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Objectives The COVID-19 pandemic is a global health problem. We, as the EMERGE (EMErging RheumatoloGists and rEsearchers) group of PReS (Pediatric Rheumatology European Society) analyzed how the pandemic has affected pediatric rheumatology practice. Methods An online survey was developed to assess changes in pediatric rheumatology practice due to the pandemic. Results were analyzed using descriptive statistics. Results From 70 countries, 493 pediatric rheumatologists (80.3% in pediatric rheumatology practice for ≥5 years) responded to the survey. Around 70% disagreed that the pandemic led to reduced prescription of nonsteroidal anti-inflammatory drugs, conventional synthetic and biologic disease-modifying antirheumatic drugs. Almost half were more likely to taper corticosteroids faster. One-fifth hesitated to switch the major immunosuppressant during a flare. Patients encountering difficulties obtaining hydroxychloroquine and tocilizumab due to shortages were noted by 192 (38.9%) and 44 (8.9%), respectively. Twenty to 30% indicated that their patients had experienced a flare or delay in diagnosis/intervention due to postponed appointments.53% mentioned use of phone calls/smartphone applications while 47% shifted towards video consultations for patient care. Respondents indicated an increased number of patients with Kawasaki disease (30%), macrophage activation syndrome (15.6%), unusual vasculitic rashes (31.4%), and hyperinflammation (33.5%) during the pandemic. Conclusion This is the largest survey to date addressing changes in pediatric rheumatology practice due to the COVID-19 pandemic. Primary changes were due to delays in clinic appointments, increase in use of virtual technologies, and concerns about the use of immunosuppressive therapies. An increased number of patients with Kawasaki disease/hyperinflammation mentioned by the respondents is noteworthy., • COVID-19 pandemic threatens millions of lives worldwide. • As pediatric rheumatologists, we take care of a vulnerable population. • The main changes in pediatric rheumatology practice during the COVID-19 pandemic were due to delays in clinic appointments, increase in use of virtual technologies to decrease in-person visits, use of anti-rheumatic drugs treatment/prophylaxis, and concerns about using immunosuppressive therapies. • An increase in the number of patients with Kawasaki disease/hyperinflammation was also mentioned by the respondents of the survey. • Understanding the challenges imposed by the COVID-19 pandemic on the community of pediatric rheumatologists will help tailor future recommendations regarding the management of pediatric rheumatology patients during the pandemic according to the needs in daily clinical practice.

Background: Recent studies have suggested association between the ABO blood group and inflammation, which was a crucial pathological process of primary knee osteoarthritis. The aim of this study was to investigate the association between the ABO blood group and primary knee osteoarthritis ​and the severity of primary knee osteoarthritis evaluated by the Kellgren/Lawrence score, as well as the histopathologic association in a subgroup of patients. Methods: We performed a retrospective review of patients with primary knee osteoarthritis that served as the case group ​and a random sampling of healthy blood donors that served as the control group. The severity of knee osteoarthritis at the first outpatient visit was evaluated by the Kellgren/Lawrence scoring system. Further study was performed to investigate the expression of blood group antigens in synovial tissue of the knee in both cases and controls. Results: A total of 1126 cases and 30299 controls were involved. The proportion of AB blood group was higher in the case group than in the control group (9.7% vs. 7.8%), and logistic regression revealed that the AB blood group was a risk factor of primary knee osteoarthritis (P ​= ​0.025 and 0.048 for univariate and multivariate analysis, respectively), independent of age (P ​= ​0.973) and sex (P ​= ​0.520). Patients of the blood group AB had a higher Kellgren/Lawrence score (P ​= ​0.017). The immunohistochemical study indicated association between LeY antigen and primary knee osteoarthritis (P ​= ​0.029). Conclusions: This study suggested that the blood group AB was associated with primary knee osteoarthritis, as well as its radiological severity. Further study indicated that LeY antigen, which was related to the blood group, was associated with primary knee osteoarthritis. Translational potential of this article: This study revealed that blood group AB and LeY antigen was associated with primary knee osteoarthritis, which shed new light on the nature of osteoarthritis, and the development of novel therapy for osteoarthritis. Keywords: Blood group, Kellgren/Lawrence, Knee, LeY antigen, Osteoarthritis

Objectives To investigate humoral responses and safety of mRNA SARS-CoV-2 vaccines in systemic autoimmune and autoinflammatory rheumatic disease (SAARD) patients subjected or not to treatment modifications during vaccination. Methods A nationwide, multicenter study, including 605 SAARD patients and 116 controls, prospectively evaluated serum anti-SARS-CoV-2 S1-protein IgG antibody titers, side-effects, and disease activity, one month after complete vaccination, in terms of distinct treatment modification strategies (none, partial and extended modifications). Independent risk factors associated with hampered humoral responses were identified by data-driven multivariable logistic regression analysis. Results Patients with extended treatment modifications responded to vaccines similarly to controls as well as SAARD patients without immunosuppressive therapy (97.56% vs 100%, p = 0.2468 and 97.56% vs 97.46%, p > 0.9999, respectively). In contrast, patients with partial or without therapeutic modifications responded in 87.50% and 84.50%, respectively. Furthermore, SAARD patients with extended treatment modifications developed higher anti-SARS-CoV-2 antibody levels compared to those without or with partial modifications (median:7.90 vs 7.06 vs 7.1, p = 0.0003 and p = 0.0195, respectively). Mycophenolate mofetil (MMF), rituximab (RTX) and methotrexate (MTX) negatively affected anti-SARS-CoV-2 humoral responses. In 10.5% of vaccinated patients, mild clinical deterioration was noted; however, no differences in the incidence of deterioration were observed among the distinct treatment modification SAARD subgroups. Side-effects were generally comparable between SAARD patients and controls. Conclusions In SAARD patients, mRNA SARS-CoV-2 vaccines are effective and safe, both in terms of side-effects and disease flares. Treatment with MMF, RTX and/or MTX compromises anti-SARS-CoV-2 antibody responses, which are restored upon extended treatment modifications without affecting disease activity.

Background: Clusterin (CLU; also known as apolipoprotein J) is an ATP-independent holdase chaperone that prevents proteotoxicity as a consequence of protein aggregation. It is a ∼60 kDa disulfide-linked heterodimeric protein involved in the clearance of cellular debris and the regulation of apoptosis. CLU has been proposed to protect cells from cytolysis by complement components and has been implicated in Alzheimer’s disease due to its ability to bind amyloid-β peptides and prevent aggregate formation in the brain. Recent studies suggest that CLU performs moonlighting functions. CLU exists in two major forms: an intracellular form and a secreted extracellular form. The intracellular form of CLU may suppress stress-induced apoptosis by forming complexes with misfolded proteins and facilitates their degradation. The secreted form of CLU functions as an extracellular chaperone that prevents protein aggregation. Methods: In this review, we discuss the published literature on the biology of CLU in cartilage, chondrocytes, and other synovial joint tissues. We also review clinical studies that have examined the potential for using this protein as a biomarker in synovial and systemic fluids of patients with rheumatoid arthritis (RA) or osteoarthritis (OA). Results: Since CLU functions as an extracellular chaperone, we propose that it may be involved in cytoprotective functions in osteoarticular tissues. The secreted form of CLU can be measured in synovial and systemic fluids and may have translational potential as a biomarker of early repair responses in OA. Conclusion: There is significant potential for investigating synovial and systemic CLU as biomarkers of OA. Future translational and clinical orthopaedic studies should carefully consider the diverse roles of this protein and its involvement in other comorbidities. Therefore, future biomarker studies should not correlate circulating CLU levels exclusively to the process of OA pathogenesis and progression. Special attention should be paid to CLU levels in synovial fluid. The Translational potential of this article: There is significant potential for investigating synovial and systemic CLU as a predictive biomarker of osteoarthritis (OA) progression and response to novel treatments and interventions. Given that CLU plays diverse roles in other comorbidities such as rheumatoid arthritis (RA) and obesity, future translational and clinical orthopaedic biomarker studies should not directly correlate circulating CLU levels to the process of OA pathogenesis and progression. However, special attention should be paid to CLU levels in synovial fluid. The cytoprotective properties of CLU may support the implementation of regenerative strategies and new approaches for developing targeted therapeutics for OA.

Patients with inflammatory arthritis represent a possible high-risk group to COVID-19 due to their immunosuppressive regimen designed to maintain low disease activity. Thus, substantial effort has been put forth to understand the impact of COVID-19 on these patients. Patients with rheumatic diseases as a whole do not appear to be more susceptible to acquiring COVID-19. Furthermore, immunosuppression generally did not increase the likelihood of developing severe COVID-19, with the important exception of medium and high-dose glucocorticoid use. In addition, a small number of COVID-19 patients have developed new inflammatory arthritis; whether this represents an unmasking of previous subclinical disease or a bone fide virus-induced arthritis is unclear. Nevertheless, it appears that inflammatory arthritis patients currently on immunosuppression should continue their medication to prevent future flares and limit glucocorticoid usage. While this continues to be a rapidly evolving field, these data are reassuring to both patients with and providers treating inflammatory arthritides.

Background Pulmonary disease is a potentially serious yet underdiagnosed complication of Sjogren’s syndrome, the second most common autoimmune rheumatic disease. Approximately 16% of patients with Sjogren’s demonstrate pulmonary involvement with higher mortality and lower quality of life. Research Question Clinical practice guidelines for pulmonary manifestations of Sjogren’s were developed by the Sjogren’s Foundation after identifying a critical need for early diagnosis and improved quality and consistency of care. Study Design and Methods A rigorous and transparent methodology was followed according to American College of Rheumatology guidelines. The Pulmonary Topic Review Group (TRG) developed clinical questions in the PICO (Patient, Intervention, Comparison, Outcome) format and selected literature search parameters. Each article was reviewed by a minimum of two TRG members for eligibility and assessment of quality of evidence and strength of recommendation. Guidelines were then drafted based on available evidence, expert opinion, and clinical importance. Draft recommendations with a clinical rationale and data extraction tables were submitted to a Consensus Expert Panel for consideration and approval, with at least 75% agreement required for individual recommendations to be included in the final version. Results The literature search revealed 1,192 articles, of which 150 qualified for consideration in guideline development. Of the original 85 PICO questions posed by the TRG, 52 recommendations were generated. These were then reviewed by the Consensus Expert Panel and 52 recommendations were finalized, with a mean agreement of 97.71% (range, 79%-100%). The recommendations span topics of evaluating Sjogren’s patients for pulmonary manifestations and assessing, managing, and treating upper and lower airway disease, interstitial lung disease, and lymphoproliferative disease. Interpretation Clinical practice guidelines for pulmonary manifestations in Sjogren’s will improve early identification, evaluation, and uniformity of care by primary care physicians, rheumatologists, and pulmonologists. Additionally, opportunities for future research are identified.

Objectives The ideal goal of treatment for juvenile idiopathic arthritis (JIA) is disease remission. However, many sets of remission criteria have been developed and no systematic review of remission in JIA exists. The current systematic review investigated (1) how remission has been defined across JIA clinical cohorts and (2) the frequency of remission overall and within disease categories. Methods Studies using prospective inception cohorts published after 1972 were selected if they estimated remission in cohorts of ≥50 patients. Articles focusing on specific medical interventions, not defining remission clearly or not reporting disease duration at remission assessment were excluded. Studies were selected from Medline, Embase, PubMed and bibliographies of selected articles. Risks of selection, missing outcome data and outcome reporting biases were assessed. Results Within 17 studies reviewed, 88% had majority female participants and patient disease duration ranged from 0.5 to 17 years. Thirteen sets of criteria for clinically inactive disease and remission were identified. Uptake of Wallace’s preliminary criteria was good in studies recruiting or following patients after their publication (78%). Remission frequencies increased with longer disease duration from 7% within 1.5 years to 47% by 10 years following diagnosis. Patients with persistent oligoarticular and rheumatoid-factor positive polyarticular JIA were most and least likely to achieve remission, respectively. Conclusions Achievement of remission increased with longer disease duration, but many patients remain in active disease, even in contemporary cohorts. Multiple sets of outcome criteria limited comparability between studies.

The purpose of this study was to relate central inflammation to autonomic activity (heart rate variability (HRV)) in patients with rheumatoid arthritis (RA) and fibromyalgia (FM). RA patients had reduced parasympathetic activity and FM patients had increased sympathetic activity compared to healthy controls. Comparisons between RA and FM showed higher cerebrospinal fluid (CSF) interleukin (IL)-1β inversely correlated to parasympathetic activity in RA. The FM patients had higher concentrations of CSF IL-8, IL-1Ra, IL-4 and IL-10, but none of these cytokines correlated with HRV. In conclusion, we found different profiles of central cytokines, i.e., elevated IL-1β in inflammatory pain (RA) and elevated IL-8 in dysfunctional pain (FM)., Highlights • Different CSF profiles of cytokines/chemokines in patients with fibromyalgia and rheumatoid arthritis • Higher CSF concentrations of IL-8, IL-1Ra, IL-4 and IL-10 in fibromyalgia patients • Higher CSF concentrations of IL-1beta in patients with rheumatoid arthritis • Elevated CSF IL-1beta in rheumatoid arthritis was related to decreased parasympathetic activity.

Purpose: Systemic lupus erythematosus (SLE) is an autoimmune connective tissue disease that can affect the central nervous system. Neuropsychiatric symptoms are found in 25–70% of patients. Using diffusion tensor imaging (DTI) various studies have reported changes in white matter integrity in SLE patients with neuropsychiatric symptoms (NPSLE patients). The purpose of this study was to investigate, if regional changes in white matter integrity can also be detected in SLE patients without neuropsychiatric symptoms (non-NPSLE patients). Methods: Applying DTI and tract based spatial statistics (TBSS) we investigated 19 NPSLE patients, 19 non-NPSLE and 18 healthy controls. Groups were matched for age and sex. Image pre-processing was performed using FSL, following the TBSS pipeline (eddy current correction, estimation of fractional anisotropy (FA), normalization, skeletonization of the group mean FA image). A general linear model with threshold-free cluster enhancement was used to assess significant differences between the three groups. Results: Statistical analyses revealed several regions of decreased prefrontal white matter integrity (decreased FA) in both groups of SLE patients. The changes found in the non-NPSLE patients (as compared to healthy controls) overlapped with those in the NPSLE patients, but were not as pronounced. Conclusions: Our data suggest that changes in regional white matter integrity, in terms of a decrease in FA, are present not only in NPSLE patients, but also in non-NPSLE patients, though to a lesser degree. We also demonstrate that the way statistical maps are corrected for multiple comparisons has a profound influence on whether alterations in white matter integrity in non-NPSLE patients are deemed significant.

The BAFF system plays a key role in the development of autoimmunity, especially in systemic lupus erythematosus (SLE). This often leads to the assumption that BAFF is mostly a B cell factor with a specific role in autoimmunity. Focus on BAFF and autoimmunity, driven by pharmaceutical successes with the recent approval of a novel targeted therapy Belimumab, has relegated other potential roles of BAFF to the background. Far from being SLE-specific, the BAFF system has a much broader relevance in infection, cancer and allergy. In this review, we provide the latest views on additional roles of the BAFF system in health and diseases, as well as an update on BAFF and autoimmunity, with particular focus on current clinical trials.

Systemic lupus erythematosus (SLE) is an autoimmune disease with multi-organ involvement and results in neurological and psychiatric (NP) symptoms in up to 40% of the patients. To date, the diagnosis of neuropsychiatric systemic lupus erythematosus (NPSLE) poses a challenge due to the lack of neuroradiological gold standards. In this study, we aimed to better localize and characterize normal appearing white matter (NAWM) changes in NPSLE by combining data from two quantitative MRI techniques, diffusion tensor imaging (DTI) and magnetization transfer imaging (MTI). 9 active NPSLE patients (37 ± 13 years, all females), 9 SLE patients without NP symptoms (44 ± 11 years, all females), and 14 healthy controls (HC) (40 ± 9 years, all females) were included in the study. MTI, DTI and fluid attenuated inversion recovery (FLAIR) images were collected from all subjects on a 3 T MRI scanner. Magnetization transfer ratio (MTR), mean diffusivity (MD), fractional anisotropy (FA), radial diffusivity (RD), axial diffusivity (AD) maps and white matter lesion maps based on the FLAIR images were created for each subject. MTR and DTI data were then co-analyzed using tract-based spatial statistics and a cumulative lesion map to exclude lesions. Significantly lower MTR and FA and significantly higher AD, RD and MD were found in NPSLE compared to HC in NAWM regions. The differences in DTI measures and in MTR, however, were only moderately co-localized. Additionally, significant differences in DTI measures, but not in MTR, were found between NPSLE and SLE patients, suggesting that the underlying microstructural changes detected by MD are linked to the onset of NPSLE. The co-analysis of the anatomical distribution of MTI and DTI measures can potentially improve the diagnosis of NPSLE and contribute to the understanding of the underlying microstructural damage., Graphical abstract, Highlights • NAWM is investigated in NPSLE and SLE using MTI and DTI. • Differences in DTI and MTR between NPSLE and HC are widespread but only moderately co-localized. • Significant differences in MD between SLE and NPSLE suggest link to onset of NPSLE.

Churg–Strauss syndrome is an uncommon multisystem disorder characterized by asthma, eosinophilia and vasculitis. We report on a 12-year-old boy with asthma and deterioration of his general condition, who was eventually diagnosed with an ANCA-negative Churg–Strauss syndrome. The propositus included, 50 cases of childhood Churg–Strauss syndrome have been reported. The patient characteristics and clinical characteristics of these children are summarized. The respiratory tract is most frequently involved with pulmonary infiltrates, asthma and sinusitis. Early recognition of childhood Churg–Strauss syndrome is important as delayed diagnosis can lead to severe organ involvement, and possible fatal outcome.