Predisposition to conjunctivitis and male sex reduces drug survival of dupilumab in adults and adolescents.

BACKGROUND: There are currently limited data on dupilumab drug survival (DS), especially on factors possibly associated with drug discontinuation. MATERIALS AND METHODS: The primary endpoint of this study is to evaluate the parameters that may determine drug discontinuation and the predictive factors associated with dupilumab DS. We considered as independent associated factors: childhood onset of disease, gender, age of onset of AD, age of initiation of dupilumab, previous use of cyclosporine, initial mean EASI, atopic family history, and predisposition to allergic conjunctivitis. RESULTS: On 413 patients DS was 94.5% at 1 year, 89.5% at 2 years, and 83.7% at 3 years, and after a mean follow-up of 40.5 months (±1.6) 53 patients had discontinued the drug permanently (12.8%). Univariate analysis showed that the only factor associated with a reduction in drug survival was a predisposition to allergic conjunctivitis (p 0.009). At multivariate Cox regression, male sex (HR, 2.34; 95% CI, 1.14-4.78; p 0.02) and predisposition to allergic conjunctivitis (HR, 2.61; 95% CI, 1.37-5.00; p 0.004) were associated with lower DS of dupilumab. CONCLUSION: Male gender and predisposition to allergic conjunctivitis are negative predictors for maintenance of response to treatment with dupilumab and consequently associated with lower DS rates.

Is Dupilumab as Effective in Intrinsic Atopic Dermatitis as It Is in Extrinsic Atopic Dermatitis?

Atopic dermatitis (AD) can be subclassified into the more frequent extrinsic type (EAD), with elevated serum IgE levels and frequent association with other atopic conditions, and the less frequent intrinsic type (IAD), with normal IgE levels and no history of atopy. This retrospective study has the objective to compare the efficacy of dupilumab therapy in patients with IAD versus EAD in a real-life setting. We studied a group of 360 patients treated with dupilumab for moderate-to-severe AD of whom 49 had IAD (IgE < 200 kU/L and no history of other atopic conditions) and 311 had EAD (IgE ≥ 200 kU/L and/or history of atopy). There were no statistically significant differences in the achievement of EASI75 between IAD and EAD patients either at 16, 32, or 48 weeks (61% vs. 50%; 66% vs. 60%; and 53% vs. 65%, respectively). Similarly, there were no statistically significant differences in the achievement of EASI90 or the reduction in NRSpp, NRSsd, and DLQI at each timepoint. Additionally, mean absolute eosinophils and IgE values were significantly higher in the EAD group at all timepoints. This study confirms that dupilumab, targeting the Th2 pathway, which is known to be overexpressed in all AD phenotypes, appears to be equally effective in the two populations regardless of IgE levels.

Ocular Adverse Events in Patients With Atopic Dermatitis Treated With Upadacitinib: A Real-Life Experience.

Background: Dupilumab, an interleukin (IL)-4 receptor-α inhibitor that blocks IL-4 and IL-13 signaling pathways, is an effective and well-tolerated therapy for moderate-to-severe atopic dermatitis (AD). However, an increased incidence of dupilumab-associated conjunctivitis has been reported in patients treated with dupilumab. In contrast, upadacitinib, a selective Janus kinase 1 inhibitor, is reported to have lower incidence of conjunctivitis than dupilumab. Objective: The aim of this retrospective study was to investigate ocular adverse events in adult patients with moderate-to-severe AD treated with upadacitinib after discontinuing treatment with dupilumab. Methods: In total, 33 patients were examined at the start of treatment with upadacitinib after discontinuation of dupilumab, then again after 4 weeks and every 12 weeks up to a maximum of 72 weeks. Results: Among the patients in the study, 14 had developed dupilumab-associated conjunctivitis during dupilumab treatment and had complete resolution of ocular symptoms after the switch to upadacitinib within the 1-month follow-up visit. In addition, only 1 patient treated with upadacitinib developed an episode of conjunctivitis. This condition was of mild severity and it spontaneously resolved quickly. Interestingly, this patient had no history of dupilumab-associated conjunctivitis. Conclusions: All patients who developed dupilumab-associated conjunctivitis experienced complete remission on upadacitinib and only 3% of the patients in our sample developed conjunctivitis after the start of treatment with upadacitinib. In light of this, upadacitinib appears to be a prudent and safe treatment option for AD patients with uncontrolled ocular symptoms associated with dupilumab therapy.

Chronic Pruritus in Atopic Patients Treated with Dupilumab: Real Life Response and Related Parameters in 354 Patients.

Chronic pruritus is a major symptom of atopic dermatitis (AD). Its etiopathogenesis is complex, and an understanding of the driving factors of its pathogenesis allows for the development of new molecule-targeted therapies. Dupilumab, targeting and blocking interleukin-4 (IL-4) and interleukin-13 (IL-13) molecules, has shown great efficacy in treating AD symptoms such chronic itching. We performed a retrospective observational study to evaluate possible chronic-itch-related characteristics and parameters in 356 AD patients who received dupilumab. The objective of the study was to evaluate the factors associated with the level of pruritus reported by patients at each of the 1575 detections in the form of the peak pruritus numerical rating scale (NRSpp) and sleep disturbance numerical rating scale (NRSsd). We focused on: the eczema area and severity index (EASI), dermatology life quality index (DLQI), patient-oriented eczema measure (POEMS), eosinophilia, L-lactate dehydrogenase (LDH), immunoglobulin E (IgE) and the time from the start of dupilumab therapy. NRSpp fell from 8.6 (sd 1.7) at baseline to 1.7 (sd 2.3) at 36 months and NRSsd from 7 (sd 3) to 0. Regarding the parameters that correlate with NRSpp, all the parameters analysed were significantly correlated except for eosinophils (p = 0.136). In the multivariate analysis, both considering and not considering treatment duration, the parameters were correlated (p < 0.001); EASI, DLQI, POEM, and LDH significantly correlated with NRSpp (p < 0.001 for each, except for LDH p = 0.003); while IgE tot lost significance (p = 0.337). Similar results were obtained for the parameters correlating with NRSsd. Our results confirm the efficacy of dupilumab on pruritus. The use of questionnaires such as DLQI and POEM is advisable in clinical practice and is adequate for assessing the impact of itching on AD. The low correlation of IgE and eosinophils, the ambiguity of LDH levels with the level of pruritus, and a poor clinical validity and unclear correlation with disease severity suggest a progressive abandonment of monitoring of these values.

Identification of Risk Factors for Multiple Non-Melanoma Skin Cancers in Italian Kidney Transplant Recipients.

Background and objectives: Non-melanoma skin cancers (NMSCs) represent the most frequently encountered malignancy in organ transplant recipients and their incidence increases proportionally to the duration of immunosuppression. Furthermore, patients of this group often develop multiple and more aggressive cancers and, to date, risk factors for the development of multiple NMSCs have not been yet established. The present study aimed to identify risk factors for multiple NMSCs in a cohort of Italian kidney transplant recipients (KTRs). Materials and Methods: We consecutively included all KTRs referring to two post-transplant outpatient clinics of North-Western Italy between 2001 and 2017. In this cohort, we evaluated different clinical (endogenous and exogenous) risk factors in order to establish their correlation with NMSCs. Results: 518 KTRs were included, of which 148 (28.6%) developed keratinocyte cancers, with a single tumor in 77 subjects, two skin cancers in 31 patients, 3 in 21 patients, whereas at least 4 NMSCs developed in 19 KTRs. We observed an increased risk of the development of cutaneous neoplasms for the male gender, old age at transplantation (>50 years), light phototype, solar lentigo, history of sunburns, or chronic actinic damage. Considering patients affected by multiple keratinocyte neoplasms, we observed a significant association of actinic damage and solar lentigo with an increased risk of NMSCs; their significance was confirmed even at the multivariable model. Conclusions: Our results confirm the role played by chronic cutaneous actinic damage in carcinogenesis on KTRs and highlight the significance of individualized periodic dermatological screening.

Inflammatory Cutaneous Diseases in Renal Transplant Recipients.

Kidney transplant recipients frequently suffer from skin infections and malignancies, possibly due to the effects of long-term immunosuppressive therapy. While the relationships between immunosuppression and these pathological conditions have been widely investigated, little is known about the relative incidence and characteristics of inflammatory skin diseases in this type of patient. In this study, we analyze the incidence of a number of inflammatory cutaneous diseases in a cohort of patients who underwent kidney transplantation. Although our study shows a relatively low incidence of these pathologies in transplanted patients-in agreement with the general action of immunosuppressant therapies in reducing inflammation-we scored a different efficacy of the various immunosuppressive regimens on inflammatory and autoimmune skin diseases. This information can be key for designing immunosuppressive regimens and devising accurate follow-up protocols.

Dermatological approach to vemurafenib skin toxicity: a single centre experience.

BACKGROUND: Targeted therapies have recently changed the approach to advanced melanoma. RAF inhibitors represent the emerging standard of care for metastatic BRAF mutated melanomas. Cutaneous reactions are the most common side effects during vemurafenib treatment, and affect the quality of life. The aim of this study was to provide some practical advices to manage the drug related cutaneous reactions. METHODS: A cohort of BRAF-mutated metastatic melanoma patients treated at our institution included 20 female and 21 male patients; median age was 56 years (32-87 years). All patients were treated at a dose of 960 mg b.i.d. orally. RESULTS: After a median treatment duration of 7 months (range 0.5-25.2), 29/39 patients (74.4%) developed cutaneous toxicities. We identified 22 cases of maculo-papular rash (56%) and 18 of warts (46%); in a total of 10 cases we observed alterations of keratinization (25.6%), while 6 of our patients presented photosensitivity (15 %). Six patients developed keratoacanthomas; no second melanomas were observed. CONCLUSIONS: Skin involvement during vemurafenib treatment is frequent but in the majority of cases cutaneous side effects are self-limiting and easy to manage. Moreover, sun protection is mandatory in vemurafenib treated patients, and should be started together with BRAF inhibitor in order to minimize the impact of photosensitivity on quality of life.

Gauze-based negative pressure wound therapy: a valid method to manage pyoderma gangrenosum.

Pyoderma gangrenosum (PG) is an uncommon ulcerative, non-infective chronic inflammatory skin disorder of unknown aetiology. Systemic therapies are necessary to control the associated medical diseases, and, due to the inflammatory nature of PG, topical or systemic immunosuppressant agents are effective, but wound healing is usually slow. Negative wound pressure therapy (NPWT) has become an important tool for the management of complex skin ulcers, and usage in PG has been recently described in the literature: we present four cases of classic PG in which NPWT in association with systemic therapy achieved wound healing and a drastic pain reduction.

Skin cancers and other cutaneous diseases in renal transplant recipients: a single Italian center observational study.

Kidney transplant recipients frequently suffer from skin infections and malignancies, due to the effects of long-term immunosuppressive therapy. Herein, a dermatological screening was performed to evaluate the relationship between risk factors, cutaneous tumours and other skin diseases in a group of 282 kidney transplant patients. Infectious diseases (16.7%) were the most frequent dermatological disorders, whereas cutaneous inflammatory and autoimmune diseases were relatively rare, probably due to an indirect therapeutic role of immunosuppressive regimens. Thirty patients experienced cutaneous side effects from immunosuppressants, mainly when receiving corticosteroids (p = 0.0372). We identified 99 patients (35.1%) who developed cutaneous tumours after transplantation. Cumulative tumour incidence was observed during long-term immunosuppressive therapy; no relationships were identified between skin cancer risk and single class of drug or combination regimens. When we evaluated the eventual relevance of other risk factors for skin cancers, we demonstrated a statistical significance in univariate analysis for male gender, more advanced age at transplantation, long duration of immunosuppressive regimens, no sunscreen usage, outdoor job, absence of cherry angiomas and presence of actinic keratoses (AKs). Age at transplantation (p = 0.0174), presence of AKs (p = 0.0005) and duration of immunosuppression (p = 0.0011) also confirmed their significance in multivariate analysis.