Ultrasound versus physical examination in predicting disease flare in children with juvenile idiopathic arthritis: a systematic literature review and qualitative synthesis

In this systematic review we analyzed the published articles related to the predictive value for flare of subclinical synovitis assessed by ultrasound (US) in juvenile idiopathic arthritis (JIA). Medline, Embase and Cochrane databases were searched from 1990 to 2020 by two authors, using PICO methodology. The study is built and reported according to PRISMA guidelines. Searches identified four articles comprising a total of 187 JIA patients in clinical remission from at least 3 months. Two of the articles found US subclinical signs of synovitis to be predictive for flare, with a five times higher risk (with Power Doppler signal as an important feature), while in the other two baseline US abnormalities did not predict a clinical flare. The articles differed for protocols, definitions, and length of follow-up. US has an expanding role in pediatric rheumatology, with interest-ing applications especially during the follow-up, potentially identifying subclinical inflammatory signs predictive of flare. However, the few studies available do not allow definite conclusions at this time.

COVID-19 Vaccine Does Not Increase the Risk of Disease Flare-Ups among Patients with Autoimmune and Immune-Mediated Diseases

Background: Reports describing post-vaccine autoimmune phenomena, in previously healthy individuals, increased the concerns regarding the risk of disease flare-ups in patients with immune diseases. We aimed to assess the potential risk of disease flare-up, after receiving the COVID-19 (Coronavirus disease 2019) vaccine, during a follow-up period of 6 months. Methods: We performed a prospective cohort study, enrolling the patients with autoimmune- and immune-mediated diseases who voluntarily completed our questionnaire, both online and during hospital evaluations. Based on their decision to receive the vaccine, the patients were divided into two groups (vaccinated and non-vaccinated). Participants who chose not to receive the vaccine served as a control group in terms of flare-ups. Results: A total of 623 patients, 416 vaccinated and 207 non-vaccinated, were included in the study during hospital evaluations (222/623) and after online (401/623) enrolment. There was no difference concerning the risk of flare-up between vaccinated and non-vaccinated patients (1.16, versus 1.72 flare-ups/100 patients-months, p = 0.245). The flare-ups were associated with having more than one immune disease, and with a previous flare-up during the past year. Conclusions: We did not find an increased risk of flare-up following COVID-19 vaccination in patients with autoimmune-/immune-mediated diseases, after a median follow-up of 5.9 months. According to our results, there should not be an obvious reason for vaccine hesitancy among this category of patients.

Infection with SARS-CoV-2 causes flares in patients with juvenile idiopathic arthritis in remission or inactive disease on medication

Background Flares of juvenile idiopathic arthritis (JIA) have been described in the context of various infections. Flares of rheumatic diseases in adults have been described following infection with SARS-CoV-2 in several cohorts. So far, the effect of infection with SARS-CoV-2 on the course of JIA is unknown. Methods The database of the German Center for Pediatric and Adolescent Rheumatology was searched for patients with confirmed infection with SARS-CoV-2 and subsequent disease flare, admitted from July 2020 until June 2021. cJADAS-27, ESR and C-reactive protein, as well as uveitis activity, medication at the time of flare and treatment of flare was extracted. Patient cases were described individually. Results Out of 988 patients admitted, five patients with remission off medication (n = 2) or inactive disease on medication (n = 3) were identified, with flare symptoms up to four weeks after infection with SARS-CoV-2. Conclusions Flares can occur after infection with SARS-CoV-2 in patients with JIA in remission or inactive disease on medication. Treating physicians need to be aware of this fact, especially when counseling patients with rheumatic diseases about the respective dangers of COVID-19 and vaccination against SARS-CoV-2.

Proteomic Approaches to Defining Remission and the Risk of Relapse in Rheumatoid Arthritis

ObjectivesPatients with Rheumatoid Arthritis (RA) are increasingly achieving stable disease remission, yet the mechanisms that govern ongoing clinical disease and subsequent risk of future flare are not well understood. We sought to identify serum proteomic alterations that dictate clinically important features of stable RA, and couple broad-based proteomics with machine learning to predict future flare.MethodsWe studied baseline serum samples from a cohort of stable RA patients (RETRO, n = 130) in clinical remission (DAS28<2.6) and quantified 1307 serum proteins using the SOMAscan platform. Unsupervised hierarchical clustering and supervised classification were applied to identify proteomic-driven clusters and model biomarkers that were associated with future disease flare after 12 months of follow-up and RA medication withdrawal. Network analysis was used to define pathways that were enriched in proteomic datasets.ResultsWe defined 4 proteomic clusters, with one cluster (Cluster 4) displaying a lower mean DAS28 score (p = 0.03), with DAS28 associating with humoral immune responses and complement activation. Clustering did not clearly predict future risk of flare, however an XGboost machine learning algorithm classified patients who relapsed with an AUC (area under the receiver operating characteristic curve) of 0.80 using only baseline serum proteomics.ConclusionsThe serum proteome provides a rich dataset to understand stable RA and its clinical heterogeneity. Combining proteomics and machine learning may enable prediction of future RA disease flare in patients with RA who aim to withdrawal therapy.

Characterizing Serum Cytokine Levels in Idiopathic Multicentric Castleman Disease Reveals Increased Chemokines and a Potential Signature Compared to Related Diseases

Idiopathic multicentric Castleman disease (iMCD) is a heterogeneous and life-threatening hematologic disorder with unknown etiology. It involves extensive lymphadenopathy with characteristic histopathology, inflammatory symptoms, and life-threatening cytokine-driven multi-organ failure, if inadequately treatment. Diagnosis requires the presence of histopathological, clinical, laboratory, and radiologic findings as well as exclusion of other related diseases including infectious, autoimmune, and lymphoproliferative disorders. Despite these guidelines, definitive diagnosis remains challenging as histopathological changes, clinical features, and laboratory abnormalities are non-specific. Given that iMCD can be aggressive and life-threatening, timely diagnosis is crucial, and specific diagnostic biomarkers are needed. Interleukin-6 (IL-6) is a known disease driver in a portion of patients, but it is not consistently elevated at diagnosis and characterization of other cytokines has not been systematically performed. Previously, a plasma proteomics study identified upregulation of multiple cytokines, including several chemokines, such as C-X-C Motif Chemokine Ligand 13 (CXCL13) and C-C motif ligand 21 (CCL21), during disease flare in a small cohort. We sought to investigate whether these findings would be replicated in a larger cohort and to identify cytokines that could help to improve diagnosis of iMCD. Herein, we analyzed serum samples from 88 iMCD patients, 42 healthy donors, and 20 patients each with rheumatoid arthritis (RA), Hodgkin lymphoma (HL), and a subtype of multicentric Castleman disease caused by infection with human herpes virus 8 (HHV8+MCD). 1300 analytes were quantified by SomaLogic SOMASCAN; Uniprot database was used to select the 159 quantified cytokines for analysis. Data were log2 normalized and capped at the 2.5 th and 97.5 th percentiles. Linear models were used to identify significant differences among disease groups, with p values adjusted by Benjamini & Hochberg. Hierarchical clustering was performed using complete linkage. Of the 159 cytokines quantified, 54 (34%) were identified as significantly different between iMCD and healthy donors. The most upregulated cytokine was CXCL13 with a log2 fold-change (FC) of 1.7 (p<0.0001). The chemokines CCL21 (FC: 1.3, p<0.0001) and CCL23 (FC: 0.87, p<0.0001) were also noted among the top 10 most upregulated cytokines, consistent with the earlier plasma proteomic study. Of note, IL-6 (FC: 0.35, p=0.039) was also found, but it ranked 31 out of 54 in log2 FC magnitude. We next sought to compare cytokine elevation in iMCD to related disorders. Hierarchical clustering of all 159 cytokines appeared to differentiate iMCD from RA, HL, and HHV8+MCD (Figure 1), revealing a cluster with 72/88 (82%) iMCD and 4/60 (6%) related disease patients versus another with 16/88 (18%) iMCD and 56/60 (93%) related disease patients. Given this, we used linear models to test for significant differences in protein expression between iMCD and related diseases. We identified 12 cytokines that were significantly different between iMCD and each comparator disease (Table 1). Of these, 10 cytokines all trended in the positive direction in iMCD versus each comparator disease. CCL21 was again noted among this group and had the highest average FC for all three groups. Herein we validate earlier findings that cytokines, particularly chemokines are significantly upregulated in iMCD. While previous results compared disease flare to disease remission in a small pilot cohort, our patient sample is >10 times larger, represents a broader spectrum of disease severity, and is compared to a set of healthy donors and related diseases. Unbiased hierarchical clustering was able to separate iMCD from other diseases, and linear models identified specific cytokines that are significantly different in iMCD compared to each RA, HL, and HHV8+MCD. Further validation is need to assess whether a cytokine panel can differentiate iMCD from other related diseases, which would be crucial for timely diagnosis and treatment. Of note, CXCL13 and CCL21 are primarily produced by follicular dendritic cells and fibroblastic reticular cells, stromal cells responsible for coordinating B cell and T cell trafficking in the lymph node, respectively. Dysregulation of these cells may contribute to the dysmorphic appearance of lymph nodes and pathogenesis in iMCD. Figure 1 Figure 1. Disclosures Fajgenbaum: EUSA Pharma: Research Funding; Pfizer: Other: Study drug for clinical trial of sirolimus; 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'.

Chronic Graft-Versus-Host Disease (cGVHD) Exacerbation after Sars-Cov-2 Covid Vaccination

INTRODUCTION: Allogeneic hematopoietic cell transplant (allo-HCT) exists as a potential cure to a number of different benign and malignant hematologic conditions. About 50% of patient develop cGVHD, the most important long-term complication of allo-HCT with profound effects on immune recovery. This immunocompromised patient population requires careful consideration regarding approach to vaccination. As the SARS-CoV-2 vaccines were developed and made available at an unprecedented rate, we are learning in real-time how specific vulnerable patient populations are affected, particularly as patients with cGVHD were largely excluded from clinical trials for the SARS-CoV-2 mRNA vaccines. Though the immunomodulatory mechanisms of the Pfizer and Moderna vaccines are poorly understood, societies such as ASH and ASTCT recommend that patients with cGVHD receive it. Here, we report our experience in patients with cGVHD who received the mRNA SARS-CoV-2 vaccine. METHODS: We performed this retrospective analysis of all Huntsman Comprehensive Cancer Center patients who underwent allo-HCT between 2013 and 2020. Patients who had a diagnosis of cGVHD requiring systemic therapy and were alive in December 2020, (when the SARS-CoV-2 vaccine became available), were included in the analysis. The clinical data was queried from the bone marrow transplant (BMT) database, and medical records were individually reviewed for documentation of SARS-CoV-2 mRNA vaccination. Patients meeting criteria were screened in clinic for symptoms post-vaccination. We define worsening or flare of disease as an organ upstage of at least 1 by NIH Consensus Criteria scale, in addition to requirement of intervention with a systemic or topical therapy. All patients were consented under a University of Utah IRB-approved protocol for participation in this study. RESULTS: A total of 52 patients at our institution met the inclusion criteria of being alive with cGVHD at the time Covid mRNA vaccinations became available. Of these 52 patients, 65.4% (n=34) had had two doses of SARS-CoV-2 vaccine. Of these 34 patients, 26.5% (n=9) experienced worsening of their cGVHD manifestations after vaccination. All 9 of these patients (100%) received the Pfizer vaccine. Mean time between transplant day 0 and flare date was 1,222 days (95% CI 511-1,933). At the time of flare, 3/9 patients were on systemic treatment for cGVHD, 6/9 patients had been tapered off systemic therapy, and half of them were on topical therapies. Three patients (33.3%) experienced GVHD flare after SARS-CoV-2 vaccine dose #1. The remaining 6 (66.7%) experienced flare after dose #2, with a median time to flare of 1.5 days. Five of the 9 patients (55.6%) required systemic steroid therapy, with 2 patients (22.2%) requiring >30 days of treatment. The most common organs involved were skin and eyes. Six patients (66.7%) had resolution of flare symptoms. One patient (11.1%) subsequently developed Covid pneumonia and had relapse of AML. CONCLUSION: Though reports have emerged highlighting hematologic and other autoimmune disease recrudescence in response to SARS-CoV-2 vaccination, to our knowledge this is the first large case series demonstrating chronic GVHD flare in response to the vaccine. Almost a third of our cGVHD patients experienced disease flare shortly after vaccination, which raises questions of the degree and mechanism of such heightened immunogenicity in an mRNA vaccine. Consistent with prior studies, most of our patients (66.7%) experienced disease flare after receiving the 2 nd mRNA vaccine dose, Although correlation with vaccine administration does not necessary prove causation of GVHD flare, in counseling patients, the possibility of a severe flare should be weighed against risk of Covid infection. Figure 1 Figure 1. Disclosures Lee: Jazz,: Consultancy; Fresensius Kabi: Consultancy; Kite: Membership on an entity's Board of Directors or advisory committees; Kadmon: Membership on an entity's Board of Directors or advisory committees; CareDx: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding.