Table 5 Summary of recommendations of FMF management

General considerations

- Start treatment of FMF at the time of clinical diagnosis, without waiting for genetic testing, except if the attacks are not severe or frequent, a period of 3-month observation is recommended to confirm the pattern of the attacks before starting treatment.

- Treatment with colchicine should be started as soon as possible as the first line of treatment

1

A

8.8 ± 0.51

100%

H

Colchicine therapy considerations

- Colchicine is very efficacious in preventing FMF attacks and associated amyloidosis.

- The treatment with colchicine is usually lifelong, and a trial to reduce the dose may be attempted after five years of complete clinical and subclinical remission.

1

A

8.8 ± 0.51

100%

H

- Colchicine should not be discontinued before conception, during pregnancy or lactation; also, men do not need to stop colchicine before conception except if conception delayed as its effect on sperm count is still a controversy.

3

C

8.8 ± 0.51

100%

H

- Dose of colchicine:

a) A dose of 0.05 mg/kg/day can be used (maximum 2 mg/day). Start gradually and use the least dose to control disease. Single dose is better for compliance.

b) Starting dose of ≤ 0.5 mg/day for children < 5 years of age

c) 0.5–1.0 mg/day for children 5–10 years of age

d) 1.0–1.5 mg/day in children > 10 years of age

e) Start with a low dose and increase the dose according to:

a. The patient’s response

b. Tolerance

f) Patients with amyloidosis or very high disease activity may start with higher doses.

g) The maximum dose in children 2 mg/day

- Dosing can be in single or divided doses, depending on:

• Tolerance (divide if diarrhea or related abdominal pain)

• Patient compliance

3

C

8.61±0.86

95.2%

H

- Colchicine side effects:

• The most common side effects of the treatment are diarrhea and vomiting. These side effects are dose-dependent and more common at higher doses. Other uncommon side effects are myelosuppression, myopathy, neuropathy, hepatotoxicity, nephrotoxicity, and hypersensitivity reaction

• If liver enzymes are elevated more than twofold the upper limit of normal, colchicine should be reduced and the cause of elevation should be further investigated.

3

C

8.71 ± 0.46

100%

H

- Colchicine tolerance and compliance:

a) There is a high rate of poor compliance with colchicine therapy among patients.

Reason includes concerns about:

I. Lifelong use of the drug

II. Adverse effects such as bloating and diarrhea

III. Fertility

IV. Embarrassment and laziness

b) Lack of compliance should be considered in all patients with FMF in with colchicine ineffectiveness.

c) Lactose intolerance and diarrhea have been reported and may affect compliance; in these patients, we may try:

I. Temporary reduction of dairy products

II. Split doses

III. Dose reduction

IV. Anti-diarrheal and spasmolytic

V. Once resolved return to regular dose in a gradual stepwise fashion

d) Increasing compliance and decreasing side effects may be through:

I. Dietary modification (i.e., temporary reduction of dairy products)

II. Increase the dose in a gradual stepwise fashion

III. Gastric prokinetics substances and spasmolytic agents

IV. Patient education (particularly for teenagers)

4

C

8.33±0.79

100%

H

- Colchicine resistance and failure

• Ensure:

a. Optimum patient compliance and adherence to therapy

b. The dose has been increased up to a maximum tolerated dose of colchicine (up to 2mg in children up to 3mg in adults)

• Compliant patients not responding to the maximum tolerated dose of colchicine for more than 6 months can be considered non-respondent or resistant (7)

• Those non-responders or resistant patients; additional biological treatments are indicated (after confirming compliance)

2

B

8.61±0.6

95.2%

H

- Dose reduction after remission:

• If a patient is in complete remission with no attacks for more than 5 years and no elevated APR especially serum amyloid A, gradual dose reduction could be considered after expert consultation with strict continued monitoring to avoid subclinical amyloidosis.

• Dose reduction after remission is considered extremely rare and appropriate only in a small minority of patients

5

D

8.29 ± 1.87

90.5%

H

Anti-interleukin 1 (IL-1) therapy: Anakinra and Canakinumab.

- IL-1 inhibitors are considered the second line of treatment of FMF in patients who showed intolerance to colchicine or have colchicine-resistant FMF.

• Dose: Anakinra: - children ≥2 years and adolescents: subcutaneous: 1 to 2 mg/kg/dose once daily. Canakinumab: 2 mg/kg SC q2-4wk; may increase to 4 mg/kg q4wk if the clinical response is not adequate. >40 kg: 150 mg SC q4wk.

• Duration: continuous therapy in addition to colchicine

• Il-1 inhibitors can be used as bridging therapy for 1–3 months in addition to colchicine then continue colchicine monotherapy.

2

C

8.57±0.81

95.2%

H

Tumor necrosis factor (TNF)-alpha inhibitors and IL-6 inhibitor (tocilizumab):

- They have been used with promising results in some cases, but the real efficacy is still not established.

5

D

8.28 ± 1.14

90.5%

H

Management of acute attacks

- When suspecting an attack, always consider other possible causes.

- During the attacks:

a) Continue the usual dose of colchicine and use NSAID

b) In protracted febrile myalgia, low dose steroids lead to the resolution of symptoms; NSAID and IL-1-blockade might also be a treatment option.

c) NSAIDs are suggested for the treatment of leg pain

d) Chronic arthritis in a patient with FMF might need additional medications, such as DMARDS (e.g., methotrexate), intra-articular steroid injections or biologics (anti-TNF) without preference of specific type of anti-TNF than another.

4

C

8.61 ± 0.67

100%

H

Monitoring of therapy

a) At the onset of treatment, follow up patients for 3–6 months to monitor its therapeutic effect on attack frequency and severity (clinical diary and APR)

b) In controlled compliant patients, follow-up frequency may be up to 1 year.

c) Identifying possible trigger may help in preventing possible attacks through temporarily increasing the colchicine dose.

d) The persistence of attacks and/or of subclinical inflammation represents an indication to increase the colchicine dose

e) Monitoring for possible colchicine toxicity especially with possibility of:

• Drug interactions (as with cyclosporine and CYP3A4 inhibitors)

• Consumption of grapefruit or grapefruit juice

f) CBC with differential, liver enzymes (elevated greater than twofold the upper limit reduce colchicine AND investigate the cause), CRP, urine analysis, kidney functions, and serum amyloid are investigations needed in follow-up visits every 3 months

3

C

8.71±0.56

100%

H

A. Amyloidosis complicating FMF

a. Prevention

• By good control of FMF and maintaining normal SAA protein concentration between attacks

b. Treatment

• Colchicine is still the corner stone which can stabilize or even improve proteinuria in FMF-associated amyloidosis

• IL-1 inhibitors could be used

• End-stage renal disease should be treated the same way as other causes of renal failure, including transplantation. After renal transplantation, tight control of inflammation should be continued

4

C

8.61 ± 0.8

95.2%

H