sitagliptin-phosphate and Arthritis--Rheumatoid

Biologics are structurally heterogeneous and can undergo biotransformation in the body. Etanercept (ETN) is a fusion protein composed of a soluble tumor necrosis factor (TNF) receptor and the Fc portion of human immunoglobulin G1. The N-terminus of ETN has a putative sequence cleaved by dipeptidyl peptidase-4 (DPP-4). The purpose of this study was to investigate the biotransformation of ETN in humans and mice and evaluate its effects on functional properties.. An analytical method using liquid chromatography-mass spectrometry (LC-MS/MS) was established. The N-terminal heterogeneity of ETN was assessed in the serum of patients with rheumatoid arthritis or mice receiving ETN. The in vitro N-terminal truncation was explored using recombinant DPP-4. The binding affinity to TNF-α or TNF-β was investigated using an in-house enzyme-linked immunosorbent assay.. In the formulations, about 90% of ETN had an intact N-terminus, while the N-terminal truncated form was most abundant in the serum of the patients with rheumatoid arthritis and mice. Recombinant human DPP-4 cleaved two amino acids from the N-terminus of ETN in vitro. Sitagliptin, a DPP-4 inhibitor, inhibited N-terminal truncation both in vivo and in vitro. However, N-terminal truncation did not affect the binding ability to TNF-α or TNF-β and the pharmacokinetics of ETN. ETN biosimilars exhibited similar characteristics to the reference product in vivo and in vitro.. ETN undergoes N-terminal truncation in the body, and DPP-4 cleaves exogenous ETN via N-terminal proteolysis. The application of an MS-based assay will detect novel biotransformation of therapeutic proteins.

Topics: Amino Acids; Animals; Antirheumatic Agents; Arthritis, Rheumatoid; Biosimilar Pharmaceuticals; Chromatography, Liquid; Dipeptidyl-Peptidase IV Inhibitors; Etanercept; Humans; Lymphotoxin-alpha; Mice; Sitagliptin Phosphate; Tandem Mass Spectrometry; Treatment Outcome; Tumor Necrosis Factor-alpha

Sitagliptin is a dipeptidyl peptidase-4 inhibitor commonly used in the treatment of type 2 diabetes mellitus for glycaemic control. Concerns have arisen regarding adverse events caused by this drug, particularly concerning arthralgias. Here, we report on a 56-year-old man being treated with sitagliptin who developed inflammatory arthritis after taking the drug for 6 months. The patient presented with pain, swelling and erythema in multiple joints and was eventually diagnosed with seronegative rheumatoid arthritis (RA) under the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria. His symptoms continued for several months after stopping sitagliptin and eventually went into remission after a tapered course of steroids, hydroxychloroquine and methotrexate. Furthermore, the patient is HLA-DRB3 positive, a genetic marker that is still being investigated for its role in the pathogenesis of RA and that may have been a predisposing factor in the development of this patient's inflammatory arthropathy.

Topics: Arthritis, Rheumatoid; Diabetes Mellitus, Type 2; Diagnosis, Differential; Dipeptidyl-Peptidase IV Inhibitors; HLA-DRB3 Chains; Humans; Hypoglycemic Agents; Male; Middle Aged; Sitagliptin Phosphate

A dipeptidyl peptidase (DPP)-4 inhibitor, commonly used to treat patients with type 2 diabetes, has caused concern because of immune system side effects. We report a 48-year-old woman with type 2 diabetes who was diagnosed with rheumatoid arthritis (RA) after continued polyarthritis and an increase in rheumatoid factor up to 86 IU/mL after three months of treatment with sitagliptin, a DPP-4 inhibitor. The shared epitope (SE)-containing human leukocyte antigen (HLA)-DRB1 alleles, which are important predisposing factors for RA, were positive. RA might have been triggered by sitagliptin due to a predisposing condition.

Topics: Alleles; Arthritis, Rheumatoid; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Genetic Predisposition to Disease; HLA-DRB1 Chains; Humans; Middle Aged; Pyrazines; Rheumatoid Factor; Sitagliptin Phosphate; Triazoles