Background/Objective Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Interstitial lung disease (ILD) is an extra-articular manifestation of RA. We investigated incidence rates of ILD in patients with RA, receiving tofacitinib 5 or 10 mg twice daily, and identified potential risk factors for ILD. Methods This post hoc analysis comprised a pooled analysis of patients receiving tofacitinib 5 or 10 mg twice daily or placebo from 2 phase (P)1, 10 P2, 6 P3, 1 P3b/4, and 2 long-term extension studies. Interstitial lung disease events were adjudicated as “probable” (supportive clinical evidence) or “possible” (no supportive clinical evidence) compatible adverse events. Incidence rates (patients with events per 100 patient-years) were calculated for ILD events. Results Of 7061 patients (patient-years of exposure = 23,393.7), 42 (0.6%) had an ILD event; median time to ILD event was 1144 days. Incidence rates for ILD with both tofacitinib doses were 0.18 per 100 patient-years. Incidence rates generally remained stable over time. There were 17 of 42 serious adverse events (40.5%) of ILD; for all ILD events (serious and nonserious), 35 of 42 events (83.3%) were mild to moderate in severity. A multivariable Cox regression analysis identified age 65 years or older (hazard ratio 2.43 [95% confidence interval, 1.13–5.21]), current smokers (2.89 [1.33–6.26]), and Disease Activity Score in 28 joints–erythrocyte sedimentation rate score (1.30 [1.04–1.61]) as significant risk factors for ILD events. Conclusions Across P1/2/3/4/long-term extension studies, incidence rates for ILD events were 0.18 following tofacitinib treatment, and ILD events were associated with known risk factors for ILD in RA.

The effect of inhibition of disaccharidases on the degree of absorption of glucose, lactose, and sucrose was examined utilizing an in vivo model in the rat. Acarbose, a competitive alpha-glucosidase inhibitor was utilized to selectively inhibit small intestinal mucosal enzymes. Adult rats (250-350 g body weight) were the subjects of intraduodenal bolus infusion experiments with either sugar alone or sugar plus acarbose. All sugars were infused at a dose of 0.5 g/kg body weight. Portal venous blood glucose was determined at 30-min intervals from 0 to 150 min. Glucose (monosaccharide) and lactose (beta-galactoside) absorption were not altered by the presence of acarbose. In contrast, sucrose (alpha-glucosidase) absorption was significantly diminished in the presence of acarbose. Sucrose absorption in the presence of increasing acarbose doses (0.7-5.6 mg/kg body weight) was depressed in a dose-dependent fashion. Linear regression analysis revealed a high degree of correlation between residual sucrase activity and area under blood glucose curve (r = 0.9837). Similar degrees of correlation were found between acarbose dose and area under blood glucose curve (r = -0.9322), and between residual sucrase activity and acarbose dose (r = -0.9695). These data confirm that acarbose is a selective alpha-glucosidase inhibitor that does not affect monosaccharidase transport. In the presence of acarbose, alpha-glucosidase absorption is diminished in a dose-dependent fashion. Postprandial glucose rise following an alpha-glucosidase meal seems to be determined, in the presence of graded acarbose inhibition, by residual mucosal alpha-glucosidase activity.

BackgroundTofacitinib is an oral JAK inhibitor for the treatment of RA. Tofacitinib can be given as monotherapy or with csDMARDs. Published data on real world (RW) tofacitinib use in Latin America (LA) are limited. We characterise the patient (pt) population starting tofacitinib and gain insights into the safety profile in the RW LA setting.MethodsInitial tofacitinib therapies in adult RA pts from 10 private/public centres in 6 countries (Argentina, Brazil, Colombia, México, Panamá, Perú) were considered. Data were retrospectively obtained via a standardised format, focusing on demographics, drug history, adverse events (AEs), safety events of special interest, latent tuberculosis (TB) screening, selected confirmed laboratory abnormalities and discontinuation rates. Tofacitinib use as monotherapy or with csDMARDs was at the rheumatologist's discretion.Results288 pts with severe active RA were included; most were female (n=263; 91%), mean (SD) age was 51.3 (6.36) years (yrs) and mean (SD) disease duration was 10.4 (4.0) yrs. 89% of pts were RF+ or ACPA+. The max (range) follow-up period was 22 (10–34) months. Tofacitinib was given as 2nd-line therapy (post-csDMARD) in 44% of pts, after one biologic DMARD (bDMARD) in 18% of pts and after ≥2 bDMARDs in 38% of pts. Tofacitinib was given as monotherapy in 117/283 (41%) pts and with csDMARDs in 171/283 (59%) pts. Tofacitinib usage corresponds to 13% of advanced therapies (JAK inhibitors, bDMARDs and biosimilars). Thirty-eight AEs were observed; upper respiratory infections (n=11), skin infection (n=5), herpes zoster (HZ; n=4) and urinary infections (n=4) were most common. Gastrointestinal intolerance was seen in 2 pts. Three (1%) pts had serious infection events (SIEs); no opportunistic infections (OIs), including TB, occurred. All HZ cases (n=4; 1.4%) were monomeric, non-serious and resolved without complication after antiviral therapy. Before starting tofacitinib, 5 pts (1.7%) were vaccinated against HZ and 5.6% were diagnosed with latent TB. No active TB cases occurred with tofacitinib treatment. One malignancy (thyroid cancer) was reported. Severe (>3 ULN) elevation of liver enzymes or increases of CPK above normal were infrequent (<1%); no severe cytopenias were reported. Lipid increases occurred in 10% of pts. Tofacitinib was withdrawn in 40 pts (13.9%) due to lack of efficacy (n=20; 7%), AEs (n=11; 3.8%) or other reasons (n=9; 3.1%), such as loss of follow-up, pregnancy, access issues or travel. Limitations include limited pt numbers and follow-up of exposure.ConclusionsIn the RW LA setting, tofacitinib was used mostly as 2nd-line therapy; no new safety signals emerged vs clinical trials. SIEs and HZ were uncommon; no cases of TB/other OIs occurred, but were seen in the clinical program.AcknowledgementsThis study was sponsored by Pfizer Inc. Editorial support was provided by K Irving of CMC and funded by Pfizer Inc.Disclosure of InterestE. Schneeberger: None declared, A. Salas Speakers bureau: AbbVie, Pfizer Inc, L. F. Medina: None declared, J. B. Zacariaz: None ...

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Lubrol solubilized microsomes of liver from JJ and jj rats were salt fractionated and the 60% (NH ) precipitate was redissolved, dialyzed and further fractionitid by DEAE cellulose chromatography . After initial protein elution with 10 mM PO buffer, pH8.0, a linear salt gradient from 0-0.5M KC1 was begun.4 Three separate elution fractions (El, F2, F3) were collected with BGt activity for bilirubin (B). The DE-52, F3 fractions from both JJ and jj rats activated the BGt activity of the El fraction of JJ rats 5-10 fold (n=20). The A was separated from the BGt in F3 by Sephacryl-300 (5-300) sieving into two molecular weight fractions BGtn230 kD and Aa60 kn. Further purification of the BGt from El and F3 of JJ liver was performed by affinity chromatography. After adsorption on UDP-hexanolamine Sepharose 4-B, the purified BGt was eluted by 5mM UDPGA which showed by polyacrylamide gel electophoresis (PAGE) a subunit couplet of 52 and 54 kD. This purified BGt was activitated 5-8 fold by the A from the S-300 eluate of both JJ and jj microsomes. The subunit size of A by PAGE is similar to its size after S-300 sieving ("60 kD).It is heat labile, has no BGt activity, is precipitated by TCA, inactivated by alkylation but not by trypsin or iodoacetamide. The A has no effect on the purified transferase (Gt) for p-nitrophenol. Thus in addition to separate Gts in microsomes additional cofactors appear important in determining their substrate specificity. The A increases the formation of both the mono-and diglucuronides of B by BGt. 1. GO. 3x10~'. REGULATION OF INTESTINAL EPITHELIAL C E L L ATTACHMENT AND GROWTH BY EXTRACELLULAR MATRIX (ECMPhase contrast microscopy showed t h a t the substrate h a d a pronounced effect on cell morphology: after 24 h cells on G M formed cylindrical arrays w h i c h penetrated t h e gel, whereas c e l l s on a l l other substrates were polygonal a n d showed little aggregation. The adherence of bacteria to intestinal mucosa is an important initial event in the pathogenesis of enteric infections. Such infections occur frequently in association with undernutrition. We investigated the adherence of two strains of ST to enterocytes from ad-libitum fed and nutrient restricted rats in order to study the effects of nutrient restriction on the adherence of ST to enterocytes. An animal model of malnutrition was produced by feeding young male adult rats 50% of the daily intake in control ad-libitum fed rats. Enterocytes were isolated from proximal and distal small intestinal segments by agitation in isolation medium. Adherence was studied using fimbriated (S7471F) and non-fimbriated (S7471N) strains of ST labelled with 3H-adenine. Labelled bacteria were incubated with freshly isolated enterocytes for 30 min. at 37 C. and the free bacteria were separated from those bound to enterocytes by membrane filtration and washing. The bound bacteria was quantitated by liquid scintillation. Adherence was significantly higher with S7471F both with proximal and distal intestinal enterocytes. There was no significant di...

BackgroundNon-alcoholic fatty liver disease, characterised by hepatic steatosis (HS), is a major cause of chronic liver disease in many countries. Limited data are available on liver enzyme elevation in patients (pts) with HS who are receiving medications for inflammatory conditions, such as rheumatoid arthritis (RA), psoriatic arthritis (PsA) and psoriasis (PsO). Tofacitinib is an oral Janus kinase inhibitor for the treatment of RA and PsA, and has also been studied in PsO.ObjectivesTo describe baseline characteristics and liver enzyme abnormalities in pts from the tofacitinib RA, PsA and PsO clinical programmes with/without HS at baseline.MethodsPts randomised to the tofacitinib (5 or 10 mg twice daily; doses pooled) and placebo arms of 25 studies in the RA, PsA and PsO programmes were included in this pooled post hoc analysis. Most studies allowed or mandated concomitant treatment with disease-modifying antirheumatic drugs. HS was determined by the investigator and captured per the Medical Dictionary for Regulatory Activities term at baseline. Baseline characteristics, incidence of elevated total bilirubin, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) >1 x and >3 x the upper limit of normal (ULN) up to Month (M) 3, and change from baseline in C-reactive protein (CRP) at M3 – all by HS at baseline – are reported.ResultsA total of 10 212 pts were included in the analysis. The prevalence of HS was 1.6% across indications (RA: 87/6729 [1.3%]; PsA: 27/710 [3.8%]; PsO: 45/2773 [1.6%]). Baseline characteristics were generally similar in pts with or without HS (table 1). However, baseline obesity, diabetes, triglycerides and liver enzymes were numerically higher, and CRP was numerically lower, in pts with HS than in those without HS (table 1). In both tofacitinib- and placebo-treated pts, incidence of elevated total bilirubin, AST and ALT>1 x ULN up to M3 was higher in pts with HS than in those without HS, across indications (table 1). Incidence of elevated total bilirubin, AST and ALT>3 x ULN up to M3 was low across indications, irrespective of HS (table 1). Among tofacitinib-treated pts, CRP was reduced at M3 in pts with or without HS, but to a lesser extent in those with HS, across indications. Among placebo-treated pts, changes in CRP were small, irrespective of HS (table 1).Abstract FRI0099 – Table 1Baseline characteristics and liver function up to Month 3, by HS at baselineConclusionsIn this exploratory analysis, prevalence of HS at baseline was 1.6% across the tofacitinib RA, PsA and PsO programmes. After up to 3 months of tofacitinib treatment, incidence of mildly elevated liver enzymes was higher in pts with HS than in those without HS. Incidence of severely elevated liver enzymes was low overall, and similar in pts with or without HS. Further studies are needed to evaluate the effects of tofacitinib on CRP and liver enzymes, and the potential impact on clinical response, in pts with RA, PsA or PsO who have comorbid HS.AcknowledgementsStudy sponsored by Pfizer Inc. Medical writing suppor...

Background:Depression/anxiety are common in RA pts. SF-36 MCS ≤38 can identify probable major depressive disorder and/or probable generalised anxiety disorder (pMDD/pGAD) in RA pts. Tofacitinib is an oral JAK inhibitor for the treatment of RA.Objectives:To assess pMDD/pGAD prevalence in the tofacitinib RA program and efficacy by baseline (BL) pMDD/pGAD status.Methods:Data from pts receiving tofacitinib, ADA, or PBO were pooled from 5 Phase (P)3 and 1 P3b/4 trials. Demographics/BL characteristics were reported by BL pMDD/pGAD (SF-36 MCS ≤38, presence; >38, absence). Month (M)3/6/9/12 SF-36 MCS change from BL (Δ) was estimated, and % with pMDD/pGAD reported. M3/6/12 efficacy outcomes compared tofacitinib-treated pts by BL pMDD/pGAD.Results:BL pMDD/pGAD was seen in 44.5% (tofacitinib 5 mg BID), 39.8% (tofacitinib 10 mg BID), 45.4% (ADA 40 mg Q2W) and 39.1% (PBO) of pts. pMDD/pGAD pts had higher BL CRP and worse disability, fatigue, pain and sleep vs pts without. SF-36 MCS increases were greater for tofacitinib vs PBO/ADA (Fig 1a). The % of pts with BL pMDD/pGAD who continued to have pMDD/pGAD reduced over time, and was generally lower for tofacitinib vs PBO/ADA (Fig 1b). Regardless of BL pMDD/pGAD, efficacy was generally similar for tofacitinib 5 mg BID (Table) and 10 mg BID.Conclusion:~40% of RA pts had BL pMDD/pGAD. SF-36 MCS improvements were greater for tofacitinib vs PBO/ADA. With tofacitinib, % of pts with SF-36 MCS ≤38 reduced by ~60% at M12. Tofacitinib efficacy was similar in pts with/without BL pMDD/pGAD. Limitations include using SF-36 MCS to identify probable rather than confirmed MDD or GAD. Future research using gold standard psychiatric interviews to validate use of SF-36 MCS ≤38 is needed.Table.M3/6/12 efficacy with tofacitinib 5 mg BID, by BL pMDD/pGADaSF-36 MCS ≤38SF-36 MCS >38OR (95% CI)P valueACR20 (%)b,cM355.157.90.89 (0.74, 1.08)0.2330M661.762.80.96 (0.79, 1.16)0.6511M1258.458.60.99 (0.80, 1.22)0.9279ACR50 (%)b,cM325.929.20.85 (0.70, 1.03)0.1022M636.038.00.92 (0.76, 1.11)0.3724M1233.834.30.98 (0.80, 1.20)0.8366ACR70 (%)b,cM310.111.00.91 (0.69, 1.18)0.4704M616.516.51.00 (0.79, 1.26)0.9901M1218.317.51.06 (0.83, 1.34)0.6560DAS28-4(ESR)<2.6 (%)b,cM35.47.40.72 (0.49, 1.05)0.0872M65.98.50.68 (0.49, 0.94)0.0199*M128.011.90.64 (0.47, 0.89)0.0073**ΔHAQ-DI, LS meanc,dSF-36 MCS ≤38SF-36 MCS >38Difference (95% CI)P valueM3-0.41-0.430.01 (-0.04, 0.06)0.6008M6-0.49-0.48-0.01 (-0.06, 0.04)0.6617M12-0.52-0.52-0.01 (-0.06, 0.05)0.8475*p<0.05; **p<0.01 Data pooled from 5 P3 and 1 P3b/4 tofacitinib trialsaBL pMDD/pGAD = SF-36 MCS ≤38;bLogistic regression fit;cFor PBO pts advancing to tofacitinib post-M3, only PBO data were included;dMixed-effects linear model fitΔ, change from baseline; ACR, American College of Rheumatology; BID, twice daily; BL, baseline; CI, confidence interval; DAS28-4(ESR), Disease Activity Score in 28 joints, erythrocyte sedimentation rate; HAQ-DI, Health Assessment Questionnaire-Disability Index; LS, least squares; M, month; MCS, Mental Component Summary score; OR, odds ratio; P, Phase; pGAD, probable generalised anxiety disorder; PBO, placebo; pMDD, probable major depressive disorder; pt, patient; RA, rheumatoid arthritis; SF-36, Short Form-36 health surveyAcknowledgments:Study sponsored by Pfizer Inc. Medical writing support was provided by Sarah Piggott of CMC Connect and funded by Pfizer Inc.Disclosure of Interests:Gustavo Citera Grant/research support from: AbbVie, Amgen, Eli Lilly, Gema, Genzyme, Novartis and Pfizer Inc, Consultant of: AbbVie, Amgen, Eli Lilly, Gema, Genzyme, Novartis and Pfizer Inc, Rakesh Jain Grant/research support from: Allergan, Eli Lilly, Lundbeck, Otsuka, Pfizer Inc, Shire and Takeda, Consultant of: Acadia, Alfasigma, Allergan, Eisai, Eli Lilly, Evidera, Impel, Janssen, Lundbeck, Merck, Neos Therapeutics, Neurocrine Biosciences, Osmotica, Otsuka, Pamlab, Pfizer Inc, Shire, Sunovion, Supernus, Takeda and Teva, Speakers bureau: Alkermes, Allergan, Eli Lilly, Janssen, Lundbeck, Merck, Neos Therapeutics, Neurocrine, Otsuka, Pamlab, Pfizer Inc, Shire, Sunovion, Takeda, Teva and Tris Pharmaceuticals, Fedra Irazoque-Palazuelos Consultant of: Bristol-Myers Squibb, Janssen, Pfizer Inc, Roche and UCB, Renato Guzman: None declared, Hugo Madariaga: None declared, David C Gruben Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Lisy Wang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Lori Stockert Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Ming-Ann Hsu Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Karina Santana Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Abbas Ebrahim Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, Dario Ponce de Leon Shareholder of: Pfizer Inc, Employee of: Pfizer Inc

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