Cambio en analisis de estudios de inmunoterapias en cancer

Abril 15, 2021

Long-Term Survival Rates for Immunotherapies Could Be Misinterpreted

Immune checkpoint inhibitors have transformed cancer care to the point where the popular Cox proportional-hazards model provides misleading estimates of the treatment effect, according to a study published in JAMA Oncology.

The findings suggest that some of the published survival data for these immunotherapies should be re-analysed for potential misinterpretation.

Yu Shyr, PhD, Vanderbilt University Medical Center, Nashville, Tennessee, and colleagues have proposed an adjustment to convert the inappropriate Cox proportional-hazards model to the appropriate cure model. The adjustment utilizes the Cox-TEL (Cox PH-Taylor expansion for long-term survival data) method.

"The Cox proportional-hazards model has become ingrained as the preferred choice for survival analysis in clinical trials for many reasons, including its robustness; however, researchers should not blindly use this in immunotherapy trials," said Dr. Shyr. "Because the model's proportional hazards assumption is clearly violated in some immunotherapy trials, the results and conclusions based on this model are inaccurate and misleading."

"We wanted to create an approach that would not only correct the hazard ratio of the Cox proportional-hazards model, but also be interpretable and practical for both clinicians and statisticians," he said. "We believe Cox-TEL will be used widely to avoid misinterpretation of clinical trials with long-term survival."

The team of researchers initiated their work because of the common observance of long tails and crossovers in survival curves with immune checkpoint inhibitors. These observances violate the proportional hazards assumption in the widely-used Cox proportional-hazards model.

Dr. Shyr and colleagues looked at simulated data and real-world data from published immune checkpoint inhibitor trials. In comparing the Cox proportional-hazards model to the Cox-TEL adjustment method, they determined that the Cox-TEL adjustment method was more accurate in assessing long-term survival.

"Comprehensive simulations show the strength of the proposed method in terms of power, bias, and type I error rate," the authors wrote. "The magnitude of potential difference between reported and adjusted HRs using real-world immune checkpoint inhibitor trial results is demonstrated. For example, in the CheckMate 067 trial (nivolumab/ipilimumab combination therapy vs ipilimumab), the Cox HR was 0.54 (95% confidence interval, 0.44-0.67), and the Cox-TEL HR was 0.90 (95% confidence interval, 0.73-1.11)."

"The findings of this study suggest the need to revisit published immune checkpoint inhibitor survival data analysis to address potential misinterpretation," the authors concluded. "The Cox-TEL method not only is designed for this purpose, but also is user friendly and easy to implement using published clinical trial data and a freely available R software package.

Reference: https://jamanetwork.com/journals/jamaoncology/article-abstract/2778199

SOURCE: Vanderbilt University Medical Center

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DO NOT GET BURNED BY MISSING STAPHYLOCOCCAL SCALDED SKIN SYNDROME

By Warren Heymann, MD
April 28, 2021
Vol. 3, No. 17

I would be surprised if any first-year dermatology resident could not differentiate Staphylococcal scalded skin syndrome (SSSS) from toxic epidermal necrolysis (TEN). What is straightforward now was a source of confusion for decades. The following is an elegant summation by Mockenhaupt et al of how dermatology has arrived at the current understanding of SSSS: 

"Staphylococcal scalded skin syndrome (SSSS) is a rare, systemic blistering skin disorder. The clinical features were first described in 1878 by Baron Gottfried Ritter von Rittershain, who observed 297 cases among children in a single Czechoslovakian foundling asylum in a 10-y period Presumably in 1891 Staphylococcus aureus (S. aureus) was isolated from a patient with SSSS. The disease received little attention until Alan Lyell in 1956 described toxic epidermal necrolysis (TEN), a skin eruption resembling scalding of the skin. It soon became apparent that exfoliation associated with S. aureus infection occurred specifically in the zona granulosa of the epidermis, whereas the condition without association to bacteria showed splitting at the dermoepidermal junction. Based on these histological features, the former condition was renamed SSSS and the latter TEN. Nevertheless, the confusion persisted for decades, because both diseases were often referred to as 'Lyell's syndrome,' sometimes also called 'staphylococcal TEN or Lyell's syndrome 'versus drug TEN.' Involvement of toxins from S. aureus in SSSS was proved in 1970 after injection of sterile fluids obtained from intact bullae and from culture medium of phage II S. aureus into neonatal mice. Meanwhile, four different serotypes of exfoliative toxins named ETA, ETB, ETC, and ETD are identified. Biochemical, molecular biological, and crystallographical data of ETA and ETB indicate that both toxins are atypical glutamic acid-specific trypsin-like serine proteases, which have no significant binding to any part of the body apart from the skin. Therefore, wherever the toxin is released from a toxin-producing bacterial colony in the body, the toxin accumulates in the skin and causes disruption of desmosomes via proteolytic cleavage of desmoglein I." (1)

Image from DermNetNZ, provided by Prof. Raimo Suhonen.

What can possibly be new about SSSS? Four aspects – 1) epidemiology; 2) causation; 3) the clinical spectrum; and 4) therapeutic approach.

Epidemiology 

The incidence of SSSS seems to be increasing in recent years. The Nationwide Inpatient Sample 2008-2012 was analyzed, including a 20% sample of U.S. hospitalizations and 589 cases of SSSS. The mean annual incidence of SSSS was 7.67 per million U.S. children, with 45.1 cases per million U.S. infants age < 2 years. (2) Utilizing the same database, the annual incidence among U.S. adults was 0.98 cases per million. (3).

Causation 

To date, the exfoliative toxins have been associated with only certain strains of S. aureus, most of which have been methicillin-susceptible S. aureus (MSSA). As noted above, strains causing SSSS were usually reported as belonging to phage group II. More recent studies have reported isolates belonging to sequence types (ST) 15, ST121, ST 2126, and ST2993, using multilocus sequence typing (MLST). Of these, ST121 has been most commonly reported as a cause of SSSS. (4) Doudoulakakis et al had observed a sharp increase in SSSS settings since 2015, with 31 cases having been documented during the period 2014-2017. The molecular investigation of strains from that period demonstrated the emergence of a methicillin-susceptible, mupirocin- and fusidic acid-resistant Staphylococcus aureus clone belonging to the ST121 complex and carrying both epidermolysin (eta/etb) genes. (5) Additionally, while the SSSS exfoliation has been mainly attributed to the effects of the ETs, studies have also reported the Panton-Valentine leukocidin (PVL) genes associated with SSSS isolates. (4)

Clinical spectrum

Mazori et al note that SSSS classically presents with acute‐onset, generalized, tender erythema with flexural accentuation, flaccid blisters, periorificial crusting and radial fissuring; the Nikolsky sign is positive. As previously discussed, although the blisters of SSSS are sterile, S. aureus may be cultured from sites of infection or colonization where the toxins originate prior to dissemination, notably the conjunctivae, nares, perioral skin, axillae, umbilicus and anus. Patients are characteristically febrile, irritable, lethargic and anorexic. Although this classic severe phenotype is widely recognized in children, SSSS is spectrum of disease with mild and moderate variants. The authors presented four variant cases in infants. Physical examination demonstrated varying degrees of nontender erythema and superficial desquamation with periorificial, flexural and/or acral accentuation. All patients had a negative Nikolsky sign. One patient was febrile; vital signs were otherwise normal in all patients. One patient had leukocytosis. Although the reason for the SSSS phenotypic variability is unknown, it has been hypothesized that toxin load may play a role, with milder phenotypes having increased renal toxin clearance and/or higher levels of neutralizing antibodies. The authors emphasize that appreciating the variability of SSSS is crucial as the condition is potentially fatal; however, with medical management, the mortality rate in children is as low as 0.33%. (6)

SSSS in adults is a different story. Patients at risk include those who are immunosuppressed (notably HIV/AIDS), have severe renal impairment or failure, or in those with malignancies. The mortality rate is much higher in adults than children, having been reported as high as 59%. (7)

Therapeutic approach

Wang et al retrospectively studied 51 patients with SSSS; sensitivity data were available for 28 patients. Resistance to clindamycin was observed in 17 isolates (63%), erythromycin in 18 isolates (69%), and trimethoprim/sulfamethoxazole in 2 isolates (7%). No isolates were resistant to oxacillin or vancomycin. The authors concluded SSSS-associated isolates were more likely to be clindamycin-resistant and less likely to be methicillin-resistant compared to overall staphylococcal infections. They favor cephalosporins and penicillinase-resistant penicillins (eg, oxacillin) for empiric management of SSSS, with consideration of adding MRSA coverage in communities with high MRSA prevalence or failure to improve following several days of treatment. Although clindamycin has been touted to reduce toxin production, the authors found no benefit to adding clindamycin to the regimen. (8) 

Supportive care for management of dehydration, thermoregulation, and nutritional support is crucial. Emollients and non-adherent dressing should be applied to the skin and denuded areas to promote healing and reduce heat loss. (7)

In conclusion, even though it has been more than 140 years since it was first described, SSSS is a dynamic disorder with a spectrum of clinical presentations and an altered microbiology that demands our attention.

Point to remember: SSSS may present on a clinical spectrum and has been increasing in incidence. Although vastly more common in infants, adults with immunosuppression and renal impairment are at risk, with a much greater mortality. Changes in pathogenesis may be related to mupirocin resistance. 

Our expert's viewpoint

Bernard Cohen, MD
Professor of Dermatology and Pediatrics
Johns Hopkins University School of Medicine

There is clear evidence that the incidence of SSSS has increased dramatically in the United States over the last 2 decades. As a result, it is important that we train our medical colleagues, particularly pediatricians, to recognize the clinical findings and to distinguish SSSS from toxic epidermal necrolysis/Stevens-Johnson syndrome. They need to know that the toxins target desmoglein 1, which is present high in the epidermis, but not in mucous membranes.

Interestingly, in our series at the Johns Hopkins Children's Center none of the affected children had an identifiable primary bacterial infection; positive cultures were obtained from sites of colonization including the nares, conjunctivae, umbilicus, and perianal area. There was some variability in the clinical presentations, but most demonstrated classical findings including diffuse erythema, erosions around sites of minor trauma (particularly intertriginous and periorificial areas), and a positive Nikolsky sign. In our series we excluded 2 children who developed SSSS during prolonged hospitalizations for complications of prematurity. None of our patients were immunodeficient, on immunosuppressive medications, or had decreased renal function. 

Moreover, the length of hospitalization in our patients averaged 2 days, regardless of the antibiotic administered and whether or not the organism was sensitive or resistant to the antibiotic. Many clinicians have pushed for use of clinidamycin because it suppresses toxin production, but even in those patients who were given clindamycin montherapy, there was no change in length of hospitalization. Additionally, resistance of the causative organisms to clindamycin is approaching or exceeding 50%. 

It makes me wonder if an antibiotic is helpful when a primary infection is not identified in otherwise healthy immunocompetent patients. I understand that the standard of care is administration of systemic antibiotics, and in light of our finding that 100% were MSSA, we recommend a cephalosporin and penicillinase-resistant penicillins with consideration of adding MRSA coverage in communities with a high incidence of MRSA, until culture and sensitivities are available.

Management of pain, fluids and electrolytes, and good skin care is critical. We discouraged narcotics since pain usually decreased dramatically within 36-48 hours with aggressive use of topical emollients — non-stick dressings and debridement was a no-no! Frequent application of emollients to the crusty vermillion border was critical to maintain oral intake in all patients, including bottle and breast feeding in young infants.

In short, SSSS is not rare, hospitalization in otherwise healthy children is usually short with proper management, and primary infections in healthy children is uncommon. Therapeutically, use of antibiotics may not change the generally favorable outcome if good skin care is provided; however, in children and adults with immunosuppression and/or renal disease the risk of morbidity and mortality is significant, and these patients need to be evaluated and treated aggressively.

1. Mockenhaupt M, Idzko M, Grosber M, Schöpf E, Norgauer J. Epidemiology of staphylococcal scalded skin syndrome in Germany. J Invest Dermatol 2005; 124: 700-703.

2. Staiman A, Hsu DY, Silverberg JI. Epidemiology of staphylococcal scalded skin syndrome in US children. Br J Dermatol 2018; 178: 704-708. 

3. Staiman A, Hsu DY, Silverberg JI. Epidemiology of staphylococcal scalded skin syndrome in US adults.

4. Hultén KG, Kok M, King KE, Lamberth LB, Kaplan SL. Increasing number of Staphylococcal scalded skin syndrome caused by ST121 in Houston, Texas. Pediatr Infect Dis J 2020; 39: 30-34. 

5. Doudoulakakis A, Spilopoulou I, Syridou G, Giormezis N, et al. Emergence of staphylococcal scalded skin syndrome associated with a new toxinogenic, methicillin-susceptible Staphylococcus aureus clone. J Med Micobiol 2019; 68: 48-51. 

6. Mazori DR, Leonard A, Alexander JB, Glick SA. The spectrum of staphylococcal scalded skin syndrome: A case series in children. Br J Dermatol 2020; 45: 333-336. 

7. Ross A, Shoff HW. Staphylococcal scalded skin syndrome. StatPearls [Internet], Treasure Island (FL). StatPearls Publishing; 2020 Jan. 

8. Wang Z, Feig JL, Mannschreck DB, Cohen BA. Antibiotic sensitivity and clinical outcomes in staphylococcal scalded skin syndrome. Pediatr Dermatol 2020; 37: 222-223.

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Treatment of Patients Experiencing Dupilumab Facial Redness With Itraconazole and Fluconazole Journal of the American Academy of Dermatology

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• At a single institution, patients with dupilumab–induced facial redness treated with either oral itraconazole or fluconazole were evaluated. Facial redness occurred in 5.3% of all patients treated with dupilumab and began at an average 8.5 months after treatment initiation. In the itraconazole group, 11 of 16 patients were clear or almost clear up to 6 months later. In contrast, none of the 4 patients treated with fluconazole saw resolution of their symptoms.

• Systemic antifungal therapies appear to be effective in many patients with dupilumab–induced facial redness. While the sample size was small, these findings suggest that itraconazole may be more effective than fluconazole when used for this purpose.

–  Margaret Hammond, MD

Abstract

Dupilumab facial redness (DFR) is a recently described adverse event of dupilumab use.1 Prior cases of treatment with itraconazole have been reported.2 In this retrospective study, we investigated the management of DFR with itraconazole or fluconazole. This study was approved by the Tufts Medical Center (TMC) Institutional Review Board. Patients at TMC Dermatology who were on dupilumab for at least 16 weeks, had a diagnosis of DFR, and completed at least two weeks of daily fluconazole or itraconazole 200 milligrams (mg) were included. Investigator global assessment (IGA) before and after azole use, dupilumab associated ocular surface disease (DOSD), and self-reported improvement (%), obtained from a routine pharmacist phone call two weeks after azole initiation, were recorded. DOSD was defined as irritation, dryness, tearing, or conjunctivitis.

Journal of the American Academy of Dermatology

Treatment of Patients Experiencing Dupilumab Facial Redness With Itraconazole and Fluconazole: A Single Institutional Retrospective Medical Record Review

J Am Acad Dermatol 2021 Mar 25;[EPub Ahead of Print], DX Gao, S Song, JS Kahn, SR Cohen, K Fiumara, N Dumont, D Rosmarin 

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Skin Care Physicians of Costa Rica

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Contact Allergy in Patients With Chronic Venous Leg Ulcers

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• In this study, 97 patients with chronic leg ulcers (CLUs) due to venous stasis present for more than 6 weeks (mean duration of ulcer, 3.8 years) were patch tested using the Leg Ulcer Series (LUS), which contains 27 chemicals and 5 additional substances pertinent for wound treatment. Of these, 52 patients underwent additional patch testing with the European Baseline Series (EBS). Patch testing was positive for 31 of 97 patients (32%) for the LUS and 5 additional substances with wood tar mix, benzalkonium chloride, fusidic acid, INTRASITE Gel, budesonide, and hydrocortisone-17-butyrate being the most frequent allergens. Of the 52 patients, 27 (52%) tested to the EBS had positive patch test readings with Myroxylon pereirae, fragrance mix, and colophonium being the most frequent allergens in this series.

• Although this study is limited as readings were only performed on day 3, the authors noted a high prevalence of contact allergy in chronic venous leg ulcer patients. They also identified multiple relevant allergens that are commonly used in this patient population and recommend patch testing with the LUS and EBS to avoid using treatments that could hinder wound healing.

– Alex Noble, MD

Written by

 

 

Christen Maria Mowad MD

Chronic leg ulcers are a common clinical problem in the dermatologist's office. Leg ulcerations can be due to numerous underlying etiologies but can also be complicated by contact allergy, which can delay wound healing. Allergic contact dermatitis can be increased in this setting due to the impaired epidermal barrier and the multitude of products and dressings applied to the wounds.

This study from Norway evaluated contact allergy in patients with chronic leg ulcers due to venous stasis that were present for 6 weeks or more. Patch testing was performed with the Leg Ulcer Series and the European Baseline Series (EBS). The patients removed the patches themselves after 48 hours and presented to clinic for one reading conducted at day 3. The most frequent allergens in the leg ulcer series were to wood tar mix, benzalkonium chloride, and fusidic acid, as well as INTRASITE Gel and topical steroids. The most common allergens in the EBS were Myroxylon pereirae, fragrance mix, colophonium, and thiuram mix. In this study, 40% of patients with a positive patch test had one reaction, 33% had two reactions, 10% had three reactions, and 17% had four or more reactions, reminding us that multiple allergens can be common in this scenario due to the reality that numerous potential allergens are applied to the wound. 

The study is limited by the solitary reading at day 3 and is also limited in part by the geographic differences in products and wound dressing practices that may not translate to similar allergens being generalizable to other regions or countries. However, the study does highlight the need for clinicians to consider contact allergy in the setting of chronic leg ulcerations.

Dermatologists should consider contact allergy in the setting of any chronic wounds when routine wound care does not result in typical healing, there is significant surrounding dermatitis, significant pruritus, or if a wound was progressing and then halts or worsens. The potential allergens include all topical preparations, both-over-the counter and prescription, as well as the dressings particular to the patient and the clinic where he/she is being treated.

Abstract 

Contact allergy (CA) is prevalent in patients with chronic leg ulcers (CLUs) due to venous stasis1and may delay wound healing. Exposure to different ointments and wound dressings over time, combined with occlusive bandaging, may predispose to contact sensitization.2The spectrum of allergens depends on wound care practices.3, 4 Studies on CA in patients with CLUs from Norway are lacking. To determine the occurrence of CA in patients with CLUs, patch testing was performed with the Leg Ulcer Series (LUS) containing 27 chemicals and five additional substances relevant to wound treatment: Caine mix III and V, hydrocortisone, IntraSite gel (propylene glycol 20%, Smith & Nephew), and Brulidine (dibrompropamidine 0.15%, Sanofi‐Aventis) (Table S1). Fifty‐two of the 97 patients were also tested with the European Baseline Series (EBS) (Table S2).

Contact Dermatitis

Contact Allergy in Patients With Chronic Venous Leg Ulcers

Contact Derm 2020 Dec 27;[EPub Ahead of Print], AH Lossius, M Lorentzen, J Austad, TK Bergersen 

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Skin Care Physicians of Costa Rica

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Association Between Topical Calcineurin Inhibitor Use and Risk of Cancer JAMA Dermatology

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• The authors conducted a systematic review to determine the pooled relative risk (RR) estimates for overall cancer risk and specific cancer types in patients using topical calcineurin inhibitors (TCIs). There was no association between TCI use and overall cancer risk compared with nonactive comparators. There was also no significant association between TCI use and skin cancers, including melanomas and keratinocyte carcinomas. There was an increased risk of lymphoma noted with TCI use compared with nonactive (RR, 1.86) and corticosteroid comparators (RR, 1.35).

• Although this meta-analysis identified an increased RR of lymphoma with TCI use, the authors suggest that this increment translates to a very small increase in the risk of lymphoma for each patient, as the absolute risk of lymphoma is low.

–  Alex Noble, MD

Abstract

IMPORTANCE

Topical calcineurin inhibitors (TCIs) are commonly used as second-line treatment for atopic dermatitis. In 2006, the US Food and Drug Administration issued a black box warning against TCI use, citing data from case reports and animal studies indicating a potential risk of cancer.

OBJECTIVE

To evaluate the association between TCI use and risk of malignant neoplasms compared with nonactive and active comparator groups.

DATA SOURCES

Electronic searches were conducted in MEDLINE via Ovid, Embase via Ovid, and Web of Science from database inception to August 21, 2020.

STUDY SELECTION

Observational studies investigating the association between treatment with TCIs (ie, tacrolimus and pimecrolimus) and the development of cancer with nonactive or active comparators were included. The population of interest was not limited to any specific disease state, age, or sex. All articles were assessed independently and in duplicate by 2 reviewers. Risk of bias was assessed using the Newcastle-Ottawa scale. Of 2464 nonduplicate records retrieved from the search, 11 studies met the inclusion criteria.

DATA EXTRACTION AND SYNTHESIS

Data extraction was conducted independently by 2 reviewers according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Random-effects meta-analyses were used to derive pooled relative risk (RR) estimates. Data were analyzed from July 25 to October 25, 2020.

MAIN OUTCOMES AND MEASURES

Risk of cancer overall and risk of specific cancer types (lymphoma, melanoma, and keratinocyte carcinoma).

RESULTS

Eight unique cohort studies (408 366 treated participants [55.1% female], 1 764 313 nonactive comparator controls, and 1 067 280 controls using topical corticosteroids) and 3 unique case-control studies (3898 cases [55.0% male] and 14 026 cancer-free controls [52.4% male]) were included. There was no association between TCI use and cancer overall compared with nonactive comparators (RR, 1.03; 95% CI, 0.92-1.16). Lymphoma risk was elevated with TCI use with both nonactive (RR, 1.86; 95% CI, 1.39-2.49) and topical corticosteroid comparators (RR, 1.35; 95% CI, 1.13-1.61). No significant association was found between TCI use and increased skin cancer (melanoma and keratinocyte carcinoma).

CONCLUSIONS AND RELEVANCE

The findings of this systematic review and meta-analysis suggest an association between TCI use and risk of lymphoma but not other cancers. Combined with the low absolute risk of lymphoma, the potential increased risk attributable to TCI use for any individual patient is likely very small.

JAMA Dermatology

Association Between Topical Calcineurin Inhibitor Use and Risk of Cancer, Including Lymphoma, Keratinocyte Carcinoma, and Melanoma: A Systematic Review and Meta-Analysis

JAMA Dermatol 2021 Mar 31;[EPub Ahead of Print], M Lam, JW Zhu, M Tadrous, AM Drucker

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Skin Care Physicians of Costa Rica

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Contact Sensitizations to Disinfectants Containing Alcohols or Quaternary Ammonium Compounds Contact Dermatitis

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• The patch test results of 145 patients with suspected contact allergy to disinfectants were retrospectively evaluated to determine if ethanol, 1-propanol, and isopropanol could represent relevant allergens. There were no strong positive reactions but 8 patients reacted positively to one of these components. Each of the patients testing positive to any of the alcohols underwent repetitive open application tests (ROATs) and only 1 had a positive ROAT to 1-propanol. In addition, 85 of these patients underwent patch testing with didecyldimethylammonium chloride (DDAC) 0.03% and DDAC 0.05%. Additionally, none of the positive DDAC patch tests were deemed clinically relevant.

• Alcohols and DDAC are rarely implicated in allergic contact dermatitis in disinfectants and testing for other potential allergens should be pursued in these cases. The authors recommend ROATs to confirm positive patch test results given that disinfectants can also lead to irritant skin reactions.

–  Alex Noble, MD

Written by

Christen Maria Mowad MD

Disinfectants have been used daily in the medical field. The COVID-19 pandemic has made the use of disinfectants ubiquitous in society as well as we all try and adhere to important infection-control recommendations. Frequent use of these products can result in clinical findings that could be allergic or irritant contact dermatitis. By nature of the compounds, irritant contact dermatitis is likely part of the process. This study investigated allergic contact dermatitis to these disinfectants in a retrospective manner. The authors evaluated 145 patients with suspected allergic contact dermatitis to disinfectants. The patients were tested to different alcohols: ethanol, 1-propanol, and isopropanol, as well as didecyldimethylammonium chloride (DDAC), a quaternary ammonium compound used for disinfection. The authors point out that optimal patch test concentrations have not been determined and that no commercially available patch test for DDAC is available. Only 1 patient had a possible allergy to 1-propanol. Only 1 patient reacted to DDAC, but it had no clinical relevance. The authors concluded that DDAC and alcohols are rare allergens. Irritant contact dermatitis, as well as other allergens, including fragrances, emollients, and preservatives, should be considered when evaluating possible causes for clinical findings upon exposure to disinfectants. Patch testing should be considered in these situations; however, this study concludes that the alcohols and the DDAC compounds are rarely the problem.

Abstract

BACKGROUND

The use of disinfectants is part of the everyday life of people, especially in the medical profession. During the coronavirus disease 2019 (COVID-19) pandemic, the use of disinfectants continues to increase and is of fundamental importance in infection control.

OBJECTIVES

To determine the frequency of sensitization and the value of patch testing to didecyldimethylammonium chloride (DDAC) and the alcohols ethanol, 1-propanol, and isopropanol.

METHODS

Clinical patch test data of 145 patients with suspected contact allergy to disinfectants were retrospective analysed.

RESULTS

Among the 145 patients patch tested with the different alcohols, only one nurse was detected with a possible allergy to 1-propanol. Additional patch testing in 84 patients with DDAC 0.05% resulted in five patients with weakly positive reactions only, without clinical relevance. Patch testing with DDAC 0.03% showed no positive reactions at all on day 3 readings.

CONCLUSIONS

DDAC and alcohols are rarely responsible for allergic contact dermatitis. The accused products of the patients should be checked for other allergens and further additives with skin-irritating properties. Individual susceptibility and mishandling of the disinfectants should be considered.

Contact Dermatitis

Contact Sensitizations to Disinfectants Containing Alcohols or Quaternary Ammonium Compounds Are Rarely of Clinical Relevance

Contact Derm 2021 Mar 24;[EPub Ahead of Print], K Kreipe, S Forkel, KE Heinemann, K Amschler, T Fuchs, J Geier, T Buhl

Nonavalent HPV Vaccine for the Treatment of Multiple Recalcitrant Warts Journal of the American Academy of Dermatology

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• A cohort of 45 adults with recalcitrant plantar or periungual warts was treated with the recombinant 9-valent human papilloma virus (HPV) vaccine at 0, 2, and 6 months. Complete clearance 3 months after the final vaccination dose was seen in 62.2% of patients, while 8.9% had a partial response, and 28.9% showed no response. The mean time to response was 12.8 weeks after the first injection. In the complete response group, no recurrence was observed, but the follow-up time was not specified.

• In some patients, a course of the 9-valent HPV vaccine may lead to complete clearance of recalcitrant warts. Further prospective trials would be useful to confirm these findings, but this treatment modality can be added to the existing array of wart treatments.

–  Margaret Hammond, MD

Written by




Alfredo Siller Jr., MD

Written by




Austinn Miller MD

Written by




Stephen K. Tyring MD, PhD

Despite the numerous modalities available to treat warts, those which are recalcitrant continue to represent a challenge among experienced clinicians. An increasing number of reports have mentioned recalcitrant warts treated with intralesional human papillomavirus (HPV) vaccine. In 2019, Waldman et al performed a retrospective cohort study reviewing 16 cases of recalcitrant warts treated with intralesional quadrivalent HPV vaccine. Results were promising, with 7 (44.0%) demonstrating complete clearance, comparable to outcomes reported for warts treated with Candida antigen, imiquimod, and squaric acid dibutylester, which are all among therapies study participants had previously failed.

More recently, this article presents an open-label, uncontrolled, single-arm study exploring the use of intralesional 9-valent HPV vaccine in 45 patients with recalcitrant warts. The majority of patients had plantar/periungual warts and were injected at 0, 2, and 6 months, with a final assessment performed 3 months after completing all vaccinations. Complete clearance was seen in 28 patients (62.2%). No recurrence was observed during this period. Interestingly, the response rate in patients aged >26 years (55.0%) was lower than that in patients aged 9 to 26 years (84.0%). This indicates that the efficacy of HPV vaccination might decrease with increasing age.

Given these results, it appears the HPV vaccine (especially the 9-valent) is a promising modality for recalcitrant warts. It possesses advantages of less pain and convenience over conventional destructive methods. Although controlled studies comparing the nonavalent vaccine to adjuvant are needed to determine its true effectiveness, clinicians should consider intralesional administration of a 9-valent HPV vaccine for recalcitrant warts. Moreover, it deserves consideration for eligible (aged <46 years with insurance) candidates who require HPV vaccination to prevent HPV-related anogenital cancer.

Beyond HPV vaccines, numerous intralesional treatments for recalcitrant warts are being explored. Preliminary studies on therapeutic agents that have demonstrated approximately ≥90% clearance include vitamin D, zinc, bleomycin, and cidofovir.

Abstract

Although there are various therapeutic modalities for the management of warts, no single treatment has proven definitive. Recently, an increasing number of reports have mentioned warts treated with the human papillomavirus (HPV) vaccine. The mechanism of action of the HPV vaccine might be considered as a cross-protective effect and systemic response.¹ Only a few cases treated with 9-valent HPV vaccine have been reported. We performed an open-label, uncontrolled, single arm study of a 9-valent HPV vaccine for the treatment of multiple recalcitrant warts. The study was approved by the institutional review board of Pusan National University Hospital (IRB No.05-2020-255).

Journal of the American Academy of Dermatology

Nonavalent Human Papilloma Virus Vaccine for the Treatment of Multiple Recalcitrant Warts: An Open Label Study

J Am Acad Dermatol 2021 Mar 27;[EPub Ahead of Print], JO Shin, JH Son, J Lee, HS Kim, HC Ko, BS Kim, MB Kim, K Shin

MTX en AA

Oral Methotrexate Monotherapy for Severe Alopecia Areata

TAKE-HOME MESSAGE

• In this retrospective review, 15 adults and children with severe alopecia areata refractory to other therapies were treated with oral methotrexate monotherapy. Improvement was observed in 13 patients, all of whom demonstrated maximal improvement within the first year of therapy. Nausea was reported by 2, but none discontinued therapy due to side effects. No laboratory abnormalities were observed in the short term but long-term laboratory follow-up was not available.

• Oral methotrexate may be an effective and accessible treatment option for severe alopecia areata patients, but larger prospective trials are needed to verify these results.

–  Margaret Hammond, MD

Written by

Amos Gilhar MD

Alopecia areata (AA) negatively affects quality of life and may lead to psychological disorders. However, treatment of AA remains challenging. The reasons for this are that topical treatments are largely unsuitable for severe AA, whereas long-term systemic treatment has problematic safety profiles and rapid relapse. Therefore, significant unmet needs exist in the treatment of AA. 

The aim of the Kinoshita-Ise study was to determining the efficacy and risk of MTX as a monotherapy in AA. A total of 15 severe AA patients were included in the study, among them 9 males and 6 females; 8 patients were under the age of 18 years. The results of the study demonstrated complete hair regrowth in 13 patients after 1 year of treatment, without major side effects, indicating that MTX monotherapy may serve as an optional therapy for severe AA patients. However, the small number of patients did not allow us to assess fully the benefits and risks of MTX treatment in pediatric patients and adults following long-term MTX treatment, as well as the treatment's efficacy in the different types of AA, in gender, and in different ages of onset.

Furthermore, there is no control group in this study that includes MTX monotherapy combined with corticosteroids. MTX has been used as monotherapy and an adjuvant to corticosteroids, so it's quite crucial to compare the efficacy of both modes of treatment. 

According to previous publications and the current one, it appears that MTX monotherapy is reasonably effective in treating severe AA. However, the recently revealed therapeutic potential of JAK inhibitors in AA management created a huge buzz worldwide and raised hope for a breakthrough in treating AA. JAK inhibitors, just like other systemic treatments for AA, might also have increased the risk of malignancy and infections as they inhibit important immunosurveillance mechanisms. Therefore, it is urgent to identify and explore additional therapeutic targets for AA immunotherapy.

Abstract

BACKGROUND

Although several therapeutic options have been suggested for alopecia areata (AA), none of them are consistently effective, thus making the management of severe or refractory cases challenging. Several studies have recently reported the usage of methotrexate (MTX) in AA; however, the pure effect of MTX monotherapy remains elusive.

OBJECTIVE

To evaluate efficacy and safety of oral methotrexate monotherapy for AA.

METHODS

We retrospectively reviewed the clinical course of AA patients including pediatric cases treated with MTX monotherapy. Their detailed clinical data including original severity of AA, final treatment outcome, the duration until the maximum response, and side effects, were assessed. Statistical analysis was performed to evaluate if the clinical factors including the duration of current alopecia, age, the presence of body hair loss, and sex were associated with treatment response.

RESULTS

All included patients had severe AA and failed standard therapies. Thirteen out of 15 cases demonstrated improvement during the monotherapy, and all responders demonstrated the maximum response within 1 year. Female patients had significantly better outcomes than male patients. Other factors did not significantly influence on the treatment outcome. None of the patients experienced side effects that were severe enough to terminate the treatment.

CONCLUSIONS

Our results support MTX monotherapy as a feasible option for severe AA patients who fail other standard therapies or for whom systemic corticosteroids are contraindicated.

Journal of cutaneous medicine and surgery

Oral Methotrexate Monotherapy for Severe Alopecia Areata: A Single Center Retrospective Case Series

J Cutan Med Surg 2021 Mar 09;[EPub Ahead of Print], M Kinoshita-Ise, M Sachdeva, SA Martinez-Cabriales, NH Shear, P Lansang

Laser en pelo junto con OC

Combined Oral Contraceptives or Metformin Plus Laser Treatment in Polycystic Ovarian Syndrome Hirsute Patients

Journal of Drugs in Dermatology

 1 Expert Comment

TAKE-HOME MESSAGE

• In this study 150 patients with polycystic ovarian syndrome (PCOS) and hirsutism were divided into treatment groups undergoing laser hair removal (LHR) alone, LHR plus metformin, or LHR plus combined oral contraceptives.

• All patients showed improvement in visual analog scale scores and quality of life scores after treatment, but those treated with LHR in combination with oral contraceptives showed significantly more improvement in quality of life than other treatment groups.

–  Caroline K. Crabtree, MD

Dermatology

Written by



Dee Anna Glaser MD

Hirsutism in women is a common clinical problem in the dermatologist's office. Medical management alone be inadequate in my experience, and hair removal procedures are helpful but need long-term maintenance.

This study from Egypt evaluated 150 females with facial hirsutism with a confirmed diagnosis of polycystic ovarian syndrome (PCOS) and no contraindication to receiving laser or hormonal therapy. They were randomized into treatment with diode 810 nm laser only (group 1), laser plus metformin 500 mg daily (group 2), or laser plus oral contraceptive containing 35 μg ethinyl estradiol and 2 mg cyproterone daily (group 3). There were 6 monthly laser sessions in all groups, with follow-up at 3 and 6 months post laser.

Quality measures (DLQI), a hirsutism questionnaire (HLQI) and a visual analog scale were used throughout, with no significant differences among groups prior to treatment. All three groups had improvement in the DLQI and HLQI relative to pretreatment, and this continued at 3 and 6 months of follow-up. Group 3, however, had a higher level of improvement in DLQI and HQLI at each session and at 3 and 6 months post treatment when compared with groups 1 and 2. In this study, laser hair removal let to improvement in the quality measures, but it was not maintained 6 months following the laser sessions. Also, the addition of metformin to laser hair removal failed to induce a greater improvement in quality measures with laser sessions or at 3 and 6 months' follow-up.

This study is limited by small numbers in each group and the short follow-up period, but does reinforce current practice that laser hair removal alone may not be sufficient to treat hirsutism in the setting of PCOS and that hormonal therapy as used in this study with ethinyl estradiol / cyproterone when combined with laser hair removal is superior. Finding non-hormonal therapy is still needed as, in my experience, many of patients with PCOS have fertility issues and can spend significant time trying to get pregnant. A key take-home point is that therapy for hirsutism must be maintained even with laser systems, and that combination therapies can be beneficial; good counseling about expectations is very important.

abstract

This abstract is available on the publisher's site.

Background

Hirsutism is estimated to affect 10% to 20% of females, provoking significant psychological damage and social embarrassment. Polycystic ovary syndrome is a major cause of hirsutism.

Aim

Assessing the impact of adding combined oral contraceptives (COCs) or metformin to laser hair removal on the quality of life of polycystic ovarian syndrome (PCOS) patients with hirsutism.

Methodology

One-hundred-fifty PCO patients diagnosed with hirsutism were included in this study. Patients were randomized into three groups: group 1 received laser hair removal alone, group 2 received metformin and laser hair removal, and group 3 received COCs and laser hair removal. A diode laser with a wavelength of 810 nm was used for hair removal in all patients according to a protocol of 6 monthly sessions followed by another two sessions after three and six months. Patients were assessed using a visual analog scale (VAS) and Dermatology Life Quality Index (DLQI) and a customized questionnaire (Hirsutism Life Quality Index; HLQI).

Results

All patients showed a significant improvement in both quality indices (DLQI and HLQI) after treatment relative to pretreatment. Group 3 showed significantly better improvements when compared with group 2 and group 1. At three and six months, group 3 showed non-significantly better DLQI and HLQI as compared with at zero months. On the other hand, group 2 patients displayed significant worsening of both DLQI and HLQI scores at three months, with subsequent improvements again at six. Finally, group 1 patients showed nonsignificant worsening at three months, and significant worsening at 6 months.

Conclusion

Combining hormonal treatment with laser hair removal can achieve greater hair reduction, significant improvements in patients' QOL, and better maintenance as compared with when combining metformin with laser hair removal or conducting alone.

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Journal of Drugs in Dermatology

Adding Combined Oral Contraceptives or Metformin to Laser Treatment in Polycystic Ovarian Syndrome Hirsute Patients

J Drugs Dermatol 2021 Mar 01;20(3)302-306, N Dorgham, A Sharobim, H Haggag, M El-Kalioby, D Dorgham