Faculty Bibliography

Over the 2 months since coronavirus first appeared in China, cases have emerged on every continent, and it is clear that patients with autoimmune diseases might also be affected. Coronavirus disease 2019 (COVID-19) is a highly contagious viral illness with a mortality rate approaching 2%. Here we discuss the challenges that patients with autoimmune diseases might face and the information on using immunomodulatory therapies like chloroquine, tocilizumab and baricitinib to quench the cytokine storm in patients with very severe COVID-19 pneumonia.

OBJECTIVES/OBJECTIVE:In this study we aimed to investigate foetal and maternal pregnancy outcomes from a large multicentre cohort of women diagnosed with MCTD and anti-U1RNP antibodies. METHODS:This multicentre retrospective cohort study describes the outcomes of 203 pregnancies in 94 consecutive women ever pregnant who fulfilled the established criteria for MCTD with confirmed U1RNP positivity. RESULTS:The foetal outcomes in 203 pregnancies were as follows: 146 (71.9%) live births, 38 (18.7%) miscarriages (first trimester pregnancy loss of <12 weeks gestation), 18 (8.9%) stillbirths (pregnancy loss after 20 weeks gestation) and 11 (5.4%) cases with intrauterine growth restriction. Maternal pregnancy outcomes were as follows: 8 (3.9%) developed pre-eclampsia, 2 (0.9%) developed eclampsia, 31 (15.3%) developed gestational hypertension and 3 (1.5%) developed gestational diabetes. Women with MCTD and aPL and pulmonary or muscular involvement had worse foetal outcomes compared with those without. Moreover, we report a case of complete congenital heart block (0.45%) and a case of cutaneous neonatal lupus, both born to a mother with positive isolated anti-U1RNP and negative anti-Ro/SSA antibodies. CONCLUSION/CONCLUSIONS:In our multicentre cohort, women with MCTD had a live birth rate of 72%. While the true frequency of heart block associated with anti-U1RNP remains to be determined, this study might raise the consideration of echocardiographic surveillance in this setting. Pregnancy counselling should be considered in women with MCTD.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Mothers giving birth to children with manifestations of neonatal lupus (NL) represent a unique population at risk for the development of clinically evident pathologic autoimmunity since many are asymptomatic and only become aware of anti-SSA/Ro positivity (anti-Ro+) based on heart block in their fetus. Accordingly, we hypothesized that the microbiome in saliva is associated with the development of autoreactivity and in some cases the progression in health status from benign to overt clinical disease including Sjögren's syndrome (SS) and systemic lupus erythematosus (SLE). The study comprised a clinical spectrum of anti-Ro+ mothers, all of whom gave birth to a child with NL: 9 were asymptomatic or had an undifferentiated autoimmune disease (Asym/UAS) and 16 fulfilled criteria for SS and/or SLE. Microbial diversity was reduced across all levels from kingdom to species for the anti-Ro+ mothers vs healthy controls; however, there were no significant differences between Asym/UAS and SS/SLE mothers. Relative abundance of Proteobacteria and more specifically class Betaproteobacteria decreased with clinical severity (healthy controls < Asym/UAS < SS/SLE). These ordered differences were maintained through the taxonomic hierarchy to three genera (Lautropia, Comamonas, and Neisseria) and species within these genera (L. mirabilis, N. flavescens and N. oralis). Biometric analysis comparing von Willebrand Factor domains present in human Ro60 with L. mirabilis proteins support the hypothesis of molecular mimicry. These data position the microbiome in the development of anti-Ro reactivity and subsequent clinical spectrum of disease.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by pathologic T cell-B cell interactions and autoantibody production. Defining the T cell populations that drive B cell responses in SLE may enable design of therapies that specifically target pathologic cell subsets. Here we evaluated the phenotypes of CD4+ T cells in the circulation of 52 SLE patients drawn from multiple cohorts and identified a highly expanded PD-1hi CXCR5- CD4+ T cell population. Cytometric, transcriptomic, and functional assays demonstrated that PD-1hi CXCR5- CD4+ T cells from SLE patients are T peripheral helper (Tph) cells, a CXCR5- T cell population that stimulates B cell responses via IL-21. The frequency of Tph cells, but not Tfh cells, correlated with both clinical disease activity and the frequency of CD11c+ B cells in SLE patients. PD-1hi CD4+ T cells were found within lupus nephritis kidneys and correlated with B cell numbers in kidney. Both IL-21 neutralization and CRISPR-mediated deletion of MAF abrogated the ability of Tph cells to induce memory B cell differentiation into plasmablasts in vitro. These findings identify Tph cells a highly expanded T cell population in SLE and suggest a key role for Tph cells in stimulating pathologic B cell responses.

Background/Purpose : SLE diagnostic criteria are important for reliable epidemiologic data. The prevalence of SLE in West Africa is falsely low due to barriers including limited access to both resource and labor-intensive diagnostic testing. Recently, the ACR and EULAR have proposed a weighted classification tool which is thought to improve diagnostic sensitivity and specificity compared to the established ACR and SLICC criteria. Here we aim to investigate the performance of each classification criteria in two West African cohorts--Korle bu Teaching Hospital, Accra Ghana (GH); and Lagos University Teaching Hospital, Lagos, Nigeria (N)--compared to an NYU Langone-African American (AA) cohort. Methods : We collected data on a total of 355 SLE patients: AA: n=151, GH: n=110, and N: n=94, diagnosed by expert clinicians. Clinical information including demographics, SLE criteria, SLEDAI scores, SLICC damage indexes, vital signs, and laboratory values as available was obtained at the initial patient encounter. Longitudinal data was collected over the course of at least 1 year at 6 month intervals during routine clinical visits. Where necessary, clinical charts were retrospectively reviewed, and the proportion of patients in each cohort meeting ACR, SLICC and the ACR/EULAR classification criteria was calculated. Results : The demographics per cohort were as follows: Age (in yrs): AA=43.1, GH=32.4yrs, N=35.5; percent female: AA=90, GH=100, N=97; Mean SLE disease duration (yrs): AA=14.3, GH=2.2, N=4.4. In each cohort, the percentage of patients meeting ACR, SLICC, and ACR/EULAR criteria were AA=96%, 96%, and 95%; GH=85%, 84%, 62%; N=90%, 87%, 61%. This discrepancy was largely due to missing laboratory data particularly with regard to immunologic and hematologic studies. ANA was missing in 0% of the AA cohort, 26% of the GH cohort, and 33% of the N cohort respectively. Compared to the GH and N cohorts, the reference AA cohort was more likely to meet ACR, SLICC, and ACR/EULAR criteria with likelihood ratios (LR) of GH=10.2 p< 0.001 and N=3.0 p=0.08; GH=11.5, p< 0.001 and N=6.3, p=0.01; and GH=46.1 P< 0.001 and N=44.9, p< 0.001 respectively. On average, the mean number of ACR/EULAR points by cohort was AA: 26.1+/-11.8, GH: 21.3+/-8.1, and N: 19.0+/-6.2. While the ANA entry criteria greatly diminished the new ACR/EULAR diagnostic utility in the GH and N cohorts, the weighted point system performed better than either of the ACR or SLICC criteria with 96% of the AA cohort, 92%of the GH, and 95% of the N cohort meeting criteria (LR: AA vs GH=1.9, p=0.2; AA vs N=0.23, p=0.6). Conclusion : Due to a relative lack of resources, supportive laboratory assays including an ANA may be more difficult to attain in developing nations. SLE is a clinical syndrome that may be efficiently diagnosed using the new weighted ACR/EULAR criteria. The entry criteria of ANA 1:80 greatly diminished the diagnostic utility of this classification system in the Ghanaian and Nigerian cohorts compared to the African American cohort. Clinical trials should consider offering wide ANA testing to cohorts in the developing world

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Background/Purpose : The impact of glucocorticoid (GC) use on major organ damage in SLE patients has not been formally studied by amalgamating the relevant data published in the literature over the past 40 years. We aimed to study the association between GC use and the occurrence of major organ damage in SLE patients by performing meta-analyses of observational studies published between 1970 and December 2018. Methods : Literature search on PubMed (from 1966 to December 2018) for prevalence and longitudinal studies which reported GC exposure (proportion of GC users in the cohort [%GC use] and/or GC use in defined doses) and the occurrence (prevalence/incidence) of major organ damage in SLE patients using the keywords cataract, cerebrovascular (CVA), stroke, cardiovascular (CVS), angina, myocardial infarction (MI), coronary artery bypass, osteoporosis, avascular necrosis (AVN) and osteonecrosis in respective combinations with lupus was conducted. Studies with sample size < 50 and observation duration < 12 months were excluded. The logit of the proportion of patients with disease damage was modelled as a random effect in the meta-analysis, which was employed to study the association between the proportion of patients with organ damage and variables of GC use (mean daily [mg/day] and cumulative [gm] prednisone [PDN] doses and %GC use). A 2-stage estimation of the random-effects logistic regression models was used with restricted maximum likelihood estimation. Univariate associations between organ damage and moderators were examined for statistical significance, and variables related to GC use were adjusted for SLE disease duration in multivariate models if their univariate P values were < 0.2. Results : Out of 8,882 publications screened, 212 articles involving 205,619 SLE patients were eligible for the metaanalyses (Figure 1), of which 97 were prevalence and 115 were longitudinal studies. Univariate analyses of prevalence studies revealed that mean daily PDN dose (odds ratio [OR]=1.10, p=0.007) and lower proportion of female in the cohort (OR=0.002, p=0.002) were associated with the prevalence of overall CVS events. Mean daily PDN dose (OR=1.52, p< 0.001) and %GC use (OR=2,255.2, p< 0.001) were associated with the prevalence of AVN. A significant association between cumulative PDN dose and prevalence of CVA was found after multivariate adjustment for SLE disease duration (OR=1.07, p=0.017). In longitudinal studies, a significant association was identified between cumulative PDN dose and incidence of cataracts after adjustment for SLE disease duration (OR=1.04, p=0.013). While the incidence of MI in SLE patients has dropped over the past 40 years (OR=0.94, p=0.002), it was associated with % GC use after adjustment for SLE disease duration (OR=8.18, p=0.012). Interestingly, significant univariate associations were found between antimalarial use and lower prevalence of MI (OR=0.05, p=0.002) and lower incidence of CVA (OR=0.20, p=0.032). Conclusion : Independent of SLE disease duration, cumulative PDN dose was associated with higher prevalence of CVA and incidence of cataracts, and higher incidence of MI was associated with overall GC use