Table 1 Studies and case reports that discussed the use of Anakinra in FMF

Chae et al. [42]

A 20-year-old male homozygous for the M694 V mutation affected by secondary amyloidosis (SAA) who developed signs of gastrointestinal toxicity to colchicine.

Anakinra allowed the control of both SAA and CRP levels. The patient remained clinically stable after several months.

Belkhir et al. [43]

A 68-year-old woman with FMF homozygous for the M694 V mutation of the MEFV gene was refractory to colchicine treatment and bedridden.

She responded clinically to Anakinra, and remained stable after 5 months.

Gattringer at al [45].

A 29-year-old woman was having recurrent FMF attacks despite being on colchicine for 26 years.

Administration of anakinra every second day improved the clinical and laboratory markers except when dose was interrupted.

Gattringer et al. [45]

A 32-year-old woman homozygous for the M694 V mutation of the MEFV gene was having recurrent FMF attacks every 2 weeks despite being on colchicine.

Improvement in clinical and laboratory markers for 1 month. Drug was stopped because of local reactions at the site of the injections and pneumonia episode.

Kuijk et al. [46]

A 14-year-old FMF patient with mutated MEFV gene was unresponsive to colchicine therapy.

Clinical and laboratory markers improvement for a period of 9 months.

Calligaris et al. [44]

A 15-year-old was having recurrent FMF attacks despite high dose colchicine.

Interrupting Anakinra lead to a relapse. Re-introduction lead to a good quality of life for 15 months.

Mitroulis et al. [47]

A 34-year-old male FMF patient, homozygous for pyrin M694 V mutation, had signs colchicine resistance after several years of successful treatment.

The clinical benefits of anakinra pulses were observed in the following six-month period.

Roldan et al. [48]

A 9-year-old child heterozygote for E148Q mutation in the MEFV gene with inefficacy to colchicine treatment.

A favorable clinical and biochemical responses have persisted over 6 months with no side effects.

Moser et al. [49]

A 43-year-old male developed colchicine resistance after 13 years of diagnosis.

The symptoms and inflammatory markers settled after dose was adjusted because of a kidney transplantation. A good clinical outcome in a 20 months period.

Petropoulo et al. [50]

A 22-year-old male patient who underwent bone marrow transplantation for idiopathic aplastic anemia from his FMF-affected brother acquired the M694 V mutation.

The patient had recurrent FMF flares until 110 days after transplantation despite colchicine. Anakinra was started. In a 4-month follow-up, neither FMF crisis nor any side effect of anakinra treatment has been observed.

Ozen et al. [51]

Five children and an adult patient (3 female, 3 male) had recurrent FMF attacks despite regular regular colchicine.

The patients were given Anakinra or Etanercept. Etanercept was considered ineffective. Anakinra reduced the number of attacks and lowered the levels of acute-phase reactants for a 4-year period.

Alpay et al. [52]

A 52-year-old patient with FMF, secondary amyloidosis, and renal transplant was resistant to colchicine treatment.

Clinical and biochemical markers improved significantly in a 1-month period. The efficacy of anakinra persisted in the following 2-month period.

Bilginer et al. [53]

An 8-year old girl who had typical attacks of FMF (M694 V/M694 V) developed features of Behçet’s disease despite colchicine.

Complete remission of both diseases was observed. After 18 months of anakinra, proteinuria reappeared.

Hennig et al. [54]

A 35-year old male with FMF associated with serum amyloid A amyloidosis and chronic obstructive pulmonary disease developed pneumonia as a consequence of an FMF bout 1 week after stopping Anakinra.

Colchicine was suspended. On 4 consecutive days, the patient was treated with anakinra leading to immediate improvement of clinical symptoms, inflammation signs, and radiological findings.

Stojanovic et al. [55]

Four cases of patients with FMF-associated amyloidosis homozygous for the M694 V mutation were colchicine resistant.

Complete remission of attacks with improvement of biochemical markers for a follow-up period of at last 6 months.

Estublier et al. [56]

A 39-year-old man with FMF homozygous for the M694I mutation in the MEFV gene developed myositis of the right quadriceps muscle. He had frequent and severe arthralgias, despite colchicine, then etanercept and adalimumab, impairing his quality of life.

Anakinra therapy lead to dramatic improvement of muscular and articular symptoms. Patient remained stable for 10 months after the new therapy.

Soriano et al. [57]

A 63-year-old FMF male patient homozygous for M694 V mutation, affected by IgA nephropathy and type 2 diabetes mellitus with impaired renal function, developed colchicine resistance.

The 1-year follow-up confirmed patient’s good clinical conditions, with complete disappearance of FMF flares and stabilization of renal function. Re-appearance of mild myalgia after reducing anakinra to sub-optimal dose.

Celebi et al. [58]

46-year-old woman with FMF homozygote for M694 V mutation developed colchicine resistance after 26 years of usage.

At the eighth month of follow-up after anakinra initiation, the patient remained asymptomatic, and had good quality of life.

Mercan et al. [59]

A 41-year-old female patient with FMF heterozygous for M694 V mutation presented with severe calf and thigh pain. Her MRI revealed remarkable muscle edema in her calf muscles which was consistent with protracted febrile myalgia syndrome.

Patient was started on anakinra after refusing prednisone. Her complaints completely resolved after two doses of anakinra. Her ESR and CRP returned to normal levels within a week. No recurrence was observed in her 3-month follow-up.

Mercan et al. [59]

A 44-year-old female with FMF homozygous for M694 V mutation presented with severe right thigh pain. On the basis of her symptoms and findings she was diagnosed with PFMS. Her attacks were considered colchicine resistant.

She showed more than 50% improvement even after the first dose of anakinra and complete recovery after the second dose.

Sevillano et al. [60]

A 67-year-old patient with FMF and biopsy-proven amyloidosis presented with nephrotic syndrome despite colchicine treatment.

Anakinra was started and a dramatic complete remission of nephrotic syndrome was observed in the following months. Patient remained clinically and biochemically stable 42 months after treatment.

Ben-Zvi et al. [61]

25 patients with colchicine-resistant FMF were enrolled, of whom 12 were randomized to receive anakinra and 13 to receive placebo.

The mean number of attacks per patient per month was lower in those receiving anakinra. 6 patients in the anakinra group, compared to none in the placebo group, had < 1 attack per month. Patients on anakinra had a better quality of life. There were no severe adverse events over a 20-month period follow-up.

Pecher et al. [62]

13 patients with colchicine resistant FMF were enrolled.

5 patients reached complete remission, whereas the other 8 patients had a partial remission to anakinra. 1 patient quit anakinra intermittently owing to a lack of compliance. No serious adverse events was observed, except for one respiratory infection which required antibiotic treatment.

Ilgen et al. [63]

A 27-year-old female with heterozygous M680I/M694 V MEFV gene mutation had colchicine resistance after 13 years of use.

After 4 months of treatment with anakinra, she was attack-free and IVF was planned. She had a successful pregnancy. The infant at 13 months of age had normal anticipated development and was breastfed from the time of birth without any health problem. The mother was still on anakinra with no attacks after delivery.

Venhoff et al. [64]

Data from 3 patients with a total of 4 pregnancies under anakinra therapy were analyzed. All patients had a molecular genetic mutation in the MEFV gene. Due to treatment failure with colchicine therapy, anakinra was initiated.

In 3 pregnancies, Anakinra was continued throughout the pregnancy, and in 1 was only used in the second trimester of pregnancy for uncontrolled disease activity. The fetal development was inconspicuous in all pregnancies All children showed an inconspicuous early childhood development without evidence of an existing disease.

Laskari et al. [65]

14 patients (7 men) with genetically confirmed FMF, with median disease duration of 14 years and active disease despite colchicine (n = 9) or both colchicine and anakinra (n = 5), received Canakinumab 150 mg subcutaneously (sc) every 4 (n = 7) or 6 (n = 2) or 8 weeks (n = 5) for a median of 18 months.

11 out of 14 patients (79%) achieved complete clinical remission while normalization of all laboratory parameters associated with inflammation occurred in 92% of patients. The remaining patients achieved partial responses. Canakinumab was well tolerated; one patient experienced an urinary tract infection and another one a viral gastroenteritis. Follow-up period was 12 months.

Babaoglu et al. [66]

A total of 78 patients were treated with IL-1 inhibitors in the cohort. Among these, 15 patients were identified who received on-demand anakinra.

On-demand anakinra prevented progression of prodromes to full-blown attacks which was demonstrated by decrease in the rate of attack/prodrome ratio.