How Does FMF Affect Adolescent Females? Study Offers New Details

Girls and young women who frequently suffer painful attacks of familial Mediterranean fever (FMF) around the time they menstruate can expect good outcomes when treated according to recent evidence, Turkish researchers found in a small study.

Seventeen of 35 adolescents experiencing such attacks benefited merely from either starting colchicine or, if they were already using it, upping the dose, according to Ezgi Deniz Batu, MD, MSc, of Hacettepe University in Ankara, Turkey, and colleagues.

Other strategies that appeared at least moderately successful included allowing patients to use medications including nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, or anakinra (Kineret) at will, the researchers wrote in Rheumatology.

Their analysis of a total of 151 young female patients with FMF also included a proposed treatment algorithm that clinicians elsewhere can use to guide management.

Batu and colleagues are well positioned to conduct such a study. Turkey has some of the highest FMF rates in the world, with about 1 case in 1,000; prevalence is even higher (1 in 500) in people of Armenian ancestry, of whom Turkey has many. In comparison, the FMF rate among people of Ashkenazi Jewish heritage has been estimated at between 1 in 3,000-5,000 and 1 in 73,000.

FMF is a genetic disorder affecting just a single gene called MEFV, although many different mutations can produce clinical symptoms. Severity and duration are associated with particular mutations, but other factors appear to play a role too. The disease manifests as attacks of symptom constellations (typically including fever, obviously), with the frequency varying from a few days to several years.

"Although the pattern of attacks is random in most FMF patients, some triggering factors such as psychological stress, physical exercise, menstruation, and infections have been described in some patients," Batu and colleagues explained. Those associated with menstruation, however, had garnered little research -- a gap that the group sought to fill with the new study.

They identified 151 adolescents and young women who had been treated for FMF during calendar year 2022 at their institution's pediatric unit. Of these, 35 had a pattern of attacks around menstruation.

As is typical in FMF, most patients were small children (median age 4) when they had their first attacks and were usually diagnosed about 2 years later. Median time from diagnosis to their most recent evaluation was 11 years.

The first attack tended to come much earlier in patients later reporting menstruation-associated attacks (age 2.4 vs 5.0, P=0.004), Batu and colleagues found. Dysmenorrhea was also twice as common in this group (74.3% vs 38.8% prevalence, P<0.001). Particular symptoms, however, did not differ significantly between those with menstruation-associated attacks and those without.

Oral colchicine is commonly considered the primary first-line treatment, for prophylaxis and for mitigating acute attacks. Steroids, NSAIDs, and drugs targeting interleukin-1 such as anakinra can be used in stubborn cases.

In their proposed algorithm, Batu and colleagues recommended that when patients aren't responding adequately to colchicine as prescribed, first check that patients are actually taking the pills as instructed.

If colchicine is clearly not working, further management steps depend on whether attacks occur only around menstruation. In such cases, as long as subclinical inflammation is not detected, adding NSAIDs is recommended, to be followed by on-demand anakinra. Otherwise, for patients experiencing attacks at random times, or if there is subclinical inflammation, Batu and colleagues suggested first increasing the colchicine dose again, and if that fails, going straight to anti-interleukin-1 treatment, which could be anakinra or canakinumab (Ilaris).

Why would the menstrual cycle influence FMF attacks? That "remains unclear," the researchers wrote, but they suggested that "the most viable hypothesis" is that declines in estrogen levels that accompany menstruation are responsible, through effects on interleukin-1-mediated processes.

Limitations to the study included the small number of patients and its conduct in Turkey; Batu and colleagues also cited the reliance on patient self-reports for key data and the related possibility that some younger patients mistook dysmenorrhea from other causes for FMF attacks.

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