in vitro resistance of dermatophytes to antifungals by antifungal susceptibility testing is essential as it may help in appropriate management. The practical problem in the interpretation of antifungal susceptibility testing is the absence of clinical breakpoints and epidemiologic cutoff values. In their absence, evaluation of the upper limit of a minimal inhibitory concentration of wild type isolates may be beneficial for managing dermatophytosis and monitoring the emergence of isolates with reduced susceptibility. In the current scenario, most of the cases are unresponsive to standard dosages and duration of treatment recommended until now. This has resulted in many ex-cathedra modalities of treatment that are being pursued without any evidence. There is an urgent need to carry out methodical research to develop an evidence base to formulate a rational management approach in the current scenario.

Risk of tuberculosis with anti-tumor necrosis factor-alpha therapy in patients with psoriasis and psoriatic arthritis in Indian population.

Anti-tumor necrosis factor-alpha (TNF-α) immunotherapy has revolutionized the treatment of inflammatory diseases, such as psoriasis and psoriatic arthritis. However, a major concern is that patients receiving this therapy have an increased risk of infection, particularly of reactivation of latent tuberculosis (TB). There were an estimated 10.4 million new cases of tuberculosis in 2016, worldwide, and India has one of the largest TB case burden with an estimated incidence of 2.79 million cases of TB in the same year. Anti-TNF agents like etanercept and infliximab are available in India approved for psoriasis and psoriatic arthritis. But long-term use of these agents possesses a risk of reactivation of latent TB. In this review article, we assessed the risk of TB with anti-TNF therapy especially in patients with psoriasis and psoriatic arthritis in India. At the end of the article, we have also suggested a recommendation for screening of latent tuberculosis and its management, before starting anti-TNF-α therapy.

Use of Topical Corticosteroids in Dermatology: An Evidence-based Approach.

Topical corticosteroids (TCs) are the pillars of dermatotherapeutics. These drugs are the "magic molecules," provided they are used judiciously and appropriately, following a rational prescription. On exhaustive literature search in multiple databases, we found a significant evidence favoring the use of TCs in atopic eczema, localized vitiligo, psoriasis, chronic hand eczema, and localized bullous pemphigoid. However, contrary to conventional wisdom, we did not find any high-level scientific evidence in support of prescribing TCs in cutaneous lichen planus, sarcoidosis, and seborrhoeic dermatitis. Besides, evidence clearly advocates judicious use of mild-to-moderate corticosteroids (if required) in pregnancy and lactation and there is no risk of any fetal abnormality.