Abstract
Background
The risk of severe COVID-19 and its determinants remain largely unknown in patients with autoimmune and inflammatory rheumatic diseases. The objective of this study was to assess ...the prevalence of COVID-19 infection in patients followed for rare autoimmune diseases as well as the predictors of COVID-19 and disease flare-ups.
Methods
Cross-sectional phone survey from April 9, 2020, to July 2, 2020, during which patients with autoimmune diseases followed at the National Reference Center for Rare Autoimmune diseases of Strasbourg were systematically contacted by phone and sent a prescription for a SARS-CoV-2 serology.
Results
One thousand two hundred thirty-two patients were contacted. One thousand fifty-five patients with a confirmed diagnosis of systemic autoimmune disease were included (4 unreachable, 4 moves abroad, 5 deaths before pandemic, 50 without consent, and 114 without autoimmune disease). Among them, 469 (44.5%) patients were tested for SARS-CoV-2 serology.
Thirty-nine patients (7.9%) had SARS-CoV-2 infection (either through chest CT-scan n = 5, RT-PCR on nasopharyngeal swab n = 14, or serology n = 31) among the 496 who underwent at least one of those 3 diagnosis modalities. Of the 39 proven cases, 33 had clinical manifestations (6 asymptomatic patients were diagnosed through systematic serology testing), 31 were managed by home care, 3 were hospitalized due to a need for oxygenation, two required admission to an intensive care unit, and one died. Among patients with confirmed SARS-CoV-2 infection, reported flares were more frequent than in uninfected patients (26.3% 10/38 vs. 7.0% 32/457, p < 0.0001). Preventive sick leave had no significant impact on the prevalence of SARS-CoV-2 infection (5.8% 3/53) compared to work continuation (7.6% 30/397, p = 0.64).
Overall, the seroprevalence of SARS-CoV-2 was 6.6% (31/469) which was numerically lower to the Grand-Est general population estimated to be 9.0%.
Conclusions
This systematic survey of more than 1000 patients with rare systemic autoimmune diseases reports a low prevalence of proven SARS-CoV-2 infection and very rare severe infections, probably related to good compliance with prophylactic measures in these patients.
It is now widely accepted that antiphospholipid antibodies (aPL) have direct pathogenic effects and that B cells, notably through aPL production, play a key role in the development of ...antiphospholipid syndrome (APS). Recent findings strengthened the implication of B cells with the description of specific B cell phenotype abnormalities and inborn errors of immunity involving B cell signaling in APS patients. In addition, it has been shown in preclinical models that cross-reactivity between APS autoantigens and mimotopes expressed by human gut commensals can lead to B cell tolerance breakdown and are sufficient for APS development. However, B cell targeting therapies are surprisingly not as effective as expected in APS compared to other autoimmune diseases. Elucidation of the B cell tolerance breakdown mechanisms in APS patients may help to develop and guide the use of novel therapeutic agents that target B cells or specific immune pathway.
•The hypercoagulable state in antiphospholipid syndrome (APS) is related to pathogenic antiphospholipid antibodies (aPL).•B cells, notably through aPL production, have a central role in the pathogenesis of APS.•aPL development may result from mono/polygenic inborn errors of immunity and specific interactions with commensal hosts.•Paradoxically, B cell targeting therapies are disappointing in APS as compared to experiences in other autoimmune diseases.
Down syndrome (DS) is the most common form of viable chromosomal abnormality. DS is associated with recurrent infections, auto-immunity and malignancies in children. Little is known about immunity ...and infections in DS at adulthood.
We studied two separate group of adults (> 18 years old) with DS in a single referral tertiary center (Strasbourg University Hospital). The first group included 37 ambulatory DS patients between November 2014 and May 2017. We analyzed exhaustive serological and immunobiological parameters, at one point, together with the prevalence of infections, autoimmune manifestations and malignancies. The second group included 64 hospitalized patients (138 stays) in the same center, between January 2005 and December 2016.
One hundred and one adult patients with DS were included. Unlike children and despite a global lymphopenia, adults with DS underwent few infections in our ambulatory group. They did not experience any malignancy and, apart from hypothyroidism, they presented only occasional autoimmune manifestations. Hospitalized DS patients were older than ambulatory ones (median age 47 years (18-73) vs. 27 (18-52), p < 0.0001) and admitted mostly for infections (76.8%). Infections were associated with epilepsy and dementia (OR 6.5 (2.2-19), p = 0.001; p = 0.0006 in multivariate analysis) and higher mortality (OR 7.4 (1.4-37), p = 0.01).
Despite persistent immunobiological abnormalities at adulthood, young ambulatory adults with DS remain healthy with a low rate of infections. Infections are associated with neurological degeneration and increase the mortality arguing for a dedicated support of older DS patients.
ClinicalTrials.gov: NCT01663675 (August 13, 2012). Hospital Clinical Research Program (PHRC): number 2012-A00466-37 (Dr Y. Alembik).
Introduction
Among immune cells, activated monocytes play a detrimental role in chronic and viral-induced inflammatory pathologies, particularly in Juvenile Idiopathic Arthritis (JIA), a childhood ...rheumatoid arthritis (RA) disease. The uncontrolled activation of monocytes and excessive production of inflammatory factors contribute to the damage of bone-cartilage joints. Despite the moderate beneficial effect of current therapies and clinical trials, there is still a need for alternative strategies targeting monocytes to treat RA.
Methods
To explore such an alternative strategy, we investigated the effects of targeting the CXCR4 receptor using the histamine analog clobenpropit (CB). Monocytes were isolated from the blood and synovial fluids of JIA patients to assess CB's impact on their production of key inflammatory cytokines. Additionally, we administered daily intraperitoneal CB treatment to arthritic mice to evaluate its effects on circulating inflammatory cytokine levels, immune cell infiltrates, joints erosion, and bone resorption, as indicators of disease progression.
Results
Our findings demonstrated that CXCR4 targeting with CB significantly inhibited the spontaneous and induced-production of key inflammatory cytokines by monocytes isolated from JIA patients. Furthermore, CB treatment in a mouse model of collagen-induce arthritis resulted in a significant decrease in circulating inflammatory cytokine levels, immune cell infiltrates, joints erosion, and bone resorption, leading to a reduction in disease progression.
Discussion
In conclusion, targeting CXCR4 with the small amino compound CB shows promise as a therapeutic option for chronic and viral-induced inflammatory diseases, including RA. CB effectively regulated inflammatory cytokine production of monocytes, presenting a potential targeted approach with potential advantages over current therapies. These results warrant further research and clinical trials to explore the full therapeutic potential of targeting CXCR4 with CB-like molecules in the management of various inflammatory diseases.
The management of lymphoma in patients with primary immunodeficiency (PID) is challenging because of its poor prognosis and complex therapeutic approaches. We conducted a systematic literature review ...of case-reports, case-series, and cohorts indexed in MEDLINE reporting the association of lymphoma and PID. One hundred and eighty-two articles were selected out of 787. We identified 386 cases. Median age at diagnosis of PID and lymphoma was 9.5 and 12 years old, respectively. T-cell deficiencies were the main PIDs associated with lymphoma (57%). The most prevalent lymphoma was diffuse large B-cell lymphoma (33.5%). Epstein-Barr Virus-driven lymphomas were mostly observed in innate immunodeficiencies (when reported). Complete response to treatment was observed in 65.8% of the cases. Death occurred in 38.2%. Few allogenic stem cell transplantations were performed (29 cases). Our detailed analysis of the literature provides a landscape of lymphoma's occurrence in PID. Devoted studies in specific sub-groups of patients at risk are needed to develop dedicated protocols.
If relevant, AIRE expression in thymic B cells may repress or induce the expression of other genes, as the induction of TRAs expression in medullary thymic epithelial cells (mTECs).8 Little is known ...about the nature of TRAs expressed by murine thymic B cells, and there is only a very limited overlap of TRAs between mTECs and extrathymic Aire-expressing cells,3 suggesting that thymic B cells may regulate the expression of a unique set of TRAs.\n50 4.62 x 10-21 ZMIZ1 Zinc finger, MIZ-type containing 1 5.49 9.73 x 10-54 PER1 Period circadian clock 1 5.43 2.24 x 10-10 LRP8 Low-density lipoprotein receptor-related protein 8, apolipoprotein e receptor 5.41 6.15 x 10-15 FOLR2 Folate receptor 2 (fetal) 5.38 9.01 x 10-08 TIE1 Tyrosine kinase with immunoglobulin-like and EGF-like domains 1 5.35 5.38 x 10-07 WDR62 WD repeat domain 62 5.33 2.73 x 10-09 SMIM24 Small integral membrane protein 24 5.29 2.67 x 10-05 ROR1 Receptor tyrosine kinase-like orphan receptor 1 5.11 1.08 x 10-20 INPP1 Inositol polyphosphate-1-phosphatase 5.06 3.31 x 10-18 GBP2 Guanylate binding protein 2, interferon-inducible 5.03 9.60 x 10-26 HLX H2.0-like homeobox 4.99 1.35 x 10-16 CYB5R2 Cytochrome b5 reductase 2 4.93 4.08 x 10-09 TMEM132A Transmembrane protein 132A 4.92 1.79 x 10-21 LPIN1 Lipin 1 4.80 1.00 x 10-27 CSRNP1 Cysteine-serine-rich nuclear protein 1 4.75 4.98 x 10-24 PLXNB1 Plexin B1 4.74 5.54 x 10-05 BAMBI BMP and activin membrane-bound inhibitor 4.74 3.73 x 10-08 MS4A4A Membrane-spanning 4-domains, subfamily A, member 4A 4.72 2.31 x 10-04 MMP14 Matrix metallopeptidase 14 (membrane-inserted) 4.69 6.63 x 10-04 ANK2 Ankyrin 2, neuronal 4.62 7.80 x 10-04 HERC5 HECT and RLD domain containing E3 ubiquitin protein ligase 5 4.59 2.30 x 10-27 RTN2 Reticulon 2 4.59 6.66 x 10-05 CYP2J2 Cytochrome P450, family 2, subfamily J, polypeptide 2 4.59 2.71 x 10-09 EPS8L1 EPS8-like 1 4.57 6.50 x 10-04 SCN1B Sodium channel, voltage gated, type I beta subunit 4.53 6.70 x 10-06 ZYX Zyxin 4.53 1.03 x 10-24 TUBA1C Tubulin, alpha 1c 4.52 1.14 x 10-06 SPHK1 Sphingosine kinase 1 4.49 4.47 x 10-05 STIL SCL/TAL1 interrupting locus 4.46 3.05 x 10-03 TLN2 Talin 2 4.43 5.89 x 10-05 CIT Citron rho-interacting serine/threonine kinase 4.41 5.57 x 10-03 AKAP12low *E12,E13 A kinase (PRKA) anchor protein 12 4.40 7.01 x 10-08 NAB2 NGFI-A binding protein 2 (EGR1 binding protein 2) 4.38 5.71 x 10-10 PDE9A Phosphodiesterase 9A 4.36 6.26 x 10-07 NET1 Neuroepithelial cell transforming 1 4.32 2.17 x 10-14 CISH Cytokine inducible SH2-containing protein 4.28 4.96 x 10-11 ABCG1 ATP-binding cassette, subfamily G (WHITE), member 1 4.27 2.57 x 10-30 NLRP2 NLR family, pyrin domain containing 2 4.26 8.94 x 10-08 PAK6 p21 protein (Cdc42/Rac)-activated kinase 6 4.24 4.01 x 10-06 IZUMO4 IZUMO family member 4 4.22 6.26 x 10-15 CALHM2 Calcium homeostasis modulator 2 4.20 4.17 x 10-10 ZDHHC11 Zinc finger, DHHC-type containing 11 4.20 2.63 x 10-03 LRRC36 Leucine rich repeat containing 36 4.20 1.15 x 10-16 MS4A14 Membrane-spanning 4-domains, subfamily A, member 14 4.20 3.88 x 10-13 FAM101B Family with sequence similarity 101, member B 4.16 4.65 x 10-06 ESR1 Estrogen receptor 1 4.16 7.03 x 10-08 METRNLlow *E14 Meteorin, glial cell differentiation regulator-like 4.13 1.92 x 10-08 KLF4 Kruppel-like factor 4 (gut) 4.10 2.91 x 10-02 SH2D2A SH2 domain containing 2A 4.09 1.79 x 10-04 PTP4A3 Protein tyrosine phosphatase type IVA, member 3 4.03 6.07 x 10-10 Table E2 List of TRAs expressed in thymic B cells compared with peripheral B cells
From a 1-year survival of less than 50% before the discovery of glucocorticoids to over 90% at 10 years in most dedicated centres, the spectrum of SLE has profoundly evolved. Despite this ...improvement, several major challenges currently remain. The aim of this review is to analyse what are, according to us, the 10 most important contemporary challenges in the management of SLE. Among those are the need to treat to target to favour disease remission (or low disease activity), limit the use of glucocorticoids, derive more comprehensive tools for the evaluation of disease activity, develop more effective drugs (yielding successful trials), dissect the heterogeneity of the disease both at the molecular and genetic levels, identify relevant biomarkers for individualised treatment, manage fertility and pregnancy, tackle comorbidities such as cardiovascular risk, the prevention of infections and osteoporosis, improve the network of care (from the patients’ perspective), and favour a holistic approach (integrating fatigue, adherence to treatment, physical activity). Altogether, these 10 contemporary challenges in SLE may be considered as a roadmap for those involved in the daily care of patients with SLE, as well as for researchers who may wish to contribute to an improved management of this rare and complex disease.
Adolescence is a time of physical, psychological and social changes between childhood and adulthood. All adolescents and young adults (AYAs) are in transition and experience key underlying processes ...that will influence their later life. It is a critical period, particularly for AYAs with a chronic medical condition. Diseases can start at any point during adolescence. The transition of care will concern health care providers, as well as more unexpected actors such as social workers, teachers, business managers and the family. In this review, we focus on transition in primary immunodeficiencies (PIDs) and autoimmune diseases (AIDs). We describe the challenges and needs of transition in the field. Questions that AYAs with PID and/or AID must face during transition in their familial, professional and personal life are discussed. We expose a practical, AYA centered approach to help physicians in their daily practice, and we propose a position for the future.
•Transition of care is a critical time for youth affected with chronic immune disorders.•Transition is a continuous process starting the day of the diagnosis in childhood until adulthood.•There is a need for coordinated and personalized programmes.
Hyper-IgE syndromes and chronic mucocutaneous candidiasis constitute rare primary immunodeficiency syndromes with an overlapping clinical phenotype. In recent years, a growing number of underlying ...genetic defects have been identified. To characterize the underlying genetic defects in a large international cohort of 275 patients, of whom 211 had been clinically diagnosed with hyper-IgE syndrome and 64 with chronic mucocutaneous candidiasis, targeted panel sequencing was performed, relying on Agilent HaloPlex and Illumina MiSeq technologies. The targeted panel sequencing approach allowed us to identify 87 (32 novel and 55 previously described) mutations in 78 patients, which generated a diagnostic success rate of 28.4%. Specifically, mutations in
DOCK8
(26 patients),
STAT3
(21),
STAT1
(15),
CARD9
(6),
AIRE
(3),
IL17RA
(2),
SPINK5
(3),
ZNF341
(2),
CARMIL2
/
RLTPR
(1),
IL12RB1
(1), and
WAS
(1) have been detected. The most common clinical findings in this cohort were elevated IgE (81.5%), eczema (71.7%), and eosinophilia (62.9%). Regarding infections, 54.7% of patients had a history of radiologically proven pneumonia, and 28.3% have had other serious infections. History of fungal infection was noted in 53% of cases and skin abscesses in 52.9%. Skeletal or dental abnormalities were observed in 46.2% of patients with a characteristic face being the most commonly reported feature (23.1%), followed by retained primary teeth in 18.9% of patients. Targeted panel sequencing provides a cost-effective first-line genetic screening method which allows for the identification of mutations also in patients with atypical clinical presentations and should be routinely implemented in referral centers.
Naturally-occurring autoantibodies to certain components of autophagy processes have been described in a few autoimmune diseases, but their fine specificity, their relationships with clinical ...phenotypes, and their potential pathogenic functions remain elusive. Here, we explored IgG autoantibodies reacting with a panel of cytoplasmic endosomal/lysosomal antigens and individual heat-shock proteins, all of which share links to autophagy. Sera from autoimmune patients and from MRL/lpr and NZB/W lupus-prone mice reacted with the C-terminal residues of lysosome-associated membrane glycoprotein (LAMP)2A. No cross-reaction was observed with LAMP2B or LAMP2C variants, with dsDNA or mononucleosomes, or with heat-shock protein A8. Moreover, administering chromatography-purified LAMP2A autoantibodies to MRL/lpr mice accelerated mortality. Furthermore, flow cytometry revealed elevated cell-surface expression of LAMP2A on MRL/lpr B cells. These findings reveal the involvement of a new class of autoantibodies targeting the C-terminus of LAMP2A, a receptor for cytosolic proteins targeted for degradation via chaperone-mediated autophagy. These autoantibodies could affect the autophagy process, which is abnormally upregulated in lupus. The data presented support a novel connection between autophagy dysregulation, autoimmune processes and pathophysiology in lupus.
•This study describes a new class of autoantibodies that target the C-terminus of lysosomal-associated membrane protein 2A.•Affinity-purified LAMP2A-reacting autoantibodies accelerate disease progression in MRL/lpr mouse.•Certain immune cells express LAMP2A at their surface, possibly providing an entryway for LAMP2A antibodies into these cells.•Blocking cell-surface LAMP2A or LAMP2A antibodies may be of therapeutic interest to control the progression of lupus disease.
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