We reviewed the evidence about the effect of treatments (e.g. colchicine, anakinra, rilonacept, etanercept, infliximab, thalidomide, interferon-alpha, ImmunoGuard™ (a herbal supplement) and non-steroidal anti-inflammatory drugs) on people with familial Mediterranean fever.
Familial Mediterranean fever is a hereditary inflammatory disease, with symptoms of an attack often including fever over 38℃, pain and inflammation of the peritoneum (the membrane surrounding a joint or covering the lungs and chest cavity). We wanted to discover whether these drugs were better for reducing inflammation for people with familial Mediterranean fever than placebo (a dummy treatment containing no active medicine) or no treatment, and also to compare these drugs with each other.
The evidence is current to: 21 May 2014.
The review included four studies including 75 people with familial Mediterranean fever aged between three and 53 years old. The studies compared three of the drugs, colchicine, rilonacept and ImmunoGuard™, with placebo. Participants were chosen to receive one drug or placebo at random over a period ranging from one to three months.
We aimed to report on the number of participants experiencing an attack, the timing of attacks, any side effects of treatment and the levels of a number of markers of inflammation during an attack. Not all studies reported on these outcomes. Given the differences in treatments and study design, it was not possible to combine any of the results that we did obtain from these studies. One study (15 participants) found that oral colchicine at a dose of 0.6 mg three times a day could help to reduce the numbers of people with attacks of familial Mediterranean fever. However, oral colchicine administrated at a dose of 0.5 mg twice a day (22 participants) or rilonacept (14 participants) did not reduce the numbers of people with attacks of familial Mediterranean fever. ImmunoGuard™ (24 participants) did not reduce levels of the markers of inflammation in the blood which are raised during the attack phase of familial Mediterranean fever; these include the rate of fall of red blood cells when placed in a test tube, the white blood cell count and the presence of C-reactive protein (a protein which is produced in the liver).
Quality of the evidence
One study was well designed, while the others had some design problems which might affect the results. Two studies did not report clearly how the people were assigned to each treatment group. Two studies did not report whether researchers who assessed the study outcomes, knew which volunteers were assigned to which treatment. Two studies did not clearly explain the reasons for people withdrawing from a study. Two studies did not report the severity of familial Mediterranean fever in groups at the beginning of treatment. We could not confirm whether each planned outcome was reported in two studies.
There were limited randomized controlled studies assessing interventions for people with familial Mediterranean fever. Based on the evidence, colchicine appears to reduce the number of people experiencing attacks; however, only a few low-quality randomized controlled studies contributed data for analysis. Further randomized controlled studies examining active interventions, not only colchicine, are necessary before a comprehensive conclusion regarding the efficacy and safety of interventions for reducing inflammation in familial Mediterranean fever can be drawn.
Familial Mediterranean fever, a hereditary auto-inflammatory disease, mainly affects ethnic groups living in the Mediterranean region. Early studies reported colchicine as a potential drug for preventing attacks of familial Mediterranean fever. For those people who are colchicine-resistant or intolerant, drugs such as rilonacept, anakinra, etanercept, infliximab, thalidomide and interferon-alpha might be beneficial.
To evaluate the efficacy and safety of interventions for reducing inflammation in people with familial Mediterranean fever.
We used detailed search strategies to search the following databases: CENTRAL; MEDLINE; Embase; Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure Database (CNKI); Wan Fang; and VIP. In addition, we also searched the clinical trials registries including ClinicalTrials.gov, the International Standard Randomized Controlled Trial Number Register, the WHO International Clinical Trials Registry Platform and the Chinese Clinical Trial Registry, as well as references listed in relevant reports.
Date of last search: 21 May 2014.
Randomized controlled studies of people with diagnosis of familial Mediterranean fever, comparing active interventions (including colchicine, anakinra, rilonacept, etanercept, infliximab, thalidomide, interferon-alpha, ImmunoGuard™ (a herbal dietary supplement) and non-steroidal anti-inflammatory drugs) with placebo or no treatment, or comparing active drugs to each other.
The authors independently selected studies, extracted data and assessed risk of bias. We pooled data to present the risk ratio or mean difference with their 95% confidence intervals. We assessed overall evidence quality according to the GRADE approach.
We included four randomized placebo-controlled studies with a total of 75 participants (aged three to 53 years); three were of cross-over and one of parallel design. Two studies used the active intervention of oral colchicine (0.6 mg three times daily or 0.5 mg twice daily), one study used oral ImmunoGuard™ and the fourth used rilonacept as a subcutaneous injection. The duration of each study arm ranged from one to three months.
The two most recent studies were generally well-designed, except for an unclear risk of detection bias in one of these. However, some inadequacy existed in the other two older studies, where each had an unclear risk of selection bias, a high risk of attrition bias, an unclear risk of reporting bias and a high risk of other potential bias (baseline characteristics such as mutation status and disease severity were not described); one of these studies additionally had an unclear risk of detection bias.
We aimed to report on the number of participants experiencing an attack, the timing of attacks, any adverse drug reactions and the response of a number of biochemical markers from the acute phase of an attack, but data were not available for all outcomes across all comparisons.
Based on one study (15 participants), there was a significant reduction in the number of people experiencing attacks at three months when colchicine was administered at a dose of 0.6 mg three times daily (14% versus 100%), risk ratio 0.21 (95% confidence interval 0.05 to 0.95); however, the GRADE evidence quality was low. Based on two further studies, there was no significant reduction in the number of participants experiencing attacks at two months when colchicine was administered at a dose of 0.5 mg twice daily (22 participants) in people with familial Mediterranean fever, or at three months when rilonacept was used in individuals who were colchicine-resistant or colchicine-intolerant (14 participants). In the ImmunoGuard™ study (24 participants) acute phase response indicators (including erythrocyte sedimentation rate, white blood cell count and C-reactive protein) were not reduced after one month treatment.