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Does RA Have a Prodrome?

A pattern of increased primary care visits and joint complaints during the 2 years before rheumatoid arthritis (RA) was diagnosed were predictive of the diagnosis, a British case-control study found.

During the 24 months prior to RA diagnosis, the incidence rate ratio for primary care consultation in each month was 1.22 (95% CI 1.21-1.22) among cases compared with controls, and in the final month before diagnosis, patients consulted their primary care physician at 2.68 (95% CI 2.61-2.76) times the rate of controls, according to Sara Muller, PhD, of Keele University in Keele, England, and colleagues.

In addition, during the final month before diagnosis, joint symptoms in general were strongly associated with the subsequent diagnosis of RA, with an adjusted odds ratio of 14.82 (95% CI 12.48-17.60), the researchers reported in Seminars in Arthritis & Rheumatism.

It is now well recognized that early, intensive treatment of RA can induce remission and prevent long-term damage to the joints, and that delay in diagnosis can seriously interfere with disease control.

"Primary care delay continues to be a significant contributor to overall diagnostic delay for people with RA," Muller's group observed. Potential explanations for this include a lack of awareness among primary care providers of the urgency of diagnosis and uncertainty about the specific symptoms that might constitute red flags, they stated.

To explore the possibility that prodromal symptoms could help the early identification and referral of patients with RA, they analyzed data from the U.K. Clinical Practice Research Datalink, which collects data from health records of some 7% of the U.K. population who are considered representative of the wider population in age, gender, and ethnicity.

They identified 3,577 individuals enrolled in the database from 2007 to 2012 who were diagnosed with RA, matching them with 14,287 controls. Mean age was 59, two-thirds were women, and more cases than controls were current or former smokers.

Throughout the 2 years before RA diagnosis, symptoms involving the hand showed the strongest association. From months 12 to 24 before diagnosis, the adjusted OR for subsequent RA was 2.70 (95% CI 2.05-3.56), while from months 12 to 0, the OR rose to 23.75 (95% CI 18.49-30.51). In months 6 to 0, the adjusted OR increased further, to 39.10 (95% CI 27.80-55), and in the final month before diagnosis, it reached 61.07 (95% CI 31.58-118.10).

Other symptoms that were predictive in the year before diagnosis included morning stiffness (OR 9.72, 95% CI 3.84-24.60) and muscle pain (OR 3.15, 95% CI 2.22-4.47).

During the 6 months before diagnosis, significant associations were seen for all joint problems, including symptoms in the shoulder, neck, foot, and jaw. Then, in the final month before diagnosis, significant associations were found for involvement of these joints (other than the hand):

  • Shoulder: OR 3.28 (95% CI 2.14-5.05)
  • Neck: OR 2.44 (95% CI 1.36-4.4)
  • Foot: OR 3.46 (95% CI 2.13-5.62)

For nonarticular symptoms, during the 6 months before diagnosis, associations with subsequent RA were seen for morning stiffness (OR 17.18, 95% CI 4.88-60.43), unintentional weight loss (OR 1.87, 95% CI 1.04-3.36), muscle pain (OR 4.52, 95% CI 2.83-7.24), and carpal tunnel syndrome (OR 7.20, 95% CI 4.66-11.13), while in the final month before diagnosis, adjusted ORs showing significant associations were seen for muscle pain (OR 13.83, 95% CI 5.11-37.42) and carpal tunnel syndrome (OR 2.96, 95% CI 1.38-6.34). During that time period, the association of morning stiffness could not be estimated because, although 14 cases reported this symptom, no cases did so.

Flu-like symptoms appeared to have an association with later RA during the period 12 to 24 months before diagnosis (OR 1.46, 95% CI 1.04-2.07), though not in the 12 months immediately preceding diagnosis. This observation "may suggest that rather than being part of an RA prodrome, flu-like symptoms may be a marker of an insult to the immune system that reflects the phase of immune tolerance breakage," the researchers explained.

"Primary care professionals should be aware of the range of articular and non-articular features, specifically hand symptoms, muscle pain, carpal tunnel syndrome, and unintentional weight loss, accompanied by an increased rate of consultation, as potentially forming a prodromal syndrome for RA," they stated.

One possible way to increase primary care clinicians' index of suspicion for RA could be the incorporation into the electronic health record automated alerts for these symptoms as has been done for sepsis, they noted.

A study limitation was the inability of the authors to identify primary care clinicians' reasons for referral or nonreferral.

The study was funded by the National Institute for Health Research.

Muller and co-authors disclosed relevant relationships with Bristol-Myers Squibb, AbbVie, Pfizer, and UCB.

The author has no conflicts of interest to disclose related to this subject

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