A deep look into the storm: Israeli multi-center experience of coronavirus disease 2019 (COVID-19) in patients with autoimmune inflammatory rheumatic diseases before and after vaccinations.

Objective: We aimed to characterize the course of COVID-19 in autoimmune inflammatory rheumatic disease (AIIRD) patients in Israel, taking into consideration several remarkable aspects, including the outcomes of the different outbreaks, the effect of vaccination campaigns, and AIIRD activity post-recovery. Methods: We established a national registry of AIIRD patients diagnosed with COVID-19, including demographic data, AIIRD diagnosis, duration and systemic involvement, comorbidities, date of COVID-19 diagnosis, clinical course, and dates of vaccinations. COVID-19 was diagnosed by a positive SARS-CoV-2 polymerase chain reaction. Results: Israel experienced 4 outbreaks of COVID-19 until 30.11.2021. The first three outbreaks (1.3.2020 - 30.4.2021) comprised 298 AIIRD patients. 64.9% had a mild disease and 24.2% had a severe course; 161 (53.3%) patients were hospitalized, 27 (8.9%) died. The 4th outbreak (delta variant), starting 6 months after the beginning of the vaccination campaign comprised 110 patients. Despite similar demographic and clinical characteristics, a smaller proportion of AIIRD patients had negative outcomes as compared to the first 3 outbreaks, with regards to severity (16 patients,14.5%), hospitalization (29 patients, 26.4%) and death (7 patients, 6.4%). COVID-19 did not seem to influence the AIIRD activity 1-3 months post-recovery. Conclusions: COVID-19 is more severe and has an increased mortality in active AIIRD patients with systemic involvement, older age and comorbidities. Vaccination with 3 doses of the mRNA vaccine against SARS-CoV-2 protected from severe COVID-19, hospitalization and death during the 4th outbreak. The pattern of spread of COVID-19 in AIIRD patients was similar to the general population.

The Effect of Different Ethnic Origins in Israel on the Clinical Manifestations and Outcomes of Systemic Lupus Erythematous.

BACKGROUND: Epidemiological studies have shown a connection between ethnic origin and the incidence and outcome of systemic lupus erythematosus (SLE). OBJECTIVES: To evaluate the SLE outcomes among Ashkenazi Jews, non-Ashkenazi Jews, and Arabs. METHODS: We conducted a retrospective study of patients who were diagnosed with SLE and followed in lupus clinics at two large tertiary medical centers. The data were obtained from patient medical records. Patients were stratified into three ethnic origins: Ashkenazi Jews, non-Ashkenazi Jews, and Arabs. The primary outcomes were all-cause mortality, development of end-stage kidney disease (ESKD), and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) 2K ≤ 4 at last visit. RESULTS: We included 570 patients in this study. The Arab group showed the highest number of SLE classification criteria at diagnosis and last encounters compared to non-Ashkenazi and Ashkenazi Jewish groups (6.0 vs. 5.0 and 4.0, respectively at diagnosis, P < 0.001; 8.0 vs. 7.0 and 6.0 at last visit, P = 0.01). In multivariate models, Arab patients had three times higher risk of all-cause mortality than Ashkenazi Jews (hazard ratio 2.99, 95% confidence interval [95%CI] 1.32-6.76, P = 0.009). ESKD was similar among the study groups. Low disease activity (SLEDAI 2K ≤ 4) at last visit was lower in the Arab group than the Ashkenazi Jews (odds ratio 0.50, 95%CI 0.28-0.87, P = 0.016), depicting a medium-to-high disease activity among the former. CONCLUSIONS: Physicians should consider the influence of the ethnicity of the SLE patient when deciding on their care plan.

Urine soluble triggering receptor expressed on myeloid cells-1 is a novel biomarker for active lupus nephritis: a case-control study.

OBJECTIVES: To determine the value of plasma and urine sTREM-1 levels as a biomarker of lupus nephritis (LN) as well as extra-renal systemic lupus erythematosus (SLE). METHODS: Consecutive adult patients with SLE attending a tertiary lupus clinic in 2016-2018 were prospectively divided into 3 groups according to SLEDAI-2K and renal-SLEDAI scores: active renal lupus (ARL), active non-renal lupus (ANL), and inactive lupus (IL). Blood and spot urine samples from each group and matched healthy subjects were analysed by means of ELISA for plasma and urine sTREM-1 levels. RESULTS: The cohort included 59 patients (mean age 41.5+2.9 years, 85% female) with SLE: 15 ARL, 14 ANL, and 30 IL. The ARL group had higher scores on the SLEDAI-2K and renal-SLEDAI, and higher urine protein/creatinine ratio than the other patient groups (p=0.0001 for all). Plasma sTREM-1 level was highest in the ANL group (p=0.0085). Urine sTREM-1 level was higher in the whole SLE cohort than the healthy controls (p=0.0249), and higher in the ARL group than the others (p=0.0044). Neither plasma nor urine sTREM-1 level was associated with non-renal SLE features. On Spearman correlation analysis, urine sTREM-1 level, but not plasma sTREM-1 level, was correlated positively with renal-SLEDAI score (r=0.34, p=0.018), inversely with serum C3 and C4 levels (r=-0.42, p=0.0027 and r=-0.28, p=0.056, respectively), and positively with proteinuria (UPCR: r=0.32, p=0.0305). CONCLUSIONS: Urine sTREM-1 might serve as a potential biomarker of active renal SLE.

Lower socioeconomic status worsens outcome of patients with systemic lupus erythematosus independently of access to healthcare.

OBJECTIVES: Socioeconomic status (SES) has been found to be associated with worse outcomes of systemic lupus erythematosus (SLE). The impact of national health insurance on SLE outcomes has not been explored. METHODS: A retrospective inception cohort of patients older than 18 years with SLE diagnosed and followed in lupus clinics of two large tertiary medical centers were included. Patients were stratified into three groups by SES: lower 25th quantile, middle 25th-75th quantile, and upper 75th quantile. Primary outcomes were all-cause mortality, development of end-stage kidney disease (ESKD), and score ≤ 4 on the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI 2K) at the last visit. RESULTS: We identified 617 patients (548 females, 88.8%) with a median follow-up of 15 years (range, 8.0-23.0). Compared to the middle and upper SES groups, the lower SES group was characterized by younger age at disease onset (31.5 years vs. 34.3 and 37.4 years, respectively, p = 0.011) and higher rate of lupus nephritis (42.7% vs. 35.7% and 23.8%, respectively, p = 0.002). In multivariate models, patients in the middle and upper SES groups had a significantly lower risk of mortality (HR = 0.45; 95% CI, 0.24-0.82, p = 0.010) and ESKD (HR = 0.24; 95% CI, 0.08-0.73, p = 0.012), with no effect on the rate of SLEDAI 2K ≤ 4 (OR = 1.49; 95% CI, 0.92-2.40, p = 0.09). CONCLUSION: Even within a health system that provides high and equal accessibility to medical care, low SES is associated with worse outcomes of SLE. Policymakers should focus on managing possible barriers that prevent patients of lower SES from obtaining optimal care.

A Cross-sectional Survey on the Preference of Patients with Rheumatoid Arthritis for Route of Administration of Disease-Modifying Anti-Rheumatic Drugs: Oral Target-Specific Versus Parenteral Biologic.

BACKGROUND: Guidelines recommend initiation of parenteral biologic or oral target-specific disease-modifying anti-rheumatic drugs (bDMARDs/tsDMARDs) in rheumatoid arthritis (RA) patients who do not adequately respond to conventional DMARDs. OBJECTIVES: To compare the preferred route of administration of bDMARDs or tsDMARDs in RA patients who were previously treated with at least one type. METHODS: A cross-sectional survey was conducted of consecutive RA patients previously prescribed bDMARDs or tsDMARDs. We analyzed the factors associated with patients' preferred route of administration. RESULTS: The cohort included 95 patients, mostly female (72.6%), seropositive (81.05%), mean age 63.4 ± 11.9 years. The oral route was preferred by 39 patients (41%) and 56 (59%) preferred the parenteral route. Most patients (65.9%) preferred to continue with their current route (P < 0.001). Switching from a current route was less common with patients who were currently using the oral route (13.3% vs. 38.2%, P = 0.04). Many patients (53.8%) who preferred the oral route had never experienced it before, while this was rare (3.6%) regarding the parenteral route (P = 0.0001). Employment status was associated with preference of the subcutaneous route over the intravenous route of bDMARDs (P = 0.01). Of the 21 patients who had previously experienced both parenteral and oral treatment, 16 (76.2%) preferred the oral route. CONCLUSIONS: RA patients preferred to continue treatment with an administration route they have already experienced. However, when choosing an unexperienced route, significantly more patients preferred the oral route. Our results strengthen the understanding of patient preferences, which could improve drug adherence, compliance, and disease outcome.

Elevated plasma level of soluble triggering receptor expressed on myeloid cells-1 is associated with inflammation activity and is a potential biomarker of thrombosis in primary antiphospholipid syndrome.

BACKGROUND: Soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) is an innate-immune receptor found in blood. Its presence reflects innate immune cell activation. We sought to investigate plasma sTREM-1 levels in patients with primary antiphospholipid syndrome (PAPS). METHODS: A cross-sectional, case-control design was used. Plasma sTREM-1 levels were analyzed by enzyme-linked immunosorbent assay (ELISA) in consecutive patients diagnosed with PAPS or asymptomatic antiphospholipid antibody (APLA) carriers and controls. RESULTS: The study cohort included 33 patients with PAPS, 10 asymptomatic APLA carriers, and 73 controls. Mean plasma sTREM-1 levels were significantly higher in patients with PAPS (299.2 ± 146.7 pg/ml) and thrombotic PAPS-ever (current and past thrombotic event) (327.2 ± 151.3 pg/ml) compared with controls (230.2 ± 85.5 pg/ml; p = 0.006 and p = 0.003, respectively), patients with thrombotic PAPS compared with patients with past obstetric APS (195.12 ± 58.52 pg/ml, p = 0.01) and APLA carriers (215.8 ± 51.6 pg/ml, p = 0.02), patients with current thrombotic PAPS (429.5 ± 227.5 pg/ml) compared with patients with past thrombotic PAPS (289.5 ± 94.65 pg/ml, p = 0.01), and patients with PAPS who had ever had a stroke or venous thromboembolic event compared with patients who had not (p = 0.007 and p = 0.02, respectively). On receiver operator characteristic curve analysis, plasma sTREM-1 levels differentiated patients with current thrombotic PAPS from asymptomatic APLA carriers and controls, with an area under the curve of 0.7292 (p = 0.0014) and 0.88 (p < 0.0001), respectively. Multivariate regression analysis to identify sTREM-1 predictors (thrombotic PAPS-ever, age, and sex) yielded an independent association of sTREM-1 levels with thrombotic PAPS (p < 0.0001). CONCLUSIONS: Plasma sTREM-1 levels are significantly elevated in patients with thrombotic PAPS. Levels of sTREM-1 might serve as a biomarker for thrombosis in patients with PAPS.

[IgG4-RELATED DISEASE].

INTRODUCTION: IgG4-related disease is a syndrome of unknown etiology, which can affect any organ. It is characterized by lymphoplasmacytic infiltration of the affected organs that is rich in IgG4-positive plasma cells, fibrosis, and sometimes increased blood levels of IgG4. Treatment is determined according to the organs involved and the severity of involvement. Corticosteroids are considered to be the first line of treatment. In steroid-resistant or recurrent disease, immunosuppressive drugs or rituximab are used, although their efficacy has not been proven in clinical trials. This review describes the current understanding of the pathogenesis, clinical features, diagnosis and treatment of IgG4-related disease.

Guanine polynucleotides are self-antigens for human natural autoantibodies and are significantly reduced in the human genome.

In the course of investigating anti-DNA autoantibodies, we examined IgM and IgG antibodies to poly-G and other oligonucleotides in the sera of healthy persons and those diagnosed with systemic lupus erythematosus (SLE), scleroderma (SSc), or pemphigus vulgaris (PV); we used an antigen microarray and informatic analysis. We now report that all of the 135 humans studied, irrespective of health or autoimmune disease, manifested relatively high amounts of IgG antibodies binding to the 20-mer G oligonucleotide (G20); no participants entirely lacked this reactivity. IgG antibodies to homo-nucleotides A20, C20 or T20 were present only in the sera of SLE patients who were positive for antibodies to dsDNA. The prevalence of anti-G20 antibodies led us to survey human, mouse and Drosophila melanogaster (fruit fly) genomes for runs of T20 and G20 or more: runs of T20 appear > 170,000 times compared with only 93 runs of G20 or more in the human genome; of these runs, 40 were close to brain-associated genes. Mouse and fruit fly genomes showed significantly lower T20/G20 ratios than did human genomes. Moreover, sera from both healthy and SLE mice contained relatively little or no anti-G20 antibodies; so natural anti-G20 antibodies appear to be characteristic of humans. These unexpected observations invite investigation of the immune functions of anti-G20 antibodies in human health and disease and of runs of G20 in the human genome.

Soluble triggering receptor expressed on myeloid cells-1 is a biomarker of anti-CCP-positive, early rheumatoid arthritis.

OBJECTIVES: To assess serum soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) levels in disease-modifying antirheumatic drug (DMARD)-naïve early rheumatoid arthritis (ERA), to investigate the association of sTREM-1 levels with Disease Activity Score in 28 joints (DAS28) and seropositivity for anti-cyclic citrullinated peptide (CCP) antibody and to determine the predictive value of sTREM-1 with respect to clinical response to DMARD therapy. METHODS: Twenty-two consecutive patients with DMARD-naïve ERA were prospectively evaluated for serum sTREM-1 by means of ELISA at diagnosis and at the following clinic visit after prednisone and/or DMARD has been administered, and related to DAS28 and serum level of anti-CCP antibody. We compared the sTREM-1 level to that of 31 patients with established RA as well as to 24 controls. RESULTS: Serum sTREM-1 level was significantly higher in the DMARD-naïve ERA group (212.9 ± 388.9 ρg/mL) compared to established RA group (1478.0 ± 280.0 ρg/mL, P = 0.001) and normal control (34.4 ± 7.4 ρg/mL, P < 0.001). In the ERA group, elevated basal sTREM-1 level correlated with higher DAS28-CRP score (P = 0.001, HR 3.23, 95% CI 1.4-8.12), DAS28-ESR (P = 0.04, HR 2.34 95% CI 0.1-8.12), as well as predicted higher DAS28 score at the following encounter after DMARD treatment was administered (P = 0.001, HR 3.2 95% CI 1.1-7.2). Higher serum level of sTREM-1 correlated with higher titres of anti-CCP antibody (P < 0.001). CONCLUSIONS: Our results suggest that serum sTREM-1 may provide a novel biomarker for DMARD-naïve ERA as well as for seropositivity for anti-CCP antibody and RA activity.

Evolution of chronic kidney disease in patients with systemic lupus erythematosus over a long-period follow-up: a single-center inception cohort study.

The objective is to investigate the accrual rate and risk factors of chronic kidney disease (CKD) in an inception cohort of patients with systemic lupus erythematosus (SLE) followed at a single tertiary center. A prospectively collected database of 256 consecutive patients with SLE followed over a 25-year period was systematically interrogated for demographic, disease manifestations, co-morbidities, and outcome. Standardized SLE activity and damage scores were determined for the first and last study visits, and estimated glomerular filtration rate (eGFR; MDRD formula) was calculated at the time of diagnosis and at each year of the follow-up. CKD was defined as eGFR <60 ml/min/1.73 m(2). Results were analyzed with univariate and multivariate models and Kaplan-Meier curves, as appropriate. The cohort was predominantly female (90 %) and Jewish (91.1 %). Mean age at diagnosis was 38 ± 15.5 years, mean SLE activity score 6.4 ± 3.8, mean disease duration 8.8 ± 6.6 years, and mean damage score 0.2 ± 0.6. Seventy-five patients (30.8 %) were diagnosed with American College of Rheumatology (ACR)-defined lupus renal disease during the study period. There was a progressive decrease in eGFR over time. The prevalence of CKD was 46.7 % in patients with ACR-defined renal lupus disease and 16.4 % in those without. The hazards ratio for CKD was significantly higher in patients with lupus nephritis (LN) than without (p < 0.001). Earlier CKD was positively associated with hypertension (p = 0.01), older age at diagnosis (p = 0.01), and LN (p < 0.001), and negatively associated with hydroxychloroquine treatment (p < 0.001). The prevalence of CKD increases cumulatively in patients with SLE, also in those without overt lupus renal disease. Lupus renal disease poses a significant hazard for earlier development of CKD, and hypertension is a major risk factor for patients with and without nephritis. Antimalarial treatment is associated with renal preservation only in patients with lupus nephritis.

Epstein-Barr virus antibodies mark systemic lupus erythematosus and scleroderma patients negative for anti-DNA.

Systemic lupus erythematosus (SLE) is an autoimmune disease that can attack many different body organs; the triggering event is unknown. SLE has been associated with more than 100 different autoantibody reactivities - anti-dsDNA is prominent. Nevertheless, autoantibodies to dsDNA occur in only two-thirds of SLE patients. We previously reported the use of an antigen microarray to characterize SLE serology. We now report the results of an expanded study of serology in SLE patients and scleroderma (SSc) patients compared with healthy controls. The analysis validated and extended previous findings: two-thirds of SLE patients reacted to a large spectrum of self-molecules that overlapped with their reactivity to dsDNA; moreover, some SLE patients manifested a deficiency of natural IgM autoantibodies. Most significant was the finding that many SLE patients who were negative for autoantibodies to dsDNA manifested abnormal antibody responses to Epstein-Barr virus (EBV): these subjects made IgG antibodies to EBV antigens to which healthy subjects did not respond or they failed to make antibodies to EBV antigens to which healthy subjects did respond. This observation suggests that SLE may be associated with a defective immune response to EBV. The SSc patients shared many of these serological abnormalities with SLE patients, but differed from them in increased IgG autoantibodies to topoisomerase and centromere B; 84% of SLE patients and 58% of SSc patients could be detected by their abnormal antibodies to EBV. Hence an aberrant immune response to a ubiquitous viral infection such as EBV might set the stage for an autoimmune disease.

Serum soluble triggering receptor on myeloid cells-1 (sTREM-1) is elevated in systemic lupus erythematosus but does not distinguish between lupus alone and concurrent infection.

We sought to determine serum triggering receptor expressed on myeloid cell-1 (sTREM-1) level in a cohort of patients with systemic lupus erythematosus (SLE). Serum sTREM-1 level of 98 patients with SLE and 49 healthy controls was assayed by ELISA. Serum sTREM-1 level was significantly elevated in a cohort of 78 unselected consecutively recruited patients with SLE (mean 1.1 ± 2.8 ρg/ml, median 0.02 ρg/ml) compared to that of the controls (mean 0.11 ± 0.3 ρg/ml, median 0 ρg/ml; p < 0.0001). We also determined serum sTREM-1 level of 20 SLE patients with a concurrent infection (mean 0.6 ± 1.1 ρg/ml, median 0.12 ρg/ml) and found it not statistically significant compared with that of the patients without infection. Serum sTREM-1 level did not correlate with SLE disease activity. Our finding of elevated serum sTREM-1 level suggests an increased shedding of TREM-1 in SLE and a possible novel pathway of innate immune response in autoimmunity.

CpG-oligodeoxynucleotide-induced TLR9 activation regulates macrophage TREM-1 expression and shedding.

CpG-oligonucleotide (ODN)-induced TLR9 activation exerts anti-inflammatory effects. TREM-1 is a DAP12-associated receptor, which is up-regulated in response to LPS-mediated TLR4 activation, and plays an essential role in innate immune response by augmenting the production of pro-inflammatory chemokines and cytokines. TREM-1 up-regulation resulted in a grave outcome in animal models, and in patients with sepsis and rheumatoid arthritis, while its soluble form (sTREM-1) exerted anti-inflammatory effects. We hypothesized that CpG-ODN regulates membrane TREM-1 expression and sTREM-1 shedding. The effect of CpG-ODN-induced TLR9 activation on TREM-1 expression and shedding was studied in mouse peritoneal macrophages and the mouse macrophage cell line RAW 264.7. While TREM-1 expression was not altered by CpG-ODN alone, stimulation with both LPS and CpG-ODN significantly abrogated TREM-1 LPS-induced up-regulation. Moreover, CpG-ODN-induced TLR9 activation either alone or in combination with LPS resulted in a significant increase of supernatant sTREM-1. The release of sTREM-1 was correlated positively with MMP-9 activity and was inhibited by chloroquine. These results suggest (i) a novel CpG-ODN-induced TLR9 pathway for the regulation of macrophage TREM-1 expression and MMP-9-mediated TREM-1 shedding; and (ii) a novel mechanism for an anti-inflammatory effect of CpG-ODN through abrogation of LPS-induced membrane TREM-1 up-regulation and increased MMP-9-mediated TREM-1 shedding.

Capnocytophaga bacteraemia following rituximab treatment.

A case is presented of Capnocytophaga bacteraemia, in a juvenile chronic arthritis (JCA) patient receiving steroids, methotrexate and rituximab. This Gram-negative bacillus commonly found in dog saliva has been described to cause illness in immune compromised hosts such as oncology patients, those receiving cytotoxic or biological drugs, alcoholics or postsplenectomy. To the best of our knowledge, this is the first report of Capnocytophaga bacteraemia following rituximab treatment.