Covid 19 in Patients with Rheumatic Diseases

Objectives: BIOBADAGUAY is the Paraguayan/Uruguayan registry of adverse events in patients with inflammatory rheumatic conditions under biologic therapy (BT). Three years have elapsed from the first case of coronavirus and data about South American patients with COVID are still scarce. In this study we analyzed the frequency and clinical outcomes of COVID-19 in a cohort of patients with rheumatic diseases from Paraguay. Method(s): A cross sectional study of Paraguayan patients with rheumatic diseases from BIOBADAGUAY and controls without BT. Clinical, epidemiological, and COVID-19 data were analyzed. Only cases confirmed by SARSCoV-2 positive PCR test were included. Descriptive analysis were performed for this study. Result(s): 832 patients were included (696 under BT and 136 controls). 116 (13.9%) had COVID-19. 22 had a second infection and 9 a third reinfection. Table 1 shows characteristic of COVID-19 patients. The most frequent diagnosis was rheumatoid arthritis (n = 93, 80.2%) followed by ankylosing spondylitis (n = 6, 5.2%), undifferentiated spondylarthritis (n = 5, 4.3%), psoriatic arthritis (n = 4, 3.4%), juvenile onset arthritis (n = 2, 1.7%), vasculitis (n = 2, 1.7%). Only 1 case (0.8%) were registered for Still's disease, enteropathic spondylarthritis, systemic sclerosis and seronegative polyarthritis, respectively. When comorbidities were analyzed, 46 (39.6%) patients had at least one (Table 1). Of the total treatments received: 65 (56.0%) had methotrexate, 53 (45.7%) leflunomide, 3 (2.5%) sulfasalazine, 15 (12.9%) hydroxychloroquine, 25 (21.5%) glucocorticoid, 52 (44.8%) anti-TNF and 20 (17.2%) non-anti-TNF. COVID-19 severity outcomes were: 101(87%) non severe, 31 (26.7%) severe and 1 fatal(0.8%). 189 (90.9%) patients received vaccination and the mean number of doses were 2.5 doses. 55 (26.4%) had COVID prior to vaccination Conclusion(s): In this study we examined the frequency of COVID-19 in Paraguayan patients with rheumatic diseases. In this cohort of rheumatologic patients, COVID 19 severity was similar to the one in the general population.

An Evaluation of the Causes and Outcomes of Haemophagocytic Lymphohistiocytosis in Sheffield Teaching Hospitals: 2016 to 2021

Background/Aims Haemophagocytic lymphiohistiocytosis (HLH) is a rare, underrecognised hyperinflammatory syndrome, characterised by immune dysregulation. Without treatment, the ensuing cytokine storm leads to high mortality. Secondary HLH (sHLH) is triggered by malignancy, infection, autoimmunity and medicines;treatment with immunosuppression is consensus- rather than evidence-based and extrapolated from primary HLH. Sheffield hosts a mature HLH multidisciplinary advisory group (MDAG). Here we evaluate the cause, treatment, requirement for critical care and mortality of people with HLH managed through the MDAG in a period including the coronavirus pandemic but prior to NHS England approval of anakinra (IL-1 antagonist) for HLH. Methods This retrospective evaluation (approved locally STH 10850) identified patients from MDAG records 1st October 2016 to 30th September 2021. Data from electronic/paper records was analysed using Microsoft Excel. Results HLH triggers were infection (viral 34%, bacterial 10%), haematological (35%), rheumatological (13%) and other (8%). Rheumatological causes were Still's disease (n=5);antiphospholipid syndrome (n=2);JO1 dermatomyositis (n=1);SLE (n=1);and rheumatoid arthritis (n=1). Other causes included unknown (n=3);combined systemic JIA and sickle cell crisis (n=1);medication (alemtuzumab) (n=1);and primary HLH (n=1). Overall mortality was 53% and highest in HLH with a haematological malignancy trigger (82%) Prior to the COVID19 pandemic (pre-March 2020), the commonest trigger of HLH was haematological malignancy (47%);after March 2020, the commonest trigger was infection (64%);COVID-19 explained 42% of cases. Mortality fell from 72% to 31%. Conclusion In this real-world series of people with HLH, mortality and critical care requirement was high. HLH triggers reflect published evidence as does poor prognosis in haematological malignancy-associated HLH. No-HLH associated with non-haematological malignancy was identified;we may need to improve MDAG reach into oncology. Seeming reduction in mortality following the COVID-19 pandemic may reflect increased recognition of COVID-19 induced hyperinflammation along with locallyagreed access to anakinra for COVID-19-induced HLH. The increase in infection related HLH cases since March 2020 is explained largely by COVID-19 cases. This has led to a relative reduction in cases related to haematological malignancy. HLH requires multidisciplinary management and better research to improve treatment. (Table Presented).

Immunological examination of patients with rheumatological involvement after Covid-19 infection

Background: The emergence of autoinflammatory/autoimmune disorders in COVID-19 patients has necessitated the development of new strategies for the management of these phenomena. Several viruses have been shown to cause autoimmunity by boosting the production of autoreactive lymphocytes, resulting in a lack of tolerance in the host's immune response. The SARS-CoV- 2 virus and/or its proteins can cause autoimmunity by molecular mimicry, superantigen activity, and disruption of type I IFN production. Method(s): The data of three patients who applied to the outpatient clinics of pediatric immunology and rheumatology at Uludag University Hospital between March 2020 and December 2021 and were followed up with autoimmune/autoinflammatory disease following CCovid-19- 19 infection were analyzed retrospectively. Result(s): All patients were female and aged between 2-17 years. They had SARS-COV- 2 infection which was mild a few months ago. Before the Covid-19 infection, all of the patients were in good health. The patients had no history of frequent infections or familial predisposition to rheumatic diseases. Following the Covid-19- infection, all of our patients showed fever, rash, joint discomfort, and muscle soreness. Despite the fact that myalgia affects the whole body, arthralgia was present on the wrists and knees of patients. CRP, sedimentation rate, and acute phase reactants increased in all of them. According to the American College of Rheumatology's diagnostic criteria, our first patient was diagnosed with systemic lupus erythematosus (SLE) and was treated with hydroxychloroquine, intravenous immunoglobulin treatment and anakinra. Two of three were diagnosed with systemic juvenile idiopathic arthritis (sJIA) according to the League of Associations for Rheumatology (ILAR) criteria. Only one patient had low IgG and IgA levels (Table 1). Two patients showed a decrease in CD19+ naive cells percent and numbers. Conclusion(s): Following SARS-CoV- 2 infection, autoimmune and autoinflammatory disorders such as rheumatoid arthritis, psoriatic arthritis, type 1 diabetes and Still disease have been documented in adult cases. There are limited pediatric cases on this issue. It has been suggested that the persistence of the latent immune response after COVID-19 infection happens by sensitizing the immune system to viral particles long after they have been eliminated from organisms. Is the autoimmune process the effect of a viral infection or mis-targeted immune system? These questions need deep research and discussion.

Kawasaki Disease in Children and Pediatric Multisystem Inflammatory Syndrome Associated with SARS-CoV-2 During the Pandemic (Clinical Lecture).

The article presents modern data about Kawasaki disease, which is a genetically determined systemic vasculitis with damage to the coronary arteries and multisystem manifestations. The etiology is not fully understood, but there is considered a possible role of viruses in the initiation of the aggravated immune response with possible development of macrophage activation syndromes and shock, which can lead to death. There are difficulties in diagnosing Kawasaki disease due to a variety of symptoms that are typical for a lot of infectious and autoimmune diseases (scarlet fever, measles, yersiniosis, systemic juvenile idiopathic arthritis). Early diagnosis and treatment (in the first 10 days of illness) using high doses of intravenous immunoglobulin and aspirin are associated with a low risk of development of coronary aneurysms and other complications. The authors also presented the data on the characteristics of severe Kawasaki-like diseases, which were recorded in several countries of Europe and America at the peak of the COVID-19 pandemic, and diagnostic criteria for the pediatric multisystem inflammatory syndrome associated with SARS-CoV-2, proposed by the Royal College of Pediatrics and Children Health (UK).Copyright © 2020, Professionalnye Izdaniya. All rights reserved.

Kawasaki Disease in Children and Pediatric Multisystem Inflammatory Syndrome Associated with SARS-CoV-2 During the Pandemic (Clinical Lecture).

The article presents modern data about Kawasaki disease, which is a genetically determined systemic vasculitis with damage to the coronary arteries and multisystem manifestations. The etiology is not fully understood, but there is considered a possible role of viruses in the initiation of the aggravated immune response with possible development of macrophage activation syndromes and shock, which can lead to death. There are difficulties in diagnosing Kawasaki disease due to a variety of symptoms that are typical for a lot of infectious and autoimmune diseases (scarlet fever, measles, yersiniosis, systemic juvenile idiopathic arthritis). Early diagnosis and treatment (in the first 10 days of illness) using high doses of intravenous immunoglobulin and aspirin are associated with a low risk of development of coronary aneurysms and other complications. The authors also presented the data on the characteristics of severe Kawasaki-like diseases, which were recorded in several countries of Europe and America at the peak of the COVID-19 pandemic, and diagnostic criteria for the pediatric multisystem inflammatory syndrome associated with SARS-CoV-2, proposed by the Royal College of Pediatrics and Children Health (UK).Copyright © 2020, Professionalnye Izdaniya. All rights reserved.

Overlapping clinical features of systemic juvenile idiopathic arthritis and SARS-CoV-2-related multisystem inflammatory syndrome in children.

Introduction: Differential diagnosis of the systemic juvenile idiopathic arthritis (sJIA) is often complicated, because of the variability in clinical presentation and the absence of specific signs. Material and methods: The PubMed/Medline and Scopus databases from the years 2013-2022 were analysed for full articles in English and the following key words were used: "juvenile idiopathic arthritis" and "MIS-C"; "juvenile idiopathic arthritis" and "Kawasaki disease". As an example of the problem the case description of a 3-year-old patient is presented. Results: In the first step 167 publications were identified; however, after exclusion of duplicated articles and those not relevant to the topic, only 13 were included in the analysis. We analysed studies that describe overlapping clinical features of sJIA and Kawasaki disease (KD) or multisystem inflammatory syndrome in children (MIS-C). The main issues we discussed were the search for the specific features that would distinguish one disease from another. Fever refractory to intravenous immunoglobulin treatment was the most frequent indicator among the features of clinical courses. Among other clinical signs prolonged, recurrent fever, rash, an incomplete KD phenotype, Caucasian race, splenomegaly, and complicated macrophage activation syndrome also supported sJIA diagnosis. Among laboratory tests, high ferritin and serum interleukin-18 levels were found to be the most useful in differentiation. The present case demonstrates that prolonged, unexplained, recurrent fever with a specific pattern should be the reason to suspect sJIA. Conclusions: Overlapping features of sJIA and SARS-CoV-2-related MIS-C complicates diagnosis in the era of the COVID-19 pandemic. Our case presentation adds symptoms of prolonged, spiking, unexplained, recurrent fever with a specific pattern for supporting systemic juvenile idiopathic arthritis diagnosis.

Tocilizumab as a promising treatment for MIS-C in JIA: Implications for countries with inaccessible anti-IL1 agents

Background: Multisystem inflammatory syndrome in children (MIS-C), causing high morbidity and mortality, is the hyperinflammatory response following COVID-19 infection (CI). According to the MISC management guideline, Anakinra (anti-IL1) is the preferable agent among other biologic agents: Infliximab, Tocilizumab (TCZ), and baricitinib if the patient is refractory to intravenous immunoglobulin (IVIG) and systemic corticosteroid (CS). However, these are not available in a number of countries, including Thailand. Our case represents refractory MIS-C in a systemic juvenile idiopathic arthritis (SJIA) patient responding well to TCZ. Method(s): Diagnostic investigations, including basic and immunological blood tests, and echocardiography assessment, were conducted. Result(s): A 12-year- old boy has been diagnosed with SJIA since he was 2 years old, according to the presentation of prolonged fever, hepatomegaly, and evanescent rash. CS, cyclosporin-a, and TCZ have been prescribed, and he has been in clinical remission off medication for two years. He experienced acute fever, rash, shortness of breath, nausea and vomiting for few days. Physical examination revealed a febrile boy with respiratory failure, compensated shock, and a generalized persistent maculopapular rash. The other was unremarkable. MIS-C was one of the possible diagnoses according to fever accompanied by more than two systems involved and his previous CI four weeks prior. Laboratory investigation revealed an elevated inflammatory response (Figure 1). The echocardiography was done by an experienced cardiologist with concern for myocardial dysfunction in MIS-C and showed a significant poor ejection fraction of the left ventricle of 42% under dobutamine, milrinone, and norepinephrine. Broad spectrum antibiotics and IVIG (1 g/kg/dose for two days) were initiated. After hemoculture did not report bacteria growth, pulse intravenous methylprednisolone (IVMP) 1000 mg for 3 days was given for the MIS-C treatment. After initial aggressive treatment with IVIG and pulse IVMP, the patient still has a high grade fever with laboratory revealed ongoing elevated inflammatory markers. The other possible causes of fever, such as infection and active SJIA were suspected. Immunological profiles returned with positive SAR-COV2 IgG, negative SAR-COV2 IgM, which confirmed the diagnosis of MIS-C with refractory to IVIG and CS. After multidisciplinary team discussion, TCZ was given. He had neither fever, dyspnea, nor heart failure. His clinical condition gradually improves together with laboratory parameters (Figure 1). Conclusion(s): In conclusion, our case demonstrated TCZ as a potential therapeutic agent in refractory MIS-C patients living in countries with limited access to anti-IL1 agents. The multidisciplinary care team together with prompt management is advisable to the best benefit of the patient. (Figure Presented).

First report of a patient meeting criteria for both multisystem inflammatory syndrome in children and adult onset Still's disease.

BACKGROUND: COVID-19 is associated with a postinfectious hyperinflammatory disorder, multisystem inflammatory syndrome in children (MIS-C), that shares characteristics with still's disease, known as systemic juvenile idiopathic arthritis (SJIA) in children younger than 16, and adult onset Still's disease (AOSD) in children 16 and older. Both MIS-C and SJIA/AOSD can be complicated by macrophage activation syndrome (MAS), a potentially fatal condition of cytokine storm. CASE PRESENTATION: We present a 16 year-old male who developed quotidian fever, headache, conjunctival injection, sore throat, nausea and vomiting, diarrhea, rash, and symmetrical polyarticular arthralgia/arthritis 4 weeks after exposure to SARS-CoV-2 and 2 weeks after his first vaccination against COVID-19. Our patient's laboratory results were significant for elevated inflammatory markers and acute phase reactants. He met criteria for diagnosis with both MIS-C and AOSD. After receiving first-line treatment for both diseases, IVIG and methylprednisolone, our patient improved. CONCLUSION: MAS is a life-threatening rheumatological emergency, and physicians must be able to identify diseases, like MIS-C and AOSD, that may be complicated by MAS. Our patient's distinguishing feature on presentation was symmetrical polyarticular arthralgia/arthritis, which has not been associated with MIS-C. Simultaneously, AOSD-which is associated with polyarticular arthralgia/arthritis-is only now being recognized as a possible post-infectious entity in the aftermath of COVID-19 infection. In patients like our own, who meet criteria for both MIS-C and AOSD, administering first line treatment for both diseases may be best practice.

Post COVID-19 Systemic Juvenile Idiopathic Arthritis in Children

Background: COVID-19 has been reported to cause a variety of signs and symptoms during its three known phases. The hyperinfammatory state in the third stage of the disease can induce multisystem infammatory syndrome in children (MIS-C). Case presentation: We report a 7 years-old boy and a 2.5 years-old girl with COVID-19, which presented the pictures of Kawasakilike syndrome classifed as MIS-C and a fnal diagnosis of systemic juvenile idiopathic arthritis (systemic JIA). The children had prolonger high-spiky-fever and systemic clinical features including arthritis, salmon-pink patches, serositis, generalized lymphadenopathy. This disease is an auto-infammatory phenotype with unknown etiology. Some environmental factors including viral infections have been proposed to trigger the disease in genetically susceptible children. So far, systemic JIA following COVID-19 has not been reported in the literature. Conclusion(s): COVID-19 may trigger systemic JIA in children.

Biomarkers in Systemic Juvenile Idiopathic Arthritis, Macrophage Activation Syndrome and Their Importance in COVID Era.

Systemic juvenile idiopathic arthritis (sJIA) and its complication, macrophage activation syndrome (sJIA-MAS), are rare but sometimes very serious or even critical diseases of childhood that can occasionally be characterized by nonspecific clinical signs and symptoms at onset-such as non-remitting high fever, headache, rash, or arthralgia-and are biologically accompanied by an increase in acute-phase reactants. For a correct positive diagnosis, it is necessary to rule out bacterial or viral infections, neoplasia, and other immune-mediated inflammatory diseases. Delays in diagnosis will result in late initiation of targeted therapy. A set of biomarkers is useful to distinguish sJIA or sJIA-MAS from similar clinical entities, especially when arthritis is absent. Biomarkers should be accessible to many patients, with convenient production and acquisition prices for pediatric medical laboratories, as well as being easy to determine, having high sensitivity and specificity, and correlating with pathophysiological disease pathways. The aim of this review was to identify the newest and most powerful biomarkers and their synergistic interaction for easy and accurate recognition of sJIA and sJIA-MAS, so as to immediately guide clinicians in correct diagnosis and in predicting disease outcomes, the response to treatment, and the risk of relapses. Biomarkers constitute an exciting field of research, especially due to the heterogeneous nature of cytokine storm syndromes (CSSs) in the COVID era. They must be selected with utmost care-a fact supported by the increasingly improved genetic and pathophysiological comprehension of sJIA, but also of CSS-so that new classification systems may soon be developed to define homogeneous groups of patients, although each with a distinct disease.

Does Tocilizumab Influence the Outcome of Patients with COVID-19 Pneumonia Compared to the Standard Therapy? Retrospective Analysis of Data Obtained during Phase I COVID Pandemic

BACKGROUND: No gold standard therapy was approved globally for COVID-19 pneumonia to the date of this study. The pathophysiology of SARS-CoV-2 infection displayed the predominance of hyperinflammation and immune dysregulation in inducing multiorgan damage. Therefore, the potential benefits of both immune modulation and suppression in COVID-19 have been extensively discussed as a modality to control cytokine release syndrome (CRS). Abnormally high levels of interleukin-6 (IL-6) are a common finding in COVID-19 patients with pneumonia and acute respiratory distress syndrome, so the use of IL-6 antagonist was tested as a therapeutic option in controlling the disease. Tocilizumab is a recombinant humanized anti-human IL-6 receptor monoclonal antibody that can specifically bind the membrane-bound IL-6 receptor and soluble IL-6 receptor, thereby inhibiting signal transduction. Tocilizumab is currently FDA approved for the management of rheumatoid arthritis, giant cell arthritis, polyarticular juvenile idiopathic arthritis, and systemic juvenile idiopathic arthritis. This study is a retrospective analysis of data polled during Phase I of COVID pandemic, adopted by the isolation hospital of Kasr Al-Ainy Medical School, Cairo University, during the period from May to September 2020. AIM: The aim of this study is to evaluate tocilizumab influence in the outcome;in terms of reducing the hospital stay, risk and duration of mechanical ventilation (invasive and noninvasive), mortality, and the incidence of complications related to drugs use (secondary bacterial infection and GIT bleeding) in patients with moderate-to-severe COVID-19. METHODS: This retrospective, observational cohort study included adults (between 18 and 80 years) with moderate-to-severe COVID-19 pneumonia, who were admitted to isolation hospital of Kasr Al-Ainy Medical School, Cairo University, between May and September 2020. We segregated the patients into two groups: Group A: In addition to the standard care protocol according to the local guidelines of the Egyptian Ministry of Health and Population in that period (supplemental oxygen, steroids in a dose of 1–2 mg/kg methylprednisolone for 5–10 days, broad-spectrum antibiotics, vitamins, and prophylactic dose of anticoagulation with low-molecular-weight heparin, proton-pump inhibitor, and poly-vitamins), they received tocilizumab intravenously in a dose of 8 mg/kg bodyweight (up to a maximum of 800 mg per dose), divided in two shots 12–24 h apart. Group B: Those received the standard care protocol alone, noting that guidelines were adjusted later on according to the updated scientific publications and WHO recommendations. The primary endpoint was to evaluate the effect of different regimens in controlling the disease, the need for mechanical ventilation and its duration (either invasive or non-invasive), length of ICU stay, hospital stay, and in-hospital mortality. Comparisons between quantitative variables were done using the non-parametric Mann–Whitney U-test. For comparison of serial measurements within each patient, the non-parametric Wilcoxon signed-rank test was used. For comparing categorical data, Chi-square (2) test was performed. Exact test was used instead when the expected frequency was <5. Correlations between quantitative variables were done using Spearman correlation coefficient. RESULTS: During this period, 166 patients were admitted to ICU, suffering from severe hypoxemia with moderate to severe COVID-19 pneumonia, 10 of them were excluded (three were over 80 years old, other three had advanced stages of malignancy, two were on steroids therapy and non-invasive home ventilation due to chronic chest condition, and two were presented with MODs and deceased in <48 h from admission), thus, 156 were included in the study. Group A: Seventy-six patients (49%) received tocilizumab in addition to standard therapy, Group B: Eighty patients (51%) received standard therapy only. In Group A, the mean length of ICU stay was 8.96 days with mean length of hospital stay 13.76, compared to mean length f ICU stay 9 days in Group B (p = 0.57) and mean length of hospital stay 12.46 days (p = 0.117). In Group A, 35 patients (46%) needed non-invasive mechanical ventilation (MV),12 patients of the 35 needed invasive MV in later stage, compared to 26 patients (32%) in Group B, 14 patients of the 26 needed invasive MV in later stage (p = 0.16). In Group A, 14 patients (18.4%) needed invasive mechanical ventilation, compared to 19 patients (23.7%) in Group B (p = 0.213). In Group A, 6 (7.9%) of 76 patients died, compared to 13 (16.3%) of 80 in Group B p = 0.11. The incidence of secondary bacterial infection in Group A was 16 patients (21%) compared to 21 (26%) in Group B (p = 0.44). CONCLUSION: In this study, we did not detect statistical difference in both groups of patients coming during CRS-associated COVID-19 pneumonia, regarding (ICU stay, need for and length of MV, the incidence of secondary bacterial infection, and in-hospital mortality) for COVID-19 moderate-to-severe pneumonia.

Diagnostic value of FDG-PET/CT in fever of unknown origin

Background: Fever of unknown origin (FUO) is a challenging clinical problem in medicine that needs collaboration of various diagnostic techniques to establish the accurate diagnosis. We evaluated the diagnostic performance of 18F-FDG PET/CT in patients who presented themselves with FUO. Our study included 40 patients with FUO who underwent PET/CT examination and their results were compared to the results of laboratory, histopathological, microbiological investigations and/or response to therapy. Results: The final diagnosis included malignancy in 20 patients (50%), infectious causes in 7 patients (17.5%) and non-infectious inflammatory causes in 6 patients (15%). Fever resolved without diagnosis in 4 patients (10%), while no definite diagnosis was reached in 3 patients (7%). PET/CT successfully contributed to diagnosis of 35 out of 40 patients with diagnostic accuracy of 87.5%. The sensitivity, specificity, positive predictive value and negative predictive value of PET/CT in our study were 93.5%, 66.7%, 90.6% and 75%, respectively. Conclusion: PET/CT is a useful tool to investigate and diagnose the cause of FUO. It provides information that can guide the treatment strategy of the patients.

Association between Insufficient Interleukin-6 (IL-6) Inhibition and Worsening Outcomes in COVID-19 and Idiopathic Multicentric Castleman Disease (iMCD), and a Mathematical Model to Predict Optimal Dosing to Completely Block IL-6 Activity

Dysregulated inflammatory responses are characterized by inappropriate levels of inflammatory markers, speed of generation, degree, and major site of production, such as a vital organ. COVID-19 severity and mortality are strongly associated with interleukin (IL)-6 levels. High IL-6 levels are also observed in idiopathic Multicentric Castleman Disease (iMCD). Previously, we developed the first anti-IL-6 monoclonal antibody (mAb) treatments and showed that C-reactive protein (CRP) production could be fully controlled by IL-6 in humans. Using mathematical modeling, with CRP as an IL-6 surrogate marker, we predicted the ability of an anti-IL-6 mAb to block plasma IL-6 activity and showed IL-6 inhibition was dependent on the extent of whole-body IL-6 production. We postulate that in patients (pts) in whom IL-6 concentration at the site of inflammation is higher than in the plasma, full blockade of plasma IL-6 activity, shown by complete CRP inhibition, is the minimum requirement to achieve clinical efficacy. CRP inhibition with tocilizumab (TCZ) in pts with COVID-19. We identified 35 published studies evaluating the efficacy or potential role of anti-IL-6 therapy in pts with severe COVID-19. Surprisingly, only one (Luo et al. J Med Virol 2020;92:814) reported dynamics of CRP reduction for individual patients throughout treatment. We fitted a hypothetical curve of CRP reduction required to completely block IL-6, based on the half-life of CRP, and added data points of CRP serum levels from pts treated with anti-IL-6 receptor (IL-6R) therapy, TCZ, in this study. Complete reduction of CRP was not achieved in all patients: 3 pts who died had CRP levels ≥12.8 mg/l. Of 2 pts whose disease worsened, CRP levels were 93.5 mg/l and 6.3 mg/l. However, pts whose condition stabilized (n=9), or whose symptoms improved (n=1), had CRP levels close to the theoretical curve that is likely required to fully block IL-6 (CRP levels ≤5.0 mg/l). Half of these pts had been given repeated doses of TCZ. Siltuximab (SIL) treatment (NCT01024036 trial) for pts with iMCD. To assess the impact of baseline CRP levels on response to anti-IL-6 therapy, SIL, patients were divided into low and high CRP groups based on a baseline CRP level threshold of 40 mg/l (corresponding to ~40 pg/ml of IL-6;Fig 1). In patients with low baseline CRP levels (<40 mg/l;n=35), CRP levels were significantly reduced with SIL treatment on day 8 (n=26;P=0.0003) and day 15 (n=22;P=0.0043) post-dosing. In patients with high baseline CRP levels (>40 mg/l;n=17), CRP levels were significantly reduced on day 8 (n=17;P<0.0001) and day 15 (n=15;P<0.0001) post-dosing (Fig 1). A significant increase in CRP levels from day 8 to day 15 was observed in these patients (P=0.0120);this increase was not observed in patients with low baseline CRP levels (P=0.243;Fig 1). There was a negative correlation between maximum CRP and hemoglobin change (P<0.001). Inhibition of IL-6 activity by anti-IL-6 (SIL 700 mg) and anti-IL-6R (TCZ 800 mg) as monotherapy, intensified, or combined therapy. To evaluate the effect of therapy on IL-6 activity, our algorithm modeled inhibition of IL-6-(IL-6R/soluble IL-6R)-gp130 transducer complexes. This serves as a proxy for IL-6 bioactivity and accounts for the buffering capacity of gp130, which can be overwhelmed in inflammatory situations with high IL-6 concentrations. Due to uncertainty over the concentration of mAbs in alveoli relative to plasma, we modeled the effects of SIL and TCZ at local concentrations of 100%, 10%, and 1% (Fig 2) of those in plasma. Our model demonstrated that anti-IL-6 was associated with stronger inhibition of CRP than anti-IL-6R. However, only the association of both anti-IL-6 and anti-IL-6R mAbs was associated with a total blockade of CRP, which is probably necessary when IL-6 levels are associated with high risk to the patient. Different administration schedules to intensify anti-IL-6 therapy were modeled, including the repeated or combined use of anti-IL-6 and anti-IL-6R mAbs. The results form a basis to optimize treatment trategies to avoid the cytokine storm in several diseases, including cancer, iMCD, and autoimmune disorders. The feasibility of the theoretically defined approaches needs to be evaluated, particularly the potential side-effect profile for a combined treatment approach. In conclusion, in clinical practice, IL-6 inhibition should be individualized based on pathophysiology and regular CRP monitoring. [Formula presented] Disclosures: Rossi: E-SANA Inc: Other: Co-founder of E-SANA Inc;EUSA Pharma: Consultancy;LEO Pharma: Consultancy;NPO Petrovax Pharm: Consultancy. Levon: E-SANA Inc: Other: Co-founder of E-SANA Inc. Kanhai: EUSA Pharma: Current Employment. Fajgenbaum: EUSA Pharma: Research Funding;N/A: Other: Holds pending provisional patents for ‘Methods of treating idiopathic multicentric Castleman disease with JAK1/2 inhibition’ and ‘Discovery and validation of a novel subgroup and therapeutic target in idiopathic multicentric Castleman disease’;Pfizer: Other: Study drug for clinical trial of sirolimus. OffLabel Disclosure: Siltuximab is approved for the treatment of iMCD. Tocilizumab is approved for the treatment of Rheumatoid arthritis, Giant cell arteritis, Cytokine release syndrome, Systemic juvenile idiopathic arthritis and Polyarticular juvenile idiopathic arthritis. Combination therapy using Siltuximab and Tocilizumab has not yet been approved.

A rare disease in the community hospital: Hemophagocytic lymphohistiocytosis (HLH) needs immediate local attention for early recognition and individualized treatment

Purpose: HLH is a severe hyperinflammatory syndrome characterized by highly active cytotoxic T-cells, NK-cells, and macrophages. If undiagnosed, HLH can lead to multiorgan damage and death. Conditions triggering HLH are infections, malignancies and autoimmune/-inflammatory (MAS-HLH) disorders. Immunosuppressive patients are prone to develop infection triggered HLH. The incidence in the European community hospital is unknown, as is the number of unrecorded cases. HLH-patients, diagnosed at a single communal hospital with an adjacent catchment area of 500,000 citizens, were reviewed in the context of national and international guidelines. Methods: From 08/2016 to 11/2020, 13 HLH patients were analysed retrospectively. Both HLH-2004 criteria and the web-based Hscore were used to diagnose HLH. The collected data depicts clinical presentation, underlying disease, laboratory findings, and treatment. Results: This Study includes 13 HLH-patients (10 male). Median age at diagnosis was 53, ranging from 27-80 years. Most common triggers in our cohort were infections (n=7) and malignancies(n=4). MAS-HLH (n=1) was seen in a Still's disease patient. HLH-related gene mutation was identified (n=1) with a heterozygote mutation in Perforin (PrfA91). Lymphomas of B-as well as T-cell origin (n=2) and AML (n=3) represented main cause in malignancy associated HLH. Viral infections i.e., COVID-19(n=1), RSV (n=1) and EBV (n=1), also bacterial infections like M. tuberculosis (n=1), and the attenuated strain BCG (n=2) were seen in infection associated HLH. Most patients presented with fever (n=9) and splenomegaly (n=4). HLH patients show pancytopenia, peak ferritin levels ranging 1352-185000 ng/ml (median=21600), peak soluble IL-2 receptor levels ranging 2571-21660 U/ml (median=6606), and peak triglyceride levels ranging 175-610 mg/ml (median=227). Hemophagocytosis in bone marrow was found in 6 patients. First line therapy was glucocorticoids (n=12) combined with polyvalent immunoglobulins. Etoposide (n=5) and chemotherapy (n=4) were given to malignancy triggered HLH. Rituximab was applied in EBV-triggered HLH. Anakinra (n=3) and Ruxolitinib (n=4) was given to selected patients. Two patients received cytokine-depletion using adsorption columns Cytosorb®. Multiorgan failure (n=5) was the most common cause of death. Conclusion: This data provides incidence estimation of HLH in adult patients. Institutional and national measures will be presented to prevent death due to HLH.

Clinical course of COVID-19 in children with rheumatic disease under biologic therapy from Turkey

Introduction: What a biological disease-modifying antirheumatic drugs (bDMARDs)? and/or underlying rheumatological diseases, which we frequently use in our pediatric rheumatology practice, affect the clinical course of COVID-19 has not been fully demonstrated. Objectives: Here, we aimed to reveal the course of COVID-19 infection in patients with rheumatic disease and receiving bDMARD treatment. Methods: This was a retrospective, multicenter study in patients with a biological treatment had been initiated. This real-life study is based on secondary data collection from medical records of patients evaluated at the 14 Pediatric Rheumatology Clinics in Turkey from April 2020 to April 2021. The diagnosis of COVID-19 was confirmed in 101 patients by nasal PCR and in 10 patients by antibody test. Results: The study population of 112 patients consisted of 70 females (63.6%). The mean age of patients was 12.87 ± 4.69 years. The primary diagnosis of patients was as follows;59 juvenile idiopathic arthritis, 33 systemic autoinflammatory diseases, 10 vasculitis, 8 connective tissue diseases. The mean duration of primary disease was 4.62±3.65 years. Nineteen patients had also additional comorbid diseases (hypertension, Chron's disease, hereditary spherocytosis, and chronic renal failure, astma, cardiomyopathy, adrenal insufficiency in individual patients). Prior to COVID-19 infection, 35 patients (31.8%) were using canakinumab, 10 were infliximab (9.1%), 25 were adalimumab (21.8%), 18 were etanercept (16.4%), 9 were tocilizumab (8.2%), 4 were anakinra (3.6%), 6 were rituximab (5.5%), 1 was abatacept (0.9%), and 3 was tofacitinib (2.7%). The median exposure time of a biologic drug was 13.5 months. Additionally, 66 patients were using DMARD, and 27 patients were also receiving corticosteroid. 70 (63.6%) patients had at least one COVID-19-related symptom (fever, cough, diarrhea, myalgia, anosmia and/or rash), while 40 (36.4%) patients were asymptomatic. Respiratory findings were seen in 26% of all patients, 7 patients also had pathology in computed tomography. Hospitalization was required in 25 patients (22.7%) at median of 6 days (IQR: 4-10). Five patients developed MIS-C and 2 of these patients were followed up in the pediatric intensive care unit. Laboratory tests revealed that fourteen patients had elevated acute phase reactants, ten had elevated D-dimer levels, 5 had lymphopenia (< 1000/mm3), and five had hyperferritinemia. Conclusion: In patients with underlying comorbidities, COVID-19 can have a severe course regardless of the use of bDMARD. In the light of these findings, it would not be correct to say that the currently used bDMARDs worsen the course of COVID-19 infection or to say whether they affect the severity of the disease, but still, the disease findings-modifying effects of these drugs, especially high fever and myalgia, have been observed.

Was it COVID19 or the vaccine a rare case of SARS-COV2 infection or post-vaccine triggered flare in juvenile dermatomyositis

Introduction: Vaccines and infection can cause flares of inflammatory conditions. Objectives: We describe a rare, rapid flare of Juvenile Dermatomyositis (JDM) preceded by confirmed Sars-Cov2 antibodies (asymptomatic infection or first vaccination). Methods: Data was extracted from electronic medical records and a literature review undertaken. Results: We present a 16 year old female of Bangladeshi origin with JDM diagnosed August 2019 (CK 29691, CMAS 23;Mi-2b, Ku, Mi-2a positive). On a background of suboptimal control with low grade inflammation (CK 659;CMAS 51) medications were altered in May 2020 adding Adalimumab and Mycophenolate Mofitil (MMF), to Methotrexate and Intravenous Immunoglobulin (IVIG). CK rose in August 2020 (15969). IVIG continued and physiotherapy input increased. After a stable 5 months (CK 100-300), CK grew to 2307 but as CMAS remained 50 treatment was not altered. Four weeks prior (Jan 2021) the patient received their first dose of Pfizer SARS-CoV2 vaccination. A family member was confirmed to be COVID-19 positive 8 weeks prior and the family isolated together. Our patient did not report any known COVID-19 symptoms. In March 2021 she presented with a 4 day history of acute active inflammation as demonstrated by malaise, increased rash, muscle pain and reduced function (CMAS 3, CK 52848). She was admitted for Multidisciplinary management of an acute flare and found to be SARS-CoV2 IgG positive consistent with prior infection. Adalimumab and MMF were swopped with tacrolimus alongside intravenous methylprednisolone, oral prednisolone and physiotherapy. CMAS scores remained considerably low (5) over the following 6 weeks, with a rapid rise (34) at week 7 with the patient discharged home. Literature review has identified a case of Anti-MDA5 JDM increased interstitial lung disease associated with active SARS-CoV2 infection1. Similarly there is a case presentation of Macrophage Activation Syndrome in Systemic Onset Juvenile Idiopathic Arthritis temporally associated with SARS-CoV2 infection2. There are no reported cases of vaccine mediated hyperinflammation of muscle or skin disease in JDM or Paediatric Inflammatory Multisystem Syndrome Temporally associated with COVID-19 (PIMSTS)3. Conclusion: This was a rare case of a rapid deterioration in function and hyperinflammation at a time of PIMSTS and other similar reactions in adolescents with Rheumatic diseases. We hypothesise that this such case may have been triggered by recent asymptomatic COVID-19 infection or following SARS-Cov2 vaccination.

Efficacy, safety and tolerance of anakinra in paediatric rheumatology and periodic fever clinics: Real life experience

Introduction: Interleukin 1 (IL-1) induced proinflammatory signals were discovered as a causative aetiology in a spectrum of diseases. Efficacy and safety of the recombinant IL-1 receptor antagonist anakinra across autoinflammatory and autoimmune diseases has been demonstrated in many studies. Despite the recommended dosage in patients above 8 months and weighing more than 10 kg, use of higher doses or earlier onset of therapy have been occasionally reported. Objectives: To an institutional review of data on efficacy, safety and tolerance of anakinra in patients with autoinflammatory diseases (AID). Methods: A single-centre retrospective review of electronic records of patients treated with anakinra between August 2007 and May 2021. Results: A total of 47 patients (30 children, 17 adults) were identified. The median follow-up was 35 months (range 1-165 months). Patients have been treated for diagnosis of systemic juvenile idiopathic arthritis (sJIA) (n = 18;38%), cryopyrinopathy (CAPS) (n = 10;21%), mevalonate-kinase deficiency (MKD) (n = 7;15%), undifferentiated AID (uAID) (n = 6;13%), PIMS-TS (n = 3;6%), NLRC4-GOF (n = 1, 2%), PAPA syndrome (n = 1;2%) and polyarticular JIA (n = 1, 2%). The most frequent indication for starting anakinra was macrophage activation syndrome (MAS) (n = 20;42,5%) which occurred in patients with sJIA (n=14, 70%), uAID (n=3, 15%), PIMS (n=1, 5%), NLRC4-GOF (n=1, 5%) or polyarticular JIA (n=1, 5%). Fourteen patients with sJIA (78%) received anakinra due to macrophage activation syndrome. MAS was the first manifestation of sJIA in 6 patients (33%). Recommended dosing of anakinra (1-4 mg/kg/day) was exceeded in 44,6% of patients (n=21) with the following dose range: 4-6 mg/kg (n = 8;38%), 6-9,9mg/kg (n = 4;19%), ≥10 mg/kg (n = 9;43%). Paediatric cohort received anakinra in very wide dosing range of 1,4 -26,1 mg/kg (average 5,59 mg/kg, median 4,15 mg/kg). The highest dose (10-26mg/kg) was required by patients with uAID (n=1, 8 days of age), sJIA/MAS (n=2, 3 and 5 years of age), CINCA (n=1, 4 years of age) and NLRC4-GOF (n=1, 4 weeks of age). The median dose of anakinra in adult patients was 1,6 mg/kg (range 0,9-7,7mg/kg). In severely sick patients the daily dose was divided into 2-4 intravenous applications, one patient received continuous anakinra i.v. infusion. Rapid therapeutic effect (within 24-48 hours from starting anakinra) was observed in all patients. The most frequent recorded adverse effects were already well-known injection-site reaction in 25,5% (n = 12) of patients which disappeared within one month in all of them. Persistent eosinophilia (highest values 3,6 and 2,3x10 ∗9 cells) was documented in 2 sJIA patients. Mild asymptomatic neutropenia (ANC min 0,8 x10 ∗9/L) and transient liver transaminase elevation (up to 3-times ULN) both occurred in 4,2% (n = 2) of patients each. Conclusion: Use of anakinra in a wide dosing range was reported. Our observation illustrates the need as well as safety of higher anakinra dosing in younger age groups including 2 newborns. No serious adverse effects that would require discontinuation or termination of anakinra were observed at all dosing regimens.

Adult and Paediatric Case-based Conference 2020

The proceedings contain 60 papers. The topics discussed include: a rare case of reactive arthritis secondary to COVID-19;parechovirus in a pathologist;adult onset PIMS-TS with secondary haemophagocytic lymphistiocytosis: into the eye of the cytokine storm;persistent non-fulminant COVID-19 infection in a GPA patient on rituximab;a case of hyperinflammatory COVID-19 that responded to tocilizumab therapy;active Bechet's with life threatening arterial disease, complicated by concurrent COVID-19 infection at the peak of the COVID-19 pandemic: did immunosuppression help or hinder?;isolated muscular sarcoidosis revealed by calcitriol-mediated hypercalcaemia and fluorodeoxyglucose positron emission tomography;pulseless electrical activity arrest in a young woman: could renal tubular acidosis due to Sjogren's syndrome be the underlying cause?;back to the future: attempting to distinguish between inflammatory and non-inflammatory back pain;and recognition of subclinical macrophage activation syndrome in an adolescent systemic juvenile idiopathic arthritis patient receiving tocilizumab: a case report.

Differences and similarities of multisystem inflammatory syndrome in children, Kawasaki disease and macrophage activating syndrome due to systemic juvenile idiopathic arthritis: a comparative study.

To compare the clinical and laboratory findings of multisystem inflammatory syndrome in children (MIS-C), patients with Kawasaki disease (KD) and with macrophage activating syndrome due to systemic juvenile idiopathic arthritis (sJIA-MAS) on real-life data. Patients diagnosed with MIS-C, KD, and sJIA-MAS from 12 different centers in Turkey who were followed for at least 6 months were included in the study. Demographic, clinical, and laboratory findings of all patients were analyzed. A total of 154 MIS-C, 59 KD, and 31 sJIA-MAS patients were included. The median age of patients with MIS-C were higher than those with KD while lower than those with sJIA-MAS (8.2, 3, 12 years, respectively). Myalgia (39.6%), cardiac (50.6%), gastrointestinal (72.7%), and neurological (22.1%) involvements were more common in patients with MIS-C compared to others. MIS-C patients had lower levels of lymphocyte (950 vs 1700 cells/µl) and thrombocyte (173,000 vs 355,000 cells/µl) counts and higher pro-BNP (1108 vs 55 pg/ml) levels than KD. Ferritin levels were higher in patients with MIS-C compared to patients with KD while they were lower than patients with sJIA-MAS (440, 170, 10,442 ng/ml, respectively). Patients with MIS-C had a shorter duration of hospitalization than sJIA-MAS (p = 0.02) while they required intensive care unit admission more frequently (55 vs 8 patients, p < 0.001). The median MAS/sJIA score of MIS-C patients was - 1.64 (- 5.23 to 9.68) and the median MAS/sJIA score of sJIA-MAS patients was -2.81 ([- 3.79] to [- 1.27]). MIS-C patients displayed certain differences in clinical and laboratory features when compared to KD and sJIA-MAS. Definition of the differences and similarities between MIS-C and the other intense inflammatory syndromes of childhood such as KD and MAS will help the clinicians while making timely diagnosis.