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Therapeutic Advances in Gastroenterology 2023Pruritus is a symptom of several cholestatic liver diseases (CLDs) that can impair health-related quality of life (HRQoL). Despite evidence-based guideline therapy,... (Review)
Review
BACKGROUND
Pruritus is a symptom of several cholestatic liver diseases (CLDs) that can impair health-related quality of life (HRQoL). Despite evidence-based guideline therapy, managing cholestatic pruritus (CP) remains challenging, thus making the need for newer, more effective therapeutic agents more evident.
OBJECTIVE
Our study evaluated the efficacy of existing CP therapies.
DESIGN
Systematic review.
DATA SOURCES
From inception until March 2023, we conducted a comprehensive search of MEDLINE, Cochrane, EMBASE, Scopus, ClinicalTrial.gov, and other sources, including pharmaceutical webpages and conference proceedings published in English that reported on CP interventions.
METHODS
Two reviewers independently conducted screening and full-text review of articles with extraction conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. The methodological quality of studies included in our qualitative synthesis was assessed by using the Cochrane ROBINS-I and ROBINS-II tools for interventional studies and the National Heart, Lung, and Blood Institute Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. The primary outcome assessed in our systematic review was the severity of CP after therapy.
RESULTS
Of 3293 screened articles, 92 studies were eligible for inclusion in the qualitative synthesis. Some patients' HRQoL improved with evidence-based standard therapy. Others, particularly those with severe and refractory CP, often required conversion to or addition of experimental noninvasive (e.g., ondansetron) or extracorporeal liver support to alleviate CP. In addition, studies investigating a newer class drug, the ileal bile acid transporter inhibitor (IBATi), demonstrate its effectiveness in reducing serum bile acid and alleviating CP with sustained improvement noted in patients with the inherited childhood cholestatic disorders - progressive familial intrahepatic cholestasis and Alagille syndrome.
CONCLUSION
Our findings consolidate data on the efficacy of guideline-based approaches and newer therapies for CP. While the initial findings are promising, additional clinical trials will be needed to determine the full extent of IBATi's efficacy and potential use in treating other common CLDs. These results provide a foundation for future research and highlight the need for continued investigation into the management and treatment of CLDs.
PubMed: 37255856
DOI: 10.1177/17562848231172829 -
International Journal of Women's... Jun 2023Acquired vulvar lymphangioma (AVL) is not well-characterized. Diagnosis is delayed and the condition is often refractory to therapy. (Review)
Review
UNLABELLED
Acquired vulvar lymphangioma (AVL) is not well-characterized. Diagnosis is delayed and the condition is often refractory to therapy.
OBJECTIVE
The objective of this study was to provide a systematic review of AVL including risk factors, disease associations, and management options.
METHODS
A primary literature search was conducted using 3 databases: PubMed, CINAHL, and OVID, from all years to 2022.
RESULTS
In total, 78 publications with 133 patients (48 ± 17 years) were included. Most studies were case reports/series. The most common disease association was prior malignancy (70 patients, 53% of cases) and inflammatory bowel disease (6 patients, 5% of cases). The most common malignancy was cervical cancer (57 patients, 43% of cases). Most patients had prior radiation or surgery, with 36% (n = 48) treated with radiation, 30% (n = 40) with lymph node dissection, and 27% (n = 36) with surgical resection. Common presenting symptoms included discharge/oozing, pain, and pruritus. Most patients underwent surgical treatment for AVL with 39% treated with excision, 12% with laser therapy (the majority used CO), and 11% with medical therapies. Most patients had failed prior therapies and there was a diagnostic delay.
LIMITATIONS
Retrospective nature. Most studies were limited to case reports and case series, with interstudy variability and result heterogeneity.
CONCLUSION
AVL is an underrecognized entity and should be considered in patients with a history of malignancy or radiation to the urogenital area. Treatment should include multidisciplinary care and address underlying lymphatic changes, manage any existing inflammatory conditions, and utilize skin-directed therapies and barrier agents while addressing symptoms of pruritus and pain. Prospective studies are needed to further characterize AVL and develop treatment guidelines.
PubMed: 37234958
DOI: 10.1097/JW9.0000000000000087 -
Biomolecules Mar 2023Dupilumab was first approved for the treatment of atopic dermatitis (AD) and blocks the signaling of interleukin (IL)-4 and -13. Several other chronic skin conditions... (Review)
Review
Dupilumab was first approved for the treatment of atopic dermatitis (AD) and blocks the signaling of interleukin (IL)-4 and -13. Several other chronic skin conditions share mechanistic overlaps with AD in their pathophysiology, i.e., are linked to type 2 inflammation. Most recently, dupilumab was approved by the U.S. Food and Drug Administration for prurigo nodularis (PN). Given its relatively good safety profile, effective off-label use of dupilumab has been reported for a multitude of dermatologic diseases and several clinical trials for dermatologic skin conditions are currently ongoing. We conducted a systematic review of applications of dupilumab in dermatology other than AD and PN by searching the databases PubMed/Medline, Scopus, Web of Science and Cochrane Library as well as the clinical trial registry ClinicalTrials.gov. We found several reports for effective treatment of bullous autoimmune diseases, eczema, prurigo, alopecia areata, chronic spontaneous urticaria, Netherton syndrome and a variety of other chronic inflammatory skin diseases.
Topics: Humans; Prurigo; Antibodies, Monoclonal, Humanized; Dermatitis, Atopic; Skin
PubMed: 37189381
DOI: 10.3390/biom13040634 -
Diagnostics (Basel, Switzerland) May 2023(1) Background: BCC is a sporadic disease that develops in areas of the skin not exposed to the sun. Perianal BCC, which occurs in the anorectal region, accounts for... (Review)
Review
(1) Background: BCC is a sporadic disease that develops in areas of the skin not exposed to the sun. Perianal BCC, which occurs in the anorectal region, accounts for less than 0.2% of all BCC cases. There have been only a few reported cases of the disease, with fewer than 200 cases reported in total. Given the diagnostic challenges and potential for misdiagnosis, we conducted a systematic review of perianal basal cell carcinoma using real-world data to provide comprehensive and detailed information on the disease. (2) Methods: The study was reported based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, 2020. Patients' clinical pathologic features, tumor characteristics, treatment modalities, and outcomes were presented. (3) Results: The results of 41 studies involving 140 patients were analyzed. The most common symptoms reported by patients at presentation were anorectal bleeding, pain, and pruritus. Ulceration was the most frequently observed tumor characteristic. The majority of patients underwent local excision as their primary treatment, with only eight patients experiencing a recurrence. Our analysis did not reveal any statistically significant differences in the outcomes of different treatment modalities. (4) Conclusions: Identifying perianal BCC poses a significant challenge as it closely resembles other anal diseases, thereby making it difficult to differentiate between the different conditions. However, a wide local excision with clear margins is considered an effective treatment option for most patients. Alternative treatments, such as radiotherapy, may be recommended for patients who are unable to undergo surgery.
PubMed: 37175041
DOI: 10.3390/diagnostics13091650 -
International Journal of Surgery... Jun 2023Available evidence shows that the incidence of toxicities associated with cancer immunotherapy, such as programmed cell death 1 (PD-1) and programmed cell death 1 ligand... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Available evidence shows that the incidence of toxicities associated with cancer immunotherapy, such as programmed cell death 1 (PD-1) and programmed cell death 1 ligand 1 (PD-L1)-related toxicities, is estimated to be between 0.3 and 1.3%.
OBJECTIVE
This systematic review aimed to investigate cancer patients' susceptibility to toxicities associated with PD-1/PD-L1 inhibitors and establish a clinically relevant landscape of side effects of PD-1/PD-L1 inhibitors.
DATA SOURCES
Relevant publications from PubMed, Embase, Cochrane Library, Web of Science, and China National Knowledge Infrastructure (CNKI) between 2014 and 2019.
STUDY ELIGIBILITY CRITERIA, PARTICIPANTS, AND INTERVENTIONS
We searched randomized controlled trials (RCTs) reporting treatment-related toxicities associated with PD-1 and PD-L1 inhibitors in the treatment of cancers. The primary endpoint was to assess the difference in the incidences of toxicities between cancer patients who did and did not receive PD-1/PD-L1 inhibitors. A total of 29 RCTs, incorporating 8576 patients, met the eligibility criteria.
STUDY APPRAISAL AND SYNTHESIS METHODS
We calculated the pooled relative risks and corresponding 95% CIs using a random-effects model and assessed the heterogeneity between different groups. The subgroup analyses were conducted based on cancer type, toxicity grade (severity), system and organ, treatment regimens in the intervention arm and the control arm, PD-1/PD-L1 inhibitor drug type, and cancer type.
RESULTS
A total of 11 categories (e.g. endocrine toxicity), and 39 toxicity types (e.g. hyperthyroidism) were identified. For toxicities at any grade, those treated with PD-1/PD-L1 inhibitors were at lower risks for gastrointestinal toxicity, hematologic toxicity, and treatment event leading to discontinuation; and were at higher risks for respiratory toxicity (all P <0.05). Those treated with PD-1/PD-L1 inhibitors were at lower risks for fatigue, asthenia, and peripheral edema and were at higher risks for pyrexia, cough, dyspnea, pneumonitis, and pruritus.
LIMITATIONS
The present research is a meta-analysis at the study level rather than at the patient level; insights on risk factors associated with the development of toxicities cannot be found in our study. There was a possible overlap in Common Terminology Criteria for Adverse Events (CTCAE) definitions which prevents understanding the true rates of specific toxicities.
CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS
For most toxicity types based on system and organ, the incidence proportions for patients in the intervention arm were lower than those in the control arm, which suggested the general safety of PD-1/PD-L1 inhibitors against conventional chemotherapy and cytotoxic t-lymphocyte-associated protein 4 (CTLA-4) inhibitors. Future research should focus on taking effective targeted measures to decrease the risks of different toxicities for different patient populations.
SYSTEMATIC REVIEW REGISTRATION NUMBER
We registered the research protocol with PROSPERO (registration number CRD42019135113).
Topics: Humans; Immune Checkpoint Inhibitors; Programmed Cell Death 1 Receptor; Neoplasms; Risk; Incidence
PubMed: 37132038
DOI: 10.1097/JS9.0000000000000368 -
British Journal of Clinical Pharmacology Jul 2023New topical agents have been developed for the treatment of atopic dermatitis (AD) in recent years. This systematic review is intended to synthesize the clinical trial... (Review)
Review
AIM
New topical agents have been developed for the treatment of atopic dermatitis (AD) in recent years. This systematic review is intended to synthesize the clinical trial literature and concisely report the updated safety and adverse effects of topical medications used to treat atopic dermatitis in children.
METHODS
A systematic search of Cochrane Library, Embase, PubMed and ClinicalTrials.gov from inception to March 2022 was conducted for trials of topical medications used to treat AD in patients <18 years (PROSPERO #CRD42022315355). Included records were limited to English-language publications and studies of ≥3 weeks duration. Phase 1 studies and those that lacked separate paediatric safety reporting were excluded.
RESULTS
A total of 5005 records were screened; 75 records met inclusion criteria with 15 845 paediatric patients treated with tacrolimus, 12 851 treated with pimecrolimus, 3539 with topical corticosteroid (TCS), 700 with crisaborole and 202 with delgocitinib. Safety data was well reported in tacrolimus trials with the most frequently reported adverse events being burning sensation, pruritus and cutaneous infections. Two longitudinal cohort studies were included, one for tacrolimus and one for pimecrolimus, which found no significant increased risk of malignancy with topical calcineurin inhibitor (TCI) use in children. Skin atrophy was identified as an adverse event in TCS trials, which other medications did not. Systemic adverse events for the medications were largely common childhood ailments.
CONCLUSION
Data discussed here support the use of steroid-sparing medications (tacrolimus, pimecrolimus, crisaborole, delgocitinib) as safe options with minimal adverse events for managing paediatric AD, although a larger number of TCI studies reported burning and pruritus compared to TCS studies. TCS was the only medication class associated with reports of skin atrophy in this review. The tolerability of these adverse events should be considered when treating young children. This review was limited to English-language publications and the variable safety reporting of trial investigators. Many newer medications were not included due to pooled adult and paediatric safety data that did not meet inclusion criteria.
Topics: Adult; Child; Humans; Child, Preschool; Dermatitis, Atopic; Tacrolimus; Longitudinal Studies; Calcineurin Inhibitors; Dermatologic Agents; Pruritus; Treatment Outcome
PubMed: 37075252
DOI: 10.1111/bcp.15751 -
Drug Design, Development and Therapy 2023Despite current advances in acute postoperative pain management, prevalence remains high. Inadequate treatment could lead to poor outcomes and even progression to... (Review)
Review
Despite current advances in acute postoperative pain management, prevalence remains high. Inadequate treatment could lead to poor outcomes and even progression to chronic pain. Opioids have traditionally been the mainstay for treatment of moderate to severe acute pain. However, their use has been associated with opioid-related adverse events (ORAEs), such as respiratory depression, sedation, nausea, vomiting, pruritus, and decreased bowel motility. In addition, their liberal use has been implicated in the current opioid epidemic. As a result, there has been renewed interest in multimodal analgesia to target different mechanisms of action in order to achieve a synergistic effect and minimize opioid usage. Oliceridine is a novel mu-opioid receptor agonist that is part of a new class of biased ligands that selectively activate G-protein signaling and downregulate β-arrestin recruitment. Since G-protein signaling has been associated with analgesia while β-arrestin recruitment has been associated with ORAEs, there is potential for a wider therapeutic window. In this review, we will discuss the clinical evidence behind oliceridine and its potential role in acute postoperative pain management. We have systematically searched the PubMed database using the keywords , and . All articles identified were reviewed and evaluated, and all clinical trials were included.
Topics: Humans; Analgesics, Opioid; Morphine; Pain, Postoperative; GTP-Binding Proteins
PubMed: 36987403
DOI: 10.2147/DDDT.S372612 -
Psychosomatic Medicine May 2023In past decades, the field of nocebo research has focused on studying how sensory perception can be shaped by learning. Nocebo effects refer to aggravated sensory... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
In past decades, the field of nocebo research has focused on studying how sensory perception can be shaped by learning. Nocebo effects refer to aggravated sensory experiences or increased sensitivity to sensations such as pain and itch resulting from treatment-related negative experiences. Behavioral conditioning and verbal suggestions of a negative treatment outcome may aggravate pain and itch perception. Gaining a comprehensive view of the magnitude of nocebo effects and contributing factors will help steer nocebo research toward fruitful directions for understanding complex sensory phenomena.
METHODS
We conducted a systematic review and meta-analysis of a total of 37 distinct experimental nocebo studies on healthy participants (all published in English between 2008 and 2021), with four separate meta-analyses for nocebo effects on pain or itch. We conducted subgroup analyses and meta-regression on factors such as type and intensity of sensory stimuli, and length of conditioning paradigms.
RESULTS
This meta-analysis showed that, on average, effect sizes of nocebo effects were moderate to large (Hedges g between 0.26 and 0.71 for the four primary outcomes). The combination of conditioning and verbal suggestions yielded stronger nocebo responses on pain in particular. Subgroup analyses, including factors such as the type of sensory stimulation, did not explain the moderate heterogeneity in nocebo magnitudes between different studies. Risk of bias was generally low and was not related to nocebo magnitudes either.
CONCLUSIONS
We discuss these results in relation to the role of conditioning and aversive learning, and we recommend more consistency in designing and reporting nocebo experiments.
Topics: Humans; Nocebo Effect; Placebo Effect; Pain; Learning; Pruritus
PubMed: 36961347
DOI: 10.1097/PSY.0000000000001194 -
ESMO Open Apr 2023Programmed death-ligand 1[PD-(L)1], cytotoxic T-lymphocyte associated protein 4 (CTLA-4), and lymphocyte-activation gene 3 (LAG-3) inhibitors are recent breakthroughs in... (Review)
Review
Programmed death-ligand 1[PD-(L)1], cytotoxic T-lymphocyte associated protein 4 (CTLA-4), and lymphocyte-activation gene 3 (LAG-3) inhibitors are recent breakthroughs in cancer treatment, however not all patients benefit from it. Thus new therapies are under investigation, such as anti-TIGIT [anti-T-cell immunoreceptor with immunoglobulin (Ig) and immunoreceptor tyrosine-based inhibitory motif domains] antibodies. TIGIT is an immune checkpoint inhibiting lymphocyte T cells by several mechanisms. In vitro models showed its inhibition could restore antitumor response. Furthermore, its association with anti-PD-(L)1 therapies could synergistically improve survival. We carried out a review of the clinical trial about TIGIT referenced in the PubMed database, finding three published clinical trials on anti-TIGIT therapies. Vibostolimab was evaluated in a phase I alone or in combination with pembrolizumab. The combination had an objective response rate of 26% in patients with a non-small-cell lung cancer (NSCLC) naïve of anti-programmed cell death protein 1 (anti-PD-1). Etigilimab was tested in a phase I alone or in combination with nivolumab, but the study was stopped due to business reasons. In the phase II CITYSCAPE trial, tiragolumab demonstrated higher objective response rate and progression-free survival in combination with atezolizumab than atezolizumab alone in advanced PD-L1-high NSCLC. The ClinicalTrials.gov database references 70 trials of anti-TIGIT in patients with cancer, 47 of them with ongoing recruitment. Only seven were phase III, including five about patients with NSCLC, mostly with combination therapy. Data from phase I-II trials highlighted that targeting TIGIT represents a safe therapeutic approach, with an acceptable toxicity profile maintained when adding anti-PD-(L)1 antibodies. Frequent adverse events were pruritus, rash, and fatigue. Grade 3-4 adverse events were reported in nearly one in three patients. Anti-TIGIT antibodies are under development as a novel immunotherapy approach. A promising research area includes the combination with anti-PD-1 therapies in advanced NSCLCs.
Topics: Humans; Antibodies, Monoclonal; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Nivolumab
PubMed: 36933320
DOI: 10.1016/j.esmoop.2023.101184 -
Digestive Diseases and Sciences Jun 2023We conducted a systematic literature review to understand the evidence supporting treatment decisions for cholestatic pruritus associated with primary biliary...
BACKGROUND AND AIMS
We conducted a systematic literature review to understand the evidence supporting treatment decisions for cholestatic pruritus associated with primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC).
METHODS
Studies that enrolled ≥ 75% participants with PBC or PSC and reported ≥ 1 endpoint(s) related to efficacy, safety, health-related quality of life (HRQoL) or other patient-reported outcomes were included. Bias was assessed using the Cochrane risk of bias tool for randomised controlled trials (RCTs) and the Quality of Cohort studies tool for non-RCTs.
RESULTS
Thirty-nine publications were identified, covering 42 studies and six treatment classes (including investigational and approved products): anion-exchange resins, antibiotics (rifampicin/derivatives), opiates, selective serotonin reuptake inhibitors, fibrates, ileal bile acid transporter inhibitors and other agents not categorised in these six classes. Across studies, median sample size was small (n = 18), 20 studies were over 20 years old, 25 followed patients for ≤ 6 weeks, only 25 were RCTs. Pruritus was assessed using several different tools, with inconsistencies in their application. Cholestyramine, considered first-line therapy for moderate-severe cholestatic pruritus, was assessed in six studies (two RCTs) including 56 patients with PBC and 2 with PSC, with evidence of efficacy demonstrated in only three studies, among which, two RCTs were assessed as having a high risk of bias. Findings were similar for other drug classes.
CONCLUSIONS
There is a lack of consistent and reproducible evidence available on efficacy, impact on HRQoL, and safety of cholestatic pruritus treatments, leaving physicians to rely on clinical experience rather than evidence-based medicine for treatment selection.
Topics: Humans; Young Adult; Adult; Liver Cirrhosis, Biliary; Cholangitis, Sclerosing; Pruritus; Fibric Acids; Quality of Life
PubMed: 36933112
DOI: 10.1007/s10620-023-07862-z