Review question
Can treatments such as colchicine, anakinra, rilonacept, canakinumab, etanercept, infliximab, adalimumab, thalidomide, tocilizumab, interferon-α and ImmunoGuard (a herbal supplement)) reduce inflammation in people with familial Mediterranean fever (FMF)?
Background
FMF is a hereditary inflammatory disease, with symptoms of an attack often including fever over 38 °C, pain and inflammation of the membrane surrounding the chest cavity, the joints or the lungs. We wanted to discover whether these medicines 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 medicines with each other.
Search date
The evidence is current to 17 August 2021.
Study characteristics
The review included 10 studies with 312 people with FMF aged between three and 53 years. Eight studies compared five medicines, colchicine, rilonacept, ImmunoGuard, anakinra and canakinumab, with placebo. Participants received one medicine or placebo at random over one to four months. The remaining two studies compared colchicine 1 mg per day once daily with colchicine two or 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 (which is a reaction to a chronic inflammatory disease or infection leading to a build-up of an abnormal protein called amyloid in organs and tissues throughout the body stopping them working properly), and any side effects of treatment and the levels of a number of markers of inflammation during an attack. Not all studies reported 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) with oral colchicine 0.6 mg three times a day and another study (63 participants) with subcutaneous (under the skin) canakinumab 150 mg every four weeks for 16 weeks may help to reduce the numbers of people with attacks of FMF. However, oral colchicine 0.5 mg twice a day (20 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 that is produced in the liver). Anakinra and canakinumab reduced C-reactive protein levels. Colchicine taken once daily and two or three times daily might not result in different outcomes including the timing of attacks, sider effects of the medicine and acute-phase response indicators.
Quality of the evidence
Four studies were well-designed, while the others had some design problems that might have affected 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.
There were limited RCTs assessing interventions for people with FMF. Based on the evidence, three times daily colchicine may reduce the number of people experiencing attacks, colchicine single dose and divided dose may not be different for children with FMF, canakinumab probably reduces the number of people experiencing attacks, and anakinra or canakinumab probably reduce CRP 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 FMF can be drawn.
Familial Mediterranean fever (FMF), a hereditary auto-inflammatory disease, mainly affects ethnic groups living in the Mediterranean region. Early studies reported colchicine may potentially prevent FMF attacks. For people who are colchicine-resistant or intolerant, drugs such as anakinra, rilonacept, canakinumab, etanercept, infliximab or adalimumab might be beneficial. This is an update of the review last published in 2018.
To evaluate the efficacy and safety of interventions for reducing inflammation in people with FMF.
We searched CENTRAL, MEDLINE, Embase and four Chinese databases on in August 2021. We searched clinical trials registries and references listed in relevant reports.
The last search was 17 August 2021.
We included randomized controlled trials (RCTs) of people with FMF, comparing active interventions (including colchicine, anakinra, rilonacept, canakinumab, etanercept, infliximab, adalimumab, thalidomide, tocilizumab, interferon-α and ImmunoGuard (herbal dietary supplement)) with placebo or no treatment, or comparing active drugs to each other.
We used standard Cochrane methodology. We assessed certainty of the evidence using GRADE.
We included 10 RCTs with 312 participants (aged three to 53 years), including five parallel and five cross-over designed studies. Six studies used oral colchicine, one used oral ImmunoGuard, and the remaining three used rilonacept, anakinra or canakinumab as a subcutaneous injection. The duration of each study arm ranged from one to eight months.
There were inadequacies in the design of the four older colchicine studies and the two studies comparing a single to a divided dose of colchicine. However, the four studies of ImmunoGuard, rilonacept, anakinra and canakinumab were generally well-designed.
We aimed to report on the number of participants experiencing an attack, the timing of attacks, the prevention of amyloid A amyloidosis, adverse drug reactions and the response of a number of biochemical markers from the acute phase of an attack; but no study reported on the prevention of amyloid A amyloidosis.
Colchicine (oral) versus placebo
After three months, colchicine 0.6 mg three times daily may reduce the number of people experiencing attacks (risk ratio (RR) 0.21, 95% confidence interval (CI) 0.05 to 0.95; 1 study, 10 participants; low-certainty evidence). One study (20 participants) of colchicine 0.5 mg twice daily showed there may be no difference in the number of participants experiencing attacks at two months (RR 0.78, 95% CI 0.49 to 1.23; low-certainty evidence).
There may be no differences in the duration of attacks (narrative summary; very low-certainty evidence), or in the number of days between attacks: (narrative summary; very low-certainty evidence).
Regarding adverse drug reactions, one study reported loose stools and frequent bowel movements and a second reported diarrhea (narrative summary; both very low-certainty evidence).
There were no data on acute-phase response.
Rilonacept versus placebo
There is probably no difference in the number of people experiencing attacks at three months (RR 0.87, 95% CI 0.59 to 1.26; moderate-certainty evidence).
There may be no differences in the duration of attacks (narrative summary; low-certainty evidence) or in the number of days between attacks (narrative summary; low-certainty evidence).
Regarding adverse drug reactions, the rilonacept study reported there may be no differences in gastrointestinal symptoms, hypertension, headache, respiratory tract infections, injection site reactions and herpes, compared to placebo (narrative summary; low-certainty evidence).
The study narratively reported there may be no differences in acute-phase response indicators after three months (low-certainty evidence).
ImmunoGuard versus placebo
The ImmunoGuard study observed there are probably no differences in adverse effects (moderate-certainty evidence) or in acute-phase response indicators after one month of treatment (moderate-certainty evidence).
No data were reported for the number of people experiencing an attack, duration of attacks or days between attacks.
Anakinra versus placebo
A study of anakinra given to 25 colchicine-resistant participants found there is probably no difference in the number of participants experiencing an attack at four months (RR 0.76, 95% CI 0.54 to 1.07; moderate-certainty evidence).
There were no data for duration of attacks or days between attacks.
There are probably no differences between anakinra and placebo with regards to injection site reaction, headache, presyncope, dyspnea and itching (narrative summary; moderate-certainty evidence).
For acute-phase response, anakinra probably reduced C-reactive protein (CRP) after four months (narrative summary; moderate-certainty evidence).
Canakinumab versus placebo
Canakinumab probably reduces the number of participants experiencing an attack at 16 weeks (RR 0.41, 95% CI 0.26 to 0.65; 1 study, 63 colchicine-resistant participants; moderate-certainty evidence).
There were no data for the duration of attacks or days between attacks.
The included study reported the number of serious adverse events per 100 patient-years was probably 42.7 with canakinumab versus 97.4 with placebo among people with colchicine-resistant FMF (moderate-certainty evidence).
For acute-phase response, canakinumab probably caused a higher proportion of participants to have a CRP level of 10 mg/L or less compared to placebo (68% with canakinumab versus 6% with placebo; 1 study, 63 participants; moderate-certainty evidence).
Colchicine single dose versus divided dose
There is probably no difference in the duration of attacks at three months (MD −0.04 hours, 95% CI −10.91 to 10.83) or six months (MD 2.80 hours, 95% CI −5.39 to 10.99; moderate-certainty evidence).
There were no data for the number of participants experiencing an attack or days between attacks.
There is probably no difference in adverse events (including anorexia, nausea, diarrhea, abdominal pain, vomiting and elevated liver enzymes) between groups (narrative summary; moderate-certainty evidence).
For acute-phase response, there may be no evidence of a difference between groups (narrative summary; low- to moderate-certainty evidence).