Morning Stiffness: A Prognostic Indicator in RA?

van Nies JA, Alves C, Radix-Bloemen ALS, et al., Reappraisal of the diagnostic and prognostic value of morning stiffness in arthralgia and early arthritis: results from the Groningen EARC, Leiden EARC, ESPOIR, Leiden EAC and REACH. Arthritis Research & Therapy 2015;17:108  doi:10.1186/s13075-015-0616-3. Published: 23 April 2015

Boers M, Buttgereit F, Saag K, et al., What is the relationship between morning symptoms and measures of disease activity in patients with rheumatoid arthritis? Arthritis Care & Research. Online March 25, 2015; Accepted article. doi: 10.1002/acr.22592

New attention is being paid to one of theclassic symptoms of rheumatoid arthritis (RA), morning stiffness. It may have some clinical utility as a predictor of disease, an indicator of disease activity, and way to measure the effectiveness of treatment, according to these two studies.

As yet, stiffness severity is not part of RA criteria core sets, including that of the American College of Rheumatology (ACR), or other composite measures of disease activity, such as DAS28.

The first article above, involving more than 5,000 arthritis patients in three large cohorts in the Netherlands, suggests that morning stiffness-especially stiffness lasting more than an hour-appears to be associated with RA independent from other diagnostic variables.

These data show that patients with RA are more likely than those with other types of arthritis to have morning stiffness that lasts longer than 60 minutes, an insight that could imform diagnostic criteria.

The second report above finds an association between prolonged morning stiffness and RA disease activity, either radiological progression or drug-free sustained remission.

Those researchers followed 350 patients in the Circadian Administration of Prednisone in Rheumatoid Arthritis (CAPRA2) trial with symptomatic RA despite treatment with disease-modifying anti-rheumatic drugs who had been randomized to additional treatment with delayed-release prednisone or placebo.

They found correlations between duration and severity of morning stiffness, intensity of pain on awakening, and measures of disease activity (such as DAS28, ACR20, and the HAQ-DI). Placebo-treated patients had more severe symptoms.

Severity of stiffness had a larger effect size than the other measures.

“Morning stiffness is associated with elevated nocturnal levels of the inflammatory cytokine, interleukin 6 (IL-6), which may be suppressed with exogenous glucocorticoids,” they note.

Delayed-release prednisone taken around 8 pm releases glucocorticoid after a “programmed delay of 4–6 hours, to optimize suppression of the nocturnal peak in inflammatory cytokines.”

In the 12-week, double-blind, placebo-controlled CAPRA-2, delayed-release prednisone significantly reduced the duration and severity of morning stiffness and pain intensity, as well as increasing ACR response rates significantly.

The researchers found only modest associations between stiffness and disease activity associated with this treatment effect. They note that severity of stiffness has better measurement properties than its duration.

(The CAPRA studies are supported by Horizon Pharma, maker of RAYOS (Prednisone) Delayed-Release Tablets. Several of the researchers report receiving honoraria, grant support, and consultancy fees from Horizon.)