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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