Targeted Systemic Therapies for Adults with Atopic Dermatitis: Selecting from Biologics and JAK Inhibitors.

Therapeutic options for people with moderate or severe atopic dermatitis refractory to topical therapy have rapidly expanded in recent years. These new targeted immunomodulatory agents-biologics and Janus kinase (JAK) inhibitors-have each demonstrated high levels of efficacy and acceptable safety in mostly placebo-controlled clinical trials for atopic dermatitis, but there is no universally applicable algorithm to help choose between them for a given patient. Hence, patients and physicians should utilize shared decision making, discussing efficacy, safety, mode of delivery, monitoring, costs, speed of onset, and other factors to reach individualized treatment decisions. In this review, we try to aid shared decision making by summarizing the efficacy, safety, and monitoring of biologics and oral JAK inhibitors for adults with atopic dermatitis. Network meta-analyses suggest that higher doses of abrocitinib and upadacitinib are more effective than biologics. They also show that, among biologics, dupilumab is likely more effective than tralokinumab and lebrikizumab. Biologics are generally considered safer than JAK inhibitors, although concerns about JAK inhibitors are mainly extrapolated from older generation JAK inhibitors used in higher-risk populations. We also outline evidence and considerations for choosing and using systemic immunomodulatory treatments for special populations including pregnant individuals, those with human immunodeficiency virus (HIV), hepatitis B and C, end stage kidney disease, and older adults.

Comparing binary efficacy outcomes for systemic immunomodulatory treatments for atopic dermatitis in a living systematic review and network meta-analysis.

BACKGROUND: Systemic treatments for atopic dermatitis (AD) are evaluated primarily in placebo-controlled trials with binary efficacy outcomes. In a living systematic review and network meta-analysis (NMA), we previously analysed continuous efficacy measures. OBJECTIVES: To compare binary efficacy outcomes of systemic treatments for AD. METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Latin American and Caribbean Health Science Information (LILACS) database, Global Resource for Eczema Trials (GREAT) database and trial registries up to 1 March 2023. We included randomized trials examining ≥ 8 weeks of treatment with systemic immunomodulatory medications for moderate-to-severe AD. We screened titles, abstracts and full texts and abstracted data independently, in duplicate. Outcomes included the proportion of patients achieving at least 50%, 75% and 90% improvements in Eczema Area and Severity Index (EASI 50, EASI 75 and EASI 90, respectively) and Investigator Global Assessment (IGA) success. We performed random-effects Bayesian NMAs to calculate odds ratios (OR) and 95% credible intervals (CrIs) between each intervention for each outcome. RESULTS: Eighty-three trials with 22 122 participants were included in the systematic review. In analyses limited to trials of 8-16 weeks' duration with predominantly adult populations, abrocitinib 200 mg daily (OR 1.5, 95% CrI 1.1-2.2) and upadacitinib 15 mg daily (OR 1.7, 95% CrI 0.9-3.3) and 30 mg daily (OR 2.5, 95% CrI 1.3-5.0) were associated with higher odds of achieving EASI 50 vs. dupilumab. Abrocitinib 100 mg daily (OR 0.7, 95% CrI 0.5-1.0), baricitinib 2 mg daily (OR 0.4, 95% CrI 0.3-0.5) and 4 mg daily (OR 0.5, 95% CrI 0.3-0.7), and tralokinumab (OR 0.4, 95% CrI 0.3-0.6) were associated with lower odds of achieving EASI 50 vs. dupilumab. Results were similar for EASI 75, EASI 90 and IGA success. CONCLUSIONS: Supporting results for continuous outcome measures, upadacitinib 30 mg daily and abrocitinib 200 mg daily are the most efficacious with regard to binary efficacy endpoints up to 16 weeks in adults with moderate-to-severe AD, followed by upadacitinib 15 mg daily, dupilumab and abrocitinib 100 mg daily. Dupilumab and both doses of upadacitinib and abrocitinib are more efficacious than baricitinib 4 and 2 mg daily and tralokinumab.

Systemic Therapy for Atopic Dermatitis in Older Adults and Adults With Comorbidities: A Scoping Review and International Eczema Council Survey.

BACKGROUND: Clinical trials of systemic therapies for atopic dermatitis (AD) often exclude patients based on age and comorbidities. OBJECTIVES: We conducted a scoping review of observational studies and survey of International Eczema Council (IEC) members on the treatment of AD in patients with liver disease, renal disease, viral hepatitis, HIV, or history of malignancy. METHODS: We searched MEDLINE via Ovid, Embase via Ovid, and Web of Science from inception to September 14, 2020. We mapped the available evidence on the use of cyclosporine, methotrexate, azathioprine, mycophenolate, systemic corticosteroids, and dupilumab for AD in older adults (≥65 years) and adults with the previously mentioned comorbidities. We surveyed IEC members on their preferred systemic medications for each patient population. RESULTS: We identified 25 studies on the use of systemic medications in special populations of adults with AD. Although IEC members preferred dupilumab as the first-line systemic agent across all special populations, many could not identify viable third-line systemic therapy options for some populations. CONCLUSIONS: Data on systemic therapy for AD for older adults and adults with comorbidities are limited. Although IEC members' access to systemic therapies differs geographically, expert opinion suggests that dupilumab is preferred for those patients.

A systematic review of oral retinoids for treatment of acneiform eruptions induced by epidermal growth factor receptor inhibitors.

Epidermal growth factor receptor inhibitors (EGFRi) are now standard of care in patients with EGFR mutations in non-small cell lung cancer (NSCLC) and are increasingly being used in other EGFR mutated cancers, including gastrointestinal, and head and neck. However, EGFRi are well known to cause acneiform eruptions, which are shown to positively correlate with tumor response to treatment, but may be severe enough to cause interruption of their treatment. Although most guidelines call for the use of tetracyclines to treat these acneiform eruptions, there is mounting evidence for the use of systemic retinoids instead. The objective of this review is to summarize available data on the use of systemic retinoids for management of acneiform eruptions on EGFRi. This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. MEDLINE and EMBASE were searched from database inception until December 10th, 2021. All articles were screened and relevant data extracted independently in duplicate by two reviewers. In total, 16 case reports, case series and retrospective reviews were included. Forty-three patients were treated with retinoids for their acneiform eruption due to EGFRi. The majority (77%) noted moderate to significant improvement after treatment initiation with minimal adverse events (16%). The findings of this systematic review suggest that systemic retinoids are a safe and effective therapy for the management of acneiform eruptions induced by EGFRi.

The Impact of Acne Treatment on Skin Bacterial Microbiota: A Systematic Review.

BACKGROUND: Microbial strains such as Cutibacterium acnes have been examined as contributors to the pathogenesis of acne. Given the prevalence of the disease among adolescents and adults, the overutilization of antimicrobial agents may breed resistance and alter commensal microflora. OBJECTIVES: To characterize the impact of acne treatment on the diversity and relative abundance of the cutaneous microbial community, particularly of the bacterial flora. METHODS: An electronic search was conducted of Embase, MEDLINE, and the Cochrane Central Register of Controlled Trials (CENTRAL) on June 5, 2020. Interventional and observational studies examining patients receiving acne treatment with culture-independent, community-level analysis of the cutaneous microbiome were included. RESULTS: Nine studies with 170 treated acne patients were included. Five studies reported a significant change in alpha diversity following treatment, 3 of which examining systemic antibiotics reported significant increases in diversity. Two of 3 studies examining effects of benzoyl peroxide reported a decrease in diversity. However, trends in diversity were heterogeneous among studies. CONCLUSIONS: While individual variability in microbiome composition, and study-level heterogeneity in study sampling techniques may limit quantitative synthesis, our results support findings that acne treatment, including those not considered to have antimicrobial properties, alters the composition of the cutaneous microbiome.PROSPERO registration: CRD42020190629.

Racial Differences in the Prognosis and Survival of Cutaneous Melanoma From 1990 to 2020 in North America: A Systematic Review and Meta-Analysis.

BACKGROUND: Factors influencing the difference in the diagnosis and treatment of melanoma in racial minority groups are well-described in the literature and include atypical presentations and socioeconomic factors that impede access to care. OBJECTIVE: To characterize the differences in melanoma survival outcomes between non-Hispanic white patients and ethnic minority patients in North America. METHODS: We conducted searches of Embase via Ovid and MEDLINE via Ovid of studies published from 1989 to August 5, 2020. We included observational studies in North America which reported crude or effect estimate data on patient survival with cutaneous melanoma stratified by race. RESULTS: Forty-four studies met our inclusion criteria and were included in this systematic review. Pooled analysis revealed that black patients were at a significantly increased risk for overall mortality (HR 1.42, 95% CI, 1.25-1.60), as well as for melanoma-specific mortality (HR 1.27, 95% CI, 1.03-1.56). Pooled analyses using a representative study for each database yielded similar trends. Other ethnic minorities were also more likely report lower melanoma-specific survival compared to non-Hispanic white patients. CONCLUSION: Our results support findings that melanoma patients of ethnic minorities, particularly black patients, experience worse health outcomes with regards to mortality. Overall survival and melanoma-specific survival are significantly decreased in black patients compared to non-Hispanic white patients. With the advent of more effective, contemporary treatments such as immunotherapy, our review identifies a gap in the literature investigating present-day or prospective data on melanoma outcomes, in order to characterize how current racial differences compare to findings from previous decades.

Effect of Bariatric Surgery on Natriuretic Peptide Levels: A Systematic Review and Meta-Analysis.

The effect of bariatric surgery on natriuretic peptide levels in patients with obesity is unclear. The purpose of this study was to conduct a systematic review and meta-analysis to determine the effect of bariatric surgery on B-type natriuretic peptide (BNP) and aminoterminal BNP (NT-proBNP) levels. MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials were searched to February 2020. Primary outcomes included change in NT-proBNP or BNP levels following bariatric surgery and change in weight and body mass index. Secondary outcomes included change in blood pressure, echocardiographic findings, and heart failure symptoms. MINORS tool was used to assess quality of evidence. Twelve studies with 622 patients were included. Most patients underwent Roux-en-Y gastric bypass (RYGB) (70.5%). Mean absolute reduction in body mass index was 23%. NT-proBNP levels increased significantly from baseline at 6 months (mean difference [MD] 53.67 pg/mL; 95% confidence interval [CI], 28.72-78.61; P ≤ 0.001, I2 = 99%; 8 studies) and 12 months (MD 51.16 pg/mL; 95% CI, 20.46-81.86; P = 0.001, I2 = 99%; 8 studies) postbariatric surgery. BNP levels also increased significantly at 6 months (MD 17.57 pg/mL; 95% CI, 7.62-27.51; P < 0.001, I2 = 95%; 4 studies). Systolic and diastolic blood pressure decreased significantly 12 months after surgery. Studies measuring echocardiographic findings saw improvement in left ventricle mass and the E/A ratio, but no significant change in ejection fraction. Bariatric surgery is associated with increased natriuretic peptide levels in the absence of deteriorating cardiac function, and may be associated with improved cardiac and metabolic function after the procedure.

Therapeutic Options for the Treatment of Darier's Disease: A Comprehensive Review of the Literature.

Darier's disease (also known as keratosis follicularis or dyskeratosis follicularis) is an autosomal dominant inherited disorder which manifests as hyperkeratotic greasy papules in the first or second decade of life. Aside from symptom management and behavioral modifications to avoid triggers, there are currently no validated treatments for Darier's disease (DD). However, a variety of treatments have been proposed in the literature including retinoids, steroids, vitamin D analogs, photodynamic therapy, and surgical excision. The purpose of this review article is to identify therapeutic options for treating DD and to outline the evidence underlying these interventions. A search was conducted in Medline for English language articles from inception to July 4, 2020. Our search identified a total of 474 nonduplicate studies, which were screened by title and abstract. Of these, 155 full text articles were screened against inclusion/exclusion criteria, and 113 studies were included in our review. We identified Grade B evidence for the following treatments of DD: oral acitretin, oral isotretinoin, systemic Vitamin A, topical tretinoin, topical isotretinoin, topical adapalene gel, topical 5-flououracil, topical calciptriol and tacalcitol (with sunscreen), grenz ray radiation, and x-ray radiation. All other evidence for treatments of DD consisted of case reports or case series, which is considered grade C evidence. Considering the quality and quantity of evidence, clinicians may consider initiating a trial of select topical or oral retinoids first in patients with localized or generalized DD, respectively.

The Use of Teledermatology in Medical Education.

Certain aspects of medical education have transitioned to virtual platforms since the start of the COVID-19 pandemic. This commentary explores advantages and barriers to teledermatology in medical education, which has the potential to reach an extensive pool of learners and preceptors but may be limited by logistical and security considerations of a virtual platform. Dermatology in particular lends itself to an online platform as a highly visual specialty, although clinical exam would be highly dependent on quality of images captured. With teledermatology, learners can begin developing an approach to delivering care remotely, and becoming accustomed to virtual platforms.

Sudden Sensorineural Hearing Loss and Metabolic Syndrome: A Systematic Review and Meta-analysis.

OBJECTIVE: The objective of this systematic review and meta-analysis is to examine the association between sudden sensorineural hearing loss (SSNHL) and risk of metabolic syndrome (MetS), and the association between MetS and prognosis of SSNHL. DATABASES REVIEWED: We systematically searched MEDLINE, Embase, and Cochrane Central Register electronic databases from their dates of conception to February 4, 2020. METHODS: We included observational studies analyzing 1) the prevalence of MetS among SSNHL patients, or 2) the prognosis of SSNHL patients in MetS patients. A standardized form was completed in duplicate extracting data on study characteristics, participant demographics, and SSNHL outcome or recovery measures. Random-effects meta-analyses were performed pooling odds ratios using the generic inverse method. Risk of bias was assessed using the Newcastle Ottawa Scale. RESULTS: Three studies examining the prevalence of MetS among patients with SSNHL (11,890 total participants; 3,034 SSNHL participants) yielded a significantly increased risk of MetS among SSNHL, with a pooled odds ratio of 1.88 (95% CI, 1.01-3.50). Three studies examining the association of SSNHL prognosis in patients with MetS (608 SSNHL participants, 234 concomitant SSNHL, and MetS participants) demonstrated that SSNHL patients with MetS were significantly more likely to have poorer recovery compared to SSNHL patients without MetS (pooled odds ratio 2.77; 95% CI, 2.33-3.28). CONCLUSION: Our findings suggest an association between prevalence of MetS and SSNHL, as well as poorer prognosis of SSNHL in patients with concomitant MetS.

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

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.

Safety of Systemic Medications Among Older Adults With Psoriasis and Atopic Dermatitis: A Systematic Review of Observational Studies.

BACKGROUND: Psoriasis and atopic dermatitis are common among older adults (≥65 years old), but clinical trials often exclude that population. OBJECTIVE: To synthesize evidence from observational studies on the safety of systemic therapies (conventional or biologic) for psoriasis and atopic dermatitis among older adults in a systematic review. METHODS: We searched MEDLINE and EMBASE (inception to October 31, 2019) and included observational studies reporting adverse events among older people treated with systemic therapy for psoriasis or atopic dermatitis. Outcomes were death, hospitalization, emergency department visits, infections, major cardiovascular events, renal toxicity, hepatotoxicity, and cytopenias. We assessed study quality using the Newcastle-Ottawa Scale. RESULTS: We included 22 studies on treatment for psoriasis and 2 for atopic dermatitis. Most studies were small and non-comparative and 20 of 24 were low quality. Studies comparing safety between medications or medication classes or between older and younger adults did not show apparent differences but had wide confidence intervals around relative effect estimates. Heterogeneity of study design and reporting precluded quantitative synthesis. CONCLUSIONS: There is scant evidence on the safety of conventional systemic and biologic medications for older adults with psoriasis or atopic dermatitis; older adults and their clinicians should be aware of this evidence gap.

Hidradenitis suppurativa and Down syndrome: A systematic review and meta-analysis.

BACKGROUND: Hidradenitis suppurativa (HS), characterized by inflammatory nodules, sinus tracts, and abscesses, has been linked to several factors, including immune dysfunction and obesity, which are thought to contribute to its development. Several follicular disorders have also been associated with Down syndrome (DS), a common chromosomal disorder, including HS, although studies on this topic are limited. OBJECTIVES: To characterize HS in Down syndrome patients and to further examine the association between HS and DS compared to HS patients without DS. METHODS: We systematically searched MEDLINE, Embase, Web of Science, and CENTRAL electronic databases from their dates of conception to February 2020. Random-effects meta-analyses were performed analyzing (a) HS characteristics between DS and non-DS participants, and (b) prevalence or association between HS and DS compared to non-DS individuals. RESULTS: Twelve studies were included in this systematic review, with a total of 358 participants presenting with both HS and DS. Pooled analysis of mean differences between DS and non-DS participants presenting with HS found a significantly younger age of HS symptom onset for DS patients (-6.24; 95% CI, -10.01--2.24). A meta-analysis examining the association between HS and DS found a significantly increased likelihood of HS in DS patients (OR 9.61; 95% CI, 5.70-16.20). CONCLUSIONS: Our findings suggest an association between HS and DS, with DS patients suffering from an earlier onset of HS symptoms compared to non-DS patients.

The Incidence and Prevalence of Uveitis in Psoriasis: A Systematic Review and Meta-Analysis.

BACKGROUND: The systemic effects and comorbidities of psoriasis include ocular disorders, such as uveitis. Patients with psoriatic arthritis in particular have been demonstrated to have an elevated risk for developing uveitis. Presently, the risk of uveitis in psoriasis has yet to be fully elucidated and this systematic review seeks to address this gap. OBJECTIVE: To examine the prevalence and incidence of uveitis in psoriasis patients compared to non-psoriasis patients. METHODS: We conducted a systematic review search on MEDLINE, Embase, and CENTRAL electronic databases with no lower limit on year of publication. RESULTS: Fourteen articles met our inclusion criteria, with a total of 234 143 psoriasis subjects. Two studies found that participants with severe psoriasis were at a greater risk of uveitis than those with mild psoriasis. A random-effects meta-analysis of the 3 studies, which reported risk of incidence of uveitis in psoriasis patients compared to non-psoriasis controls, found a pooled risk ratio of 1.29 (95% CI, 1.10-1.51), indicating an increased risk of uveitis in psoriasis. Three studies compared risk of uveitis in psoriatic arthritis with psoriasis-only participants, all finding that psoriatic arthritis was associated with a greater risk of uveitis. CONCLUSIONS: In summary, our findings suggest that psoriasis is associated with an increased risk of uveitis, with or without psoriatic arthritis.

Inclusion of Older Adults in Randomized Clinical Trials for Systemic Medications for Atopic Dermatitis: A Systematic Review.

Importance: Despite increasing evidence that atopic dermatitis is common in older adults, it is unclear whether the evidence base for treating atopic dermatitis with systemic therapy is generalizable to that population. Older adults are most at risk for adverse events from medications, given age-related alterations in drug metabolism, increased comorbidity, and polypharmacy. Objective: This systematic review examines the representation of older adults in randomized clinical trials (RCTs) of systemic immunomodulatory treatments for atopic dermatitis and whether safety and efficacy data are reported specifically for older individuals. Evidence Review: The Cochrane Central Register of Controlled Trials, Embase, MEDLINE databases, and the ClinicalTrials.gov trial register were searched from inception (MEDLINE via Ovid, 1946; Embase via Ovid, 1974) to November 7, 2019. RCTs investigating systemic immunomodulatory treatments for adults with atopic dermatitis were included. Titles, abstracts, and full-text papers were screened, and data were extracted in duplicate. Findings: A total of 32 trials with 4547 participants were reviewed. The mean (SD) age of trial participants was 34.4 (5.4) years. The median number of participants per trial was 44 (range, 10-740). Eleven trials (34%) reported explicit upper age limits ranging from 42 to 70 years of age. Most of these trials (n = 9) examined safety and effectiveness of cyclosporine. Twenty-two trials (69%) had other exclusion criteria that might disproportionately exclude older adults. In total, 10 trials (31%) included adults aged 65 years or older. Within 7 trials that reported the proportion of participants aged 65 and older (all evaluating dupilumab), 112 of 2964 participants (4%) were 65 years or older. None of the included trials reported stratified safety or effectiveness data for older adults. Conclusions and Relevance: Study results suggest that older adults are underrepresented in RCTs of systemic treatment for atopic dermatitis, resulting in a lack of evidence supporting safe clinical use for older adults. Clinicians and patients should be aware of this evidence gap when prescribing systemic therapy for atopic dermatitis. Randomized trials and observational studies that include older patients with atopic dermatitis are needed.