Tissue gene expression profiles and communication networks inform candidate blood biomarker identification in psoriasis and atopic dermatitis.

Overlapping clinical and pathomechanistic features can complicate the diagnosis and treatment of inflammatory skin diseases, including psoriasis and atopic dermatitis (AD). Spatial transcriptomics allows the identification of disease- and cell-specific molecular signatures that may advance biomarker development and future treatments. This study identified transcriptional signatures in keratinocytes and sub-basal CD4+ and CD8+ T lymphocytes from patients with psoriasis and AD. In silico prediction of ligand:receptor interactions delivered key signalling pathways (interferon, effector T cells, stroma cell and matrix biology, neuronal development, etc.). Targeted validation of selected transcripts, including CCL22, RELB, and JUND, in peripheral blood T cells suggests the chosen approach as a promising tool also in other inflammatory diseases. Psoriasis and AD are characterized by transcriptional dysregulation in T cells and keratinocytes that may be targeted therapeutically. Spatial transcriptomics is a valuable tool in the search for molecular signatures that can be used as biomarkers and/or therapeutic targets.

[Arthritis and osteomyelitis in childhood and adolescence-Bacterial and nonbacterial]. / Arthritis und Osteomyelitis im Kindes- und Jugendalter ­ bakteriell und nichtbakteriell.

Bacterial arthritis and osteomyelitis are usually acute diseases, which in this way differ from the often insidious course of nonbacterial osteomyelitis; however, there is often an overlap both in less acute courses of bacterial illnesses and also in nonbacterial osteitis. The overlapping clinical phenomena can be explained by similar pathophysiological processes. In bacteria-related illnesses the identification of the pathogen and empirical or targeted anti-infectious treatment are prioritized, whereas no triggering agent is known for nonbacterial diseases. The diagnostics are based on the exclusion of differential diagnoses, clinical scores and magnetic resonance imaging (MRI). An activity-adapted anti-inflammatory treatment is indicated.

Defining remission in childhood-onset lupus: PReS-endorsed consensus definitions by an international task force.

OBJECTIVE: To derive childhood-onset SLE (cSLE) specific remission definitions for future treat-to-target (T2T) trials, observational studies, and clinical practice. METHODS: The cSLE International T2T Task Force conducted Delphi surveys exploring paediatric perspectives on adult-onset SLE remission targets. A modified nominal group technique was used to discuss, refine, and agree on the cSLE remission target criteria. RESULTS: The Task Force proposed two definitions of remission: 'cSLE clinical remission on steroids (cCR)' and 'cSLE clinical remission off steroids (cCR-0)'. The common criteria are: (1) Clinical-SLEDAI-2 K = 0; (2) PGA score < 0.5 (0-3 scale); (4) stable antimalarials, immunosuppressive, and biologic therapy (changes due to side-effects, adherence, weight, or when building up to target dose allowed). Criterion (3) in cCR is the prednisolone dose ≤0.1 mg/kg/day (maximum 5 mg/day), whereas in cCR-0 it is zero. CONCLUSIONS: cSLE definitions of remission have been proposed, maintaining sufficient alignment with the adult-SLE definition to facilitate life-course research.

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

OBJECTIVE: Chronic 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. METHODS: A 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). RESULTS: Responses 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. CONCLUSIONS: Agreement 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.

Gathering expert consensus to inform a proposed trial in chronic nonbacterial osteomyelitis (CNO).

Chronic nonbacterial osteomyelitis (CNO) is an autoinflammatory bone disease that primarily affects children and adolescents. CNO is associated with pain, bone swelling, deformity, and fractures. Its pathophysiology is characterized by increased inflammasome assembly and imbalanced expression of cytokines. Treatment is currently based on personal experience, case series and resulting expert recommendations. Randomized controlled trials (RCTs) have not been initiated because of the rarity of CNO, expired patent protection of some medications, and the absence of agreed outcome measures. An international group of fourteen CNO experts and two patient/parent representatives was assembled to generate consensus to inform and conduct future RCTs. The exercise delivered consensus inclusion and exclusion criteria, patent protected (excludes TNF inhibitors) treatments of immediate interest (biological DMARDs targeting IL-1 and IL-17), primary (improvement of pain; physician global assessment) and secondary endpoints (improved MRI; improved PedCNO score which includes physician and patient global scores) for future RCTs in CNO.

PReS-endorsed international childhood lupus T2T task force definition of childhood lupus low disease activity state (cLLDAS).

OBJECTIVE: To achieve a consensus-based definition of Low Disease Activity (LDA) for use in cSLE trials. METHODS: The International cSLE T2T Task Force, comprising of paediatric rheumatologists/nephrologists, and adult rheumatologists undertook a series of Delphi surveys/consensus meetings to discuss, refine, and vote upon cSLE LDA criteria. RESULTS: The Task Force agreed that LDA should be based upon the adult-SLE Lupus Low Disease Activity State definition (LLDAS), with modifications to make it applicable to cSLE (cLLDAS). They agreed upon five cLLDAS criteria: (1) SLE Disease Activity Index (SLEDAI)-2 K ≤4, with no activity in major organ systems; (2) no new features of lupus disease activity compared with the last assessment; (3) Physician Global Assessment score of ≤1 (0-3 scale); (4) prednisolone dose of ≤0.15 mg/kg/day, 7.5 mg/day/maximum; while on (5) stable antimalarials, immunosuppressives, and biologics. CONCLUSIONS: A cSLE-appropriate definition of cLLDAS has been generated, maintaining alignment with the adult-SLE definition to promote life-course research.

TNF-inhibitors or bisphosphonates in chronic nonbacterial osteomyelitis? - Results of an international retrospective multicenter study.

Chronic nonbacterial osteomyelitis (CNO) can cause significant morbidity, including bone pain and damage. In the absence of clinical trials, treatments include non-steroidal anti-inflammatory drugs, corticosteroids, TNF-inhibitors (TNFi) and/or bisphosphonates. In a retrospective chart review in the United Kingdom and Germany, we investigated response to TNFi and/or pamidronate. Ninety-one patients were included, receiving pamidronate (n = 47), TNFi (n = 22) or both sequentially (n = 22). Patients with fatigue [p = 0.003] and/or arthritis [p = 0.002] were more frequently treated with TNFi than pamidronate. Both therapies were associated with clinical remission at 6 months, and reduction of bone lesions on MRI at 12 months. While not reaching statistical significance, pamidronate resulted in faster resolution of MRI lesions. Fewer flares were observed with TNFi. Failure to respond to pamidronate was associated with female sex [p = 0.027], more lesions on MRI [p = 0.01] and higher CRP levels [p = 0.03]. Randomized clinical trials are needed to confirm observations and generate evidence.

Classification of systemic lupus erythematosus in children and adults.

Systemic Lupus Erythematosus (SLE) is an autoimmune multisystem disease with a variable clinical phenotype and no single clinical, laboratory or pathological feature that can be used as a gold standard for disease classification or diagnosis. Classification criteria have been developed in an attempt to define homogenous groups of SLE patients for clinical research. They have been mainly validated in adult cohorts, given the much lower prevalence of SLE before puberty. The three commonly used sets of current classification criteria and their validation studies to date are described in this review. Challenges relating to classification of SLE patients, including important differences across age-groups and ethnicities, are explored along with future directions in the classification of SLE.

Systemic Lupus Erythematosus in Children and Young People.

PURPOSE OF REVIEW: Juvenile-onset systemic lupus erythematosus ((j)SLE) is an autoimmune/inflammatory disease that results in significant damage and disability. When compared to patients with disease onset in adulthood, jSLE patients exhibit increased disease activity, damage and require more aggressive treatments. This manuscript summarises age-specific pathogenic mechanisms and underscores the need for age group-specific research, classification and treatment. RECENT FINDINGS: Genetic factors play a significant role in the pathophysiology of jSLE, as > 7% of patients develop disease as a result of single gene mutations. Remaining patients carry genetic variants that are necessary for disease development, but require additional factors. Increased 'genetic impact' likely contributes to earlier disease onset and more severe phenotypes. Epigenetic events have only recently started to be addressed in jSLE, and add to the list of pathogenic mechanisms that may serve as biomarkers and/or treatment targets. To allow meaningful and patient-oriented paediatric research, age-specific classification criteria and treatment targets require to be defined as currently available tools established for adult-onset SLE have limitations in the paediatric cohort. Significant progress has been made in understanding the pathophysiology of jSLE. Meaningful laboratory and clinical research can only be performed using age group-specific tools, classification criteria and treatment targets.

[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.

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.

Differential analysis of serum and urine S100 proteins in juvenile-onset systemic lupus erythematosus (jSLE).

Up to 80% of juvenile-onset systemic lupus erythematosus (jSLE) patients develop lupus nephritis (LN) that affects treatment and prognosis. Easily accessible biomarkers do not exist to reliably diagnose LN, leaving kidney biopsies as the gold-standard. Calcium-binding S100 proteins are expressed by innate immune cells and epithelia and may act as biomarkers in systemic inflammatory conditions. We quantified S100 proteins in the serum and urine of jSLE patients, matched healthy and inflammatory (IgA vasculitis) controls. Serum S100A8/A9, and serum and urine S100A12 are increased in jSLE patients when compared to controls. Furthermore, serum S100A8/A9, and serum and urine S100A12 are increased in jSLE patients with active as compared to patients with inactive/no LN. No differences in S100A4 levels were seen between groups. This study demonstrates potential promise for S100A8/A9 and S100A12 as biomarkers for jSLE and active LN. Findings require to be confirmed and tested prospectively in independent and larger multi-ethnic cohorts.

Defining consensus opinion to develop randomised controlled trials in rare diseases using Bayesian design: An example of a proposed trial of adalimumab versus pamidronate for children with CNO/CRMO.

INTRODUCTION: Chronic nonbacterial osteomyelitis (CNO) is a rare autoinflammatory bone disorder primarily affecting children and adolescents. It can lead to chronic pain, bony deformities and fractures. The pathophysiology of CNO is incompletely understood. Scientific evidence suggests dysregulated expression of pro- and anti-inflammatory cytokines to be centrally involved. Currently, treatment is largely based on retrospective observational studies and expert opinion. Treatment usually includes nonsteroidal anti-inflammatory drugs and/or glucocorticoids, followed by a range of drugs in unresponsive cases. While randomised clinical trials are lacking, retrospective and prospective non-controlled studies suggest effectiveness of TNF inhibitors and bisphosphonates. The objective of the Bayesian consensus meeting was to quantify prior expert opinion. METHODS: Twelve international CNO experts were randomly chosen to be invited to a Bayesian prior elicitation meeting. RESULTS: Results showed that a typical new patient treated with pamidronate would have an 84% chance of improvement in their pain score relative to baseline at 26 weeks and an 83% chance on adalimumab. Experts thought there was a 50% chance that a new typical patient would record a pain score of 28mm (pamidronate) to 30mm (adalimumab) or better at 26 weeks. There was a modest trend in prior opinion to indicate an advantage of pamidronate vs adalimumab, with a 68% prior chance that pamidronate is superior to adalimumab by some margin. However, it is clear that there is considerable uncertainty about the precise relative merits of the two treatments. CONCLUSIONS: The rarity of CNO leads to challenges in conducting randomised controlled trials with sufficient power to provide a definitive outcome. We address this using a Bayesian design, and here describe the process and outcome of the elicitation exercise to establish expert prior opinion. This opinion will be tested in the planned prospective CNO study. The process for establishing expert consensus opinion in CNO will be helpful for developing studies in other rare paediatric diseases.

Outcomes following mycophenolate mofetil versus cyclophosphamide induction treatment for proliferative juvenile-onset lupus nephritis.

BACKGROUND: Juvenile-onset systemic lupus erythematosus (JSLE) is more severe than adult-onset disease, including more lupus nephritis (LN). Despite differences in phenotype/pathogenesis, treatment is based upon adult trials. This study aimed to compare treatment response, damage accrual, time to inactive LN and subsequent flare, in JSLE LN patients treated with mycophenolate mofetil (MMF) versus intravenous cyclophosphamide (IVCYC). METHODS: UK JSLE Cohort Study participants, ≤16 years at diagnosis, with ≥4 American College of Rheumatology criteria for SLE, with class III or IV LN, were eligible. Mann-Whitney U tests, Fisher's exact test and Chi-squared tests were utilized for statistical analysis. RESULTS: Of the patients, 34/51 (67%) received MMF, and 17/51 (33%) received IVCYC. No significant differences were identified at 4-8 and 10-14 months post-renal biopsy and last follow-up, in terms of renal British Isles Lupus Assessment Grade scores, urine albumin/creatinine ratio, serum creatinine, ESR, anti-dsDNA antibody, C3 levels and patient/physician global scores. Standardized Damage Index scores did not differ between groups at 13 months or at last follow-up. Inactive LN was attained 262 (141-390) days after MMF treatment, and 151 (117-305) days following IVCYC ( p = 0.17). Time to renal flare was 451 (157-1266) days for MMF, and 343 (198-635) days for IVCYC ( p = 0.47). CONCLUSION: This is the largest study to date investigating induction treatments for proliferative LN in children, demonstrating comparability of MMF and IVCYC.

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-1ß 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.

IL10 promoter haplotypes may contribute to altered cytokine expression and systemic inflammation in celiac disease.

Celiac disease (CD) is an autoimmune/inflammatory condition triggered by dietary gluten intake in genetically predisposed individuals. Though associations with MHC class II HLA-DQ2 or -DQ8 are the primary and necessary genetic predisposition for CD, >97% of genetically predisposed individuals never develop CD. Cytokines were measured in the serum of CD patients and controls. Possible associations with IL10 promoter variants were investigated. Cytokine expression from PBMCs was monitored in response to gluten exposure, or CD3/TCR complex stimulation in the absence or presence of recombinant IL-10. Serum cytokines varied between patients with CD at the time of diagnosis, after dietary elimination of gluten, and healthy controls. Serum IL-17A reflected disease activity. Reduced IL-10 serum levels and altered IL-10 expression by PBMCs coincided with IL10 promoter haplotypes that encode for "low" IL-10 expression (ATA). Increased prevalence of ATA IL10 promoter haplotypes and subsequently reduced IL-10 expression may be an immunological cofactor in individuals genetically predisposed for the development of CD. Resulting cytokine imbalances may be utilized as disease biomarkers in CD.

TCRαß+CD3+CD4-CD8- (double negative) T cells in autoimmunity.

TCRαß+CD3+CD4-CD8- "double negative" (DN) T cells comprise a small subset of mature peripheral T cells. The origin and function of DN T cells are somewhat unclear and discussed controversially. While DN T cells resemble a rare and heterogeneous T cell subpopulation in healthy individuals, numbers of TCRαß+ DN T cells are expanded in several inflammatory conditions, where they also exhibit distinct effector phenotypes and infiltrate inflamed tissues. Thus, DN T cells may be involved in systemic inflammation and tissue damage in autoimmune/inflammatory conditions, including SLE, Sjögren's syndrome, and psoriasis. Here, the current understanding of the origin and phenotype of DN T cells, and their role in the instruction of immune responses, autoimmunity and inflammation will be discussed in health and disease.

[Still's disease in children and adults]. / Morbus Still im Kindes- und Erwachsenenalter.

Systemic juvenile idiopathic arthritis (sJIA) is characterized by fever, arthritis, and other signs of systemic inflammation. Historically, sJIA was named Still's disease after George Frederic Still, who first reported patients. Individuals who manifest after the 16th birthday are diagnosed with adult onset Still's disease (AOSD). The pathophysiology of sJIA and AOSD are incompletely understood. Increased activation of inflammasomes and the expression of proinflammatory cytokines play a central role. S100 proteins, which can activate Toll-like receptors, thus, maintaining positive feedback loops, have also been detected at increased levels in sera from sJIA patients. Reduced expression of the immune-modulatory cytokine IL-10 may further contribute to immune cell activation and the production of proinflammatory molecules. Here, we discuss the clinical picture, differential diagnoses, the current pathophysiological understanding, and treatment options in sJIA and AOSD.