Secukinumab in adult patients with lichen planus: Efficacy and safety results from the randomised, placebo-controlled, proof-of-concept PRELUDE study.

BACKGROUND: Patients with lichen planus (LP) refractory to available therapies often experience a high disease burden; representing a population with a clear unmet need for new treatments. OBJECTIVES: To evaluate the efficacy and safety of secukinumab 300 mg over 32 weeks in adult patients with biopsy-proven cutaneous LP (CLP), mucosal LP (MLP) or lichen planopilaris (LPP), inadequately controlled by topical corticosteroids. METHODS: PRELUDE was a, randomised, double-blind, placebo-controlled, Phase 2 proof-of-concept study that enrolled patients with CLP, MLP or LPP. Eligible patients were randomised to eithersecukinumab 300 mg every 4 weeks for 32 weeks (SECQ4W), or placebo for 16 weeks followed by secukinumab 300 mg every 2 weeks (SECQ2W) for 16 weeks. The primary endpoint was achievement of the newly designed Investigator's Global Assessment (IGA) score ≤2 at Week 16. RESULTS: Overall, 111 patients were randomised (n=37 each) to CLP, MLP and LPP cohorts. As the proof-of-concept criteria were not met for any of the 3 cohorts, the primary objective was not met. A numerically higher proportion of patients achieved IGA ≤2 response at Week 16 with SECQ4W vs. placebo in the MLP (37.5% [95% credibility interval (Crl): 20.3-57.2] vs. 23.1% [95% Crl: 6.5-49.2]) and LPP cohorts (37.5% [95% Crl: 20.2-57.3] vs. 30.8% [95% Crl: 10.8-57.6]). In the LPP cohort, a sustained response for IGA ≤2 from Week 16 to Week 32 was achieved with SECQ4W (Week 16: 37.5%; Week 32: 45.8%), and a substantial improvement was observed in IGA ≤2 response in patients of this cohort switching from placebo (Week 16: 30.8%) to SECQ2W after Week 16 (Week 32: 63.6%). The safety profile was consistent with the known profile of secukinumab and showed no new or unexpected signals. CONCLUSIONS: PRELUDE is the first randomised controlled basket trial evaluating interleukin-17A inhibition with secukinumab across 3 subtypes of LP. Secukinumab was well-tolerated and safe, showing different response rates across the 3 subtypes, with numerical IGA improvements in MLP and LPP, and no response in CLP. The study raises the question of a differential role of interleukin-17A across LP subtypes. The novel IGA score showed significant correlation with patient as well as physician reported outcome measurements. TRIAL REGISTRATION NUMBER: NCT04300296.

Evaluating the Appropriateness of Existing Health-Related Quality of Life Measures in Lichen Planus.

INTRODUCTION: Lichen planus (LP) is an inflammatory skin disorder that can present in various forms across the body, including lesions on the skin (cutaneous LP [CLP]), scalp (lichen planopilaris [LPP]) and mucosal regions (mucosal LP [MLP]). Several existing patient-reported outcome measures (PROMs) were identified for potential use in LP clinical development programs. This study aimed to assess the content validity and psychometric measurement properties of the Dermatology Life Quality Index (DLQI), Epworth Sleepiness Scale (ESS), Scalpdex and Oral Lichen Planus Symptom Severity Measure (OLPSSM) in an LP population. METHODS: Patients completed the PROs at various time points as part of an international Phase 2 clinical study in adults with MLP (n = 37), LPP (n = 37) and CLP (n = 37). Test-retest reliability, construct validity and sensitivity to change were assessed. In addition, qualitative cognitive debriefing interviews were conducted with adults with MLP (n = 20), LPP (n = 19) and CLP (n = 19) in the USA and Germany to examine the PROM content validity. RESULTS: The DLQI demonstrated adequate reliability and validity, although its ability to detect change was modest and most items were considered not relevant in qualitative interviews. The ESS had good reliability but limited evidence of validity and ability to detect change. Conceptual relevance varied according to the qualitative interview data. The Scalpdex was miscellaneous across domains, but the 'Symptoms' domain performed well overall. Overall, Scalpdex concepts were reported as relevant by most LPP patients interviewed. The OLPSSM demonstrated good psychometric properties and strong evidence of content validity. CONCLUSIONS: The psychometric and qualitative findings support the use of the OLPSSM and Scalpdex within specific LP subtypes but cautioned use of the DLQI. Administration of the ESS is not recommended in LP because of its poor psychometric performance. Given these limitations, further validation of non-specific disease measures is needed and/or the development of additional LP-specific PROMs. TRIAL REGISTRATION: NCT04300296.

Patient Experience of Lichen Planus: A Qualitative Exploration of Signs, Symptoms, and Health-Related Quality of Life Impacts.

INTRODUCTION: Lichen planus (LP) is an inflammatory skin disorder that can present in various forms across the body, including lesions on the skin (cutaneous LP [CLP]), scalp (lichen planopilaris [LPP]), and mucosal regions (mucosal LP [MLP]). Qualitative exploration of the patient experience of LP, notably symptoms and impacts on health-related quality of life (HRQoL), is limited. A scarcity of research was also identified relating to emotional wellbeing impacts of CLP patients. Two qualitative studies were conducted with LP patients to address these gaps. METHODS: Study 1 consisted of exit interviews conducted with a subset of adult patients with MLP (n = 5), CLP (n = 4), and LPP (n = 4) enrolled in an LP clinical study in the United States (US) to explore the patient experience. Study 2 consisted of independent qualitative interviews conducted with adult CLP patients (n = 13) from the US and Germany to further explore impacts on emotional wellbeing. RESULTS: Exit interviews found that itch , pain, and skin lesions were most frequently reported as signs/symptoms of LP. Itch and skin lesions were experienced across all LP subtypes, while pain was only reported by CLP and MLP patients. These signs/symptoms impacted HRQoL including emotional wellbeing (frustration, embarrassment), daily activities (oral hygiene, clothing options), social functioning (intimacy, social activities), and physical functioning (chewing/swallowing, opening/moving mouth). Impacts on activities of daily living (ADL) and physical functioning were mostly experienced by MLP patients. Independent qualitative interviews, which further explored impacts of CLP on patients' emotional wellbeing, identified frustration, worry, sadness, embarrassment, and depression as the most frequently experienced. CONCLUSION: The findings contribute to the literature by providing qualitative insights into signs/symptoms and HRQoL impacts of LP, from the adult patient perspective. The findings also highlight the importance of considering assessment of HRQoL impacts in future clinical LP research, particularly impacts on emotional wellbeing when selecting instruments for assessment of HRQoL in the CLP population. TRIAL REGISTRATION: NCT04300296.

Single-cell analysis of germinal-center B cells informs on lymphoma cell of origin and outcome.

In response to T cell-dependent antigens, mature B cells are stimulated to form germinal centers (GCs), the sites of B cell affinity maturation and the cell of origin (COO) of most B cell lymphomas. To explore the dynamics of GC B cell development beyond the known dark zone and light zone compartments, we performed single-cell (sc) transcriptomic analysis on human GC B cells and identified multiple functionally linked subpopulations, including the distinct precursors of memory B cells and plasma cells. The gene expression signatures associated with these GC subpopulations were effective in providing a sc-COO for ∼80% of diffuse large B cell lymphomas (DLBCLs) and identified novel prognostic subgroups of DLBCL.

Serum Free Light Chains in Common Variable Immunodeficiency Disorders: Role in Differential Diagnosis and Association With Clinical Phenotype.

We report on an observational, multicenter study of 345 adult CVID patients, designed to assess the diagnostic value and the clinical association of serum free light chain (sFLC) pattern in Common Variable Immunodeficiency disorders (CVID). Sixty CVID patients were tested twice in order to assess intraindividual variability of sFLC. As control groups we included 138 patients affected by undefined primary antibody defects (UAD), lymphoproliferative diseases (LPDs), and secondary antibody deficiencies not related to hematological malignancies (SID). CVID patients presented lower κ and λ chain concentration compared to controls, showing low intraindividual sFLC variability. On the basis of the sFLC pattern, patients were classified into four groups: κ-λ+, κ+λ-, κ-λ-, κ+λ+. The most common pattern in CVID patients was κ-λ- (51%), followed by κ-λ+, (25%), κ+λ+ (22%), and κ+λ- (3%). In UAD, LPD, and SID groups κ+λ+ was the most common pattern observed. By analyzing the possible association between sFLC patterns and disease-related complications of CVID, we observed that patients belonging to the κ-λ- group presented more commonly unexplained enteropathy compared to the κ+λ+ group and showed higher frequency of bronchiectasis and splenomegaly compared to both the κ-λ+ and κ+λ+ patients. When compared to the other groups, κ-λ- had also lower serum IgG, IgA, and IgM concentrations at diagnosis, lower frequency of CD27+IgD-IgM- switched memory B cells, and higher frequency of CD21low B cells, receiving earlier CVID diagnosis. Thus, lower levels of sFLC might be an epiphenomenon of impairment in B cell differentiation, possibly leading κ-λ- patients to a higher risk for bacterial infections and chronic lung damage. Based on these results, we suggest adding sFLC assay to the diagnostic work-up of hypogammaglobulinemia and during follow-up. The assay may be useful to differentiate CVID from other causes of hypogammaglobulinemia and to early detect monoclonal lymphoproliferation occurring over years. Moreover, since the sFLC pattern seems to be related to disease phenotypes and clinical manifestations of CVID and after confirmation by further studies, sFLC assay might be considered a promising prognostic tool for identifying patients at higher risk of developing enteropathy and chronic lung damage or splenomegaly. This will allow designing a tailored follow-up for CVID patients.

Rituximab in refractory sarcoidosis: a single centre experience.

Sarcoidosis is a granulomatous disease whose outcome varies from spontaneous remission to chronic refractory disease. Provided that steroids represent the gold standard as a first line treatment, many immune suppressants drugs are currently used in the disease management. However, refractory disease is still a great challenge. Rituximab is an anti-CD20 chimeric monoclonal antibody, currently used for the treatment of B cell malignancies and systemic autoimmune diseases. There are few case reports describing the successful use of Rituximab in refractory sarcoidosis with lung, eye, lymph nodes and skin involvement. In this paper we described three different case reports in which Rituximab has been used to treat refractory sarcoidosis and we reviewed the existing literature.

Immunoglobulin replacement therapy in secondary hypogammaglobulinemia.

Immunoglobulin (Ig) replacement therapy dramatically changed the clinical course of primary hypogammaglobulinemias, significantly reducing the incidence of infectious events. Over the last two decades its use has been extended to secondary antibody deficiencies, particularly those related to hematological disorders as lymphoproliferative diseases (LPDs) and multiple myeloma. In these malignancies, hypogammaglobulinemia can be an intrinsic aspect of the disease or follow chemo-immunotherapy regimens, including anti-CD20 treatment. Other than in LPDs the broadening use of immunotherapy (e.g., rituximab) and immune-suppressive therapy (steroids, sulfasalazine, and mycophenolate mofetil) has extended the occurrence of iatrogenic hypogammaglobulinemia. In particular, in both autoimmune diseases and solid organ transplantation Ig replacement therapy has been shown to reduce the rate of infectious events. Here, we review the existing literature about Ig replacement therapy in secondary hypogammaglobulinemia, with special regard for subcutaneous administration route, a safe, effective, and well-tolerated treatment approach, currently well established in primary immunodeficiencies and secondary hypogammaglobulinemias.

Subcutaneous immunoglobulin in lymphoproliferative disorders and rituximab-related secondary hypogammaglobulinemia: a single-center experience in 61 patients.

Intravenous immunoglobulin replacement therapy represents the standard treatment for hypogammaglobulinemia secondary to B-cell lymphoproliferative disorders. Subcutaneous immunoglobulin infusion is an effective, safe and well-tolerated treatment approach in primary immunodeficiencies but no extensive data are available on their use in secondary hypogammaglobulinemia, a frequent phenomenon occurring after treatment with anti-CD20 monoclonal antibodies in lymphoproliferative disorders. In this retrospective study we evaluated efficacy (serum IgG trough levels, incidence of infections per year, need for antibiotics) and safety (number of adverse events) of intravenous (300 mg/kg/4 weeks) versus subcutaneous (75 mg/kg/week) immunoglobulin replacement therapy in 61 patients. In addition, the impact of the infusion methods on quality of life was compared. All patients were treated with subcutaneous immunoglobulin, and 33 out of them had been previously treated with intravenous immunoglobulin. Both treatments appeared to be effective in replacing Ig production deficiency and in reducing the incidence of infectious events and the need for antibiotics. Subcutaneous immunoglobulin obtained a superior benefit when compared to intravenous immunoglobulin achieving higher IgG trough levels, lower incidence of overall infection and need for antibiotics. The incidence of serious bacterial infections was similar with both infusion ways. As expected, a lower number of adverse events was registered with subcutaneous immunoglobulin, compared to intravenous immunoglobulin, with no serious adverse events. Finally, we observed an improvement in health-related quality of life parameters after the switch to subcutaneous immunoglobulin. Our results suggest that subcutaneous immunoglobulin is safe and effective in patients with hypogammaglobulinemia associated to lymphoproliferative disorders.