Effect Of Tofacitinib Research Articles

The JAK-Inhibitor Tofacitinib Rescues Human Intestinal Epithelial Cells and Colonoids from Cytokine-Induced Barrier Dysfunction.

Alterations to epithelial tight junctions can compromise the ability of the epithelium to act as a barrier between luminal contents and the underlying tissues, thereby increasing intestinal permeability, an early critical event in inflammatory bowel disease (IBD). Tofacitinib (Xeljanz), an orally administered pan-Janus kinase (JAK) inhibitor, was recently approved for the treatment of moderate to severe ulcerative colitis. Nevertheless, the effects of tofacitinib on intestinal epithelial cell functions are largely unknown. The aim of this study was to determine if JAK inhibition by tofacitinib can rescue cytokine-induced barrier dysfunction in intestinal epithelial cells (IECs). T84 IECs were used to evaluate the effects of tofacitinib on JAK-signal transducer and activator of transcription (STAT) activation, barrier permeability, and expression and localization of tight junction proteins. The impact of tofacitinib on claudin-2 promoter activity was assessed in HT-29 IECs. Tofacitinib rescue of barrier function was also tested in human colonic stem cell-derived organoids. Pretreatment with tofacitinib prevented IFN-γ-induced decreases in transepithelial electrical resistance (TER) and increases in 4 kDa FITC-dextran permeability (FD4), partly due to claudin-2 transcriptional regulation and restriction of ZO-1 rearrangement at tight junctions. Although tofacitinib administered after IFN-γ challenge only partially normalized TER and claudin-2 levels, FD4 permeability and ZO-1 localization were fully recovered. The IFN-γ-induced FD4 permeability in primary human colonoids was fully rescued by tofacitinib. These data suggest differential therapeutic efficacy of tofacitinib in the rescue of pore vs leak-tight junction barrier defects and indicate a potential contribution of improved epithelial barrier function to the beneficial effects of tofacitinib in IBD patients.

Inhibition of JAK-STAT and NF-κB signalling systems could be a novel therapeutic target against insulin resistance and type 2 diabetes

AimsChronic inflammation is associated with the production of high levels of proinflammatory cytokines via the JAK-STAT and NF-κB signalling pathways which are known to be inhibited by tofacitinib and aspirin respectively. High levels of these cytokines increase the synthesis of suppressors of cytokines (SOCS), which at high levels inhibit insulin signalling leading to insulin resistance. The effects of tofacitinib and aspirin on the degree of insulin resistance in type 2 diabetic rats were determined. Materials and methodsRats were induced with type 2 diabetes (T2D) by administration of 10% fructose solution (ad libitum) followed by streptozotocin injection (40 mg/kg BW) and treated with different doses of tofacitinib (10 and 20 mg/kg BW), aspirin (100 and 200 mg/kg BW) and combination of the two drugs at both doses for 9 weeks. Key findingsResults showed that separate treatment with 10 mg/kg BW tofacitinib and 100 mg/kg BW aspirin significantly (P < 0.05) decreased tumour necrosis factor-α (TNF-α), interleukin 6 (IL-6) and serum amyloid A when compared to diabetic untreated rats. However, the combined therapy (10 mg/kg BW tofacitinib and 100 mg/kg BW aspirin) significantly decreased the levels of TNF-α, IL-6, serum amyloid A, HOMA-IR, blood glucose level and SOC-3 gene expression but significantly (P < 0.05) improved glucose homoestasis, insulin secretion, HOMA-β and GLUT-4 gene expression when compared to diabetic untreated rat. ConclusionIt was concluded that simultaneous inhibition of the JAK-STAT and NF-κB signalling pathways with tofacitinib and aspirin respectively, could mitigate insulin resistance and hyperglycemia in T2D.

STING-Associated Vasculopathy with Onset in Infancy in Three Children with New Clinical Aspect and Unsatisfactory Therapeutic Responses to Tofacitinib.

STING-associated vasculopathy with onset in infancy (SAVI) is a new rare auto-inflammatory disease. The purpose of this study is to report new cases and summarize the manifestations and outcome of SAVI. We made a retrospective analysis of three pediatric patients diagnosed with SAVI between March 2016 and July 2018 in Beijing Children's Hospital. Three patients comprised one boy and two girls. The median age of onset was 4months. All patients had the same de novo heterozygous mutation (c.463G>A, p. V155M) of TMEM173. All patients presented with interstitial lung disease and one coexisted with diffuse alveolar hemorrhage. Rashes were presented in two patients. Other clinical manifestations include febrile attacks, failure to thrive, arthritis, myositis, cerebrovascular involvement, ureteral calculus, gastroesophageal reflux, and malnutrition. Ground-glass opacities were the most common features of chest computed tomography, followed with cysts and reticular opacities. Transbronchial lung biopsy was performed in one patient revealing pulmonary vasculitis. Skin biopsy was performed in one patient with changes of vasculitis. All patients were treated with corticosteroids and two patients received combined treatment of tofacitinib. The therapeutic effects of tofacitinib were limited on interstitial lung disease in both patients and were poor on rashes in one patient. One patient under the treatment of tofacitinib died. New clinical aspect of diffuse alveolar hemorrhage is first reported to be associated with SAVI. Unsatisfactory therapeutic effects of tofacitinib are observed in this study and further evaluations are needed.

701 Item-Level Improvements in Inflammatory Bowel Disease Questionnaire Scores in Patients With Ulcerative Colitis Treated With Tofacitinib Induction Therapy

INTRODUCTION: Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). Significant improvements have been reported in all Inflammatory Bowel Disease Questionnaire (IBDQ) domains for tofacitinib vs placebo (PBO) in patients (pts) with UC in OCTAVE Induction 1 &amp; 2 and OCTAVE Sustain. 1 The effect of tofacitinib on items within each IBDQ domain has not yet been analyzed. METHODS: We examined the effect of tofacitinib induction (10 mg twice daily [BID]) on individual IBDQ items in adults with moderate to severe UC. Data were pooled from the randomized, Phase 3 OCTAVE Induction 1 &amp; 2 studies (NCT01465763 &amp; NCT01458951). 2 Pts self-administered the IBDQ at baseline (BL), Week (Wk) 4, and Wk 8. IBDQ domains are: bowel symptoms (10 items), systemic symptoms (5 items), emotional function (12 items), and social function (5 items); higher scores indicate better health-related quality of life (HRQoL). 1,3 Change from BL (CFB) in IBDQ items was analyzed for tofacitinib vs PBO using a linear mixed-effects model, with fixed effects (treatment, study, prior tumor necrosis factor inhibitor treatment, BL corticosteroid use, geographical region, week, treatment-by-week interaction, and BL score) and a random effect (pts). No multiplicity adjustment was performed. RESULTS: Significant improvements (P &lt; 0.05) were observed in all IBDQ items with tofacitinib 10 mg BID vs PBO at Wks 4 and 8. The largest treatment differences (CFB; domain) were: “bowel movements been loose” at Wks 4 and 8 and also “problem with rectal bleeding” at Wk 8 (all 1.1 points) for the bowel symptoms domain; “getting a good night's sleep” at Wk 4 (0.8) and 8 (0.9) for the systemic symptoms domain; “fear of not finding a washroom” at Wk 4 (0.6) and 8 (0.8) and also “felt embarrassed” and “felt angry” at Wk 4 (both 0.6) for the emotional function domain; and “avoid attending events” at Wk 4 (0.8) and 8 (1.0) and also “difficulty doing leisure/sports” at Wk 8 (1.0) for the social function domain (Table 1). CONCLUSION: Tofacitinib improved all bowel-related and systemic symptoms, and all emotional and social functioning IBDQ items vs PBO, highlighting the broad impact of tofacitinib on HRQoL. This analysis provides a useful perspective on the most improved IBDQ domains with tofacitinib induction therapy, which may facilitate patient-physician dialogue.

P4434The first report of significantly improvement of NT-proBNP level in rheumatoid arthritis patients treated with tofacitinib during 12-month follow-up

Abstract Objectives To prospectively investigate the effect of tofacitinib (TOFA), the first oral reversible inhibitor of JAK approved for RA treatment, on the levels of NT-proBNP, as a predictor of congestive heart failure (CHF) in patients (pt) with active RA. Methods Twenty six RA pt (median age 54 [40; 62] years, 81% female, disease duration 44 [24; 63,0] month (m), moderate to high activity (SDAI–27 (22; 35)), positive for ACCP (73%)/RF (77%), who were non-responders to methotrexate (MTX) at least 15 mg/week and other synthetic DMARDs) free of clinical overt cardiovascular disease were treated with TOFA and followed for 12 m. TOFA therapy was started in all pt in dose 5 mg BID per os with dose escalation to 10 mg BID in 8 (31%) pt. TOFA used in combination with MTX in 24 (92%) pt, leflunomide in 1 (4%). Low-dose oral corticosteroids (&lt;10 mg/day prednisone or equivalent) were received by 9 (35%) pt. Remission was achieved in 38,5% (SDAI). Cardiovascular risk factors (CVRF) and the NT-proBNP levels were measured at baseline and after 12m. At baseline the most of pt had multiple CVRF and subclinical organ damage. Cardioprotective therapy received 16 (57%) pt (beta-AB–7, ARA/ACE inhibitors–11, statins–11, dihydropyridine CCB-7). Twenty controls matched for CVRF were included for comparison of normal NT-proBNP levels. Results The NT-proBNP level was significantly higher in RA pt than in the control group (median 62.2 (26.9–101.7) pg/mL vs 44.0 (34.0–54.3) pg/mL, p&lt;0.05). At baseline NT-proBNP level was higher in female than in male (p=0,019). All 3 (11,5%) RA pt with a NT-proBNP level over 125 pg/mL were asymptomatic and exhibited normal echocardiography. Median SDAI were significantly reduced following TOFA treatment (from 26.8 to 4.7, p&lt;0.001, respectively). During follow-up, no RA pt exhibited a cardiovascular event or CHF. NT-proBNP levels decreased by 63% over the 12-m of TOFA treatment (from 62.16 pg/mL to 14.8 pg/mL, p=0.011). The incidence rate of arterial hypertention (58% vs 65%), overweight (62% vs 62%), abdominal obesity (58% vs 62%), smokers (27% vs 27%), menopausal status (52% vs 52%), DM type 2 (7% vs 7%), mSCORE≥5% (23% vs 27%), subclinical carotid atherosclerosis (58% vs 58%) did not change significantly. An increase in body mass index (BMI) was observed from 26.5 [22.9; 29.0] to 26.9 [24.0; 30.1], p&lt;0.001 and in HDL level from 1.37 [1.06; 1.87] to 1.90 [1.29; 2.16], p&lt;0.01. The percentage change in the NT-proBNP level significantly correlated with the percentage change in the BMI (r=0,6, p=0,007), SDAI (r=0.51, p=0.009). Changes in NT-proBNP levels in RA pt with remission was greater than that observed in pt who didn't achieve remission (−87% vs −26%, p=0,005). The percentage change in the NT-proBNP level was not correlated with the percentage change in other CVRF. Conclusion TOFA decreased the NT-proBNP level in patients with RA without clinical overt cardiovascular disease and CHF. TOFA may have a cardioprotective effect in those with active RA.

706 Impact of Baseline Corticosteroid Therapy on Tofacitinib Induction Efficacy and Infection Risk in Patients With Ulcerative Colitis: Data From Global Clinical Trials

INTRODUCTION: Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Oral corticosteroids (CS) can be used as induction therapy, but side effects are a concern. 1 METHODS: We evaluated efficacy and infection risk with tofacitinib 10 mg twice daily (BID) based on baseline CS use in UC induction studies. Remission (total Mayo score ≤2, no individual subscore &gt;1, rectal bleeding subscore 0), mucosal healing (Mayo endoscopic subscore ≤1) and clinical response (decrease from baseline total Mayo score of ≥3 points and ≥30%, and decrease in rectal bleeding subscore of ≥1 point or absolute rectal bleeding subscore of 0 or 1) were evaluated in the 8-week, Phase 3 tofacitinib OCTAVE Induction 1 &amp; 2 studies (NCT01465763 &amp; NCT01458951; pooled data). Induction studies allowed stably dosed CS (25 mg/day maximum). Efficacy and safety data were summarized by oral CS use at induction baseline (BLC-Yes/No). Infections of interest included herpes zoster (HZ), serious infections (SIs), and adjudicated opportunistic infections (OIs). RESULTS: Of 1139 patients (pts) (placebo [PBO]: n = 234; 10 mg BID: n = 905) in OCTAVE Induction 1 &amp; 2, 525 (46.1%) were on CS at baseline (&lt;15 mg daily dose: 32.8%; ≥15 mg daily dose: 67.2%). A statistically significant treatment effect of tofacitinib 10 mg BID vs PBO was observed for remission, mucosal healing, and clinical response at Week 8, for both subgroups of pts with and without baseline oral CS use (Table 1). Differences vs PBO were numerically greater for pts not receiving oral CS at baseline. In OCTAVE Induction 1 &amp; 2, infections of interest occurred with similar frequency among both subgroups of pts: the proportion of PBO-treated pts with HZ was 0.8% for BLC-No vs 0.0% for BLC-Yes; and 0.2% for BLC-No vs 1.0% for BLC-Yes with 10 mg BID. The proportion of PBO-treated pts with SIs was 0.0% for BLC-No vs 0.0% for BLC-Yes; and 1.0% for BLC-No vs 0.2% for BLC-Yes with 10 mg BID. The proportion of PBO-treated pts with OIs was 0.0% for BLC-No vs 0.0% for BLC-Yes; and 0.2% for BLC-No vs 0.5% for BLC-Yes with 10 mg BID. CONCLUSION: Tofacitinib demonstrated significant induction efficacy vs PBO for both subgroups of pts with and without baseline CS use. Proportions of HZ, SIs, and OIs in OCTAVE Induction 1 &amp; 2 were generally similar for both subgroups of pts. The relatively small number of events and short duration of follow-up (8 weeks) are limitations.

Tofacitinib facilitates the expansion of myeloid-derived suppressor cells and ameliorates interstitial lung disease in SKG mice

BackgroundRheumatoid arthritis-associated interstitial lung disease (RA-ILD) is a sometimes life-threatening complication in RA patients. SKG mice develop not only arthritis but also an ILD resembling RA-ILD. We previously reported that tofacitinib, a JAK inhibitor, facilitates the expansion of myeloid-derived suppressor cells (MDSCs) and ameliorates arthritis in SKG mice. The aim of this study was to elucidate the effect of tofacitinib on the ILD in SKG mice.MethodsWe assessed the effect of tofacitinib on the zymosan (Zym)-induced ILD in SKG mice histologically and examined the cells infiltrating the lung by flow cytometry. The effects of lung MDSCs on T cell proliferation and Th17 cell differentiation were assessed in vitro. We also evaluated the effects of tofacitinib on MDSCs and dendritic cells in vitro.ResultsTofacitinib significantly suppressed the progression of ILD compared to the control SKG mice. The MDSCs were increased, while Th17 cells, group 1 innate lymphoid cells (ILC1s), and GM-CSF+ILCs were decreased in the lungs of tofacitinib-treated mice. MDSCs isolated from the inflamed lungs suppressed T cell proliferation and Th17 cell differentiation in vitro. Tofacitinib promoted MDSC expansion and suppressed bone marrow-derived dendritic cell (BMDC) differentiation in vitro.ConclusionTofacitinib facilitates the expansion of MDSCs in the lung and ameliorates ILD in SKG mice.

Tofacitinib is a modern solution to the problem of resistant rheumatoid arthritis

Objective: to analyze the efficacy of tofacitinib (TOFA) in patients with an advanced stage of rheumatoid arthritis (RA) and previous methotrexate (MTX) failure according to comprehensive clinical and laboratory examination.Patients and methods. Nineteen patients (11 women and 8 men aged 29 to 71 years (mean age 53.47±10.53 years)) with a reliable diagnosis of RA according to the 2012 American College of Rheumatology (ACR) criteria were followed up. Due to a high disease activity (DAS28 averaged 5.84±0.89), the patients were prescribed TOFA 10 mg/day taken for 12 months. The disease activity indicators were assessed at baseline, 3, 6, and 12 months after the start of the study.Results and discussion. The effect of TOFA developed quite quickly: at 3 months of therapy, there were positive clinical, laboratory, and instrumental changes in most patients; 5 (26.3%) patients achieved the goal of treatment. At 12 months of therapy, 8 patients achieved DAS28 remission and 3 patients had a low disease activity; moderate RA activity persisted in 7 patients; and a high disease activity was seen in 1 patient; these SDAI activity indicators were observed in 2, 8, 7, and 2 patients, respectively. According to the ACR criteria, 20, 50, and 70% improvements were achieved by 8, 6, and 3 patients, respectively. No serious adverse reactions were recorded. The findings confirm the good efficacy and safety of TOFA in the treatment of patients with an advanced stage of RA.Conclusion. The innovative mechanism of TOFA allows a significant number of patients, in whom MTX therapy was not effective enough, to achieve the goal of treatment.

Sa1872 – Measuring the Mediating Effects of Tofacitinib on Health Status in Ulcerative Colitis: Data from the Octave Program

Sa1872 – Measuring the Mediating Effects of Tofacitinib on Health Status in Ulcerative Colitis: Data from the Octave Program

Effects of tofacitinib on the clinical features of periodontitis in patients with rheumatoid arthritis: two case reports

BackgroundThe pathobiology of rheumatoid arthritis (RA) is similar to that of periodontitis in that proinflammatory cytokines play an important pathologic role. There is evidence to suggest that inhibitors of tumor necrosis factor (TNF) and interleukin-6 (IL-6) receptor for the treatment of RA ameliorated periodontal inflammation. However, no study has evaluated the effect of tofacitinib, an oral Janus kinase inhibitor for the treatment of RA, on periodontitis.Case presentationThe present report cases are 51- and 43-year-old non-smoking women with RA who demonstrated localized moderate chronic periodontitis. Both cases showed improvement in the periodontal inflammatory condition after 3 months of tofacitinib therapy, although the teeth count and supragingival bacterial plaque level were relatively unchanged. Improvements were also observed in the serum levels of IL-6 in both cases as well as in the serum levels of TNF-α and anti-cyclic citrullinated peptide immunoglobulin G in one case and of rheumatoid factor and matrix metalloproteinase-3 in the other case. Patients who received tofacitinib exhibited an inconsistent clinical response, likely due to the low disease activity of RA at the start of the administration.ConclusionsThese are the first reported cases in which tofacitinib may have a beneficial effect on periodontitis. However, more research is required to understand the relationship between periodontitis and tofacitinib therapy.

Evaluation of the Short-, Mid-, and Long-Term Effects of Tofacitinib on Lymphocytes in Patients With Rheumatoid Arthritis.

ObjectiveTofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). Altered lymphocyte cell counts and a potential association with increased infection rates have been reported in RA patients treated with JAK inhibitors. This analysis was undertaken to evaluate the short‐, mid‐, and long‐term effects of tofacitinib on lymphocytes and infection rates in patients with RA.MethodsIn this post hoc analysis, absolute lymphocyte counts (ALCs) were obtained from phase III studies (12–24 months; n = 717–958) and phase I/II/III/long‐term extension studies of tofacitinib (≤117 months) (All RA population; n = 7,061); lymphocyte subset counts (LSCs) were from phase II studies (1.5–6 months’ exposure; n = 236–486), an ORAL Sequel vaccine substudy (~22 months; n = 198), and an ORAL Sequel lymphocyte substudy (~50 months; n = 55–1,035) of tofacitinib. The reversibility of ALC/LSC changes was evaluated. The relationship of ALC and LSC to infections was analyzed in the All RA population. The value of monitoring ALC alone was assessed by examining correlations between ALCs and LSCs.ResultsTofacitinib treatment resulted in an initial increase in ALC versus pretreatment baseline, which gradually declined to steady state by ~48 months. CD4+ and CD8+ T cell counts decreased over long‐term treatment, and ALC and LSC changes were reversible upon treatment cessation. Patients with ALCs of <500 cells/mm3 had an increased risk of serious infections. There was no strong association between CD4+ T cell, CD8+ T cell, B cell, or natural killer cell counts and serious infection incidence rates. ALC and CD4+ or CD8+ T cell counts correlated well (R = 0.65–0.86).ConclusionOur findings indicate that monitoring of ALC alone appears to be adequate to assess infection risk in tofacitinib‐treated patients with RA.

P143 Measuring the mediating effects of tofacitinib on health status in ulcerative colitis: data from the OCTAVE programme

P143 Measuring the mediating effects of tofacitinib on health status in ulcerative colitis: data from the OCTAVE programme

Effect of tofacitinib on patient-reported outcomes in patients with active psoriatic arthritis and an inadequate response to tumour necrosis factor inhibitors in the phase III, randomised controlled trial: OPAL Beyond

ObjectivesTofacitinib is an oral Janus kinase inhibitor for treatment of psoriatic arthritis (PsA). Patient-reported outcomes (PROs) were evaluated in patients with PsA with inadequate responses to tumour necrosis factor inhibitors...

Effect of tofacitinib on cardiovascular events and all-cause mortality in patients with immune-mediated inflammatory diseases: a systematic review and meta-analysis of randomized controlled trials.

Background:We aimed to systematically assess a possible association of tofacitinib therapy with cardiovascular events (CVEs) and all-cause mortality.Methods:Systematic searches of PubMed, Embase, and Cochrane Library were conducted from inception through March 2019. Randomized controlled trials in patients with immune-mediated inflammatory diseases (IMIDs) reporting safety data were included. Included studies compared tofacitinib with placebo or 5 mg tofacitinib with 10 mg tofacitinib. The primary and secondary outcome measures were all CVEs [major adverse cardiovascular events (MACEs)/venous thromboembolism events (VTEs)] and all-cause mortality.Results:29 studies randomizing 13,611 patients were included. Compared with placebo, there was no significant increased risk of all CVEs (OR = 1.07, 95% CI 0.49–2.34), MACEs (OR 1.54, 95% CI 0.42–5.59), or all-cause mortality (OR = 1.13, 95% CI 0.26–4.95), but a decreased rate of VTEs (OR 0.03, 95% CI 0.00–0.21) in patients with IMIDs initiating tofacitinib. Meanwhile, paired comparison showed 10 mg tofacitinib twice daily was associated with a significantly lower incidence of all CVEs (OR = 0.56, 95% CI 0.33–0.96), MACEs (OR = 0.48, 95% CI 0.22–1.05), or all-cause mortality (OR = 0.47, 95% CI 0.19–1.17), but a trend toward an increase in VTEs risk (OR = 1.47, 95% CI 0.25–8.50), compared with the 5 mg regimen.Conclusion:Compared with placebo, there was no augmented risk of CVEs and all-cause mortality in patients with IMIDs following tofacitinib treatment in a short-term perspective, whereas 10 mg twice daily tofacitinib appeared to be associated with reduction in cardiovascular and all-cause mortality risks, except VTEs, relative to the 5 mg twice daily dose. Long-term studies and postmarketing risk monitoring are increasingly needed to develop a better understanding.

Efficacy of tofacitinib in patients with moderate-to-severe psoriasis who had inadequate responses to prior biologics

This retrospective observational study examined the effect of tofacitinib in two Phase 3 controlled studies. Patients (n = 15) were randomized to receive either tofacitinib 5 or 10 mg or placebo, twice daily. Most patients in both groups were responsive to tofacitinib at week 16. Four patients (25%) used two or more biological agents before tofacitinib. Two of these refractory patients demonstrated a response. In conclusion, tofacitinib provides a comparable therapeutic effect in both prior biologics responders and nonresponders during the initial 16 weeks, especially those exposed to etanercept. Tofacitinib remains a treatment choice in refractory patients who failed multiple previous biologics.

Effects of tofacitinib in early arthritis-induced bone loss in an adjuvant-induced arthritis rat model.

Objectives The main goal of this work was to analyse how treatment intervention with tofacitinib prevents the early disturbances of bone structure and mechanics in the rat model of adjuvant-induced arthritis. This is the first study to access the impact of tofacitinib on the skeletal bone effects of inflammation. Methods Fifty Wistar rats with adjuvant-induced arthritis were randomly housed in experimental groups, as follows: non-arthritic healthy group (n = 20); arthritic non-treated group (n = 20); and 10 animals undergoing tofacitinib treatment. Rats were monitored during 22 days after disease induction for the inflammatory score, ankle perimeter and body weight. Healthy non-arthritic rats were used as controls for comparison. After 22 days of disease progression, rats were killed and bone samples collected for histology, micro-CT, three-point bending and nanoindentation analysis. Blood samples were also collected for quantification of bone turnover markers and systemic cytokines. Results At the tissue level, measured by nanoindentation, tofacitinib increased bone cortical and trabecular hardness. However, micro-CT and three-point bending tests revealed that tofacitinib did not reverse the effects of arthritis on the cortical and trabecular bone structure and on mechanical properties. Conclusion Possible reasons for these observations might be related to the mechanism of action of tofacitinib, which leads to direct interactions with bone metabolism, and/or to the kinetics of its bone effects, which might need longer exposure.

Selective Immunomodulation of Inflammatory Pathways in Keratinocytes by the Janus Kinase (JAK) Inhibitor Tofacitinib: Implications for the Employment of JAK-Targeting Drugs in Psoriasis.

IFN-γ and IL-22 are deeply involved in the pathogenesis of psoriasis, as they boost the expression of inflammatory genes and alter proliferative and differentiative programs in keratinocytes. The JAK1/JAK2/STAT1 and JAK1/TYK2/STAT3 pathways triggered by IFN-γ and IL-22, respectively, are aberrantly activated in psoriasis, as highlighted by the peculiar STAT1 and STAT3 signatures in psoriatic skin lesions. To limit the detrimental consequences of IFN-γ and IL-22 excessive stimulation, psoriatic keratinocytes activate suppressor of cytokine signaling (SOCS)1 and SOCS3, which in turn dampen molecular signaling by inhibiting JAK1 and JAK2. Thus, JAK targeting appears to be a reasonable strategy to treat psoriasis. Tofacitinib is an inhibitor of JAK proteins, which, similarly to SOCS, impedes JAK phosphorylation. In this study, we evaluated the immunomodulatory effects of tofacitinib on epidermal keratinocytes in in vitro and in vivo models of psoriasis. We demonstrated the selectivity of tofacitinib inhibitory action on IFN-γ and IL-22, but not on TNF-γ or IL-17 proinflammatory signaling, with suppressed expression of IFN-γ-dependent inflammatory genes, and restoration of normal proliferative and differentiative programs altered by IL-22 in psoriatic keratinocyte cultures. Tofacitinib also potently reduced the psoriasiform phenotype in the imiquimod-induced murine model of psoriasis. Finally, we found that tofacitinib mimics SOCS1 or SOCS3 activities, as it impaired the same molecular pathways in IFN-γ or IL-22-activated keratinocytes.

Disease-specific composite measures for psoriatic arthritis are highly responsive to a Janus kinase inhibitor treatment that targets multiple domains of disease

BackgroundThe multiple disease domains affected in psoriatic arthritis (PsA) may make composite endpoints appropriate for assessing changes in disease activity over time. Tofacitinib is an oral Janus kinase inhibitor for the treatment of PsA. Data from two phase 3 studies of patients with PsA were used to evaluate the effect of tofacitinib on composite endpoints.MethodsOral Psoriatic Arthritis triaL (OPAL) Broaden was a 12-month study of tumor necrosis factor inhibitor (TNFi)-naïve patients with an inadequate response to at least one conventional synthetic disease-modifying anti-rheumatic drug; OPAL Beyond was a 6-month study of patients with inadequate response to TNFi. Patients with active PsA received tofacitinib 5 or 10 mg doses twice daily (BID), adalimumab 40 mg subcutaneous injection once every 2 weeks (OPAL Broaden only), or placebo advancing at month 3 to tofacitinib 5 or 10 mg BID. The disease-specific composites were Psoriatic Arthritis Disease Activity Score (PASDAS), Disease Activity Index for Reactive Arthritis/Psoriatic Arthritis (DAPSA), and Composite Psoriatic Disease Activity Index (CPDAI). Change from baseline in composite endpoints was also assessed for minimal disease activity (MDA) responders versus non-responders.ResultsOverall, 422 patients from OPAL Broaden and 394 patients from OPAL Beyond were treated. The mean changes from baseline to month 3 for tofacitinib 5 mg BID, tofacitinib 10 mg BID (standard error; effect size) were OPAL Broaden: PASDAS, −2.0 (0.14; 1.73), −2.4 (0.14; 2.4); DAPSA, −20.2 (1.72; 0.9), −24.4 (1.73; 1.23); and CPDAI, −2.9 (0.34; 1.03), −4.2 (0.36; 1.53); OPAL Beyond: PASDAS, −1.9 (0.14; 1.53), −2.1 (0.14; 1.84); DAPSA, −22.5 (1.67; 0.81), −21.0 (1.70; 0.84); and CPDAI, −3.3 (0.31; 1.41), −3.4 (0.31; 1.45). Greater changes from baseline to month 3 (P ≤0.05) were seen with both doses of tofacitinib versus placebo for all endpoints except CPDAI for tofacitinib 5 mg BID in OPAL Broaden. Effect sizes generally increased from 3 to 6 months. Mean changes from baseline were greater in MDA responders than MDA non-responders for all composite endpoints across all time points and treatments.ConclusionsThis analysis suggests that disease-specific composite measures are appropriate for evaluating treatment efficacy on multiple disease domains in PsA.Trial registrationOPAL Broaden: ClinicalTrials.gov Identifier: NCT01877668, first posted June 12, 2013; OPAL Beyond: ClinicalTrials.gov Identifier: NCT01882439, first posted June 20, 2013.

JAK/STAT Blockade Alters Synovial Bioenergetics, Mitochondrial Function, and Proinflammatory Mediators in Rheumatoid Arthritis.

To examine the effects of tofacitinib on metabolic activity, mitochondrial function, and proinflammatory mechanisms in rheumatoid arthritis (RA). Ex vivo RA synovial explants and primary RA synovial fibroblasts (RASFs) were cultured with 1 μM tofacitinib. RASF bioenergetics were assessed using an XF24 analyzer, and key metabolic genes were assessed by reverse transcription-polymerase chain reaction (RT-PCR) analysis. Mitochondrial function was assessed using specific cell fluorescent probes and by mitochondrial gene arrays. Mitochondrial mutagenesis was quantified using a mitochondrial random mutation capture assay, and lipid peroxidation was quantified by enzyme-linked immunosorbent assay (ELISA). The effect of tofacitinib on spontaneous release of proinflammatory mediators from RA whole tissue synovial explants was quantified by ELISAs/MSD multiplex assays, and metabolic markers were quantified by RT-PCR. Finally, RASF invasion, matrix degradation, and synovial outgrowths were assessed by transwell invasion/Matrigel outgrowth assays and ELISA. Tofacitinib significantly decreased mitochondrial membrane potential, mitochondrial mass, and reactive oxygen species production by RASFs and differentially regulated key mitochondrial genes. Tofacitinib significantly increased oxidative phosphorylation, ATP production, and the maximal respiratory capacity and the respiratory reserve in RASFs, an effect paralleled by a decrease in glycolysis and the genes for the key glycolytic enzymes hexokinase 2 (HK2), glycogen synthase kinase 3α (GSK-3α), lactate dehydrogenase A, and hypoxia-inducible factor 1α. Tofacitinib inhibited the effect of oncostatin M (OSM) on interleukin-6 (IL-6) and monocyte chemotactic protein 1 and reversed the effects of OSM on RASF cellular metabolism. Using RA whole tissue synovial explants, we found that tofacitinib inhibited the key metabolic genes for glucose transporter 1, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3, 3'-phosphoinositide-dependent protein kinase 1, HK2, and GSK-3α, the proinflammatory mediators IL-6, IL-8, IL-1β, intercellular adhesion molecule 1, vascular endothelial growth factor, and TIE-2, and RASF outgrowth from synovial explants, RASF invasion, and matrix metalloproteinase 1 activity. This study demonstrates that JAK/STAT signaling mediates the complex interplay between inflammation and cellular metabolism in RA pathogenesis.

Effect of tofacitinib on the expression of noggin/BMP-4 and hair growth stimulation in mice.

Many hair loss disorders, including non-scaring alopecia, are caused by the arrest of hair follicles at the telogen phase, and the failure to enter the growth phase. Several studies report the efficacy of tofacitinib in promoting hair growth, by mechanisms not precisely known. The aim of this study was to identify other mechanisms by which tofacitinib, applied topically, promotes hair growth. The results showed that histopathological studies in mice treated topically with tofacitinib increased number of hair follicles, ratio of hair follicles in anagen phase, and length of hair infundibulum, and a reduced interfollicular epidermal thickness, compared to DMSO-treated mice. RT-PCR experiments showed significant increases in the expression of noggin (P < 0.05) and BMP4 (P < 0.05) mRNAs, which were greater than those in the vehicle-controlled group. Moreover, the expression of noggin and BMP4 mRNAs was significantly higher in the tofacitinib-treated group than in the minoxidil-treated group. This study would help understand the efficacy and mechanism by which tofacitinib, applied topically, triggers noggin and BMP4 mRNA expression, both being important molecules involved in the onset of the growth phase of hair growth cycles.