Hemolytic anemia following intravenous immunoglobulins in children with PIMS-TS: Two case reports.

This is the first case report on two children presenting with immediate and severe hemolytic anemia following the administration of high-dose intravenous immunoglobulins (IVIGs) in the context of pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS). Hemolytic anemia was described as a significant decrease in hemoglobin and an increase in lactate dehydrogenase after the second administration of high-dose IVIGs was performed. Both patients were found to have AB blood group. One of our patients showed massive pallor, weakness, and inability to walk in association with hemolysis. However, in both cases, the anemia was self-limiting and transfusion of red blood cells was not required: both patients recovered without persistent impact. Nonetheless, we aim to draw attention to this widely unknown adverse effect of IVIG, especially in the context of PIMS-TS. We suggest determining the patient's blood group prior to high-dose IVIG infusion and replacing the second IVIG through high-dose steroids or anticytokine therapy. Using IVIGs containing lower titers of specifically anti-A or anti-B antibodies to avoid isoagglutinin-caused hemolytic anemia is desirable; however, the information is not routinely available.

LONG-TERM SAFETY of CANAKINUMAB in PATIENTS with AUTOINFLAMMATORY DISEASES-INTERIM ANALYSIS of the RELIANCE REGISTRY

Background: Autoinfammatory diseases (AID) are characterized by severe systemic and organ infammation as well as high burden of disease for patients and their families. Treatment with the monoclonal antibody canakinumab (CAN), an interleukin-1β inhibitor, has been proven to be safe and effective in clinical trials and real-life. Objectives: The present study explores the long-term efficacy and safety of CAN in routine clinical practice conditions in pediatric (age ≥2 years) and adult patients with CAPS (cryopyrin-associated periodic syndromes), FMF (familial Mediterranean fever), TRAPS (tumor necrosis factor receptor-associated periodic syndrome) and HIDS/MKD (hyperimmunoglobulinemia D syndrome/meva-lonate kinase defciency). Methods: RELIANCE is a prospective, non-interventional, observational study based in Germany. Patients with clinically confrmed diagnoses of AID routinely receiving CAN are enrolled. Besides efficacy parameters regarding disease activity and remission, safety parameters were recorded at baseline and assessed at 6-monthly intervals. Results: Here, we present the interim analysis of patients with AID (N=199) enrolled in the RELIANCE Registry between October 2017 and December 2021. Mean age in this cohort was 24.4 years (2-79 years) and the proportion of female patients was 53% (N=104). At baseline, median duration of prior CAN treatment was 2 years (0-12 years). A total of 123 patients (62%) experienced any AE (N=653) among which naso-pharyngitis, increase of infammatory markers and pyrexia were the most frequent AE with incidence rates per 100 patient years (IR) of 8.3, 6.2, and 6.2, respectively. 29 patients (15%) were affected by severe AE (SAE, total number N=90) including 11 patients (6%) with SAE suspected to be drug-related (SADR;total number N=30) with IR from 0.2 to 0.7 (Table 1). Overall, 16 AE comprised upper respiratory tract infections (URI). One death (COVID-19, not related) and one malignancy (skin papilloma, not related) were reported. No vertigo and no hyper-sensitivity reactions were observed. N=10 (IR 2.36) vaccination reactions were reported (no SAE). Conclusion: The interim data from the RELIANCE study, the longest running real-life canakinumab registry, confrm safety of long-term canakinumab treatment across the entire study population. A trend for dose-related increase of SAE/SADR requires continuous close monitoring and awareness in patient groups (children, severe phenotypes, certain genotypes) requiring greater than standard dose treatment regimens.

Paediatric Inflammatory Multisystem Syndrome (PIMS) in the COVID-19 Pandemic

Following a SARS-CoV-2 infection, usually mild, a small proportion of children develop multisystemic hyperinflammation (paediatric inflammatory multisystem syndrome (PIMS)) within approximately 6-8 weeks. Clinically, these patients present with signs of Kawasaki syndrome ortoxic shock syndrome. The cardiac manifestation, in particular, with a marked limitation of cardiac function, requires intensive medical treatment in many individuals. The pathophysiology is still unclear although tremendous knowledge has been gained over the past one and a half years. A key role may be played by superantigens which, by binding to a specific beta-chain of T-cell receptors, lead to polyclonal stimulation of T cells. In addition to intensive care management, intravenous immunoglobulins, steroids, and biologics are used to control inflammation.

LONG-TERM EFFICACY AND SAFETY OF CANAKINUMAB IN PATIENTS WITH FAMILIAL MEDITERRANEAN FEVER (FMF) - INTERIM ANALYSIS OF THE RELIANCE REGISTRY

Background:Familial Mediterranean Fever (FMF) is characterized by recurrent attacks of fever and serositis as well as elevated inflammatory markers. FMF treatment goals according to EULAR are to control acute attacks and subclinical inflammation and to improve patients´ quality of life1. In a phase 3 pivotal study (CLUSTER study), FMF patients treated with the interleukin-1β inhibitor canakinumab met all these goals2.Objectives:The present study explores the long-term efficacy and safety of canakinumab (CAN) in routine clinical practice in pediatric (age ≥2 years) and adult FMF patients.Methods:RELIANCE is a prospective, non-interventional, multi-center, observational study based in Germany with a three-year follow-up period. Patients with clinically confirmed diagnosis of FMF who routinely receive CAN were enrolled in order to evaluate effectiveness and safety of CAN under standard clinical practice conditions. Disease activity and remission by physicians´ assessment, disease activity, fatigue and impact on social life by patients’ assessment, inflammatory markers and AIDAI (Auto-Inflammatory Diseases Activity Index) score were recorded at baseline and were assessed at 6-monthly intervals within the three-year observation period of the study.Results:This interim analysis of FMF patients (N=54) enrolled by December 2020 includes baseline as well as 6-, 12- and 18-month data. Mean age in this cohort was 25 years (4−56 years) and the proportion of female patients was 46 % (N=25). At baseline, median duration of prior CAN treatment was 2.0 years (0−6 years).While physician ratings report around 62% of patients in disease remission, 52% with absent and 34% with mild-moderate disease activity, patient-reported disease activity decreased from moderate (PPA 3.0) to low (PPA 2.0) during the observation period. A decrease was observed regarding disease activity parameters, in particular in patients without prior CAN therapy (Table 1, Figure 1). A total of 11 serious adverse events was reported, of which one case of tonsillectomy was classified as drug-related.Conclusion:Interim data of FMF patients from the RELIANCE study, the longest running real-life CAN registry, confirm efficacy and safety of long-term CAN treatment.References:[1]Ozen S, et al. EULAR recommendations for the management of familial Mediterranean fever. Ann Rheum Dis 2016;75:644–651. doi:10.1136/annrheumdis-2015-208690[2]De Benedetti F, et al. Canakinumab for the treatment of autoinflammatory recurrent fever syndromes. N Engl J Med 2018;378:1908–19.Table 1.Baseline characteristics and third interim analysis data of patients with FMFBaseline6 months12 months18 monthsAll patients ;patients without prior CAN therapyNumber of patients, N5411357275163Number (%*) of patients in disease remission (physician assessment)18 (48.6)1 (20.0)19 (73.1)3 (75.0)13 (65.0)1 (50.0)8 (61.5)1 (100.0)Physician Global Assessment, percentage* of absent/mild-moderate/severe rating43/38/110/40/6065/27/050/50/055/35/00/50/046/46/00/100/0Patient assessment of current disease activity;0–10, median (min;max)3.0 (0;10)7.0 (0;10)2.5 (0;7)2.0 (0;5)2.0 (0;7)2.0 (0;2)2.0 (0;6)0.5 (0;1)Patient assessment of current fatigue;0–10, median (min;max)5.0 (0;10)5.0 (0;9)3.5 (0;10)3.0 (1;6)3.0 (0;10)0.0 (0;4)3.0 (0;7)0.5 (0;1)Number (%*) of patients without impairment of social life by the disease19 (46.3)3 (37.5)18 (66.7)3 (75.0)14 (66.7)4 (80.0)5 (55.6)2 (66.7)CRP, median (mg/dl)0.21.10.20.10.20.00.10.5SAA, median (mg/dl)0.76.80.80.40.80.60.60.7ESR, median (mm/h)9.018.56.05.05.54.08.05.0SAENumber of eventsIncidence rate per 100 patient yearsTotal1116.23Arthritis57.38SARS-CoV-2 infection22.95Familial Mediterranean Fever11.48Intestinal Hemorrhage11.48Pyrexia11.48Tonsillectomy (SADR)11.48*not reported for all patientsCRP, c-reactive protein;ESR, erythrocyte sedimentation rate;n. a., not annotated;SAA, serum amyloid A;SADR, serious adverse drug reaction;SAE, serious adverse eventDisclosure of Interests:Jörg Henes Consultant of: Novartis, AbbVie, Sobi, Roche Janssen, Boehringer-Ingelheim, Grant/research support from: Novartis, Roche, J. B. Kuemmerle-Deschner Consultant of: Novartis, AbbVie, Sobi, Grant/research support from: Novartis, AbbVie, Sobi, Tilmann Kallinich Consultant of: Sobi, Novartis, Roche, Grant/research support from: Novartis, Frank Dressler Consultant of: Abbvie, Mylan, Novartis, Pfizer, Grant/research support from: Novartis, Frank Weller-Heinemann: None declared, Birgit Kortus-Goetze Consultant of: Novartis, Ivan Foeldvari Consultant of: Novartis, Gerd Horneff Speakers bureau: bbVie, Bayer, Chugai, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Grant/research support from: AbbVie, Chugai, Merck Sharp & Dohme, Novartis, Pfizer, Roche, Markus Hufnagel Grant/research support from: Novartis, Florian Meier Speakers bureau: Novartis, Julia Weber-Arden Employee of: Novartis, Norbert Blank Consultant of: Novartis, Sobi, Lilly, Pfizer, Abbvie, BMS, MSD, Actelion, UCB, Boehringer-Ingelheim, Roche, Grant/research support from: Novartis, Sobi

Clinical manifestations of SARS-CoV2 infections in children and adolescents with rheumatic and musculuskeletal diseases-survey data from Germany

Background: Although children and adolescents are less likely to develop COVID-19 and generally show milder disease courses, it is unclear what impact the SARS-CoV2 infection has on children and adolescents with rheumatic and musculoskeletal disease (RMD). Due to their underlying disease as well as therapeutic immunosuppression these patients may be at higher risk of being more severely affected by SARS-CoV2. Furthermore, SARS-CoV2 infection might trigger a flare of the underlying disease. Objectives: To evaluate clinical characteristics and disease course of COVID-19 in children and adolescents with RMD and to analyze possible effects of SARSCoV2 infection on the underlying disease under different therapeutic regimens. Methods: Data from juvenile patients with RMD recorded via the SARS-CoV2 questionnaire within the National Pediatric Rheumatology Database and the registry for hospitalized children and adolescents with COVID-19 of the German Society for Pediatric Infectious Diseases were analyzed. In addition to age, sex and diagnosis, information was collected about the date and method of a positive SARS-CoV2 testing, reason for testing, on clinical manifestations, disease course, treatment and outcome of COVID-19, on drug therapy at the time of virus detection, on disease activity (NRS 0 -10, 0 = best) of the underlying disease at the last visit before and after the SARS-CoV2 infection. Results: From April 17th 2020 until January 25th 2021, data of 67 patients with RMD and confirmed SARS-CoV2 infection were collected. Mean age was 13.5 ± 3.9 years with equal sex distribution. The majority of patients were diagnosed with juvenile idiopathic arthritis (JIA, 64%), 12 (18%) patients had an autoinflammatory disease (FMF, CAPS, PFAPA, TRAPS) and 5 (7%) a connective tissue disease. Fifty-two patients (78%) were treated with a disease modifying antirheumatic drug (DMARD), 39% with a biological DMARD and 9% systemic glucocorticoids at the time of SARS-CoV-2 infection. Nineteen patients (28%) were tested for SARS-CoV-2 because of typical symptoms, the majority (67%) because of contact to an infected person. PCR was used most often (in 60 %). 52 patients (78%) developed symptoms of COVID-19, 15 patients remained asymptomatic. The most common symptom of COVID-19 was rhinitis (42%) and fever (38%), followed by fatigue (34%), taste/smell disorder (33%), sore throat (27%) and cough (23%). Disease severity was graded as mild in 44 of 52 (85%) symptomatic patients, only two patients were hospitalized, one of whom required intensive care and died of cardiorespiratory failure 3 days after symptom onset. In 22 of 26 (85%) SARS-CoV2-positive patients, no relevant increase in disease activity (difference in NRS ≤ 1 before/after infection) of the underlying disease was observed 31 days after symptom onset (median, IQR 17-52 days). One patient, who had paused tocilizumab for 2 doses, experienced a flare of his seronegative polyarthritis 2 months after asymptomatic SARS-CoV-2 infection. Conclusion: In our cohort, the clinical picture of COVID-19 in children and adolescents with RMD was similar to that of healthy peers. The majority of patients showed mild disease course with good outcome under various medications, however, one patient with a severe course of COVID-19 died. In addition, SARSCoV2 infection does not appear to have a relevant impact on the underlying disease activity, whereas discontinuation of therapy might pose a risk of flare.

[COVID-19: treatment strategies of German-speaking pediatric rheumatologists : Results of an online survey]. / COVID-19: Behandlungsstrategien der deutschsprachigen Kinderrheumatologen : Ergebnisse einer Online-Umfrage.

BACKGROUND: Reliable data on the course and treatment of pediatric COVID-19 ("corona virus disease 2019") in immunosuppressed patients with rheumatic diseases are missing. AIM: Delineation of individual strategies of the members of the Society for Pediatric Rheumatology (GKJR) in cases of COVID-19. METHODS: In May 2020 all GKJR members were invited to take part in an online survey. Opinion data regarding an approach using disease-modifying anti-rheumatic drugs (DMARD) in cases of COVID-19 as well as the readiness to use new therapeutic agents in patients in different stages of the disease were collected. RESULTS: A total of 71 respondents (27.3% of all contacted pediatric rheumatologists) took part in the survey. Of these 28.2% had treated patients with COVID-19. Over 95% of the respondents did not support a preventive adaptation of the anti-rheumatic treatment during the SARS-CoV­2 pandemic. In the case of outpatients under immunosuppression with proven COVID-19 more than 50% of the respondents would refrain from administering intravenous high-dose steroids, cyclophosphamide, anti-CD20 antibodies as well as BAFF, CTLA­4 and TNF-alpha blockades. Conversely, >70% of the respondents would continue the treatment with nonsteroidal anti-inflammatory drugs, hydroxychloroquine (HCQ), oral steroids, mycophenolate, IL­1 blockade and immunoglobulins (Ig). In the case of inpatients 74.6% of respondents would consider targeted COVID-19 treatment. In stable patients with oxygen treatment (stage I) HCQ (18.3%), azithromycin (16.9%) and Ig (9.9%) were most frequently used. In cases of early signs (stage II) or a manifest cytokine storm (stage III) anakinra (40.8% for stage II and 46.5% for stage III), tocilizumab (26.8% and 40.8%, respectively), steroids (25.4% and 33.8%, respectively) and remdesivir (29.6% and 38.0%, respectively) were most frequently used. The need for a personalized approach based on the current clinical situation was emphasized by many respondents. CONCLUSION: The currently low prevalence of COVID-19 in Germany limits the general clinical experience. Therefore, the presented results have to be interpreted with caution and mostly as hypothetical treatment considerations. It is to be expected that there will always be a limited amount of evidence on pediatric COVID-19; therefore, a continuous and critical exchange of expert opinions on the treatment strategies is important.