Juvenile-onset systemic lupus erythematosus (jSLE) - Pathophysiological concepts and treatment options

© 2018 Elsevier Ltd. The systemic autoimmune/inflammatory condition systemic lupus erythematosus (SLE) manifests before the age of 16 years in 10-20% of all cases. Clinical courses are more severe, and organ complications are more common in patients with juvenile SLE. Varying gender distribution in different age groups and increasing severity with younger age and the presence of monogenic disease in early childhood indicate distinct differences in the pathophysiology of juvenile versus adult-onset SLE. Regardless of these differences, classification criteria and treatment options are identical. In this article, we discuss age-specific pathomechanisms of juvenile-onset SLE, which are currently available and as future treatment options, and propose reclassification of different forms of SLE along the inflammatory spectrum from autoinflammation to autoimmunity

Vasculitis in juvenile-onset systemic lupus erythematosus

© 2019 Smith, Lythgoe and Hedrich. Juvenile-onset systemic lupus erythematosus (JSLE) is a rare, heterogeneous multisystem autoimmune disease that can affect any organ, and present with diverse clinical and serological manifestations. Vasculitis can be a feature of JSLE. It more commonly presents as cutaneous vasculitis than visceral vasculitis, which can affect the central nervous system, peripheral nervous system, lungs, gut, kidneys, heart and large vessels. The incidence and prevalence of vasculitis in JSLE has not been well described to date. Symptoms of vasculitis can be non-specific and overlap with other features of JSLE, requiring careful consideration for the diagnosis to be achieved and promptly treated. Biopsies are often required to make a definitive diagnosis and differentiate JSLE related vasculitis from other manifestations of JSLE, vasculopathies and JSLE related antiphospholipid syndrome. Visceral vasculitis can be life threatening, and its presence at the time of JSLE diagnosis is associated with permanent organ damage, which further highlights the importance of prompt recognition and treatment. This review will focus on the presentation, diagnosis, management and outcomes of vasculitis in JSLE, highlighting gaps in the current evidence base

COVID-19: treatment strategies of German-speaking pediatric rheumatologists Results of an online survey

Zusammenfassung Hintergrund Zuverlässige Daten zu Verlauf und Therapie von COVID-19 („corona virus disease 2019“) bei Kindern mit rheumatischen Erkrankungen unter Immunsuppression fehlen. Ziel der Arbeit Abbildung individueller Strategien der Mitglieder der Gesellschaft für Kinder- und Jugendrheumatologie (GKJR) im Umgang mit COVID-19. Methodik Mittels Online-Umfrage wurden im Mai 2020 das Meinungsbild der GKJR-Mitglieder zum Umgang mit DMARDs („disease-modifying anti-rheumatic drugs“) bei COVID-19-Erkrankung sowie die Bereitschaft zum Einsatz spezieller Therapieansätze bei Patienten mit unterschiedlicher Schwere von COVID-19 erhoben. Ergebnisse Es nahmen 71 Kollegen (27,3 % aller befragten ärztlichen Mitglieder) an der Umfrage teil; davon hatten 28,2 % bereits Patienten mit COVID-19 betreut. Über 95 % der Teilnehmer lehnten eine präventive Anpassung der antirheumatischen Therapie im Rahmen der SARS-CoV-2-Pandemie ab. Bei ambulanten Patienten unter Immunsuppression mit nachgewiesener COVID-19-Erkrankung würden mehr als 50 % der Teilnehmer folgende Therapien aussetzen: intravenöse hoch dosierte Steroide, Cyclophosphamid, Anti-CD20-Antikörper, sowie eine BAFF-, CTLA-4-, TNF-α-Blockade. Hingegen würden nichtsteroidale Antiphlogistika, Hydroxychloroquin (HCQ), orale Steroide, Mycophenolat, IL-1-Blockade sowie Immunglobuline (Ig) von >70 % der Kollegen weiter fortgeführt. Bei stationären Patienten mit COVID-19 würden insgesamt 74,6 % der Kollegen eine COVID-19-gerichtete Therapie erwägen. Bei stabilem Verlauf unter O 2 -Therapie (Stufe I) würden am häufigsten HCQ (18,3 %), Azithromycin (16,9 %) und Ig (9,9 %) in Betracht gezogen. Bei drohendem (Stufe II) bzw. manifestem Zytokinsturm (Stufe III) würden am häufigsten Anakinra (40,8 % bei Stufe II bzw. 46,5 % bei Stufe III), Tocilizumab (26,8 % bzw. 40,8 %), Steroide (25,4 % bzw. 33,8 %) und Remdesivir (29,6 % bzw. 38,0 %) eingesetzt. Von vielen Kollegen wurde betont, dass die Therapiestrategie individuell und der klinischen Situation entsprechend angepasst werden soll. Diskussion Die Ergebnisse der Online-Umfrage sind vor dem Hintergrund einer aktuell in Deutschland niedrigen Prävalenz von COVID-19 zu sehen und spiegeln somit theoretische Überlegungen der Befragten wider. Da Kinder derzeit nicht im Fokus von prospektiven COVID-19-Studien stehen, scheint der kontinuierliche und kritische kollegiale Fachaustausch bei Therapieentscheidungen umso wichtiger zu sein

CD14(+) monocytes contribute to inflammation in chronic nonbacterial osteomyelitis (CNO) through increased NLRP3 inflammasome expression

The pathophysiology of chronic nonbacterial osteomyelitis (CNO) remains incompletely understood. Increased NLRP3 inflammasome activation and IL-1β release in monocytes from CNO patients was suggested to contribute to bone inflammation. Here, we dissect immune cell infiltrates and demonstrate the involvement of monocytes across disease stages. Differences in cell density and immune cell composition may help to discriminate between BOM and CNO. However, differences are subtle and infiltrates vary in CNO. In contrast to other cells involved, monocytes are a stable element during all stages of CNO, which makes them a promising candidate in the search for “drivers” of inflammation. Furthermore, we link increased expression of inflammasome components NLRP3 and ASC in monocytes with site-specific DNA hypomethylation around the corresponding genes NLRP3 and PYCARD. Our observations deliver further evidence for the involvement of pro-inflammatory monocytes in the pathophysiology of CNO. Cellular and molecular alterations may serve as disease biomarkers and/or therapeutic targets

Priorities in Chronic nonbacterial osteomyelitis (CNO) - results from an international survey and roundtable discussions

ObjectiveChronic nonbacterial osteomyelitis (CNO) is an autoinflammatory bone disorder that predominantly affects children and young people. The pathophysiology and molecular mechanisms of CNO remain poorly understood, and diagnostic criteria and biomarkers are lacking. As a result, treatment is empiric and follows personal experience, case series and expert consensus plans.MethodsA survey was designed to gain insight on clinician and patient experiences of diagnosing and treating CNO and to collate opinions on research priorities. A version containing 24 questions was circulated among international expert clinicians and clinical academics (27 contacted, 21 responses). An equivalent questionnaire containing 20 questions was shared to explore the experience and priorities of CNO patients and family members (93 responses).ResultsResponses were used to select topics for four moderated roundtable discussions at the "International Conference on CNO and autoinflammatory bone disease" (Liverpool, United Kingdom, May 25-26th, 2022). The group identified deciphering the pathophysiology of CNO to be the highest priority, followed by clinical trials, necessary outcome measures and classification criteria. Surprisingly, mental wellbeing scored behind these items.ConclusionsAgreement exists among clinicians, academics, patients and families that deciphering the pathophysiology of CNO is of highest priority to inform clinical trials that will allow for the approval of medications for the treatment of CNO by regulatory agencies

Attainment of Low Disease Activity and Remission Targets reduces the risk of severe flare and new damage in Childhood Lupus

Objectives: To assess the achievability and effect of attaining low disease activity (LDA) or remission in childhood (cSLE). / Methods: Attainment of three adult-SLE derived definitions of LDA (LLDAS, LA, Toronto-LDA), and four definitions of remission (clinical-SLEDAI-defined remission on/off treatment, pBILAG-defined remission on/off treatment) was assessed in UK JSLE Cohort Study patients longitudinally. Prentice-Williams-Petersen-GAP recurrent event models assessed the impact of LDA/remission attainment on severe flare/new damage. / Results: LLDAS, LA and Toronto-LDA targets were reached in 67%, 73% and 32% of patients, after a median of 18, 15 or 17 months, respectively. Cumulatively, LLDAS, LA and Toronto-LDA was attained for a median of 23%, 31% and 19% of total follow-up-time, respectively. Remission on-treatment was more common (61% cSLEDAI-defined, 42% pBILAG-defined) than remission off-treatment (31% cSLEDAI-defined, 21% pBILAG-defined). Attainment of all target states, and disease duration (>1 year), significantly reduced the hazard of severe flare (p 0.05). Attainment of all targets reduced the hazards of new damage (p< 0.05). / Conclusions: This is the first study demonstrating that adult-SLE-derived definitions of LDA/remission are achievable in cSLE, significantly reducing risk of severe flare/new damage. Of the LDA definitions, LLDAS performed best, leading to a statistically comparable reduction in the hazards of severe flare to attainment of clinical-remission

Clinical and laboratory characteristics in juvenile-onset systemic lupus erythematosus across age groups

BACKGROUND Systemic lupus erythematous (SLE) is a systemic autoimmune/inflammatory condition. Approximately 15–20% of patients develop symptoms before their 18th birthday and are diagnosed with juvenile-onset SLE (JSLE). Gender distribution, clinical presentation, disease courses and outcomes vary significantly between JSLE patients and individuals with adult-onset SLE. This study aimed to identify age-specific clinical and/or serological patterns in JSLE patients enrolled to the UK JSLE Cohort Study. METHODS Patient records were accessed and grouped based on age at disease-onset: pre-pubertal (≤7 years), peri-pubertal (8–13 years) and adolescent (14–18 years). The presence of American College of Rheumatology (ACR) classification criteria, laboratory results, disease activity [British Isles Lupus Assessment Group (BILAG) and Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2 K) scores] and damage [Systemic Lupus International Collaborating Clinics (SLICC) damage index] were evaluated at diagnosis and last follow up. RESULTS A total of 418 JSLE patients were included in this study: 43 (10.3%) with pre-pubertal disease onset; 240 (57.4%) with peri-pubertal onset and 135 (32.3%) were diagnosed during adolescence. At diagnosis, adolescent JSLE patients presented with a higher number of ACR criteria when compared with pre-pubertal and peri-pubertal patients [pBILAG2004 scores: 9(4–20] vs. 7(3–13] vs. 7(3–14], respectively, p = 0.015] with increased activity in the following BILAG domains: mucocutaneous (p = 0.025), musculoskeletal (p = 0.029), renal (p = 0.027) and cardiorespiratory (p = 0.001). Furthermore, adolescent JSLE patients were more frequently ANA-positive (p = 0.034) and exhibited higher anti-dsDNA titres (p = 0.001). Pre-pubertal individuals less frequently presented with leukopenia (p = 0.002), thrombocytopenia (p = 0.004) or low complement (p = 0.002) when compared with other age groups. No differences were identified in disease activity (pBILAG2004 score), damage (SLICC damage index) and the number of ACR criteria fulfilled at last follow up. CONCLUSIONS Disease presentations and laboratory findings vary significantly between age groups within a national cohort of JSLE patients. Patients diagnosed during adolescence exhibit greater disease activity and “classic” autoantibody, immune cell and complement patterns when compared with younger patients. This supports the hypothesis that pathomechanisms may vary between patient age groups