Dupilumab has been shown effective for prurigo nodularis (PN). However, precise data about efficacy of dupilumab as off-label use in PN is missing. We aggregated current evidence to assess efficacy ...of dupilumab in PN and to identify possible response predictors
Five electronic databases were searched. Our primary outcome was improvement in pruritus measured by numerical rating scale (NRS). We collected data on NRS before (NRSpre) and after (NRSpost) the dupilumab therapy and designed two categorical variables: 'NRS_50' and 'NRS_100' defined as whether one patient reaches 50% and 100% reduction of the NRSpre. Secondary outcomes included: time until patient perceived any improvement (Time_First) and time until patient reported absence of pruritus (Time_Final).
Data on 45 patients from eleven articles were analyzed. The NRSpre was 8.58 ± 1.89 and the NRSpost was 1.78 ± 2.29. Time_First was 10.15 ± 10.56 weeks, while Time_Final was 19.28 ± 13.71 weeks. 22/45 patients (48.88%) presented with complete resolution (NRS_100) and 37/45 patients (82.22%) had itch half dropped (NRS_50). Time_First was significantly longer in subjects that did not reach NRS_100 (13.13 ± 13.77) than in subjects that did (7.34 ± 7.86, p= .05). Time_First was significantly longer in atopic dermatitis (AD) patients (16.08 ± 16.18) than in subjects without AD (7.02 ± 5.69, p=.01). NRS_50 and NRS_100 presented with a significant association (p=.05)
Dupilumab is an effective target-to-treat agent. In comparison with AD, the clinical response to dupilumab initiates later and, two months of therapy are required until significant itch relieves. Complete remission is rarely observed before 4 months of therapy. Notably, AD-related PN patients need longer treatment than non-AD related PN patients to find any relief. Two early signs of improvement are promising predictors of response to dupilumab: The Time_First and NRS_50. What's already known about this topic?
Dupilumab has been shown to be an efficacious treatment for prurigo nodularis (PN)
However, literature data on this topic are scattered. What does this study add?
This work presents the largest cohort of PN patients treated with dupilumab.
Our findings demonstrate dupilumab is a novel and effective choice
In comparison with atopic dermatitis, the clinical response to dupilumab initiates later.
Two months of therapy are required until the itch relieves. Complete remission is rarely observed before 4 months of therapy.
Atopic dermatitis-related PN patients need more weeks of treatment than non-atopic dermatitis-related PN patients
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The tachykinins, exemplified by substance P, are one of the most intensively studied neuropeptide families. They comprise a series of structurally related peptides that derive from alternate ...processing of three Tac genes and are expressed throughout the nervous and immune systems. Tachykinins interact with three neurokinin G protein-coupled receptors. The signaling, trafficking, and regulation of neurokinin receptors have also been topics of intense study. Tachykinins participate in important physiological processes in the nervous, immune, gastrointestinal, respiratory, urogenital, and dermal systems, including inflammation, nociception, smooth muscle contractility, epithelial secretion, and proliferation. They contribute to multiple diseases processes, including acute and chronic inflammation and pain, fibrosis, affective and addictive disorders, functional disorders of the intestine and urinary bladder, infection, and cancer. Neurokinin receptor antagonists are selective, potent, and show efficacy in models of disease. In clinical trials there is a singular success: neurokinin 1 receptor antagonists to treat nausea and vomiting. New information about the involvement of tachykinins in infection, fibrosis, and pruritus justifies further trials. A deeper understanding of disease mechanisms is required for the development of more predictive experimental models, and for the design and interpretation of clinical trials. Knowledge of neurokinin receptor structure, and the development of targeting strategies to disrupt disease-relevant subcellular signaling of neurokinin receptors, may refine the next generation of neurokinin receptor antagonists.
The cytokine interleukin‐31 has been implicated in the pathophysiology of multiple atopic disorders such as atopic dermatitis (AD), allergic rhinitis, and airway hyper‐reactivity. In AD, IL‐31 has ...been identified as one of the main “drivers” of its cardinal symptom, pruritus. Here, we summarize the mechanisms by which IL‐31 modulates inflammatory and allergic diseases. TH2 cells play a central role in AD and release high levels of TH2‐associated cytokines including IL‐31, thereby mediating inflammatory responses, initiating immunoregulatory circuits, stimulating itch, and neuronal outgrowth through activation of the heterodimeric receptor IL‐31 receptor A (IL31RA)/Oncostatin M receptor (OSMRβ). IL31RA expression is found on human and murine dorsal root ganglia neurons, epithelial cells including keratinocytes and various innate immune cells. IL‐31 is a critical cytokine involved in neuroimmune communication, which opens new avenues for cytokine modulation in neuroinflammatory diseases including AD/pruritus, as validated by recent clinical trials using an anti‐IL‐31 antibody. Accordingly, inhibition of IL‐31‐downstream signaling may be a beneficial approach for various inflammatory diseases including prurigo. However, as to whether downstream JAK inhibitors directly block IL‐31‐mediated‐signaling needs to be clarified. Targeting the IL‐31/IL31RA/OSMRβ axis appears to be a promising approach for inflammatory, neuroinflammatory, and pruritic disorders in the future.
Rosacea is a chronic relapsing inflammatory skin disease with high prevalence worldwide. Recent research suggests that dysregulation of innate and adaptive immune pathways as well as neurovascular ...changes is present, with different degrees of importance in the various subtypes. Neither the aetiology, genetics nor pathophysiological basis of the vascular, inflammatory or fibrotic changes is well understood. The clinical spectrum comprises a huge variability from erythema (vasodilation) to papules/pustules (inflammatory infiltrate) to phymata (fibrosis, glandular hyperplasia) making it a valuable human disease model to understand the interplay between the neurovascular and immune systems as well as the progression from chronic inflammation to fibrosis in skin. The lack of appropriate animal models emphasizes the importance of further translational research validating observed molecular pathways under disease conditions. A wide spectrum of physical (UV, temperature), biological (microbiota, food) and endogenous (genetic, stress) stimuli has been discussed as “trigger factors” of rosacea. Novel findings implicate keratinocytes, smooth muscle cells, endothelial cells, macrophages, mast cells, fibroblasts, Th1/Th17 cells, antibody‐producing B cells and neurons in the pathobiology of rosacea. So far, pattern recognition receptors like TLR2, transient receptor potential ion channels, cytokines, chemokines and proteases have been implicated as critical receptors/mediators. However, our understanding of the interactive networks on the molecular level is very limited. Identification of critical molecular components of the inflammatory cascade including antimicrobial peptides, the IL‐1β inflammasome, TNF, IFN‐γ, proteases and neuropeptides may provide the basis for novel pathomechanism‐based therapeutic approaches for this frequent and bothersome skin disease.
Chimeric Antigen Receptor (CAR)-T cell therapy is an exciting development in the field of cancer immunology, wherein immune T-cells from patients are collected, engineered to create 'CAR'-T cells, ...and infused back into the same patient. Currently, two CAR-T-cell-based therapies, Tisagenlecleucel and Axicabtagene ciloleucel, are approved by FDA for the treatment of hematological malignancies, acute lymphoblastic leukemia and large B-cell lymphomas. Their approval has been a culmination of several phase I and II clinical studies, which are the subject of discussion in this review article. Over the years, CAR-T cells have evolved to be significantly more persistent in patients' blood, resulting in a much-improved clinical response and disease remission. This is particularly significant given that the target patient populations of these therapies are those with relapsed and refractory disease who have often progressed on multiple therapies. Despite the promising clinical results, there are still several challenges that need to be addressed. Of particular note are the associated toxicities exemplified by cytokine release syndrome (CRS) and the neurotoxicity. CRS has been addressed by an FDA-approved therapy of its own-tocilizumab. This article focuses on the progress related to CAR-T therapy: the pertinent clinical studies and their major findings, their associated adverse effects, and future perspective.
In the last decade, Chimeric Antigen Receptor (CAR)-T cell therapy has emerged as a promising immunotherapeutic approach to fight cancers. This approach consists of genetically engineered immune ...cells expressing a surface receptor, called CAR, that specifically targets antigens expressed on the surface of tumor cells. In hematological malignancies like leukemias, myeloma, and non-Hodgkin B-cell lymphomas, adoptive CAR-T cell therapy has shown efficacy in treating chemotherapy refractory patients. However, the value of this therapy remains inconclusive in the context of solid tumors and is restrained by several obstacles including limited tumor trafficking and infiltration, the presence of an immunosuppressive tumor microenvironment, as well as adverse events associated with such therapy. Recently, CAR-Natural Killer (CAR-NK) and CAR-macrophages (CAR-M) were introduced as a complement/alternative to CAR-T cell therapy for solid tumors. CAR-NK cells could be a favorable substitute for CAR-T cells since they do not require HLA compatibility and have limited toxicity. Additionally, CAR-NK cells might be generated in large scale from several sources which would suggest them as promising off-the-shelf product. CAR-M immunotherapy with its capabilities of phagocytosis, tumor-antigen presentation, and broad tumor infiltration, is currently being investigated. Here, we discuss the emerging role of CAR-T, CAR-NK, and CAR-M cells in solid tumors. We also highlight the advantages and drawbacks of CAR-NK and CAR-M cells compared to CAR-T cells. Finally, we suggest prospective solutions such as potential combination therapies to enhance the efficacy of CAR-cells immunotherapy.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Rosacea is a common chronic inflammatory skin disease of the central facial skin and is of unknown origin. Currently, two classifications of rosacea exist that are based on either "preformed" ...clinical subtypes (erythematotelangiectatic, papulopustular, phymatous, and ocular) or patient-tailored analysis of the presented rosacea phenotype. Rosacea etiology and pathophysiology are poorly understood. However, recent findings indicate that genetic and environmental components can trigger rosacea initiation and aggravation by dysregulation of the innate and adaptive immune system. Trigger factors also lead to the release of various mediators such as keratinocytes (for example, cathelicidin, vascular endothelial growth factor, and endothelin-1), endothelial cells (nitric oxide), mast cells (cathelicidin and matrix metalloproteinases), macrophages (interferon-gamma, tumor necrosis factor, matrix metalloproteinases, and interleukin-26), and T helper type 1 (T
H1) and T
H17 cells. Additionally, trigger factors can directly communicate to the cutaneous nervous system and, by neurovascular and neuro-immune active neuropeptides, lead to the manifestation of rosacea lesions. Here, we aim to summarize the recent advances that preceded the new rosacea classification and address a symptom-based approach in the management of patients with rosacea.
Several therapies for psoriasis have been described as triggers of biologic-induced bullous pemphigoid (BIBP). The real incidence of BIBP in psoriatic patients is still unknown. Hence, we compilated ...and analyzed current literature to identify the frequency and burden of this adverse event for psoriasis patients treated with biologics.
We systematically searched literature records involving psoriatic patients developing BIBP. Electronic searches were conducted in Pubmed, EMBASE and Scopus in April 2021. To assess the causal relationship between BP and the biologic drug, we applied the Naranjo adverse reaction probability scale and the Karch-Lasagna algorithm.
Our systematic review identified 586 records through the three electronic databases. We identified 15 case reports of BIBP. These cases implicated two cases induced by adalimumab, three by efalizumab, three by etanercept, six by ustekinumab, and one case by secukinumab. Mean period of latency until the BIBP developed was time 5.12 ± 3.44 weeks for TNF-α blockers, and 28.66 ± 26.27 weeks for ustekinumab (p = .09). Most of the cases were assessed as "probable" consistently in both the Naranjo scale and the Karch-Lasagna algorithm.
This work presents an accurate estimation on the frequency and burden of BIBP. Ustekinumab presents with the largest evidence of BIBP, especially in patients with previous failure to TNF-α agents. Distinct patterns in the cytokinic pathways and clinical course exist between the BP induced by TNF-α blockers and ustekinumab. A close monitoring of skin condition is highly advisable in patients receiving biologic therapies for psoriasis. Knowledge of BIBP is of great importance to determine the preventive measures and select optimal treatment options.
What's already known about this topic?
The widespread use of biologic drugs has led dermatologists to encounter increasing situations of biologic-induced BP (BIBP).
A lack of data exists on the real incidence of BIBP in psoriatic patients.
BIBP is an important adverse event to know when managing patients with psoriasis using biologics.
What does this study add?
This work presents an accurate estimation on the raised burden of BIBP.
Ustekinumab presents with the largest evidence of BIBP, especially in patients with previous failure to TNF-α agents.
Mean period of latency until the BIBP developed was time 5.12 ± 3.44 weeks for TNF-α blockers, and 28.66 ± 26.27 weeks for ustekinumab.
Distinct patterns in the cytokine pathways and clinical course exist between the BP induced by TNF-α blockers and ustekinumab.
A careful screening of previous history of bullous diseases and a baseline immunologic study in psoriatic patients should be advisable prior to commencing any biologic therapy.
A close monitoring of skin condition is highly advisable in patients receiving biologic therapies for psoriasis.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Atopic dermatitis (AD) is a common chronic inflammatory condition. Ustekinumab is a human monoclonal antibody approved for psoriasis, that targets the interleukin (IL)-12 and IL-23, and it may also ...play a role in AD. Administration of ustekinumab in AD is presented in anecdotal reports with conflicting results. Our aim was to evaluate the precise value of ustekinumab on AD.
We systematically reviewed published data involving AD treated with ustekinumab. The main outcome was clinical improvement. We classified this in three categories: 'complete response,' 'partial response,' and 'no response.' A multivariant model was used to assess the effectiveness and the following potential predictive factors: gender, age, duration of AD, asthma, previous use of biologics, previous systemic therapies,levels of IgE and duration of ustekinumab therapy.
Data on 23 patients were analyzed. Complete AD remission was reported in 8 patients (34.8%), while the absence of response was observed also in 8 patients (34.8%). Partial response was reported in 7 patients (30.4%). No differences were observed with the predictive factors.
The IL-12/23 pathway is likely not an attractive target for AD. Other effective treatments are available and should be prioritized with a good safety profile.
WHAT'S ALREADY KNOWN ABOUT THIS TOPIC?
Administration of ustekinumab in AD (atopic dermatitis) has been presented in anecdotical reports with conflicting results.
WHAT DOES THIS STUDY ADD?
This work presents the largest cohort of AD patients treated with ustekinumab in a real-world setting.
Ustekinumab resulted in similar rates of complete, partial, and negative responses.
Our findings demonstrate the IL-12/23 pathway is not an attractive target in AD.
More novel and effective treatments for AD are available and should be prioritized.
The impact of anti-IL-12/IL-23p40 therapy in AD is still unclarified due to limited controlled trials.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Unlike conventional itch, neuropathic itch develops in normal skin from excess peripheral firing or dampened central inhibition of itch pathway neurons. Neuropathic itch is a symptom of the same ...central and peripheral nervous system disorders that cause neuropathic pain, such as sensory polyneuropathy, radiculopathy, herpes zoster, stroke, or multiple sclerosis, and lesion location affects symptoms more than aetiology. The causes of neuropathic itch are heterogeneous, and thus diagnosis is based primarily on recognising characteristic, disease-specific clinical presentations. However, the diagnosis of neuropathic itch is challenging, different subforms exist (eg, focal vs widespread, peripheral vs central), and the mechanisms of neuropathic itch are poorly understood, resulting in reduced treatment availability. Currently available strategies include treating or preventing causal diseases, such as diabetes or herpes zoster, and topical or systemic medications that calm excess neuronal firing. Discovery of itch mediators such as gastrin releasing peptide, receptors (eg, neurokinin-1), and pathways (eg, Janus kinases) might encourage much needed new research into targeted treatments of neuropathic itch.
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