The value of SPECT/CT imaging of lacrimal glands as a means of assessing the activity of Graves’ orbitopathy

Background: Graves’ orbitopathy (GO) is an autoimmune disease with mechanical impairment of orbital muscles and lacrimal gland dysfunction. The frequently used methods of assessing GO activity include: Clinical Activity Score (CAS), computed tomography (CT), and magnetic resonance imaging (MRI). These approaches are mainly associated with orbital muscles, however, there are not many studies that focus on the lacrimal gland inflammation of GO patients. Objective: The aim of this study is to assess the usefulness of 99mTc-DTPA SPECT/CT in evaluating the lacrimal gland inflammation in Graves orbitopathy, as compared with other methods. Methods: A retrospective analysis of 48 patients with active GO compared with 33 controls was conducted. All subjects underwent clinical-endocrinological analyses, CAS evaluation, CT scans, and SPECT/CT examination. Lacrimal gland dimensions were determined and analyzed. Results: The lacrimal glands in patients with GO were significantly larger in all measured dimensions (p < 0.001) on CT scans relative to those in controls. Increased lacrimal gland DTPA uptake ratios (p < 0.001) were displayed in active GO patients compared to controls and were also correlated with TRAb levels. The cut-off value for discriminating active and inactive disease was calculated to be 1.735, with specificity of 82.6% and sensitivity of 74.2%. SPECT/CT uptake ratios and CAS values were positively correlated in all GO patients. SPECT/CT uptake ratios were also positively correlated with CT measurements including lacrimal gland volume and coronal width in GO patients. Conclusions: These data indicated that lacrimal gland SPECT/CT images can serve as a good tool for assessing the inflammation and disease activity of GO.

Kidney infiltrating NK cells and NK-like T cells in lupus nephritis – presence, localization and the effect of immunosuppressive treatment

Systemic lupus erythematosus (SLE) is a multi-organ inflammatory disease with kidney inflammation, lupus nephritis (LN), being one of the most severe manifestations. Immune complex deposits, particularly in glomeruli, and T cells, B cells, and myeloid cells, mainly with extraglomerular localization, contribute to the inflammatory process. Natural killer (NK) cells have been suggested to play a role in autoimmune diseases, but have not been investigated in detail in renal lupus before. In this exploratory study, we performed the first characterization of NK cell number and distribution in LN kidney biopsies. Twelve SLE patients were analysed in the active phase of disease and five patients following immunosuppressive therapy. CD56 + cells, corresponding to NK cells or NKlike T cells, were identified in all patients, however, with reduced numbers in four out of five patients at follow up. Furthermore, cells were present in the kidney interstitium and peri-glomerular areas, but only rarely in glomeruli. Fluorescent co-staining of CD56 or NKp46 and CD3 revealed the presence of both CD56 +/NKp46 +CD3 -NK cells and CD56 +/NKp46 +CD3 +NK-like T cells. Compared to healthy kidney sections, one out of four LN patients showed increased numbers of NK cells. A correlation between CD56 + or NK cells with clinical parameters could not be observed, perhaps due to the small patient cohort. In conclusion, we have identified NK cells and NKlike T cells in LN kidney and performed the first detailed analysis of their localization during active and inactive disease. Their role in LN pathogenesis is, however, unclear and deserves further studies.

Metabolomics Defines Complex Patterns of Dyslipidaemia in Juvenile-SLE Patients Associated with Inflammation and Potential Cardiovascular Disease Risk

Cardiovascular disease (CVD) is a leading cause of mortality in patients with juvenile-onset systemic lupus erythematosus (JSLE) associated with atherosclerosis. The interplay between dyslipidaemia and inflammation—mechanisms that drive atherosclerosis—were investigated retrospectively in adolescent JSLE patients using lipoprotein-based serum metabolomics in patients with active and inactive disease, compared to healthy controls (HCs). Data was analysed using machine learning, logistic regression, and linear regression. Dyslipidaemia in JSLE patients was characterised by lower levels of small atheroprotective high-density lipoprotein subsets compared to HCs. These changes were exacerbated by active disease and additionally associated with significantly higher atherogenic very-low-density lipoproteins (VLDL) compared to patients with low disease activity. Atherogenic lipoprotein subset expression correlated positively with clinical and serological markers of JSLE disease activity/inflammation and was associated with disturbed liver function, and elevated expression of T-cell and B-cell lipid rafts (cell signalling platforms mediating immune cell activation). Finally, exposing VLDL/LDL from patients with active disease to HC lymphocytes induced a significant increase in lymphocyte lipid raft activation compared to VLDL/LDL from inactive patients. Thus, metabolomic analysis identified complex patterns of atherogenic dyslipidaemia in JSLE patients associated with inflammation. This could inform lipid-targeted therapies in JSLE to improve cardiovascular outcomes.

Efficacy And Safety of Canakinumab As A Second-Line Biologic After Tocilizumab Treatment Failure in Children With Systemic Juvenile Idiopathic Arthritis: A Single-Center Cohort Study Using Routinely Collected Health Data

Background: A significant number of systemic juvenile idiopathic arthritis (sJIA) patients discontinue biologic disease-modifying antirheumatic drugs (DMARDs) due to lack of efficacy or safety concerns. Studies of biologic therapy switch regimens in sJIA are required.Methods: Patients with sJIA who switched from tocilizumab (due to lack of efficacy or safety) to canakinumab (4 mg/kg every 4 weeks) and were hospitalized at the rheumatology department from August 2012 to July 2020 were included. Primary efficacy outcomes were 30% or greater improvement based on the pediatric criteria of the American College of Rheumatology (ACR30), achievement of inactive disease (JADAS‑71 =0) and clinical remission (ACR sJIA clinical inactive disease criteria). Follow-up was 12 months or the closest time point (not less than 6 and not more than 18 months). Data were extracted from outpatient medical records.Results: During the study period, 46 patients with sJIA switched from tocilizumab to canakinumab. Median age at canakinumab initiation was 8.2 (interquartile range 4.0; 12.9) years, and median sJIA duration was 1.8 (0.8; 5.8) years; 37 (80%) patients received at least one non-biologic DMARD (oral corticosteroids, methotrexate and/or cyclosporine A). Study outcomes were followed up in 45 patients (one patient did not attend the follow-up for an unknown reason); median follow-up was 359 (282; 404) days. During the follow-up, canakinumab was discontinued in one patient (due to tuberculosis detection) and the dose was reduced or the injection interval increased in four (9%) patients. In total, 27 (60%) patients continued to receive at least one non-biologic DMARD. Improvement according to the ACR30 criteria was achieved in 43 patients (96%; 95% confidence interval, 85–99), inactive disease in 42 (93%; 82–98), and clinical remission in 37 (82%; 69‑91); after adjustment for actual time-at-risk, the rates were 83, 85 and 73 events per 100 person-years, respectively. During follow-up, 23 adverse events (most frequently infections) were reported in 19/45 (42%) patients; 5/45 (11%) patients developed macrophage activation syndrome, with a favorable outcome in all cases.Conclusions: Short-term (about 12 months) canakinumab therapy was found to be potentially effective as second-line biologic therapy after discontinuation of tocilizumab in patients with sJIA. Trial registration: CACZ885G2301E1 (G2301; NCT00891046 registered on April 29, 2009) and CACZ885G2306 (G2306; NCT02296424 registered on November 20, 2014).

To Compare the Graft Uptake in Permeatal versus Postaural Approaches in Myringoplasty

Objective: To compare the graft uptake in permeatal versus postaural approaches in myringoplasty. Study design: Cross sectional comparative Place and Duration of Study: Department of ENT, Head and Neck Surgery, Pakistan Institute of Medical Sciences/Shaheed Zulfiqar Ali Bhutto Medical University, Islamabad Pakistan from 1st March 2018 to 31st December 2018. Methodology: Seventy two patients were classified into two equal groups. Thirty six patients underwent myringoplasty by permeatal approach and thirty six patients underwent postaural approach. Those patients were included who had mucosal type moderate central perforation with inactive disease with age 15-42 years and those patients were excluded who had small, subtotal, total, squamosal type atticoantral tympanic membrane perforation, with comorbidities and pregnancy. Results: Thirty seven were (51.4 %) males and 35 (48.6%) were females. In both the groups the success of graft uptake was 52 (72.2%) patients and graft rejection in 20 (27.8%) patients. In each group there were 36 patients. The graft uptake in permeatal approach was 30 patients (83.3%), while the graft uptake in postaural approach was 22 (61.1%) patients. The overall graft uptake in permeatal approach is more as compared to postaural approach (p=0.035). Conclusion: The permeatal approach is better than the postaural approach in terms of graft uptake in medium sized central perforations in myringoplasty. Key words: Myringoplasty, Tympanoplasty, Permeatal, Postauricular

A unique circulating miRNA profile highlights thrombo-inflammation in Behçet’s syndrome

ObjectivesBehçet’s syndrome (BS) is a rare systemic vasculitis often complicated by thrombotic events. Given the lack of validated biomarkers, BS diagnosis relies on clinical criteria.In search of novel biomarkers for BS diagnosis, we determined the profile of plasmatic circulating microRNAs (ci-miRNAs) in patients with BS compared with healthy controls (HCs).Methodsci-miRNA profile was evaluated by microarray in a screening cohort (16 patients with BS and 18 HCs) and then validated by poly(T) adaptor PCR (PTA-PCR) in a validation cohort (30 patients with BS and 30 HCs). Two disease control groups (30 patients with systemic lupus erythematosus (SLE) and 30 patients with giant cell arteritis (GCA) were also analysed.ResultsFrom the microarray screening, 29 deregulated (differentially expressed (DE)) human ci-miRNAs emerged. A hierarchical cluster analysis indicated that DE ci-miRNAs clearly segregated patients from controls, independently of clinical features. PTA-PCR analysis on the validation cohort confirmed the deregulation of miR-224-5p, miR-206 and miR-653-5p. The combined receiver operating characteristic (ROC) curve analyses showed that such ci-miRNAs discriminate BS from HCs (and BS with active vs inactive disease), as well as BS from patients with SLE and GCA.The functional annotation analyses (FAAs) showed that the most enriched pathways affected by DE ci-miRNAs (ie, cell–matrix interaction, oxidative stress and blood coagulation) are related to thrombo-inflammatory mechanisms. Accordingly, the expression of the three ci-miRNAs from the validation cohort significantly correlated with leucocyte reactive oxygen species production and plasma lipid peroxidation.ConclusionsThe ci-miRNA profile identified in this study may represent a novel, poorly invasive BS biomarker, while suggesting an epigenetic control of BS-related thrombo-inflammation.

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.

Juvenile Dermatomyositis Magnetic Resonance Imaging Score (JIS) does not correlate with criteria for clinically inactive disease: a single-centre retrospective evaluation

The Paediatric Rheumatology International Trials Organisation (PRINTO) criteria for clinically inactive disease (CID) and their proposal for glucocorticoid tapering do not consider MRI findings, despite the growing use of MRI and development of reliable MRI scoring tools. We aim to evaluate how CID correlates with MRI scores and physician decision making. We retrospectively used the Juvenile Dermatomyositis Imaging Score (JIS) to score MRIs of all children with JDM over a 10-year period. Demographic, diagnosis, treatment and core set measures data were collected. Correlation between CID and JIS was assessed as well as correlation with the physician treatment decision. There were 25 patients with 59 follow-up episodes to analyse correlation between physician treatment decision and JIS; and 50 episodes for the CID category and JIS correlation. JIS was not significantly associated with the CID category but did correlate with the physician decision. No significant association was found between clinical decision and CID category. The JIS area under the ROC curve (AUC) was 0.80 (95% CI 0.62–0.99) with a score ≥ 8 to predict an escalation. JIS sensitivity and specificity were both 78% with accuracy of 78%, compared to only 67%, 46% and 49%, respectively, for the CID criteria. Clinical criteria alone are not sufficient to assess disease activity status. Clinical decision trends correlated to MRI findings but not PRINTO CID criteria. Multi centre prospective studies are needed to replicate our findings and establish how to best use MRI as a biomarker of disease activity.

Predictors of long-term clinical response in patients with non-radiographic axial spondyloarthritis receiving certolizumab pegol

Background Identification of predictive clinical factors of long-term treatment response may contribute to improved management of non-radiographic axSpA (nr-axSpA) patients. This analysis aims to identify whether any baseline characteristics or Week 12 clinical outcomes in nr-axSpA patients with elevated C-reactive protein (CRP) and/or sacroiliitis on magnetic resonance imaging (MRI) enrolled in the C-axSpAnd study are predictive of achieving clinical response after 1 year of certolizumab pegol (CZP). Methods C-axSpAnd (NCT02552212) was a phase 3, multicentre study, including a 52-Week double-blind, placebo-controlled period. Enrolled patients were randomised to CZP 200 mg Q2W or placebo. Predictors of Week 12 (CZP group only) and Week 52 clinical response were identified using a multivariate stepwise logistic regression analysis. Response variables included Ankylosing Spondylitis Disease Activity Score major improvement (ASDAS-MI), Assessment of SpondyloArthritis International Society 40% response (ASAS40), Bath Ankylosing Spondylitis Disease Activity Index 50% response (BASDAI50) and ASDAS inactive disease (ASDAS-ID). Predictive factors assessed included demographic and baseline characteristics and clinical outcomes at Week 12. A p-value <0.05 was required for forward selection into the model and p ≥0.1 for backward elimination. Missing data or values collected after switching to open-label treatment were accounted for using non-responder imputation. Sensitivity analyses accounted for patients with changes in non-biologic background medication. Results Of 317 enrolled patients, 159 and 158 were randomised to CZP and placebo, respectively. Younger age and male sex were identified as predictors of Week 12 response across all assessed efficacy outcomes in CZP-treated patients. Consistent predictors of Week 52 response, measured by ASDAS-MI, ASAS40 and BASDAI50, included human leukocyte antigen (HLA)-B27 positivity and sacroiliitis on MRI at baseline. MRI positivity was also predictive of achieving ASDAS-ID at Week 52. Sensitivity analyses were generally consistent with the primary analysis. In placebo-treated patients, no meaningful predictors of Week 52 response were identified. Conclusions In this 52-Week, placebo-controlled study in nr-axSpA patients with elevated CRP and/or active sacroiliitis on MRI at baseline, MRI sacroiliitis and HLA-B27 positivity, but not elevated CRP or responses at Week 12, were predictive of long-term clinical response to CZP. Findings may support rheumatologists to identify patients suitable for TNFi treatment. Trial registration ClinicalTrials.gov, NCT02552212. Registered on 15 September 2015