Rat Adjuvant-induced Arthritis Model Research Articles

MiR-375 regulates the canonical Wnt pathway through FZD8 silencing in arthritis synovial fibroblasts

Whether the rheumatoid arthritis (RA) pathogenesis is regulated by microRNA (miRNA) is not entirely clear. In this study, we found that miR-375 was down-regulated significantly in fibroblast-like synoviocytes (FLS) in adjuvant-induced arthritis (AIA) rat model compared with control. Because the web-based software TargetScan and PicTar predict Frizzled 8 (FZD8) as the target of miR-375, we investigated whether up-regulated miR-375 plays a role in the activation of the canonical Wnt signaling by targeting the FZD8. Furthermore, the purpose of the present experiments was also to determine the role of miR-375 in the pathogenesis of AIA rat model and to ascertain the effects of FZD8 in this process. Real time qPCR, Western blotting, ELISA and ChIP assay were used to assess the inhibited role of miR-375 in the pathogenesis of AIA rat model and the canonical Wnt signaling. RNA interference was also used to detect the role of knockdown of dephosphorylated β-catenin. Luciferase reporter gene and related methods were performed to determine the FZD8 as the target of miR-375. The increased miR-375 inhibited the pathogenesis of AIA rat model as indicated by decreases in the several disease markers, such as MMP3 and fibronectin. Interestingly, miR-375 also inhibited the canonical Wnt signaling, and the stabilized form of β-catenin blocked the miR-375 effects. FZD8 was identified as the target of miR-375 in AIA rat model by the firefly luciferase reporter gene. In summary, our results demonstrate that miR-375 regulates the pathogenesis of AIA rat model through the canonical Wnt signaling pathway. This discovery may provide new targets for therapeutic intervention to benefit RA patients.

Dietary supplementation with arachidonic acid increases arachidonic acid content in paw, but does not affect arthritis severity or prostaglandin E2 content in rat adjuvant-induced arthritis model.

BackgroundArachidonic acid (ARA) is an essential fatty acid and a major constituent of biomembranes. It is converted into various lipid mediators, such as prostaglandin E2 (PGE2), which is involved in the development of rheumatoid arthritis (RA). However, the effects of dietary ARA on RA are unclear. Our objective was to clarify the effects of dietary ARA on an experimental rat arthritis model.MethodsLew rats were fed three contents of ARA diet (0.07%, 0.15% or 0.32% ARA in diet (w/w)), a docosahexaenoic acid (DHA) diet (0.32% DHA), or a control diet. After 4 weeks, arthritis was induced by injection of Freund’s complete adjuvant into the hind footpad. We observed the development of arthritis for another 4 weeks, and evaluated arthritis severity, fatty acid and lipid mediator contents in the paw, and expression of genes related to lipid mediator formation and inflammatory cytokines. Treatment with indomethacin was also evaluated.ResultsThe ARA content of phospholipids in the paw was significantly elevated with dietary ARA in a dose-dependent manner. Dietary ARA as well as DHA did not affect arthritis severity (paw edema, arthritis score, and bone erosion). PGE2 content in the paw was increased by arthritis induction, but was not modified by dietary ARA. Dietary ARA did not affect the contents of other lipid mediators and gene expression of cyclooxygenase (COX)-1, COX-2, lipoxgenases and inflammatory cytokines. Indomethacin suppressed arthritis severity and PGE2 content in the paw.ConclusionThese results suggest that dietary ARA increases ARA content in the paw, but has no effect on arthritis severity and PGE2 content of the paw in a rat arthritis model.Electronic supplementary materialThe online version of this article (doi:10.1186/1476-511X-14-3) contains supplementary material, which is available to authorized users.

Expression and effects of B-lymphocyte stimulator and its receptors in T cell-mediated autoimmune arthritis.

The objective of this study was to determine the expression and effects of B-lymphocyte stimulator (BLyS) in T cell-mediated autoimmune arthritis, a rat model of human rheumatoid arthritis (RA). Rat adjuvant-induced arthritis (AA) was induced by intradermal injection of 0.1ml complete Freund's adjuvant. Arthritis was evaluated by the histopathological examination of joint ankle. The BLyS expression was detected by immunohistochemical analysis. The level of BLyS and interleukin (IL)-17 were assayed by enzyme-linked immunosorbent assay. The gene expression of BLyS and its receptors (TACI, BCMA and BAFF-R) were assessed by quantitative reverse-transcription polymerase chain reaction. The effect of BLyS on the function of T cell was investigated by transwell assay. Using an AA rat model, we detected dysregulated expression and level of BLyS and its receptors in the local joint synovium tissue, peripheral lymphoid organs (spleen) and immune cells (macrophage, dendritic cells (DC) and T cell) at the peak of inflammation. In vitro, BLyS-treated DC induced IL-17 producing T cells. Neutralization of BLyS by the TACI-Ig fusion protein attenuated these stimulating effects of BLyS. These data suggest that the overproduction of BLyS may contribute to T cell responses and may be an attractive target for control of autoimmune diseases, such as RA, that involves both T and B cells.

Therapeutic effect of Captopril on rheumatoid arthritis in rats.

To investigate the therapeutic effect of the intervention treatment with different doses of Captopril on TNF-αcontents in serum of rheumatoid arthritis (RA) rats, and to provide the theoretical proofs for clinical application of Captopril in treatments of rheumatoid diseases. Fifty Wistar rats were randomly divided into 5 groups, namely, Group A, Group B, Group C, Group D, Group E with 10 rats in each group. Injection of Freund's complete adjuvant was employed to establish adjuvant-induced arthritis model in rats. Group A was model group; after model establishment, rats were treated with 20 mL normal saline as placebo (ip.). Rats in Group B were treated with 8 mg/kg cyclophosphamide (ip.). Rats in Group C, D and E were intraperitoneally injected with 30 mg/kg, 100 mg/kg and 300 mg/kg Captopril respectively. Rats in each group were subjected to continuous treatment for 3 weeks, and then sacrificed. Eyeballs of rats were excised and blood was collected. TNF-αcontent in serum were detected using ELISA; each group rats were compared for the hind legs arthrocele. Right ankle tissues of rats were collected to prepare section, and microscopic observation of pathological changes was performed. TNF-αcontent in serum of Group A rats was significantly higher than that of rats in other 4 groups (P<0.05). TNF-αcontent in serum of Group B rats was significantly lower compared with that of rats in Groups C, D and E. The highest TNF-αcontent in serum of rats treated with Captopril was found in Group C, followed by Groups D and E (P<0.05). Right ankle arthrocele of rats in Groups B, C, D and E in early stage showed no statistical difference compared with that of Group A rats (P>0.05). From Day 8, ankle arthrocele of rats in Groups B, C, D and E was obviously relieved compared with that of Group A rats; the anti-inflammatory effects were gradually enhanced with the extension of medication time. Treatments of Groups C, D and E showed significant activities against tardive arthrocele; the degree of ankle arthrocele in rats of these three groups was lower than that of Group A rats (P<0.01). Histological observation showed that large amount of inflammatory cells and plasmocyte infiltration was found in ankle synovial tissues of Group A rats. Relief of hyperaemia and edema of right ankle synovial tissues as well as significant decrease in synoviocyte layer hyperplasia, intra-articular inflammatory cells infiltration and cartilago articularis damage degree etc. were observed in Groups B, C, D and E. Intervention treatment with Captopril can effectively reduce the TNF-αcontent in serum of rheumatoid arthritis rats and inhibit the generation of inflammatory factors, so as to achieve the therapeutic effect.

Effect of AS2521780, a novel PKCθ selective inhibitor, on T cell-mediated immunity

T cell-mediated immunity is central to the pathogenesis of autoimmune diseases, and is a target in the development of alternative therapeutic strategies with reduced adverse effects on other cell types and organs. Protein kinase C (PKC) is a family of serine/threonine kinases, with knockout of the PKCθ isoform in mice resulting in defective T cell activation. However, the effects of selective inhibition of PKCθ by small-molecule compounds on T cell signaling are still unknown. Here, we evaluated the effect of the novel PKCθ inhibitor AS2521780 on T cell activation and joint inflammation in a rat model of arthritis. AS2521780 exerted potent inhibition of recombinant human PKCθ enzyme activity (IC50=0.48nM), which was more than 30-fold higher than that of other PKC isoforms. Further, AS2521780 exerted little or no inhibition on other protein kinases. AS2521780 suppressed CD3/CD28-induced Interleukin-2 (IL-2) gene transcription in Jurkat T cells and proliferation of human primary T cells. AS2521780 also suppressed concanavalin A-induced cytokine production by rat splenocytes and monkey peripheral blood mononuclear cells with similar potency. Moreover, AS2521780 significantly reduced paw swelling in a dose-dependent manner in a rat model of adjuvant-induced arthritis. These results indicate that PKCθ is an attractive drug target and AS2521780 is a potential immunosuppressant for T cell-mediated autoimmune diseases.

Histamine H3 and H4 receptor ligands modify vascular histamine levels in normal and arthritic large blood vessels in vivo.

Growing evidence associates histamine with arthritis, but its implication in shaping vascular function in chronic inflammation remains largely elusive. This study explored the involvement of vascular histamine in the extra-articular responses in peripheral large blood vessels using a rat model of adjuvant-induced arthritis. Histamine levels were increased in the abdominal aorta and the inferior vena cava of arthritic animals. Contrary to the H1 receptor antagonist dimetindene, histamine induction was observed following administration of the H3 and H4 receptor ligands GSK334429 and JNJ7777120, respectively. In arthritis, prophylactic treatment with GSK334429 partially attenuated the clinical signs and restored basal histamine levels only in the abdominal aorta. This study is the first to implicate the H3 and H4 receptors in a concerted constitutive regulation of basal vascular histamine in the rat large blood vessels and to identify the H3 receptor as a component that may influence arterial histamine during the onset of arthritis.

Effect of orexin-A (hypocretin-1) on hyperalgesic and cachectic manifestations of experimentally induced rheumatoid arthritis in rats

Orexin-A has been shown to modulate pain sensation and increase appetite. Rheumatoid arthritis (RA) is characterized by joint destruction, deformity, hyperalgesia, and weight reduction. Evaluate the possible effect of orexin-A on hyperalgesic and cachectic manifestations in an adjuvant-induced arthritis (AIA) rat model. Forty adult male Wistar rats were distributed among 4 groups; I, normal controls; II, rats with AIA induced by intradermal injection of Mycobacterium butyricum, but with no other treatment; III, AIA rats treated daily with an intravenous injection of orexin-A for 8 days; and IV, AIA rats treated orally with dexamethasone for 8 days. The parameters we assessed were pain-associated behavior, body mass, hind paw volume, serum levels of nerve growth factor (NGF) and neuropeptide Y (NPY). Orexin-A caused a significant reduction in pain sensation and NGF levels, and increased body mass and the levels of NPY, whereas treatment with dexamethasone led to significant reductions in paw swelling and pain sensation. Orexin-A has hypoalgesic properties and increases body mass, whereas dexamethasone has a potent anti-inflammatory effect. Therefore, the combination of orexin-A and dexamethasone should have a greater effect with respect to attenuating the manifestations and complications associated with RA.

Characterization and Evaluation of Triamcinolone, Raloxifene, and Their Dual-Loaded Microspheres as Prospective Local Treatment System in Rheumatic Rat Joints

In this study, injectable microspheres were developed for the local treatment of joint degeneration in rheumatoid arthritis (RA). Microspheres loaded with triamcinolone (TA), a corticosteroid drug, and/or raloxifene (Ral), a cartilage regenerative drug, were prepared with a biodegradable and biocompatible polymer, polycaprolactone (PCL). Microspheres were optimized for particle size, structural properties, drug release, and loading properties. In vitro release of Ral was very slow because of the low solubility of the drug and hydrophobic nature of PCL. However, when coloaded with TA, both drugs were released at higher amounts compared with their single forms. Smallest particle sizes were obtained in dual drug-loaded microspheres. In vitro cytotoxicity tests showed biocompatibility of microspheres. In vivo bioefficacy of these microspheres was also examined in adjuvant-induced arthritis model in rats. In vivo histological studies of control groups showed development of RA with high median lesion score (5.0). Compared with control and intra-articular free drug injections, microsphere treatment groups showed lower lesion scores and better healing outcomes in histological evaluations. Results suggest that a controlled delivery system of TA and RAL by a single injection in inflamed joints holds promise for healing and suppressing inflammation.

Downregulation of inflammatory mediators and pro-inflammatory cytokines by alkaloids of jeevaneeya rasayana in adjuvant-induced arthritis

Jeevaneeya rasayana is an ayurvedic polyherbal formulation, with antirheumatic potential. The present study investigates the therapeutic efficacy of isolated total alkaloid fraction of Jeevaneeya Rasayana (AJR) in treating rheumatoid arthritis in a rat model of Adjuvant-induced arthritis (AIA). Paw swelling, inflammatory mediators such as cyclooxygenase-2 (COX-2), matrix metalloproteinase-9 (MMP-9), level of prostaglandin E2 (PGE2), expression of cytokines and serum nitric oxide (NO) level were analyzed in experimental rats after an experimental period of 21 days. Arthritic induction significantly increased paw edema, and up regulated the inflammatory mediators and cytokines. Administration of AJR significantly reversed the paw edema, reduced the level of PGE2, serum NO and decreased the COX-2 activity in the paw tissue. AJR treatment also downregulated mRNA expression of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and MMP-9 in paw tissue. HPTLC analysis revealed the presence of 5 different alkaloid compounds in AJR. These findings suggest that the AJR have the therapeutic potential against adjuvant-induced arthritis.

Anti-arthritic activity of N′-[(2,4-dihydroxyphenyl)methylidene]-2-(3,4-dimethyl-5,5-dioxidopyrazolo[4,3-c][1,2]benzothiazin-1(4H)-yl)acetohydrazide

Benzothiazine and pyrazole derivatives possess anti-inflammatory properties. Previously, synergism of both heterocyclic moieties into a single nucleus has shown to produce biologically active N′-arylmethylidene-2-(3,4-dimethyl-5,5-dioxidopyrazolo(4,3-c)(1,2)benzothiazin-2(4H)yl)acetohydrazides) compound. Present study investigates the anti-arthritic effect and possible mechanism of 2,4-dihydroxyphenyl derivative (DHP) in Freund׳s complete adjuvant-induced arthritic rat model. Ankle joint histopathology was performed with Hematoxylin & Eosin staining, while serum C-reactive protein (CRP) levels were measured by agglutination method. mRNA expression levels and protein levels of proinflammatory markers were measured by real time reverse transcription polymerase chain reaction and Enzyme linked immunosorbent assay (ELISA), respectively. in vitro Concanavalin A (ConA)-stimulated splenocyte proliferation was also measured by ELISA reader. DHP treatment reduced the macroscopic arthritic score, CRP levels, synovial inflammation, bone erosion and pannus formation. Levels of cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), Prostaglandin-E2 (PGE2), and 5-lipoxygenase (5-LOX), were significantly attenuated by DHP. It also significantly decreased the levels of toll-like receptor 2, nuclear factor-kappaB (NF-ĸB), and tissue necrosis factor-α (TNF-α) and non-significantly elevated interleukin-4 (IL-4) levels. Piroxicam, used as reference drug, significantly reduced the levels of COX-1, COX-2, PGE2, NF-ĸB, and TNF-α, but did not show reduction in 5-LOX and toll-like receptor 2 levels. However piroxicam significantly enhanced the levels of IL-4. Both DHP and piroxicam suppressed ConA-stimulated splenocyte proliferation. DHP normalized all altered hematological markers and did not show any sign of hepatotoxicity or nephrotoxicity as determined by alanine transaminase, aspartate aminotransferase, urea, and creatinine levels. Results showed that DHP possesses significant anti-arthritic activity which may be attributed to its immunomodulatory and anti-inflammatory effects.

FRI0367 Celastrol Inhibits Osteoclastogenesis and Bone Resorption in Rankl-Induced Raw264.7 via Nf-κB and MAPK Pathways and Attenuates Bone Erosion in Collagen-Induced Arthritis

BackgroundCelastrus have been long used to treat various inflammatory disorders including Rheumatoid arthritis (RA), SLE and Ankylosing Spondylitis in China. Celastrol is one of the main bioactive component of Celastrus....

Metabonomic study of Wu-tou decoction in adjuvant-induced arthritis rat using ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry

A urinary metabonomics method based on the ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS) had been established to investigate the holistic efficacy of Wu-tou decoction (WTD), a traditional Chinese medicine (TCM) formula used to treat rheumatoid arthritis (RA), in adjuvant-induced arthritis (AIA) rat model. Multivariate statistical approaches, such as principal component analysis (PCA) and orthogonal projection to latent structures squares-discriminant analysis (OPLS-DA) were used to distinguish healthy control group, AIA model group and WTD treated group and find potential biomarkers. There was a clear separation among the three groups in PCA model. Sixteen potential biomarkers had been identified using OPLS-DA, and 11 of them was considered to be in response to therapeutic effects of WTD involved in tryptophan metabolism, phenylalanine metabolism, tricarboxylic acid (TCA) cycle, bile acid biosynthesis, steroid hormone biosynthesis and valine metabolism. In this study, WTD also showed good anti-inflammatory and antioxidant activities in vivo, and it could suppress histopathological changes of AIA rats. There might be a correlation between these results and the regulation of the disturbed metabolites in urine. This study demonstrates that metabonomics is a powerful methodology to gain insight in the mechanism of TCM formula in therapy.

A4.10 Early bone microarchitecture changes in adjuvant-induced arthritis rats

Background and ObjectivesHallmarks of rheumatoid arthritis (RA) are joint synovitis and subchondral bone erosions, resulting in loss of joint function. However, occurrence and kinetics of periarticular bone loss remain unclear...

Nanomedicines for Inflammatory Arthritis: Head-to-Head Comparison of Glucocorticoid-Containing Polymers, Micelles, and Liposomes

As an emerging research direction, nanomedicine has been increasingly utilized to treat inflammatory diseases. In this head-to-head comparison study, four established nanomedicine formulations of dexamethasone, including liposomes (L-Dex), core-cross-linked micelles (M-Dex), slow releasing polymeric prodrugs (P-Dex-slow), and fast releasing polymeric prodrugs (P-Dex-fast), were evaluated in an adjuvant-induced arthritis rat model with an equivalent dose treatment design. It was found that after a single i.v. injection, the formulations with the slower drug release kinetics (i.e., M-Dex and P-Dex-slow) maintained longer duration of therapeutic activity than those with relatively faster drug release kinetics, resulting in better joint protection. This finding will be instructional in the future development and optimization of nanomedicines for the clinical management of rheumatoid arthritis. The outcome of this study also illustrates the value of such head-to-head comparison studies in translational nanomedicine research.

Antiallergic and Antiarthritic Effects of Stem Bark Extract ofGlyphaea brevis(Spreng) Monachino (Tiliaceae) in Murine Models

Background. Various parts of Glyphaea brevis (Spreng) Monachino (Tiliaceae) find a use in traditional medicine in the treatment of pain and oedema among others. This study evaluates the anti-inflammatory, antiallergic, and antiarthritic effects of a 70% (v/v) aqueous ethanol extract of the stem bark of Glyphaea brevis in murine models. Materials and Methods. The effect of the aqueous ethanol extract of Glyphaea brevis extract (GBE) was assessed on the maximal and total oedema responses in the carrageenan-induced paw oedema in mice to evaluate the acute anti-inflammatory actions of the extract. Systemic anaphylaxis was induced with compound 48/80 and survival rates monitored for 1 h in mice with prior treatment with GBE to assess the anti-allergic action of the extract. The indirect antihistamine effect of GBE was evaluated on clonidine-induced catalepsy. Rat adjuvant-induced arthritis model was used to study GBE's antiarthritic action. Results. GBE significantly suppressed the mean maximal swelling and the total paw swellings over 6 h in the carrageenan-induced paw oedema when administered either prophylactically or therapeutically. GBE dose dependently increased the time for compound 48/80-induced mortality. Administered either prophylactically or therapeutically, GBE inhibited clonidine-induced catalepsy while it had no effect on haloperidol-induced catalepsy. GBE caused a significant dose-dependent suppression of Freund's adjuvant-induced arthritis. Conclusion. Glyphaea brevis inhibits the in vivo degranulation of mast cells and thereby suppress allergy. In addition it exhibits anti-inflammatory action and attenuates Freund's adjuvant-induced arthritis. The results of this work contribute to validate the traditional use of Glyphaea brevis in the management of inflammatory disorders.

Suppression of NF-κB p65 nuclear translocation and tumor necrosis factor-α by Pongamia pinnata seed extract in adjuvant-induced arthritis

Pongamia pinnata is a plant known for its therapeutic usage in Indian traditional medicine. Despite the controversy regarding toxic flavonoid and erucic acid content, the seed of this plant is consumed in tribal medicine and its oil is used in Ayurveda to treat psoriasis and arthritis. This study explored the potential anti-arthritic effects of a P. pinnata seed (hexane) extract (PSE) at non-lethal doses in an adjuvant-induced arthritic rat model; possible mechanisms of any observed effects were also explored. After establishing the lethal doses arising from oral exposure to the extract, the material was administered per os daily at two doses (0.3 g/kg/day; 0.5 g/kg/day) to arthritic rats. Other rats received indomethacin or vehicle (control). Treatments were performed for a total of 14 days. One day after the final exposure, the rats were euthanized to permit harvest of various cells, blood, and tissues for analyses. Paw diameter and tissue myeloperoxidase activity in the paws were evaluated as indices for edema and neutrophil infiltration into the tissue. The severity of arthritis in the experimental rats was assessed via measures of urinary hydroxyproline (HP) and glucosamine, and of serum pro-inflammatory TNFα and anti-inflammatory IL-10. The extent of NF-κB p65 nuclear translocation in peritoneal macrophages harvested from naïve rats and then treated in vitro was also assessed. The results indicated that exposure to PSE significantly decreased paw diameter, tissue myeloperoxidase level, and levels of urinary HP and glucosamine, as well as of serum TNFα and IL-10 in adjuvant-injected (arthritic) rats. In vitro PSE treatment also resulted in a marked inhibition of NF-κB p65 nuclear translocation in primary cultures of peritoneal macrophages. Thus, PSE appears to be able to prevent experimental arthritis, in part, by helping to maintain the balance between pro- and anti-inflammatory cytokines and by inhibiting NF-κB activation.

Inhibitory effects of polyphenol punicalagin on type-II collagen degradation in vitro and inflammation in vivo

Cartilage destruction is a crucial process in arthritis and is characterized by the degradation of cartilage proteins, proteoglycans, and type II collagen (CII), which are embedded within the extracellular matrix. While proteoglycan loss can be reversed, the degradation of CII is irreversible and has been correlated with an over-expression and over-activation of matrix metalloproteinases (MMPs). Among the various MMPs, the collagenase MMP-13 possesses the greatest catalytic activity for CII degradation. Here we show that the pomegranate-derived polyphenols, punicalagin (PA) and ellagic acid (EA), inhibit MMP-13-mediated degradation of CII in vitro. Surface plasmon resonance studies and molecular docking simulations suggested multiple binding interactions of PA and EA with CII. The effects of PA on bovine cartilage degradation (stimulated with IL-1β) were investigated by assaying proteoglycan and CII release into cartilage culture media. PA inhibited the degradation of both proteins in a concentration-dependent manner. Finally, the anti-inflammatory effects of PA (daily IP delivery at 10 and 50mg/kg for 14days) were tested in an adjuvant-induced arthritis rat model. Disease development was assessed by daily measurements of body weight and paw volume (using the water displacement method). PA had no effect on disease development at the lower dose but inhibited paw volume (P<0.05) at the higher dose.

AB0179 The specific inhibitor of RORγT transcriptional activity and TH17 polarization digoxin reduces the severity of adjuvant-induced arthritis

BackgroundWe have previously reported an increase of interleukin (IL)-17 levels during the first weeks of rheumatoid arthritis (RA) onset.ObjectivesOur main goal here was to investigate whether administration of digoxin, a...

THU0101 ASP015K: A Novel Jak Inhibitor Demonstrated Potent Efficacy in Adjuvant-Induced Arthritis Model in Rats

BackgroundThe Janus kinase (JAK) family of enzymes plays a key role in cytokine signaling, which is involved in the pathogenic events of immune-mediated disorders such as rheumatoid arthritis (RA).ObjectivesThe aim...

AB0160 Effects of TOFACITINIB (CP-690,550) on lipid biomarkers in rat adjuvant-induced arthritis (AIA) model and in patients with active rheumatoid arthritis

BackgroundTofacitinib (CP-690,550) is a novel, oral Janus kinase (JAK) inhibitor being investigated as a targeted immunomodulator and disease-modifying therapy in rheumatoid arthritis (RA). Administration of tofacitinib to patients (pts) with...