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Sacroiliitis in children and adolescents with familial Mediterranean fever

Sacroiliitis in children and adolescents with familial Mediterranean fever Background: Familial Mediterranean fever (FMF) is an autoinflammatory disease characterized by recurrent episodes of fever and serositis. Sacroiliitis can be observed in some FMF patients. This study aimed to compare the demographic, clinical, and laboratory findings, and treatment in children with FMF and sacroiliitis, and children with juvenile spondyloarthropathy (JSpA). Methods: In total, 1687 pediatric FMF patients that were followed-up between May 2010 and June 2020 were evaluated retrospectively. Among them, those with sacroiliitis (n = 63) were included in the study and compared to patients with JSpA (n = 102). Results: The study included 63 FMF patients with sacroiliitis (38 males [60.3%] and 25 females [39.7%]) with a mean age of 15.2 ± 4.1 years. Mean age at symptom onset was 7.2 ± 5.05 years and mean age at diagnosis was 9.74 ± 4.67 years. The most common mutation in the FMF patients was M694V/M694V (n = 22). Patients were diagnosed with sacroiliitis with a mean of 12 months (range: 6–36 months) after the diagnosis of FMF. Among the FMF patients, 28 (44.4%) had enthesitis, 23 (36.5%) had heel pain, and 11 (17.4%) had low back pain. The study also included 102 JSpA patients (90 males [88.2%] and 12 females [11.8%]). Mean age of patients with JSpA was 16.1 ± 2.8 years. As compared to 102 JSpA patients, patients with FMF and sacroiliitis had higher acute phase reactants, whereas HLA- B27 positivity rate was lower. In addition, axial involvement rate was higher in the JSpA patients. Conclusion: Sacroiliitis is a common co-morbidity in FMF patients. The phenotypic features of these patients are different from patients with JSpA. Keywords: Familial Mediterranean fever, Enthesitis-related arthritis, Spondyloarthropathy, Sacroiliitis, Childhood Introduction sacroiliitis [1]. The increased frequency of sacroiliitis Familial Mediterranean fever (FMF) is an autoinflamma- have been reported among FMF patients. Patients with tory disease characterized by self-limited recurrent FMF and sacroiliitis usually present with unilateral or febrile attacks and polyserositis accompanied by elevated bilateral sacroiliitis, recurrent enthesitis, and inflamma- acute phase reactants. Joint involvement is one of the tory back or neck pain [1]. most common features during the disease course and Sacroiliac involvement in FMF patients can resemble about 75% of patients have arthritis during FMF attacks. spondyloarthropathy (SpA); however, in patients with Acute recurrent monoarthritis is the most common FMF and sacroiliitis, the presence of HLA-B27 or spinal form of musculoskeletal involvement in FMF patients, involvement is unusual, whereas SpA is a group of sero- whereas about 5% of FMF patients can develop negative arthritis type characterized by enthesitis, asym- metrical oligoarthritis of the lower extremities, axial * Correspondence: nurayaktay@gmail.com involvement, HLA-B27 positivity, and age at onset < 16 Department of Pediatric Rheumatology, Istanbul University Medical School, years. However, it is still controversial whether sacroilii- Istanbul, Turkey tis is a part of FMF or it is related with the coexistence Full list of author information is available at the end of the article © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Kaçmaz et al. Advances in Rheumatology (2021) 61:29 Page 2 of 5 of two diseases; FMF and SpA. Revealing the differences Smirnov and Shapiro-Wilk’s tests) to determine the nor- and similarities between these two diseases may help cli- mality of their distribution. Descriptive analyses are pre- nicians to clarify this controversy. Therefore; the present sented as percentage, mean, standard deviation, median, study aimed to determine the differences between FMF and range, as appropriate. Categorical parameters were patients with sacroiliitis, and patients with juvenile SpA compared with the Chi-square test or Fisher test when (JSpA). appropriate. The Student’s T test was used to compare normally distributed variables between the 2 groups. The Materials and methods Mann-Whitney U test was used to compare non-normally The files of 1687 FMF patients and 548 JIA patients that distributed variables between the 2 groups. The level of were followed-up by the pediatric rheumatology out- statistical significance was set at P <0.05. patient clinic between May 2010 and June 2020 were retrospectively reviewed. Among 1687 FMF patients, Results those with concurrent sacroiliitis were included in the Among 1687 FMF patients that were followed-up by the study (n = 63, group 1). Furthermore, among 548 JIA pa- pediatric rheumatology outpatient clinic, 63 had concur- tients, those with JSpA were also included in the study rent sacroiliitis (group 1). The most common mutation (n = 102, group 2). Patients having psoriasis and inflam- was M694V/M694V (n = 22). Moreover, 44 FMF patients matory bowel disease or a follow-up period of less than had ≥1 M694V mutations (Table 1). Mean duration of 6 months or missing data were excluded. follow-up was 60.9 ± 40 months. The median colchicine − 1 − 1 FMF was diagnosed according to pediatric FMF diag- dose was 3 mg d (range: 2–3mg d ). The median nostic criteria [2] and JSpA was diagnosed according to monthly FMF attack frequency was 1 (range: 0–2). The ILAR criteria [3]. median disease severity score was 9 (range: 7–12). Ac- Demographic findings (age, gender, age at diagnosis, and cording to the Pras severity score, 1 (1.6%) of the FMF family history of HLA-B27-associated disease or FMF), clin- patients was classified as mild, 39 (61.9%) as moderate, ical findings (fever, abdominal pain, nausea, vomiting, and 23 (36.5%) as severe. diarrhea, constipation, chest pain, duration of attacks, joint The FMF patients were diagnosed with sacroiliitis with pain, joint swelling, muscle pain, prolonged febrile myalgia, a mean of 12 months (range: 6–36 months) after being erysipelas-like erythema, enthesitis, waist and hip pain, heel diagnosed with FMF. In all, 28 (44.4%) of the FMF pa- pain, and morning stiffness), and laboratory findings tients had enthesitis, 23 (36.5%) had heel pain, and 11 (complete blood count, the erythrocyte sedimentation rate (17.4%) had lower back pain. Upon physical examination [ESR], C-reactive protein [CRP], anti-nuclear antigen sacroiliac joint tenderness was detected in 26 (42%) pa- [ANA], HLA-B27, and MEFV gene results) were retro- tients. MRI findings of sacroiliac joints were compatible spectively obtained from the patients’ files. with unilateral sacroiliitis in 2 of the FMF patients and The frequency of FMF attacks, disease severity scores, bilateral sacroiliitis in 61. Among group I, 32 patients use of colchicine, and colchicine resistance were evalu- fulfilled the classification criteria for JSpA. In total, 15 ated. Treatments were also documented from medical files. The resistance to colchicine treatment was defined Table 1 Demographical and clinical findings of patients with as experiencing ≥1 attack per month despite receiving familial Mediterranean fever (FMF) the maximally tolerated dose for ≥6 months. Findings Number of patients Disease severity was determined via the Pras score, which Female/Male 25/38 was readjusted according to the colchicine dose [4, 5]. The mean age of patients, years 15.1 ± 4.1 MRI was performed using a 1.5 T (T) device. Active The mean age at symptom onset, years 7.2 ± 5.05 sacroiliitis was determined via MRI according to Assess- ment in Spondyloarthritis International Society (ASAS) The mean age at diagnosis, years 9.7 ± 4.6 criteria. Groups 1 and 2 were compared in terms of The mean duration of disease, years 7.4 ± 5.3 demographic findings, clinical and laboratory findings, The frequency of consanguineous marriage, n (%) 24 (38.1) and treatment. The history of FMF in family 22 (34.9) The study protocol was approved by the local ethics The history of FMF in siblings 10 (15.9) committee (Approval no. KAEK/2020.06.69). Recurrent fever, n (%) 35 (55.6) Statistical analysis Abdominal pain, n (%) 38 (60.3) Statistical analysis was performed using IBM SPSS Statis- Chest pain, n (%) 15 (23.8) tics for Windows v.21 (IBM Corp., Armonk, NY). The Exertional leg pain, n (%) 22 (34.9) study variables were investigated using visual (histogram Erysipelas-like erythema (ELE), n (%) 19 (30.2) and probability plots) and analytic methods (Kolmogorov- Kaçmaz et al. Advances in Rheumatology (2021) 61:29 Page 3 of 5 FMF patients received anti-TNF (adalimumab: n = 6; eta- in the form of acute transient monoarthritis affecting the nercept: n = 9) and 6 patients were treated with toci- ankles or knees; however, some patients can also have lizumab. At the time of study, all patients were inactive chronic arthritis affecting the hips or small joints. The both clinically and laboratory means. presence of M694V mutation is associated with musculo- The study also included 102 JSpA patients (group 2), skeletal symptoms [6]. Inflammatory back or hip pain can of which 90 (88.2%) were male and 12 (11.8%) were fe- occur in FMF patients with sacroiliac joint involvement. male. Mean age in group 2 was 16.1 ± 2.8 years and Generally, such patients are negative for HLA-B27 antigen mean age at diagnosis of JSpA was 13.2 ± 2.6 years. Mean and spinal involvement is rare. The frequency of sacroilii- diagnostic delay was 8.3 ± 6.1 months. In all, 4 (3.9%) of tis is higher in Turkish and Jewish FMF patients than in the JSpA patients had anterior uveitis. ANA test results those of other ethnicities [7, 8]; however, sacroiliac joint were positive in 13 (12.7%) patients and HLA-B27 posi- involvement is relatively rare in children. Earlier adult tivity was noted in 51 (50%). Ankylosis developed in 4 FMF studies noted that the frequency of sacroiliitis is 0.4– (3,9%) patients, as follows: both ankles (n = 1); right 10.5% [7–10]. In addition, HLA-B27 antigen is generally ankle (n = 1); left ankle (n = 2). Among the JSpA patients, negative, but positive cases are also reported, although 24 (23.5%) received methotrexate and 87 (85.7%) re- rarely. In the present study concomitant sacroiliitis was ceived salazopyrin. Biological therapy was administered noted in 63 (3.7%) of 1687 pediatric FMF patients, of to 32 (27.1%) patients, as follows: etanercept: n = 23; ada- which only 4 were HLA-B27 antigen positive. Moreover, limumab: n = 9. None of the patients in group II carried 44 of the patients had ≥1 M694V mutations. MEFV mutations. Langevitz et al. [9] evaluated 3000 adult FMF patients Acute phase reactants were higher (CRP; 14.4 versus living in Israel and reported that the frequency of sacroi- 4.6, P < 0.001 and ESR; 32 versus 16, P < 0.001) and liitis was 0.4% and that 11 patients had seronegative HLA-B27 positivity rate was lower in group 1 than in SpA, of which 9 were male and 2 were female with mean group 2 (6.3% versus 50%, P < 0.001). Moreover, axial in- age at diagnosis of 32.4 ± 7.1 years. These 11 patients volvement was not observed in group 1, but was noted were followed-up with the diagnosis of FMF for a mean in 4.9% of the patients in group 2 (P = 0.07) (Table 2). 27.4 ± 5.1 years. They also reported that all of these 11 The biological treatment rate in group 1 was 33.3% (n = patients had inflammatory back pain, and neck pain 21), versus 31.3% (n = 32) in group 2 (P = 0.79). Only (n = 4), bilateral or unilateral stage 3–4 sacroiliitis (n = anti-TNF drugs were used as biological agents in group 7), bilateral stage 2 sacroiliitis (n = 4), monoarthritis (n = 2, whereas 15 of the patients in group 1 were treated 5), oligoarthritis (n = 6), enthesitis (n = 6), and heel pain with anti-TNF drugs and 6 with anti-interleukin 6 (n = 7). HLA-B27 antigen was negative in all of them [9]. (tocilizumab). In the present study sacroiliitis was noted in 3.7% (n = 63) of 1687 FMF patients. Patients were diagnosed with Discussion sacroiliitis with a mean of 12 months (range 6–36 Musculoskeletal symptoms are very common in patients months) following diagnosis of FMF; 28 of these patients with FMF. Joint swelling in FMF patients usually occurs had enthesitis and 11 had lower back pain. Table 2 Comparison of Group 1 and Group II patients Findings Group I (n = 63) Group II (n = 102) P value Gender (Female/Male), n (%) 25/38 (39.7)/ (60.3) 12/90 (11.8)/ (88.2) < 0.001 Enthesitis, n (%) 28 (44.4) 36 (35.2) 0.18 Heel pain, n (%) 23 (36.5) 42 (41.1) 0.62 Low back pain, n (%) 11 (17.4) 48 (47.0) < 0.001 Ankylosis, n (%) 0 (0) 5 (4.9) 0.07 Positivity of HLA-B27, n (%) 4 (6.3) 51 (50) < 0.001 3 3 Leukocyte count, (× 10 /mm ) 9800 (7200–12,000) 9720 (6800–11,800) 0.33 CRP (mg/L) (normal range:0–5) 14.4 (0.8–142) 4.6 (0.1–137) < 0.001 ESR (mm/hour) (normal range:0–20) 32 (20–120) 16 (1–112) < 0.001 Methotrexate, n (%) 19 (30.1) 24 (23.5) 0.22 Salazopyrin, n (%) 46 (73.1) 87 (85.2) 0.06 Biologic drugs, n (%) 21 (33.3) 32 (31.3) 0.79 CRP C-reactive protein, ESR erythrocyte sedimentation rate, HLA-B27 Human- leucocyte antigen-B27 These values are the values at the time of diagnosis of spondyloarthropathy Kaçmaz et al. Advances in Rheumatology (2021) 61:29 Page 4 of 5 Why sacroiliitis occurs in FMF patients remains a mat- receiving tocilizumab achieved remission in terms of FMF ter of debate; however, a family history of SpA in some and sacroilliitis. This suggests that FMF and sacroillitis patients suggests a genetic relationship. Akar et al. [11] has different pathogenetic mechanisms than JSpA. reported an increased risk of sacroiliitis in adult patients The limitation of the present study is its retrospective with FMF and their families (the risk ratio is 3.3 [95% design, whereas the large number of patients included is CI: 2–5] in first-degree relatives and 2.9 [95% CI: 1.3– a strength. 6.4] in individuals with FMF). Of the 63 FMF patients with sacroiliitis in the present study, 22 had a family his- Conclusion tory of FMF, but none had a family history of SpA. To the best of our knowledge the present study is the Sacroiliitis has also been reported in pediatric FMF pa- largest such study to date, highlighting the association tients. Sonmez et al. [12] compared 15 children diag- between FMF disease and sacroiliitis. These patients nosed with FMF and sacroiliitis, and 30 juvenile SpA may show different phenotype than classical JSpA pa- patients, observing that the FMF patients with sacroiliitis tients. Further delineation of the clinical and laboratory had higher inflammatory markers, whereas the frequency findings in pediatric FMF patients with sacroiliitis will of enthesitis, axial involvement, and HLA-B27 antigen facilitate easier diagnosis and prevent delays in treat- positivity was lower. Aydın et al. [13] analyzed 650 chil- ment. Although clinical differences are revealed, studies dren with FMF and reported that 17 (2.6%) had sacroilii- on etiopathogenesis are needed to show the main differ- tis, of which 90% carried the M694V mutation. Özdel ences of these two diseases. et al. [14] compared 18 children with FMF and sacroilii- tis, and 38 children diagnosed with JSpA, noting that Acknowledgments there was no difference between the 2 groups in HLA- None. B27 antigen positivity, family history, clinical findings, enthesitis, or treatment. In the present study the patients Authors’ contributions with FMF and sacroiliitis had higher acute phase reac- HK conceptualized and designed the study, drafted the initial manuscript, tants and a lower HLA-B27 antigen positivity rate, as and had full access to all the data in the study; EA, AT, SGK, MÇ, HES and well as no axial involvement. In addition, there wasn’ta NAA designed the study, conducted the data analyses, drafted the initial manuscript, and had full access to all the data in the study. All authors significant difference between groups 1 and 2 in terms reviewed and revised the manuscript and approved the final version of the of the presence of enthesitis. manuscript. There is no standard treatment for FMF associated with sacroiliitis. Sonmez et al. [12] reported treating all Funding such patients with non-steroidal anti-inflammatory None. drugs, and that 9 patients were treated with methotrex- ate, 9 with sulfasalazine, and 10 with anti-TNF (etaner- Availability of data and materials cept). Aydın et al. [13] reported that of 17 patients Not applicable. diagnosed with FMF and sacroiliitis, 14 were treated with non-steroidal anti-inflammatory drugs in addition Declarations to colchicine, 10 received sulfasalazine, and 7 received Ethics approval and consent to participate biological drugs. Özdel et al. [14]] compared 18 children The study protocol was approved by the local ethics committee (Approval with FMF and sacroiliitis, and 38 children diagnosed no. KAEK/2020.06.69). with JSpA, reporting that there was no difference between the 2 groups in terms of treatment. Cherqaoui et al. [15] Consent for publication observed that patients diagnosed with FMF and JSpA re- All authors gave consent for publication. quired fewer non-steroidal anti-inflammatory drugs and anti-TNF drugs than patients with other JSpA. In the Competing interests present study anti-TNF drugs were given to 15 of the The authors have declared no conflicts of interest. FMF patients with sacroiliitis (adalimumab: n =6; etaner- Author details cept: n = 9) in addition to colchicine, and 6 patients were 1 Department of Pediatric Rheumatology, University of Health Sciences, using tocilizumab. Moreover, the biological drug use rate Kanuni Sultan Süleyman Research and Training Hospital, Istanbul, Turkey. Department of Pediatric Rheumatology, University of Health Sciences, did not differ significantly between groups 1 and 2, but Başakşehir Çam ve Sakura City Hospital, Istanbul, Turkey. Department of the preferred biological therapy varied. Tocilizumab failed Pediatric Rheumatology, Istanbul University Medical School, Istanbul, Turkey. to achieve remission in the adult patients with spondyloar- Department of Pediatric Rheumatology, Sadi Konuk Research and Training Hospital, Istanbul, Turkey. Department of Pediatric Rheumatology, University thritis [16]. However, previous studies have reported suc- of Health Sciences, Zeynep Kamil Research and Training Hospital, Istanbul, cessful results with tocilizumab in FMF patients [17, 18]. 6 Turkey. Department of Pediatric Rheumatology, Kocaeli University, Istanbul, In presented study, all 6 patients with FMF and sacroiliitis Turkey. Kaçmaz et al. Advances in Rheumatology (2021) 61:29 Page 5 of 5 Received: 15 January 2021 Accepted: 20 May 2021 Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. References 1. Younes M, Kahn MF, Meyer O. Hip involvement in patients with familial Mediterranean fever. A review of ten cases. Joint Bone Spine. 2002;69(6): 560–5. https://doi.org/10.1016/S1297-319X(02)00452-9. 2. Yalcinkaya F, Ozen S, Ozcakar ZB, Aktay N, Cakar N, Duzova A, et al. A new set of criteria for the diagnosis of familial Mediterranean fever in childhood. Rheumatology (Oxford). 2009;48(4):395–8. https://doi.org/10.1093/rheuma tology/ken509. 3. Petty RE, Southwood TR, Manners P, Baum J, Glass DN, Goldenberg J, et al. International league of associations for rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol. 2004;31(2):390–2. 4. Ozen S, Aktay N, Lainka E, Duzova A, Bakkaloglu A, Kallinich T. Disease severity in children and adolescents with familial Mediterranean fever: a comparative study to explore environmental effects on a monogenic disease. Ann Rheum Dis. 2009;68(2):246–8. https://doi.org/10.1136/ard.2008.092031. 5. Pras E, Livneh A, Balow JE, Pras E, Kastner DL, Pras M, et al. Clinical differences between north African and Iraqi Jews with familial Mediterranean fever. Am J Med Genet. 1998;75(2):216–9. https://doi.org/10.1 002/(SICI)1096-8628(19980113)75:2<216::AID-AJMG20>3.0.CO;2-R. 6. Akkoc N, Gul A. Familial Mediterranean fever and seronegative arthritis. Curr Rheumatol Rep. 2011;13(5):388–94. https://doi.org/10.1007/s11926-011-0191-9. 7. Cefle A, Kamali S, Sayarlioglu M, Inanc M, Ocal L, Aral O, et al. A comparison of clinical findings of familial Mediterranean fever patients with and without amyloidosis. Rheumatol Int. 2005;25(6):442–6. https://doi.org/10.1007/s002 96-004-0471-z. 8. Kasifoglu T, Calisir C, Cansu DU, Korkmaz C. The frequency of sacroiliitis in familial Mediterranean fever and the role of HLA-B27 and MEFV mutations in the development of sacroiliitis. Clin Rheumatol. 2009;28(1):41–6. https:// doi.org/10.1007/s10067-008-0980-3. 9. Langevitz P, Livneh A, Zemer D, Shemer J, Pras M. Seronegative spondyloarthropathy in familial Mediterranean fever. Semin Arthritis Rheum. 1997;27(2):67–72. https://doi.org/10.1016/S0049-0172(97)80007-8. 10. Tunca M, Akar S, Onen F, Ozdogan H, Kasapcopur O, Yalcinkaya F, et al. Familial Mediterranean fever (FMF) in Turkey: results of a nationwide multicenter study. Medicine (Baltimore). 2005;84:1–11. 11. Akar S, Soysal O, Balci A, Solmaz D, Gerdan V, Onen F, et al. High prevalence of spondyloarthritis and ankylosing spondylitis among familial Mediterranean fever patients and their first-degree relatives: further evidence for the connection. Arthritis Res Ther. 2013;15:R21. 12. Sonmez HE, Batu ED, Demir S, Bilginer Y, Ozen S. Comparison of patients with familial Mediterranean fever accompanied with sacroiliitis and patients with juvenile spondyloarthropathy. Clin Exp Rheumatol. 2017;108:124–7. 13. Aydin F, Ozcakar ZB, Cakar N, Celikel E, Uncu N, Celikel Acar B, et al. Sacroiliitis in children with familial Mediterranean fever. J Clin Rheumatol. 2019;25(2):69–73. https://doi.org/10.1097/RHU.0000000000000770. 14. Ozdel S, Baglan E, Cakici EK, Yazilitas F, Gur G, Celikkaya E, et al. Similarities between pediatric FMF patients with sacroiliitis and pediatric juvenile spondyloarthropathy patients with sacroiliitis: a preliminary study. Acta Clin Belg. 2020:1–6. https://doi.org/10.1080/17843286.2020.1724450. 15. Cherqaoui B, Rossi-Semerano L, Georgin-Lavialle S, Dusser P, Galeotti C, Piram M, et al. Boundaries between familial Mediterranean fever and juvenile spondyloarthritis: analysis of three French retrospective cohorts. Joint Bone Spine. 2018;85(6):733–9. https://doi.org/10.1016/j.jbspin.2018.01. 16. Sieper J, Porter-Brown B, Thompson L, Harari O, Dougados M. Assessment of short-term symptomatic efficacy of tocilizumab in ankylosing spondylitis: results of randomised, placebo-controlled trials. Ann Rheum Dis. 2014;73(1): 95–100. https://doi.org/10.1136/annrheumdis-2013-203559. 17. Kuemmerle-Deschner JB, Gautam R, George AT, Raza S, Lomax KG, Hur P. A systematic literature review of efficacy, effectiveness and safety of biologic therapies for treatment of familial Mediterranean fever. Rheumatology (Oxford). 2020;59(10):2711–24. https://doi.org/10.1093/rheumatology/keaa205. 18. Umeda M, Aramaki T, Fujikawa K, Iwamoto N, Ichinose K, Terada K, et al. Tocilizumab is effective in a familial Mediterranean fever patient complicated with histologically proven recurrent fasciitis and myositis. Int J Rheum Dis. 2017;20(11):1868–71. https://doi.org/10.1111/1756-185X.12776. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Advances in Rheumatology Springer Journals

Sacroiliitis in children and adolescents with familial Mediterranean fever

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Abstract

Background: Familial Mediterranean fever (FMF) is an autoinflammatory disease characterized by recurrent episodes of fever and serositis. Sacroiliitis can be observed in some FMF patients. This study aimed to compare the demographic, clinical, and laboratory findings, and treatment in children with FMF and sacroiliitis, and children with juvenile spondyloarthropathy (JSpA). Methods: In total, 1687 pediatric FMF patients that were followed-up between May 2010 and June 2020 were evaluated retrospectively. Among them, those with sacroiliitis (n = 63) were included in the study and compared to patients with JSpA (n = 102). Results: The study included 63 FMF patients with sacroiliitis (38 males [60.3%] and 25 females [39.7%]) with a mean age of 15.2 ± 4.1 years. Mean age at symptom onset was 7.2 ± 5.05 years and mean age at diagnosis was 9.74 ± 4.67 years. The most common mutation in the FMF patients was M694V/M694V (n = 22). Patients were diagnosed with sacroiliitis with a mean of 12 months (range: 6–36 months) after the diagnosis of FMF. Among the FMF patients, 28 (44.4%) had enthesitis, 23 (36.5%) had heel pain, and 11 (17.4%) had low back pain. The study also included 102 JSpA patients (90 males [88.2%] and 12 females [11.8%]). Mean age of patients with JSpA was 16.1 ± 2.8 years. As compared to 102 JSpA patients, patients with FMF and sacroiliitis had higher acute phase reactants, whereas HLA- B27 positivity rate was lower. In addition, axial involvement rate was higher in the JSpA patients. Conclusion: Sacroiliitis is a common co-morbidity in FMF patients. The phenotypic features of these patients are different from patients with JSpA. Keywords: Familial Mediterranean fever, Enthesitis-related arthritis, Spondyloarthropathy, Sacroiliitis, Childhood Introduction sacroiliitis [1]. The increased frequency of sacroiliitis Familial Mediterranean fever (FMF) is an autoinflamma- have been reported among FMF patients. Patients with tory disease characterized by self-limited recurrent FMF and sacroiliitis usually present with unilateral or febrile attacks and polyserositis accompanied by elevated bilateral sacroiliitis, recurrent enthesitis, and inflamma- acute phase reactants. Joint involvement is one of the tory back or neck pain [1]. most common features during the disease course and Sacroiliac involvement in FMF patients can resemble about 75% of patients have arthritis during FMF attacks. spondyloarthropathy (SpA); however, in patients with Acute recurrent monoarthritis is the most common FMF and sacroiliitis, the presence of HLA-B27 or spinal form of musculoskeletal involvement in FMF patients, involvement is unusual, whereas SpA is a group of sero- whereas about 5% of FMF patients can develop negative arthritis type characterized by enthesitis, asym- metrical oligoarthritis of the lower extremities, axial * Correspondence: nurayaktay@gmail.com involvement, HLA-B27 positivity, and age at onset < 16 Department of Pediatric Rheumatology, Istanbul University Medical School, years. However, it is still controversial whether sacroilii- Istanbul, Turkey tis is a part of FMF or it is related with the coexistence Full list of author information is available at the end of the article © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. Kaçmaz et al. Advances in Rheumatology (2021) 61:29 Page 2 of 5 of two diseases; FMF and SpA. Revealing the differences Smirnov and Shapiro-Wilk’s tests) to determine the nor- and similarities between these two diseases may help cli- mality of their distribution. Descriptive analyses are pre- nicians to clarify this controversy. Therefore; the present sented as percentage, mean, standard deviation, median, study aimed to determine the differences between FMF and range, as appropriate. Categorical parameters were patients with sacroiliitis, and patients with juvenile SpA compared with the Chi-square test or Fisher test when (JSpA). appropriate. The Student’s T test was used to compare normally distributed variables between the 2 groups. The Materials and methods Mann-Whitney U test was used to compare non-normally The files of 1687 FMF patients and 548 JIA patients that distributed variables between the 2 groups. The level of were followed-up by the pediatric rheumatology out- statistical significance was set at P <0.05. patient clinic between May 2010 and June 2020 were retrospectively reviewed. Among 1687 FMF patients, Results those with concurrent sacroiliitis were included in the Among 1687 FMF patients that were followed-up by the study (n = 63, group 1). Furthermore, among 548 JIA pa- pediatric rheumatology outpatient clinic, 63 had concur- tients, those with JSpA were also included in the study rent sacroiliitis (group 1). The most common mutation (n = 102, group 2). Patients having psoriasis and inflam- was M694V/M694V (n = 22). Moreover, 44 FMF patients matory bowel disease or a follow-up period of less than had ≥1 M694V mutations (Table 1). Mean duration of 6 months or missing data were excluded. follow-up was 60.9 ± 40 months. The median colchicine − 1 − 1 FMF was diagnosed according to pediatric FMF diag- dose was 3 mg d (range: 2–3mg d ). The median nostic criteria [2] and JSpA was diagnosed according to monthly FMF attack frequency was 1 (range: 0–2). The ILAR criteria [3]. median disease severity score was 9 (range: 7–12). Ac- Demographic findings (age, gender, age at diagnosis, and cording to the Pras severity score, 1 (1.6%) of the FMF family history of HLA-B27-associated disease or FMF), clin- patients was classified as mild, 39 (61.9%) as moderate, ical findings (fever, abdominal pain, nausea, vomiting, and 23 (36.5%) as severe. diarrhea, constipation, chest pain, duration of attacks, joint The FMF patients were diagnosed with sacroiliitis with pain, joint swelling, muscle pain, prolonged febrile myalgia, a mean of 12 months (range: 6–36 months) after being erysipelas-like erythema, enthesitis, waist and hip pain, heel diagnosed with FMF. In all, 28 (44.4%) of the FMF pa- pain, and morning stiffness), and laboratory findings tients had enthesitis, 23 (36.5%) had heel pain, and 11 (complete blood count, the erythrocyte sedimentation rate (17.4%) had lower back pain. Upon physical examination [ESR], C-reactive protein [CRP], anti-nuclear antigen sacroiliac joint tenderness was detected in 26 (42%) pa- [ANA], HLA-B27, and MEFV gene results) were retro- tients. MRI findings of sacroiliac joints were compatible spectively obtained from the patients’ files. with unilateral sacroiliitis in 2 of the FMF patients and The frequency of FMF attacks, disease severity scores, bilateral sacroiliitis in 61. Among group I, 32 patients use of colchicine, and colchicine resistance were evalu- fulfilled the classification criteria for JSpA. In total, 15 ated. Treatments were also documented from medical files. The resistance to colchicine treatment was defined Table 1 Demographical and clinical findings of patients with as experiencing ≥1 attack per month despite receiving familial Mediterranean fever (FMF) the maximally tolerated dose for ≥6 months. Findings Number of patients Disease severity was determined via the Pras score, which Female/Male 25/38 was readjusted according to the colchicine dose [4, 5]. The mean age of patients, years 15.1 ± 4.1 MRI was performed using a 1.5 T (T) device. Active The mean age at symptom onset, years 7.2 ± 5.05 sacroiliitis was determined via MRI according to Assess- ment in Spondyloarthritis International Society (ASAS) The mean age at diagnosis, years 9.7 ± 4.6 criteria. Groups 1 and 2 were compared in terms of The mean duration of disease, years 7.4 ± 5.3 demographic findings, clinical and laboratory findings, The frequency of consanguineous marriage, n (%) 24 (38.1) and treatment. The history of FMF in family 22 (34.9) The study protocol was approved by the local ethics The history of FMF in siblings 10 (15.9) committee (Approval no. KAEK/2020.06.69). Recurrent fever, n (%) 35 (55.6) Statistical analysis Abdominal pain, n (%) 38 (60.3) Statistical analysis was performed using IBM SPSS Statis- Chest pain, n (%) 15 (23.8) tics for Windows v.21 (IBM Corp., Armonk, NY). The Exertional leg pain, n (%) 22 (34.9) study variables were investigated using visual (histogram Erysipelas-like erythema (ELE), n (%) 19 (30.2) and probability plots) and analytic methods (Kolmogorov- Kaçmaz et al. Advances in Rheumatology (2021) 61:29 Page 3 of 5 FMF patients received anti-TNF (adalimumab: n = 6; eta- in the form of acute transient monoarthritis affecting the nercept: n = 9) and 6 patients were treated with toci- ankles or knees; however, some patients can also have lizumab. At the time of study, all patients were inactive chronic arthritis affecting the hips or small joints. The both clinically and laboratory means. presence of M694V mutation is associated with musculo- The study also included 102 JSpA patients (group 2), skeletal symptoms [6]. Inflammatory back or hip pain can of which 90 (88.2%) were male and 12 (11.8%) were fe- occur in FMF patients with sacroiliac joint involvement. male. Mean age in group 2 was 16.1 ± 2.8 years and Generally, such patients are negative for HLA-B27 antigen mean age at diagnosis of JSpA was 13.2 ± 2.6 years. Mean and spinal involvement is rare. The frequency of sacroilii- diagnostic delay was 8.3 ± 6.1 months. In all, 4 (3.9%) of tis is higher in Turkish and Jewish FMF patients than in the JSpA patients had anterior uveitis. ANA test results those of other ethnicities [7, 8]; however, sacroiliac joint were positive in 13 (12.7%) patients and HLA-B27 posi- involvement is relatively rare in children. Earlier adult tivity was noted in 51 (50%). Ankylosis developed in 4 FMF studies noted that the frequency of sacroiliitis is 0.4– (3,9%) patients, as follows: both ankles (n = 1); right 10.5% [7–10]. In addition, HLA-B27 antigen is generally ankle (n = 1); left ankle (n = 2). Among the JSpA patients, negative, but positive cases are also reported, although 24 (23.5%) received methotrexate and 87 (85.7%) re- rarely. In the present study concomitant sacroiliitis was ceived salazopyrin. Biological therapy was administered noted in 63 (3.7%) of 1687 pediatric FMF patients, of to 32 (27.1%) patients, as follows: etanercept: n = 23; ada- which only 4 were HLA-B27 antigen positive. Moreover, limumab: n = 9. None of the patients in group II carried 44 of the patients had ≥1 M694V mutations. MEFV mutations. Langevitz et al. [9] evaluated 3000 adult FMF patients Acute phase reactants were higher (CRP; 14.4 versus living in Israel and reported that the frequency of sacroi- 4.6, P < 0.001 and ESR; 32 versus 16, P < 0.001) and liitis was 0.4% and that 11 patients had seronegative HLA-B27 positivity rate was lower in group 1 than in SpA, of which 9 were male and 2 were female with mean group 2 (6.3% versus 50%, P < 0.001). Moreover, axial in- age at diagnosis of 32.4 ± 7.1 years. These 11 patients volvement was not observed in group 1, but was noted were followed-up with the diagnosis of FMF for a mean in 4.9% of the patients in group 2 (P = 0.07) (Table 2). 27.4 ± 5.1 years. They also reported that all of these 11 The biological treatment rate in group 1 was 33.3% (n = patients had inflammatory back pain, and neck pain 21), versus 31.3% (n = 32) in group 2 (P = 0.79). Only (n = 4), bilateral or unilateral stage 3–4 sacroiliitis (n = anti-TNF drugs were used as biological agents in group 7), bilateral stage 2 sacroiliitis (n = 4), monoarthritis (n = 2, whereas 15 of the patients in group 1 were treated 5), oligoarthritis (n = 6), enthesitis (n = 6), and heel pain with anti-TNF drugs and 6 with anti-interleukin 6 (n = 7). HLA-B27 antigen was negative in all of them [9]. (tocilizumab). In the present study sacroiliitis was noted in 3.7% (n = 63) of 1687 FMF patients. Patients were diagnosed with Discussion sacroiliitis with a mean of 12 months (range 6–36 Musculoskeletal symptoms are very common in patients months) following diagnosis of FMF; 28 of these patients with FMF. Joint swelling in FMF patients usually occurs had enthesitis and 11 had lower back pain. Table 2 Comparison of Group 1 and Group II patients Findings Group I (n = 63) Group II (n = 102) P value Gender (Female/Male), n (%) 25/38 (39.7)/ (60.3) 12/90 (11.8)/ (88.2) < 0.001 Enthesitis, n (%) 28 (44.4) 36 (35.2) 0.18 Heel pain, n (%) 23 (36.5) 42 (41.1) 0.62 Low back pain, n (%) 11 (17.4) 48 (47.0) < 0.001 Ankylosis, n (%) 0 (0) 5 (4.9) 0.07 Positivity of HLA-B27, n (%) 4 (6.3) 51 (50) < 0.001 3 3 Leukocyte count, (× 10 /mm ) 9800 (7200–12,000) 9720 (6800–11,800) 0.33 CRP (mg/L) (normal range:0–5) 14.4 (0.8–142) 4.6 (0.1–137) < 0.001 ESR (mm/hour) (normal range:0–20) 32 (20–120) 16 (1–112) < 0.001 Methotrexate, n (%) 19 (30.1) 24 (23.5) 0.22 Salazopyrin, n (%) 46 (73.1) 87 (85.2) 0.06 Biologic drugs, n (%) 21 (33.3) 32 (31.3) 0.79 CRP C-reactive protein, ESR erythrocyte sedimentation rate, HLA-B27 Human- leucocyte antigen-B27 These values are the values at the time of diagnosis of spondyloarthropathy Kaçmaz et al. Advances in Rheumatology (2021) 61:29 Page 4 of 5 Why sacroiliitis occurs in FMF patients remains a mat- receiving tocilizumab achieved remission in terms of FMF ter of debate; however, a family history of SpA in some and sacroilliitis. This suggests that FMF and sacroillitis patients suggests a genetic relationship. Akar et al. [11] has different pathogenetic mechanisms than JSpA. reported an increased risk of sacroiliitis in adult patients The limitation of the present study is its retrospective with FMF and their families (the risk ratio is 3.3 [95% design, whereas the large number of patients included is CI: 2–5] in first-degree relatives and 2.9 [95% CI: 1.3– a strength. 6.4] in individuals with FMF). Of the 63 FMF patients with sacroiliitis in the present study, 22 had a family his- Conclusion tory of FMF, but none had a family history of SpA. To the best of our knowledge the present study is the Sacroiliitis has also been reported in pediatric FMF pa- largest such study to date, highlighting the association tients. Sonmez et al. [12] compared 15 children diag- between FMF disease and sacroiliitis. These patients nosed with FMF and sacroiliitis, and 30 juvenile SpA may show different phenotype than classical JSpA pa- patients, observing that the FMF patients with sacroiliitis tients. Further delineation of the clinical and laboratory had higher inflammatory markers, whereas the frequency findings in pediatric FMF patients with sacroiliitis will of enthesitis, axial involvement, and HLA-B27 antigen facilitate easier diagnosis and prevent delays in treat- positivity was lower. Aydın et al. [13] analyzed 650 chil- ment. Although clinical differences are revealed, studies dren with FMF and reported that 17 (2.6%) had sacroilii- on etiopathogenesis are needed to show the main differ- tis, of which 90% carried the M694V mutation. Özdel ences of these two diseases. et al. [14] compared 18 children with FMF and sacroilii- tis, and 38 children diagnosed with JSpA, noting that Acknowledgments there was no difference between the 2 groups in HLA- None. B27 antigen positivity, family history, clinical findings, enthesitis, or treatment. In the present study the patients Authors’ contributions with FMF and sacroiliitis had higher acute phase reac- HK conceptualized and designed the study, drafted the initial manuscript, tants and a lower HLA-B27 antigen positivity rate, as and had full access to all the data in the study; EA, AT, SGK, MÇ, HES and well as no axial involvement. In addition, there wasn’ta NAA designed the study, conducted the data analyses, drafted the initial manuscript, and had full access to all the data in the study. All authors significant difference between groups 1 and 2 in terms reviewed and revised the manuscript and approved the final version of the of the presence of enthesitis. manuscript. There is no standard treatment for FMF associated with sacroiliitis. Sonmez et al. [12] reported treating all Funding such patients with non-steroidal anti-inflammatory None. drugs, and that 9 patients were treated with methotrex- ate, 9 with sulfasalazine, and 10 with anti-TNF (etaner- Availability of data and materials cept). Aydın et al. [13] reported that of 17 patients Not applicable. diagnosed with FMF and sacroiliitis, 14 were treated with non-steroidal anti-inflammatory drugs in addition Declarations to colchicine, 10 received sulfasalazine, and 7 received Ethics approval and consent to participate biological drugs. Özdel et al. [14]] compared 18 children The study protocol was approved by the local ethics committee (Approval with FMF and sacroiliitis, and 38 children diagnosed no. KAEK/2020.06.69). with JSpA, reporting that there was no difference between the 2 groups in terms of treatment. Cherqaoui et al. [15] Consent for publication observed that patients diagnosed with FMF and JSpA re- All authors gave consent for publication. quired fewer non-steroidal anti-inflammatory drugs and anti-TNF drugs than patients with other JSpA. In the Competing interests present study anti-TNF drugs were given to 15 of the The authors have declared no conflicts of interest. FMF patients with sacroiliitis (adalimumab: n =6; etaner- Author details cept: n = 9) in addition to colchicine, and 6 patients were 1 Department of Pediatric Rheumatology, University of Health Sciences, using tocilizumab. Moreover, the biological drug use rate Kanuni Sultan Süleyman Research and Training Hospital, Istanbul, Turkey. Department of Pediatric Rheumatology, University of Health Sciences, did not differ significantly between groups 1 and 2, but Başakşehir Çam ve Sakura City Hospital, Istanbul, Turkey. Department of the preferred biological therapy varied. Tocilizumab failed Pediatric Rheumatology, Istanbul University Medical School, Istanbul, Turkey. to achieve remission in the adult patients with spondyloar- Department of Pediatric Rheumatology, Sadi Konuk Research and Training Hospital, Istanbul, Turkey. Department of Pediatric Rheumatology, University thritis [16]. However, previous studies have reported suc- of Health Sciences, Zeynep Kamil Research and Training Hospital, Istanbul, cessful results with tocilizumab in FMF patients [17, 18]. 6 Turkey. Department of Pediatric Rheumatology, Kocaeli University, Istanbul, In presented study, all 6 patients with FMF and sacroiliitis Turkey. Kaçmaz et al. Advances in Rheumatology (2021) 61:29 Page 5 of 5 Received: 15 January 2021 Accepted: 20 May 2021 Publisher’sNote Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. References 1. Younes M, Kahn MF, Meyer O. Hip involvement in patients with familial Mediterranean fever. 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