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Biallelic mutations in any of the four mismatch repair genes MSH2, MSH6, MLH1 and PMS2 result in one of the most aggressive childhood cancer predisposition syndromes, termed constitutional mismatch repair deficiency (CMMRD) syndrome. In addition to a very high tumour risk, the CMMRD phenotype is often characterised by the presence of signs reminiscent of neurofibromatosis type 1. Although paediatric systemic lupus erythematosus (pSLE) has been reported so far in three patients with CMMRD, it has not been considered a diagnostic feature of the syndrome. We report here two additional female patients with pSLE and CMMRD due to biallelic pathogenic variants in MSH6. Hence, there are a total of five out of approximately 200 (2.5%) currently reported patients with CMMRD that also have pSLE, suggesting pSLE should raise the suspicion of a diagnosis of CMMRD, especially if supported by additional indicative features

Background:The fact that mental state may serve as a trigger for attacks of periodic fever diseases is known in Familial Mediterranean fever (FMF). There is a lack of information regarding the role of emotional triggers for PFAPA attacks.Objectives:To examine whether emotional distress may trigger PFAPA attacks.Methods:Enrolled were patients with active PFAPA, from two Israeli medical centers. Researchers contacted their parents by phone in two occasions: a. within the two weeks of returning to school after the first COCID-19 lockdown; b. during the summer vacation (i.e., non-stressful period). Parents were asked regarding the occurrence of PFAPA attacks within the two weeks preceding the calls. The relative stress levels of the two periods were validated by an emotional distress scale questionnaire. Differences between occurrences of attacks during these two periods of time were recorded.Results:One-hundred and six pediatric patients enrolled in the study. Mean age was 7.37± 2.9. In the stressful period, 41 (38.7%) reported at least one attack during the preceding 2 weeks, compared to 24 (22.6%) in the non-stressful period (p = 0.017). Scores for the mean emotional distress questionnaire were higher in the stressful period compared to the non-stressful period (35.6± 8.1 vs. 32.1± 7.7, respectively, P = 0.047).Conclusion:This study shows that during a period of stress for children there were more PFAPA attacks compared to a relaxed period. These findings indicate that mental factors such as stress or excitement may be triggers for PFAPA attacks.Table 1.Attacks status during prior 2 weeks during stressful or non-stressful eventOutcomeFirst call(May 2020)Second call (August 2020)P-valuePediatric emotional distress score (PEDS), mean (±SD)35.6 (±8.1)32.1 (±7.7)0.047Any attacks during last 2 week, n (%)41 (39.8%)24 (24.2%)0.017Number of attacks0.04 One, n (%)27 (25.5%)19 (17.9%) Two, n (%)14 (13.2%)5 (4.7%)References:[1]Marshall GS, Edwards KM, Butler J, Lawton AR. Syndrome of periodic fever, pharyngitis, and aphthous stomatitis. J Pediatr. 1987;110(1):43-46. doi:10.1016/S0022-3476(87)80285-8[2]Feder HM, Salazar JC. A clinical review of 105 patients with PFAPA (a periodic fever syndrome). Acta Paediatr Int J Paediatr. 2010;99(2):178-184. doi:10.1111/j.1651-2227.2009.01554.x[3]Hall, J, Lindorff A. Children’s Transition to School: Relationships Between Preschool Attendance, Cortisol Patterns, and Effortful Control. The Educational and Developmental Psychologist. Educ Dev Psychol. 2017;34(1):1-18[4]Stokes SJ, Saylor CF, Swenson CC, Daugherty TK. A comparison of children’s behaviors following three types of stressors. Child Psychiatry Hum Dev. 1995;26(2):113-123. doi:10.1007/BF02353235[5]Førsvoll J, Kristoffersen EK, Øymar K. The immunology of the periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis syndrome; what can the tonsils reveal. A literature review. Int J Pediatr Otorhinolaryngol. 2020;130. doi:10.1016/j.ijporl.2019.109795[6]Gidron Y, Berkovitch M, Press J. Psychosocial correlates of incidence of attacks in children with Familial Mediterranean Fever. J Behav Med. 2003;26(2):95-104. doi:10.1023/A:1023038504481[7]Makay B, Emiroğlu N, Ünsal E. Depression and anxiety in children and adolescents with familial Mediterranean fever. Clin Rheumatol. 2010;29(4):375-379. doi:10.1007/s10067-009-1330-9[8]Kraszewska-Głomba B, Matkowska-Kocjan A, Szenborn L. The Pathogenesis of Periodic Fever, Aphthous Stomatitis, Pharyngitis, and Cervical Adenitis Syndrome: A Review of Current Research. Mediators Inflamm 2015;2015:563876. doi:10.1155/2015/563876Disclosure of Interests:None declared

Background:The “European League Against Rheumatism” and “American College of Rheumatology” 2019 (EULAR/ACR-19) criteria for the diagnosis of Systemic Lupus Erythematosus (SLE) were recently published, with the stated goal of maintaining the level of sensitivity and raising the level of specificity for classification of SLE in adults.Objectives:We aimed to examine the function of the new EULAR/ACR-19 criteria in a population of children and compare them to the SLICC-12 and ACR-97 criteria.Methods:In this multicenter study the charts of jSLE patients from three tertiary medical centers were reviewed and compared to patients with non-jSLE diagnosis. Pediatric rheumatologists, blinded to the original diagnosis, reviewed and diagnosed all cases. Pediatric patients’ clinical and laboratory data were retrospectively extracted and then examined with regard to how they met the new and old criteria.Results:Included were 225 patients (112 jSLE, 113 non-SLE). When applied to juvenile SLE classification, the sensitivity of the new EULAR/ACR-19 criteria was 0.96 (0.9-.0.99) and the specificity was 0.89 (0.82-0.94). These were comparable to the Systemic Lupus International Collaborating Clinics (SLICC) criteria. The sensitivity of the EULAR/ACR-19 criteria improves over time and was 0.83 twelve months following disease onset, reaching 0.96 after longer than 24 months.Conclusion:Among a cohort of jSLE patients, sensitivity of the new EULAR/ACR-19 criteria was found to be high and specificity may have improved slightly compared to the SLICC-12 criteria. We support the use of the new classification criteria for pediatric patients in future jSLE studies, but it should be noted that its specificity is lower than for adults.ACR-97SLICC-12EULAR/ACR-19Sensitivity (95% CI)0.79 (0.70-0.86)0.96 (0.9-0.99)0.96 (0.9-.0.99)Specificity (95% CI)0.94 (0.88-0.97)0.85 (0.77-0.91)0.89 (0.82-0.94)Accuracy (95% CI)0.86 (0.81-0.9)0.9 (0.86-0.94)0.92 (0.88-.0.96)Positive Likelihood Ratio (95% CI)12.7(6.1-26.2)6.35(4.1-9.9)9.0 (5.3-15.4)Negative Likelihood Ratio (95% CI)0.23(0.16-0.33)0.05(0.02-0.12)0.05(0.02-0.12)Diagnostic odds ratio (95% CI)55.5(22.80-135.0)120.85(43.0-340.0)180.1(61.3-529.4)References:[1]Smith EMD, Lythgoe H, Midgley A, Beresford MW, Hedrich CM. Juvenile-onset systemic lupus erythematosus: Update on clinical presentation, pathophysiology and treatment options. Clin Immunol 2019 published on December 2019. doi: 10.1016/j.clim.2019.108274[2]Massias JS, Smith EMD, Al-Abadi E, Armon K, Bailey K, Ciurtin C, et al. Clinical and laboratory characteristics in juvenile-onset systemic lupus erythematosus across age groups. Lupus 2020;29(5):474–81.[3]Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997 Sep;40(9):1725[4]Petri M, Orbai AM, Alarcõn GS, Gordon C, Merrill JT, Fortin PR, et al. Derivation and validation of the systemic lupus international collaborating clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum 2012 Aug;64(8):2677-86[5]Hartman EAR, van Royen-Kerkhof A, Jacobs JWG, Welsing PMJ, Fritsch-Stork RDE. Performance of the 2012 Systemic Lupus International Collaborating Clinics classification criteria versus the 1997 American College of Rheumatology classification criteria in adult and juvenile systemic lupus erythematosus. A systematic review and meta-an. Autoimmun Rev. 2018;17(3):316–22.[6]Aringer M, Costenbader K, Daikh D, Brinks R, Mosca M, Ramsey-Goldman R, et al. 2019 European League Against Rheumatism/American College of Rheumatology Classification Criteria for Systemic Lupus Erythematosus. Arthritis Rheumatol 2019;71(9):1400–12.Disclosure of Interests:None declared

Background Recurrent episodes of acute rheumatic fever (RF) may contribute to the development or worsening of rheumatic heart disease (RHD) and was estimated to occur in 50–70% of RF patients prior to the introduction of penicillin. Meta-analyses from the United States showed that secondary penicillin prophylaxis (SPP) may reduce the incidence of RHD. Moreover, SPP using monthly Intra muscular (IM) Benzathine Penicillin was more effective in prevention of RF recurrences than daily oral SPP. Objectives We aimed to evaluate the long-term adherence to SPP in RF patients using real-life data. Methods The study population included children up to 18 years old in Maccabi Healthcare Services (MHS), a 2-million member health organization in Israel, who were diagnosed with acute RF between 1/1996 to 5/2015 and were dispensed at least one monthly pack of penicillin (either in oral or IM form). Treatment persistence was defined as continuation of drug use for the entire duration of therapy or until age 18, whichever occurred first. Adherence to treatment refers to the extent of drug use during the period of persistence, expressed as mean proportion of days covered (PDC). This was calculated by dividing the quantity of penicillin dispensed by the total time span between index date and age 18, leaving MHS, or 31 April 2015, whichever occurred first. Results A total of 842 RF patients were identified. Mean (SD) ages at diagnosis among patients on oral (n=734) and IM (n=108) initial therapy were 8.6y (3.7y) and 10.9y (3.2y), respectively. The median PDC for the treatment regimens were oral: 8% [interquartile range (IQR) 2–33%] and IM: 10% (IQR 3–28%). Overall, days covered with SPP (figure 1) decreased exponentially from 103 days in the first year of therapy to 20 days in the 10th year. Conclusions Adherence and persistence to secondary penicillin prophylaxis among Israeli children diagnosed with RF is poor. Although less effective, oral SPP was the preferred regimen. Intervention plans to increase adherence and persistence to SPP must be implemented in countries where RF still exists. Disclosure of Interest None declared

Background Systemic juvenile idiopathic arthritis (sJIA) is a severe categori of JIA, which includes systemic features such as fever, rash, elevated inflammatory markers along with poly-arthritis. It is frequently resistant to treatment. Until recently, patients were treated mainly with large doses of glucocorticoids. Breakthroughs in understanding the pathogenesis of sJIA have led to the evaluation of biologics, which block the pro-inflammatory cytokines interleukin (IL)-1 or IL-6 and their receptors. Objectives To define the optimal biological agent for sJIA based on safety and efficacy data from randomised controlled trial (RCT). Methods Through a systematic literature search, sJIA RCTs evaluating biological agents were identified. The primary efficacy outcome was defined as 30% improvement according to modified JIA American College of Rheumatology response criteria (JIA ACR30). The primary safety outcome was defined as serious adverse events (SAEs). Outcomes were analysed by pairwise and network meta-analyses. Quality of evidence between biological agents was assessed by applying the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. Results From the 493 citations original identified, 5 RCTs were eligible for inclusion – one for each of anakinra, canakinumab, and tocilizumab, and two for rilonacept: all vs. placebo. The canakinumab trial distinguished itself from the other trials, as it included patients having high systemic involvement and low joint involvement. Conversely, the tocilizumab trial included patients with more joint involvement compared with most other trials. While all evaluated biological agents were effective, the network meta-analysis indicated with low-quality evidence (due to indirect comparison and inconsistency) that rilonacept-treated patients were less likely to respond than those treated with canakinumab (modified JIA ACR30: odds ratio 0.10 [95%CI 0.02 to 0.38], P =0.001) or tocilizumab (0.12 [0.03 to 0.44], P =0.001). Risks of SAEs were similar among the biological agents (supported by very low-quality evidence) and not different from placebo. Conclusions Despite heterogeneous eligibility criteria and study designs across the 5 studies, and different modified JIA ACR30 criteria, this meta-analysis of short-term RCTs presents empirical evidence that canakinumab and tocilizumab are more effective than rilonacept. Our study also indicated that canakinumab should be considered mainly in patients with high systemic involvement and limited joint involvement, which to some extent also might be true for anakinra, whereas tocilizumab seems to be appropriate in patients with extensive joint involvement. Biological agents in sJIA seem safe and comparable with respect to SAE risk in the short term. We recognize that further data will be needed before these conclusions can be interpreted with high confidence. Protocol registration PROSPERO CRD42013004736 Acknowledgements We wish to thank The Oak Foundation for supporting the Musculoskeletal Statistics Unit, Parker Institute with unrestricted research grants. Disclosure of Interest S. Tarp Grant/research support from: paid to institute: AbbVie, Bristol-Myers Squibb, Mundipharma, and Roche, Speakers bureau: paid to institute: AstraZeneca, Pfizer, and Norpharma, G. Amarilyo Grant/research support from: Novartis, Consultant for: Novartis, I. Foeldvari Consultant for: Abbott, and Chugai, Speakers bureau: Pifzer, R. Christensen Grant/research support from: paid to institute: Abbott, Axellus, Bayer HealthCare Pharmaceuticals, Biogen Idec, Bristol-Myers Squibb, Cambridge Weight Plan, Ipsen, Laboratoires Expanscience, MSD, Mundipharma, Norpharma, Pfizer, Roche, and Wyeth, Consultant for: paid to institute: Abbott, Axellus A/S, Bristol-Myers Squibb, Cambridge Weight Plan, Norpharma, Pfizer, Roche, Mundipharma, and Roche, J. Woo: None declared, N. Cohen: None declared, T. Pope: None declared, D. Furst Grant/research support from: AbbVie, Actelion, Amgen, BMS, Gilead, GSK, NIH, Novartis, Pfizer, Roche/Genentech, UCB, Consultant for: AbbVie, Actelion, Amgen, BMS, Janssen, Gilead, GSK, NIH, Novartis, Pfizer, Roche/Genentech, UCB, Speakers bureau: AbbVie, Actelion, and UCB

Background As part of the review process of new drug applications in the USA, the Food and Drug Administration (FDA) performs an independent analysis after receiving raw data from clinical trials conducted by the sponsor. From this FDA review, a critical report is available to third parties, describing the FDA analysis and conclusions. Despite the availability of these critical data, the medical community derives much of its information from journal published papers. Objectives To ascertain if there are differences between the FDA analysis and those data which are published, we undertook a direct comparison between FDA and published results of Biologics Agents (BAs) in RA, using ACR20 responses as the target outcome (often used in drug development). Methods We obtained reviews of the approved BAs for RA available on the FDA Web site, and subsequently identified phase 2 and 3 trials. We then identified matching publications in scientific journals. From both sources we extracted ACR20s and calculated odds ratios (ORs) for all active trial arms vs. controls. To compare the ORs from the FDA review and the corresponding published paper, the Ratio of ORs (ROR) were calculated for all pair-wise comparisons when ACR20 was reported in both sources. The ROR was calculated as Exp {ln(OR[FDA]) - ln(OR[Pub])}. The anticipated correlation between the two lnORs measures was estimated empirically across all the pair-wise comparisons to estimate the corresponding variance of ROR. Results RA trials were reported on 7 BAs with a total of 30 trials (2-6 trials in each FDA review) on the FDA Web site. All except one trial were published. Five trials were excluded from the analysis: in 2 trials ACR20 was reported in neither the FDA nor published paper; in 2 published papers, no ACR20 was shown and in 1 trial the FDA described no ACR20s. Out of these five, only the unpublished trial had ACR20 as the primary outcome. ACR20 was reported in 25 trials in both sources: in 21 trials the ACR20 was the primary outcome, 3 had other primary efficacy outcomes, and in 1, safety was the primary outcome. From the 25 trials, a total of 55 pair-wise comparisons were evaluated: 19 (34.6%) were in disagreement (9 were statistically significantly different, p Conclusions Discrepancies between results in published scientific journals and the FDA reviews occurred in one third of the submitted trials and comparisons. These differences can be attributed to multiple reasons. While real discrepancies occurred, there was no empirical evidence to suggest biased estimates between the FDA and published results. Increased transparency in publications would increase the credibility of published results. Acknowledgements This study was supported by a grant from Danish Medicines Agency and unrestricted grants from The Oak Foundation. *G. Amarilyo & S. Tarp contributed equally to this work. Disclosure of Interest None Declared