PFAPA Syndrome and Related Diseases Treatment

PFAPA syndrome and its related
diseases

Prof Ariyanto Harsono MD PhD
SpA(K)

Introduction
The recently described PFAPA (Periodic Fever,
Aphthous stomatitis, Pharyngitis and Adenitis)
syndrome is characterised by periodic fever,
aphthous stomatitis, pharyngitis and adenitis .
However, there are currently relatively few
data on the natural history of this syndrome.
Keywords: PFAPA, reccurent episodic fever, IL1, Hyper IgD
syndrome, periodic fever syndrome, auto inflammatory syndrome
Prof Ariyanto Harsono MD PhD SpA(K)

2

Etiology
PFAPA is frequently discussed together with other
periodic fever syndromes, but it is unknown
whether the cause is primarily genetic or due to
an initial infection.
According to recent information that has been
gathered, there has been some genetic links that
are possible.
.


3

The condition is a disturbance of innate immunity. The changes
in the immune system include increased expression of
complement related genes (C1QB, C2, SERPING1), interleulkin1-related genes (interleukin-1B, interleukin 1 RN, CASP1,
interleukin 18 RAP) and interferon induced (AIM2, IP10/CXCL10) genes. T cell associated genes (CD3, CD8B) are
down regulated. Flares are accompanied by increased serum
levels of activated T lymphocyte chemokines (IP-10/CXCL10,
MIG/CXCL9), G-CSF and pro-inflammatory cytokines
(interleukin 6, interleukin 18). Flares also manifest with a
relative lymphopenia. Activated CD4(+)/CD25(+) T-lymphocyte
counts correlated negatively with serum concentrations of IP10/CXCL10, whereas CD4(+)/HLA-DR(+) T lymphocyte counts
correlated positively with serum concentrations of the counterregulatory IL-1 receptor antagonist. Fever is considered related
to inflammatory effect of IL1

4

Symptoms
This syndrome includes:
 recurrent episodes of fever with
 aphthous stomatitis (mouth sores) and pharyngitis (sore
throat with redness) (Figure 1a).
 Occasionally, there also may be exudate white patches on
the tonsils (Figure 1b)
 usually the lymph nodes in the neck are enlarged
(adenitis)(Figure 1c).
 Some children have other symptoms like joint pain,
abdominal pain, rash (Figure 1d), headache, vomiting or
diarrhea. Children are completely well between episodes.
Episodes of fever start suddenly and last for 3-7 days. Fevers
occur routinely every few weeks; often, families know the
exact day when an episode will start.

5

The disease may last for several years but usually
will resolve by itself in the second decade of life.
However, in nearly 15 percent of patients
episodes (although less frequent) may continue
to occur during adulthood. Over time, the time
between the episodes will increase. Children with
PFAPA continue to grow and develop normally.


6

Figure 1a. This syndrome includes recurrent episodes of fever
with aphthous stomatitis (mouth sores) and pharyngitis (sore
throat with redness)

7

Figure 1b. there also may be exudate (white
patches on the tonsils)


8

Figure 1c. Cervical adenitis


9

Figure 1d. Rash


10

The key symptoms of PFAPA are those in its
name: periodic high fever at intervals of about
3–5 weeks, as well as aphthous ulcers,
pharyngitis and/or adenitis. In between
episodes, and even during the episodes, the
children appear healthy. At least 6 months of
episodes.


11

Diagnosis
There are no laboratory tests specific for diagnosing
PFAPA. The disease is diagnosed based on symptoms
and physical examination. White blood cell counts,
sedimentation rate and the C-reactive protein, all of
which can be measured with a blood test, increase
during attacks. It is important to exclude all other
diseases that may present with similar symptoms
(especially a Streptococcus infection) before confirming
the diagnosis. The dramatic response to treatment also
helps diagnose PFAPA. In cases without a classic
presentation it may be necessary to exclude other
causes of recurrent fever (see other patient sheets on
this topic).

12

Raised IgD levels may represent a non-specific
epiphenomenon, which frequently accompanies
PFAPA syndrome as well as MKD. Because of the
overlapping clinical and laboratory features,
genetic testing of the MVK gene is indicated to
differentiate these two conditions, if clinical
criteria for both are fulfilled. Diagnosis requires
recurrent negative throat cultures and that
other causes (such as EBV, CMV, FMF) be
excluded

13

The PFAPA syndrome may resemble other periodic fevers, such
as familial Mediterranean fever, hyper IgD syndrome, and the
autosomal dominant familial fevers. Because PFAPA
syndrome is a diagnosis of exclusion, cardinal signs and symptoms
must be carefully observed for a differential diagnosis, such as:
 onset in early childhood, before the age of 5 years (male
predominance has been described);
 periodic abrupt onset of febrile episodes that last 4–5 days and
occur every 4–6 weeks on average;
 episodes that are often accompanied by intra-oral ulcers,
pharyngitis, and cervical lymph node enlargement.


14

Treatment
The aim of the treatment will be:
 to control symptoms during the episodes of fever,
 to shorten the duration of the episodes,
 to prevent next episodes from occurring.
The fever usually does not respond well to
acetaminophen or nonsteroidal anti-inflammatory
drugs like ibuprofen. A single dose of steroids (usually
prednisone), given when the symptoms first start, has
been shown to shorten—and often even end—the
episode. However, the time between episodes also
may be shortened with this treatment, and the next
episode may occur earlier than expected.

15

Medications like cimetidine and colchicine, when
used regularly, may prevent future episodes in
about a third of the children. Several studies have
found that a tonsillectomy (removing the tonsils
by surgery) cures PFAPA in the majority of patients
(more than 80%) but the role and timing of
surgery in treating PFAPA has still not been fully
clarified.


16

A possible treatment for PFAPA is a single dose of
prednisone(1–2 mg per kg body mass) at the beginning of
each fever episode. A single dose usually terminates the
fever within several hours. However, in some children,
prednisone causes the fever episodes to occur more
frequently (and more regularly). Parents might then want
to consider colchicine, which is used in the treatment of
FMF. In several studies, adeno tonsilectomy was found to
completely resolve symptoms. Yet other studies had
differing results, most being positive. Parents of children
with PFAPA regularly report improvements after the
children have had surgical treatment. Some children stop
having episodes, others have a break in the cycle for a few
months and then it comes back but the episodes are less
intense. Interleukin-1 inhibition appears to be effective in
treating this condition.

17

Figure 2. Meta analysis of Medical therapies

18

The use of antibiotics in PFAPA syndrome is
ineffective (P < 0.00001; OR, 0.01; 95% CI, 0.00–
0.01). The use of cimetidine [4,14,16,17,19,22] is
also ineffective (P = 0.02; OR, 0.15; 95% CI, 0.03–
0.75). There is evidence that the use of steroids is
effective in the resolution of symptoms (P <
0.00001; OR, 43.82; 95% CI, 10.68–179.69).


19

Figure 3.
Meta-analysis of surgical therapy for the resolution of PFAPA
syndrome (


20

Tonsillectomy (+/ adenoidectomy) as a treatment of
PFAPA was reported in fourteen studies. It was
found to be an effective intervention for resolution
of symptoms. (P < 0.00001; OR, 27.26; 95% CI, 6.70–
110.91).


21

Figure 4. Meta-analysis of surgical (tonsillectomy, +/ adenoidectomy)
versus medical therapies

22

Meta-analysis of surgery versus cimetidine, and
surgery versus antibiotics, demonstrated that surgery
is a significantly more effective treatment for PFAPA
syndrome (P = 0.0003; OR, 11.89; 95% CI, 2.36–
60.02) and (P < 0.00001; OR, 106.49; 95% CI, 30.28–
374.44), respectively. A comparison of treatment
with steroids or surgery did not show any statistically
significant difference, confirming the effectiveness of
both therapies for the resolution of PFAPA syndrome
(P = 0.83;OR, 0.90; 95% CI, 0.36–2.26).

23

The most effective non-surgical therapy is
corticosteroids. However, they do not prevent
future fever cycles. The results of this meta-analysis
showed that tonsillectomy (+/ adenoidectomy) is the
most effective intervention for long-term resolution
of PFAPA syndrome symptoms.


24

During PFAPA flare-ups, the researchers detected
decreased numbers of activated T cells, white blood
cells that play a role in the cell's innate immune
response. They suspect that these activated T cells
migrated to the lymph nodes in the neck, where they
accumulate. They also detected over-expression of
genes activated in innate immune responses,
including interleukin-1, a molecule that is important
in triggering fever and inflammation.
It is hypothesized that anakinra, a drug that prevents
interleukin-1 from binding to its receptor, could be
therapeutic. They administered anakinra by injection
to five children on the second day of their PFAPA
fevers and all showed a reduction in fever and
inflammatory symptoms within hours.

25

Prognosis
According to present research, PFAPA does not
lead to other diseases and spontaneously
resolves as the child gets older, with no long
term physical effects. However, PFAPA has
been found in adults and may not
spontaneously resolve.


26

Hyper IgD Syndrome

SpA(K)

Introduction
 PFAPA Syndrome is to be related with
Hyperimmunoglobulinaemia D because the
similarity of periodic fever, is more commonly
known as hyper-IgD syndrome or HIDS. It is a rare
inherited auto inflammatory syndrome that
presents with recurrent episodes of fever, skin
rash, abdominal pain, headaches and enlarged
lymph glands that begin in infancy.
 Mevalonic aciduria is a severe variant of HIDS.

28

 Hyper-IgD syndrome is a rare autosomal recessive disorder
in which recurring attacks of chills and fever begin during
the first year of life. Episodes usually last 4 to 6 days and
may be triggered by physiologic stress, such as vaccination
or minor trauma.
 Hyper-IgD syndrome clusters in children of Dutch, French,
and other Northern European ancestry and is caused by
mutations in the gene coding mevalonate kinase, an
enzyme important for cholesterol synthesis. Reduction in
the synthesis of anti-inflammatory isoprenylated proteins
may account for the clinical syndrome.
Keywords: higds, mevalonate kinase, IL1, inborn error of
metebolism, recurrent fever

29

Etiology
Virtually all patients with the syndrome have
mutations in the gene for mevalonate kinase,
which is part of the HMG-CoA reductase
pathway, an important cellular metabolic
pathway. Indeed, similar fever attacks (but
normal IgD) have been described in patients
with mevalonic aciduria - an inborn error of
metabolism now seen as a severe form of
HIDS.

30

Pathophisiology
 The hyper-IgD syndrome is caused by mutations in the
gene encoding mevalonate kinase (MVK)
 In addition to HMG-CoA reductase, mevalonate kinase
is involved in the biosynthesis of cholesterol and
isoprenoids, and catalyses the conversion of
mevalonate to 5-phospho mevalonic acid in the
mevalonate metabolism. The enzyme mevalonate
kinase is involved in the isoprenoid pathway of
cholesterol biosynthesis. The enzyme deficiency results
accumulation of mevalonic acid and increased
interleukin 1. The mechanism of mevalonate kinase
deficiency to cause hyper IgD is not kown.
31

It is not known how mevalonate kinase mutations
cause the febrile episodes, although it is
presumed that other products of the cholesterol
biosynthesis pathyway, the prenylation chains
(geranylgeraniol and farnesol) might play a role.


32

Immunoglobulins are proteins produced by certain
white blood cells. There are five classes of
immunoglobulins known as IgA, IgD, IgE, IgG, and
IgM. Immunoglobulins play a role in defending the
body against foreign substances or microorganisms
by destroying them or coating them so they are
more easily destroyed by white blood cells. While
the specific function of other immunoglobulins is
well-known, the specific function of IgD within the
immune system is unknown.

33

Clinical Symptoms
In addition to chills and fever, patients may have:
abdominal pain,
vomiting or diarrhea,
headache, and
arthralgias.
Signs include cervical lymphadenopathy,
splenomegaly, arthritis, skin lesions
(maculopapular rash, petechiae, or purpura), and
orogenital aphthous ulcers

34

 Cutaneous signs of HIDS
o Skin rash affects up to 80% of patients. A number of skin eruptions or rashes
have been described in this syndrome, and these resolve slowly after the
febrile episode settles.

The rashes seen in HIDS are most commonly described as follows:
 small flat spots (macules)
 raised bumps (small papules or larger nodules)
 measles-like rash (morbilliform)
 hive-like rash (urticarial).
 Less common or rare skin presentations include:
 Henoch-Schönlein purpura
 erythema elevatum diutinum
 petechiae (tiny bleeding spots or purpura)
 erythema nodosum.

o Oral and/or vaginal aphthous ulcers affect 50% of patients.


35

Symptom

Features



over 40C



preceding chills and malaise



affects up to 80%



various presentations (see below)

Headache



nonspecific

Enlarged lymph nodes in neck



characteristic



bilateral



painful



severe



diarrhoea and vomiting



peritonitis



arthralgia (pain) or arthritis (swelling)



most common in young patients



affects large joints



symmetrical, polyarticular, non-destructive



symptoms occur with abdominal pain and settle slowly



affects 50% of children

Fever

Skin rash

Abdominal pain

Joint pain

Enlarged liver and spleen (hepatosplenomegaly)

36
Tendonitis

Trigger
Acute episodes may be triggered by:
o Vaccinations – more than 50% report at least
one episode in childhood following an
immunisation
o Infection
o Physical and emotional stress
o Trauma, including surgery


37

Diagnosis
The characteristic recurrent acute febrile attacks
without a clear infectious or autoimmune cause,
suggest the need for investigation.
 Clinical criteria
In addition to the the of febrile attacks outlined above,
clinical diagnostic criteria should include:
o Onset before the age of 5 years
o Episodes last less than 14 days
o MVK gene mutations are unlikely if these features are
not present.

38

IgD levels
Raised levels of IgD can be found in many but not
all patients, especially in children under 3 years of
age. Levels are raised not only during an attack
but between attacks. Elevations of IgD levels can
occur in other periodic fever syndromes such
as familial Mediterranean fever and TRAPS, and
other chronic inflammatory conditions, so it
should be interpreted with caution.


39

 Other useful tests
o Urine organic acids measured during an acute attack usually
show raised levels of mevalonic acid.
o During an attack:
 leukocytosis,
 Increase erythrocyte sedimentation rate (ESR),
 increaseC-reactive protein (CRP) and serum amyloid A (SAA).
 Serum IgA levels may also be increased.
o Radiometric assay testing can demonstrate reduced
mevalonate kinase activity in white blood cells or cultured
fibroblasts.
o Skin biopsy may show a mild vasculitis which may extend
deeply. Changes may resemble Sweet disease or cellulitis.

40

DNA analysis
DNA analysis showing two disease-linked
mutations in the MVK gene is used to confirm the
diagnosis of HIDS. In most cases the patient has
two different mutations, called compound
heterozygosity.


41

Treatment of HIDS
Many treatments have been tried in HIDS, none with uniform
success:
 Colchicine – is generally unhelpful although there are case
reports of its successful use
 Non-steroidal anti-inflammatory drugs (NSAID)
 Statins – such as simvastatin, inhibit HMGCoA-reductase
resulting in reduced production of mevalonic acid
 Systemic corticosteroids – a single dose at the start of an
attack may reduce the severity and duration (1mg/kg)


42

Dapsone
Ciclosporin
Thalidomide
Intravenous immunoglobulin (IVIG)
Biologic agents– including anakinra (interleukin-1
receptor antagonist) and etanercept (tumour
necrosis factor alfa inhibitor) have been reported
to reduce the frequency and/or severity of attacks
in 80%. However there have also been cases
where these agents have increased the frequency
and/or prolonged attacks.

43

Prognosis
 There is a tendency to improve with age, with
less frequent and less severe attacks by
adulthood. Between episodes, health is normal.
 A small subgroup of affected patients develop
neurologic abnormalities in adulthood, similar to
mevalonic aciduria.
 Unlike familial Mediterranean fever, amyloidosis
is rarely seen in HIDS, affecting less than 3%.
 Life expectancy is usually normal, however this
can be affected by renal failure due to
amyloidosis or severe infections.

44

Mevalonic aciduria
Mevalonic aciduria involves the same gene and
enzyme as HIDS, however the resulting enzyme
deficiency is virtually complete. The condition is also
called mevalonate kinase deficiency. The gene
mutations so far identified have been localised to
one end of the enzyme. Mevalonic aciduria results
in neurological effects that mainly arise because of
inadequate cholesterol, which is required for brain
and nerve development.


45

 Patients with mevalonic aciduria suffer the same
febrile episodes as in HIDS, but in addition develop
profound developmental delay, retinal dystrophy
(visual defects) and cataracts, mild facial deformities,
and liver/spleen enlargement. Those less severely
affected have mental retardation, failure to thrive,
progressive cerebellar ataxia (unsteadiness) and
anaemia. In childhood and adolescence, eye problems
develop, including cataracts and uveitis. Myopathy
(muscle weakness) can occur. In those severely
affected, mevalonic aciduria is commonly fatal in
infancy/childhood.


46

High levels of mevalonic acid are detected in
the urine at all times.
Genetic counselling should be performed for
families with an affected child and prenatal
testing should be considered.


47

Periodic fever syndromes
SpA(K)

PFAPA Syndrome and Periodic fever syndromes are
conditions in which the patient experiences recurrent
episodes of fever with associated inflammatory
symptoms, in the absence of infection, allergy,
malignancy, immunodeficiency or autoimmune
conditions. They are one category of autoinflammatory
syndromes.
Familial Mediterranean fever (FMF) is the most
common and best known of the hereditary periodic
fever syndromes. Inherited (genetic) forms of periodic
fever syndromes are also known as hereditary recurrent
fever syndromes.

49

Periodic fever syndromes can be genetic conditions.
Therefore some periodic fever syndromes are seen
predominantly in specific racial groups. Familial
Mediterranean fever, for example, affects races
originating from around the eastern Mediterranean
area.
The hereditary periodic fever syndromes can be
classified by the type of inheritance:
Autosomal recessive
 Autosomal dominant

50

Autosomal recessive periodic fever syndromes
Genetic conditions with this type of inheritance require two
copies of the abnormal gene; one copy inherited from each
parent. Although the defective gene is usually the same in
each parent, the actual mutation may be different, i.e.,
heterogeneous homozygotes or compound heterozygotes.
The parents are asymptomatic carriers of the defect.
Autosomal recessive periodic fever syndromes with skin
involvement include:
 Familial Mediterranean fever (FMF)
 Hyperimmunoglobulinaemia D syndrome (hyperIgD
syndrome, HIDS)


51

Autosomal dominant periodic fever syndromes
Only a single copy of the defective gene is required to develop
symptoms and signs of an autosomal dominant periodic fever
syndrome. Therefore the condition is usually inherited from an
affected parent or, less commonly, is due to a spontaneous
mutation in the affected child.
Autosomal dominant periodic fever syndromes with skin
involvement include:
 Tumour necrosis factor receptor-associated periodic fever
(TRAPS)
 Cryopyrin-associated periodic syndromes (CAPS)
 Familial cold autoinflammatory syndrome (FCAS)
 Muckle-Wells syndrome (MWS)

52

Molecular biology of periodic fever syndromes
The defective gene has been identified for these
hereditary periodic fever syndromes. The defective
gene is different for each of the syndromes with the
exception being the three clinically distinct syndromes
that are now clustered as the cryopyrin-associated
periodic syndromes (CAPS).
All periodic fever syndromes result in overstimulation
of the innate immune system, usually due to overactivity of interleukin 1.

53

Nonhereditary periodic fever syndromes with
skin involvement include:
PFAPA syndrome
Schnitzler syndrome
The cause of these syndromes is not yet known.


54

Symptoms
The one clinical feature in common between all the
periodic fever syndromes is the recurrent episodes of
fever in the absence of infection, autoimmune disease
or malignancy.
The frequency of febrile attacks can vary between
individuals and syndromes from daily to once every ten
years. The duration of the fever during an attak may be
hours or be virtually continuous, but is usually typical
for a particular syndrome. The height of the fever may
range from a slight elevation of temperature to over 40
degrees Celsius.

55

The age at which the febrile attacks begin is also
highly variable between the different syndromes
with some beginning at or shortly after birth but
others being delayed even as late as middle age.
In some periodic fever syndromes there are wellrecognised triggers for a febrile attack, such as
generalised exposure to cold triggering a fever in
familial cold autoinflammatory syndrome (FCAS) But
in others no trigger is identified.


56

Most periodic fever syndromes have associated
symptoms and signs of inflammation at the same
time as the fever. Commonly these affect the serosal
surfaces, joints, eyes and skin. In some forms the
predominant associated symptom is severe
abdominal pain often leading to unnecessary
exploratory surgery. In others, joint or neurological
involvement can result in major disability.


57

Quality of life can be severely impacted, particularly
if febrile attacks are frequent or in those forms of
periodic fever syndrome that develop joint or
neurological complications.
Secondary systemic amyloidosis develops in some
periodic fever syndromes and this can result in lifethreatening complications.


58

Diagnosis
Periodic fever syndromes should be suspected
clinically when the patient presents with recurrent
episodes of fever associated with other
inflammatory symptoms. However this can be
difficult if the attacks are very infrequent, such once
every few years, or continuous. A family history of
such episodes is not always present, but is helpful if
known.

59

Periodic fever syndromes can only be considered
after infections, allergies, malignancy,
immunodeficiencies and autoimmune diseases are
excluded.
In children, it can be difficult to distinguish
hereditary periodic fevers from the much
commoner PFAPA syndrome as there are
overlapping clinical features. The Gaslini score may
help identify those most likely to benefit from
genetic testing, and then to determine the order in
which genes should be sequenced.

60

Some specific periodic fever syndromes can be
diagnosed on biochemical testing or challenge with
the known trigger. An example of the former is HIDS,
which typically is associated with a very high level of
IgD in the blood. Triggering of an attack within hours
of generalised exposure to cold in FCAS is an
example of the latter category.


61

Genetic testing is often definitive if positive, but not
all mutations are known or easily tested for. A
negative test does not exclude the diagnosis. In
these cases, the diagnosis must be reached on
clinical criteria. Genetic testing of the MEFV,
TNFRSF1A and MVK genes detects a mutation in
20% of patients with clinical symptoms suggestive of
a periodic fever syndrome.


62

A rapid and complete response to a trial of therapy
may support the clinical diagnosis. Familial
Mediterranean fever (FMF) responds to colchicine in
over 90% of cases. Interleukin-1 blockade
with biologic agents results in dramatic resolution of
symptoms within hours of the first injection in some
specific syndromes.


63

Treatment
Acute attacks of hereditary periodic fever
syndromes are usually treated with bed rest, antiinflammatory agents, analgesics and
sometimes systemic corticosteroids. The fever does
not respond to aspirin or paracetamol.
Avoidance of triggers, where known, can reduce the
frequency of attacks. Sufferers of familial coldassociated syndrome (FCAS) often move to
temperate climates to avoid cold winters and hot
summers, for example.

64

To prevent febrile episodes, improve quality of life
and minimise longterm complications, continuous
treatment may be required for some forms. Apart
from colchicine for familial Mediterranean fever,
treatment of the hereditary periodic fever
syndromes is with biologic agents such as anakinra,
given by subcutaneous injection. Treatment should
be started as early as possible to prevent the
development of life-threatening complications in
such periodic fever syndromes.


65

Autoinflammatory syndromes
SpA(K)

PFAPA is to be related with Auto inflammatory
syndromes because the similarity of periodic fever, are
defined as conditions caused by an exaggerated innate
immune system response resulting in episodes of
spontaneous inflammation affecting multiple organs. An
auto inflammatory syndrome can only be diagnosed
when infective conditions, malignancy, allergic
and immunodeficiency conditions have been excluded.
Compared to classical autoimmune diseases, auto
inflammatory syndromes lack pathogenic
autoantibodies and antigen-specific T cells.

67

Classification of autoinflammatory syndromes
Autoinflammatory syndromes may be inherited
through mutations to a single gene (monogenic
autoinflammatory syndromes), or, more commonly,
are polygenic immune conditions that resemble
autoimmune collagen disorders. The number of
conditions included is increasing as molecular and
genetic studies reveal disease mechanisms.
A classification system, with examples of syndromes
with dermatologic manifestations, follows.

68

Hereditary fever syndromes
Familial Mediterranean fever (FMF)
Tumour necrosis factor receptor-associated
periodic fever syndrome (TRAPS)
Hyper-IgD syndrome (HIDS)


69

 Other monogenic autoinflammatory syndromes
 Cryopyrin-associated periodic syndromes (CAPS)
o Familial cold autoinflammatory syndrome ( FCAS)
o Muckle-Wells syndrome (MWS)
o Neonatal onset multisystem inflammatory disease/chronic
Infantile neurologic cutaneous arthropathy syndrome
(NOMID/CINCA)

 Syndrome of pyogenic arthritis, pyoderma gangrenosum
and acne (PAPA syndrome, PAPAS, PAPGA syndrome)
 Juvenile systemic granulomatosis (Blau syndrome, early
onset sarcoidosis)
 Deficiency of interleukin-1 receptor antagonist (DIRA)
 Mevalonic aciduria
 Majeed syndrome

70

Nonhereditary or polygenic disorders
 Schnitzler syndrome
 Crohn disease
 Behcet disease
 Psoriatic arthritis
 Syndrome of periodic fever, aphthous stomatitis,
pharyngitis and adenitis (PAPAS, PFAPA syndrome)
 Systemic-onset juvenile idiopathic arthritis
 Adult-onset Still disease

71

Treatment
Treatment varies with the actual syndrome. In many
forms, systemic corticosteroids have only a modest
effect. Biologic agents such as anakinra (which
targets IL-1) result in a dramatic and consistent
improvement in those syndromes where a clear link
to IL-1 has been shown. There is less consistent
benefit in other conditions where a direct link with
IL-1 has not been found.


72

Thank you


73

PFAPA Syndrome and Related Diseases Treatment

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