Inflammasome and immune disorders (30)
Autoimmune and Inflammatory Disorders Research (27)
Kawasaki Disease and Coronary Complications (15)
Systemic Lupus Erythematosus Research (13)
Rheumatoid Arthritis Research and Therapies (11)
Yabanci Erten ES, Koru L, Kaya F, Kucuk E, Aydin Z , et al.
Pediatric research •
Data on prophylaxis in children with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) are limited for probiotics. We aimed to evaluate clinical responses of probiotic and colchicine. We included PFAPA patients receiving colchicine or probiotic (Lactobacillus plantarum HEAL9 (5×10 cfu/tablet), Lactobacillus paracasei 8700:2 (5 × 10 cfu/tablet) and a vitamin mixture (0.75 μg/tablet vitamin D3, 0.38 μg/tablet, vitamin B12, 30 μg/tablet folic acid)) for ≥3 months. Disease activity was assessed using Auto-Inflammatory Disease Activity Index (AIDAI). Monthly AIDAI scores from 3-month periods before and after prophylaxis were compared retrospectively. Early clinical response was defined as AIDAI score change from the month before to after prophylaxis. The time to first attack was compared. The study included 130 patients (colchicine: n = 97; probiotics: n = 33). Significant early clinical response occurred in both groups, with median AIDAI scores decreasing from the month before to after prophylaxis (colchicine: p < 0.001; probiotics: p < 0.001). Time to first attack was longer in the colchicine group than probiotic group (p = 0.048). Colchicine and probiotics showed similar short-term improvement in PFAPA activity. However, differences exist in time to first attack and adverse effects and should be discussed with families when selecting prophylaxis. This study provides one of the first evaluations of clinical responses to colchicine and probiotic prophylaxis in children with PFAPA syndrome using objective disease activity scoring. By demonstrating clinical improvements in both groups, the study contributes to the growing body of evidence supporting probiotic use. The identification of gastrointestinal symptoms as a factor affecting colchicine response may contribute to a more personalized treatment approach. These findings contribute valuable data to the limited literature on PFAPA prophylaxis and support shared decision-making in clinical practice.
Koru L, Erten ESY, Dursun HK, Dizman EN, Kaya F , et al.
European journal of pediatrics •
We aimed to evaluate the efficacy of prophylactic colchicine treatment in periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) using the Auto-Inflammatory Diseases Activity Index (AIDAI) score measured before and during treatment. We also aimed to determine the optimal treatment duration for observing clinical response and to identify factors predicting response to treatment. Children with PFAPA receiving colchicine were included in the study. We utilized AIDAI scoring system by evaluating the sore throat, tonsillitis, and oral aphthae under the general symptoms heading. This form of AIDAI was given to the families, and they were asked to document their symptoms on a daily basis. AIDAI scores were calculated for the month before colchicine initiation and for the first and third months after. Data were obtained retrospectively. The mean age of patients was 4.4 ± 2.13 years, and almost two third of them (50/76) were male. The difference in AIDAI scores between the month before colchicine treatment and the 1st month after the treatment was significant, while the difference between the 1st and 3rd month after the treatment was not (p = 0.002 vs. p = 0.463). Patient treatment responses were: 44 (57.9%) complete response, 15 (19.7%) partial response, and 17 (22.4%) unresponsive to colchicine. Based on this finding, we can conclude that in the case of partial response to colchicine treatment after the first month, dose escalation, review of treatment compliance and the need for prophylaxis should be reevaluated. • Colchicine prophylaxis is recommended in PFAPA patients; however, the optimal time point for response assessment remains unclear. • The AIDAI score is suggested for measuring disease activity in autoinflammatory conditions. • This is the first repeated-measure study evaluating colchicine response in PFAPA patients using the AIDAI score. • Clinical response predominantly emerged within the first month, suggesting this period may be critical for evaluation.
Aydin Z, Kaya F, Kucuk E, Koru L, Dizman EN , et al.
European journal of pediatrics •
Recurrent aphthous stomatitis (RAS) is a common condition in pediatric age. Since there are significant genetic commonalities among idiopathic cases, periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome (PFAPA), and Behçet's disease (BD), they were proposed to be considered in one clinical spectrum termed Behçet's Spectrum Disorders (BSDs). This retrospective study aimed to evaluate the efficacy of colchicine on oral ulcers in children with BSD related RAS (BSD-RAS). Secondary aim was to compare the disease groups in terms of clinical and laboratory benefits. Data at admission and one year-after the treatment initiation were compared. A total of 317 patients with RAS were evaluated, and 186 patients classified as BSD-RAS (Female: n = 105, 56%). The median age at symptom onset was 5 (0.5-16.5) years. Colchicine was started to 142 (76%) patients. We observed a significant reduction in the frequency and duration of oral ulcers, as well as in the visual analogue scale (VAS) scores reported by patients/families and physicians, and the erythrocyte sedimentation rate during symptom-free periods across all three groups. In patients with PFAPA, both difference between initial and final recorded values (Δ) patient/families and Δ physician VAS scores were significantly higher than in other groups (p < 0.001). Furthermore, both Δ duration (p = 0.005) and Δ frequency of oral aphthae (p = 0.012) were significantly higher in idiopathic cases than those with PFAPA. These findings demonstrate a substantial reduction in both clinical symptoms and laboratory markers following colchicine treatment, supporting its effectiveness as a therapeutic option for BSD-RAS. •Recurrent aphthous stomatitis, PFAPA, and Behçet's disease may manifest with similar oral ulcers in pediatric patients. •Colchicine is frequently used in this clinical spectrum known as Behçet's Spectrum Disorders, although there is a scarcity of pediatric data. •Colchicine treatment significantly improved clinical and laboratory outcomes across all groups. •Idiopathic group had greater reductions in oral ulcer frequency and duration while PFAPA associated cases showed highest improvement in visual analogue scale scores.
Gozen ED, Yildiz M, Kara S, Tevetoglu F, Haslak F , et al.
Rheumatology international •
Periodic fever, aphthous stomatitis, pharyngitis, adenitis (PFAPA) syndrome is one of the most common autoinflammatory fever disorders in the childhood which may co-exists with familial Mediterranean fever (FMF) causing treatment complexity. As the role of surgery in PFAPA syndrome is still controversial, in this paper, our aim is to present our results of tonsillectomy/adenotonsillectomy in the treatment of PFAPA syndrome. Archives of a tertiary care hospital were investigated for patients who underwent tonsillectomy or adenotonsillectomy due to PFAPA Syndrome between 2010 and 2020. 344 patients were found but only 281 of them were accessible. Through phone call interview and chart review methods, preoperative and postoperative the number and severity of the attacks and general satisfaction after the operation were recorded and analyzed. Also, patients with concomitant FMF were analyzed separately. A total of 281 patients were included in the study. There was no improvement in 10 (3.55%) patients. Eight (2.84%) patients showed mild improvement, 29 (10.32%) patients had moderate improvement and 234 (83.27%) patients had full recovery after tonsillectomy. There were 266 PFAPA patients without FMF. No improvement, mild improvement, moderate improvement, and full recovery in this patient group were 5 (1.9%), 6 (2.3%), 25 (9.4%) and 230 (86.5%), respectively. FMF was present in 5.33% (15/281) of the patients. In PFAPA + FMF group 5 patients had no improvement (33.3%), 2 had mild improvement (13.3%), 4 had moderate improvement (26.7%) and 4 had full recovery (26.7%). Benefit of tonsillectomy was significantly lower in the patients with concomitant FMF when compared to the patients who did not have FMF (p < 0.001). Age of diagnosis, age of operation, severity of the disease, type of operation, and gender were found to have no significant relationship with the benefit from surgery (p < 0.05). According to the findings of this study, tonsillectomy is an effective long-term treatment for PFAPA syndrome with success rate of 83.27%. Also, preoperatively FMF should be considered in these patients, which dramatically reduces surgical efficacy.
Kaynak D, Yildiz M, Sahin S, Haslak F, Gunalp A , et al.
Clinical rheumatology •
Although most of the autoinfammatory disorders have a confirmed genetic cause, periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome still has an unknown genetic background. However, familial cases of PFAPA syndrome have been reported suggesting a genetic its basis. PFAPA syndrome may also be considered an infammasome disorder as variants in infammasome-associated genes such as CARD8, NLRP3, and MEFV have been reported to contribute to the disease. Polymerase chain reaction (PCR)/Sanger sequencing analysis was performed for the detection of the variations in 71 PFAPA patients and 71 healthy controls. NLRP3 concentrations in serum were measured in 71 PFAPA patients and 71 healthy controls. No statistically significant differences were observed in the allele or genotype frequencies of the NLRP3 polymorphisms between the controls and patients (P > 0.05). We found no significant differences for NLRP3 serum levels between PFAPA patients and controls (p > 0.05). Mutations in the MEFV gene were detected in 32.5% of our patients (13/40). It seems that the synergistic effect of different genes plays a role in the formation of PFAPA syndrome. For this reason, it may be useful to examine the presence of mutations in genes such as NLRP3, MEFV, and CARD8 together while investigating the genetics of PFAPA syndrome. Key points • Familial cases of PFAPA syndrome have been reported suggesting a genetic basis for this syndrome. • Elevated serum or plasma levels of IL-1β, IL-6, and IL-18 have been demonstrated during PFAPA flares in several studies. • It seems that the synergistic effect of different genes plays a role in the formation of PFAPA syndrome.
Konte EK, Haslak F, Yildiz M, Gucuyener N, Ulkersoy I , et al.
European journal of pediatrics •
Despite the advanced knowledge concerning autoinflammatory diseases (AID), more data regarding the optimal treatment options and outcomes of the children who met the criteria of more than one AID are required. This study aimed to describe the demographic and clinical characteristics of children from familial Mediterranean fever (FMF)-endemic countries who meet both the FMF and the periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome criteria. Moreover, we aimed to measure the response rates to colchicine and tonsillectomy and evaluate the factors affecting the colchicine response in these patients. The study was conducted at pediatric rheumatology tertiary centre. A total of 131 patients (58 females; 73 males) who met both the modified Marshall and pediatric FMF criteria were included. The median age at onset was 18 months (1-77 months), and the mean age at diagnosis was 47 ± 21.88 months. The median interval between episodes was 21 (7-90) days. The median disease duration was 46 (6-128) months. Consanguineous marriage was detected in 17 (13%) of the patients. The most common clinical finding was fever (100%), followed by exudative pharyngitis (88.5%), abdominal pain (86.3%), arthralgia (61.8%), stomatitis (51.1%), adenitis (42%), myalgia (28.7%), chest pain (16%), maculopapular rash (12.2%), arthritis (8.4%), and erysipelas-like rash (4.6%). MEFV gene variants were identified in 106 (80.9%) patients. The most common variants were M694V heterozygous (29%). We found that patients with tonsillopharyngitis, aphthous stomatitis, and PFAPA family history were more likely to be colchicine-resistant and tonsillectomy responsive, while those with exon 10 MEFV gene mutations were more prone to have a favorable response to colchicine. Conclusion: PFAPA syndrome patients with exon 10 MEFV gene mutation, showing typical FMF symptoms, should be treated with colchicine, even after tonsillectomy. In multivariate analysis, PFAPA family history and lack of exon 10 MEFV gene mutations were independent risk factors for colchicine resistance. Thus, tonsillectomy may be recommended as a possible treatment option for these patients. It has yet to be clarified when colchicine treatment will be discontinued in patients whose attacks ceased after tonsillectomy that was performed due to colchicine unresponsiveness. What is Known: • A certain number of patients with periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome concomitantly fulfill the familial Mediterranean fever (FMF) criteria. • While colchicine is proposed as a first treatment choice in familial Mediterranean fever (FMF), corticosteroids are recommended as a first-line treatment in PFAPA syndrome patients. What is New: • In patients with concomitant PFAPA syndrome and FMF, PFAPA family history and lack of exon 10 MEFV gene mutation are predictive factors of colchicine resistance. • The presence of exon 10 MEFV gene mutations in patients with concomitant FMF and PFAPA syndrome has a favourable effect on response to colchicine treatment.
Yıldız M, Haslak F, Adrovic A, Ülkersoy İ, Gücüyener N , et al.
Turkish archives of pediatrics •
The purpose of this study is to share our experience about clinical findings, natural course, and treatment response rates of a large cohort of patients with periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome. Medical records of patients who were diagnosed with PFAPA syndrome between January 2010 and May 2021 at Istanbul University-Cerrahpasa Cerrahpasa Medical Faculty pediatric rheumatology department were reviewed retrospectively. A total of 607 patients (females: 277, males: 330) with PFAPA syndrome were included. The median duration of episodes was 3 (1-15; interquartile range (IQR) 3-5) days, and the median interval between episodes was 20 days (5-120; IQR 15-30). The median age at the last attack and median disease duration were 66 (24-168; IQR 48-84) months and 40 (4-132; IQR 27.5-60) months, respectively. Fever (100%) was the most common clinical finding, followed by pharyngitis/exudative tonsillitis in 594 (97.9%), aphthous stomatitis in 308 (50.7%), cervical lymphadenopathy in 278 (45.8%), abdominal pain in 249 (41%), and arthralgia in 228 (37.6%) of the patients. Among the clinical findings, there was no statistical difference according to gender, except for cervical lymphadenitis being higher in males (P < .001). Of the patients who were given steroids during attacks, 94.6% were responsive. Colchicine was effective in 93 (63.7%) patients. The disease episodes ceased in 313 (95.4%) of patients who had tonsillectomy/adenoidectomy. Clinicians should be alert for additional symptoms such as abdominal pain, arthralgia, and headache apart from the cardinal signs. Although tonsillectomy is highly effective, its use is controversial. Colchicine may be a good alternative for prophylaxis.
Yildiz M, Haslak F, Adrovic A, Gucuyener N, Ulkersoy I , et al.
Clinical rheumatology •
Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome is a polygenic disease with unknown etiology. In this retrospective cohort study, we aimed to evaluate the risk factors for the resolution of PFAPA syndrome within 4 years after the onset. In total, 466 patients with PFAPA syndrome that are being followed up our department were included into the study. Between May 2020 and September 2020, medical charts of the patients were reviewed retrospectively. The median age of the patients at the time of the study and at disease onset were 8.6 (2.9-20.5; IQR 6.9-10.6) years and 18 (1-84; IQR 11-31) months. On univariate analysis age at disease onset (p = 0.003), positive family history of PFAPA syndrome (p = 0.04), absence of myalgia (p = 0.04), and absence of headache (p = 0.003) were all associated with the resolution of PFAPA syndrome within 4 years after the onset. Multivariate logistic regression analysis revealed that age at disease onset (OR 1.04, 95% CI 1.01-1.07, p = 0.002), positive family history of PFAPA syndrome (OR 2.69, 95% CI 1.12-6.48, p = 0.02), and absence of headache (OR 0.2, 95% CI 0.05-0.74, p = 0.01) were independent risk factors for the resolution of PFAPA syndrome within 4 years after the onset. We report later age of disease onset, positive family history of PFAPA syndrome, and absence of headache as independent risk factors for resolution of PFAPA syndrome within 4 years after the onset. • Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome is a multifactorial disease with unknown etiology. • Although, PFAPA syndrome usually resolves within 3-5 years after the disease onset, it can persist for years and even continue into adulthood. With our current knowledge, there is no clue to predict which patients will have a long disease course and which patients will not. • Later age of disease onset, positive family history of PFAPA syndrome and absence of headache as independent risk factors for resolution of PFAPA syndrome within 4 years after the onset.
Yildiz M, Adrovic A, Ulkersoy I, Gucuyener N, Koker O , et al.
European journal of pediatrics •
This study was conducted to investigate the relationship between clinic features and Mediterranean fever gene (MEFV) variants in patients with periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome. In total, 167 patients with PFAPA syndrome were included in the study. Female:male ratio of the patients was 0.75 (72 females, 95 males). In total 59.9% of patients with PFAPA had at least one MEFV variant and the most common heterozygous variants were M694V in 29.3% of the patients (40/167), E148Q in 8.3% (14/167), and V726A in 7.1% (12/167). The median age at the disease onset was significantly higher and the median duration of the episodes was significantly lower in patient with variants in exon 10 comparing to the others (both p = 0.01). Similarly, the median age at the disease onset was significantly higher (p = 0.01) and the median duration of the episodes was significantly lower (p = 0.04) in patient with MEFV variants than in the remaining patients. There were no significant differences according to the genotypes of the patients in terms of both treatment response and the frequency of clinical findings.Conclusion: In PFAPA syndrome, MEFV variants may be a modifier for disease onset and attack duration. What is Known: • Due to periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome having clinical findings resembling familial Mediterranean fever (FMF), it can be difficult to distinguish PFAPA syndrome and FMF especially in endemic regions for FMF. • Underlying MEFV mutations could affect the periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome's clinical presentation and response to treatment. What is New: • Having one of the underlying MEFV variants is related to later disease onset and shorter episode duration in patients with PFAPA syndrome.