Drugs for reducing inflammation in people with familial Mediterranean fever

Review question

We reviewed the evidence about the effect of treatments (e.g. colchicine, anakinra, rilonacept, canakinumab, etanercept, infliximab, thalidomide, interferon-alpha, ImmunoGuard™ (a herbal supplement) and non-steroidal anti-inflammatory drugs) on people with familial Mediterranean fever (FMF).

Background

FMF is a hereditary inflammatory disease, with symptoms of an attack often including fever over 38℃, pain and inflammation of the membrane surrounding the chest cavity, the joints or the lungs. We wanted to discover whether these drugs were better for reducing inflammation for people with FMF than placebo (a dummy treatment containing no active medicine) or no treatment, and also to compare these drugs with each other.

Search date

The evidence is current to: 21 August 2018.

Study characteristics

The review includes nine studies including 249 people with FMF aged between three and 53 years old. Seven studies compared four of the drugs, colchicine, rilonacept, ImmunoGuard™ and anakinra, with placebo. Participants were chosen to receive one drug or placebo at random over a period ranging from one to four months. The remaining two studies compared colchicine 1 mg per day once daily with two to three times daily in children for six to eight months.

Key results

We aimed to report on the number of participants experiencing an attack, the timing of attacks, prevention of amyloid A amyloidosis, 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 FMF. However, oral colchicine administrated at a dose of 0.5 mg twice a day (22 participants), rilonacept (14 participants) or anakinra (25 participants) did not reduce the numbers of people with attacks. ImmunoGuard™ (24 participants) did not reduce levels of the markers of inflammation in the blood which are raised during the attack phase of FMF; 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). Anakinra reduced C-reactive protein level. Colchicine once daily and two to three times daily might not result in different outcomes including the timing of attacks, adverse drug reactions and acute phase response indicators.

Quality of the evidence

Three studies were well-designed, while the others had some design problems which might affect the results. Four studies did not report clearly how the people were assigned to each treatment group. Four studies did not report whether researchers, who assessed the study outcomes, knew which individuals were assigned to which treatment. Four studies did not clearly explain the reasons for people withdrawing from a study and one study had a high percentage of participants who did not complete study. We could not confirm whether each planned outcome was reported in five studies. Five studies did not report the severity of FMF in groups at the beginning of treatment. We judged the evidence for the reported outcomes to be of moderate- to very low-quality.

Authors' conclusions: 

There were limited RCTs assessing interventions for people with familial Mediterranean fever. Based on the evidence, three times daily colchicine appears to reduce the number of people experiencing attacks, colchicine single dose and divided dose might not be different for children with familial Mediterranean fever and anakinra might reduce C-reactive protein in colchicine-resistant participants; however, only a few RCTs contributed data for analysis. Further RCTs 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.

Read the full abstract...
Background: 

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, canakinumab, etanercept, infliximab, thalidomide and interferon-alpha might be beneficial. This is an updated version of the review.

Objectives: 

To evaluate the efficacy and safety of interventions for reducing inflammation in people with familial Mediterranean fever.

Search strategy: 

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 August 2018.

Selection criteria: 

Randomized controlled studies (RCTs) of people diagnosed with familial Mediterranean fever, comparing active interventions (including colchicine, anakinra, rilonacept, canakinumab, 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.

Data collection and analysis: 

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.

Main results: 

We included nine RCTs with a total of 249 participants (aged three to 53 years); five were of cross-over and four of parallel design. Six studies used oral colchicine, one used oral ImmunoGuard™ and the remaining two used rilonacept or anakinra as a subcutaneous injection. The duration of each study arm ranged from one to eight months.

The three studies of ImmunoGuard™, rilonacept and anakinra were generally well-designed, except for an unclear risk of detection bias in one of these. However, some inadequacy existed in the four older studies on colchicine, which had an unclear risk of selection bias, detection bias and reporting bias, and also a high risk of attrition bias and other potential bias. Neither of the two studies comparing a single to a divided dose of colchicine were adequately blinded, furthermore one study had an unclear risk of selection bias and reporting bias, a high risk of attrition bias and other potential bias.

We aimed to report on the number of participants experiencing an attack, the timing of attacks, the prevention of amyloid A amyloidosis, 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.

One study (15 participants) reported a significant reduction in the number of people experiencing attacks at three months with 0.6 mg colchicine three times daily (14% versus 100%), risk ratio 0.21 (95% confidence interval 0.05 to 0.95) (low-quality evidence). A further study (22 participants) of 0.5 mg colchicine twice daily showed no significant reduction in the number of participants experiencing attacks at two months (low-quality evidence). A study of rilonacept in individuals who were colchicine-resistant or intolerant (14 participants) also showed no reduction at three months (moderate-quality evidence). Likewise, a study of anakinra given to colchicine-resistant people (25 participants) showed no reduction in the number of participants experiencing an attack at four months (moderate-quality evidence).

Three studies reported no significant differences in duration of attacks: one comparing colchicine to placebo (15 participants) (very low-quality evidence); one comparing single-dose colchicine to divided-dose colchicine (90 participants) (moderate-quality evidence); and one comparing rilonacept to placebo (14 participants) (low-quality evidence). Three studies reported no significant differences in the number of days between attacks: two comparing colchicine to placebo (24 participants in total) (very low-quality evidence); and one comparing rilonacept to placebo (14 participants) (low-quality evidence).

No study reported on the prevention of amyloid A amyloidosis.

One study of colchicine reported loose stools and frequent bowel movements (very low-quality evidence) and a second reported diarrhoea (very low-quality evidence). The rilonacept study reported no significant differences in gastrointestinal symptoms, hypertension, headache, respiratory tract infections, injection site reactions and herpes, compared to placebo (low-quality evidence). The ImmunoGuard study observed no side effects (moderate-quality evidence). The anakinra study reported no significant differences between intervention and placebo, including injection site reaction, headache, presyncope, dyspnea and itching (moderate-quality evidence). When comparing single and divided doses of colchicine, one study reported no difference in adverse events (including anorexia, nausea, diarrhoea, abdominal pain, vomiting and elevated liver enzymes) between groups (moderate-quality evidence) and the second study reported no adverse effects were detected.

The rilonacept study reported no significant reduction in acute phase response indicators after three months (low-quality evidence). In the ImmunoGuard™ study, these indicators were not reduced after one month of treatment (moderate-quality evidence). The anakinra study, reported that C-reactive protein was significantly reduced after four months (moderate-quality evidence). One of the single dose versus divided dose colchicine studies reported no significant reduction in acute phase response indicators after eight months (low-quality evidence), while the second study reported no significant reduction in serum amyloid A concentration after six months (moderate-quality evidence).

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