Traditionally, patients with rheumatoid arthritis (RA) have been treated with immunosuppressive drugs, such as corticosteroids, disease-modifying antirheumatic drugs (DMARDs; eg, methotrexate), and nonsteroidal anti-inflammatory drugs, but in the last 1 to 2 decades, biologic DMARDs–consisting of several cytokine inhibitors and other immune modulators–have been added to this list.1 Because of the costliness of biologic DMARDs, identifying nonresponders, anti-drug antibodies, and disease progression markers as early as possible is imperative.
Seeking to evaluate the clinical effect of using infliximab, a tumor necrosis factor (TNF)-α inhibitor, in patients with advanced RA, in addition to ascertaining serum markers relevant to disease progression, remission, or prognosis, Oddgeir Selaas, Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, Norway, and colleagues conducted a longitudinal study of 39 patients with moderate-to-high disease activity over the course of 1 year. They found that interleukin (IL)-6 and vascular endothelial growth factor (VEGF)-A serum levels may be promising disease markers because they change with disease progression.
Participants had a mean age of 54 years, and a disease duration of 12 years. They were selected from an ongoing phase 4 trial of patients receiving infliximab with methotrexate and prednisolone; only patients who provided complete serum samples at baseline and at 3, 6, and 12 months after initiating infliximab treatment were included. Dr Selaas and colleagues collected clinical and serological data for analysis of 12 cytokines, 5 matrix metalloproteinases (MMPs), and 2 VEGFs in the serum. Disease activity scores were also calculated using the Disease Activity Score of 28 joints (DAS28) and Simplified Disease Activity Index (SDAI). Joint erosions were x-rayed and the Sharp/van der Heijde (SvH) score was determined.
Treatment with infliximab significantly reduced disease activity, improved disease status, and reduced further joint destruction in study participants. The majority of patients with high disease activity had an average DAS28 score of 5.3 ± 0.1 at baseline, but progressed to low and moderate disease activity, and an average DAS28 score of 4.0 ± 0.2, after 1 year. In the same group of patients with high disease activity, SDAI scores improved from an average baseline score of 38.8 ± 2.0 to 20.0 ± 2 after 1 year, and also showed progression to low and moderate disease activity. With regard to joint erosion, the study authors found that SvH scores remained relatively stable during the study period, with a mean score of 90.1 and 96.4 before and after 1 year of treatment, respectively.
"Collectively, the patient cohort disease activity and inflammation status decreased significantly, indicating that our patients benefited from the infliximab treatment," Dr Selaas and colleagues stated.
Although most of the cytokine and MMP serum levels remained unchanged throughout the study, and changes were undetermined in serum TNF-α, the study authors did find that IL-6 and VEGF-A serum levels decreased significantly after infliximab initiation. The investigators also explained that, because increased VEGF levels have been shown to induce TNF and IL-6 production–possibly leading to inflammatory reactions–a mutual relationship may exist between VEGFs and TNF/IL-6, because IL-6 and VEGF-A levels decreased in patients receiving anti-TNF treatment.
"The study population showed a significant decrease in disease activity, indicating that anti-TNF treatment is efficacious despite long duration of RA," the study authors concluded. "We observed no change in serum concentrations of many proinflammatory cytokines, TNF-α, and MMPs during treatment. Nevertheless, we found statistically significant changes in serum levels of IL-6 and VEGF-A varying with disease activity."
Dr Selaas and colleagues added that the clinical significance of their findings needs to be expounded further and confirmed in larger clinical trials before being used in the clinical setting.
- Selaas O, Nordal HH, Halse AK, et al. Serum markers in rheumatoid arthritis: a longitudinal study of patients undergoing infliximab treatment. Int J Rheumatol. 2015;2015:276815.