Background
Main text
Clinical picture and pathogenesis of FMF
Diagnosis
Management
Colchicine: diagnostic and therapeutic limitations
Anti Il-1 drugs
Study | Description | Follow-up |
---|---|---|
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. |
Study | Description | Follow-up |
---|---|---|
Mitroulis et al. [68] | A 25-year-old woman with FMF, homozygous for the MEFV gene mutation, and with longstanding articular involvement affecting her hips and left knee. She had been under treatment with colchicine since the age of 5. At the age of 19, she experienced long-lasting arthritis of her right hip and was treated with anakinra which was discontinued due to severe injection site reactions. She was switched to treatment with etanercept and low dose prednisone which induced a destructive arthritis of the right hip and chronic arthritis of her left knee. Methotrexate was added to the existing treatment. | Long-term remission was not achieved. The patient only responded to canakinumab. |
Hacihamdioglu et al. [69] | A 14-year-old girl homozygote for the M694 V mutation in the MEFV gene became colchicine resistant after 4 years of starting treatment. | The patient improved clinically and biochemically after canakinumab initiation until day 70 when she had a relapse. A second dose was administered again with full response. |
Brik et al. [70] | 7 participants received 3 subcutaneous injections of canakinumab. The primary outcome measure was the proportion of participants with ≥50% reduction in the frequency of FMF attacks during the treatment period versus the pretreatment period. Secondary outcome measures included acute-phase reactant levels, health-related quality of life, physician’s global assessment of FMF control, time to attack following the last canakinumab injection, and safety and tolerability of canakinumab. | 6 participants met the primary outcome measure with a ≥ 50% reduction (range 76–100%) in the rate of FMF attacks. 18 of 34 attacks (53%) were rated as severe or very severe during the pretreatment phase, compared with 0 of 8 during the treatment phase. There were no serious adverse events. |
Alpa et al. [71] | A 30-year old woman with FMF on colchicine for 6 years developed recurrent attacks. Increased colchicine dose was ineffective. | The effects of canakinumab were monitored over the following 6-month period. A significant improvement in the clinical symptoms was observed after the first administration. During treatment with canakinumab, the patient reported only three minor episodes of FMF. |
Gul et al. [72] | Patients who had an attack despite maximal dose of colchicine in the preceding 3 months were eligible for the study. At the first attack, patients started to receive three canakinumab 150 mg subcutaneous injections at 4-week intervals, and were then followed for an additional 2 months. | 13 patients were enrolled in the run-in period and 9 advanced to the treatment period. All 9 patients achieved a 50% or more reduction in attack frequency. C-reactive protein and serum amyloid A protein levels remained low throughout the treatment period. Only 5 patients had an attack during the 2-month follow-up. |
Sozeri et al. [73] | A 14-year-old male with colchicine-resistant FMF and amyloidosis homozygous for the M694 V mutation in MEFV gene. | Because of his poor response to colchicine, severe growth retardation, and severe proteinuria due to amyloidosis, canakinumab was started. After 26 months of follow-up, his complaints, inflammatory parameters, and proteinuria were decreased. No side effects were noted. |
Ozkan et al. [74] | This study was performed with 4 patients with colchicine-resistant FMF. None of the patients had proteinuria or amyloidosis. | First, anakinra was given to all the patients in addition to colchicine and showed a rapid and dramatic effect on attacks of FMF and inflammatory findings. There were no side effects, but daily anakinra injection therapy was changed to monthly injection of canakinumab because of easy implementation. |
Yaziltas et al. [75] | This study retrospectively evaluated 11 pediatric colchicine-resistant FMF patients who were treated with canakinumab. Three of the patients had amyloidosis and two had uveitis. | In all, three patients had FMF-associated amyloidosis, nephrotic syndrome, and CKD, of which 2 had clinical improvement with canakinumab and 1 had partial response. Among the patients, only 1 case died1 year after canakinumab cessation due to sepsis. 9 of our patients continued to receive canakinumab treatment. |
Jesenak et al. [76] | A 36-year-old man from central Europe presented with a very severe clinical FMF and intolerance to colchicine. The clinical effect of the application of anakinra was insufficient and accompanied with side effects and low tolerability. | Switching to canakinumab induced a rapid remission of the disease activity and inflammatory markers. |
De Benedetti et al. [77] | 63 colchicine-resistant FMF patients were tested for the effectiveness of canakinumab. Primary outcome was described as the resolution of the index flare by day 15 and no new episodes over 16 weeks of treatment. | The primary outcome was achieved by 61% of patients in the treatment group compared to 6% in the placebo arm. No opportunistic infections, tuberculosis, or death was observed but 3 serious infections were reported in two patients. |
Trabulus et al. [78] | A total of 9 kidney transplant recipients who developed AA amyloidosis due to FMF were enrolled. | All of the patients had rapid or gradual disappearance of FMF attacks. 1 patient developed a reaction to injection while another showed symptoms of Cytomegalovirus pneumonia. |
Study | Description | Follow-up |
---|---|---|
Hashkes et al. [89] | 8 males and 6 females were randomly assigned to one of 4 treatment sequences that each included two 3-month courses of rilonacept by weekly subcutaneous injection, and two 3-month courses of placebo. | During the treatment periods with rilonacept, patients had fewer attacks of FMF than with placebo, and more patients had a decrease to less than 50% of their previous baseline number. Patients also reported better physical aspects of quality of life with rilonacept. Patients had pain with the rilonacept injections more often than with placebo. |
Hashkes et al. [90] | 14 FMF patients with their parents completed the modified Child Health Questionnaire at baseline, and at the start and end of each of 4 treatment courses, 2 each with rilonacept and placebo. | There were significant improvements in most health-related quality of life concepts after rilonacept but not placebo. Significant differences between rilonacept and placebo were found in the physical but not psychosocial scores. |
Sakallioglu et al. [91] | A case of a 15 year-old boy with polyarthritis while on colchicine treatment for FMF. His polyarthritis was resistant to treatment with prednisolone and methotrexate when etanercept was started. | He responded dramatically to etanercept and remained in full remission until 4 months when the drug was discontinued due to social and financial causes. |
Anti TNF drugs
Study | Description | Follow-up |
---|---|---|
Aldea et al. [100] | 3 patients with fever, arthritis, abdominal attacks, and rash along with amyloidosis for 1 patient were treated with infliximab. | The attacks were discontinued or significantly improved. Patients were followed-up for 12 months except for the amyloidosis patient for 3 months. |
Metyas et al. [101] | A 30-year-old presented with recurrent fever, weight loss, intermittent bilateral knee pain and swelling, abdominal pain with intermittent vomiting, and chest pain. Amyloidosis was confirmed by Congo red stain and immunohistochemical stains. The patient was refractory to methotrexate treatment. | By the sixth dose of infliximab, the patient felt dramatically better. Arthritis, swelling, chest pain, and abdominal pain resolved. The patient was able to return to work after 2 years of disability secondary to arthritis. Laboratory markers of amyloidosis improved. |
Kaya et al. [102] | A 27-year-old male patient with FMF and Juvenile Idiopathic Arthritis (JIA) heterozygote for M694 V mutation presented for a relapse of his rheumatological diseases. He was started on menthotrexate and colchicine with steroid on board. Leflunomide was added later due to partial response to methotrexate. | At the 7th month of MTX and leflunomide treatment, Etanercept was started as joint inflammation did not subside despite methotrexate and leflunomide. His FMF attacks were improved; he had only one attack of abdominal pain after the onset of etanercept treatment. Follow-up period was 2 months. |
Ozgocmen et al. [103] | A 35-year-old woman with FMF resistant to colchicine failed a combination of colchicine, sulfasalazine, and methotrexate. Infliximab was added to the treatment regimen. | A 72-week follow-up of the patient yielded complete remission of the febrile abdominal episodes and spondylitis. The patient’s bilateral aseptic necrosis of the femoral head deteriorated and caused hip pain, discomfort, and disability. |
Daysal et al. [104] | A 21-year-old female homozygote for M694 V mutation presented for severe hip arthritis and elevated inflammatory markers which didn’t improve with colchicine, steroid, hydroxychloroquine and methotrexate. | Infliximab was given intravenously. She had a prompt response. In 4–5 days, she was able to ambulate independently. Two weeks later her ESR and CRP were negative, and steroid therapy was discontinued. Follow-up period was 2 months. |
Mor et al. [105] | A 35-year-old man presented for episodes of articular pain, episodic testicular pain, recurrent oral ulcers, episodic abdominal pain, and episodic fever. He had elevated inflammatory markers. A single V726A mutation in the MEFV gene was identified. | Colchicine was discontinued because of diarrhea. The patient was started on etanercept 25 mg twice a week, which immediately reduced the frequency, duration, and severity of the joint attacks for 3 years. |
Nakamura et al. [106] | A Japanese patient with FMF has a heterozygous mutations in the MEFV gene. Conventional treatment, such as colchicine and reserpine, failed to sufficiently control the FMF attacks. | After starting infliximab and low-dose methotrexate, the frequency of the FMF attacks dramatically decreased and the clinical effect has remained unchanged for longer than 1 year. |
Ozgocmen et al. [99] | The patients were a 37-year-old man with concomitant Crohn’s disease and amyloidosis who was treated with infliximab and switched to adalimumab, and two female patients (a 24-year-old and a 31-year-old) with FMF who developed severe spondylitis. | Adalimumab controlled FMF attacks quit effectively. |
Bilgen et al. [107] | The data for 10 FMF patients (5 male and 5 female patients) with chronic arthritis and/or sacroiliitis who were on anti-TNF agents. Frequency of FMF attacks before and after treatment with anti-TNF agents was recorded. The effects of the anti-TNF treatment were determined by using the number of tender and/or swollen joints, serum acute phase reactant levels, and Bath Ankylosing Spondylitis Disease Activity Index scores. Change in urine protein loss was also evaluated in patients with amyloidosis. | After anti-TNF treatment, in 3 patients, FMF attack frequency decreased, and in the remaining 7 patients, no attack occurred. Serum acute phase reactant levels were decreased significantly at 3 and 6 months after anti-TNF treatment. After anti-TNF treatment Bath Ankylosing Spondylitis Disease Activity Index scores were also decreased significantly. In all 3 patients with amyloidosis, urine protein loss decreased without any increase in serum creatinine levels. |
Erten et al. [108] | A 35-year-old male patient presented with fever, abdominal pain, malaise, and low back and ankle pain. He was on colchicine and sulfasalazine for FMF with homozygous M694 V mutation. Infliximab treatment was discontinued due to allergic symptoms. | The patient responded well to etanercept. Febrile abdominal attacks and joint symptoms did not recur. Urinary proteinuria and acute phase proteins returned to normal limits. He remained in an excellent condition for 4 years of follow-up. |
Kosmidou et al. [109] | A 33-year-old male patient heterozygote for M694 V mutation had been diagnosed with FMF since his adolescence. He presented for atypical abdominal pain to be diagnosed with Crohn’s disease. Steroid and azathioprine were started. 2 months after the initiation of immunosuppressive treatment, there was still no favorable response on his bowel inflammation. | In a 6-month extensive follow-up after starting infliximab, both diseases were found to be inactive. |
Anti IL6 drugs
Study | Description | Follow-up |
---|---|---|
Fujikawa et al. [110] | A 19-year-old female presented with fever, a sore throat, polyarthralgia, and fever-associated skin rashes lasting a couple of days. Inflammatory markers were elevated. Patient was heterozygote for MEFV gene mutation. Steroid and methotrexate didn’t improve the patient’s symptoms. | TCZ treatment was combined with the steroid and methotrexate therapy. The patient’s symptoms, including skin rash, disappeared promptly, so steroid and methotrexate treatment were tapered and then stopped. TCZ was then stopped. Patient remained symptom free for 4 months when he had a relapse managed by colchicine. |
Yilmaz et al. [113] | 11 patients who had AA amyloidosis secondary to FMF with renal involvement and were treated with TCZ. Before TCZ therapy, all the patients had been using colchicine and an angiotensin receptor blocker or angiotensin converting enzyme inhibitor for at least 3 months without significant response. | Among the 11 patients, 10 patients did not experience any attack during the course of treatment, and no major adverse events were observed. Even though 8 patients had the decreased level of the proteinuria after treatment, there was no case confirmed the reduction of deposition of amyloid in any organ. |
Hamanoue et al. [111] | A 51-year-old Japanese man with suspected FMF had periodic fever with abdominal pain, polyarthritis, and nephropathy. FMF was diagnosed by mutation analysis of the MEFV gene. AA amyloidosis was diagnosed by renal and gastric biopsy. Colchicine was administered, but his arthritis persisted, and serum creatinine increased. | Tocilizumab was administered on a monthly basis. Both arthritis and abdominal pain subsided rapidly, and CRP decreased. After 2 years, his serum creatinine was decreased and proteinuria was improved. Repeat gastric biopsy showed a marked decrease of AA amyloidosis. |
Umeda et al. [112] | A 64-year-old Japanese woman had been treated with prednisolone for 7 years for undiagnosed recurrent fever and myalgia. She had elevated liver enzymes and inflammatory markers. A muscle biopsy of left quadriceps revealed the infiltration of neutrophils into the fascia as well as vascular endothelium of fascia. She was hetrozygote for the MEFV gene mutation. Patient was stable on colchicine for 5 months when she had a relapse. | Since the initiation of this TCZ treatment, the FMF attacks of fever and myalgia have been completely inhibited for 9 months. |
Nikiphorou et al. [114] | A 20-year-old man with a history of chronic recurrent multifocal osteomyelitis, aseptic multiphasic disseminating encephalomyelitis, and a single mutation in the MEFV gene. Despite corticosteroids, adalimumab, colchicine, mycophenolate, and hydroxyxhloroquine normocytic anaemia and high acute phase response persisted. | A trial of anakinra resulted in only partial clinical response, leading to tocilizumab as the next treatment choice. This resulted in rapid clinical and biochemical improvement. After 5 years with ongoing tocilizumab and colchicine he remained well, with normal CRP and amyloid levels. |
Nikiphorou et al. [114] | An 18-year-old man had multiple admissions for meningoencephalitis, pyrexia, and anemia. Genetic testing revealed heterozygosity for the MEFV gene. | Sirolimus was unsuccessful in controlling symptoms, leading to a trial of tocilizumab which resulted in suppression of CRP and amyloid to normal levels and enabled steroid withdrawal. |
Aikawa et al. [115] | A 53-year-old man with recurrent episodes of large joint pain and a low-grade fever at irregular intervals for 16 years developed right knee and ankle arthralgia, watery diarrhea, and abdominal pain. Following an ileum and colon biopsy, he was diagnosed with gastrointestinal amyloidosis. FMF was suspected, and colchicine was administered colchicine; his symptoms subsequently improved. The patient had atypical FMF. Colchicine was stopped because of alopecia. | Remission was maintained by tocilizumab therapy. In addition, the amyloid deposition in the ileum and colon disappeared. |