Dermatologic Effects Research Articles

Real World Clinical Experience with Oxbryta Therapy in Individuals with Sickle Cell Disease

Background: Oxbryta is a recently approved drug for patients with Sickle Cell Disease (SCD), which decreases HbS polymerization, thus reducing red cell hemolysis and increasing hemoglobin concentration. It was first available for Expanded Access May 9, 2019 and received fast track approval for commercial use by the FDA on November 25, 2019. Objective: This analysis aims to gain insights to the real word experience for patients with SCD who are prescribed Oxbryta, identify barriers to its use, and measure health outcomes. Methods: Electronic medical records of 54 patients with SCD who were prescribed Oxbryta from January until June 2020 were reviewed and evaluated for data regarding demographics, initiation of treatment, hematological response, side effects, dosage modifications and terminal discontinuations. Results: A total of 54 patients were prescribed Oxbryta in the study period who were 96% (52/54) HbSS, and 4% HbSβ0 (2/54); 46% (25/54) male and 54% (29/54) female, and a mean age of 41 years (range 21-70). At time of initiation, 52% (28/54) of patients were taking hydroxyurea (HU). Indication for initiation of therapy was anemia and hemolysis. In this cohort, 65% of patients (35/54) were able to access drug with a mean time to obtain drug of 45 days (range 0-118 days). The most common barriers to obtaining drug were: requiring a prior authorization or appeal 9% (5/54), incomplete patient follow up 7% (4/54), missing documentation for application 6% (3/54) and high patient co-pay 6% (3/54). Of the 35 patients who started Oxbryta, 46% (16/35) experienced at least 1 side effect with 31% (11/35) reporting multiple side effects. The most common side effects reported were gastrointestinal distress (abdominal pain, nausea, vomiting and/or diarrhea) in 23% (8/35), dermatologic effects (itching and/or rash) in 17% (6/35), and experiencing an acute VOC or increase in daily pain in 11% (4/35). Twenty nine percent (10/35) of patients required a dose modification to address side effects (half who successfully continued the drug on a modified dosage), an additional 23% (8/35) of patients terminated usage of Oxbryta in response to side effects. After two to four weeks of taking Oxbryta 63% of patients had a hemoglobin increase of at least 1g/dl or greater. Conclusion: Oxbryta produces a substantial rise in hemoglobin for persons living with sickle cell and high baseline levels of hemolysis in about 60 % of patients, similarly to the results from the HOPE trial. However, there are significant barriers to access that require close follow up in the immediate period following prescription of the drug in order to minimize delays in access. Furthermore, in our cohort we observed a higher incidence of side effects than the 23% (900mg) -26% (1500mg) reported in the pivotal trial that led to its approval. While some individuals were able to be continue therapy after dose modifications, most discontinued therapy because of side effects. Figure Disclosures Minniti: CLS Behring: Consultancy; Roche: Consultancy; Emmaus: Consultancy; Forma: Consultancy; Global Blood Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Teutona: Membership on an entity's Board of Directors or advisory committees; Bluebird Bio: Other; Sodium Nitrate for SCD leg ulcers: Patents & Royalties.

Protein Binding of Lapatinib and Its N- and O-Dealkylated Metabolites Interrogated by Fluorescence, Ultrafast Spectroscopy and Molecular Dynamics Simulations.

Lapatinib (LAP) is an anticancer drug generally used to treat breast and lung cancer. It exhibits hypersensitivity reactions in addition to dermatological adverse effects and photosensitivity. Moreover, LAP binds to serum proteins and is readily biotransformed in humans, giving rise to several metabolites, such as N- and O-dealkylated products (N-LAP and O-LAP, respectively). In this context, the aim of the present work is to obtain key information on drug@protein complexation, the first step involved in a number of hypersensitivity reactions, by a combination of fluorescence, femtosecond transient absorption spectroscopy and molecular dynamics (MD) simulations. Following this approach, the behavior of LAP and its metabolites has been investigated in the presence of serum proteins, such as albumins and α1-acid glycoproteins (SAs and AGs, respectively) from human and bovine origin. Fluorescence results pointed to a higher affinity of LAP and its metabolites to human proteins; the highest one was found for LAP@HSA. This is associated to the coplanar orientation adopted by the furan and quinazoline rings of LAP, which favors emission from long-lived (up to the ns time-scale) locally-excited (LE) states, disfavoring population of intramolecular charge transfer (ICT) states. Moreover, the highly constrained environment provided by subdomain IB of HSA resulted in a frozen conformation of the ligand, contributing to fluorescence enhancement. Computational studies were clearly in line with the experimental observations, providing valuable insight into the nature of the binding sites and the conformational arrangement of the ligands inside the protein cavities. Besides, a good correlation was found between the calculated binding energies for each ligand@protein complex and the relative affinities observed in competition experiments.

Impact of occupational dust exposure on dermatologic symptoms among Korean workers.

Occupation-related dust exposure is common, especially with increased industrialization. While occupational dust-related health issues caused by inhalation or ingestion have been well studied, only a few studies have examined the dermatologic effects of occupational dust exposure. This study aimed to investigate the association between occupational dust exposure and dermatologic symptoms in Korean workers. Among the large-scale representative data from the fifth Korean Working Conditions Survey, 45,700 workers were selected for study. Occupational dust exposure level was categorized as none, moderate, and severe, and dermatologic symptoms were assessed using a questionnaire on health problems. We analyzed the association between occupational dust exposure and dermatologic symptoms using multivariate logistic regression. Risks of skin problems and work-related skin problems were significantly associated with the level of occupational dust exposure in a dose-dependent manner (odds ratio (95% confidence interval): moderate, 1.51 (1.14-2.01); severe, 2.39 (1.74-3.29) in general skin problems; moderate, 1.72 (1.22-2.42); severe, 3.06 (2.11-4.44) in work-related skin problems). We, thus, demonstrate an association between occupational dust exposure and skin problems. As skin absorption of dust is a major route of dust exposure at the workplace, it is necessary to determine the efficacy of continuous management of occupational dust exposure.

Neurofibromatosis ‐1 diagnosed from an intraoral swelling – a case series

The neurofibromatoses [NF 1, NF 2 and schwannomatosis] are a group of genetic disorders that lead to the development of nervous system tumours and have diverse dermatologic, neurologic, ophthalmic, skeletal and vascular effects. The most common is NF 1 (Neurofibromatosis 1) also known as von Recklinghausen's disease, which is one of the most common human genetic diseases. Oral manifestations of NF 1 are reported in 72% of cases and in one of our cases precipitated attendance at a general dental practitioner (GDP), subsequent diagnosis and genetic screening for family members. This disease may go undiagnosed due to its variable expressivity of symptoms. The pivotal importance of a GDP in the discovery and early referral to an oral or oral and maxillofacial surgeon for further investigation and diagnosis of this condition is highlighted. Knowledge of the most common features of neurofibromatosis can facilitate the speedy referral and subsequent diagnosis of generalized neurofibromatosis, local surgical management of benign neoplasms and long term management of its other clinical features. Dentists should be aware of the classic symptoms of this condition and of their role in long-term care in view of the risk of local recurrence and malignant transformation.

Hormonal Contraceptives and Dermatology.

Hormones play a significant role in normal skin physiology and many dermatologic conditions. As contraceptives and hormonal therapies continue to advance and increase in popularity, it is important for dermatologists to understand their mechanisms and dermatologic effects given the intricate interplay between hormones and the skin. This article reviews the dermatologic effects, both adverse and beneficial, of combined oral contraceptives (COCs), hormonal intrauterine devices (IUDs), implants, injections, and vaginal rings. Overall, the literature suggests that progesterone-only methods, such as implants and hormonal IUDs, tend to trigger or worsen many conditions, including acne, hirsutism, alopecia, and even rosacea. Therefore, it is worthwhile to obtain detailed medication and contraceptive histories on patients with these conditions. There is sufficient evidence that hormonal contraceptives, particularly COCs and vaginal rings, may effectively treat acne and hirsutism. While there are less data to support the role of hormonal contraceptives in other dermatologic disorders, they demonstrate potential in improving androgenetic alopecia and hidradenitis suppurativa.

Green argan oil extraction from roasted and unroasted seeds by using various polarity solvents allowed by the EU legislation

Argan oil (AO) has traditionally been used for its dermatologic and hepatoprotective effects and for human nutrition. Traditionally, AO extraction is carried out by Moroccan women with the help of stone mill pressing. However, it is long and slow process that frequently is achieved at deficit hygiene conditions. In this research, unroasted seeds (US) and roasted seeds (RS) of argan tree have been extracted using different extraction systems: n-hexane, n-hexane:acetone (1:1, v/v), ethyl acetate, acetone, ethanol:water (96:4, v/v), and water. The main results are; Hexane: acetone extraction yielded the highest FA amounts, at 39.7 g FA/100 g of total US seed, followed by acetone (36.5 g FA/100 g US seed). The main FA in all extracts were oleic acid, from 52.1 (ethanol:water) to 57.7% (hexane), and linoleic acid from 22.9 (hexane, US) to 29.3% (ethanol:water, RS), both of total FA. Oxidation levels, computed by conjugated diene index (CD), was extremely low for all extraction processes. CD were higher in RS in comparison with US, due to compounds produced in Maillard reactions. Colour parameters indicated a color variation from yellow (US) to brown (RS). Therefore, the conclusions can be summarized as follows. All extracting systems yielded good quality argan oil, thus, the tested procedures constitute a suitable alternative to the traditional extraction processes. The obtained oils could be used in the alimentary and cosmetic industries with different applications. Future research should be directed to check the unsaponifiable fractions of the oils here obtained. Overall, this research opens new perspectives for industries focused on argan oil extraction.

POTENTIAL OF AYURVEDIC TREATMENT MODALITIES IN RADIATION INDUCED DERMATITIS

Cancer has become one of the leading cause of deaths. The conventional treatment modalities in treat-ing cancer includes Surgery, Chemotherapy, Radiation and Immuno therapy. Amongst this, radiation therapy is one of the frequently used treatment modality. 95 % of cancer patients receiving radiation therapy will develop some form of radiodermatitis, including erythema, dry& moist desquamation, ul-cerations, necrosis etc. This kind of reactions may lead to delay in the treatment, affects the quality of life, diminishes the cosmesis and causes functional deficits. Despite the prevalence of radiation derma-titis, there is no gold standard in the prevention and management of this condition. Ayurvedic treatment modalities has the potential in reducing the dermatological effects. Local treatment modalities like Lepa, Pichu, Parishek, Rasayanas, lifestyle management may help in ameliorating the dermatological effects. This article includes radiation induced dermatitis its stages its clinical manifestation and role of Ayurve-da in managing it.

Dermatological Toxicities of Bruton's Tyrosine Kinase Inhibitors.

The development of Bruton's tyrosine kinase (BTK) inhibitors represents a major breakthrough in the treatment of chronic lymphocytic leukemia and other B cell malignancies. The first-generation inhibitor ibrutinib works by covalent irreversible binding to BTK, a non-receptor tyrosine kinase of the TEC (transient erythroblastopenia of childhood)family that plays a critical role in the B-cell receptor signaling pathway. It also induces an 'off-target' inhibition of a range of other kinases including (but not limited to) epidermal growth factor receptor (EGFR), SRC, and other kinases of the TEC family (interleukin-2-inducible T-cell kinase [ITK], Tec, BMX). Dermatological toxicities are among the most common toxicities of ibrutinib, but remain of mild to moderate intensity in most cases and are readily manageable. Their incidence is highest during the first year of treatment and declines over time. In addition, it has been postulated that ibrutinib-related dermatologic adverse events are mediated by the direct binding to both BTK and other 'off-target' kinases. Bruising, ecchymoses, and petechiae represent the most characteristic dermatologic adverse events. Nail and hair changes are also common, as skin infections (opportunistic infections including herpes simplex and herpes zoster virus reactivations, and Staphylococcus aureus superinfection), folliculitis, and other types of rashes. Panniculitis, aphthous-like ulcerations with stomatitis, neutrophilic dermatosis, peripheral edema, and skin cracking can also occur. Next-generation BTK inhibitors, acalabrutinib and zanubrutinib, have been designed to optimize BTK inhibition and minimize off-target inhibition of alternative kinases (Tec, ITK, EGFR, SRC-family kinases). These drugs have been recently FDA-approved for relapsed or refractory mantle cell lymphoma. Although the overall incidence of their toxicities is expected to be more limited, acalubrutinib and zanubrutinib are associated with a range of dermatologic toxic effects that appear to be similar to those previously described with ibrutinib, including bruising and ecchymoses, panniculitis, human herpesvirus infections, cellulitis, and skin rash. In particular, both drugs induce skin bleeding events in more than 30% of patients treated. However, the available dermatological data are still rather limited and will have to be consolidated prospectively. This review article analyses the wide spectrum of dermatological toxicities that can be encountered with first- and second-generation BTK inhibitors. Finally, recommendations for appropriate treatment as well as a synthesis algorithm for management are also proposed.

Ingestible Sensors and Medication Adherence: Focus on Use in Serious Mental Illness.

Background: Poor medication adherence is a major public health concern. Patients living with a serious mental illness (SMI) commonly present with non-adherence to their medication regimen, which can lead to relapse and hospitalizations. The high rates of antipsychotic non-adherence continue to persist despite several interventions and medication advances. This review evaluates the possible role of the ingestible sensor technology for medication adherence in different conditions, with a focus on use in the SMI schizophrenia. Methods: Literature searches were conducted in July 2019 in the PubMed database. Results: In small studies of ingestible sensor use, the average adherence ranged from 73.9% to 88.6% for SMI and ≥ 80% for cardiac and transplant (99.4%) patients. In SMI studies, patients were clinically stable, and the majority had a clinical global impression severity of “mild disease”. Patients generally experienced relatively minor dermatological adverse effects related to wearable sensor use. Conclusions: A medication with an ingestible sensor may help provide real-time objective medication-taking adherence information for clinicians. However, further studies are needed to understand the impact of use on adherence and improvement on treatment outcomes with the ingestible sensor technology.

Polycystic ovary syndrome in patients with hair thinning

To the Editor: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting women of reproductive age, involving pathways that produce metabolic, reproductive, cardiovascular, and dermatologic effects. Diagnosis is based on the Endocrine Society Clinical Practice Guideline and the 2003 Rotterdam criteria, which requires 2 of the following to establish a definitive diagnosis1,2: (1) oligo- or anovulation, (2) hyperandrogenism (clinical or biochemical), and (3) polycystic ovary morphology on transvaginal ultrasonography.

A highly effective and practical desensitization regimen: Results in comparable clinical outcomes for multiple myeloma patients with skin rash after immunomodulatory drugs.

12104 Background: Immunomodulatory drugs (IMiDs) are backbone of myeloma therapy for patients with Multiple Myeloma (MM). The incidence of IMiD-associated rash is up to 27% in some reports impeding maximal benefit of this agent. The optimal management of IMiDs-associated skin is unclear. The concurrent weekly Dexamethasone (Dex) does not diminish the incidence of skin eruptions with IMiDs (Sviggum, et al. 2006), therefore we designed a low dose daily and tapering corticosteroid regimen to tame this immune response upon restarting IMiDs and allow desensitization and reinstitution of the same IMiD. Furthermore, we assessed the impact of this desensitization regimen on clinical outcome. Methods: A total of 160 patients were evaluated. The incidence of rash was found to be 13% (n = 21). A cohort of age- and gender-matched without rash (n = 39) was randomly selected. The effects of rash on overall and progression free survival (OS and PFS) were further estimated using Cox regression controlling the effects of age and gender. Results: Median time to development of rash after IMiD initiation was 28 days (range, 2-232). Rashes were graded as low (I-II) in 89% (n = 17) and high (III-IV) in 19% of pts. All pts were managed by temporary treatment interruption and upon clearance of rash, re-institution of the same IMiD concomitantly with a standardized 3-week steroid rash prophylaxis protocol (prednisone at 10 mg daily for 10 days, followed by 5 mg daily for 10 days, followed by 5 mg on alternate days for 10 days). As a result, all patients were able to restart the same IMiD with none re-experiencing any dermatologic adverse effect afterward. Comparing to no-rash controls, there was no significant difference in PFS (0.13) or OS (p = 0.12) in multivariate regression model. Conclusions: Proposed 3-week corticosteroid regimen showed 100% success rate in reinstituting IMiDs in our cohort. It may provide a highly effective and practical short term immunosuppression required to enable patients to restart IMiDs and enjoy comparable outcome to pts without skin rash.

Dermatologic adverse effects of breast cancer chemotherapy: a longitudinal prospective observational study with a review of literature.

Breast cancer patients may experience an increased chance of survival with adjuvant chemotherapy. However dermatologic adverse effects can cause major discomfort due to physical or cosmetic problems. This study aims to describe dermatologic complications in breast cancer patients during chemotherapy. This longitudinal prospective observational study included data on women with non-metastatic breast cancer whom were treated with AC-T protocol (anthracycline, cyclophosphamide, and taxane) adjuvant chemotherapy and consecutively enrolled during two years. The study was performed in an educational and tertiary referral center. The patients' information including age, body mass index (BMI), past medical history, and different dermatologic complications were collected for all participants. Of 190 enrolled women, all patients experienced alopecia, which occurred in 131 patients (68.9%) after the first cycle. Skin, mucosal, and nail involvement were respectively seen in 46 (24.2%), 51 (26.8%), and 86 (45.2%) cases. Cutaneous complications were observed mainly between thethird and sixth chemotherapy cycles. Palmoplantar erythema and palmoplantar dysesthesia were the most common cutaneous complications. Dermatologic adverse effects were significantly more frequent in the patients with an underlying disease. These findings suggest that dermatologic adverse effects of adjuvant chemotherapy are common and could be induced by all components of AC-T regimen. These complications should be skillfully managed to increase patients' comfort.

Cutaneous toxicities of new targeted cancer therapies: must know for diagnosis, management, and patient-proxy empowerment

The world of oncology treatment is rapidly changing, and with the investigation into and utilization of molecular signaling pathways for cancer treatment, many new targeted small-molecule oral agents have been introduced as therapies, with more new drugs appearing every year. These agents, while generally considered less toxic overall than traditional chemotherapy, are not without adverse effects. The authors undertook an extensive literature search to determine the incidence, severity, and management strategies for small-molecule oral targeted agents approved by the FDA between 2013 and 2018. Dermatologic adverse effects are among the most frequently seen with many of these targeted therapies, and may include rashes, palmar-plantar dysesthesia, alopecia, secondary skin malignancies, and hair and nail changes. Rarely, more severe cutaneous toxicities are seen, such as Stevens-Johnson Syndrome and toxic epidermal necrolysis. In many cases, there is no specific management strategy suggested in the literature for these toxicities, but frequent monitoring of the skin, prophylactic management of palmar-plantar dysesthesia, use of corticosteroids and/or antihistamines, and intervention with dose interruption are suggested depending on circumstance and severity. Patient education and timely intervention is warranted in order to ensure that patient treatment is optimized.

COVID-19 Pandemic & Skin Care Guidelines for Health Care Professionals.

The Novel corona virus is bringing multiple challenges for health care professionals. Skin is the biggest organ and the first line of defense against different infections and external factors. Being the front line warriors, health care professionals are susceptible to various skin conditions due to prolonged use of personal protective equipment. These adverse skin conditions are redness, irritation, itching, contact dermatitis, and aggravation of underlying skin conditions like seborrheic dermatitis and acne vulgaris. In the current global situation, the potential incidence of such adverse dermatological effects does not in any manner cause the HCPs to deviate from the strict specific precautionary hygiene rules. These skin problems are manageable with the few precautionary measures. This article explores the different skin conditions that result from personal hygiene measures and usage of protective gear and will suggest some practical advice about how to manage and protect from these different adverse skin conditions.

What's the Price? Toxicities of Targeted Therapies in Breast Cancer Care.

Agents with mechanisms novel to breast cancer care have been approved to treat breast cancer. These agents include drugs that target cyclin-dependent kinases, phosphoinositide 3-kinase PI3KCA gene mutations, PARP, checkpoint regulation, and novel antibody-drug conjugates. However, these novel approaches bring a risk of toxicities quite different from those of conventional cytotoxic chemotherapy. Here, we review these agents and discuss related adverse events, with particular attention to endocrine, pulmonary, and dermatologic toxicities. Endocrine toxicities associated with novel cancer therapies for breast cancer are distinct and often present with symptoms related to the specific hormonal deficiencies and rarely hormonal excess. Given the complex and sometimes irreversible nature of these toxicities, once recognized, transdisciplinary management with an endocrinologist experienced with managing drug-related toxicities is encouraged. Drug-related pneumonitis is a serious concern with new targeted therapies. Presentation may not be easily distinguished, and a multidisciplinary team approach can optimize patient care. Heightened awareness is crucial for early detection and treatment. Management should follow recommendations provided by the National Cancer Institute Common Terminology Criteria for Adverse Events and agent-specific guidelines. Cutaneous toxicities from anticancer therapies represent a common and often poorly characterized challenge for patients with breast cancer. Although our understanding of dermatologic effects from novel therapies continues to improve, the breadth of toxicities spans all dermatologic conditions. Targeted therapies offer effective and often novel therapeutic strategies for patients with breast cancer but also bring new adverse event profiles. In this era, it will be important both to closely follow monitoring recommendations and to remain vigilant for emerging toxicities.

Frequent Hand Washing for COVID-19 Prevention Can Cause Hand Dermatitis: Management Tips.

Coronavirus disease 2019 (COVID-19) continues to spread globally, outpacing the capacity and resources of health systems worldwide. A therapeutic vaccine is not yet on the rise, and preventive measures are the current approach to restraint the transmission of cases. As the virus is highly contagious via respiratory route (droplets from infected persons, widely spread by coughing or sneezing) and via contact with contaminated surfaces, community transmission and spread can be decreased through the practice of regular and diligent hand hygiene. Frequent hand washing implies a prolonged exposure to water and other chemical or physical agents and may induce several pathophysiologic changes, such as epidermal barrier disruption, impairment of keratinocytes, the subsequent release of proinflammatory cytokines, activation of the skin immune system, and delayed-type hypersensitivity reactions. Adverse dermatologic effects, such as excessive skin dryness or even contact dermatitis (particularly the irritant subtype and, to a lesser extent, the allergic subtype), can occur, especially in individuals with a history of atopic dermatitis. These skin conditions are perfectly manageable, and applying a moisturizer immediately after washing hands or after using a portable hand sanitizer is the cornerstone in preventing the development of eczematous changes in the hands. In the current global context, the potential occurrence of these dermatological adverse events should in no way cause people to deviate from strict hand hygiene rules.

Protective effects of doxepin cream on radiation dermatitis in breast cancer: A single arm double-blind randomized clinical trial.

Breast cancer is the most frequently occurring cancer in women. Lumpectomy followed by radiotherapy is suggested to be as effective as a total mastectomy. Radiation-induced dermatitis often occurs as a result of breast radiotherapy. Recent studies suggest that doxepin has promising anti-inflammatory properties. This study was undertaken to evaluate the effects of doxepin therapy on radiation dermatitis. A double-blind randomized clinical trial was launched from 2016 to 2017, with a total of 48 patients who had undergone breast-conserving surgery and received postoperative radiation therapy. Radiotherapy was applied 5 days per week for 5 weeks. Adverse dermatological effects were evaluated by a physician at the beginning of the fifth week of radiotherapy and the patients were then randomly assigned (1:1 ratio) to receive either doxepin (5%) or placebo cream for 7 days. There were no significant differences in the dermatitis grade between doxepin and placebo groups at baseline (P > .5). The occurrence of acute dermatitis (grade 2 or higher) was significantly lower with the use of doxepin than with placebo (P ≤ .0001, Zα = 1.96 at 95% confidence interval). Doxepin cream prevents dermatitis grade 2 or higher during post-operative breast irradiation. Doxepin cream is easy to use, affordable and prevents pain and irritation.

Dermatologic adverse events with immune checkpoint blockade: Systematic review and meta-analysis.

84 Background: Immune checkpoint blockade is known to be associated with various dermatologic adverse events. However, these adverse effects have not been studied in a systematic manner. This is especially relevant considering the rapidly increasing number of immune checkpoint inhibitors that are now available. Methods: We searched for eligible studies in PubMed and Google scholar. We reviewed randomized controlled trials involving cancer patients treated with immune checkpoint inhibitors - PD1 inhibitors, PDL1 inhibitors and CTLA4 inhibitors and for dermatologic adverse effects. A total of 47 randomized controlled trials involving 11875 patients met eligibility criteria for our study. Results: Incidence rate of all grade dermatologic adverse effects was 40.6% (95% confidence interval [CI], 39.4-41.7%). Most common adverse effects included pruritus (17.3%) (95% confidence interval [CI] 16.6-18.1%), undifferentiated rash (15.1%) (95% confidence interval [CI] 14.4-15.9%), vitiligo (3.6%) (95% confidence interval [CI] 3.2-3.9%), maculopapular rash (2.3%) (95% confidence interval [CI] 2.1-2.6%), stomatitis (0.7%) (95% confidence interval [CI] 0.55-0.92%) and dry skin (0.7%) (95% confidence interval [CI] 0.5-0.8%). Less common adverse events include palmoplantar erythrodysesthesia, pemphigoid skin reactions, lichen planus and hyperhidrosis. Grade 3 and higher adverse effects were seen in 1.3% of patients (95% confidence interval [CI] 1.1-1.6%). Conclusions: A wide range of dermatologic adverse effects can be seen with immune checkpoint blockade. While the majority of these events are of grade 1-2, they can occasionally be severe and even life threatening. Patients receiving immune checkpoint blockade should be closely monitored for dermatologic adverse effects.

A Highly Effective and Practical Corticosteroid Regimen to Overcome Skin Rash Associated with Immunomodulatory Drugs Allowing Reinstitution of Therapy

Introduction Immunomodulatory drugs (IMiDs) are backbone of myeloma therapy in induction and maintenance therapy after transplant for patients (pts) with Multiple Myeloma (MM). The incidence of IMiD-associated rash is up to 27% (Nardone, et al, Clinical Lymphoma Myeloma and Leukemia. 2013) and importantly heralds a favorable prognosis (Kojima, et al. Blood. 2016) suggesting more robust immune stimulation by this class of drugs; however, lack of optimal management strategy of this toxicity can deprive large subset of pts from maintenance therapy after transplant and lead to potential detrimental impact on survivals. The concurrent weekly dexamethasone (Dex) does not diminish the incidence of skin eruptions with IMiDs (Sviggum, et al. Archives of dermatology. 2006), therefore we designed a low dose daily and tapering corticosteroid regimen to tame this immune response upon restarting IMiDs and allow desensitization and reinstitution of the same IMiD which may not be achieved by standard weekly Dex. Here, we present our experience with this regimen. Methods In this retrospective study, pts with MM treated with lenalidomide and pomalidomide were reviewed for any IMiD-associated dermatologic toxicity. We followed the same corticosteroid regimen for all IMiD-related rash in our clinic without changing Dex dosing. Result A total of 160 pts were evaluated. The incidence of rash was found to be 13% (n=21). IMiDs were instituted as part of induction regimen in 71% (n=15) and as maintenance therapy after transplant in 29% (n=6) of pts. Median time to development of rash after IMiD initiation was 28 days (range, 2-232). The rashes were characterized as morbilliform in 86% (n=18), urticaria in 9.5% (n=2) and blisters in 5% (n=1) of pts. Pruritis or pain was associated with 86% of rashes (n=15). According to NCI-CTCAE, rashes were graded as low (I-II) in 89% (n=17) and high (III-IV) in 19% of pts. All pts were managed by temporary treatment interruption and upon clearance of rash, re-institution of the same IMiD concomitantly with a standardized 3-week steroid rash prophylaxis protocol (prednisone at 10 mg daily for 10 days, followed by 5 mg daily for 10 days, followed by 5 mg on alternate days for 10 days). As a result, all pts were able to restart the same IMiD either at same (n=5, 24%) or reduced (n=16, 76%) dose with none re-experiencing any dermatologic adverse effect afterward. There was no association between rash development and changes in creatinine clearance (p=0.42). Median eosinophil count at rash development was observed to be significantly higher as compared to eosinophil count at IMiD initiation (380 × 106 vs 130 × 106 respectively, p=0.01). Conclusion The proposed 3-week corticosteroid regimen showed 100% success rate in terms of reinstituting IMiDs, therefore it may provide a highly effective and practical short term immunosuppression required to enable pts to restart IMiDs.

P420 A randomised, observer-blinded phase Ib multiple, ascending dose study of UTTR1147A, an IL-22Fc fusion protein, in healthy volunteers and ulcerative colitis patients

Abstract Background Inflammatory bowel disease (IBD) is characterised by gut dysbiosis, weakened epithelial barrier, and a dysregulated immune system. Interleukin-22 (IL-22), an IL-10 family cytokine, has demonstrated efficacy in animal IBD models by promoting intestinal epithelial repair, increasing antimicrobial peptide production, and increasing mucin production via goblet cells1. UTTR1147A is a fusion protein in which IL-22 is linked with the Fc portion of IgG4 to improve the pharmacokinetic (PK) characteristics. Methods A phase I study (NCT02749630) was conducted to evaluate the safety, tolerability, PK, and pharmacodynamics (PD) of repeat IV dosing of UTTR1147A in healthy volunteers (HV) and UC patients with centrally read Mayo endoscopic score ≥ 2. 38 HVs and 24 UC patients were given UTTR1147A or placebo at doses ranging from 30 to 90 µg/kg either biweekly or monthly (6:2 UTTR1147A: placebo per cohort). PK and serum PD (REG3A and CRP) were studied across multiple time points and the Mayo Clinic Score was evaluated at baseline, day 30 and day 85. Results Overall, UTTR1147A was safe and adequately tolerated in HV and UC patients. The most common adverse events were on-target dermatological effects (dry skin, erythema, and pruritus) that were manageable, monitorable and reversible. Dose-limiting non-serious dermatological toxicities (severe dry skin, erythema, exfoliation, and discomfort) were seen in two HVs and 1 UC patient dosed with 90ug/kg Q2wk. There were 2 unrelated serious adverse events (ankle fracture and cytomegalovirus infection) that eventually resolved. PK analyses showed that UTTR1147A exposures were, in general, dose proportional within HVs and within UC patients, with a mean elimination half-life of ~16 days and ~12 days, respectively. At the same dose level, UC patients showed relatively lower drug exposures than HVs, possibly due to faster drug clearance. Consistent with the Phase Ia2, UTTR1147A directly induced production of serum PD biomarkers REG3A and CRP at all dose cohorts tested compared with placebo. Notably, UC patients appear to have attenuated serum PD responses compared with HV. Clinical response was observed in 7/18 patients, and clinical remission in 5/18 patients treated with UTTR1147A compared with 1/6 and 0/6 placebo patients, respectively. Conclusion UTTR1147A demonstrated adequate safety and PK profile in healthy volunteers and UC patients. PD biomarker data demonstrated pharmacological activity of UTTR1147A providing evidence of IL-22R pathway activation. Together with the preliminary signals of efficacy, these data support further investigation of this potential, novel non-immunosuppressive therapy in IBD.