ORIGINAL RESEARCH
published: 27 April 2022
doi: 10.3389/fped.2022.822473
Number of Episodes Can Be Used as
a Disease Activity Measure in
Familial Mediterranean Fever
David Piskin 1,2 , Zehra Serap Arici 3 , Dilek Konukbay 4 , Micol Romano 5,6 , Balahan Makay 7 ,
Nuray Ayaz 8 , Yelda Bilginer 9 , Roberta A. Berard 1,5,6 , Hakan Poyrazoglu 10 ,
Ozgur Kasapcopur 11 , Ronald M. Laxer 12 , Kathy Speechley 1,2 and Erkan Demirkaya 1,2,5,6*
1
Children’s Health Research Institute, Lawson Health Research Institute, London, ON, Canada, 2 Department of Paediatrics
and Epidemiology and Biostatistics, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON,
Canada, 3 Clinical Epidemiology, McMaster University, Hamilton, ON, Canada, 4 Gulhane Faculty of Nursing, University
of Health Sciences, Ankara, Turkey, 5 Division of Paediatric Rheumatology, Department of Paediatrics, Schulich School
of Medicine and Dentistry, University of Western Ontario, London, ON, Canada, 6 Canadian Behcet’s and Autoinflammatory
Diseases Center (CAN BE AID), University of Western Ontario, London, ON, Canada, 7 Pediatric Rheumatology Unit, Dokuz
Eylül University, ízmir, Turkey, 8 Department of Pediatric Rheumatology, Istanbul University Medical School, Istanbul, Turkey,
9
Pediatric Rheumatology Unit, Faculty of Medicine, Hacettepe University, Ankara, Turkey, 10 Division of Rheumatology,
Department of Pediatrics, Faculty of Medicine, Erciyes University, Kayseri, Turkey, 11 Pediatric Rheumatology Unit,
Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey, 12 The Hospital for Sick Children, University of Toronto,
Toronto, ON, Canada
Edited by:
Marco Cattalini,
Children’s Hospital, Asst of the
Brescia Spedali Civili, Italy
Reviewed by:
Lovro Lamot,
University of Zagreb, Croatia
Hala El-Bassyouni,
National Research Centre, Egypt
Raffaele Manna,
Catholic University of the Sacred
Heart, Italy
*Correspondence:
Erkan Demirkaya
Erkan.Demirkaya@lhsc.on.ca
Specialty section:
This article was submitted to
Pediatric Rheumatology,
a section of the journal
Frontiers in Pediatrics
Received: 25 November 2021
Accepted: 28 March 2022
Published: 27 April 2022
Citation:
Piskin D, Arici ZS, Konukbay D,
Romano M, Makay B, Ayaz N,
Bilginer Y, Berard RA, Poyrazoglu H,
Kasapcopur O, Laxer RM,
Speechley K and Demirkaya E (2022)
Number of Episodes Can Be Used as
a Disease Activity Measure in Familial
Mediterranean Fever.
Front. Pediatr. 10:822473.
doi: 10.3389/fped.2022.822473
Frontiers in Pediatrics | www.frontiersin.org
Objective: To evaluate the number of episodes in the past 12 months as an indicator
of the overall disease activity status in Familial Mediterranean fever (FMF).
Methods: In this cross-sectional study, patients were recruited from tertiary pediatric
hospitals. Demographic data, main clinical symptoms of the episodes, treatment
modalities, and genetic mutations were recorded. The patients were grouped as no
episodes (Group 1), 1–4 episodes (Group 2), and more than 4 episodes (Group 3)
according to the number of episodes in the past 12 months. The Pediatric Quality
Life Inventory (PedsQL), the Children’s Depression Inventory (CDI), and the Wong-Baker
FACES Pain Rating Scale (FACES) scores were compared between groups. Concurrent
validity between the number of episodes and the patient-reported outcome measures
(PROMs) was assessed using Spearman’s rank correlation coefficient (ρ).
Results: A total of 239 patients were included. There were 74 patients (31%) in Group
1, 99 (41.4%) in Group 2, and 66 (27.6%) in Group 3. Groups were similar according
to age, age at diagnosis, gender, consanguinity, family history, history of amyloidosis,
clinical symptoms, and in terms of allele frequency (p > 0.05). According to PROMs
completed by parents, moderate correlations were found between the number of
episodes and the PedsQL score (ρ = −0.48; 95% CI = −0.58 to −0.35, p < 0.001)
and between the number of episodes and the Wong-Baker FACES score (ρ = 0.47,
95% CI = 0.35–0.57, p < 0.001).
Conclusion: The number of episodes was positively and moderately correlated with
patient- and parent-reported outcomes in our cohort. The number of episodes in
patients with FMF can be used as a single measure to assess disease activity.
Keywords: Familial Mediterranean fever, disease activity, quality of life, patient reported outcomes, convergent
validity
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April 2022 | Volume 10 | Article 822473
Piskin et al.
Disease Activity Measure in FMF
INTRODUCTION
Clinical Assessment
All patients were evaluated by a pediatric rheumatologist crosssectionally. Face-to-face interviews were used to collect data on
demographics (age, sex, age at diagnosis, consanguinity, and
history of amyloidosis), treatment, mutations, and main clinical
symptoms. The number of episodes in the past 12 months was
obtained from patients or their parents. Then, patients were
assigned into three groups by the number of FMF episodes: no
episodes (Group 1), 1–4 episodes (Group 2), and more than 4
episodes (Group 3). Among this referred population, we included
patients for whom we had data on three PROMs, the Pediatric
Quality Life Inventory (PedsQLTM ) Generic Core Scale score,
the Children’s Depression Inventory (CDI) score, and the WongBaker FACESR pain rating scale (FACESR ) score. In addition,
to see if there are any differences among the patient groups,
the elements of the AIDAI symptom scale were also collected
(7). Medication adherence was assessed for medication-taking
behavior, given that it is such an important confounder in
research and a challenge in clinical care.
Familial Mediterranean fever (FMF) (OMIM #249100) is
the most common monogenic autoinflammatory disease
(AID) characterized by recurring febrile episodes of 1–3 days
accompanied by inflammation in the serous membranes causing
peritonitis, pleuritis, or synovitis. Colchicine is the first-line
treatment, and if a patient is resistant or a non-responder,
biologics can be used to suppress episodes and systemic
inflammation. The most devastating complication is amyloidosis
in untreated and non-compliant patients with FMF. There are
some phenotypic features associated with a severe disease course,
such as the presence of one (or two) M694V mutations, ethnicity,
and country of residence (1).
Monitoring disease activity in FMF is essential to measure the
effectiveness of treatments, prevent complications, and quantify
the effect of the disease on the overall health and quality of
life (QoL). The importance of regular monitoring of disease
activity was highlighted in the international recommendations
for the management of FMF (2, 3). During the past decade,
there were several attempts to develop instruments to measure
disease severity, damage, and activity for FMF and other
autoinflammatory diseases (AIDs) (4, 5). There are a few patientreported outcome measures (PROMs) validated for use in FMF
(6). The only available patient-reported tool to measure disease
activity for FMF is the Autoinflammatory Disease Activity
Index (AIDAI) (7), which was developed and validated by an
international consortium (8), but its use in both research and
clinical practice has been limited (9). It is challenging to complete
a prospective diary for a long time, especially in adolescents with
FMF. Except for the use reported in the publication describing its
validation, there has been no uptake of the AIDAI as an outcome
instrument related to the FMF.
We propose that the number of episodes could reasonably
be used as an indicator of disease activity status in patients
with FMF. We assessed the concurrent validity of the number
of episodes as a feasible stand-alone measure of disease activity.
To do so, we developed a priori predictions of the associations
that the number of episodes in a year would have with particular
PROMS, based on the evidence in the literature regarding
observed associations with the level of disease activity in patients
with FMF. Specifically, we predicted the following associations
in children with FMF: functional status and QoL would be
negatively associated, while the level of depressive symptoms and
pain would be positively associated with the number of episodes
in the past year.
Genetic Screening
The QIAamp DNA mini kit (Qiagen, Germany) was used
for DNA extraction. A reverse-hybridization method (Vienna
Lab Diagnostics, Vienna, Austria) was performed for mutation
analysis (12). Eleven variants in the MEFV gene were genotyped,
such as E148Q, P369S, F479L, M680I (G > C and G > A), I692
del, M694V, M694I, K695R, V726A, A744S, and R761H.
Patient Reported Outcome Measures
Patients completed the following patient reported outcome
measures (PROMs) during the face-to-face interview during
their clinical visit.
The PedsQLTM Generic Core Scale
Pediatric Quality Life Inventory, developed in 1999, by Varni
et al. (13) is a short, standardized assessment tool to evaluate
children with chronic diseases according to patients’ and parents’
perceptions of health-related quality of life (HRQoL). In 2005,
the reliability and validity of the Turkish version of PedsQL
were reported (14, 15). The PedsQL Generic Core Scale includes
two summary scores with four scales and 23 items: the Physical
Health Summary Score consisting of a physical functioning
scale (8 items) and the Psychosocial Health Summary Score
consisting of emotional functioning (5 items), social functioning
(5 items), and school functioning (5 items) scales. Higher scores
indicate better HRQoL. In this study, both parents and children
reported the PedsQL.
MATERIALS AND METHODS
Children’s Depression Inventory
Participants
Kovack’s CDI (16) is a 27-item self-report questionnaire to
assess depressive symptoms experienced in the past 2 weeks
in children 7–17 years old. The validated and reliable Turkish
version was published in 1991 (17). Higher scores indicate the
necessity to refer the patient for further evaluation in terms
of clinical depression. In our research, both children and their
parent(s) completed the CDI. Higher scores indicate more
depressive symptoms.
Consecutive patients referred to the pediatric rheumatology
outpatient clinics were recruited. Patients who had a diagnosis of
FMF based on the pediatric FMF criteria or the Tel-Hashomer
criteria were eligible (10, 11). All participating parents and
children ≥ 8-year-old-age gave written informed assent and/or
consent to participate in this study. The study protocol was
approved by the institutional ethics committee.
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Piskin et al.
Disease Activity Measure in FMF
rheumatology centers in Turkey. A total of 176 forms were
completed by parents and patients, and 63 forms were completed
by parents who have children < 8 years old. There were 74
patients (31%) in the no FMF episode group (Group 1), 99
patients (41.4%) in the 1–4 episode group (Group 2), and
66 patients (27.6%) in ≥ 4 episode group (Group 3). The
median age at the time of enrollment was 11 years (IQR: 7–
14 years), the median age at disease onset was 3 years (IQR:
1–6 years), and the median age at diagnosis was 6 years (IQR: 3–
9 years). Consanguinity, family history of FMF, and amyloidosis
were reported as 29.7% (n = 71), 52.7% (n = 126), and 17.6
(n = 41), respectively. The three groups formed by the number
of FMF episodes were similar according to age, age at diagnosis,
gender, consanguinity, family history, and history of amyloidosis
(p > 0.05), but the age at disease onset was significantly higher in
Group 2 than the others (p = 0.001) (Table 1). Allele frequencies
of the MEFV gene mutations in the groups were 60.4, 57.8, and
60% for M694V; 11.4, 15.6, and 12.1% for M680I; and 11.4, 7.8,
and 9.9% for V726A, respectively (Table 1). The groups were
similar in terms of M694V and V726A alleles (p = 0.843 and
p = 0.46). Only the M680I allele was significantly more frequent
in Group 2 (p = 0.01) (Table 1). The comparison of the genotypes
for each group was also given in Table 1, and the groups
were similar for homozygosity, compound heterozygosity, and
heterozygosity (p = 0.94). Nearly all the patients (232 of 239
patients, 97.1%) were on colchicine treatment. The rest of the
patients did not use colchicine because of intolerance (n = 2)
and colchicine resistance (n = 5). Five patients were treated
with biologic disease-modifying antirheumatic drugs (DMARDs)
(2 Anakinra, 1 Canakinumab, and 2 Etanercept). Otherwise,
medication adherence was similar among the groups.
The characteristic signs and symptoms for each group are
presented in Table 2. The most common symptoms reported
were recurrent fever (92.1%), abdominal pain (91.6%), fatigue
(79.9%), arthralgia (79.9%), leg pain (65.3%), myalgia (61.5%),
headache (52.7%), and vomiting (51.9%). Groups were similar
according to the clinical symptoms (p > 0.05) (Table 2).
The groups were compared according to each item on the
AIDAI symptom scale and there were no statistically significant
differences among the groups (Table 2).
Wong-Baker FACESR Pain Rating Scale (FACESR )
The Wong-Baker FACES Pain Rating Scale (FACES) was
developed for children to communicate about their pain (18). The
FACES scale uses six hand-drawn, gender-neutral faces depicting
smiling (0) to crying (10) placed at equal intervals horizontally: 0
(no hurt) and 10 (hurts worst). In this research, pain experienced
by children < 8 years of age was evaluated by their parents.
Higher scores indicate more pain.
Autoinflammatory Disease Activity Index
The AIDAI symptom scale includes 12 variables: fever,
overall symptoms, abdominal pain, nausea/vomiting, diarrhea,
headache, chest pain, painful nodes, arthralgia, or myalgia,
swelling of the joints, eye manifestations, and skin rash. The
calculation of the score is based on simple math; the sum of
all 12 variables was divided by the number of months over
which the diary was completed (0–372 in a month of 31 days).
For the purposes of the current study, all the elements of the
AIDAI symptom scale were asked for the last 1 year to the
patients and their parents during the face-to-face interview.
Instead of calculating the scores, we compared the elements of the
AIDAI among the groups and hypothesized that the difference
in the disease activity is mainly generated by the frequency of
episodes. To test this hypothesis, we empirically chose to score
dichotomously each element of the AIDAI depending on the
presence or the absence of the individual item.
Statistical Analysis
Statistical analysis was performed using the Statistical Package
of Social Science (SPSS) for Windows, version 26.0 (SPSS
Inc., Chicago, IL). Descriptive statistics were presented as
frequencies and percentages for categorical variables and
median [interquartile range (IQR)] for continuous variables
as appropriate. The variables were investigated using visual
(histograms and probability plots) and analytical methods
(Kolmogrow–Simirnov test) to evaluate the normal distribution.
The chi-squared test or Fisher’s exact test was used to compare
categorical variables where appropriate. The Kruskal–Wallis test
was used to compare non-normally distributed variables in the
three groups. The Mann–Whitney U-test was performed to test
the significance of pairwise differences using the Bonferroni
correction to adjust for multiple comparisons. Concurrent
validity was assessed using the associations of three PROMS
with the number of FMF episodes in the past 12 months
using the Spearman rank correlation coefficient (ρ). Correlation
coefficients of ρ < 0.39 were considered as weak; 0.40–0.69 as
moderate; and ≥ 0.70 as strong (19). A p < 0.05 was considered a
statistically significant result.
Patient-Reported Outcome Measures
The PedsQL median (IQR) score was 77.3 (65.2–84.1) according
to parents and 78.4 (67.8–85.6) according to children. For
parent and child PedsQL scale scores (physical and psychosocial
functioning scales) and total scores, patients in Group 1 had
higher scores that meant better HRQoL than Group 2, and Group
2 had higher scores (better HRQoL) than Group 3 (p < 0.05)
(Table 3). The median (IQR) CDI score was 8.0 (4.0–12.0)
according to parents and 8.0 (5.0–12.0) according to children.
Patients in Group 2 had higher parent CDI scores than those
in Group 1 (p < 0.001). Child CDI scores were significantly
lower in Group 1 than Group 2 (p = 0.01), and in Group 2 than
Group 3 (p = 0.03) (Table 4). The FACES median (IQR) score
was 2.0 (0–6.0) according to both parents and children. Both
parent and child FACES scores were significantly lower in Group
1 than in Group 2 (p < 0.001), and in Group 2 than in Group 3
(p < 0.001) (Table 3).
RESULTS
Participants
There were 270 patients enrolled in the registry. A total of 31
patients were excluded from the study because of incomplete
response to PROMS, as mentioned in the Materials and Methods
section. Forms were collected on 239 patients (44.4% men
and 55.6% women) with FMF from seven different pediatric
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Disease Activity Measure in FMF
TABLE 1 | Demographic features and comparisons among the groups by the number of Familial Mediterranean fever (FMF) episodes.
Age, median (IQR) in years
Group 1 (n = 74)
Group 2 (n = 99)
Group 3 (n = 66)
Total(n = 239)
P
12.0 (8.0–14.0)
11.0 (8.0–15.0)
10.0 (7.0–13.0)
11.0 (7.0–14.0)
0.156
Symptom onset age, median (IQR) in years
3.0 (1.0–5.0)
4.0 (1.0–7.0)
2.0 (1.0–5.0)
3.0 (1.0–6.0)
0.001*
Age at diagnosis, median (IQR) in years
5.0 (3.0–8.0)
7.0 (4.0–11.0)
6.0 (3.0–9.0)
6.0 (3.0–9.0)
0.06
0.105
Gender, n (%)
Male
39 (52.7)
44 (44.4)
23 (34.8)
106 (44.4)
Female
35 (43.7)
55 (55.6)
43 (65.2)
133 (55.6)
Consanguinity, n (%)
26 (35.1)
24 (24.2)
21 (31.8)
71 (29.7)
Family history, n (%)
32 (43.2)
54 (54.5)
40 (60.6)
126 (52.7)
0.272
0.108
History of amyloidosis, n (%)
12 (16.2)
19 (19.2)
11 (16.7)
41 (17.6)
0.856
0.15
Duration of episodes
0–48 h
-
51 (61.4)
27 (49.1)
78 (56.5)
> 48 h
-
32 (38.6)
28 (50.9)
60 (43.5)
M694V
64 (60.4)
74 (57.8)
51 (63.0)
189 (60.0)
0.843
M680I
12 (11.4)
20 (15.6)
6 (7.4)
38 (12.1)
0.01*
V726A
12 (11.4)
10 (7.8)
8 (9.9)
30 (9.5)
0.46
Homozygote
26 (40.6)
34 (41.0)
29 (46.8)
89 (42.6)
Compound heterozygote
21 (32.8)
25 (30.1)
17 (27.4)
63 (30.1)
Heterozygote
17 (26.6)
24 (28.9)
16 (25.8)
57 (27.3)
Allele frequency [n (%)]
Genotype [n (%)]
0.94
No episode/year: Group 1, 1–4 episodes/year: Group 2, more than 4 episodes/year: Group 3.
*1–4 episode group is significantly higher than others.
DISCUSSION
Concurrent Validity
According to PROMs completed by parents, moderate
correlations were found between the number of episodes
and PedsQL total score (ρ = −0.48; 95% CI = −0.58 to −0.35,
p < 0.001), CDI (ρ = 0.27; 95% CI = 0.13–0.40, p < 0.001) and
between the number of episodes and FACES score (ρ = 0.47, 95%
CI = 0.35–0.57, p < 0.001). In addition, there were moderate
correlations between the number of episodes and PROMs
completed by children themselves (Table 4).
Assessment of disease activity in patients with AIDs remains a
challenge due to the nature of these disorders, such as an episodic
course, phenotypic differences, and a low likelihood of being able
to see the patient during an acute episode. We have provided
preliminary results suggesting that the number of episodes may
offer a valid measure of disease activity in patients with FMF that
can be easily administered in a clinic.
The european alliance of associations for rheumatology
(EULAR) consensus recommendations for the treatment of FMF
are that those patients should be seen two times a year (3). For
the management of AIDs, it is mandatory to evaluate the disease
activity (2). Hence, an international group of experts developed
an activity score to assess the disease activity, called AIDAI, for
four major hereditary periodic fever syndromes, such as FMF. It
has not been widely adopted, however, since it is not practical
for use in clinical trials or practice (9). Since it is not feasible
to expect families to complete a prospective diary for the long
period between clinical appointments, it is important to have
a valid measure of disease activity that is easy to administer
during clinic visits.
The AIDAI is a valid and reliable patient diary to assess the
disease activity in four major hereditary syndromes. According
to the AIDAI, a 3-month period is more suitable for surveying
FMF, and it is not easy and applicable for defining the disease
activity in FMF, especially if the patient is experiencing fewer
episodes during the year. In the AIDAI Consensus Conference,
the experts agreed that fever, joint symptoms, serositis, chest
and skin symptoms, and the number and duration of episodes
TABLE 2 | The main clinical symptoms in line with the autoinflammatory disease
activity index (AIDAI) symptom scale and their comparison among the groups by
the number of FMF episodes.
Group 2
(n = 99)
Group 3
(n = 66)
Total
(n = 165)
p
n (%)
n (%)
n (%)
Recurrent fever
90 (90.9)
62 (93.9)
152 (92.1)
0.47
Abdominal pain
90 (90.9)
60 (90.9)
150 (90.9)
1.00
Nausea-vomiting
50 (50.5)
37 (56.1)
87 (52.7)
0.48
Diarrhea
30 (30.3)
26 (39.4)
56 (33.9)
0.22
Headache
49 (49.5)
42 (63.6)
91 (55.2)
0.07
Chest pain
43 (43.4)
30 (45.5)
73 (44.2)
0.79
Arthralgia
84 (84.8)
47 (71.2)
131 (79.4)
0.03
Myalgia
69 (69.7)
37 (56.1)
106 (64.2)
0.07
Arthritis
37 (37.4)
25 (37.9)
62 (37.6)
0.94
Erysipelas like erythema
10 (10.1)
8 (12.1)
18 (10.9)
0.68
Group 2:1–4 episodes/year, Group 3: more than 4 episodes/year.
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Disease Activity Measure in FMF
TABLE 3 | The comparisons of the scores of PedsQL, FACES, and CDI among groups by the number of FMF episodes.
a
b
c
Group 1
Group 2
Group 3
Total
a–b
a–c
b–c
Median (IQR)
Median (IQR)
Median (IQR)
Median (IQR)
P
p
p
p
n = 61
n = 89
n = 57
n = 207
60.9 (53.1–62.5)
91.7 (86.7–96.7)
83.3 (79.1–87.2)
56.3 (43.7–62.5)
83.4 (74.2–93.4)
75.9 (65.5–83.3)
42.2 (31.3–59.4)
73.4 (60.8–85.0)
65.9 (54.6–76.5)
56.3 (40.6–62.5)
85.0 (73.4–93.4)
77.3 (65.2–84.1)
0.005
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
0.001
<0.001
<0.001
<0.001
<0.001
n = 56
n = 75
n = 41
n = 172
60.9 (56.3–62.5)
93.4 (86.7–98.4)
84.9 (79.1–88.8)
56.3 (41.4–62.5)
81.7 (75.0–93.4)
75.5 (68.1–84.1)
42.2 (33.6–50.0)
78.4 (69.2–90.8)
68.1 (59.1–80.4)
56.3 (40.62–62.5)
86.7 (76.7–94.6)
78.4 (67.8–85.6)
0.001
<0.001
<0.001
<0.001
<0.001
<0.001
0.001
0.89
0.02
<0.001
<0.001
<0.001
n = 63
n = 88
n = 55
n = 206
6.0 (3.0–9.0)
8.0 (4.0–12.0)
9.0 (6.0–15.0)
8.0 (4.0–12.0)
0.054
<0.001
0.09
<0.001
n = 55
n = 75
n = 42
n = 172
7.0 (2.0–10.0)
8.0 (6.0–11.0)
11.5 (6.75–16.0)
8.0 (5.0–12.0)
0.011
<0.001
0.03
<0.001
n = 74
n = 99
n = 66
n = 239
0 (0–2.0)
0 (0–6.0)
6 (0–8.0)
2 (0–6.0)
0.006
<0.001
<0.001
<0.001
0.008
<0.001
<0.001
<0.001
PedsQL
(parent)
Physical health
Psychosocial health*
Total score
PedsQL
(child)
Physical health
Psychosocial health*
Total score
CDI (parent)
CDI (child)
FACES (parent)
FACES (child)
n = 58
n = 76
n = 42
n = 176
0 (0–2.0)
2 (0–6.0)
6 (4.0–8.0)
2 (0–6.0)
No episode/year: Group 1, 1–4 episodes/year: Group 2, more than 4 episodes/year: Group 3, PedsQL, Pediatric Quality Life Inventory; CDI, Children’s Depression
Inventory; FACES, Wong-Baker FACES Pain Rating Scale.
*Representing summary of emotional, social, and school subscales.
TABLE 4 | Results of Spearmen’s correlations between the number of episodes and PROMs.
PROM
Episode groups-Spearman correlation (ρ)
95% confidence interval
Lower
Parents
Upper
PedsQL total score
−0.48
−0.58
−0.35
<0.001
PedsQL physical health score
−0.44
−0.54
−0.31
<0.001
PedsQL psychosocial health score
−0.44
−0.55
−0.31
<0.001
0.27
0.13
0.40
<0.001
CDI
FACES
Children
p-value
PedsQL total score
0.47
0.35
0.57
<0.001
−0.44
−0.56
−0.30
<0.001
PedsQL physical health score
−0.45
−0.57
−0.33
<0.001
PedsQL psychosocial health score
−0.39
−0.52
−0.24
<0.001
CDI
0.30
0.15
0.44
<0.001
FACES
0.45
0.32
0.57
<0.001
PROM, Patient-reported outcome; PedsQL, Pediatric Quality Life Inventory; CDI, Children’s Depression Inventory; FACES, Wong-Baker FACES Pain Rating Scale.
were all important in the evaluation of disease activity for
patients with FMF (7). AIDAI consists of 12 disease-related
symptoms and the calculation of the score is based on simple
math; the sum of all 12 variables divided by the number
of months over which the diary was completed (0–372 in a
month of 31 days). In terms of those criteria, there were no
differences among the groups in our cohort except for the
number of episodes. On the basis of our results, the number
of episodes itself alone is a valid indicator of disease activity in
patients with FMF.
Patients with AIDs should also be followed with clinical
evaluation, laboratory test, QoL, tolerance, and treatment
Frontiers in Pediatrics | www.frontiersin.org
adherence. Relationships of patient-parent reported outcomes
with disease activity have been studied in juvenile idiopathic
arthritis (JIA) (20–26), juvenile idiopathic myositis (23),
rheumatoid arthritis (27–29), systemic lupus erythematosus
(SLE) (30–35), Behcet disease (36), and ankylosing spondylitis
(AS) (34, 37). The data on the relationship between
disease activity and patient-parent reported outcomes
in FMF are very limited. In the present study, PedsQL,
CDI, and FACES scores were used as patient-parent
reported outcomes.
Quality of life is an important factor in determining disease
status and defining and evaluating the effects of management
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Piskin et al.
Disease Activity Measure in FMF
CONCLUSION
strategies (38). The concurrent validity of the number of
episodes was assessed using PedsQL and a moderate correlation
was found, which is not surprising in our study. PedsQL
scores differed across groups, decreasing when the number of
episodes increased in our cohort. Buskila et al. showed that
the QoL in patients with FMF is inversely correlated with
the number of FMF episodes for a year (39). Alayli et al.
compared the HRQoL between patients with FMF and healthy
people and indicated that the QoL is impaired in children with
FMF (40). Sahin et al. have reported no relationship between
QoL and the number of episodes in adult patients using SF36 (41). On the contrary, the studies conducted with FMF
patients during their episode-free period, reported that QoL
is even better in patients with FMF compared with healthy
controls (42). Taken all these together, it is clear that the
number of episodes is inversely correlated with HRQoL in
patients with FMF.
The CDI scores were higher in groups with more episodes
in our study population. Makay et al. reported that the
CDI scores of children and adolescents with FMF were
significantly higher than those of a healthy control group
(43). Sonmez et al. evaluated depression by using CDI in
patients (remission) with FMF and healthy controls and found
no difference between patients and healthy controls (44). It
was reported in adults that depression was more frequent
in patients with FMF than in healthy controls using the
Hospital Anxiety and Depression Scale (HADS) (45, 46) and
the Hamilton Depression Scale (HDS) (47). Our study is the
first one that compared the CDI scores according to the
number of episodes.
We used FACES as a pain scale in our cohort, and the
results showed that pain scores were similarly higher with more
episodes reported. We showed that worse health-related QoL
(PedsQL) and increased depression (CDI) were correlated with
the number of episodes.
The limitations of the present study need to be mentioned.
One of the major limitations of our study is that we
were not able to analyze the AIDAI score because of poor
patient and parent adherence. On this occasion, we have
faced the difficulty of using AIDAI in a large patient cohort,
especially in adolescents. Another limitation that needs to
be mentioned is that the current study was designed as
cross-sectional and it is important to see the changes with
PROMs, also prospectively, to complete all validation steps.
We just performed concurrent validity due to the nature of
the current study.
In conclusion, the present study showed that a larger number
of episodes are related to worse patient- and parent-reported
outcomes. The PedsQL, CDI, and FACES scores were
significantly different among the groups divided according to
the number of FMF episodes in a year, in a homogeneous study
population in terms of demographic features, mutation types,
clinical symptoms, and treatment adherence. This study showed
that the number of episodes is the key element of disease activity
in patients with FMF and can be used on its own to assess
disease activity.
DATA AVAILABILITY STATEMENT
The raw data supporting the conclusions of this article will be
made available by the authors, without undue reservation.
ETHICS STATEMENT
The studies involving human participants were reviewed and
approved by Clinical Trials Ethics Committee of GMMA,
Ankara, Turkey. Written informed consent to participate in this
study was provided by the participants’ legal guardian/next of kin.
AUTHOR CONTRIBUTIONS
DP and KS: data analysis and interpretation. DK, NA, BM,
YB, HP, and OK: collecting patient data and providing
clinical information. DP, ZA, and MR: writing—original draft
preparation. DP, KS, ZA, MR, RL, RB, and ED: writing—review
and editing. ED: as a PI had full access to all the data in the
study and takes responsibility for the integrity of the data and the
accuracy of the analysis. All authors have read and agreed to the
published version of the manuscript.
ACKNOWLEDGMENTS
We thank all the patients who took part in this study. MR was
the recipient of a matching fund (Department of Pediatrics,
University of Western Ontario, Canada) a bursary for an
international clinical fellowship in Behcet and Autoinflammatory
Disease Center.
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Conflict of Interest: The authors declare that the research was conducted in the
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potential conflict of interest.
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