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Giornale Italiano Di Dermatologia E... Aug 2020Psoriatic arthritis (PsA) is a seronegative inflammatory arthritis often observed in patients with skin psoriasis. Treatment of PsA, especially peripheral PsA, has... (Review)
Review
Psoriatic arthritis (PsA) is a seronegative inflammatory arthritis often observed in patients with skin psoriasis. Treatment of PsA, especially peripheral PsA, has typically relied on disease-modifying anti-rheumatic agents (DMARDs); however, these agents have limited efficacy and considerable associated toxicity. More recently, monoclonal antibodies (biologic agents) have revolutionized management of immune-mediated diseases; however, these therapies carry a high cost and require parenteral administration. Apremilast, a novel oral DMARD, was approved by the European Union for psoriatic arthritis in 2015. Apremilast inhibits the function of phosphodiesterase-4, a regulator of cyclic adenosine monophosphate, leading to a broad inhibition of proinflammatory mediators and subsequent reduction in tumour necrosis factor-alpha (TNF-α) response. The PALACE and ACTIVE trials, phase III randomized controlled trials for apremilast, showed that apremilast is effective at improving various clinical and patient-reported outcome measures for psoriatic arthritis in both DMARD-naïve and DMARD-experienced PsA patients. Efficacy was limited in patients with previous biologic DMARD failure and the overall efficacy of apremilast appears to be less than biologics agents, though no head-to-head trials exist comparing apremilast to biologic DMARDs. Apremilast is generally well tolerated, with short-lived gastrointestinal side effects being the most commonly reported adverse events. Guidelines suggest a trial of apremilast in patients who have failed traditional oral DMARDs and for whom, biologics are contraindicated. More studies directly comparing apremilast to conventional DMARDs and biologic DMARDs are needed and will be crucial in informing clinical and economic decisions about apremilast role in management of PsA.
Topics: Antirheumatic Agents; Arthritis, Psoriatic; Biological Products; Humans; Phosphodiesterase 4 Inhibitors; Randomized Controlled Trials as Topic; Thalidomide
PubMed: 33050680
DOI: 10.23736/S0392-0488.20.06640-7 -
Therapeutic Advances in Chronic Disease Oct 2018Psoriatic arthritis (PsA) is an inflammatory arthritis that commonly occurs with psoriasis and is attributed to genetic, immunologic and environmental factors. The... (Review)
Review
Psoriatic arthritis (PsA) is an inflammatory arthritis that commonly occurs with psoriasis and is attributed to genetic, immunologic and environmental factors. The T-helper (Th)-17 pathway and the interleukin (IL)-23/IL-17 axis have become prominent players in PsA and considerably increased our understanding of disease pathogenesis. In this review article, we will focus on the emerging role of IL-12/23 and its blockade, in the pathogenesis and management of PsA as well as of psoriasis and inflammatory bowel disease. Ustekinumab, is a fully human monoclonal immunoglobulin (Ig)G1 antibody that binds specifically to the p40 subunit of IL-12 and IL-23, primarily inhibiting downstream Th-17 signalling pathways. Ustekinumab produced consistent and sustained clinical efficacy in two phase III clinical trials in PsA, PSUMMIT-1 and PSUMMIT-2, with data out to 52 weeks, and no new safety signals. PSUMMIT-1 included patients with active PsA despite conventional therapy who were all naïve to anti-tumour necrosis factor (TNF) agents, whereas PSUMMIT-2 also included anti-TNF experienced patients. Similarly, ustekinumab produced consistent clinical efficacy in two phase III clinical trials in psoriasis, PHOENIX-1 and PHOENIX-2, and in both induction and maintenance of moderate-to-severe Crohn's disease, UNITI-1, UNITI-2 and IM-UNITI, without an increased safety signal. Currently, ustekinumab is used in the treatment of PsA following the failure of nonsteroidal anti-inflammatory drugs (NSAIDs) and conventional disease-modifying antirheumatic drugs (DMARDs), and as an alternative to, or after failure of an anti-TNF agent.
PubMed: 30263103
DOI: 10.1177/2040622318781760 -
Translational Andrology and Urology Jun 2018Clinical research into clinically-localized prostate cancer (PC) is a highly challenging environment. The protracted durations and large numbers required to achieve... (Review)
Review
Clinical research into clinically-localized prostate cancer (PC) is a highly challenging environment. The protracted durations and large numbers required to achieve survival endpoints have placed much pressure on validating early surrogate endpoints. Further confounding is the predominance of deaths from causes other than PC. The analysis of multiple randomized clinical trials in early PC has shown MFS to be a robust surrogate for OS, using a contemporary analytic framework that identify patient-level and trial-level associations. This could potentially save around one year of trial follow-up in some therapies. Identification of a similarly robust surrogate at a substantially earlier timepoint remains a major challenge. Multiple biochemical indices based on PSA have been proposed in the literature, but all remain to be validated at the trial-level. Operationally, many of these indices have inherent biases such as immortal-time bias (ITB) and interval censoring that potentially weakens associations and the individual- or trial-level. The complexity of a failure definition can also impact the reliability of the derived outcomes. Confounding issues such as the impact of comorbidities leading to non-cancer deaths have been largely dealt with by their exclusion using cancer-specific endpoints and advanced statistical methods, while issues such as PSA "bounce" and recovery from androgen deprivation therapy remain important to account for in cohorts treated with radiotherapy. Several potential surrogate endpoints based on serum prostate-specific antigen (PSA) levels show promising associations with PC-specific and overall survival (OS) in individual studies. Further large collaborative projects will continue to refine potential indices with these issues in mind, and explore the objective of an early surrogate of OS.
PubMed: 30050805
DOI: 10.21037/tau.2018.05.10 -
Frontiers in Immunology 2020Spondyloarthritis (SpA) is a chronic inflammatory rheumatism characterized by inflammation of sacroiliac joints, peripheral joints, and spine. The Assessment of... (Review)
Review
Spondyloarthritis (SpA) is a chronic inflammatory rheumatism characterized by inflammation of sacroiliac joints, peripheral joints, and spine. The Assessment of SpondyloArthritis Society describes three disease forms: axial (axSpA), peripheral, and enthesitic SpA. Each may be associated with extra-articular manifestations: psoriasis, inflammatory bowel disease, and acute anterior uveitis. Genome-wide association studies performed in axSpA and psoriatic arthritis (PsA) have shown a shared genetic background, especially the interleukin 23 (IL-23)/IL-17 pathway, which suggests pathophysiological similarities. The convincing positive results of clinical trials assessing the effect of secukinumab and ixekizumab (anti-IL-17A monoclonal antibodies) in axSpA and PsA have reinforced the speculated crucial role of IL-17 in SpA. Nevertheless, and obviously unexpectedly, the differential efficacy of anti-IL-23-targeted treatments between axSpA (failure) and PsA (success) has profoundly disrupted our presumed knowledge of disease pathogeny. The cells able to secrete IL-17, their dependence on IL-23, and their respective role according to the clinical form of the disease is at the heart of the current debate to potentially explain these observed differences in efficacy of IL-23/IL-17-targeted therapy. In fact, IL-17 secretion is usually mainly related to T helper 17 lymphocytes. Nevertheless, several innate immune cells express IL-23 receptor and can produce IL-17. To what extent these alternative cell populations can produce IL-17 independent of IL-23 and their respective involvement in axSpA and PsA are the crucial scientific questions in SpA. From this viewpoint, this is a nice example of a reverse path from bedside to bench, in which the results of therapeutic trials allow for reflecting more in depth on the pathophysiology of a disease. Here we provide an overview of each innate immunity-producing IL-17 cell subset and their respective role in disease pathogeny at the current level of our knowledge.
Topics: Antibodies, Monoclonal, Humanized; Arthritis, Psoriatic; Humans; Immunity, Innate; Interleukin-17; Interleukin-23; Spondylarthritis
PubMed: 33488572
DOI: 10.3389/fimmu.2020.553742 -
Therapeutic Advances in Musculoskeletal... 2023Achieving a good outcome for a person with Psoriatic Arthritis (PsA) is made difficult by late diagnosis, heterogenous clinical disease expression and in many cases,... (Review)
Review
Achieving a good outcome for a person with Psoriatic Arthritis (PsA) is made difficult by late diagnosis, heterogenous clinical disease expression and in many cases, failure to adequately suppress inflammatory disease features. Single-centre studies have certainly contributed to our understanding of disease pathogenesis, but to adequately address the major areas of unmet need, multi-partner, collaborative research programmes are now required. HIPPOCRATES is a 5-year, Innovative Medicines Initiative (IMI) programme which includes 17 European academic centres experienced in PsA research, 5 pharmaceutical industry partners, 3 small-/medium-sized industry partners and 2 patient-representative organizations. In this review, the ambitious programme of work to be undertaken by HIPPOCRATES is outlined and common approaches and challenges are identified. It is expected that, when completed, the results will ultimately allow for changes in the approaches to diagnosing, managing and treating PsA allowing for better short-term and long-term outcomes.
PubMed: 37694182
DOI: 10.1177/1759720X231192315 -
Rheumatology (Oxford, England) Dec 2021The treatment options for PsA have substantially expanded over the last decade. Approximately 40% of patients will not respond to first-line anti-TNF-α therapies. There... (Review)
Review
The treatment options for PsA have substantially expanded over the last decade. Approximately 40% of patients will not respond to first-line anti-TNF-α therapies. There is limited data to help clinicians select the most appropriate biologic therapy for PsA patients, including guidance for decisions on biologic therapy switching. In this review we will examine the current understanding of predictors of response to treatment. Imaging technology has evolved to allow us to better study psoriatic disease and define disease activity, including synovitis and enthesitis. Enthesitis is implicated in the pathogenesis, diagnosis and prognosis of PsA. It appears to be a common thread among all of the various PsA clinical presentations. Enthesitis mainly manifests as tenderness, which is difficult to distinguish from FM, chronic pain and mechanically associated enthesopathy, and it might be relevant for understanding the apparent 40% failure of existing therapy. Excess adipose tissue makes if more difficult to detect joint swelling clinically, as many PsA patients have very high BMIs. Integrating imaging and clinical assessment with biomarker analysis could help to deliver stratified medicine in PsA and allow better treatment decision making. This could include which patients require ongoing biologic therapy, which class of biologic therapy that should be, and who alternatively requires management of non-inflammatory disease.
Topics: Arthritis, Psoriatic; Biological Therapy; Biomarkers; Enthesopathy; Humans; Magnetic Resonance Imaging; Proteomics; Ultrasonography
PubMed: 34951926
DOI: 10.1093/rheumatology/keab504 -
Reviews in Urology 2013Prostate cancer (PCa) is the most frequently diagnosed malignancy and the second leading cause of cancer death in men in the United States and other parts of the world.... (Review)
Review
Prostate cancer (PCa) is the most frequently diagnosed malignancy and the second leading cause of cancer death in men in the United States and other parts of the world. The lifetime risk of being diagnosed with PCa is approximately 16%. At present, the only widely accepted screening tools for PCa are prostate-specific antigen (PSA) and digital rectal examination. PSA is known to be prostate specific, but not PCa specific, and hence lacks the sensitivity to detect a large number of tumors, especially during the early stages. The PSA level is also known to be affected by many factors, such as medication, inflammation (benign prostatic hyperplasia and prostatitis), and urologic manipulation; hence, the controversy regarding the appropriate level of serum PSA that should trigger a biopsy or have clinical relevance to prostate metastases. Attempts to determine the level of prostate cells in peripheral blood by reverse transcriptase polymerase chain reaction did not significantly improve cancer diagnosis or predict postoperative failure. Therefore, the search continues for a novel biomarker or a panel of markers as well as other possible interventions to improve the use of PSA. This article reviews several possibilities.
PubMed: 24223021
DOI: No ID Found -
Urology Dec 2022To characterize patterns of failure using prostate-specific membrane antigen positron emission tomography (PSMA PET) after radical prostatectomy (RP) and salvage...
OBJECTIVE
To characterize patterns of failure using prostate-specific membrane antigen positron emission tomography (PSMA PET) after radical prostatectomy (RP) and salvage radiotherapy (SRT).
METHODS
Patients with rising PSA post-RP+SRT underwent Ga-HBED-iPSMA PET/CT on a single-arm, prospective imaging trial (NCT03204123). Scans were centrally reviewed with pattern-of-failure analysis by involved site. Positive scans were classified using 3 failure categories: pelvic nodal, extra-pelvic nodal or distant non-nodal. Associations with failure categories were analyzed using cumulative incidence and generalized logits regression.
RESULTS
We included 133 men who received SRT a median of 20 months post-RP; 56% received SRT to the prostatic fossa alone, while 44% received pelvic SRT. PSMA PET/CT was performed a median of 48 months post-SRT. Overall, 31% of PSMA PET/CT scans were negative, 2% equivocal and 67% had at least 1 positive site. Scan detection was significantly associated with PSA level prior to PSMA PET/CT. Analysis of 89 positive scans demonstrated pelvic nodal (53%) was the most common relapse and fossa relapse was low (9%). Overall, positive scans were pelvic (n = 35, 26%), extra-pelvic nodal (n = 26, 20%) or distant non-nodal failure (n = 28, 21%), and 70% of positive scans were oligorecurrent. We observed similar cumulative incidence for all failure categories and relatively few clinicodemographic associations. Men treated with pelvic SRT had reduced odds of pelvic failure versus exclusive fossa treatment.
CONCLUSION
Pelvic, extra-pelvic nodal, and distant non-nodal failures occur with similar incidence post-SRT. Regional nodal relapse is relatively common, especially with fossa-only SRT. A high oligorecurrence rate suggests a potentially important role for PSMA-guided focal therapies.
Topics: Male; Humans; Positron Emission Tomography Computed Tomography; Gallium Isotopes; Prostate-Specific Antigen; Prospective Studies; Gallium Radioisotopes; Neoplasm Recurrence, Local; Tomography, X-Ray Computed; Prostatectomy; Prostatic Neoplasms; Salvage Therapy; Positron-Emission Tomography
PubMed: 36115426
DOI: 10.1016/j.urology.2022.08.035