Normal CRP During RA Flares: an 'Underappreciated, Persistent Phenotype'

Sara Freeman

May 04, 2023

MANCHESTER, England — Even when C-reactive protein (CRP) levels are normal, patients with seropositive rheumatoid arthritis (RA) could still be experiencing significant disease that persists over time, researchers from University College London in England have found.

Similar levels of joint erosion and disease activity were observed over a 5-year period; researchers compared patients who had high CRP levels (>5 mg/L) with patients whose CRP levels were consistently normal (<5 mg/L) at the time of an ultrasound-proven disease flare.

"Our data suggests that the phenotype of normal CRP represents at least 5% of our cohort," Bhavika Sethi, MBChB, reported in a virtual poster presentation at the British Society for Rheumatology (BSR) 2023 Annual Meeting.

"They are more likely to require biologic treatment, and this continues on even though they have equivalent DAS28 [disease activity score in 28 joints] and risk of joint damage" to high-CRP patients, she said.

These patients are a significant minority, Sethi added, and "we need to think about how we provide care for them and allocate resources."

Diagnostic Delay and Poor Outcomes Previously Seen

The study is a continuation of a larger project, the corresponding author for the poster, Matthew Hutchinson, MBChB, told Medscape Medical News.

A few years ago, Hutchinson explained, a subset of patients with normal CRP levels during RA flares were identified and were found to be more likely to have experienced diagnostic delay and worse outcomes than did those with high CRP levels.

The aim of the current study was to see whether those findings persisted by longitudinally assessing patient records and seeing what happened 1, 2, and 5 years later. They evaluated 312 patients with seropositive RA, of whom 28 had CRP <5 mg/L as well as active disease, which was determined on the basis of a DAS28 >4.5. Of those 28 patients, 16 had persistently low CRP (<5 mg/L) despite active disease. All patients who were taking tocilizumab were excluded from the study because of its CRP-lowering properties.


"Our project was showing that this group of people exist, trying to characterize them a little better" and that the study serves as a "jumping-off point" for future research, Hutchinson said.

The study was also conducted to "make people more aware of [patients with normal CRP during flare], because treating clinicians could be falsely reassured by a normal CRP," he added. "Patients in front of them could actually be undertreated and have worse outcomes if [it is] not picked up," Hutchinson suggested.

In comparison with those with high CRP levels, those with normal CRP levels were more likely to be receiving biologic treatment at 5 years (76.6% vs 44.4%; P =  .0323).

At 5 years, DAS28 was similar (P = .9615) among patients with normal CRP levels and those with high CRP levels, at a median of 2.8 and 3.2, respectively. A similar percentage of patients in these two groups also had joint damage (63.3% vs 71.4%; P = .7384).

Don't Rely Only on CRP to Diagnose and Manage RA Flares

"CRP is a generic inflammatory marker in most people," Hutchinson said. "In the majority of situations when either there is inflammation or an infection, certainly if it's systemic infection or inflammation, you will find CRP being elevated on the blood tests."

For someone presenting with joint pain, high CRP can be a useful indicator that it's more of an inflammatory process than physical injury, he added. CRP is also frequently used to calculate DAS28 to monitor disease activity.

"This study highlights that CRP may be normal during flares in some people with RA," Jeffrey A. Sparks, MD, told Medscape Medical News.

"These patients may still require advanced therapies and can accrue damage," the rheumatologist from Brigham and Women's Hospital and Harvard University in Boston, Massachusetts, added.

"Clinicians should not only rely on CRP to diagnose and manage RA flares," said Sparks, who was not involved in the study.

The study was independently supported. Hutchinson and Sethi report no relevant financial relationships. Sparks is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the R. Bruce and Joan M. Mickey Research Scholar Fund, and the Llura Gund Award for Rheumatoid Arthritis Research and Care; he has received research support from Bristol-Myers Squibb and has performed consultancy for AbbVie, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Inova Diagnostics, Janssen, Optum, and Pfizer.

British Society for Rheumatology (BSR) 2023 Annual Meeting: Abstract P124. Presented April 24, 2023.

Sara Freeman is a medical journalist based in London, United Kingdom.

For more news, follow Medscape on Facebook, Twitter, Instagram, and YouTube.

May 9, 2023 — Editor's note: This article has been updated to correct the units for C-reactive protein from mg/dL to mg/L.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.