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Psoriasis (Auckland, N.Z.) 2023Palmoplantar pustulosis (PPP) is a chronic, relapsing, inflammatory disease that can occur alone or in association with arthritis. There is still controversy about... (Review)
Review
Palmoplantar pustulosis (PPP) is a chronic, relapsing, inflammatory disease that can occur alone or in association with arthritis. There is still controversy about whether it should be separated from psoriasis or classified as pustular psoriasis. Furthermore, drug-induced paradoxical PPP is a special variant of PPP that differs from classic PPP in several ways. Treatment of PPP is still challenging, and there are a number of treatment-resistant cases. This review summarizes the risk factors for the development of PPP and the currently available treatment modalities. Female sex, smokers or ex-smokers, obesity, thyroid dysfunction, and treatment with a tumor necrosis factor (TNF)-α inhibitor have been identified as risk factors for the disease's development, severity, and course. Topical treatments and phototherapy are effective for some patients and are used as a first-line or adjuvant treatment modality. Conventional treatments including retinoids and fumaric acid show good effects and can increase the efficacy of treatment with psoralen + ultraviolet light therapy (PUVA). Ciclosporin is fast acting, but relapse mostly occurs immediately after cessation. TNF-α inhibitors are efficient, and an even better response can be achieved with IL-17 and IL-23 blockers as well as apremilast. The effect of Janus kinase inhibitors seems to be promising according to case reports, but further investigations with larger cohorts are needed.
PubMed: 37772169
DOI: 10.2147/PTT.S400402 -
Pharmacological Research Jan 2023Cucurbitacin B (CuB, CHO), the most abundant and active member of cucurbitacins, which are highly oxidized tetracyclic triterpenoids. Cucurbitacins are widely... (Review)
Review
Cucurbitacin B (CuB, CHO), the most abundant and active member of cucurbitacins, which are highly oxidized tetracyclic triterpenoids. Cucurbitacins are widely distributed in a variety of plants and mainly isolated from plants in the Cucurbitaceae family. CuB is mostly obtained from the pedicel of Cucumis melo L. Modern pharmacological studies have confirmed that CuB has a broad range of pharmacological activities, with significant therapeutic effects on a variety of diseases including inflammatory diseases, neurodegenerative diseases, diabetes mellitus, and cancers. In this study the PubMed, Web of Science, Science Direct, and China National Knowledge Infrastructure (CNKI) databases were searched from 1986 to 2022. After inclusion and exclusion criteria were applied, 98 out of 2484 articles were selected for a systematic review to comprehensively summarize the pharmacological activity, toxicity, and pharmacokinetic properties of CuB. The results showed that CuB exhibits potent anti-inflammatory, antioxidant, antiviral, hypoglycemic, hepatoprotective, neuroprotective, and anti-cancer activities mainly via regulating various signaling pathways, such as the Janus kinase/signal transducer and activator of transcription-3 (JAK/STAT3), nuclear factor erythroid 2-related factor-2/antioxidant responsive element (Nrf2/ARE), nuclear factor (NF)-κB, AMP-activated protein kinase (AMPK), mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K)/Akt, cancerous inhibitor of protein phosphatase-2A/protein phosphatase-2A (CIP2A/PP2A), Wnt, focal adhesion kinase (FAK), Notch, and Hippo-Yes-associated protein (YAP) pathways. Studies of its toxicity and pharmacokinetic properties showed that CuB has non-specific toxicity and low bioavailability. In addition, derivatives and clinical applications of CuB are discussed in this paper.
Topics: Cucurbitacins; Protein Phosphatase 2; Antioxidants; Phosphatidylinositol 3-Kinases; Triterpenes; NF-kappa B
PubMed: 36460279
DOI: 10.1016/j.phrs.2022.106587 -
Cureus Dec 2023Crohn's disease (CD) presents a formidable challenge as a chronic inflammatory condition. This systematic review aimed to comprehensively assess upadacitinib, a novel... (Review)
Review
Crohn's disease (CD) presents a formidable challenge as a chronic inflammatory condition. This systematic review aimed to comprehensively assess upadacitinib, a novel Janus kinase (JAK) inhibitor, regarding its efficacy, safety, and mechanistic insights in CD treatment. A thorough search of electronic databases identified studies investigating upadacitinib's impact on CD patients. Study characteristics, efficacy outcomes (clinical remission and endoscopic response), safety profiles, and mechanistic insights were extracted and qualitatively synthesized. Methodological quality was assessed using established tools. The synthesis of three studies consistently demonstrated improvements in clinical remission rates and endoscopic outcomes in upadacitinib-treated patients. Adverse events, such as herpes zoster, intestinal perforation, non-melanoma skin cancer, adjudicated cardiovascular events, and anemia, were reported, necessitating vigilant safety monitoring. Upadacitinib emerges as a promising therapeutic option for CD, supported by its observed clinical benefits and mechanistic implications. However, safety concerns underscore the importance of careful patient selection. These findings contribute to the ongoing discussion surrounding personalized treatment approaches for CD, emphasizing the need for further research to confirm its enduring efficacy and safety.
PubMed: 38229787
DOI: 10.7759/cureus.50657 -
Pediatric Rheumatology Online Journal Mar 2021Biologic disease modifying antirheumatic drugs (bDMARDs) and Janus Kinase (JAK) inhibitors are prescribed in adult and paediatric rheumatology. Due to age-dependent...
Biologic disease modifying antirheumatic drugs and Janus kinase inhibitors in paediatric rheumatology - what we know and what we do not know from randomized controlled trials.
BACKGROUND
Biologic disease modifying antirheumatic drugs (bDMARDs) and Janus Kinase (JAK) inhibitors are prescribed in adult and paediatric rheumatology. Due to age-dependent changes, disease course, and pharmacokinetic processes paediatric patients with inflammatory rheumatic diseases (PiRD) differ from adult rheumatology patients.
METHODS
A systematic literature search for randomized clinical trials (RCTs) in PiRD treated with bDMARDs/JAK inhibitors was conducted on Medline, clinicaltrials.gov , clinicaltrialsregister.eu and conference abstracts as of July 2020. RCTs were included if (i) patients were aged ≤20 years, (ii) patients had a predefined rheumatic diagnosis and (iii) RCT reported predefined outcomes. Selected studies were excluded in case of (i) observational or single arm study or (ii) sample size ≤5 patients. Study characteristics were extracted.
RESULTS
Out of 608 screened references, 65 references were selected, reporting 35 unique RCTs. All 35 RCTs reported efficacy while 34/3 provided safety outcomes and 16/35 provided pharmacokinetic data. The most common investigated treatments were TNF inhibitors (60%), IL-1 inhibitors (17%) and IL-6 inhibitors (9%). No RCTs with published results were identified for baricitinib, brodalumab, certolizumab pegol, guselkumab, risankizumab, rituximab, sarilumab, secukinumab, tildrakizumab, or upadacitinib. In patients with juvenile idiopathic arthritis (JIA) 25/35 RCTs were conducted. The remaining 10 RCTs were performed in non-JIA patients including plaque psoriasis, Kawasaki Disease, systemic lupus erythematosus and non-infectious uveitis. In JIA-RCTs, the control arm was mainly placebo and the concomitant treatments were either methotrexate, non-steroidal anti-inflammatory drugs (NSAID) or corticosteroids. Non-JIA patients mostly received NSAID. There are ongoing trials investigating abatacept, adalimumab, baricitinib, brodalumab, certolizumab pegol, etanercept, guselkumab, infliximab, risankizumab, secukinumab, tofacitinib and tildrakizumab.
CONCLUSION
Despite the FDA Modernization Act and support of major paediatric rheumatology networks, such as the Pediatric Rheumatology Collaborative Study Group (PRCSG) and the Paediatric Rheumatology International Trials Organization (PRINTO), which resulted in drug approval for PiRD indications, there are limited RCTs in PiRD patients. As therapy response is influenced by age-dependent changes, pharmacokinetic processes and disease course it is important to consider developmental changes in bDMARDs/JAK inhibitor use in PiRD patients. As such it is critical to collaborate and conduct international RCTs to appropriately investigate and characterize efficacy, safety and pharmacokinetics of bDMARDs/JAK inhibitors in paediatric rheumatology.
Topics: Antirheumatic Agents; Child; Humans; Janus Kinase Inhibitors; Randomized Controlled Trials as Topic; Rheumatic Diseases
PubMed: 33766063
DOI: 10.1186/s12969-021-00514-4 -
Journal of Microbiology, Immunology,... Dec 2022This study investigated the clinical efficacy and safety of oral Janus kinase inhibitors (JAKis) in the treatment of hospitalized patients with COVID-19. (Meta-Analysis)
Meta-Analysis
OBJECTIVES
This study investigated the clinical efficacy and safety of oral Janus kinase inhibitors (JAKis) in the treatment of hospitalized patients with COVID-19.
METHODS
The PubMed, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases were searched for relevant articles written before January 29, 2022. Only randomized controlled trials (RCTs) that assessed the clinical efficacy and safety of oral JAKis in patients with COVID-19 were included.
RESULTS
In the pooled analysis of the 7 RCTs, the all-cause 28-day mortality rate in the study group receiving JAKis was significantly lower than that in the control group (9.4% [183/1941] vs. 10.9% [184/1687], risk ratio [RR] = 0.69, 95% confidence interval [CI], 0.58-0.81, I = 0%). In addition, the risk of 14-day mortality was in the study group was lower than that in the control group (RR = 0.65, 95% CI, 0.46-0.92, I = 0%). Finally, the study group and the control group exhibited similar risks of any adverse events (RR = 0.96, 95% CI, 0.89-1.04, I = 0%).
CONCLUSIONS
Oral JAKis can significantly reduce the risk of death among patients with COVID-19. In addition, JAKis are tolerable for hospitalized patients with COVID-19.
Topics: Humans; COVID-19; Janus Kinase Inhibitors; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 36031531
DOI: 10.1016/j.jmii.2022.08.005 -
Dermatology and Therapy Dec 2023Treatments for alopecia areata (AA) have traditionally been prescribed off-label, and there has been no universal agreement on how to best manage the condition.... (Review)
Review
Treatments for alopecia areata (AA) have traditionally been prescribed off-label, and there has been no universal agreement on how to best manage the condition. Baricitinib is the first oral selective Janus kinase (JAK) inhibitor approved for the treatment of adults with severe AA. As a better understanding of the evidence supporting the management of AA in clinical practice is needed, we conducted a systematic literature review and subsequent narrative review to describe available evidence pertaining to the efficacy and tolerability of treatments currently recommended for adults with moderate-to-severe forms of AA. From 2557 identified records, a total of 53 records were retained for data extraction: 9 reported data from 7 randomized controlled trials (RCTs) versus placebo, and 44 reported data from unique RCTs with no placebo arm, non-randomized trials, or observational studies. Across drug classes, data were reported heterogeneously, with little consistency of data collection or clinical endpoints used. The most robust evidence was for the JAK inhibitor class, in particular the JAK1/JAK2 inhibitor baricitinib. Five RCTs (three for baricitinib) demonstrated a consistent benefit of JAK inhibitor therapy over placebo across various clinical outcomes in adult patients with at least 50% scalp hair loss. Overall, hair regrowth varied widely for the other drug classes and was generally low for patients with moderate-to-severe AA. Relapses were commonly observed during treatment and upon discontinuation. Adverse effects were generally consistent with the known safety profile of each intervention. The heterogeneity observed prevented the conduct of a network meta-analysis or an indirect comparison of different treatments. We found that the current management of patients with moderate-to-severe AA often relies on the use of treatments that have not been well evaluated in clinical trials. The most robust evidence identified supported the use of baricitinib, and other oral JAK inhibitors, in patients with severe AA.
PubMed: 37833617
DOI: 10.1007/s13555-023-01044-5 -
Journal of the European Academy of... Apr 2023Recently, the impressive efficacy of JAK-inhibitors (JAK-I) in alopecia areata (AA) has been described in several studies; however, to date, there is limited information... (Review)
Review
Recently, the impressive efficacy of JAK-inhibitors (JAK-I) in alopecia areata (AA) has been described in several studies; however, to date, there is limited information on the safety of JAK-I in AA patients. For this reason, on 18 August 2022, a systematic review was performed to collect the premarketing and postmarketing data on the safety of JAK-I in patients treated for AA, evaluating for each molecule the reported adverse events (AEs) in indexed literature and their frequency. The keywords 'alopecia areata' AND 'Jak-inhibitors OR Janus-kinase Inhibitors' were searched on PubMed, Embase and Cochrane databases. Of 407 studies retrieved, 28 papers met the requirements and were used in our review, including five RCTs and 23 case series; overall, 1719 patients were included, and the safety of 6 JAK-I was assessed (baricitinib, brepocitinib, deuruxolitinib, ritlecitinib, ruxolitinib and tofacitinib). Systemic JAK-I were well-tolerated, most of the AEs were mild, and the withdrawal rate for AEs was very low and inferior to placebo in controlled studies (1.6% vs. 2.2%). Laboratory abnormalities represented 40.1% of AEs associated with oral JAK-I, which mostly included the rise in cholesterol, transaminase, triglycerides, creatine phosphokinase (CPK) and sporadic cases of neutro/lymphocytopenia. The remaining AEs involved the respiratory tract (20.8%), the skin (17.2%), the urogenital (3.8%), or the gastroenterological (3.4%) tract. Increased rates of infections involved not only the upper (19.0%) and lower (0.3%) respiratory tract, but also the urogenital system (3.6%) and the skin (4.6%). Isolated cases of grade 3 to 4 AEs have been reported, including myocardial infarction, hypertensive urgencies, cellulitis, rhabdomyolysis, neutropenia and high elevation of creatinine kinase. No fatal outcomes were reported. AEs reported with topical formulation included scalp irritation and folliculitis. The main limit of this review is the lack of data related to postmarketing surveillance, which should be maintained on a long-term basis.
PubMed: 37013725
DOI: 10.1111/jdv.19090 -
Infection & Chemotherapy Sep 2021The cause of end-organ damage and acute respiratory distress syndrome (ARDS) in coronavirus disease 2019 (COVID-19) patients is postulated to be connected to the...
BACKGROUND
The cause of end-organ damage and acute respiratory distress syndrome (ARDS) in coronavirus disease 2019 (COVID-19) patients is postulated to be connected to the uncontrolled increase of pro-inflammatory cytokines. The upregulation of many cytokines is dependent on signaling through the Janus kinase 1 (JAK-1) and JAK-2 pathways. Ruxolitinib, a JAK-1 and JAK-2 inhibitor, is documented to have potent anti-inflammatory activity by targeting several cytokines and growth factors with proposed efficacy in the cytokine storm observed in severe COVID-19 patients; therefore, this study examines the efficacy and tolerability of ruxolitinib for adult COVID-19 patients.
MATERIALS AND METHODS
This review was conducted using preferred reporting items for aystematic reviews and meta-analyses (PRISMA) methodology. Six reviewers analyzed 1,120 results. Seven studies were selected and validated. A quantitative meta-analysis was further performed to evaluate clinical improvement at day 28, mortality at day 28, and oxygen requirements comparing treatment and standard of care groups.
RESULTS
168 individuals were involved in the studies selected: 122 in cohort studies, 4 in case reports, and 41 in randomized controlled studies. The ruxolitinib group had a higher likelihood of clinical improvement by the 28th day of treatment when assessed with the standard of care (SOC) group (odds ratio [OR]: 1.48; 95% confidence interval [CI]: 0.53 - 4.16; = 0.45; I² = 0%). The SOC group was at a higher risk of experiencing serious adverse events (OR: 0.17; 95% CI: 0.03 - 1.13; = 0.07). Notably the SOC group had a higher likelihood of death (OR: 0.51; 95% CI: 0.11-2.29; = 0.07; I² = 0%).
CONCLUSION
Prior studies on ruxolitinib have demonstrated it is able to decrease inflammatory markers. In recent studies on COVID-19, treatment with ruxolitinib decreased the time on mechanical ventilation, hospitalization time, and the need for vasopressor support. Additionally, ruxolitinib showed decreased mortality and demonstrated improvement in lung congestion as evidenced by computerized tomography imaging. These findings warrant further clinical investigation into Ruxolitinib as a potential treatment approach for severe COVID-19.
PubMed: 34623777
DOI: 10.3947/ic.2020.0126 -
RMD Open Oct 2023We conducted a systematic review and meta-analysis to determine the efficacy of non-conventional synthetic disease-modifying antirheumatic drug (ncs-DMARD) strategies on... (Meta-Analysis)
Meta-Analysis
OBJECTIVES
We conducted a systematic review and meta-analysis to determine the efficacy of non-conventional synthetic disease-modifying antirheumatic drug (ncs-DMARD) strategies on patients with rheumatoid arthritis (RA)-associated interstitial lung disease (ILD).
METHODS
PubMed, EMBASE, the Cochrane Library and Web of Science were searched for relevant articles from inception to 1 June 2022. The results obtained from the analysis were expressed as mean difference (MD), effect size and 95% CI.
RESULTS
A total of 17 studies, including 1315 patients with RA-ILD, were eligible. The ncs-DMARDs included abatacept, rituximab, tocilizumab, tumour necrosis factor and Janus kinase inhibitors. Compared with the baseline, there were no significant changes in forced vital capacity (FVC), forced expiratory volume in the first second (FEV) and diffusion lung capacity for carbon monoxide (DLCO) values in the pooled data after ncs-DMARD treatment (alone or combined with conventional therapy) (p=0.36 for FVC; p=0.96 for FEV and p=0.46 for DLCO). Of note, FVC was obviously increased in rituximab subgroup (MD=-4.62, 95% CI -8.90 to -0.33, p=0.03). Also, high-resolution CT non-progression rate and fatality rate due to ILD progression in patients with RA-ILD were 0.792 (95% CI 0.746 to 0.834, p=0.015) and 0.049 (95% CI 0.035 to 0.065, p=0.000), respectively.
CONCLUSION
ncs-DMARDs alone or combined with conventional therapy might be an optimal and promising treatment for stabilising or improving ILD in patients with RA-ILD.
PROSPERO REGISTRATION NUMBER
CRD42022356816.
Topics: Humans; Rituximab; Antirheumatic Agents; Arthritis, Rheumatoid; Lung Diseases, Interstitial; Abatacept
PubMed: 37899093
DOI: 10.1136/rmdopen-2023-003487 -
RMD Open Sep 2023To estimate the incidence of infections among patients with psoriatic arthritis (PsA) or axial spondyloarthritis (axSpA), two distinct phenotypes included in the large... (Meta-Analysis)
Meta-Analysis
Incidence of infections in patients with psoriatic arthritis and axial spondyloarthritis treated with biological or targeted disease-modifying agents: a systematic review and meta-analysis of randomised controlled trials, open-label studies and observational studies.
OBJECTIVE
To estimate the incidence of infections among patients with psoriatic arthritis (PsA) or axial spondyloarthritis (axSpA), two distinct phenotypes included in the large group of spondyloarthritis (SpA), treated with tumour necrosis-factor-inhibitors, interleukin-17-inhibitors, Janus kinase-inhibitors, IL-23 or IL-12/23-inhibitors (IL-12/23i), phosphodiesterase 4-inhibitors or cytotoxic T-lymphocyte associated protein 4-Ig.
METHODS
A meta-analysis of randomised controlled trials (RCTs), open-label extension and observational studies was conducted. Serious infections were defined as infections that were life-threatening, required intravenous antibiotics and/or hospitalisation. Non-serious infections did not meet these severity criteria. The incidence rates (IR) were reported for each diagnosis by treatment class and study type using random-effect model to create a 95% CI.
RESULTS
Among 23 333 PsA patients and 11 457 axSpA patients, there were 1.09 serious infections per 100 patient-years (PY) (95% CI 0.85 to 1.35) with similar IR in PsA (0.96 per 100 PY 95% CI 0.69 to 1.28) and axSpA (1.09 per 100 PY 95% CI 0.76 to 1.46). The IR was lower in RCTs (0.77 per 100 PY 95% CI 0.41 to 1.20) compared with observational studies (1.68 per 100 PY 95% CI 1.03 to 2.47). In PsA patients, the lowest IR value was observed with IL-12/23i (0.29 per 100 PY 95% CI 0.00 to 1.03). There were 53.0 non-serious infections per 100 PY (95% CI 43.47 to 63.55) in 7257 PsA patients and 5638 axSpA patients. The IR was higher in RCTs (69.95 per 100 PY 95% CI 61.59 to 78.84) compared with observational studies (15.37 per 100 PY 95% CI 5.11 to 30.97).
CONCLUSION
Serious infections were rare events in RCTs and real-life studies. Non-serious infections were common adverse events, mainly in RCTs.
PROSPERO REGISTRATION NUMBER
CRD42020196711.
Topics: Humans; Arthritis, Psoriatic; Incidence; Interleukin-12; Axial Spondyloarthritis; Research Design; Randomized Controlled Trials as Topic
PubMed: 37714666
DOI: 10.1136/rmdopen-2023-003064