Safety and efficacy of lirentelimab in patients with refractory indolent systemic mastocytosis: a first-in-human clinical trial.

BACKGROUND: Indolent systemic mastocytosis (ISM) is characterized by excessive mast cell (MC) accumulation and MC-driven signs and symptoms. Currently used therapies are not approved and have limited efficacy. Lirentelimab (AK002) is a monoclonal antibody against sialic acid-binding immunoglobulin-like lectin (Siglec)-8 that inhibits MC activation. OBJECTIVES: To determine the safety, tolerability and efficacy of lirentelimab in reducing the symptoms of ISM. METHODS: At a specialty centre for mastocytosis in Germany, we conducted a phase I first-in-human single-ascending and multidose clinical trial of lirentelimab in patients with ISM. Eligible adults had World Health Organization-confirmed ISM and an unsatisfactory response to available treatment. In part A, patients received a single dose of lirentelimab 0.0003, 0.001, 0.003, 0.01 or 0.03 mg kg-1; in part B, patients received one lirentelimab dose of 0.3 mg kg-1 or 1.0 mg kg-1; and in part C, patients received either 1.0 mg kg-1 lirentelimab every 4 weeks for 6 months or ascending doses of lirentelimab (one dose of 1 mg kg-1 followed by five doses of 3-10 mg kg-1 every 4 weeks). The primary endpoint was safety/tolerability. Secondary endpoints included changes from baseline in Mastocytosis Symptom Questionnaire (MSQ), Mastocytosis Activity Score (MAS) and Mastocytosis Quality of Life Questionnaire (MC-QoL) scores at 2 weeks after the final dose. RESULTS: In 25 patients with ISM (13 in parts A + B and 12 in part C; median age 51 years, 76% female, median 4.6 years from diagnosis), the most common treatment-related adverse events (AEs) were feeling hot (76%) and experiencing a headache (48%). No serious AEs occurred. Median MSQ and MAS symptom severity scores in part C improved (vs. baseline) across all symptoms [MSQ: skin (38-56%), gastrointestinal (49-60%), neurological (47-59%), musculoskeletal (26-27%); MAS: skin (53-59%), gastrointestinal (72-85%), neurological (20-57%), musculoskeletal (25%)]. Median MC-QoL scores improved across all domains: symptoms (39%), social life/functioning (42%), emotions (57%) and skin (44%). CONCLUSIONS: Lirentelimab was generally well tolerated and improved symptoms and quality of life in patients with ISM. The therapeutic potential of lirentelimab should be considered for ISM.

Sleep disturbance in adult dermatologic patients: A cross-sectional study on prevalence, burden, and associated factors.

BACKGROUND: Sleep disturbance remains insufficiently characterized in many dermatoses. OBJECTIVE: To investigate the prevalence, burden, and factors associated with sleep disturbance in dermatologic patients. METHODS: We recruited 800 patients and recorded pruritus characteristics and sociodemographic and clinical parameters. Validated questionnaires were used to assess sleep disturbance, psychological distress, health-related quality of life, and work productivity. RESULTS: Two thirds of patients met criteria of poor sleep, which was associated with psychological distress, diminished health-related quality of life, and lost work productivity. Patients with average and maximum pruritus on the visual analog scale exceeding 5 and 6.5 points, respectively, were at high risk of suffering pruritus-related sleep disturbance. Overall pruritus intensity and its nocturnal exacerbation contributed independently to sleep disturbance. Psychological distress was of even higher impact on sleep than pruritus and almost a third of the relationship between pruritus intensity and sleep was mediated by psychological distress. CONCLUSION: Sleep disturbance is prevalent in dermatologic patients and constitutes a considerable burden. CLINICAL IMPLICATION: Dermatologic patients with intense pruritus and psychological distress should be examined for sleep disorders. Adequate antipruritic therapy and complementary psychotherapy in affected patients may help them regain restorative sleep.

The characteristics and impact of pruritus in adult dermatology patients: A prospective, cross-sectional study.

BACKGROUND: Pruritus often accompanies chronic skin diseases, exerting considerable burden on many areas of patient functioning; this burden and the features of pruritus remain insufficiently characterized. OBJECTIVE: To investigate characteristics, including localization patterns, and burden of pruritus in patients with chronic dermatoses. METHODS: We recruited 800 patients with active chronic skin diseases. We assessed pruritus intensity, localization, and further characteristics. We used validated questionnaires to assess quality of life, work productivity and activity impairment, anxiety, depression, and sleep quality. RESULTS: Nine out of every 10 patients had experienced pruritus throughout their disease and 73% in the last 7 days. Pruritus often affected the entire body and was not restricted to skin lesions. Patients with moderate to severe pruritus reported significantly more impairment to their sleep quality and work productivity, and they were more depressed and anxious than control individuals and patients with mild or no pruritus. Suicidal ideations were highly prevalent in patients with chronic pruritus (18.5%) and atopic dermatitis (11.8%). CONCLUSIONS: Pruritus prevalence and intensity are very high across all dermatoses studied; intensity is linked to impairment in many areas of daily functioning. Effective treatment strategies are urgently required to treat pruritus and the underlying skin disease.

Lesions on the back of hands and female gender predispose to stigmatization in patients with psoriasis.

BACKGROUND: Psoriasis vulgaris is characterized by disfiguring and stigmatizing skin lesions. The links among lesions distribution, severity, and stigmatization remain unclear. OBJECTIVE: We sought to investigate if the involvement of visible and sensitive areas is linked to stigmatization. METHODS: In all, 115 patients with psoriasis vulgaris were assessed for disease severity, skin lesions distribution, itch, and stigmatization using the Feelings of Stigmatization Questionnaire. Quality of life was assessed with the Dermatology Life Quality Index and the World Health Organization Quality of Life-BREF. RESULTS: The localization of psoriatic lesions on the back of hands was related to higher stigmatization levels (P = .011, total score of the Feelings of Stigmatization Questionnaire), but not the involvement of nails, the palms, the face, or the genital area nor overall disease severity. All patients reported some level of stigmatization, regardless of the localization of lesions and type of psoriasis. Higher levels of stigmatization characterized patients who claimed not to be able to hide their lesions by clothing (P = .025), women (P = .001), and the unemployed (P = .004). Stigmatization was the strongest predictor of quality of life impairment. LIMITATIONS: Only hospitalized patients were included. CONCLUSIONS: Psoriatic lesions on the back of hands are debilitating and warrant effective treatment. Special attention should be paid to female patients, who are more sensitive to stigmatization.

Characterization of cells and mediators associated with pruritus in primary cutaneous T-cell lymphomas.

Patients with primary cutaneous T-cell lymphoma (CTCL) often experience severe and difficult-to-treat pruritus that negatively affects their quality of life (QoL). However, the mechanisms of pruritus in CTCL, including mycosis fungoides (MF), remain largely unknown, and detailed characteristics of CTCL-associated pruritus is not fully elucidated. To characterize pruritus in CTCL, cutaneous B-cell lymphoma (CBCL), and large plaque parapsoriasis (LPP), and to identify potential itch mediators involved in the pathogenesis of pruritus in CTCL patients. Clinical data and blood samples were collected from 129 healthy subjects and 142 patients. Itch intensity, QoL impairment, psychological distress, and sleep quality were assessed using validated questionnaires and instruments. Blood levels of BDNF, CCL24, GRP, IL-31, IL-33, sST2, substance P, TSLP, tryptase and total IgE were measured using ELISA or ImmunoCAP. Pruritus was prevalent in CTCL, LPP and CBCL patients, with higher prevalence and severity observed in CTCL. In CTCL, pruritus correlated with significant impairment in QoL, sleep, psychological distress. Compared to healthy controls, elevated levels of IL-31, IL-33, substance P, total IgE, tryptase, and TSLP were found in MF patients. A comparison of MF patients with and without pruritus revealed higher levels of IL-31, substance P, GRP, and CCL24 in the former. Itch intensity positively correlated with IL-31, GRP, CCL24, and tryptase levels. Pruritus significantly burdens CTCL patients, necessitating appropriate therapeutic management. Our findings suggest that various non-histaminergic mediators such as tryptase and IL-31 could be explored as novel therapeutic targets for managing pruritus in MF patients.

Pruritus and sleep disturbances in patients with psoriasis.

Psoriasis is a prevalent skin disease that impairs multiple domains of quality of life (QoL). Pruritus, a common symptom in patients with psoriasis, may directly affect sleep, but studies investigating this are limited. We investigated the relationships between pruritus and sleep in 104 in-patients with psoriasis, who underwent dermatological assessment and completed questionnaires to determine psoriasis severity, pruritus intensity, sleep quality, QoL (skin disease-specific and generic), depressive mood and anxiety. In total, 80% of patients reported pruritus, and 39% had sleep disturbances, most commonly awakenings during sleep (33%) and sleepiness during the daytime (30%). Sleep impairment was more frequent in patients with pruritus, who had more difficulty falling asleep (P = 0.031). Overall, 14% of all patients and 34% of the patients who reported sleep disturbances reported that their sleep problems were caused by pruritus. Patients who reported sleep disturbances had lower generic QoL. Pruritus in patients with psoriasis was frequent and relevant, as evidenced by the higher rate of sleep problems in this patient group, and it was linked to a lower QoL.

In psoriasis, levels of hope and quality of life are linked.

Psychological resources such as hope have been suggested to positively influence quality of life (QoL) in chronic disorders. Here, we determined hope levels of psoriasis vulgaris in-patients and analyzed their relation to QoL. A total of 60 (29 male) patients were assessed for their QoL with a generic tool (WHOQOL-BREF) and a skin disease-specific instrument, the Dermatology Life Quality Index (DLQI). Hope levels were determined by use of the Basic Hope Inventory. We found a positive correlation between hope and all domains of WHOQOL-BREF (physical: r = 0.446, p = 0.000; psychological r = 0.464, p = 0.000; social r = 0.302, p = 0.019; environmental r = 0.480, p = 0000; and global r = 0.501, p = 0.000) and a negative correlation with DLQI (r = -0.281, p = 0.030) indicating higher QoL in patients with high hope. Hope was not correlated with disease severity or duration. Hope may play a substantial role in preventing QoL impairment in psoriasis. Psychotherapeutic interventions aimed at strengthening hope could improve QoL in this condition.