Published: Dec 11, 2014

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By Nancy Walsh, Senior Staff Writer, MedPage Today

Among patients with gout, the risk of an attack was more than doubled during the night compared with the daytime hours, researchers reported.

During the first 8 hours of the day, from midnight until 8 a.m., the odds ratio for a gout flare was 2.36 (95% CI 2.05-2.73P<0.0001), compared with the hours of 8 a.m. until 4 p.m., according to Hyon K. Choi, MD, DPH, of Boston University, and colleagues.

Risk was also somewhat high in the evening hours of 4 p.m. until midnight, with an OR of 1.26 (95% CI 1.07-1.48,P=0.005), Choi and colleagues reported online in Arthritis and Rheumatology.

Historical data has suggested that attacks often occur at night, and plausible mechanisms for increased nocturnal risk have been advanced.

“Despite these intriguing possibilities and anecdotal observations, no study has investigated the potential varying levels of the risk of gout attacks associated with the time of day. Accurate understanding about the circadian variation of gout attacks could have practical implications about effective timing of anti-gout prophylactic measures,” the researchers wrote.

Choi’s group prospectively recruited 724 patients with gout for an Internet-based, case-crossover study in which patients acted as their own controls.

This study design has been shown to be useful in evaluating the effects of short-term risk factors on outcome events.

All participants were adults, reported having had a physician’s diagnosis of gout, and had at least one attack within the previous year.

At the time of enrollment, participants provided sociodemographic information, data relating to gout such as the age at onset and medication use, and details about other medical history.

Then, when they experienced a gout flare, they were asked to report the time of the attack, location of the pain and other symptoms, possible risk factors for the attack, and medications used during the 24 and 48 hours before the episode.

Patients’ mean age was 54, 78% were men, and most were white. A total of 68% drank alcohol, and median body mass index was 30.6 kg/m2.

Median disease duration was 5 years.

Diuretics were used by 28.6%, allopurinol by 45.4%, nonsteroidal anti-inflammatory drugs (NSAIDs) by 54.3%, and colchicine by 25.6%.

During a year of follow-up, the 724 participants reported 1,433 gout flares. Most involved the lower extremity, and particularly the metatarsophalangeal joint.

Treatments used for the attacks included NSAIDs, corticosteroids, colchicine, or combinations of these drugs.

During the first 8-hour period of the day (midnight to 8 a.m.), there were 733 attacks. In the second and third periods there were 310 and 390, respectively.

The significantly higher risk between midnight and 8 a.m. persisted among various subgroups (P<0.0001 for all):

• Alcohol users: OR 2.78 (95% CI 2.24-3.45)
• Diuretic users: OR 2.33 (95% CI 1.77-3.07)
• Allopurinol users: OR 1.90 (95% CI 1.45-2.47)
• Colchicine users: OR 3.31 (95% CI 2.08-5.27)
• Highest quintile of purine consumption: OR 1.92 (95% CI 1.49-2.49)

Moreover, the risk during that time frame was elevated even for patients who didn’t drink alcohol (OR 2.12, 95% CI 1.77-2.53, P<0.0001) and for the lowest quintile of purine intake (OR 2.37, 95% CI 1.67-3.37, P<0.0001).

The results were similar in various subanalyses, such as for patients experiencing a first attack, those with specific features such as podagra and redness, and including only those patients who used anti-gout medications during the episode.

“These findings provide the first prospective evidence for a substantially increased risk of gout attacks during the night and through early morning hours,” Choi and colleagues stated.

Among the potential reasons for this time of day being risky are the lower body temperature that might encourage the formation of uric acid crystals, and joint dehydration from lying down.

In addition, circulating levels of cortisol are at the lowest between midnight and 4 a.m., which could contribute to the onset.

“Of note, the same mechanism has been linked to typical morning stiffness in rheumatoid arthritis patients (i.e., the nocturnal dip in cortisol levels contributing to a decreased ‘anti-inflammatory’ milieu and leading to increased inflammatory symptoms in the morning),” the authors explained.

Sleep apnea — common among obese men — also may contribute, they noted. “Hypoxia associated with sleep apnea can enhance nucleotide turnover, thereby generating purines, which are metabolized to uric acid.”

In addition, sleep studies have revealed that individuals who become hypoxic during sleep typically have high levels of uric acid as shown by increases in the ratio of uric acid excretion to creatinine.

“As sleep apnea is particularly common among those with the typical profile of gout patients, and as the associated hypoxia is treatable (e.g., with continuous positive airway pressure), clarification of the role of sleep apnea on recurrent gout attacks among gout patients in future studies could add considerably to the effective management of gout,” they wrote.

A limitation of the study was the lack of specific information about sleep apnea in this cohort.