Tofacitinib Treatment Research Articles

Tofacitinib and newer JAK inhibitors in inflammatory bowel disease-where we are and where we are going.

Inflammatory bowel diseases, comprising ulcerative colitis (UC) and Crohn’s disease, are chronic, immune-mediated and progressive inflammatory disorders affecting the gastrointestinal tract. Tofacitinib is the first oral small-molecule Janus kinase (JAK) inhibitor licensed and approved by the National Institute for Health and Care Excellence (NICE) for use in moderately-to-severely active UC after intolerance, inadequate response, or loss of response to conventional treatment or biologic therapy. The pivotal OCTAVE studies demonstrated the efficacy and safety of tofacitinib for the induction and maintenance of remission in UC. A growing body of evidence from real-world data supports the positive clinical and endoscopic benefits observed with tofacitinib treatment in the OCTAVE trials. This narrative review summarizes the current literature regarding the mechanism of action of tofacitinib, data from registrational trials, emerging real-world evidence, and an overview of the most recent safety evidence. We explore evolving treatment paradigms, including the use of tofacitinib in the COVID-19 era, pregnancy and extraintestinal manifestations, as well as the emerging concept of combining tofacitinib with biological therapy. We will also present a brief overview of the next generation of JAK inhibitors in the pipeline.

Suppression of IL-12/IL-23 p40 subunit in the skin and blood of psoriasis patients by Tofacitinib is dependent on active interferon-γ signaling in dendritic cells: Implications for the treatment of psoriasis and interferon-driven diseases.

Interleukin (IL)‐12 and IL‐23 are pro‐inflammatory cytokines produced by dendritic cells (DCs) and associated with Psoriasis (Pso) and Psoriatic Arthritis (PsA) pathogenesis. Tofacitinib, a Janus kinase inhibitor, effectively suppresses inflammatory cascades downstream the IL‐12/IL‐23 axis in Pso and PsA patients. Here, we investigated whether Tofacitinib directly regulates IL‐12/IL‐23 production in DCs, and how this regulation reflects responses to Tofacitinib in Pso patients. We treated monocyte‐derived dendritic cells and myeloid dendritic cells with Tofacitinib and stimulated cells with either lipopolysaccharide (LPS) or a combination of LPS and IFN‐γ. We assessed gene expression by qPCR, obtained skin microarray and blood Olink data and clinical parameters of Pso patients treated with Tofacitinib from public data sets. Our results indicate that in DCs co‐stimulated with LPS and IFN‐γ, but not with LPS alone, Tofacitinib leads to the decreased expression of IL‐23/IL‐12 shared subunit IL12B (p40). In Tofacitinib‐treated Pso patients, IL‐12 expression and psoriasis area and severity index (PASI) are significantly reduced in patients with higher IFN‐γ at baseline. These findings demonstrate for the first time that Tofacitinib suppresses IL‐23/IL‐12 shared subunit IL12B in DCs upon active IFN‐γ signaling, and that Pso patients with higher IFN‐γ baseline levels display improved clinical response after Tofacitinib treatment.

Persistence of treatment in patients with ulcerative colitis who responded to tofacitinib therapy: data from the open‐label, long‐term extension study, OCTAVE open

SummaryBackgroundTofacitinib is an oral Janus kinase inhibitor for the treatment of ulcerative colitis (UC).AimThis post hoc analysis evaluated tofacitinib persistence in patients with UC in OCTAVE Open, an open‐label, long‐term extension study of patients receiving tofacitinib 5 or 10 mg twice daily.MethodsKaplan‐Meier estimates for tofacitinib drug survival and reasons for discontinuations were evaluated. Baseline factors were analysed as predictors of persistence.ResultsThis analysis included 603 patients: 280 entered OCTAVE Open with a clinical response (164 in remission and 116 not in remission), 220 were delayed responders, 75 were retreatment responders and 35 were dose escalation responders, treated for up to 7 years in OCTAVE Open. Of these, 118 (42.1%) responders, 121 (55.0%) delayed responders, 40 (53.3%) retreatment responders and 17 (48.6%) dose escalation responders discontinued tofacitinib with a median time to discontinuation of 5.6, 4.5, 4.0 and 4.4 years, respectively. The estimated 2‐ and 5‐year drug survival rates in the responders (including patients in remission and not in remission) were 73.9% and 54.5%, respectively. Corresponding persistence values for delayed responders were 69.5% and 45.2%, for retreatment responders, 70.7% and 40.0%, and for dose escalation responders, 74.3% and 32.8%.ConclusionIn OCTAVE Open, a high proportion of patients maintained tofacitinib treatment, with the median survival by group ranging from 4.0 to 5.6 years although these analyses are post hoc and limited by sample size. Further research should focus on factors to enhance persistence with tofacitinib treatment in patients with UC.

Adherence to Treatment with Tofacitinib in Patients with Rheumatoid Arthritis in Daily Clinical Practice.

To evaluate the adherence to treatment with tofacitinib in patients with rheumatoid arthritis (RA) using two versions of the self-questionnaire Compliance Questionnaire Rheumatology, CQR19 and CQR5, to determine the variables associated with adherence to tofacitinib and to compare the performance of both questionnaires. A cross-sectional study was carried out. We included patients ≥18years old, with RA (ACR/EULAR criteria 2010) under treatment with tofacitinib. Sociodemographic data, clinical characteristics, treatment and data on patient evaluation. All the patients completed self-questionnaires CQR19 and CQR5. Descriptive statistics. T-test or Mann Whitney to compare the continuous variables, chi2 test or Fisher's exact test for the categorical ones. Kappa concordance index. Multiple logistic regression. We included 52 patients, 82.7% women, with a median (m) age of 57.7years, disease duration m 16years, 63.5% had comorbidities. Of the patients, 86.5% were treated with tofacitinib (5mg BID) and 48% received tofacitinib as monotherapy. The median time of tofacitinib treatment was 13months, 42.3% suspended treatment, and only one patient permanently stopped treatment due to lack of provision. Median CQR19 was 89.5%, and 84.6% had an adherence ≥80%. The variables significantly associated with adherence ≥80% were the presence of comorbidities (P=.014) and older age (P=.033). Considering the CQR5, a similar percentage of patients (82.7%) were adherents to treatment, however, the concordance with CQR19 was low. In the multivariate analysis, older age was the only variable independently associated with good adherence to treatment. Treatment adherence to tofacitinib was very good for both presentations. Older age was associated with higher adherence. The agreement between the questionnaires CQR19 and CQR5 was low.

Tofacitinib Treatment in Primary Herpes Simplex Encephalitis Interferes With Antiviral Response.

Tofacitinib, a Janus kinase inhibitor, is a novel immunosuppressive drug for treatment of rheumatoid arthritis. Herpes simplex virus type 1 (HSV-1) may cause encephalitis during primary infection or following reactivation from a latent state. Long-term tofacitinib treatment may increase the risk of this life-threatening condition. The aim of this study was to investigate the effect of tofacitinib on HSV-1 primary infection using a mouse model. Mice pretreated with tofacitinib were intranasally infected with a clinical strain of HSV-1 and monitored for infection severity and antiviral response. Tofacitinib treatment of HSV-1 primary infection resulted in increased viral loads and worsened clinical outcome. Furthermore, tofacitinib promoted M2 anti-inflammatory phenotype of microglia and infiltrating monocytes, as well as inhibited production of inflammatory and antiviral cytokines by macrophages in vitro. Our findings show that treatment with tofacitinib increases severity of herpes simplex encephalitis in mice, by impairing antiviral response induced by monocytes and microglia.

Tumor necrosis factor alpha neutralization attenuates immune checkpoint inhibitor-induced activation of intermediate monocytes in synovial fluid mononuclear cells from patients with inflammatory arthritis

ObjectiveDuring treatment with immune checkpoint inhibitors (ICI) such as the anti-PD-1 antibody pembrolizumab, half of patients with pre-existing inflammatory arthritis experience disease flares. The underlying immunological mechanisms have not been characterized. Here, we investigate the effect of pembrolizumab on cells involved in inflammation and destruction in the synovial joint and how immunosuppressive treatments affect the pembrolizumab-induced immune reactions.MethodsWe included synovial fluid mononuclear cells (SFMCs, n = 28) and peripheral blood mononuclear cells (PBMCs, n = 6) from patients with rheumatoid arthritis and peripheral spondyloarthritis and PBMCs from healthy controls (n = 6). Fibroblast-like synovial cells (FLSs) were grown from SFMCs. The in vitro effect of pembrolizumab was tested in SFMCs cultured for 48 h, FLS-PBMC co-cultures and in SFMCs cultured for 21 days (inflammatory osteoclastogenesis). Cells and supernatants were analyzed by ELISA, flow cytometry, and pro-inflammatory multiplex assay. Finally, the effect of the disease-modifying anti-rheumatic drugs (DMARDs) adalimumab (TNFα inhibitor), tocilizumab (IL-6R inhibitor), tofacitinib (JAK1/JAK3 inhibitor), and baricitinib (JAK1/JAK2 inhibitor) on pembrolizumab-induced immune reactions was tested.ResultsPembrolizumab significantly increased monocyte chemoattractant protein-1 (MCP-1) production by arthritis SFMCs (P = 0.0031) but not by PBMCs from patients or healthy controls (P = 0.77 and P = 0.43). Pembrolizumab did not alter MMP-3 production in FLS-PBMC co-cultures (P = 0.76) or TRAP secretion in the inflammatory osteoclastogenesis model (P = 0.28). In SFMCs, pembrolizumab further increased the production of TNFα (P = 0.0110), IFNγ (P = 0.0125), IL-12p70 (P = 0.0014), IL-10 (P = 0.0100), IL-13 (P = 0.0044), IL-2 (P = 0.0066), and IL-4 (P = 0.0008) but did not change the production of IL-6 (P = 0.1938) and IL-1 (P = 0.1022). The SFMCs treated with pembrolizumab showed an increased frequency of intermediate monocytes (P = 0.044), and the MCP-1 production increased only within the intermediate monocyte subset (P = 0.028). Lastly, adalimumab, baricitinib, and tofacitinib treatment were able to attenuate the pembrolizumab-induced MCP-1 production (P = 0.0004, P = 0.033, and P = 0.025, respectively), while this was not seen with tocilizumab treatment (P = 0.75).ConclusionPembrolizumab specifically activated intermediate monocytes and induced the production of several cytokines including TNFα but not IL-6. These findings indicate that flares in patients with pre-existing inflammatory arthritis involve monocyte activation and could be managed with TNFα neutralization.

TOFACITINIB TREATMENT PREVENTS POST-OPERATIVE RECURRENCE OF CROHN’S DISEASE MODELED BY ILEOCECAL RESECTION IN HLA-B27 TRANSGENIC RATS

Abstract BACKGROUND Post-operative recurrence (POR) after ileocecal resection (ICR) affects most of Crohn’s disease (CD) patients within 3-5 years after surgery. Current immunomodulatory treatments have not proven efficiency in preventing POR, except for anti-TNFα biologic agents. AIM To evaluate the efficacy of the Janus Kinase inhibitor Tofacitinib to prevent POR after ICR in HLA-B27 transgenic rat model (TgB27) operated on an ICR. METHODS Thirty-three rats (strain F344, 29 TgB27, 4 control non Tg (nTg) rats) were operated on an ICR at the 12th week of life and were sacrificed at the 18th week of life. Tofacitinib (15 mg/kg, n=17) or placebo (n=16) were daily administered by oral gavage two weeks before surgery (10th week of life) until sacrifice. Anastomotic recurrence was blindly analyzed using macroscopic (from 0 to 4) and histologic (from 0 to 6) scores. Luminal microbiome was analyzed by shotgun metagenomic sequencing (Hiseq Illumina) in 9/33 rats before (week 9) and after Tofacitinib treatment or placebo (week 12), as well as 6 weeks following surgery (week 18). STAT3 phosphorylation was quantified in ileal samples by western blotting. Data were expressed by median with IQR. Comparisons were performed using not parametric two tailed Mann-Whitney analysis for unmatched data and Wilcoxon matched-pairs test for matched data. Two tailed χ2 test was used for contingency analysis. Spearman rank correlation was used for microbiota analysis. RESULTS 8/14 TgB27 rats receiving placebo (57%) showed signs of POR (macroscopic score ≥ 2) which were significantly prevented in 2/15 TgB27 rats (13%) treated with Tofacitinib (p= 0.013). nTg animals did not show macroscopic signs of POR. Macroscopic lesions were located 2 cm around the anastomosis in the TgB27 placebo group and consisted in ulcerations with a score of 2 (1-2.25). 11/15 TgB27 rats (73%) treated with Tofacitinib did not show macroscopic lesions and their score were significantly improved (0 (0-1), p= 0,0006). Histologic scores were significantly higher in TgB27 placebo group vs TgB27 Tofacitinib-treated rats (3 (2-4) vs 2 (1-3), p=0.036). Tofacitinib did not impact on alpha diversity and the relative abundance of bacterial taxa either before and after surgery. In contrast, surgery led to a significant 47% decrease of alpha diversity (p=0.0008) and loss of specific taxa in both TgB27 and nTg animals. No correlation was found between individual lesion scores and alpha diversity indexes. Ileal pSTAT3/STAT3 ratios were decreased by 80% in TgB27 rats treated with Tofacitinib (n=4) compared to placebo group (n=4) (0.3 ± 0,16 vs 1.58 ± 0,3, p=0,028). CONCLUSION We develop a reliable model of ICR in TgB27 rats mimicking the POR of CD. Tofacitinib prevents the macroscopic and histologic POR after ICR, without major modifications of the microbioma. ACKNOWLEDGMENTS Charity Foundation DigestScience and Pfizer SAS.

COST-EFFECTIVENESS OF TOFACITINIB FOR THE TREATMENT OF MODERATE TO SEVERE ACTIVE ULCERATIVE COLITIS IN COLOMBIA

Abstract OBJECTIVE To evaluate the cost-effectiveness of tofacitinib versus other treatment options currently available in Colombia for the management of adult patients with moderate-to-severe ulcerative colitis in naïve to biologics (first line) and exposed to biologics (second line). METHODS A Markov model was constructed with 8 weeks cycles. It simulates a cohort of patients with moderate-to-severe ulcerative colitis from a payer perspective in a 5-year horizon. The health states include remission, treatment response (without remission), active UC, and colectomy. The transition probabilities for the induction and maintenance phase were obtained from a network meta-analysis. Effectiveness was measured from quality-adjusted life-year (QALY) and the utilities were obtained from the literature. Unit costs were derived from official national sources, and these were expressed in US dollars 2021 at the average exchange rate of $3 693 COP/US. Probabilistic and deterministic sensitivity analyses were conducted. The threshold was defined as one gross domestic product ($5 391) per capita. RESULTS For first line, the incremental cost-effectiveness ratio (ICER) per QALY was for tofacitinib $2 611 and for infliximab $7 652 compared to adalimumab. Sensitivity analysis showed that tofacitinib is shown as cost-effective in 52% of the iterations, followed by adalimumab 25% and infliximab 23% patients. Meanwhile, adalimumab was $27 527 compared to tofacitinib in second line. Tofacitinib was cost-effective 72% of the iterations, followed by adalimumab 28% in the sensitivity analysis. Infliximab and golimumab were not included due to data limitation in network metanalysis in second line. For both lines vedolizumab was not a cost-effective alternative under the threshold assessed. CONCLUSION The analysis suggests that, in Colombia, the treatment with tofacitinib for moderate-to-severe UC patients is a cost-effective option in both lines, compare with other treatment options available.

P091 A single-cell RNAseq approach to understand and predict the efficacy of tofacitinib in Ulcerative Colitis

Abstract Background The variability and unpredictability of drug efficacy in ulcerative colitis (UC) patients, including tofacitinib, an oral JAK1 and JAK3 inhibitor, remains a perplexing reality. The aim of this study is to identify the relevant cellular subsets and genes involved in response and/or resistance to tofacitinib using single-cell RNA sequencing (scRNA-seq). Methods Colon biopsies from UC patients starting tofacitinib treatment (10 mg twice daily) were collected from the involved region at baseline (n=9), week 8 (n=7) and week 16 (n=5). Endoscopic response was evaluated at week 16 and patients were classified as responders or non-responders based on whether they had a decrease in the endoscopic Mayo score of at least 1 point from baseline. Biopsies were immediately disaggregated and single-cell suspensions were processed using 10x Genomics Next-GEM Single Cell kit assays (Chromium 3’ v3.0). After QC filtering, a total of 61,646 cells were obtained. Additional biopsies were collected at all timepoints for validating scRNA-seq results by bulk RNA analysis (qPCR). Results Four out of nine patients enrolled in this study responded to tofacitinib treatment. Analysis of the proportions of mucosal cells identified by scRNAseq revealed a partial recovery of the epithelial and stromal cell compartments and a decrease in the total number of plasma and myeloid cells in responding patients at week 8, which was sustained at week 16 (Table 1). scRNA-seq analysis revealed a significant downregulation of SOCS1 in the CD4 and B cell populations, and of both SOCS3 and IRF1 in the neutrophil and B cell populations in all patients receiving tofacitinib treatment irrespective of endoscopic response. These results were validated by qPCR of bulk biopsy RNA (p=0.0245, p=0.0299 and p=0.0230 respectively). In contrast, S100A8 and CHI3L1 were significantly downregulated only in responders, correlating with a decrease in the proportion of mucosal inflammatory cells including neutrophils, monocytes, and inflammatory fibroblasts. Regarding prediction of outcome, a scRNA-seq comparative analysis showed that high levels of IL17A-expressing T cells at baseline significatively correlated with failure to achieve response upon tofacitinib treatment. This result was validated by qPCR of bulk biopsy RNA (p=0.0059). Conclusion Our study demonstrates the potential of using scRNAseq of intestinal biopsies not only to characterize the mechanism of action of tofacitinib, but also to describe the cellular events associated with response to this therapeutic intervention. Moreover, we show the potential of scRNAseq to identify predictors of response to tofacitinib in patients with UC.

P602 Tofacitinib treatment prevents post-operative recurrence of Crohn’s Disease modeled by ileocecal resection in HLA-B27 transgenic rats

Abstract Background Post-operative recurrence (POR) after ileocecal resection (ICR) affects most of Crohn’s disease (CD) patients. Immunomodulatory treatments have not proven efficiency in preventing POR except for anti-TNFα biologic agents. We evaluate the efficacy of the JAK inhibitor Tofacitinib to prevent POR after ICR in HLA-B27 transgenic rat model (TgB27). Methods Thirty-three rats (strain F344, 29 TgB27, 4 control non Tg (nTg) rats) were operated on an ICR at the 12th week (W12) of life and were sacrificed at W18. Tofacitinib (15 mg/kg, n=17) or placebo (n=16) were daily administered by oral gavage at W10 until W18. Anastomotic recurrence were blindly analyzed using macroscopic (from 0 to 4) and histologic (from 0 to 6) scores. Luminal microbiome was analyzed by shotgun metagenomic sequencing (Hiseq Illumina) in 9/33 rats before (W9) and after Tofacitinib treatment or placebo (W12 and W18). STAT3 phosphorylation was quantified in ileal samples by western blotting. Data were expressed by median with IQR. Comparisons were performed using not parametric two tailed Mann-Whitney analysis for unmatched data and Wilcoxon matched-pairs test for matched data. Two tailed χ2 test was used for contingency analysis. Spearman rank correlation was used for microbiota analysis. Results 8/14 TgB27 rats receiving placebo (57%) showed signs of POR (macroscopic score ≥ 2) which were significantly prevented in 2/15 TgB27 rats (13%) treated with Tofacitinib (p= 0.013). nTg animals did not show macroscopic signs of POR. Macroscopic lesions were located 2 cm around the anastomosis in the TgB27 placebo group and consisted in ulcerations with a score of 2 (1–2.25). 11/15 TgB27 rats (73%) treated with Tofacitinib did not show macroscopic lesions and their score were significantly improved (0 (0–1), p= 0,0006). Histologic scores were significantly higher in TgB27 placebo group vs TgB27 Tofacitinib-treated rats (3 (2–4) vs 2 (1–3), p=0.036). Tofacitinib did not impact on alpha diversity and the relative abundance of bacterial taxa either before and after surgery. In contrast, surgery led to a significant 47% decrease of alpha diversity (p=0.0008) and loss of specific taxa in both TgB27 and nTg animals. No correlation was found between individual lesion scores and alpha diversity indexes. Ileal pSTAT3/STAT3 ratios were decreased by 80% in TgB27 rats treated with Tofacitinib (n=4) compared to placebo group (n=4) (0.3 ± 0,16 vs 1.58 ± 0,3, p=0,028). Conclusion We develop a reliable model of ICR in TgB27 rats mimicking the POR of CD. Tofacitinib prevents the macroscopic and histologic POR after ICR, without major modifications of the microbioma. Acknowledgments: Charity Foundation DigestScience and Pfizer SAS

P373 Real world evidence of tofacinitib in ulcerative colitis: short and long-term effectiveness, impact of extraintestinal manifestations and immunomediated diseases and safety

Abstract Background Main aim: To assess the retention rate of tofacitinib treatment in patients with ulcerative colitis (UC). Secondary aims: To assess the short-term effectiveness and the durability of response; to evaluate the evolution of extraintestinal manifestations (EIMs) and immunomediated inflammatory diseases (IMIDs); to assess the tolerability of tofacitinib in clinical practice. Methods Retrospective, multicenter study. UC patients who had received the first tofacitinib dose at least, 8 weeks before the start date of recruitment. Patients were followed-up from the first tofacitinib dose to treatment discontinuation or last visit, whichever came first. Only patients with active disease [Partial Mayo Score (PMS)>2] were considered in the short-term effectiveness analysis. Clinical response was based on the PMS. Variables associated with short-term remission were identified by logistic regression analysis. Kaplan-Meier curves and Cox-regression analysis were used to evaluate the long-term effectiveness and durability of tofacitinib treatment. Results 335 patients have been included so far (recruitment still ongoing) (Table 1). A total of, 70 patients (21%) would have met the criteria for entering A3921133 trial. A total of, 155 patients interrupted tofacitinib during follow-up (Figure 1a), mainly due to primary non-response (46%) and loss of response (25%); predictive factors of tofacitinib discontinuation are shown in figure 1b. Short-term effectiveness and predictive factors of remission are shown on figure 2;, 16% of non-responders and, 35% with partial response at week, 4 reached remission at week, 8, and, 19% of non-responders and, 37% of partial responders at week, 8 reached remission at week, 16. Of, 151 patients in remission at week, 8, 68 (45%) lost response (Figure 3); tofacitinib dose was increased in, 27%, and, 71% of them reached remission again. Obvious blood with stool most of the time or blood alone passed at baseline was the only variable associated with losing response over time. There were, 86 adverse events related to tofacitinib treatment (Table 2). Fifty-seven patients (17%) had EIMs or IMIDs non-active at tofacitinib start; only, 2 out of, 12 patients with peripheral arthropathy worsened., 53 patients (16%) had active EIMs or IMIDs at the start of tofacitinib and some of them improved. A total of, 17 EIMs or IMIDs occurred after starting tofacitinib but only, 1 (vasculitis) caused tofacitinib withdrawal. Conclusion Tofacitinib is effective in inducing remission even in highly refractory UC patients. A relevant proportion of patients discontinue the treatment, mainly during the first months due to primary failure. The safety profile is similar to that previously reported for tofacitinib

P286 Sustained improvement in health-related quality of life outcomes in patients with Ulcerative Colitis with long-term tofacitinib treatment in the open-label extension study, OCTAVE Open

Abstract Background Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Tofacitinib induction and maintenance therapy has previously been shown to improve health-related quality of life (HRQoL) outcomes. Here, we present HRQoL data from patients (pts) with UC who received tofacitinib 5 or 10 mg twice daily (BID) in the Phase 3 open-label, long-term extension (OLE) study (OCTAVE Open; NCT01470612), up to Month (M)72. Methods Proportions of pts with an Inflammatory Bowel Disease Questionnaire (IBDQ) total score ≥170, and EuroQol-5D (EQ-5D) and Short Form-36 Health Survey (SF-36) scores were analysed up to M72 in 4 subpopulations in the OLE study: ‘maintenance remitters’ completed OCTAVE Sustain in remission and received tofacitinib 5 mg BID in the OLE study; in contrast, ‘maintenance treatment failures’ (induction responders who experienced treatment failure), ‘maintenance non-remitters’ and ‘induction non-responders (IndNR)’ received tofacitinib 10 mg BID in the OLE study (Figure 1). Data were analysed for each subpopulation overall and stratified by prior tumour necrosis factor inhibitor (TNFi) failure, prior immunosuppressant failure and baseline corticosteroid use. Results Baseline demographics and clinical characteristics for each subpopulation are shown in Table 1. Among the 163 maintenance remitters, HRQoL outcomes were maintained up to M72: 80.0% of pts had an IBDQ total score ≥170 (Figure 1); changes from baseline in EQ-5D scores up to M72 and SF-36 scores up to M33 were minimal (eg M72 EQ-5D utility score -0.07 [standard deviation 0.10]; M33 SF-36 physical functioning score -1.3 [8.3]). Among pts continuing long-term tofacitinib treatment, improvement in IBDQ total score was maintained/achieved by M2 (first post-baseline assessment), and was stable up to M72, with maintenance treatment failures and IndNR subpopulations experiencing the largest improvements from baseline (Figure 1). Similar trends were observed for improvement in EQ-5D and SF-36 scores. Improvements in HRQoL outcomes were independent of prior TNFi failure, prior immunosuppressant failure or baseline corticosteroid use, eg in maintenance remitters with prior TNFi failure, 90.9% of pts had IBDQ total score ≥170 at M60 vs 88.9% of pts without prior TNFi failure. Conclusion Sustained beneficial effects in HRQoL were observed among pts continuing long-term tofacitinib treatment in OCTAVE Open. In maintenance remitters, improvements in all HRQoL outcomes were maintained with tofacitinib therapy. In pts who entered the OLE study not in remission and received tofacitinib 10 mg BID, HRQoL improvements were observed within the first 2 months, and were maintained up to M72, regardless of treatment history including prior TNFi failure.

P563 Association between smoking status and the efficacy and safety of tofacitinib in patients with Ulcerative Colitis: Data from the tofacitinib clinical programme

Abstract Background Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Efficacy and safety of tofacitinib were evaluated in randomised, placebo-controlled Phase (P)2 (NCT00787202) and P3 (NCT01465763; NCT01458951; NCT01458574) studies, an open-label, long-term extension (OLE) study (NCT01470612) and an ongoing P3b/4 study (NCT03281304). Ex-smokers have an increased risk of UC, but the response to therapy in these patients (pts) has not been previously evaluated. We assessed the impact of smoking status on the efficacy and safety of tofacitinib in the UC clinical programme. Methods Efficacy endpoints and adverse events (AEs) were evaluated by smoking status (ever smokers [current and ex-smokers] and never smokers) in P2 (safety only)/P3/OLE/P3b/4 studies. Efficacy endpoints were summarised by treatment allocation; pt characteristics and AEs were summarised by tofacitinib predominant dose. Results This analysis included 1156 pts (ever smokers, n=416 [36.0%; current smokers, n=59 (5.1%); ex-smokers, n=357 (30.9%)]; never smokers, n=740 [64.0%]; Table 1). Compared with never smokers, ever smokers were older and more likely to have a prior history of myocardial infarction, diabetes mellitus, or ischaemic or coronary heart disease. The proportion of pts achieving efficacy endpoints was generally similar across tofacitinib treatment groups regardless of smoking status (Table 2). AEs were reported in 88.7% of ever smokers and 83.8% of never smokers. Overall, 60.6% of ever smokers had an infection, specifically 10.8% had herpes zoster (non-serious and serious), 12.0% had a Clostridioides difficile infection and 19.5% had a lower respiratory tract infection; corresponding values for each AE among never smokers were 53.1%, 6.8%, 8.5% and 11.4% (Table 1). Major adverse cardiovascular events were reported in 1.0% of ever smokers and 0.7% of never smokers; thromboembolic events were reported in 1.0% of ever smokers and 0.9% of never smokers. Malignancies (excl. non-melanoma skin cancer [NMSC]) occurred in 2.5% of ever smokers and 1.5% of never smokers; NMSC occurred in 3.7% and 1.0%, respectively. In total, 0.6% of never smokers had colorectal cancer and there were no cases in ever smokers. Conclusion The efficacy and safety of tofacitinib were generally similar in ever smokers and never smokers. This study is limited by the combined analysis of current and ex-smokers and unknown factors such as the degree of smoking and the time between smoking cessation and UC diagnosis. These data are consistent with previous reports in the general population and pts with UC.1,2

P567 Safety analysis of tofacitinib in ulcerative colitis: Real-world outcomes from a three-year UK observational cohort study

Abstract Background Serious adverse events (SAE), including venous thromboembolism (VTE) and major adverse cardiovascular events (MACE), have been reported in tofacitinib post-marketing trials. However, safety data extending beyond six months in the real world are scarce.1 We explored the incidence rates (IR) of adverse events (AE) in a tofacitinib-treated cohort of ulcerative colitis (UC) patients at a large tertiary centre over three years. Methods We conducted a retrospective analysis of a prospectively maintained database of consecutive patients commencing tofacitinib from October 2018 to October 2021. AE details were extracted from elective and emergency visits during induction and maintenance treatment. SAEs were defined as AEs that were life-threatening or required hospitalisation. We also assessed changes in haematological and biochemical parameters, including lipid levels, during treatment. Exact Poisson confidence intervals (CI) (adjusted for PYs) were calculated to determine IRs and univariate analyses and multivariate logistic regression were performed to examine AE risk factors. Results A total of 103 patients were studied with a median follow up duration of 53 weeks (range 1–156). Median treatment duration on 10mg bd was 18 weeks (range 1–135). AEs and SAEs were recorded in 37% and 16% of the study cohort, respectively, over 118 PYs exposure. Infection was the most common AE and hospitalisation for disease progression requiring colectomy while on tofacitinib was the most frequent SAE (table 1). Overall, the IR for SAEs was 13.6 per 100 PYs (95% CI 9.1–26.0) (table 2). Single dermatomal herpes zoster (HZ) reactivation (including one case of HZ opthalmicus) occurred in 5%; all occurred on 10mg BD dosing, and all were successfully treated with antiviral therapy. Duration of high dose tofacitinib treatment, age, weight, concomitant corticosteroid use, and prior TNF exposure were not associated with AEs. Although there was a significant increase in total cholesterol (TC) and low-density lipoproteins, the TC to high-density lipoprotein ratio remained unchanged (table 3) and no patient required the introduction of a lipid lowering agent. Tofacitinib was well tolerated and excepting treatment discontinuation due to drug failure requiring surgery, AEs resulted in tofacitinib withdrawal in only one patient (headaches). There were no cases of MACE or VTE. Conclusion Although a third of our cohort had AEs, tofacitinib-treatment failure and subsequent hospitalisation and surgery was the most frequently occurring. No new safety signals were identified with extended real-world follow up. Reference 1. Taxonera C et al. Real-World Effectiveness and Safety of Tofacitinib in Patients With UC: Systematic Review and Meta-Analysis. Inflamm Bowel Dis. 2021

DOP75 Effectiveness and Safety of tofacitinib versus vedolizumab in Patients with Ulcerative Colitis; A Nationwide, ICC Registry study

Abstract Background Clinicians face difficulty in positioning biologics and JAK inhibitors in anti-TNF refractory ulcerative colitis (UC) patients. Head-to-head trials comparing the efficacy of vedolizumab and tofacitinib in UC patients are lacking. We aimed to compare the effectiveness and safety of vedolizumab and tofacitinib in anti-TNF experienced UC patients in our prospective, nationwide registry using a propensity score weighted cohort. Methods UC patients who failed anti-TNF treatment (with or without thiopurine) and initiated vedolizumab or tofacitinib treatment subsequently, were identified in the observational prospective Initiative on Crohn and Colitis (ICC) Registry. We selected patients with both clinical (Simple Clinical Colitis Activity Index (SCCAI) >2) and biochemical (C-reactive protein (CRP) >5mg/L or faecal calprotectin (FC) >250 µg/g) or endoscopic disease activity (endoscopic MAYO score ≥ 1) at initiation of therapy. Patients previously treated with vedolizumab or tofacitinib were excluded. Corticosteroid-free clinical remission (SCCAI<2), biochemical remission (CRP ≤5 mg/L and/or FC ≤250 µg/g) and safety outcomes were compared after 52 weeks of treatment. Inverse propensity scores weighted comparison was used to adjust for confounding and selection bias. Results Overall, 83 vedolizumab and 65 tofacitinib treated patients were included (table 1). Propensity score weighted analysis showed that tofacitinib treated patients were more likely to achieve corticosteroid-free clinical remission at week 12, 24 and 52 compared to vedolizumab treated patients (OR: 5.87, 95%CI:3.55–9.70, P<0.01, OR: 2.96, 95%CI: 1.85–4.73, P<0.01 and OR 2.96, 95%CI: 1.85–4.73, P<0.01, respectively) (table 2). In addition, tofacitinib treated patients were more likely to achieve biochemical remission at week 12 and week 24, remaining only statistically borderline at week 52 (OR: 2.96, 95%CI: 1.85–4.73, P<0.01, OR: 2.96, 95%CI: 1.85–4.73, P<0.01 and OR 1.68, 95%CI: 0.99–2.86, P=0.05, respectively) (table 2). There was no difference in infection rate (OR:1.057, 95%CI: 0.60–1.86, p=0.85) or severe adverse events (OR: 0.39, 95%CI: 0.03–4.33, P=0.44). No thromboembolic events were observed. Most common reason for treatment discontinuation was loss of response (table 3). Conclusion In tofacitinib treated, anti-TNF experienced, UC patients, we observed that a higher proportion of patients achieved corticosteroid-free remission after 12, 24 and 52 weeks compared to vedolizumab treated patients. In addition, more tofacitinib treated patients achieved biochemical remission at week 12 and 24. There was no statistically significant difference in severe adverse events.

COST-EFFECTIVENESS OF TOFACITINIB FOR THE TREATMENT OF MODERATE TO SEVERE ACTIVE ULCERATIVE COLITIS IN COLOMBIA

To evaluate the cost-effectiveness of tofacitinib versus other treatment options currently available in Colombia for the management of adult patients with moderate-to-severe ulcerative colitis in naïve to biologics (first line) and exposed to biologics (second line).

Acne exacerbation after tofacitinib treatment for alopecia areata

The major discovery of the novel therapeutic Janus kinase (JAK) inhibitors has been implicated in several dermatological diseases. Recently, studies have shown the efficacy and encouraging results of oral JAK inhibitors as a treatment for alopecia areata (AA). Due to the novelty of this treatment, potential side effects are not fully explored. In this paper, we present a case of a 28-year-old male with a 10-year history of alopecia totalis (AT) treated successfully with tofacitinib with encouraging effects on hair regrowth; however, a significant worsening of the patient’s facial acne was observed four months after AT treatment initiation. JAK inhibitors have promising results in the management of different dermatological conditions including moderatesevere forms of AA with few reported adverse events. Acne exacerbation is a unique observed adverse effect of this therapy. More thorough larger sized studies are needed to further characterize the association between acne exacerbation and the use of JAK inhibitors.

Real-life experience of tofacitinib in patients with treatment-resistant rheumatoid arthritis: A 5-year follow-up: Monocentric experience.

OBJECTIVEThe present study aims to assess the short- and long-term effects of tofacitinib (TOFA) therapy on efficacy, safety, and drug retention rate patients with rheumatoid arthritis (RA) refractory to conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) and/or biological disease-modifying anti-rheumatic drugs (bDMARDs).METHODSThirty-five patients with RA who received TOFA therapy for at least 3 months in rheumatology outpatient clinic between December 2015 and December 2020 were included in the study. The prospectively follow-up results of the patients obtained on the 6th month and 5th year are presented. Demographic characteristics of the patients, the disease activity score-28 for RA with erythrocyte sedimentation rate (DAS 28-4 [ESR]), change in DAS-28, health assessment questionnaire score, patient visual analog scale score, and laboratory parameters were recorded. The data at 6 months and 5 years of treatment were compared with baseline data. All side effects were recorded at each follow-up visit. Wilcoxon signed-rank tests were used for analysis.RESULTSOf the 35 patients, 23 received TOFA treatment after receiving ≥1 bDMARDs, while the remaining 12 patients received TOFA therapy were biologic naive. On the 6-month follow-up, DAS 28-4 (ESR) score and DAS28 improvement significantly decreased at the 6th months from baseline (p<0.001 and p<0.001, respectively), and moderate disease activity was achieved in 13 patients. High disease activity persisted in four patients. DAS28 improvement according to the EULAR response criteria was good response in 86% of the patients. DAS 28-4 (ESR) score and DAS28 improvement significantly decreased at 5 years from baseline (p<0.01 and p<0.001, respectively), and the moderate disease activity was achieved in 10 patients. High disease activity persisted in two patients. Drug retention rate at 5-year follow-up was 54% and the daily glucocorticoid therapy could be discontinued in 9 patients (47%). Three patients (15%) were tested positive for COVID-19. None of them required hospitalization and no deaths were occurred due to COVID-19.CONCLUSIONTOFA is effective and well-tolerated treatment options that reduce the need for steroids in patients with RA.

Putative Association between Low Baseline Gene Expression in the Peripheral Blood and Clinical Remission in Rheumatoid Arthritis Patients Treated with Tofacitinib.

We investigated the importance of the baseline expression of genes involved in energy generation, as prognostic biomarkers of the treatment response to tofacitinib in patients with rheumatoid arthritis (RA). Peripheral blood samples were obtained from 28 patients with RA who received 3 months of tofacitinib therapy from 26 healthy controls. Clinical response was evaluated based on the disease activity score, the erythrocyte sedimentation rate (DAS28-ESR), and the serum levels of ACPA, RF, CRP, and ESR. Clinical remission was assessed based on DAS28 score <2.6. Protein concentrations were measured using ELISA. Total RNA isolated from whole blood was used for gene expression analysis using quantitative RT-PCR. All patients were diagnosed with Steinbrocker’s radiographic stage II-III at baseline, and most showed erosive arthritis with ACPA and RF positivity. Tofacitinib treatment significantly decreased the disease activity. Upon study completion, seven patients showed remission. Before and after TOFA therapy, a significantly higher expression of succinate dehydrogenase and pyruvate kinase genes was observed in all the examined patients compared to healthy subjects. However, the pre-therapy expression of these genes and corresponding proteins was significantly (p ≤ 0.05) lower in patients who showed remission than in other patients with RA. Moreover, we observed that, during follow-up, patients who developed remission showed an increasing trend in the expression of the examined genes, whereas the others showed some decreases in gene expression, although this was not statistically significant. We concluded that, compared with RA patients maintaining persistent moderate or high disease activity, those with clinical remission following tofacitinib treatment showed a significantly lower baseline expression of genes involved in energy generation.

Clinical Management of Herpes Zoster in Patients With Rheumatoid Arthritis or Psoriatic Arthritis Receiving Tofacitinib Treatment.

IntroductionRisk of herpes zoster (HZ) is increased with Janus kinase inhibitor use. We evaluated clinical study data relating to HZ management in patients with rheumatoid arthritis (RA) or psoriatic arthritis (PsA) receiving tofacitinib.MethodsThis post hoc analysis included data from 21 RA and 3 PsA clinical studies; data were pooled for tofacitinib doses. Outcomes of HZ events (serious and non-serious) and tofacitinib treatment changes were evaluated in response to first and second HZ events. Median time to resolution was stratified by dermatomal involvement, history of HZ prior to tofacitinib, changes to tofacitinib treatment, anti-viral and corticosteroid use, and tofacitinib dose.ResultsSeven hundred eighty-three (11.1%, N = 7061) patients with RA experienced ≥ 1 HZ event, 63 (8.0%) of whom had ≥ 2 HZ events. In patients with PsA, 36 (4.6%, N = 783) experienced ≥ 1 HZ event, 1 (2.8%) of whom had ≥ 2 HZ events. For most HZ events, tofacitinib treatment was unchanged or temporarily discontinued. The majority of patients received anti-viral treatment, most within 3 days of onset. Post-herpetic neuralgia developed in 6.9% and 3.2% of patients with RA with first and second events, respectively, and in 2.8% of patients with PsA with a first event. Most first and second events resolved (RA: 97.6% and 96.8%, respectively; PsA: 94.4% and 100%, respectively). Median time to resolution was 22.0 days for first and 15.0 days for second events for RA and 20.5 days for first and 11.0 days for second events (n = 1) for PsA. Time to resolution of first events for RA and PsA was generally numerically shorter for patients with single dermatomal HZ, history of HZ, or anti-viral use versus those without.ConclusionAmong patients receiving tofacitinib, recurrent events were more common in patients with RA versus PsA; HZ duration was shorter for repeat events.Trial RegistrationNCT01262118, NCT01484561, NCT00147498, NCT00413660, NCT00550446, NCT00603512, NCT00687193, NCT01164579, NCT00976599, NCT01059864, NCT01359150, NCT02147587, NCT00960440, NCT00847613, NCT00814307, NCT00856544, NCT00853385, NCT01039688, NCT02187055, NCT00413699, NCT00661661, NCT01877668, NCT01882439, NCT01976364.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40744-021-00390-0.