Guselkumab is an IL-23 inhibitor; secukinumab is an IL-17A inhibitor

Guselkumab (Tremfya; Janssen), an interleukin (IL)-23 inhibitor, was found to be superior to secukinumab (Cosentyx; Novartis), an IL-17A inhibitor, in achieving Psoriasis Area Severity Index [PASI]) 90 responses in patients with moderate to severe plaque psoriasis, according to data from a Phase 3 head-to-head trial.

In the ECLIPSE study (N=1048), patients were randomized to receive guselkumab 100mg at weeks 0, 4, and 12 followed by every 8-week dosing or secukinumab 300mg at weeks 0, 1, 2 3, 4 followed by every 4-week dosing. The primary endpoint was the proportion of patients achieving a PASI 90 response at week 48.

Results showed that at 84.5% of patients treated with guselkumab achieved at least 90% improvement in their baseline PASI score vs 70% of patients treated with secukinumab (P <.001) at week 48. In addition, guselkumab was found to be noninferior to secukinumab in achieving PASI 75 response at weeks 12 and 48 (84.6% vs 80.2%; P <.001) but was not superior (P =.062). 

Other secondary endpoints included PASI 100 response and Investigator’s Global Assessment (IGA) scores of 0 and 1. At week 48, a greater proportion of guselkumab-treated patients achieved PASI 100 vs secukinumab-treated patients (58.2% vs 48.4%).  Also, 62.2% of patients receiving guselkumab achieved IGA score of 0 vs 50.4% of patients who received secukinumab; 85.0% and 74.9% of patients in the guselkumab and secukinumab  groups achieved IGA score of 1, respectively (all comparisons with nominal P ≤.001). Regarding tolerability, treatment discontinuation was seen in 5.1% of guselkumab patients and 9.3% of secukinumab patients. 

“The response-over-time curves show that maximum response rates with Tremfya are achieved after 6 months and are maintained over time through 1 year, achieving superiority at the primary endpoint of the study,” said lead study investigator Richard Langley, MD, FRCPC, Professor, Division of Clinical Dermatology & Cutaneous Science, Department of Medicine, Dalhousie University. “Results of the study confirm a slightly more rapid onset of response with Cosentyx, but importantly, in a chronic disease like psoriasis, these data provide new insights into comparative longer-term efficacy.”

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Investigators analyzed demographics, rates of reaction to nickel, strength of nickel reactions, and nickel allergy sources.

Nickel sensitivity has significantly increased in the last 20 years in North America, and incidence varies by demographics, according to a results from a retrospective, cross-sectional analysis published in the Journal of the American Academy of Dermatology.

Data from 44,097 patients patch-tested to gauge sensitivity to nickel (nickel sulfate hexahydrate 2.5% petrolatum) were collected from 1994 to 2014. Additional variables included sex, age, race, atopy (hay fever, eczema, asthma), dermatitis sites (≥3), and clinical relevance. Up to 3 final diagnoses and occupational relatedness were also recorded in the dataset.

Nickel sensitivity was defined as a mild (nonvesicular/erythematous/infiltrated/possible papules), strong (edematous/vesicular), or extreme (spreading/bullous/ulcerative) reaction to nickel at second reading.

Nickel sensitivity increased significantly over the study period, from 14.3% in 1994-1996 to 20.1% in 2013-2014 (P <.0001), with the overall frequency at 17.5% from 1994 to 2014 (7729/44,097 patients). Patients with nickel sensitivity were more likely to be female (relative risk [RR] 3.13; 95% CI, 2.94-3.33), ≤18 years of age (RR 1.49; 95% CI, 1.39-1.61), nonwhite, (RR 1.19; 95% CI, 1.14-1.27), and/or atopic (RR 1.09; 95% CI, 1.05-1.14).

Eczema (RR 1.10; 95% CI, 1.05-1.15) and asthma (RR 1.11; 95% CI, 1.05-1.17) were significantly associated with nickel sensitivity, though hay fever was not. Patients presenting with nickel sensitivity were significantly more likely to have a final diagnosis of allergic contact dermatitis (RR 2.31; 95% CI, 2.20-2.43).

Current clinical relevance increased significantly, from 44.1% in 1994-1996 to 51.6% in 2013-2014 (P <.0001). Occupational relatedness decreased from 7.9% in 1994-1996 to 1.9% in 2013-2014 (P <.0001). Jewelry consistently remained the most common source of nickel dermatitis, even after sources were stratified by age and sex.

Limitations to this study include the inability to follow up with the patients because of the study design and that potential sources of nickel dermatitis were limited to those with codes in the North American Contact Dermatitis Group source list.

Disclosures: Several authors acknowledge competing interests; please see original reference for a full list of authors’ disclosures.

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Reference

Warshaw EM, Zhang AJ, DeKoven JG, et al. Epidemiology of nickel sensitivity: retrospective cross-sectional analysis of North American Contact Dermatitis Group (NACDG) data 1994-2014 [published online October 18, 2018]. J Am Acad Dermatol. doi: 10.1016/j.jaad.2018.09.058

Two network meta-analysis studies provide validity and usefulness of systemic therapies to treat psoriasis.

Findings from a study published in the British Journal of Dermatology that analyzed 2 previously published network meta-analyses (NMA) support the validity and usefulness of systemic therapies for moderate to severe psoriasis.

This study analyzed 2 previously published NMAs that assessed systemic therapies for moderate to severe psoriasis with the outcome of either “‘clear/nearly clear’ and withdrawals from adverse events” (ZJL Study) or “improvement of 90% or more on the Psoriasis Area and Severity Index (PASI 90) and serious adverse events” (ES study). Both NMAs performed comparative analyses on the efficacy and safety of systemic therapies (ie, biologics and methotrexate in the ZJL study or traditional systemics or new oral agents in the ES study) to treat moderate to severe psoriasis. The study populations included mostly adults.

The authors noted that both previously published studies are “of high quality and provide a comprehensive summary of the evidence base and treatment effects.”

They added that both studies used best practices for conducting and reporting the systematic reviews. Both studies also used the Cochrane risk of bias tool, wherein 10 of 38 total trials had similar ratings for all domains. Discrepancies in the validity and analysis sensitivity of the assessment tool and incongruities in the analysis of the “study-level data using NMA models with random-effects for the treatment parameters” were noted.

The authors also discussed the conditional nature in treatment rankings, which is dependent upon the included treatments for comparison, and cumulative rankings previously published. Finally, the authors highlighted the correct use of a random-effect NMA model to address heterogeneity but questioned the previous studies’ analyses for consistency.

The investigators identified the following as study limitations: the need for a longer time frame for outcomes assessment, the lack of testing of newly available agents since the publication of the previous 2 studies, and the lack of real-world data to improve generalizability. 

Taken together, the authors noted the validity and usefulness of the results from both network meta-analyses in regard to “clearing of psoriasis skin lesions at relevant time-points and improvement in quality of life” for patients affected by moderate to severe psoriasis.

Disclosures: Multiple authors declare affiliations with the pharmaceutical industry. Please refer to original reference for a full list of authors’ disclosures.

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Reference

Ellis AG, Flohr C, Drucker AM. Network meta-analyses of systemic treatments for psoriasis: a critical appraisal [published online October 22, 2018]. Br J Dermatol. doi: 10.1111/bjd.17335

The recommendation to use TNFi biologics in treatment-naive patients with PsA will represent a major change in practice for many rheumatologists. Photo Credit: Hercules Robinson

A new guideline jointly issued by the American College of Rheumatology and the National Psoriasis Foundation (ACR/NPF) on the treatment of psoriatic arthritis (PsA) includes a conditional recommendation to use tumor necrosis factor inhibitor (TNFi) biologics over oral small molecule drugs as first-line therapy in patients with active disease.¹ The guideline provides evidence-based pharmacologic and nonpharmacologic recommendations on the management of treatment-naive patients with active PsA and patients who have active PsA despite therapy, with a focus on long-term treatment. The intended audience for the guideline includes both clinicians and patients at risk for or with PsA.

Dafna Gladman, MD, FRCPC, rheumatology professor of medicine at the University of Toronto and member of the NPF Medical Board who served as a content expert on the guideline’s core team, told Rheumatology Advisor that the recommendation to use TNFi biologics in treatment-naive patients with PsA will represent a major change in practice for many rheumatologists. “Most other recommendations identify methotrexate as the first line [treatment], followed by biologic agents,” she noted. “GRAPPA [Group for Research and Assessment of Psoriasis and Psoriatic Arthritis] recommendations suggest moving to biologic agents immediately if there are bad prognostic signs.”

The recommendation to use biologics as first-line treatment also diverges from recommendations by the European League for Rheumatism (EULAR) for PsA. EULAR recommends oral small molecule drugs as first-line agents for treatment-naive patients as the preferred therapy over biologics. EULAR’s recommendation was in part because of the lower cost of conventional oral small molecule agents, a consideration that the ACR/NPF panel ranked lower than the quality of evidence pointing to the benefit of TNFi biologics.^1,2

Another key recommendation in the ACR/NPF guideline is a conditional recommendation to use a treat-to-target strategy for all patients with active PsA. Treating to target involves the regular assessment of disease activity using objective outcome measures. Based on the results of these measures, treatments are adjusted until predefined therapeutic targets are achieved. The ACR/NPF guideline does not stipulate a particular target, but suggests that minimal disease activity or Disease Activity of Psoriatic Arthritis low disease activity or remission criteria be used.

“Treat-to-target is key, because it encompasses all clinical scenarios, rather than one particular clinical situation,” stated Jasvinder Singh, MD, MPH, a rheumatologist at University of Alabama at Birmingham and principal investigator for the guideline project, in a press release accompanying the guideline’s release.³ “The available evidence suggests the irreversible joint damage, associated functional limitations, joint deformities, and disability associated with PsA could possibly be avoided/delayed with optimal disease management using a targeted approach. A targeted approach can also improve pain, function, and quality of life and social participation.”

The ACR/NPF guideline also provides recommendations regarding the use of drugs in the context of comorbidities such as inflammatory bowel disease, diabetes, and serious infections; what to do with vaccinations; and recommendations for smoking cessation, exercise, physical therapy, and occupational therapy.

The guideline was created using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system. In addition to an assessment of the benefits and harms of the treatment options under consideration and the quality of evidence, the GRADE methodology takes into consideration the values and preferences of patients. An expert panel, including patients, patient advocates, rheumatologists, dermatologists, and a rheumatologist nurse practitioner determined the consensus and strength of the recommendations. A panel of 9 patients with PsA, most of whom had received biologic therapy, reviewed the evidence and provided input on recommendations, factoring in their own personal experience.

Because of limited data in some areas, the quality of evidence in the guideline was often graded low or very low. This led to 94% of recommendations being designated as “conditional,” with the remaining 6% designated as “strong.” Conditional recommendations apply to the majority of patients but may not be appropriate for all, necessitating a shared decision-making approach. Strong recommendations apply to all or nearly all patients.

The strong recommendations in the guideline include 3 that apply to adult patients with active PsA and concomitant active inflammatory bowel disease (an extra-articular manifestation of PsA) despite treatment with an oral small molecule drug such as methotrexate:

• Switch to a TNFi monoclonal antibody biologic over switching to a TNFi biologic soluble receptor biologic
• Switch to a TNFi monoclonal antibody biologic over switching to an interleukin (IL)-17i biologic
• Switch to an IL-12/IL-23i biologic over switching to an IL-17i biologic

The other strong recommendations in the guideline are:

• In adult patients with active PsA and frequent serious infections who are naive to oral small molecule and biologic drugs, start an oral small molecule drug over a TNFi biologic.
• In adult patients with active PsA, recommend smoking cessation over no smoking cessation.

Dr Gladman cautioned that the guideline does not cover all the complexities of PsA. “Further recommendations will need to be developed for other features not covered here, axial disease as an example. Moreover, the major limitation of all the guidelines and recommendations is the fact that we do not have comparative studies of the various drugs currently available. Research will concentrate on doing such studies, as well as understanding the pathogenesis, or mechanism of disease, better, so that additional target for therapeutic intervention could be developed. Moreover, we aim to develop an even better personalized approach based on clinical and biomarker information.”

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References

1. Singh JA, Guyatt G, Ogdie A, et al. 2018 American College of Rheumatology/National Psoriasis Foundation Guideline for the Treatment of Psoriatic Arthritis [published online November 30, 2018]. Arthritis Rheumatol. doi: 10.1002/art.40726
2. Gossec L, Smolen JS, Ramiro S, et al. European League Against Rheumatism (EULAR) recommendations for the management of psoriatic arthritis with pharmacological therapies: 2015 update. Ann Rheum Dis. 2016;75(3):499-510.
3. National Rheumatology and Psoriasis Organizations Release Joint Guideline for Treating Psoriatic Arthritis [press release]. Atlanta, Georgia: American College of Rheumatology. https://www.rheumatology.org/About-Us/Newsroom/Press-Releases/ID/986. Published December 4, 2018. Accessed December 4, 2018.

The ability of secukinumab vs placebo to clear nail psoriasis was evaluated using the Nail Psoriasis Severity Index.

Patients with moderate to severe nail psoriasis experienced clinically meaningful efficacy and significant quality of life improvements with secukinumab treatment, according to study results published in the British Journal of Dermatology.

Researchers in this placebo-controlled, double-blind, randomized study (TRANSFIGURE) evaluated the efficacy of secukinumab (both 150 mg and 300 mg) compared with placebo for moderate to severe plaque and nail psoriasis for a total of 132 weeks. Presented in this publication were the results from the week 32 interim analysis. This time period was chosen because fingernails typically take approximately 6 months to fully grow out to the distal edge from the nail matrix.

A total of 198 study participants were randomly assigned into a placebo group (n=65), a secukinumab 150 mg group (n=67), and a secukinumab 300 mg group (n= 66). The ability of secukinumab vs placebo to clear nail psoriasis was evaluated using the Nail Psoriasis Severity Index (NAPSI), quality of life improvements were evaluated using Nail Assessment in Psoriasis and Psoriatic Arthritis questionnaires on quality of life (NAPPA-QOL), and skin clearance was measured by the baseline Psoriasis Area and Severity Index (PASI).

At week 16, both secukinumab doses were superior to placebo (-10.8% NAPSI improvement for placebo, -37.9% for 150 mg secukinumab, and -45.3% for 300 mg secukinumab; P <.0001). Significant quality of life improvements were also seen at 16 weeks (NAPPA-QOL median scores decreased by 15.8% for placebo, 49.9% for secukinumab 150 mg, and 60.9% for secukinumab 300 mg; P <.0001).

These improvements continued through week 32 (-52.6% NAPSI improvement for 150 mg secukinumab and -63.2% for 300 mg secukinumab). Significant skin clearance was observed at week 16 (PASI 90: 1.7% for placebo and 54.0% and 72.5% for secukinumab 150 mg and 300 mg, respectively; P <.0001) and was sustained through week 32. Headache, upper respiratory tract infections, and nasopharyngitis were the most frequent adverse events, and they were not dose-related. Serious adverse events were rare and non-fatal.  

The investigators conclude that “TRANSFIGURE provides some of the most compelling evidence yet in the difficult to treat population of nail psoriasis, evidence of significant efficacy and meaningful improvements in patients’ [quality of life]. Secukinumab thus offers an effective treatment option for subjects with moderate to severe nail psoriasis.”

Disclosure: Funding and assistance for this study were provided by Novartis Pharmaceuticals. See reference for complete disclosure information. 

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Reference

Reich K, Sullivan J, Arenberger P, et al. Effect of secukinumab on clinical activity and disease burden of nail psoriasis: 32-week results from the randomized placebo-controlled TRANSFIGURE trial [published online October 26, 2018]. Br J Dermatol. doi: 10.1111/bjd.17351

Pregnant women are considered a “vulnerable” population in the eyes of clinical researchers.

In clinical research, pregnant women are considered a “vulnerable” population, due to the presence of a fetus who cannot consent to participation.¹ To obtain ethical committee approval, clinical study interventions must “[either] directly benefit [or] pose minimal risk to the mother and fetus.” In addition, consent often must be obtained from both parents.

These stringent inclusion criteria for pregnant women frequently preclude clinical trial participation. For this reason, more than 80% of pregnant patients are prescribed therapies that have not been studied in pregnancy.² In a Viewpoint piece published in JAMA,³ Drs Katrina Heyrana, Heather M Byers, and Pamela Stratton from the National Institutes of Health (NIH) in Bethesda, Maryland, advocated for the increased inclusion of pregnant women in clinical trials so that pregnant patients may have equitable access to evidence-based medicine.

In the 1960s and 1970s, clinical trials assessing the efficacy of pharmaceuticals in pregnant women led to unintended consequences for exposed fetuses. Specifically, birth defects following in utero exposure to thalidomide and diethylstilbestrol compelled the US Food and Drug Administration (FDA) to develop policies protecting “female research participants of reproductive age from [teratogens exposure].”¹ However, the investigators wrote, these guidelines initiated a legacy of excluding pregnant women from clinical trials altogether. In the 1990s, the US Food and Drug Administration (FDA) and NIH expanded on existing guidelines, stipulating that research must include female participants in the absence of any “convincing reason for…exclusion.” The Centers for Disease Control and Prevention and the NIH later released recommendations for the inclusion of pregnant women specifically, but these recommendations have lagged, the investigators wrote.⁴ Of the 213 new pharmaceuticals receiving FDA approval from 2003 to 2012, only 5% included any data from pregnant women.¹

Modern concerns regarding the Zika virus have reignited conversations surrounding the inclusion of pregnant women in clinical trials. Despite the disproportionate burden of Zika virus in pregnant women and fetuses, none of the trials of Zika virus vaccine candidates have included pregnant women.⁵ Investigating means of intervention in pregnant populations is essential to curbing Zika incidence, the researchers wrote. If provided “adequate counseling about…conditions and treatment options,” thus, pregnant women should have full capacity to make decisions regarding trial participation.

The investigators emphasized the necessity of “clear, actionable guidelines” for the inclusion of pregnant women in clinical research and addressed 3 subsequent barriers to this achievement. First, they dismissed the characterization of pregnant women as a “vulnerable” population. The researchers instead suggested reclassifying pregnant women as “scientifically complex,” in an effort to acknowledge the autonomy and decision-making capacity of their population.⁵

Second, federal regulations do not define “acceptable risk” to a woman or fetus; per the Common Rule, risk must not exceed that which may be “encountered in daily life or during…medical examinations.”¹ However, these parameters are imprecise: acceptable risk levels may be mediated by the patient’s perceptions and opinions, as well as the urgency of the clinical scenario. Acceptable risk levels must be standardized to facilitate trial participation, the investigators wrote.

Finally, the perceived legal risk following a maternal or fetal adverse outcome has an impact on the willingness of practitioners to perform research in pregnant women. Per a 2015 survey, nearly 73.6% of 4295 obstetricians reported being implicated in a malpractice lawsuit.⁶ This barrier could be mitigated by standardizing informed consent procedures. The researchers further suggested “partnerships with community leaders and ethical and legal experts” so that enrollees receive culturally competent and accessible information regarding study risks. Beyond all other considerations, they emphasized the autonomy of pregnant women and their capacity to make informed decisions when provided adequate counsel and opportunity. The need for adequately researched interventions in this population necessitates their inclusion to allow them to make informed medical decisions, a right afforded to all other patient populations.

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References

1. US Department of Health and Human Services. Protection of human subjects. www.hhs.gov/ohrp/sites/default/files/ohrp/humansubjects/regbook2013.pdf. 2009. Accessed December 3, 2018.
2. Ayad M, Costantine MM. Epidemiology of medications use in pregnancy. Semin Perinatol. 2015;39(7):508-511. doi:10.1053/j.semperi.2015.08.002
3. Heyrana K, Byers HM, Stratton P. Increasing the participation of pregnant women in clinical trials [published online November 7, 2018]. JAMA. doi:10.1001/jama.2018.17716
4. Foulkes MA, Grady C, Spong CY, Bates A, Clayton JA. Clinical research enrolling pregnant women: a workshop summary. J Womens Health (Larchmt). 2011;20(10):1429-1432.
5. Ethics Working Group on ZIKV Research and Pregnancy. Pregnant women and the Zika virus vaccine research agenda: ethics guidance on priorities, inclusion, and evidence generation. http://guidance.zikapregnancyethics.org/wpcontent/uploads/2017/08/Full+Guidance-Pregnant-Women-the-Zika-Virus-Vaccine-Research-Agenda_optimized.pdf. Accessed December 3, 2018.
6. Carpentieri AM, Lumalcuri JL, Shaw J, Joseph GF. Overview of the 2015 American Congress of Obstetricians and Gynecologists’ survey on professional liability. https://www.acog.org/-/media/Departments/Professional-Liability/2015PL SurveyNationalSummary11315.pdf. Published November 3, 2015. Accessed December 3, 2018.

Clinical morphologic testing in addition to tissue biopsy and culture are critical in distinguishing NND from NF and treating appropriately.

Lack of sufficient diagnostic criteria and biomarkers for distinguishing necrotizing neutrophilic dermatosis (NND) from necrotizing fasciitis (NF) may lead to inappropriate treatment that worsens the actual condition and prolongs disease morbidity, according to a study published in JAMA Dermatology.

In a case series of 54 patients diagnosed with NND at 3 academic institutions (University of California San Francisco, Oregon Health and Science University, and University of Minnesota) from January 1, 2015 to December 31, 2017, investigators found that 51 (94%) cases of NND were initially misdiagnosed as NF, resulting in patients receiving inappropriate treatment.

Of all the patients in the sample, 40 had pyoderma gangrenosum with systemic inflammation and 14 had necrotizing Sweet syndrome, both of which can mimic sepsis from severe infection (displaying symptoms of fever, leukocytosis, tachycardia, hypotension, and organ failure). The researchers found hematologic disorders and malignant neoplasms to be the most common disease associations in all 54 patients (n=18 [33%]), with myelodysplastic syndrome occurring in 9 patients (17%). Connective tissue disease (n=6 [11%]), endocrine disorders (n=7 [13%]), and inflammatory bowel disease (n=6 [11%]) were other common comorbidities. Potential medication triggers occurred in 7 patients (13%).

The most common cutaneous finding was erythema (n=41 [76%]), followed by other common findings of ulcers (n=25 [46%]) and necrosis (n=16 [30%]). Systemic findings included febrility (n=36 [67%]) and presentation of clinical signs resembling septic shock (n=14 [26%]). Cultures were taken in 45 cases (83%), of which 98% were negative. Elevated markers of systemic inflammation were found in 23 patients (43%), of leukocytosis in 36 patients (67%), and of leukomoid reaction in 15 patients (28%), with a mean (range) white blood cell count of 51371/μL (32,300-138,000/μL). 

The researchers also noted that “typical histopathologic findings were sparse diffuse subcutaneous and dermal inflammation with a predominance of neutrophils as well as associated leukocytoclasis and edema.” In 43% of cases, the neutrophilic infiltrate and associated necrosis often extended to the level of fascia or muscle.

Treatment therapies utilized in patients included debridement (n=42 [78%]), antibiotics (n=49 [91%]), systemic corticosteroids (n=50 [93%]), and limb amputations (n=4 [7%]). Additional immunosuppressants were used with some patients.

These findings suggest that clinical morphologic testing in addition to tissue biopsy and culture are critical in distinguishing NND from NF and treating appropriately.

This study design was limited by reliance on case reviews that were limited by publication bias of poor outcomes and missing information that affects results as well as by clinical descriptions of shock without use of formal Systemic Inflammatory Response Syndrome criteria.

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Reference

Sanchez IM, Lowenstein S, Johnson KA, et al. Clinical features of neutrophilic dermatosis variants resembling necrotizing fasciitis [published online October 31, 2018]. JAMA Dermatol. doi:10.1001/jamadermatol.2018.3890

The study concentrated on the 5 most common food allergens in the United States: egg, milk, peanut, soy, and wheat.

In patients with atopic dermatitis (AD), families and healthcare providers need to be cognizant of the risks associated with excessive testing and diet manipulation in their attempts to manage the disorder, which includes the loss of tolerance to a particular food when it is removed from the diet. According to the results of a retrospective chart review published in the Annals of Allergy, Asthma & Immunology, the frequency of oral food challenge (OFC) failure in patients who removed foods suspected of being triggers of AD was 13.3%.

The investigators recognized that the removal of foods from the diet in an attempt to manage AD, according to positive allergy tests, may lead to immediate allergic reactions upon reintroduction of that food, so they sought to examine the frequency of OFC failures in foods removed from the diet as suspected AD triggers. They focused on the 5 major food allergens in the United States: egg, milk, peanut, soy, and wheat.

The current study evaluated OFCs for the 5 major food allergens performed between 2008 and 2014 at the allergy clinic of a US children’s hospital. Oral food challenges were offered to patients according to laboratory values and history. Reasons for food avoidance were classified as food allergy (ie, immunoglobulin E-mediated reaction occurring within 2 hours), sensitization only (lack of introduction of the food because of positive test results), and removal of the food because of test results during evaluation of AD.

A total of 442 OFCs were performed, with 20.1% (89/442) considered failures. The reasons patients underwent OFCs were a history of food allergy (72.4% [320/442]), food sensitization without any introduction (17.4% [77/442]), and the presence of AD (102% [45/442]).

Of note, OFC failures in patients with food allergy (21.9% [70/320]), patients with sensitization only (16.9% [13 of 77], and patients with AD (13.3% [6 of 45]) did not differ significantly (P =.63). Wheat was significantly more likely to be avoided than the other 4 food allergens because of concerns about AD (P <.0001).

The investigators concluded that the restriction of foods in an attempt to manage AD must be conducted with caution and close monitoring. Primary care providers need to counsel families on the limits of using allergy testing and diet changes to address AD. Families should be advised to use such measures as skin hydration, topical medications, and emollients to address AD.

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Reference

Eapen AA, Kloepfer KM, Leickly FE, Slaven JE, Vitalpur G. Oral food challenge failures among foods restricted due to atopic dermatitis [published online October 13, 2018]. Ann Allergy Asthma Immunol. doi:10.1016/j.anai.2018.10.012

During development trials, 3 of 953 patients developed confirmed causes of drug reaction with eosinophilia and systemic symptoms.

NEW ORLEANS — Early results from an ongoing, multicenter, open-label safety study of cenobamate has found no cases of drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome in 1110 patients with epilepsy exposed to cenobamate for at least 6 months, according to research presented at the 72nd American Epilepsy Society Annual Meeting, held November 30 to December 4, 2018.

Patients aged 18 to 70 with uncontrolled focal (partial) seizures taking stable doses of 1 to 3 antiepileptic drugs were enrolled. Testing a hypothesis that a lower starting dose and slower titration rate of cenobamate than those utilized in earlier studies would mitigate the risk for serious cutaneous reactions like DRESS, investigators administered gradually increasing daily doses of cenobamate 12.5 mg, 25 mg, 50 mg, 100 mg, 150 mg, and 200 mg/day at 2-week intervals. Biweekly increments of 50 mg/day to increase dosage to 400 mg/day were allowed.

For the first 16 weeks of the study period, patients visited every 2 weeks and then every 1 to 3 months thereafter. Patients were screened for DRESS monthly with an in-depth review of all hypersensitivity reactions.

Serious adverse events, reported in accordance with local regulatory requirements, were seen in 114 patients (8.5%), and were most commonly seizures that required hospitalization. Other common adverse events included somnolence, dizziness, and fatigue. No cases of DRESS were identified.

A total of 1347 patients had been enrolled at the time of study data cut-off; 269 patients discontinued therapy. Four deaths were reported: sudden death with no autopsy, traumatic intracerebral hemorrhage after a fall, fatal injuries after being struck by a car, and respiratory failure in a participant with Angelman syndrome. 

In addition, no cases of DRESS were reported among the patients exposed to cenobamate for at least 6 months (n=1110) and among all patients exposed to cenobamate. The most common serious adverse event was seizure, as seen in 14 patients (1.0%). The most common treatment-emergent adverse event was reported to be somnolence (28.1%), dizziness (23.65), and fatigue (16.6%); most were mild or moderate in severity. 

These early results suggest that reducing the starting dose and slowing the titration rate of cenobamate may mitigate the risk for DRESS in patients with epilepsy experiencing uncontrolled focal (partial) seizures.

This study was supported by SK Life Science, Inc. Please refer to reference for a complete list of authors’ disclosures.

For more coverage of AES 2018, click here.

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Reference

Sperling M, Klein P, Kamin M. Safety of cenobamate (YKP3089) as adjunctive treatment for uncontrolled partial seizures in a large, multicenter, open-label study. Presentation at: 72nd Annual Meeting of the American Epilepsy Society; November 30-December 4, 2018; New Orleans, LA. Poster 1.303.