tofacitinib and Edema

To explore the effects of tofacitinib-an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA)-with or without methotrexate (MTX), on MRI endpoints in MTX-naive adult patients with early active RA and synovitis in an index wrist or hand.. In this exploratory, phase 2, randomised, double-blind, parallel-group study, patients received tofacitinib 10 mg twice daily + MTX, tofacitinib 10 mg twice daily + placebo (tofacitinib monotherapy), or MTX + placebo (MTX monotherapy), for 1 year. MRI endpoints (Outcome Measures in Rheumatology Clinical Trials RA MRI score (RAMRIS), quantitative RAMRIS (RAMRIQ) and dynamic contrast-enhanced (DCE) MRI) were assessed using a mixed-effect model for repeated measures. Treatment differences with p<0.05 (vs MTX monotherapy) were considered significant.. In total, 109 patients were randomised and treated. Treatment differences in RAMRIS bone marrow oedema (BME) at month 6 were -1.55 (90% CI -2.52 to -0.58) for tofacitinib + MTX and -1.74 (-2.72 to -0.76) for tofacitinib monotherapy (both p<0.01 vs MTX monotherapy). Numerical improvements in RAMRIS synovitis at month 3 were -0.63 (-1.58 to 0.31) for tofacitinib + MTX and -0.52 (-1.46 to 0.41) for tofacitinib monotherapy (both p>0.05 vs MTX monotherapy). Treatment differences in RAMRIQ synovitis were statistically significant at month 3, consistent with DCE MRI findings. Less deterioration of RAMRIS and RAMRIQ erosive damage was seen at months 6 and 12 in both tofacitinib groups versus MTX monotherapy.. These results provide consistent evidence using three different MRI technologies that tofacitinib treatment leads to early reduction of inflammation and inhibits progression of structural damage.. NCT01164579.

Topics: Adult; Antirheumatic Agents; Arthritis, Rheumatoid; Bone Density; Bone Marrow; Bone Marrow Diseases; Disease Progression; Double-Blind Method; Drug Therapy, Combination; Edema; Female; Hand; Humans; Magnetic Resonance Imaging; Male; Methotrexate; Middle Aged; Piperidines; Pyrimidines; Pyrroles; Synovitis; Treatment Outcome; Wrist Joint

To date, there is no standard treatment for Morbihan disease. Several studies have reported that Morbihan disease responds well to systemic corticosteroids (prednisone and prednisolone), systemic antibiotics (tetracyclines), antihistamines (ketotifen) and surgical therapy (Lymphaticovenous anastomosis). To our knowledge, Tofacitinib, as a Janus-activated kinase (JAK) inhibitor, plays a vital role in the treatment of inflammatory and autoimmune disorders. Therefore, Tofacitinib may be a promising medical option for patients with Morbihan disease.. The first case involves a 43-year-old Chinese man who presented a 12-month history of progressive painless swelling of the left upper eyelid. According to the skin biopsy, perivascular dermal edema with dilatation of lymphatic vessels and telangiectasia was observed, accompanied by mixed lymphocyte infiltrate, including histiocytes, plasma cells, and a few eosinophils. The second case involves a Chinese female patient who presented a 2-year history of progressive left-sided facial edema, which was eventually diagnosed as Morbihan disease. The skin biopsy revealed lymphocyte infiltration in the superficial vessels of dermis and some accessories. Based on patients' clinical presentation, skin biopsy results, and exclusion of differential diagnoses such as systemic lupus erythematosus (SLE), they were diagnosed with Morbihan disease. They were both treated with Tofacitinib (5mg, po twice daily).. Patient 1 underwent a trial of Tofacitinib at a dosage of 5 mg twice daily for one month, with notable improvement. His edema and erythema present on the left face were alleviated. Patient 1 reduced the dosage of Tofacitinib by half (5mg, once daily) and continued using it for 5 months. During the 6-month follow-up, the facial erythema in the patient subsided, and there was a noticeable improvement in the swelling of the left eyelid compared to before. Patient 2, her lesions gradually improved after one-week treatment. She received a one-month treatment of Tofacitinib, and during the subsequent six-month follow-up, there was no evidence of eruption recurrence.. We present the first cases of two patients receiving short-term Tofacitinib as therapy for Morbihan disease and retrieving huge succession. Tofacitinib may be a promising oral alternative for patients with Morbihan disease. However, its safety and efficacy require further assessment through clinical trials.

Topics: Adult; Anti-Bacterial Agents; Edema; Erythema; Female; Humans; Janus Kinase Inhibitors; Male; Piperidines; Skin

Tofacitinib (TOF), a Janus kinase (JAK) inhibitor, which was approved in 2012, has been recommended for the treatment of clinically active rheumatoid arthritis (RA). Dexamethasone (DEX), a potent corticosteroid, is also used in RA therapy but with limited usefulness due to dose- and time-dependent adverse effects. This pilot study examines the single and combined effects of DEX and TOF in order to explore the steroid-sparing potential of TOF. Collagen-induced arthritic (CIA) rats were subcutaneously (SC) dosed with vehicle, 1.5 mg/kg TOF, 5 mg/kg TOF, 0.225 mg/kg DEX, or a combination of 1.5 mg/kg TOF and 0.225 mg/kg DEX. Paw sizes were measured as an index of disease and drug efficacy and dynamically depicted using a logistic function for natural paw growth, a turnover model for disease progression, an indirect response model for inhibitory effects of TOF and DEX and a non-competitive interaction model for the combined effect of DEX and TOF. TOF alone exerted only a slight inhibitory effect on RA paw edema compared to DEX, which reduced edema by 40%. In combination, TOF and DEX had additive effects with an interaction factor of 0.76. Using model simulations, a single SC dose of TOF does not have a visible steroid-sparing potential, although BID oral dosing has such potential. The current study suggests an additive effect of TOF and DEX and simulations indicate that further exploration of TOF and DEX administration timing may produce desirable drug efficacy with lower DEX doses.

Topics: Animals; Anti-Inflammatory Agents; Arthritis, Experimental; Arthritis, Rheumatoid; Dexamethasone; Disease Progression; Dose-Response Relationship, Drug; Drug Therapy, Combination; Edema; Male; Pilot Projects; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Rats; Rats, Inbred Lew

Translational animal models are essential in the prediction of the efficacy and side effects of new chemical entities. We have carried out a thorough study of three distinct disease-modifying antirheumatic drugs (DMARDs) in an adjuvant-induced arthritis (AIA) model in the rat and critically appraised the results in the context of the reported clinical experience in rheumatoid arthritis (RA) patients.. Teriflunomide - a dihydroorotate dehydrogenase (DHODH) inhibitor; AL8697 - a selective p38 MAPK inhibitor; and tofacitinib - a Janus kinase (JAK) inhibitor; were selected as representatives of their class and dose-response studies carried out using a therapeutic 10-day administration scheme in arthritic rats. Paw swelling and body weight were periodically monitored, and joint radiology and histology, lymph organ weight and haematological and biochemical parameters evaluated at study completion.. All three drugs demonstrated beneficial effects on paw swelling, bone lesions and splenomegalia, with p38 inhibition providing the best anti-inflammatory effect and JAK inhibition the best DMARD effect. Leukopenia, body weight loss and gastrointestinal toxicity were dose-dependently observed with teriflunomide treatment. p38 MAPK inhibition induced leukocytosis and increased total plasma cholesterol. JAK inhibition, normalized platelet, reticulocyte and neutrophil counts, and alanine aminotransferase (ALT) levels while inducing lymphopenia and cholesterolemia.. This multiparametric approach can reveal specific drug properties and provide translational information. Whereas the complex profile for p38 inhibition in AIA is not observed in human RA, immunosuppressants such as DHODH and JAK inhibitors show DMARD properties and side effects seen in both AIA and RA.

Topics: Animals; Antirheumatic Agents; Arthritis, Experimental; Benzamides; Bridged Bicyclo Compounds, Heterocyclic; Crotonates; Dihydroorotate Dehydrogenase; Dose-Response Relationship, Drug; Edema; Enzyme Inhibitors; Gastrointestinal Tract; Half-Life; Hydroxybutyrates; Hypercholesterolemia; Immunosuppressive Agents; Janus Kinases; Joints; Leukocyte Disorders; Male; Nitriles; Oxidoreductases Acting on CH-CH Group Donors; p38 Mitogen-Activated Protein Kinases; Piperidines; Pyrimidines; Pyrroles; Rats; Rats, Wistar; Splenomegaly; Toluidines; Weight Loss