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Rheumatoid arthritis (RA) is a chronic immune-mediated inflammatory disease which can induce progressive disability if not properly treated early. Over the last 20 years, the improvement of knowledge on the pathogenesis of the disease has made available several drugs targeting key elements of the pathogenetic process, which now represent the preferred treatment option after the failure of first-line therapy with conventional drugs such as methotrexate (MTX). To this category of targeted drugs belong anti-cytokine or cell-targeted biological agents and more recently also Janus kinase inhibitors (JAKis). In the absence to date of specific biomarkers to guide the therapeutic choice in the context of true precision medicine, the choice of the first targeted drug after MTX failure is guided by treatment cost (especially after the marketing of biosimilar products) and by the clinical characteristics of the patient (age, sex, comorbidities and compliance) and the disease (presence or absence of autoantibodies and systemic or extra-articular manifestations), which may influence the efficacy and safety profile of the available products. This viewpoint focuses on the decision-making process underlying the personalized approach to RA therapy and will analyse the evidence in the literature supporting the choice of individual products and in particular the differential choice between biological drugs and JAKis. [ABSTRACT FROM AUTHOR]

Topical ruxolitinib 1.5% cream (Opzelura®), a Janus kinase (JAK) inhibitor, is the first treatment to be approved in several countries for use in patients aged ≥ 12 years with non-segmental vitiligo. In the identical phase III TRuE-V1 and TRuE-V2 trials, significantly more ruxolitinib cream recipients were able to achieve statistically significant and clinically meaningful facial and total body repigmentation, as well as reductions in vitiligo noticeability, compared with vehicle recipients. Efficacy was sustained in longer-term analyses to week 104 of treatment. Ruxolitinib 1.5% cream was generally tolerable in these trials; the most common treatment-related adverse events were acne, pruritus and exfoliation, all at the application site. As with orally administered JAK inhibitors, topical ruxolitinib carries boxed warnings in the USA for serious infections, mortality, malignancy, major adverse cardiovascular events (MACE) and thrombosis, although the incidences were low with topical application. Thus, topical ruxolitinib 1.5% cream is an effective and generally tolerable treatment option for patients aged ≥ 12 years with non-segmental vitiligo. Plain Language Summary: Non-segmental vitiligo is a chronic autoimmune disease where the skin throughout the body loses its pigmentation, and is usually managed with topical therapies, light therapy or surgery. Topical ruxolitinib 1.5% cream (Opzelura®) is the first treatment approved in several countries for patients aged ≥ 12 years with non-segmental vitiligo. It inhibits Janus kinase (JAK) proteins, reducing the destruction of skin pigment-producing cells. In two clinical trials, significantly more ruxolitinib cream recipients achieved significant and meaningful skin repigmentation compared with patients who received a non-medicated cream; these results were sustained to week 104 of treatment. Ruxolitinib 1.5% cream was generally tolerable; the most common treatment-related adverse events were acne, itchiness and exfoliation, all at the application site. Topical ruxolitinib has special warnings in the USA for major adverse cardiovascular events (MACE), blood clots, serious infections, death and cancer (associated with the use of oral JAK inhibitors), although incidence rates for these adverse events were low in the clinical trials. Topical ruxolitinib 1.5% cream is an effective and generally tolerable treatment option for patients aged ≥ 12 years with non-segmental vitiligo. [ABSTRACT FROM AUTHOR]

Momelotinib (OJJAARA) is an oral Janus kinase 1 and 2 (JAK1/JAK2) and activin A receptor, type I (ACVR1) inhibitor that has been developed for the treatment of myelofibrosis (MF). In September 2023, momelotinib was approved in the USA for the treatment of intermediate or high-risk MF, including primary MF or secondary MF [post-polycythemia vera (PV) and post-essential thrombocythemia (ET)], in adults with anemia. This article summarizes the milestones in the development of momelotinib leading to this first approval for MF. [ABSTRACT FROM AUTHOR]

Alopecia areata (AA) is a relapsing, chronic, immune-mediated disease characterized by nonscarring, inflammatory hair loss that can affect any hair-bearing site. AA clinical presentation is heterogeneous. Its pathogenesis involves immune and genetic factors and several pro-inflammatory cytokines involved in AA pathogenesis, including interleukin-15 and interferon-γ, as well as Th2 cytokines, such as IL-4/IL-13, that signal through Janus kinase (JAK) pathway. AA treatment aims to stop its progression and reverse hair loss, and JAK inhibition has been shown to stop hair loss and reverse alopecia and has exhibited promising results in treating AA in clinical trials. Baricitinib, an oral, reversible, selective JAK1/JAK2 inhibitor, was shown to be superior to placebo on hair growth after 36 weeks of treatment in adults with severe AA in a phase 2 trial and recently in two phase 3 trials (BRAVE-AA1 and BRAVE-AA2). In both studies, the most common adverse events were upper respiratory tract infections, urinary tract infection, acne, headache, and elevated creatine kinase levels. On the basis of these trial results, baricitinib was recently approved by the European Medicines Agency (EMA) and US Food and Drug Administration (FDA) for the treatment of adults with severe AA. Nevertheless, longer trials are needed to determine the long-term efficacy and safety of baricitinib in AA. Current trials are ongoing and are planned to remain randomized and blinded for up to 200 weeks. [ABSTRACT FROM AUTHOR]

Androgenetic alopecia (AGA), also known as male pattern hair loss (MPHL) or female pattern hair loss (FPHL), is the most common form of alopecia worldwide, and arises from an excessive response to androgens. AGA presents itself in a characteristic distribution unique to both sexes. Despite its prevalence, AGA can be quite challenging to treat. The condition is chronic in nature and stems from an interplay of genetic and environmental factors. There are only two US Food and Drug Administration (FDA)-approved drugs for the condition: topical minoxidil and oral finasteride. However, numerous non-FDA-approved treatments have been shown to be effective in treating AGA in various studies. Some of these treatments are relatively new and still to be explored, thus emphasizing the need for an updated review of the literature. In this comprehensive review, we discuss the evaluation of AGA and the mechanisms of action, costs, efficacies, and safety profiles of existing, alternative, and upcoming therapeutics for this widespread condition. [ABSTRACT FROM AUTHOR]

Axial symptoms (i.e., back pain) are common in the general population. At the same time 25–70% of patients with psoriatic arthritis (PsA) exhibit signs of inflammatory axial involvement (axial PsA). The presence of unexplained chronic (duration ≥ 3 months) back pain in a patient with psoriasis or PsA should trigger evaluation of the presence of axial involvement. Evaluation of axial involvement normally involves imaging of the axial skeleton (sacroiliac joints and/or spine) in addition to clinical and laboratory evaluation. Symptomatic patients with confirmed axial PsA are treated with a combination of non-pharmacologic and pharmacologic methods including the use of non-steroidal anti-inflammatory drugs, tumour necrosis factor, interleukin 17, and Janus kinase inhibitors. Interleukin 23 blockade might also be effective in the axial domain of PsA; a dedicated clinical study is ongoing at present. Safety considerations, patient preference, as well as the presence of other disease manifestations (especially of extra-musculoskeletal manifestations—clinically relevant psoriasis, acute anterior uveitis, inflammatory bowel disease), define the choice of a specific drug or drug class. [ABSTRACT FROM AUTHOR]

Despite the uncertainty of the pathogenesis of systemic lupus erythematosus, novel small molecules targeting specific intracellular mechanisms of immune cells are being developed to reverse the pathophysiological processes. These targeted molecules have the advantages of convenient administration, lower production costs, and the lack of immunogenicity. The Janus kinases, Bruton's tyrosine kinases, and spleen tyrosine kinases are important enzymes for activating downstream signals from various receptors on immune cells that include cytokines, growth factor, hormones, Fc, CD40, and B-cell receptors. Suppression of these kinases impairs cellular activation, differentiation, and survival, leading to diminished cytokine actions and autoantibody secretion. Intracellular protein degradation by immunoproteasomes, levered by the cereblon E3 ubiquitin ligase complex, is an essential process for the regulation of cellular functions and survival. Modulation of the immunoproteasomes and cereblon leads to depletion of long-lived plasma cells, reduced plasmablast differentiation, and production of autoantibodies and interferon-α. The sphingosine 1-phosphate/sphingosine 1-phosphate receptor-1 pathway is responsible for lymphocyte trafficking, regulatory T-cell/Th17 cell homeostasis, and vascular permeability. Sphingosine 1-phosphate receptor-1 modulators limit the trafficking of autoreactive lymphocytes across the blood–brain barrier, increase regulatory T-cell function, and decrease production of autoantibodies and type I interferons. This article summarizes the development of these targeted small molecules in the treatment of systemic lupus erythematosus, and the future prospect for precision medicine. [ABSTRACT FROM AUTHOR]

In recent years, better knowledge of the pathophysiology of inflammatory bowel diseases (IBD) has led to a relevant expansion of the therapeutic arsenal for these conditions. Janus kinase (JAK) inhibitors are a family of small molecules that block one or more of the intracellular tyrosine kinases, including JAK-1, JAK-2, JAK-3 and TYK-2. Tofacitinib, a non-selective small molecule JAK inhibitor, and upadacitinib and filgotinib, which are selective JAK-1 inhibitors, have been approved by the US Food and Drug Administration (FDA) for moderate-to-severe active ulcerative colitis. Compared to biological drugs, JAK inhibitors have a short half-life, rapid onset of action, and no immunogenicity. Both clinical trials and real-world evidence support the use of JAK inhibitors in the treatment of IBD. However, these therapies have been linked with multiple adverse events (AEs) including infection, hypercholesterolemia, venous thromboembolism, major adverse cardiovascular events, and malignancy. While early studies recognized several potential AEs, post-marketing trials have shown that tofacitinib may increase the risk of thromboembolic diseases and major cardiovascular events. The latter are seen in patients aged 50 years or older with cardiovascular risk factors. Hence, the benefits of treatment and risk stratification need to be considered when positioning tofacitinib. Novel JAK inhibitors with a more selective effect on JAK-1 have proven to be effective in both Crohn's disease and ulcerative colitis, offering a potentially safer and efficacious therapeutic option to patients, including those with previous non-response to other therapies such as biologics. Nevertheless, long-term effectiveness and safety data are required. [ABSTRACT FROM AUTHOR]

Pacritinib (VONJO™) is an orally administered, small molecule kinase inhibitor being developed by CTI BioPharma for the treatment of myelofibrosis and graft-versus-host disease. Pacritinib received its first approval in February 2022 in the USA for the treatment of adults with intermediate- or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis with a platelet count below 50 × 109/L. The accelerated approval was based on results from the randomized, active-controlled, phase III PERSIST-2 trial, in which spleen volume reduction was demonstrated in pacritinib recipients. This article summarizes the milestones in the development of pacritinib leading to this first approval for myelofibrosis. [ABSTRACT FROM AUTHOR]

A correction is presented to the article "Ruxolitinib Cream 1.5%: A Review in Non‑Segmental Vitiligo" published in a previous issue of the periodical.

Abrocitinib (Cibinqo®) is an oral small-molecule inhibitor of Janus kinase 1 (JAK1) being developed by Pfizer for the treatment of moderate-to-severe atopic dermatitis (AD). In September 2021, abrocitinib was approved in the UK and Japan for the treatment of moderate-to-severe AD in adults and adolescents 12 years and older who are candidates for systemic therapy. Abrocitinib has also received a positive CHMP opinion in the EU for the treatment of moderate-to-severe atopic dermatitis in adults who are candidates for systemic therapy. Regulatory applications for the drug have also been submitted for review to several other countries, including the USA and Australia. This article summarizes the milestones in the development of abrocitinib leading to this first approval for the treatment of moderate-to-severe AD. [ABSTRACT FROM AUTHOR]

Filgotinib (Jyseleca®) is an oral, ATP-competitive, reversible JAK1 preferential inhibitor that is being developed by Galapagos NV and Gilead Sciences for the treatment of inflammatory autoimmune diseases, including inflammatory arthritis and inflammatory bowel disease. The JAK-STAT signalling pathway has been implicated in the pathogenesis of inflammatory and autoimmune diseases, and filgotinib modulates this pathway by preventing the phosphorylation and activation of STATs. In September 2020, filgotinib received its first approvals in the EU and Japan. In the EU, filgotinib is indicated for the treatment of moderate to severe active rheumatoid arthritis (RA) in adults who have responded inadequately to, or who are intolerant to, one or more disease-modifying anti-rheumatic drugs (DMARDs). In Japan, filgotinib is indicated for the treatment of RA in patients who had an inadequate response to conventional therapies (including prevention of structural damage to joints). Clinical studies of filgotinib for the treatment of inflammatory autoimmune diseases are ongoing worldwide. This article summarizes the milestones in the development of filgotinib leading to this first approval. [ABSTRACT FROM AUTHOR]

A significant proportion of patients with spondyloarthritis (SpA) have peripheral enthesitis. Data suggest that psoriatic arthritis (PsA) patients with enthesitis have a higher disease burden than those without enthesitis. Over the past decade, there has been a proliferation of treatment options for spondyloarthropathy. These medications target multiple signaling pathways, including tumor necrosis factor (TNF), interleukin (IL)-17A, IL-12/23, IL-23, thymus (T)-cell co-stimulation, intracellular Janus kinases, and phosphodiesterase enzymes. As a key domain in SpA, enthesitis outcomes are included in pivotal trials of these agents and are reported as secondary outcome measures. One significant limitation is that the clinical evaluation of enthesitis relies on eliciting tenderness on palpation and is insensitive when compared with imaging. Furthermore, direct comparisons between studies are not available due to the use of different outcome measures, lack of consistent and comprehensive reporting outcomes, and subgroup analyses with a lower number of patients with enthesitis. This systematic review describes the epidemiology, pathophysiology, and available targeted therapies against enthesitis, as well as a detailed report of their efficacy. One major trend identified during this review is incomplete reporting of outcome measures, as many studies reported proportions of enthesitis prevalence. Factors that affected responsiveness in clinical trials included the entheseal instrument used, the number of subjects available for comparison, as well as the therapeutic agent. In general, anti-TNF and anti-IL-17 agents, as well as Janus kinase inhibitors, show moderate responsiveness for enthesitis. The data for IL-23 targeting is contradictory. [ABSTRACT FROM AUTHOR]

The severe acute respiratory syndrome coronavirus 2 associated coronavirus disease 2019 (COVID-19) illness is a syndrome of viral replication in concert with a host inflammatory response. The cytokine storm and viral evasion of cellular immune responses may play an equally important role in the pathogenesis, clinical manifestation, and outcomes of COVID-19. Systemic proinflammatory cytokines and biomarkers are elevated as the disease progresses towards its advanced stages, and correlate with worse chances of survival. Immune modulators have the potential to inhibit cytokines and treat the cytokine storm. A literature search using PubMed, Google Scholar, and ClinicalTrials.gov was conducted through 8 July 2020 using the search terms 'coronavirus', 'immunology', 'cytokine storm', 'immunomodulators', 'pharmacology', 'severe acute respiratory syndrome 2', 'SARS-CoV-2', and 'COVID-19'. Specific immune modulators include anti-cytokines such as interleukin (IL)-1 and IL-6 receptor antagonists (e.g. anakinra, tocilizumab, sarilumab, siltuximab), Janus kinase (JAK) inhibitors (e.g. baricitinib, ruxolitinib), anti-tumor necrosis factor-α (e.g. adalimumab, infliximab), granulocyte–macrophage colony-stimulating factors (e.g. gimsilumab, lenzilumab, namilumab), and convalescent plasma, with promising to negative trials and other data. Non-specific immune modulators include human immunoglobulin, corticosteroids such as dexamethasone, interferons, statins, angiotensin pathway modulators, macrolides (e.g. azithromycin, clarithromycin), hydroxychloroquine and chloroquine, colchicine, and prostaglandin D2 modulators such as ramatroban. Dexamethasone 6 mg once daily (either by mouth or by intravenous injection) for 10 days may result in a reduction in mortality in COVID-19 patients by one-third for patients on ventilators, and by one-fifth for those receiving oxygen. Research efforts should focus not only on the most relevant immunomodulatory strategies but also on the optimal timing of such interventions to maximize therapeutic outcomes. In this review, we discuss the potential role and safety of these agents in the management of severe COVID-19, and their impact on survival and clinical symptoms. [ABSTRACT FROM AUTHOR]

Janus kinase (JAK) is a signal transducer and activator of a protein transcription system that transduces signals from cell surface cytokine and growth factor receptors to the nucleus. Recently developed JAK inhibitors (JAKinibs) inhibit JAKs non-selectively or selectively and down-regulate the effects of corresponding ligands (i.e. cytokines and growth factors). JAKinibs are efficacious against rheumatoid arthritis and other immune-mediated inflammatory diseases and are being increasingly prescribed clinically. Regarding safety, JAKinib use is associated with common or unique changes in laboratory parameters; however, incidence rates of serious adverse drug reactions (ADRs) associated with these changes are low. Opportunistic and other infections, including tuberculosis, are the most critical ADRs of treatment with JAKinibs, and screening and monitoring of patients should be carefully performed. Incidence rates of herpes zoster (HZ) in patients receiving JAKinibs are high in Japan and Korea, and modestly high in other countries. Filgotinib may not be associated with an elevated risk for HZ, but long-term safety data are lacking. Data from clinical development programmes and post-marketing surveillance have indicated no increased risk for malignancy or serious cardiac events; however, long-term observational studies are necessary. Despite the non-elevated risk of gastrointestinal perforations, patients with older age and/or a history of diverticulitis or receiving non-steroidal anti-inflammatory drugs should be carefully evaluated to determine the risk-benefit balance. The incidence rates of venous thromboembolism with all approved doses are similar to that expected in the population, although there are discrepancies in the placebo-controlled portion of the baricitinib clinical development programmes. Regulatory agencies in the USA and Europe suggested a higher risk for thrombotic events in patients receiving JAKinibs. Pharmacokinetic studies demonstrated that dose adjustment should be considered for JAKinib use in patients with moderate-to-severe renal or hepatic dysfunction, depending on the metabolism of each drug. Long-term observational studies enrolling patients with diverse clinical backgrounds are required to strike a risk-benefit balance in clinical settings. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a prevalent inflammatory skin condition that, depending on its severity, can cause enormous morbidity. Corticosteroids and systemic immunosuppression, traditionally standard of care for difficult-to-treat disease, have many undesirable side effects. The desire for targeted treatments along with an improved understanding of the pathophysiology of AD has spurred the development of novel treatments. In this article, we review promising new treatments and discuss how their targets—IL-13, IL-31, OX40 (CD134), and the Janus kinase family of proteins—participate in the pathogenesis of AD. We review the published phase II and III data for dupilumab, tralokinumab, lebrikizumab, nemolizumab, anti-OX40 antibody, baricitinib, abrocitinib, and upadacitinib. The introduction of new agents may offer new options, but it remains to be seen how narrow-acting agents, like single interleukin inhibitors, will compare in safety and efficacy to broad-acting agents such as JAK inhibitors. [ABSTRACT FROM AUTHOR]

Two new biological drugs (vedolizumab and ustekinumab) and one small molecule (tofacitinib) have been recently approved for the treatment of inflammatory bowel disease. Therefore, we must be familiar with the safety of these "new" drugs during pregnancy and breastfeeding. In the present article, we critically review available data on the safety of new biologics (vedolizumab and ustekinumab) and small molecules (tofacitinib) during pregnancy and breastfeeding, with special focus on women with inflammatory bowel disease. Bibliographical searches (MEDLINE) up to April 2020 were performed. The timing and mechanisms of placental transfer of vedolizumab and ustekinumab are expected to be similar to anti-TNF agents. Animal studies show no evidence of adverse effects on pre- or post-natal development after administration of vedolizumab and ustekinumab. Just a few studies including patients treated with vedolizumab or ustekinumab during pregnancy have been published, reporting uneventful pregnancies in most cases. The clinical programme of both drugs and post-marketing studies showed no new safety concerns. Due to the expected safety of vedolizumab and ustekinumab during pregnancy, it may be recommended to plan the final pregnancy dose approximately 8 or 12 weeks, respectively, before the estimated date of delivery. Live vaccines should be avoided for up to a year in children exposed in utero to vedolizumab or ustekinumab unless drug elimination has been documented. Miniscule amounts of vedolizumab and ustekinumab are transferred to breast milk, so breastfeeding is probably safe. There is no evidence of adverse effect of vedolizumab or ustekinumab paternal exposure. Regarding tofacitinib, it is reasonable to assume that this molecule crosses the placenta from the beginning of pregnancy. In animal studies, tofacitinib was feticidal and teratogenic in rats and rabbits, although at exposures many times greater than the standard human dose. Reported outcomes of pregnancy cases identified from tofacitinib randomised controlled trials, post-approval and non-interventional studies, and spontaneous adverse-event reporting appear similar to those observed in the general population. Nevertheless, at present, the use of tofacitinib during pregnancy should be avoided. Although no human studies have reported outcomes of breastfeeding with small molecules such as tofacitinib, this drug is present in lactating rat milk so, at present, breastfeeding should be avoided. Pregnancy among patients with paternal exposure to tofacitinib appears to be safe. In summary, we can conclude that new biologic agents (vedolizumab and ustekinumab) and small molecules (tofacitinib) should be used during pregnancy only if the benefits to the mother outweigh the risks to the mother and unborn child. [ABSTRACT FROM AUTHOR]

Alopecia areata (AA) is an autoimmune condition that affects up to 2% of the general population. Currently available treatment options for AA are of limited efficacy and can be associated with adverse effects. The advancement in understanding of the genetic and molecular mechanisms of AA has led to the development of novel treatment options, with the Janus kinase (JAK) inhibitor class of drugs at the forefront of ongoing clinical trials. Platelet-rich plasma, fecal transplants, and cytokine-targeted therapy with ustekinumab and dupilumab have also been shown to regrow hair in patients with AA in individual case reports or small studies. Several other novel therapies have preliminary data or are being tested in clinical trials. [ABSTRACT FROM AUTHOR]

Delgocitinib, a janus kinase (JAK) inhibitor, is being developed by Japan Tobacco for the treatment of autoimmune disorders and hypersensitivity, including inflammatory skin conditions. The JAK family of tyrosine kinases plays an important role in mediating the biological effects of several inflammatory cytokines, e.g. IL-4, IL-13 and IL-31, which are elevated in patients with atopic dermatitis. Delgocitinib inhibits all members of the JAK family [JAK1, JAK2, JAK3 and tyrosine kinase 2]. Topical delgocitinib (Corectim®) is approved in Japan for the treatment of atopic dermatitis. This article summarizes the milestones in the development of delgocitinib leading to this first approval for the treatment of adults with atopic dermatitis. Clinical development of the topical formulation is also underway for alopecia areata, chronic hand eczema, discoid lupus erythematosus, inverse psoriasis and atopic dermatitis in several countries worldwide. Clinical development of an oral formulation of delgocitinib is also underway in Japan for the treatment of autoimmune disorders and hypersensitivity. [ABSTRACT FROM AUTHOR]

Upadacitinib (Rinvoq™), an orally-administered Janus kinase 1 (JAK-1) inhibitor, is being developed by AbbVie for the treatment of rheumatoid arthritis. In August 2019, based on positive results from multinational phase III trials conducted in patients with rheumatoid arthritis, upadacitinib received marketing approval in the USA for the treatment of moderately to severely active rheumatoid arthritis and an inadequate response or intolerance to methotrexate. This article summarizes the milestones in the development of upadacitinib leading to this first approval for the treatment of rheumatoid arthritis. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is a curative treatment for many hematological malignant and non-malignant diseases. A major complication of the procedure is the donor T-cell-mediated graft-versus-host disease (GvHD). GvHD accounts for about 10% of early mortality after transplantation. GVHD is also the major cause of morbidity and disability in the late follow-up phase of transplanted patients, mainly because of the low response to first-line steroids, and the lack of efficient second-line standard treatments. The increasing knowledge regarding GVHD pathogenesis provides new pharmacological targets, potentially exploitable in clinical practice, in order to prevent and treat this complication. This review provides a description of GVHD pathogenesis, with a focus on the central role of the Janus kinase-related mechanisms. The first inflammatory innate-immunity response is triggered by a JAK/STAT dependent pathway, and JAK inhibition impairs antigen-presenting cell differentiation and activation and downregulates the expression of signals for T-cell triggering. The chronic evolution of alloreactivity, characterized by the long-term maintenance of inflammation and fibrosis, is also dependent on JAK/STAT activation. Based on preclinical data, we reviewed the rationale behind the clinical use of JAK-inhibitors in GVHD, presenting available results of clinical trials and reports, and looked at future implementation of this new promising treatment approach. [ABSTRACT FROM AUTHOR]

Prior to the biologic era, the medical management of patients with inflammatory bowel disease (IBD) was dominated by the use of aminosalicylates, corticosteroids, and immunosuppressants. In the past two decades, the advent of biologic agents that target specific components of the immune response has greatly improved the care of patients with Crohn's disease and ulcerative colitis (UC). However, not all patients respond or maintain response to biologic therapy and some patients develop adverse events that necessitate treatment discontinuation. Furthermore, sensitization with formation of anti-drug antibodies is an inherent limitation to administration of monoclonal antibodies. This circumstance has generated renewed interest in the development of novel oral small-molecule drugs (SMDs) that are effective and well tolerated. Several classes of SMDs are currently progressing through the pipeline and offer the promise of oral delivery and high potency. In this review, we summarize different mechanisms of oral drug delivery to the gastrointestinal tract, highlight key findings from phase II and III randomized trials of novel oral SMDs, and discuss how oral SMDs are likely to be integrated into future IBD treatment paradigms. The most advanced development programs currently involve evaluation of compounds blocking Janus kinase (JAK) receptors or modulating sphingosine-1-phosphate (S1P) receptors. Tofacitinib, an oral JAK inhibitor, was recently approved for the treatment of moderate-to-severe UC. Several more selective JAK-1 inhibitors, including filgotinib and upadacitinib, have also shown positive results in phase II studies and are currently enrolling in phase III development programs. Similarly, ozanimod, an S1P1 and S1P5 receptor agonist, has shown early favorable results and is enrolling in phase III trials. As these and other novel oral SMDs come to market, several questions will need to be answered. The cost effectiveness, comparative treatment efficacy, predictors of response, and relative safety of oral SMDs compared to existing therapies will need to be evaluated. Given the modest efficacy rates observed with both biologic therapies and novel SMDs to date, the potential for combination therapy based on a non-sensitizing oral option is promising and may be facilitated by development of organ-specific therapies with pharmacodynamic activity restricted to the gut to minimize systemic toxicity. [ABSTRACT FROM AUTHOR]

Increases in cancer diagnosis have tremendous negative impacts on patients and their families, and major societal and economic costs. The beneficial effect of chemotherapeutic agents on tumor suppression comes with major unwanted side effects such as weight and hair loss, nausea and vomiting, and neuropathic pain. Chemotherapy-induced peripheral neuropathy (CIPN), which can include both painful and non-painful symptoms, can persist 6 months or longer after the patient's last chemotherapeutic treatment. These peripheral sensory and motor deficits are poorly treated by our current analgesics with limited effectiveness. Therefore, the development of novel treatment strategies is an important preclinical research focus and an urgent need for patients. Approaches to prevent CIPN have yielded disappointing results since these compounds may interfere with the anti-tumor properties of chemotherapeutic agents. Nevertheless, the first (serotonin noradrenaline reuptake inhibitors [SNRIs], anticonvulsants, tricyclic antidepressants) and second (5% lidocaine patches, 8% capsaicin patches and weak opioids such as tramadol) lines of treatment for CIPN have shown some efficacy. The clinical challenge of CIPN management in cancer patients and the need to target novel therapies with long-term efficacy in alleviating CIPN are an ongoing focus of research. The endogenous cannabinoid system has shown great promise and efficacy in alleviating CIPN in preclinical and clinical studies. In this review, we will discuss the mechanisms through which the platinum, taxane, and vinca alkaloid classes of chemotherapeutics may produce CIPN and the potential therapeutic effect of drugs targeting the endocannabinoid system in preclinical and clinical studies, in addition to cannabinoid compounds diffuse mechanisms of action in alleviation of CIPN. [ABSTRACT FROM AUTHOR]

Peficitinib [Smyraf® (Astellas Pharma)] is a Janus kinase (JAK)1, JAK2, JAK3 and tyrosine kinase (Tyk)2 (pan-JAK) inhibitor recently approved in Japan for the treatment of rheumatoid arthritis. Inhibition of JAK suppresses the activation of cytokine signalling pathways involved in inflammation and joint destruction in rheumatoid arthritis. Peficitinib has been shown to significantly improve ACR20 and other measures of disease severity and to reduce the mean modified total Sharp score change from baseline in clinical trials. This article summarizes the milestones in the development of peficitinib leading to this first approval as a treatment for rheumatoid arthritis in patients who have an inadequate response to conventional therapies. [ABSTRACT FROM AUTHOR]

Solriamfetol (Sunosi™) is an orally active, selective dopamine and norepinephrine reuptake inhibitor that was recently approved in the USA as a treatment for excessive daytime sleepiness (hypersomnia) associated with narcolepsy and obstructive sleep apnoea (OSA). Norepinephrine and dopamine influence various physiologic functions, including sleep-wake regulation, and excessive sleepiness has been linked with dysregulation of dopaminergic and norepinephrine systems. This article summarizes the milestones in the development of solriamfetol leading to this first approval as a treatment for excessive daytime sleepiness associated with narcolepsy and OSA. [ABSTRACT FROM AUTHOR]

Tofacitinib (Xeljanz®) is the first Janus kinase (JAK) inhibitor approved at a dosage of 5 mg twice daily (BID) in the EU and the USA for the treatment of active psoriatic arthritis (PsA), where it is indicated in combination with methotrexate for patients who have had an inadequate response or who have been intolerant to a prior therapy with a disease-modifying antirheumatic drug (DMARD). Two well-designed phase III trials (OPAL Broaden and OPAL Beyond) in patients with PsA with or without prior tumour necrosis factor inhibitor (TNFi) therapy showed that tofacitinib 5 mg BID (co-administered with methotrexate or another approved conventional synthetic DMARD) significantly improved the key clinical signs/symptoms and disability associated with PsA after 3 months of treatment, while also improving skin psoriasis, enthesitis, dactylitis, physical function and fatigue. According to interim data, the improvements in clinical signs/symptoms were maintained for up to 30 months in the ongoing long-term extension study OPAL Balance, with minimal radiographic progression seen after 12 months' therapy in the OPAL Broaden study. Tofacitinib 5 mg BID had an acceptable tolerability profile, with low incidences of serious infections, malignancies, cardiovascular events and gastrointestinal perforations over 36 months. Changes in laboratory parameters generally remained stable over 36 months of treatment. Although further studies are required to more definitively establish its efficacy and safety, currently available evidence indicates that tofacitinib expands the treatment options available for the treatment of PsA in patients who have had an inadequate response or who have been intolerant to a prior DMARD therapy. [ABSTRACT FROM AUTHOR]

A correction to the article "Abrocitinib: First Approval" by Emma D. Deeks and Sean Duggan, which appeared in the March 11, 2022 online issue of the magazine is presented.

Pruritus is an enigmatic, seriously disabling symptom accompanying cholestatic liver diseases and a broad range of other disorders. Most recently, novel itchspecific neuronal pathways, itch mediators and their relevant receptors have been identified. In addition, new antipruritic therapeutic strategies have been developed and/or are under evaluation. This review highlights recent experimental and clinical findings focusing on the pathogenesis and actual treatment of pruritus in cholestatic liver disease. Evidence-based therapeutic recommendations, including the use of anion exchange resins cholestyramine, colestipol and colesevelam, the microsomal enzyme inducer rifampicin, the opioid receptor antagonists naltrexone and naloxone, and the serotonin reuptake inhibitor sertraline, are provided. [ABSTRACT FROM AUTHOR]

Depression in patients with acute coronary syndromes (ACS) is common and associated with impaired cardiovascular prognosis in terms of cardiac mortality and new cardiovascular events. It remains unclear whether antidepressant treatment may reverse these effects. In this review, the literature is evaluated on (i) the antidepressant efficacy of selective serotonin reuptake inhibitors (SSRIs) for depression in patients with ACS; (ii) the pleiomorphic effects of SSRIs that may be associated with cardiovascular prognosis; and (iii) the effects of SSRIs on cardiovascular prognosis. SSRIs provide modest relief of depressive symptoms in selected subgroups of depressed patients with ACS. With respect to the pleiomorphic effects of SSRIs, three mechanisms of how SSRIs may improve cardiovascular prognosis are discussed: via platelet function, via the autonomic nervous system (ANS) and via vasomotor tone. Some studies show that SSRIs may reduce platelet activity and sympathetic nervous system activation, but results are inconclusive. SSRIs are associated with vasodilation but this needs to be confirmed with in vivo experiments. Some non-experimental studies describe favourable effects of SSRIs on cardiovascular prognosis. Despite recent developments, much of the effect of SSRIs on cardiovascular prognosis remains unclear. Although some studies suggest effects of SSRIs on platelet function, ANS and vasomotor tone, which may lead to improved cardiovascular prognosis, results are largely inconclusive. More well designed studies addressing these questions are needed. Moreover, since the effects of SSRIs on depression itself are limited, efforts should be dedicated to study the diagnostic validity and homogeneity of depression in the context of ACS and the presence of clinically relevant subtypes. [ABSTRACT FROM AUTHOR]

Pharmacotherapy for anxiety disorders is an active area of research. A variety of drug groups have been shown to be effective in treating many of the anxiety disorders, with selective serotonin reuptake inhibitors (SSRIs) being considered first-line agents for virtually all anxiety disorders. There is a clinical need for alternative drug treatments, as many patients do not achieve a complete response and experience significant adverse effects. The successful use of antiepileptic drugs in mood disorders has led clinicians and researchers to investigate their potential efficacy in other psychiatric disorders, particularly in anxiety disorders. There have been a number of investigations conducted in the form of case reports, case series and open-label trials, suggesting the potential usefulness of antiepileptic drug treatment in a variety of anxiety disorders. More reliable evidence for the use of antiepileptic drugs in anxiety disorders can be gleaned from recent placebo-controlled trials. Thus far, the strongest placebo-controlled evidence has demonstrated the efficacy of pregabalin in treating social phobia and generalised anxiety disorder, while smaller or less robust controlled trials have suggested the potential efficacy of gabapentin in social phobia, lamotrigine in post-traumatic stress disorder, and valproic acid in panic disorder. Antiepileptic drugs may have a place in the treatment of anxiety disorders; however, further investigation is warranted to determine in what circumstances they should be used as monotherapy or as augmenting agents in individuals who are partially or non-responsive to conventional therapy. [ABSTRACT FROM AUTHOR]

The OROS®-based oxybutynin extended-release (ER) formulation (Lyrinel XL™; Ditropan XL®) represents a new form of oral delivery for oxybutynin, a muscarinic receptor antagonist used in the treatment of overactive bladder (OAB). The release of oxybutynin from oxybutynin ER occurs in a sustained manner, resulting in a smoother plasma concentration-time profile and a lower maximum plasma concentration than those seen with oxybutynin immediate-release (IR). The ER formulation has been developed with the aim of improving the tolerability of oxybutynin therapy and facilitating once-daily administration. Moreover, oxybutynin ER offers greater flexibility in dosage (5-30 mg/day) than the other available treatment options. At dosages of 5-30mg once daily, oxybutynin ER produced significant decreases from baseline in weekly urinary urge incontinence in patients with OAB. In addition, there were significant decreases in weekly total incontinence episodes and micturition frequency. In two randomised, double-blind studies in patients with OAB, the improvement in all the symptoms with once-daily oxybutynin ER 5-30 mg/day was similar to that produced by oxybutynin IR 5-20 mg/ day given one to four times daily. Once-daily oxybutynin ER 10mg was superior to tolterodine IR 4 mg/day given as two daily doses and as effective as once-daily tolterodine ER 4 mg/day in decreasing urinary incontinence; the decreases in micturition frequency with oxybutynin ER were significantly greater than those seen with either of tolterodine formulations. Oxybutynin ER was well tolerated in all the trials, with adverse events usually being mild to moderate and transient. In direct comparisons, the overall tolerability profile of oxybutynin ER was better than that of oxybutynin IR. Oxybutynin ER was similar to tolterodine (IR and ER) with respect to the incidence of clinically important dry mouth. A large 12-month tolerability study demonstrated no significant risks associated with the long-term use of oxybutynin ER. A few noncomparative studies have shown promising results with oxybutynin ER in the treatment of adult and paediatric patients with neurogenic bladder dysfunction secondary to neuronal injury. Long- and short-term studies have reported significant improvements in health-related quality of life with oxybutynin ER therapy. In addition, pharmacoeconomic studies have suggested that oxybutynin ER is more cost effective than oxybutynin IR and at least as cost effective as tolterodine IR. In conclusion, oxybutynin ER shows excellent efficacy in the treatment of symptoms associated with OAB in adults and the elderly with a good tolerability profile over a prolonged period of use (12 months). The ER formulation of oxybutynin provides a smooth plasma concentration profile over the 24-hour dosage interval, facilitating once-daily administration. Hence, given its overall efficacy/tolerability profile and dosage flexibility, oxybutynin ER provides an excellent treatment option in the first-line pharmacotherapy of OAB. [ABSTRACT FROM AUTHOR]

The article Filgotinib: First Approval, written by Sohita Dhillon and Susan Keam [ABSTRACT FROM AUTHOR]