Familial Mediterranean fever EULAR guidelines, case based, Ahmed Yehia, MD internal medicine, clinical immunology, Beni-Suef university Interactive cases stepwise approach

1. Abdominal Pain!!
Is This Familial
Mediterranean
fever?
Ahmed Yehia, MD
Internal medicine,
immunology
(Allergy and
rheumatology)

2. Doctor, I have
severe abdominal
pain
In the ER

3. Migration of pain
Anorexia & nausea
• Right lower quadrant tenderness
Rebound tenderness
Temp: 39 c
Acute abdomen

4. MANTRELS

5. Appendicectomy

6. Cholecystectomy
2 months later, he
developed acute
abdomen with pain more
in the right
hypochondrial area.

7. This patient had recurrent abdominal pain.

8. His family physician suspected FMF
based on its cardinal feature
•The paroxysm.

9. Ideally, FMF should be diagnosed & initially treated
by a physician with experience in FMF; after
diagnosis & initiation of therapy, patients can also be
followed by their primary care physician in
conjunction with the referral center, but, if possible,
patients should be seen by a physician with
experience of FMF at least once per year in the long
term.

10. “ ‫المستشار‬
‫مؤتمن‬ ”

12. • Abdominal pain & tenderness may initially be
localized then progress to become more
generalized.
• Since the cause of the abdominal pain is
inflammation of the peritoneum, signs of
peritonitis such as guarding, rebound tenderness,
rigidity, & adynamic ileus are often present.
• These findings can be mistaken for an acute
surgical abdomen leading to diagnosis delay &
sometimes even to futile operations.
Localised?!!

13. • Acute attacks of FMF are accompanied
by elevation of serum markers of
systemic inflammation. Common
laboratory findings include
leukocytosis with a predominance of
neutrophils as well as elevated acute
phase reactants such as the erythrocyte
sedimentation rate (ESR), C-reactive
protein (CRP), serum amyloid A (SAA)
protein, and fibrinogen.
To complicate more

14. Your text here
How old
are you? 24 years
old

15. FMF is a disease of pediatric onset. Could this
be FMF?
The initial attack
occurs at the ages of
< 10 years
in 65%
< 20 years
In 90%
> 50 years
in rare
cases

16. He requested the MEFV
gene mutation by PCR.
• It came back negative.
• So, this patient…..
certainly, doesn’t have FMF.
Still may have FMF.

17. He requested the MEFV
gene mutation by PCR.
• It came back negative.
• So, this patient…..
certainly, doesn’t have FMF.
Still may have
FMF.

18. An expert
committee of
European
pediatric
rheumatologist
s'
recommendatio
ns for genetic
diagnosis of
FMF
• FMF is a clinical diagnosis; it can be
supported but not excluded by genetic
testing.
• FMF patients carrying two of the
common mutated alleles (homozygotes
or compound heterozygotes), especially
for M694V mutation or mutations at
position 680 to 694 on exon 10, must be
considered at risk of having a more
severe disease.

19. ??????
My sister is homozygous
for M694V mutation, but she has
no symptoms.

20. An expert
committee of
European
pediatric
rheumatologist
s'
recommendatio
ns for genetic
diagnosis of
FMF
• Patients homozygous for M694V mutation are
at risk for early-onset disease and at very high
risk of developing a severe phenotype; those
who are not reporting symptoms should be
evaluated and followed closely in order to
consider therapy.
• Patients with two pathogenic mutations for FMF
who do not report symptoms but have risk
factors for AA amyloidosis (eg, country of origin;
family history; persistently elevated
inflammatory markers, particularly serum
amyloid A protein), should have close follow-up
and be considered for treatment.
• The E148Q variant is common and of unknown
pathogenic significance; its presence as the
only MEFV variant does not support the
diagnosis of FMF.

21. 3 scenarios
Clinical Genetic Diagnosis Action
Compatible Compatible
Highly
suspicious
Negative
Negative Typical

22. 3 scenarios
Clinical Genetic Diagnosis Action
Compatible Compatible Typical FMF Treat with
colchicine
Highly
suspicious
Negative Suspicious Colchicine
trial
Negative Typical Not FMF Follow up
closely

23. Tel-Hashomer
diagnosis
criteria

25. Diagnose FMF by 2 out of 5

26. New Eurofever/PRINTO classification criteria
for FMF
1. Duration of episodes 1–3 days.
2. Arthritis.
3. Chest pain.
4. Abdominal pain
Confirmatory MEFV genotype
and at least one criterion
Non-Confirmatory MEFV
genotype
and at least two criteria

27. You fulfill the
criteria for FMF
Should I start the treatment
now or wait for the next
attack?

28. Treatment with
colchicine should be
started as soon as a
clinical diagnosis is
made.

29. • It is recommended in all patients
regardless of the frequency and
intensity of attacks. Use of
intermittent high-dose colchicine only
for treatment of acute attacks of FMF
is not recommended since it does not
protect from the development of
amyloidosis resulting from low-grade
inflammation that can occur during
asymptomatic intervals

30. What is the treatment and
dose?
Colchicine 0,5 mg tab.
twice daily

31. We recommend the following
starting dose of colchicine
For children <5 years of age, ≤0.5 mg/day (≤0.6 mg/day in case tablets contain 0.6 mg).
For children 5 to 10 years of age, 0.5 to 1 mg/day (0.6 to 1.2 mg/day in case tablets contain0.6
mg).
For children >10 years of age and adults, 1 to 1.5 mg/day (1.2 to 1.8 mg/day in case
tabletscontain 0.6 mg).
With preexisting complications (eg, renal amyloidosis) or greater disease activity(ie, high attack
frequency, long duration of each attack, multiple sites during the attack &joint affection), higher
initial doses (up to 2 mg/day), provided that kidney & liver function are normal

32. Can I take the 2 tablets
once as I fear to miss the
2nd dose?
No problem.

33. Colchicine can be given
in single or divided
doses, depending on
tolerance and
compliance.

34. • Adherence with colchicine is
higher with once-daily dosing,
and its efficacy is the same as
with splitting the dose into two
divided daily doses.

35. For how log should
I be treated?
Indefinitely but…

36. •If a patient is stable, with no attacks
for > 5 years & no elevation in acute
phase reactants (eg, serum amyloid
A protein, C-reactive protein), dose
reduction could be considered after
expert consultation and with
continued monitoring.

37. Do I need follow
up?
Yes. Waiting for you.

38. Dr. I have developed
diarrhea. Should I stop
colchicine?
No. Split the dose.

39. • Adherence with colchicine is higher with once-
daily dosing, and its efficacy is the same as with
splitting the dose into two divided daily doses.
• We do not split the colchicine dose unless the
patient does not tolerate once-daily dosing due
to side effects, which are most commonly
gastrointestinal.

40. Doctor, I have
severe abdominal
pain

41. What to do
further?
Are you compliant
with colchicine?

42. Yes. No single
dose is missed.
We’ll increase
colchicine dose.

43. • We generally start with a lower dose and
increase the dose by 0.5 to 0.6 mg
according to the patient’s response &
tolerance
• The maximum recommended daily dose of
colchicine
• 2 mg for children < 12 years
• 3 mg for adults.

44. Do I need to increase
colchicine dose during
the attack?
No

45. • Administering colchicine only during an acute
FMF attack or increasing its dose during the
acute attack usually has no impact on the
attack symptoms. In addition, high-dose
colchicine is associated with significant side
effects. We do not administer colchicine
intravenously because of the risk of serious
adverse effects.

46. •If an attack is suspected, always
consider other possible causes;
during attacks, continue the usual
dose of colchicine and use
nonsteroidal anti inflammatory drugs
(NSAIDs).

47. What investigations
needed for follow up?
????

48. Response, toxicity & compliance
should be monitored every 6 months.
Liver enzymes should be monitored
regularly in patients with FMF treated
with colchicine.

49. • After initiation of colchicine, patients should be followed
closely for 3:6 months to observe its therapeutic effect on
attack frequency and severity.
1. Laboratory testing for colchicine toxicity includes a CBC to
assess for leukopenia.
2. For monitoring disease response, we check ESR, CRP, &,
when available, serum amyloid A (SAA).
3. Urine for proteinuria, which may be the first sign of renal
amyloidosis.
4. Liver & kidney functions annually to ensure that no
modification of the colchicine dose is required.

50. Dr. ALT is 55 (N. up to: 40)
??????

51. If elevations greater than twofold the
upper limit of normal occur, the
colchicine dose should be reduced,
and the cause further investigated.

52. Now. I have 1 attack
only/month. What about
colchicine dose?
Increase by 1 tab.

53. •The ultimate goal of treatment in
FMF is to obtain complete control
of unprovoked attacks.

54. Now. I have no attacks. Can I
stop colchicine?
No

55. •The ultimate goal of treatment in
FMF is to obtain complete control
of unprovoked attacks and
minimize subclinical inflammation
between attacks.

56. Persistent attacks or subclinical
inflammation represent an
indication to increase the
colchicine dose.

57. Dr. I have severe abdominal
pain when I play football.
??????

58. •Periods of physical or
emotional stress can trigger
FMF attacks, and it may be
worth temporarily increasing
the dose of colchicine.

59. Now. I have again 1 attack
only/month. I am on
colchicine 3 mg daily.
Maximal dose?!

60. •Compliant patients who continue to
have 1 or more attacks each month
despite receiving the maximally
tolerated dose of colchicine for at least
6 months can be considered
nonresponders or resistant.

61. •Biological treatments are indicated in these
patients; colchicine should be
coadministered with biological therapies, as
it may reduce the risk of amyloidosis despite
persistence of attacks.

63. Urine: albumin++
Do urine protein
creatinine ratio

64. UPCR: 3000 mg/gm
Treatment
modification?
Renal biopsy?

65. •FMF treatment needs to be
intensified in AA amyloidosis,
using the maximal tolerated dose
of colchicine and supplemented
with biologics as required.

66. Renal biopsy?

67. FMF presenting with
nephrotic syndrome

69. ??????
My sister is now diagnosed with
FMF on colchicine. Can she get
pregnant?

70. •Colchicine should not be
discontinued during conception,
pregnancy, or lactation; current
evidence does not justify
amniocentesis.

71. •Men need not stop colchicine
prior to conception; in the rare
case of azoospermia or
oligospermia proven to be related
to colchicine, temporary dose
reduction or discontinuation may
be required.

72. ‫خيرا‬ ‫هللا‬ ‫جزاكم‬
.
‫هلل‬ ‫الحمد‬

73. ‫خيرا‬ ‫هللا‬ ‫جزاكم‬