Infliximab Plus Naproxen Attains 70% Partial Remission in AS
Expert Commentary by Nigil Haroon, MD, PhD, DM and Gleb Slobodin, MD
Patients with Ankylosing Spondylitis (AS) who were given infliximab (IFX) and naproxen (NPX) achieved a 70.5% partial remission rate in a post hoc analysis of the Infliximab as First Line Therapy in Patients with Early Active Axial Spondyloarthritis Trial (INFAST). The results were recently published online in Rheumatology.
Joachim Sieper MD, from University Medicine Berlin and colleagues divided the INFAST axial spondyloarthritis (axSpA) participants into those with AS and those with non-radiographic axial spondyloarthritis (nr-axSpA) to evaluate partial remission rates and predictors of partial remission in these two groups.
The INFAST Study
The INFAST study involved early (≤3 years), active, moderate-severe axSpA patients aged 18-48, who were either NSAID-naïve or taking less than the maximal dose. Participants were randomized for 28 weeks to either intravenous (IV, infusion) infliximab 5 mg/kg (n=106) or IV placebo (n=52). Both groups also received 1000mg/day of NPX. Results showed a better rate of Assessment of SpondyloArthritis international Society (ASAS) partial remission in the IFX+NPX group (61.9%) compared to the placebo+NPX (35.3%) group.
Results of the Post Hoc Analysis
At baseline, 94 patients met the criteria for AS (61: IFX+NPX; 33: placebo+NPX) and 56 met the criteria for nr-axSpA (40: IFX+NPX; 16: placebo+NPX). Patients with AS had more male participants and higher baseline levels of C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), human leukocyte antigen B27 (HLA-B27) positivity, and Berlin MRI scores.
The primary efficacy measure was the percentage of patients who achieved ASAS partial remission at week 28. In AS patients 70.5% achieved partial remission in the IFX+NPX sub-group compared with 33.3% in the placebo+NPX subgroup (P=.0009). However, in nr-axSpA patients, although partial remission was higher in the IFX+NPX sub-group compared to the placebo+NPX sub-group (50% vs 37.5%), this failed to reach significance (P=.55).
Secondary efficacy measures included questionnaires (Bath Ankylosing Spondylitis Disease Activity Index, Ankylosing Spondylitis Disease Activity Score, Bath Ankylosing Spondylitis Functional Index, and EuroQol), and clinical measures (MRI sacroiliac joint and Berlin spine scores, CRP and ESR). According to the authors, several of these secondary measures showed greater improvement in patients who received IFX+NPX compared to placebo+NPX in both AS and nr-axSpA patients, although the improvement was smaller in nr-axSpA patients.
A prediction model using all the axSpA patients found IFX+NPX to be the most significantly associated with ASAS partial remission (OR: 5.786, P< .0001). A positive HLA-B27 test (OR: 3.209, P=.0472) and younger age (OR: .937, P=.01) were also significantly associated with partial remission.
CRP and MRI sacroiliac joint scores were not associated with partial remission in the prediction model. However, in those receiving IFX+NPX, remission rates for CRP levels equal to or above normal were 88.1% compared to 53.1% in those who had a CRP less than the upper limit of normal. In those receiving placebo+NPX, rates were similar for those with and without elevated CRP at 34.4% and 35.3% respectively. Similarly, in those receiving IFX+NPX, remission rates for elevated MRI sacroiliac joint scores (≥3.9) were 78.4% compared to 46% in those who had a normal score. In those receiving placebo+NPX, rates were similar in those with and without elevated MRI scores at 34.5% and 35% respectively.
According to the authors, CRP and MRI scores have been shown to be predictive of outcomes in previous studies during TNF antagonist treatment. Therefore, additional prediction models were performed on the IFX+NPX group to determine if CRP and MRI scores were predictive of partial remission. CRP was not predictive, while MRI scores were associated with an increased likelihood of partial remission (P=.006). Also, when controlling for CRP, the odds of partial remission were 2.4 times higher in the AS group than the nr-axSpA group. Similarly, when controlling for MRI scores, the odds of partial remission were 2.5 times higher in the AS group compared to the nr-axSpA group (P<.05).
“The most important baseline difference that might explain the difference in the clinical response rate between the AS and nr-axSpA groups is the higher HLA-B27 positivity in the AS group at baseline,” the authors stated.
Commenting on the significance of this finding, Dr. Haroon told SpineUniverse, “So far we do not have a biological explanation as to why HLA-B27 would increase the TNF antagonist response. In this very early cohort of back pain patients, HLA-B27 may increase the likelihood of a correct diagnosis of axSpA, especially in the non-radiographic arm. It is possible that in a group of back pain patients with a positive MRI and HLA-B27 as opposed to a group with MRI positivity alone, there are more definite axSpA patients and therefore, a greater likelihood of TNF inhibitor response.”
Dr. Haroon feels the most important factor differentiating the AS and nr-axSpA groups was the low numbers of patients. “It is possible that lower numbers in the nr-AxSpA group led to the lack of statistically significant benefits of infliximab treatment in the nr-AxSpA group.”
Dr. Slobodin agreed saying, “I am not sure that the study had enough power. The numbers are too small, in my opinion, to draw conclusions.”
Patients in the INFAST study had not failed NSAID treatment and had a short average disease duration (≤2 years) which lead to a very good clinical response to NPX. According to the researchers, these results can be generalized to other AS or nr-axSpA patients not refractory to NSAIDs. However, the high partial remission rate achieved in the IFX+NPX group are not generalizable to a population refractory to NSAIDs.
Disclosures: The authors declared financial relationships with Abbott, AstraZeneca, Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, Pfizer, UCB, Janssen, Janssen-Cilag, and Roche. Some authors are employees of Merck Sharp & Dohme, and the study was supported by Merck Sharp & Dohme.