Use Of Janus Kinase Inhibitors Research Articles

The Retention Rate and Safety of JAK Inhibitors in Rheumatoid Arthritis: Real Word Data from a Monocentric Cohort.

Background/Objectives: To date, the literature concerning real-world data on the retention rate and safety of Janus kinase inhibitors (JAKis) is limited. To retrospectively evaluate the overall drug retention rate (DRR) of different JAKis in a monocentric cohort of patients with rheumatoid arthritis (RA). Methods: Patients diagnosed with RA and treated with JAKis who were evaluated at our outpatient clinic from March 2017 to December 2023 were included in the study. Demographic, clinical characteristics, and comorbidities were recorded. The DRR was evaluated as the time to drug discontinuation, and baseline predictors of drug discontinuation were investigated through Cox regression after adjusting for baseline confounders. Results: The global DRR for JAKis was 51.3%. The DRR was 37.5% for tofacitinib, 46.6% for baricitinib, 69.4% for upadacitinib, and 53.5% for filgotinib. Considering all JAKis, the only significant predictor of drug discontinuation was the use of JAKis as a first-line treatment (HR 95% CI [0.25 (0.13-0.46)]. When considering each JAKi individually, a longer disease duration predicted TOF discontinuation (HR95% CI [1.05 (1.01-1.09)], while seropositivity protected against TOF being withdrawn (HR95% CI [0.41 (0.17-0.97)]. No independent predictors emerged for other JAKis. Conclusions: the use of JAKis as a first-line treatment as well as disease duration and serology may impact the DRR of JAKis, which may inform tailored treatment strategies in clinical practice.

Highlight of 2023: Advances in pediatric immunology.

In this article for the Highlights of 2023 Series, significant advancements in pediatric immunology are discussed, focusing on new diagnostic and therapeutic approaches. Key studies include the integration of genomic and proteomic profiling for better diagnosis of inborn errors of immunity, the impact of nongenetic factors such as autoantibodies on immune responses, the promising use of Janus kinase inhibitors and chimeric antigen receptor-T cell therapy for treating immune deficiencies and autoimmune diseases and the potential for a curative approach using prime editing. These developments mark a shift toward personalized and precision medicine in pediatric immunology.

Janus kinase inhibitors and the changing landscape of vitiligo management: a scoping review.

Vitiligo is a chronic skin condition caused by an autoimmune response that results in the progressive loss of melanocytes and recent studies have suggested that Janus kinase inhibitors (JAKi) are emerging as a promising new treatment modality. Therefore, to assess and understand the extent of knowledge in the emerging field of JAKi use in vitiligo, a scoping review of the literature was undertaken. The reviewed articles explored a wide variety of JAKi administered either orally or topically for vitiligo. There were no injectable JAKi studied. Tofacitinib was the most commonly studied oral JAKi in 16 of the 35 studies selected for review, followed by baricitinib (n = 3), and one study each with ritlecitinib, ruxolitinib, and upadacitinib. Ruxolitinib (n = 6) and tofacitinib (n = 6) were the most often studied topical JAKi, followed by delgocitinib (n = 1). Potential benefits may vary between JAKi based on their receptor selectivity profile and coexistent autoimmune diseases. A topical JAKi would be advantageous in limited body area involvement and in adolescents. Concurrent use of JAKi with phototherapy or sun exposure appears beneficial. Most studies permitted the use of other topical agents. Acne-related events, though frequent yet mild, were reported with both oral and topical JAKi. Nasopharyngitis, upper respiratory tract infections, and headaches were the most common adverse effects seen in the larger trials with JAKi. No serious or clinically meaningful hematology or thromboembolic events were detected. Treatment of vitiligo with oral or topical JAKi seems to be promising and the growing evidence shows a favorable risk-benefit profile.

Management of Patients Affected by Moderate-to-Severe Atopic Dermatitis with JAK Inhibitors in Real-World Clinical Practice: An Italian Delphi Consensus.

Several systemic therapies have been approved for the treatment of severe AD. In particular, Janus kinase inhibitors (JAKi), including abrocitinib, baricitinib, and upadacitinib, recently received approval for the treatment of patients with severe AD after being evaluated in several clinical trials. However, a few concerns have been raised regarding their long-term safety and the management of these drugs in real-world clinical practice. In this article we described the results of a Delphi consensus aimed at describing the knowledge on JAKi and focusing, in particular, on providing clinical recommendations for dermatologists in daily practice regarding the use of these drugs. Twelve Italian dermatologists reviewed the most recent literature regarding the efficacy and safety profiles of JAKi and proposed 24 statements. Agreement was reached for statements focusing on three main topics: (1) place in therapy of JAKi in patients with moderate-to-severe AD; (2) effectiveness and safety of JAK inhibitors in different phenotypes; (3) different approaches to the management of patients treated with JAKi in clinical practice. The panel proposed several recommendations regarding all the statements. Given the wide use of JAKi in clinical practice, it is crucial to establish a specific follow-up for each patient's phenotype in order to achieve the best possible clinical outcome and minimize potential adverse events.

JANUS KINASE INHIBITORS FOR RELAPSING POLYCHONDRITIS TREATMENT: A HYPOTHESIS

Relapsing polychondritis (RP) is a rare autoimmune disease marked by recurrent episodes of inflammation impacting cartilaginous structures. The underlying mechanism has not been fully elucidated; however, comprehensive genetic and histopathological evaluations have revealed the involvement of specific genes, cell-mediated immunity, and humoral immunity in the pathogenesis of RP. The spectrum of symptoms associated with this condition ranges from mild manifestations to severe, life-threatening presentations. Treatment options vary depending on the disease severity. Non-steroidal anti-inflammatory drugs, colchicine, dapsone, and systemic corticosteroids are commonly utilized as first-line therapeutic options. Furthermore, cyclophosphamide, methotrexate, azathioprine, cyclosporine, and biological disease-modifying anti-rheumatic drugs are employed as second-line treatment. Nevertheless, there is insufficient data regarding the use of Janus kinase inhibitors (JAKi) in RP patients as a treatment option. This hypothesis suggests that JAKi may be a viable treatment option for relieving symptoms in these patients.

Short-term and long-term outcomes of patients with anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis.

Anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive dermatomyositis (MDA5-DM) is a subtype of dermatomyositis characterized by frequent interstitial lung disease and reduced muscle involvement. This study aimed to determine the short-term and long-term outcomes of patients with MDA5-DM. Information on baseline characteristics, treatments, and short-term and long-term outcomes of patients with MDA5-DM including survival, relapse, and the titer of anti-MDA5 antibody, was retrospectively collected. Descriptive statistics regarding clinical outcomes were calculated, and a comparison of clinical parameters between patients with and without relapse was performed. The short-term survival according to the use of Janus kinase inhibitors (JAKi) was also assessed. A total of 154 patients with MDA5-DM were included in the study. Forty patients (25.9%) died during the remission induction phase, with respiratory failure being the most common cause of mortality. Among the 114 patients who survived the remission induction phase, the 5-year cumulative survival and relapse-free survival rates were 96.8% and 77.4%, respectively, and 7.9% of patients achieved complete drug-free remission. Fifty-four patients achieved normalization of anti-MDA5 antibody titers and only two of them relapsed after normalization. In the severe patients, the 6-month survival rate became significantly higher after the emergence of the JAKi treatment compared with before its existence (p= 0.03). Although relapse often occurs, the long-term survival of MDA5-DM patients who survived the remission induction phase is generally favorable. The status of the anti-MDA5 antibody is associated with relapse. JAKi may improve the survival of refractory patients with severe MDA5-DM.

Treatment of atopic dermatitis: Recently approved drugs and advanced clinical development programs.

Atopic dermatitis (AD) represents the most common skin disease characterized by heterogeneous endophenotypes and a high disease burden. In Europe, six new systemic therapies for AD have been approved: the biologics dupilumab (anti-interleukin-4 receptor (IL-4R) α in 2017), tralokinumab (anti-IL-13 in 2021), lebrikizumab (anti-IL-13 in 2023), and the oral janus kinase (JAK) inhibitors (JAKi) targeting JAK1/2 (baricitinib in 2020 in the EU) or JAK1 (upadacitinib in 2021 and abrocitinib in 2022). Herein, we give an update on new approvals, long-term safety, and efficacy. Upadacitinib and abrocitinib have the highest short-term efficacy among the approved systemic therapies. In responders, dupilumab and tralokinumab catch up regarding long-term efficacy and incremental clinical benefit within continuous use. Recently, the European Medicines Agency has released recommendations for the use of JAKi in patients at risk (cardiovascular and thromboembolic diseases, malignancies, (former) smoking, and age ≥65 years). Furthermore, we give an overview on emerging therapies currently in Phase III trials. Among the topical therapies, tapinarof (aryl hydrocarbon receptor), ruxolitinib (JAK1/2i), delgocitinib (pan-JAKi), asivatrep (anti-transient receptor potential vanilloid), and phosphodiesterase-4-inhibitors (roflumilast, difamilast) are discussed. Among systemic therapies, current data on cord-blood-derived mesenchymal stem cells, CM310 (anti IL-4Rα), nemolizumab (anti-IL-31RA), anti-OX40/OX40L-antibodies, neurokinin-receptor-1-antagonists, and difelikefalin (κ-opioid-R) are reported.

Janus kinase inhibitors : Indications, efficacy, uses, what should be taken into account?

Janus kinase inhibitors (JAKi) represent an immunomodulatory targeted therapy in various dermatoses. Throughout the past few years, JAKi have been approved for atopic dermatitis (AD), psoriasis vulgaris (PSO), alopecia areata (AA), and vitiligo. Further indications are currently under investigation. In this article the various systenic and topical JAKi used in dermatology are being presented regarding their efficacy and safety profile. A specific focus will be set on handling with safety issues including screening and control measures during treatment with JAKi. In addition, future use of JAKi in various dermatological diseases for which nowadays only insufficient therapy options are available is being discussed.

Atopic Dermatitis in the Elderly Population.

Atopic dermatitis is a common inflammatory disease with a chronic and relapsing course. Although considered a childhood disease, it is now evident that atopic dermatitis is also common in adulthood and in the elderly population. Atopic dermatitis typically manifests with bilateral and symmetrical eczematous lesions on the face, trunk and skin folds. Itch is invariably present and may be very severe, markedly affecting daily life and sleep. In older adults, atopic dermatitis may have a high level of impact on quality of life, frequently burdening an already complex comorbid situation. The full assessment of disease burden (localizations, itch severity, sleep alterations, impact on quality of life, disease history, comorbidities) is crucial to identify the most appropriate treatment. In many cases, moderate-to-severe atopic dermatitis in the elderly population can be successfully and safely treated with biological agents inhibiting the interleukin-4/-13 pathway, whereas the use of Janus kinase inhibitors may pose concerns about the safety profile.

Expert consensus on the management of interstitial lung disease during the COVID-19 epidemic

Expert consensus on the management of interstitial lung disease during the COVID-19 epidemic

Factors associated to long-term retention rate of Janus kinase inhibitors in a multi-failure rheumatoid arthritis population.

We aimed to retrospectively evaluate retention rate and causes of discontinuation of JAKi in rheumatoid arthritis (RA) patients with particular regards to difficult-to-treat subgroups. The diffusion of Janus kinase inhibitors (JAKi) for the treatment of RA has rapidly increased in recent years due to their effectiveness, even in difficult-to-treat subgroups of patients. After the publication of the Oral Surveillance study, the labelling of JAKi was modified, advising against their use in elderly patients and those at risk for cardiovascular events and malignancies. Demographic, clinical, serological and therapeutic characteristics of RA patients treated with JAKi were recorded, including smoking habit and comorbidities. Three hundred and thirty consecutive RA patients were enrolled in the study. Among them, 50.3% patients had previously failed at least two biologic DMARDs. Risk factors for the use of JAKi were reported in 75.5% of patients, 41.5% of them were older than 65 years, 37.6% had smoked, while 48.8% had increased cardiovascular or cancer risk. Anticitrullinated peptide antibodies (ACPA) and combination therapy with conventional synthetic DMARDs were associated with a longer drug persistence and ACPA remained independently associated to a higher retention rate of JAKi also in the subgroup of difficult-to-treat patients. In conclusion, our study supports the clinical effectiveness of JAKi in RA, even in the multi-failure subgroup of patients, where the risk/benefit ratio overcomes the safety risk. The presence of ACPA and the concurrent use of + cs-DMARD may increase the survival on JAKi in the long term.

Efficacy of olokizumab in patients with mild or moderate COVID-19 and risk factors of progression

The COronaVIrus Disease 2019 (COVID-19) is a common infectious disease characterized by hyperactivation of the immune response and the development of a “cytokine storm” upon progression. The aim of this study was to obtain additional information about the efficacy of the drug olokizumab in comparison with the Janus kinase inhibitor upadacitinib in real clinical practice in patients with mild to moderate COVID-19 and combined risk factors for disease progression. Methods. A single-center, non-interventional, prospective study was conducted in specialized day hospital patients (n = 125) who received therapy with olokizumab (n = 62) (64 mg once intravenously) and the Janus kinase inhibitor upadacitinib (n = 63) (orally, according to selected dosing regimen). The primary endpoint was the frequency of hospitalizations in the 24-hour hospital over the entire observation period. We also analyzed the frequencies of intensive care unit (ICU) transfer, prescription of respyratory therapy, use of “rescue” therapy (monoclonal antibodies/therapeutic proteins acting on interleukins (IL) and their receptors: IL-6 receptor inhibitors and Janus kinase inhibitors (baricitinib, tofacitinib, upadacitinib, etc.)), mortality, dynamics of laboratory and instrumental parameters, as well as frequency of negative and positive changes according to the clinical progression scale of the World Health Organization. Results. All study subjects showed rapid clinical improvement and recovery. Patients in both groups did not experience any negative clinical events, such as admission to a 24-hour hospital, prescription of respyratory therapy, use of “rescue” therapy, etc. Thus, the hyperinflammatory reaction and adverse clinical outcomes are effectively prevented by the timely use of both drugs. Those who received olokizumab had slightly higher levels of C-reactive protein (CRP) at baseline than those who received upadacitinib (p < 0.001). The median CRP value returned to normal on the 4th day in both groups. Patients treated with olokizumab showed a more pronounced change in CRP levels relative to baseline values. A similar trend was also established in body temperature. Conclusion. The study confirmed that early administration of olokizumab in patients with mild to moderate COVID-19 with several risk factors for the severe course is as effective a method of preemptive anti-inflammatory therapy as the use of Janus kinase inhibitors but more stronger suppression of markers and symptoms of intoxication.

Weight gain secondary to the use of Janus kinase inhibitors.

Weight gain secondary to the use of Janus kinase inhibitors.

Cardiovascular comorbidities in atopic dermatitis: Potential implications for the use of Janus kinase inhibitors

Cardiovascular comorbidities in atopic dermatitis: Potential implications for the use of Janus kinase inhibitors

JAK inhibitor: Introduction.

The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway is a key regulatory signaling system for cellular proliferation, differentiation, and apoptosis. In addition, JAK signaling pathway plays critical roles in orchestrating immune response through its interactions with the cytokine receptors and the transcriptions factors. Several key cytokines use JAK-STAT signaling proteins to transduce intra-cellular signals which are involved in the pathogenesis of autoimmune and inflammatory diseases such as in psoriatic disease (psoriasis, psoriatic arthritis), atopic dermatitis, alopecia areata, vitiligo, rheumatoid arthritis, ankylosing spondylitis, lupus erythematosus, Sjogren's syndrome, and other autoimmune diseases. In recent years, understandings of the molecular mechanisms of JAK-STAT pathway in the inflammatory proliferative cascades of autoimmune diseases has led to the development of JAK inhibitors and has opened a new dimension for the treatment of systemic and cutaneous inflammatory diseases. In this symposium we have provided a broad perspective on the use of Janus kinase inhibitors in cutaneous autoimmune diseases.

A detailed look at the European Medicines Agency's recommendations for use of Janus kinase inhibitors in patients with atopic dermatitis.

Oral Janus kinase inhibitors (JAKi) have been approved for the treatment of several chronic inflammatory conditions, including rheumatoid arthritis (RA) and atopic dermatitis (AD). Prompted by new evidence, the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) recently reassessed the benefit-risk balance of oral JAKi. The PRAC recommended that oral JAKi should be used only if no suitable alternatives are available in patients ≥65 years of age, or who have a history of atherosclerotic cardiovascular (CV) disease, other CV risk factors (e.g. history of long-term smoking) or have malignancy risk factors, and used with caution in patients at risk of pulmonary embolism or deep vein thrombosis. The European Commission's final decision was issued in March 2023. Our goal was to highlight the PRAC recommendations, especially in the context of oral JAKi use in AD. Authors summarized the PRAC recommendations, the new clinical evidence on oral JAKi safety and key differences between patients with RA and AD. Risk of developing adverse events of special interest (e.g. cardiovascular events, malignancy) is higher in patients with RA than in patients with AD, because of the higher prevalence of the underlying risk factors. The benefit-risk profile of JAKi approved for AD remains favourable, including use as first-line systemic therapy for patients with AD <65 years of age and without CV or malignancy risk factors.

E072 Real-world single-centre experience of JAK inhibitor use in RA

Abstract Background/Aims The use of Janus Kinase Inhibitors (JAKi) has been gradually increasing overtime in the management of rheumatoid arthritis (RA) and other inflammatory arthritis and these appeal to patients. being oral agents. Nevertheless, rheumatologists have become cautious about their use since recent trials have shown safety concerns about VTEs, MACE and malignancies. Methods We decided to study use of JAKi at our centre in Princess of Wales Hospital Bridgend. The aim was to assess whether appropriate patients were selected (considering cautions about MACE, VTEs and malignancies). We also wanted to see whether all patients had required pre-treatment safety testing and post-treatment monitoring performed. Results These were 70 patients; 59 were females and 11 were males. All of them were diagnosed as RA. Average age was 61.1 years (20—85), average duration of disease 129.9 months (16—340) and average duration of treatment was 58.1 weeks. The most common JAKi being used was baricitinib (84%) followed by tofacitinib (12%) and upadacitinib (4%). 50% patient were on concomitant csDMARDs among whom two-thirds were on methotrexate. Looking at previous biologic use, 9 patients were biologic naïve, 22 had one biologic, 15 had two biologics used in the past. All patients were appropriately selected (severe RA and no significant risk factors for MACE, VTEs and malignancies). All patients had pre-treatment Hepatitis B, Hepatitis C, latent TB, FBC and LFTs checked. All patients had FBC and LFTs monitored post treatment. No patient developed VTE, MACE or cancer on treatment. 84.2% patients had lipids tested before starting JAKi. 22.8% patients had abnormal lipids before Rx initiation and 62.5% of these were on lipid lowering Rx. All patients had lipids tested post treatment, but the timing was quite variable and only 62.5% of patients had lipids tested on the recommended time. There were 2 deaths recorded in this cohort. One of those was an 80-year-old RA patient on baricitinib 2 mg OD, who died due to chest infection on the background of ILD. He was not on steroids or csDMARDs. The second patient was 63 years' old (on baricitinib 4mg OD), and died due to respiratory sepsis, and was also on azathioprine. She had RA with advanced ILD. The reasons for discontinuing JAKi were inefficacy (46%), side effects (39%) and both inefficacy and side effects (15%). 41.4 % of patient experienced side effects due to JAKi. These included infection 28%, deranged lipids 17%, cytopenia 14%, deranged LFTs 14%, GI side effects 10%, skin rash 7% and varicella zoster 3%. Conclusion There has been steady increase in the use of tsDMARDs for RA and other rheumatic conditions. Due to short half-life, these drugs became a popular choice during COVID-19 pandemic but on the other hand safety monitoring became extremely challenging during this time. Disclosure A. Anjum: None. K. Ghanem: None. S. Smale: None. U. Srinivasan: None. S. Duffill: None. C. Jenkins: None.

JAK inhibitors in systemic juvenile idiopathic arthritis.

Systemic juvenile idiopathic arthritis (SJIA) is characterized by excessive and inappropriate production of proinflammatory cytokines. Janus kinase inhibitors (JAKi) can block the downstream pathway of many cytokines. The use of JAKi in SJIA or macrophage activation syndrome (MAS) has only been described in a limited number of case reports. In this study, we aimed to assess the efficacy and potential adverse effects of JAKi in SJIA patients. Patients with SJIA who received JAKi and underwent at least one assessment of efficacy and safety after JAKi initiation were eligible for this study. Data were collected retrospectively from inpatient or outpatient medical records at JAKi initiation, at 1, 3, 6, 9, and 12 months, after disease flare, after JAKi discontinuation, or at the last follow-up. Ten patients with SJIA were included in the study. At the start of JAKi treatment, all patients presented with active disease; five showed variable adverse effects secondary to glucocorticoids. Seven patients received tofacitinib (one later switched to ruxolitinib). Of these, only two patients showed a complete response of persistent arthritis associated with tocilizumab; tofacitinib was used without a biological DMARD only in two patients, together with MTX, showing a partial response; three patients were nonresponders. Four patients with SJIA-related MAS or persistent hyperferritinemia were treated with ruxolitinib. Ruxolitinib allowed a good response on MAS parameters in three of them. All these four patients required an adjunction or switch to canakinumab later. The median decrease in the daily glucocorticoid dose between JAKi initiation and the last follow-up was 90.6% in patients with complete remission and 77.4% in other patients. Three patients discontinued glucocorticoid treatment after the introduction of JAKi. Severe adverse events, notably serious infection or thrombosis, were not observed during JAKi treatment. JAKi may be an alternative or adjuvant agent for SJIA patients, especially in those with persistently active disease, glucocorticoid-related adverse reactions, or SJIA-MAS.

The recurrent course of atopic dermatitis: therapeutic options for management of disease and prolongation of remissions

Atopic dermatitis is a common inflammatory skin disease, which is most frequently occurred in children. The disease is characterized as chronic, but only 20% of children have severe atopic dermatitis, while the other 80% achieve a long-term remission by the age of 8. The article summarizes the main details about atopic dermatitis, including statistical epidemiological data, signs of a severe course of atopic dermatitis, criteria for determining the severity of the disease and the main aspects of a stepwise approach to the therapy. The authors paid special attention to the factors worsening the course of atopic dermatitis: the role of allergens and provoking factors, secondary infection, drug hypersensitivity, concomitant diseases, breach of dermatologist’s prescriptions. Despite the large arsenal of modern therapeutic methods, the therapy of a long, persistent course of atopic dermatitis may not produce a proper effect, and this is the reason why the disease acquires a torpid course. Such clinical cases call for finding new therapeutic methods, in particular the use of Janus kinase inhibitors. In the article, the authors described a clinical case: a 17-year-old patient K. complained of widespread rashes on the skin of the trunk accompanied by intense itching; the patient had been suffering from atopic dermatitis since early childhood, the skin process had a recurrent character with alternating periods of remissions and exacerbations about 2 times a year. The case describes the successful use of Janus kinase inhibitor that was capable to reduce the signaling of many cytokines that contribute to the development of signs and symptoms of the disease, in a patient with severe relapsing atopic dermatitis, who showed insufficient efficacy of therapy with standard methods.

Potential Use of Janus Kinase Inhibitors in the Treatment of Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a chronic, autoimmune disease with unclear pathogenesis. One characteristic of SLE is pro-inflammatory and anti-inflammatory cytokine imbalance. Janus kinase (JAK) is an intracellular non-receptor tyrosine kinase essential for many cytokine signaling pathways. Dysregulation of the JAK/signal transduction and transcriptional activator (STAT) pathway is an important process in SLE pathogenesis. Targeting JAK/STAT proteins can simultaneously block the functions of multiple cytokines. Current SLE treatment with non-specific corticosteroids and immunosuppressants can cause many adverse reactions. Therefore, treatments designed to control specific molecular targets for SLE are desirable. JAK inhibitors (JAKis) are a potential treatment for rheumatic diseases; however, the use of targeted signaling pathways to treat SLE remains a challenge, and its efficacy has not been determined. JAKis have shown positive results in reducing the use of glucocorticoids and/or non-specific immunosuppressants for SLE. JAKis are currently undergoing several clinical trials and expected to be the next stage in the treatment of SLE. Therefore, inhibition of the JAK/STAT pathway through JAKis may improve traditional treatment strategies for SLE.