Patients with nonradiographic axial spondyloarthritis (axSpA) who have normal C-reactive protein (CRP) levels at baseline but have high disease activity should have the CRP test repeated after at least 4 weeks to clarify whether they should be eligible for treatment with anti-tumor necrosis factor (TNF) treatment, European researchers stated.
They reached this conclusion after observing in a post-hoc analysis of a randomized trial that among patients whose CRP was normal at baseline, 50% had an elevated level of this inflammatory marker by week 16, according to Robert Landewé, MD, of the University of Amsterdam, and colleagues.
The spectrum of disease known as axSpA includes ankylosing spondylitis, in which inflammation of the spine and sacroiliac joints is visible on x-rays, and nonradiographic axSpA, which is considered to have a similar disease burden as ankylosing spondylitis but lacks radiographic evidence of inflammation.
In the United States, TNF inhibitor therapy is approved for ankylosing spondylitis but not for the nonradiographic disease variant, whereas in Europe four TNF inhibitors have been approved for active nonradiographic axSpA for patients who have objective signs of inflammation either on MRI or with CRP elevations.
"Many axSpA patients with normal CRP levels are classified as CRP "negative" despite having levels close to the upper limit of normal and are therefore formally ineligible for treatment. The natural degree of CRP fluctuation in patients who have not received anti-TNF therapy is not well understood and should be investigated further," the investigators wrote in .
Therefore, to explore this, they analyzed data from a phase III trial known as RAPID-axSpA, which evaluated the safety and efficacy of certolizumab pegol (Cimzia) in 325 patients with active axSpA. Active disease was defined as a score of 4 or higher on the Bath Ankylosing Spondylitis Disease Activity Index, a spinal pain score of 4 or higher on a scale of 0 to 10, CRP above 7.9 mg/L, and/or sacroiliitis on MRI. CRP tests were repeated nine times through week 24.
Elevated CRP is considered an important measure of inflammation in axSpA, and also is thought to predict response to anti-TNF therapy.
The current analysis included the 106 patients who were randomized to placebo until week 16 or 24, to see if CRP levels changed over time without anti-TNF treatment.
Among these 106 patients, 26 had normal CRP levels on the first test, but in 13, levels were elevated on subsequent testing. Moreover, among the 80 patients whose CRP was elevated at baseline, 25 subsequently had at least one normal level.
Tests that were repeated within 1 to 2 weeks had similar CRP findings. Only after an interval of at least 4 weeks were differences seen.
Further analyses suggested that 10.8% of CRP test results below 3 mg/L could have elevated levels above 7.9 mg/L if tested 4 weeks later, as would 53.1% of those whose initial level was between 6 and 7.9 mg/L.
In addition, 7% of CRP tests above 15 mg/L would be within normal levels after 4 weeks, as would 28.3% of tests that initially were between 7.9 and 10 mg/L.
"These results are in agreement with those from the study, in which 24.6% (14/57) of placebo-treated patients with normal CRP levels at baseline developed elevated CRP levels after 12 weeks, suggesting that a change in a patient's CRP status is more common than previously thought," Landewé and colleagues observed.
They concluded that because patients with high disease activity but normal CRP levels may obtain benefit from anti-TNF treatment, CRP testing after 4 weeks is justified.
"There is a substantial chance of finding elevated CRP levels on subsequent testing, thus making the patient eligible for treatment options such as anti-TNF therapies," they wrote.
Disclosures
The study was sponsored by UCB.
The authors reported financial relationships with UCB, AbbVie, Ablynx, Amgen, AstraZeneca, Bristol-Myers Squibb, Centocor, GlaxoSmithKline, Novartis, Merck, Pfizer, Roche, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme, and Schering Plough.
Primary Source
Arthritis Research & Therapy
Landewé R, et al "A single determination of C-reactive protein does not suffice to declare a patient with a diagnosis of axial spondyloarthritis CRP negative" Arthritis Res Ther 2018; doi:10.1186/s13075-018-1707-8.