tofacitinib and Skin-Neoplasms

The impact of new and emerging therapies on the microenvironment of primary cutaneous lymphomas (PCLs) has been recently raised in the literature. Concomitantly, novel treatments are already used or registered (dupilumab, upadacitinib) and others seem to be added to the armamentarium against atopic dermatitis. Our aim was to review the literature on interleukins 4, 13, 22, and 31, and JAK/STAT pathways in PCLs to elucidate the safety of using biologics (dupilumab, tralokinumab, fezakinumab, nemolizumab) and small molecule inhibitors (upadacitinib, baricitinib, abrocitinib, ruxolitinib, tofacitinib) in the treatment of atopic dermatitis. We summarized the current state of knowledge on this topic based on the search of the PubMed database and related references published before 21 October 2021. Our analysis suggests that some of the mentioned agents (dupilumab, ruxolitinib) and others may have a direct impact on the progression of cutaneous lymphomas. This issue requires further study and meticulous monitoring of patients receiving these drugs to ensure their safety, especially in light of the FDA warning on tofacitinib. In conclusion, in the case of the rapid progression of atopic dermatitis/eczema, especially in patients older than 40 years old, there is a necessity to perform a biopsy followed by a very careful pathological examination.

Topics: Antibodies, Monoclonal, Humanized; Azetidines; Dermatitis, Atopic; Humans; Interleukins; Janus Kinases; Lymphoma; Lymphoma, Primary Cutaneous Anaplastic Large Cell; Nitriles; Piperidines; Purines; Pyrazoles; Pyrimidines; Signal Transduction; Skin Neoplasms; STAT Transcription Factors; Sulfonamides; Tumor Microenvironment

With a rapidly evolving complement of advanced targeted therapies in inflammatory bowel disease, additional safety and side effect concerns emerge. It is the purpose of this review to consider various risks with biologic therapies in inflammatory bowel disease and discuss mitigating strategies.. Two recently approved monoclonal antibodies (vedolizumab and ustekinumab) and a Janus kinase inhibitor small molecule (tofacitnib) have introduced a number of novel safety and risk considerations. We review the clinical trial and real-world safety data to date on these agents as well as review new data and considerations with anti-tumor necrosis factor agents. New vaccines for varicella zoster virus, hepatitis B virus, and high-dose influenza have been studied, and we discuss the clinical importance of these findings. Lastly, we make management recommendations in the event of particular side effects or complications. Understanding the risks of new agents in inflammatory bowel disease, potential mitigating strategies, and management considerations is important to achieving and maintaining clinical outcomes in IBD patients.

Topics: Antibodies, Monoclonal, Humanized; Biological Products; Demyelinating Diseases; Deprescriptions; Drug Substitution; Gastrointestinal Agents; Humans; Infections; Inflammatory Bowel Diseases; Lymphoma; Melanoma; Neoplasms; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Risk; Risk Assessment; Skin Neoplasms; Tumor Necrosis Factor-alpha; Ustekinumab

The use of biologics such as anti-tumor necrosis factor and oral Janus kinase inhibitors have revolutionized the treatment of rheumatoid arthritis (RA). The risk of malignancies such as lymphomas, lung cancer, and nonmelanoma skin cancers (NMSCs) is greater in patients with RA compared with the general population. The incidence of all malignancy (excluding NMSC) was similar in tofacitinib users compared with the general population. The rates of overall and site-specific malignancies in patients with RA treated with tofacitinib are similar to what is expected in the RA population and not different from disease-modifying antirheumatic drugs and biologics.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Humans; Incidence; Janus Kinases; Neoplasms; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Skin Neoplasms

Tofacitinib is an oral small molecule Janus kinase [JAK] inhibitor for the treatment of ulcerative colitis. We report an integrated summary of tofacitinib safety [exposure: ≤7.8 years] from the global clinical programme.. Patients receiving tofacitinib 5 or 10 mg twice daily [BID] from completed phase [P]2/3 placebo-controlled studies, an open-label, long-term extension study [final data cut-off: August 24, 2020], and interim analysis of a P3b/4 study (interim data cut-off: February 20, 2020; Overall plus P3b/4 [2020] Cohort) were included. Proportions with adverse events [AEs] and serious AEs, and incidence rates [IRs; unique patients with events/100 patient-years] for deaths and AEs of special interest [AESI] were evaluated. Opportunistic infections, malignancies, major adverse cardiovascular events [MACE] and gastrointestinal perforations were adjudicated.. In total, 1157 patients received one or more dose of tofacitinib (mean duration: 946.9 days); 955/1157 [83%] received a predominant dose of 10 mg BID; 412/1157 [35.6%] received tofacitinib for >4 years; 992/1157 [85.7%] had AEs, 244/1157 [21.1%] had serious AEs and 134/1157 (11.6%) discontinued use due to AEs. IRs [95% confidence intervals] for all tofacitinib doses were: deaths, 0.23 [0.09-0.46]; serious infections, 1.69 [1.26-2.21]; herpes zoster [non-serious and serious], 3.30 [2.67-4.04]; opportunistic infections, 1.03 [0.70-1.46]; malignancies (excluding non-melanoma skin cancer [NMSC]), 0.84 [0.55-1.24]; NMSC, 0.73 [0.45-1.10]; MACE, 0.29 [0.13-0.55]; deep vein thrombosis, 0.03 [0.00-0.18]; pulmonary embolism, 0.19 [0.07-0.42]; gastrointestinal perforations, 0.10 [0.02-0.28].. AESI IRs were stable to 7.8 years and generally <2.0 in the Overall plus P3b/4 [2020] Cohort, with the exception of herpes zoster [a known risk of tofacitinib treatment]. ClinicalTrials.gov:NCT00787202;NCT01465763;NCT01458951;NCT01458574;NCT01470612;NCT03281304JCC Topic/keyword selection: 3. Clinical trials.

Topics: Colitis, Ulcerative; Herpes Zoster; Humans; Janus Kinase Inhibitors; Opportunistic Infections; Protein Kinase Inhibitors; Pyrroles; Skin Neoplasms; Treatment Outcome

To evaluate malignancies and their associations with baseline risk factors and cardiovascular risk scores with tofacitinib versus tumour necrosis factor inhibitors (TNFi) in patients with rheumatoid arthritis (RA).. In an open-label, randomised controlled trial (ORAL Surveillance; NCT02092467), 4362 patients with RA aged ≥50 years with ≥1 additional cardiovascular risk factor received tofacitinib 5 (N=1455) or 10 mg two times per day (N=1456) or TNFi (N=1451). Incidence rates (IRs; patients with first events/100 patient-years) and HRs were calculated for adjudicated malignancies excluding non-melanoma skin cancer (NMSC), NMSC and subtypes. Post hoc analyses for malignancies excluding NMSC, lung cancer and NMSC included risk factors identified via simple/multivariable Cox models and IRs/HRs categorised by baseline risk factors, history of atherosclerotic cardiovascular disease (HxASCVD) and cardiovascular risk scores.. IRs for malignancies excluding NMSC and NMSC were higher with tofacitinib (combined and individual doses) versus TNFi. Risk of lung cancer (most common subtype with tofacitinib) was higher with tofacitinib 10 mg two times per day versus TNFi. In the overall study population, the risk of malignancies excluding NMSC was similar between both tofacitinib doses and TNFi until month 18 and diverged from month 18 onwards (HR (95% CIs) for combined tofacitinib doses: 0.93 (0.53 to 1.62) from baseline to month 18 vs 1.93 (1.22 to 3.06) from month 18 onwards, interaction p=0.0469). Cox analyses identified baseline risk factors across treatment groups for malignancies excluding NMSC, lung cancer and NMSC; interaction analyses generally did not show statistical evidence of interaction between treatment groups and risk factors. HxASCVD or increasing cardiovascular risk scores were associated with higher malignancy IRs across treatments.. Risk of malignancies was increased with tofacitinib versus TNFi, and incidence was highest in patients with HxASCVD or increasing cardiovascular risk. This may be due to shared risk factors for cardiovascular risk and cancer.. NCT02092467, NCT01262118, NCT01484561, NCT00147498, NCT00413660, NCT00550446, NCT00603512, NCT00687193, NCT01164579, NCT00976599, NCT01059864, NCT01359150, NCT02147587, NCT00960440, NCT00847613, NCT00814307, NCT00856544, NCT00853385, NCT01039688, NCT02281552, NCT02187055, NCT02831855, NCT00413699, NCT00661661.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Humans; Lung Neoplasms; Pyrroles; Risk Factors; Skin Neoplasms; Treatment Outcome; Tumor Necrosis Factor Inhibitors

Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). We present integrated analyses of nonmelanoma skin cancer (NMSC) incidence in the tofacitinib UC clinical program.. Nonmelanoma skin cancer events were evaluated from 3 randomized, placebo-controlled studies: 2 identical, 8-week induction studies (NCT01465763, NCT01458951), a 52-week maintenance study (NCT01458574), and an open-label, long-term extension study (NCT01470612). Cohorts analyzed were: Induction, Maintenance, and Overall (patients receiving ≥1 dose of tofacitinib 5 mg or 10 mg twice daily [BID]). An independent adjudication committee reviewed potential NMSC. Proportions and incidence rates (IRs; unique patients with events per 100 patient-years of exposure) for NMSC were evaluated. A Cox proportional hazards model was used for risk factor analysis.. Nonmelanoma skin cancer was evaluated for 1124 patients (2576.4 patient-years of tofacitinib exposure; ≤6.8 years' treatment). In the Induction Cohort, NMSC IR was 0.00 for placebo and 1.26 for 10 mg BID. Nonmelanoma skin cancer IR was 0.97 for placebo, 0.00 for 5 mg BID and 1.91 for 10 mg BID in the Maintenance Cohort, and 0.73 (n = 19) in the Overall Cohort. No NMSC was metastatic or led to discontinuation. In the Overall Cohort, Cox regression identified prior NMSC (hazard ratio [HR], 9.09; P = 0.0001), tumor necrosis factor inhibitor (TNFi) failure (3.32; P = 0.0363), and age (HR per 10-year increase, 2.03; P = 0.0004) as significant independent NMSC risk factors.. For patients receiving tofacitinib, NMSC occurred infrequently. Older age, prior NMSC, and TNFi failure, which are previously reported NMSC risk factors in patients with UC, were associated with increased NMSC risk.

Topics: Colitis, Ulcerative; Humans; Piperidines; Pyrimidines; Skin Neoplasms

In patients with ulcerative colitis (UC), risks of infection and malignancies increase with age. Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of UC. This analysis assessed age as a risk factor for adverse events of special interest (AESI) in the tofacitinib UC clinical program.. Data were from phase 2 and 3 induction studies, a phase 3 maintenance study, and an open-label, long-term extension study. Efficacy and/or safety outcomes were analyzed in the Induction, Maintenance, and Overall Cohorts (patients who received ≥ 1 dose of tofacitinib), stratified by age. The effects of baseline demographic and disease-related factors on AESI incidence were assessed by Cox proportional-hazards regression analysis.. In the Overall Cohort (1157 patients with ≤ 6.8 years' tofacitinib treatment), age was a statistically significant predictor of herpes zoster (HZ), malignancies excluding nonmelanoma skin cancer (NMSC), and NMSC. Other statistically significant predictors included prior tumor necrosis factor inhibitor failure for HZ, NMSC, and opportunistic infection events, and prior duration of UC for malignancies excluding NMSC. In the Induction and Maintenance Cohorts, a higher proportion of tofacitinib-treated than placebo-treated patients (numerical difference) achieved the efficacy endpoints (endoscopic improvement, clinical remission, clinical response) across all age groups.. Older individuals receiving tofacitinib as induction and maintenance therapy to treat UC may have an increased risk of HZ, malignancies (excluding NMSC), and NMSC versus similarly treated younger patients, consistent with findings from the general population. Across all age groups, tofacitinib demonstrated greater efficacy than placebo as an induction and maintenance therapy.. NCT00787202; NCT01465763; NCT01458951; NCT01458574; NCT01470612.. Age was assessed as a risk factor for adverse events of special interest in the tofacitinib ulcerative colitis clinical program. Older individuals receiving tofacitinib may have an increased risk of herpes zoster, malignancies (excluding nonmelanoma skin cancer), and nonmelanoma skin cancer versus similarly treated younger patients.

Topics: Colitis, Ulcerative; Herpes Zoster; Herpesvirus 3, Human; Humans; Janus Kinase Inhibitors; Piperidines; Skin Neoplasms

Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). Here, we performed an integrated analysis of malignancy events from the tofacitinib phase 3 UC clinical development program (excluding nonmelanoma skin cancer [NMSC]).. Data (up to May 2019) were pooled from two phase 3 induction studies, a phase 3 maintenance study, and an ongoing, open-label, long-term extension (OLE) study, and analyzed as 3 cohorts: induction (N = 1139), maintenance (N = 592), and overall (induction, maintenance, and ongoing OLE study; N = 1124). Proportions and incidence rates (IRs; unique patients with events per 100 patient-years [PY] of exposure) for malignancies confirmed by adjudication were calculated.. The overall cohort consisted of patients who received at least 1 dose of tofacitinib at 5 or 10 mg twice daily, for up to 6.8 years, with an exposure of 2576.4 PY. Of the 1124 overall cohort tofacitinib-treated patients, 20 developed a malignancy (excluding NMSC; IR, 0.75; 95% confidence interval, 0.46-1.16), of which 17 occurred in patients treated with tofacitinib 10 mg twice daily; importantly, more than 80% of patients predominantly received this dose. Furthermore, there was no apparent clustering of malignancy types, and IRs were stable over time.. In the tofacitinib UC clinical development program, malignancy events were infrequent, and rates were comparable with those in the tofacitinib rheumatoid arthritis and psoriatic arthritis clinical development programs, and for biologic UC treatments. ClinicalTrials.gov: NCT01465763, NCT01458951, NCT01458574, and NCT01470612.

Topics: Clinical Trials, Phase III as Topic; Colitis, Ulcerative; Humans; Janus Kinase Inhibitors; Neoplasms; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Skin Neoplasms; Treatment Outcome

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Female; Fibroma; Humans; Middle Aged; Neurofibromatosis 1; Piperidines; Pyrimidines; Pyrroles; Skin Neoplasms

Topics: Administration, Topical; Back; Child; Dermatologic Agents; Humans; Lip Neoplasms; Male; Nevus, Halo; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Skin Neoplasms

Aberrant activation of Janus kinase-3 (Jak3) and its key down-stream effectors, Signal Transducer and Activator of Transcription-3 (STAT3) and STAT5, is a key feature of malignant transformation in cutaneous T-cell lymphoma (CTCL). However, it remains only partially understood how Jak3/STAT activation promotes lymphomagenesis. Recently, non-coding microRNAs (miRNAs) have been implicated in the pathogenesis of this malignancy. Here, we show that (i) malignant T cells display a decreased expression of a tumor suppressor miRNA, miR-22, when compared to non-malignant T cells, (ii) STAT5 binds the promoter of the miR-22 host gene, and (iii) inhibition of Jak3, STAT3, and STAT5 triggers increased expression of pri-miR-22 and miR-22. Curcumin, a nutrient with anti-Jak3 activity and histone deacetylase inhibitors (HDACi) also trigger increased expression of pri-miR-22 and miR-22. Transfection of malignant T cells with recombinant miR-22 inhibits the expression of validated miR-22 targets including NCoA1, a transcriptional co-activator in others cancers, as well as HDAC6, MAX, MYCBP, PTEN, and CDK2, which have all been implicated in CTCL pathogenesis. In conclusion, we provide the first evidence that de-regulated Jak3/STAT3/STAT5 signalling in CTCL cells represses the expression of the gene encoding miR-22, a novel tumor suppressor miRNA.

Topics: Cell Line, Tumor; Genes, Tumor Suppressor; Humans; Janus Kinase 3; Lymphoma, T-Cell, Cutaneous; MicroRNAs; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Signal Transduction; Skin Neoplasms; STAT3 Transcription Factor; STAT5 Transcription Factor; Transfection