Uncoupling interferons and the interferon signature explains clinical and transcriptional subsets in SLE.

Systemic lupus erythematosus (SLE) displays a hallmark interferon (IFN) signature. Yet, clinical trials targeting type I IFN (IFN-I) have shown variable efficacy, and blocking IFN-II failed to treat SLE. Here, we show that IFN type levels in SLE vary significantly across clinical and transcriptional endotypes. Whereas skin involvement correlated with IFN-I alone, systemic features like nephritis associated with co-elevation of IFN-I, IFN-II, and IFN-III, indicating additive IFN effects in severe SLE. Notably, while high IFN-II/-III levels without IFN-I had a limited effect on disease activity, IFN-II was linked to IFN-I-independent transcriptional profiles (e.g., OXPHOS and CD8+GZMH+ cells), and IFN-III enhanced IFN-induced gene expression when co-elevated with IFN-I. Moreover, dysregulated IFNs do not explain the IFN signature in 64% of patients or clinical manifestations including cytopenia, serositis, and anti-phospholipid syndrome, implying IFN-independent endotypes in SLE. This study sheds light on mechanisms underlying SLE heterogeneity and the variable response to IFN-targeted therapies in clinical trials.

Xist ribonucleoproteins promote female sex-biased autoimmunity.

Autoimmune diseases disproportionately affect females more than males. The XX sex chromosome complement is strongly associated with susceptibility to autoimmunity. Xist long non-coding RNA (lncRNA) is expressed only in females to randomly inactivate one of the two X chromosomes to achieve gene dosage compensation. Here, we show that the Xist ribonucleoprotein (RNP) complex comprising numerous autoantigenic components is an important driver of sex-biased autoimmunity. Inducible transgenic expression of a non-silencing form of Xist in male mice introduced Xist RNP complexes and sufficed to produce autoantibodies. Male SJL/J mice expressing transgenic Xist developed more severe multi-organ pathology in a pristane-induced lupus model than wild-type males. Xist expression in males reprogrammed T and B cell populations and chromatin states to more resemble wild-type females. Human patients with autoimmune diseases displayed significant autoantibodies to multiple components of XIST RNP. Thus, a sex-specific lncRNA scaffolds ubiquitous RNP components to drive sex-biased immunity.

East-Asian lupus nephritis in the Hopkins Lupus Cohort.

Background and Objective: East Asian systemic lupus erythematosus (SLE) is under represented in lupus cohorts outside of East Asia. We asked whether lupus nephritis was more common and more severe in East Asians than in other ethnicities in a large United States SLE cohort. Methods: The Hopkins Lupus Cohort, a longitudinal cohort of 2802 patients (53.5% Caucasian, 39.2% African-American, 3.2% East Asian) was studied. The SLICC/ACR Damage Index was used to assess renal outcomes. Results: East Asian patients had the same prevalence of lupus nephritis as African-Americans and both were higher than Caucasians. East Asians were not significantly different in frequency of end stage kidney disease compared with African-Americans. East Asians were more likely than Caucasians to have anti-Sm, low C3 and low C4. East Asians were more likely than African-Americans to have low C3 and low C4. Conclusion: East Asians living in the United States were more likely to have lupus nephritis than Caucasians. Poor outcomes such as end stage kidney disease occurred at an equal frequency in East Asians as in African-Americans. Lupus nephritis was both more frequent and more severe in East Asians than in African-Americans.

Uncoupling interferons and the interferon signature explain clinical and transcriptional subsets in SLE.

Interferons (IFN) are thought to be key players in systemic lupus erythematosus (SLE). The unique and interactive roles of the different IFN families in SLE pathogenesis, however, remain poorly understood. Using reporter cells engineered to precisely quantify IFN-I, IFN-II and IFN-III activity levels in serum/plasma, we found that while IFNs play essential role in SLE pathogenesis and disease activity, they are only significant in specific subsets of patients. Interestingly, whereas IFN-I is the main IFN that governs disease activity in SLE, clinical subsets are defined by the co-elevation of IFN-II and IFN-III. Thus, increased IFN-I alone was only associated with cutaneous lupus. In contrast, systemic features, such as nephritis, were linked to co-elevation of IFN-I plus IFN-II and IFN-III, implying a synergistic effect of IFNs in severe SLE. Intriguingly, while increased IFN-I levels were strongly associated with IFN-induced gene expression (93.5%), in up to 64% of cases, the IFN signature was not associated with IFN-I. Importantly, neither IFN-II nor IFN-III explained IFN-induced gene expression in patients with normal IFN-I levels, and not every feature in SLE was associated with elevated IFNs, suggesting IFN-independent subsets in SLE. Together, the data suggest that, unlike the IFN signature, direct quantification of bioactive IFNs can identify pathogenic and clinically relevant SLE subsets amenable for precise anti-IFN therapies. Since IFN-I is only elevated in a subset of SLE patients expressing the IFN signature, this study explains the heterogeneous response in clinical trials targeting IFN-I, where patients were selected based on IFN-induced gene expression rather than IFN-I levels.

The XIST lncRNA is a sex-specific reservoir of TLR7 ligands in SLE.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with a dramatic sex bias, affecting 9 times more women than men. Activation of Toll-like receptor 7 (TLR7) by self-RNA is a central pathogenic process leading to aberrant production of type I interferon (IFN) in SLE, but the specific RNA molecules that serve as TLR7 ligands have not been defined. By leveraging gene expression data and the known sequence specificity of TLR7, we identified the female-specific X-inactive specific transcript (XIST) long noncoding RNA as a uniquely rich source of TLR7 ligands in SLE. XIST RNA stimulated IFN-α production by plasmacytoid DCs in a TLR7-dependent manner, and deletion of XIST diminished the ability of whole cellular RNA to activate TLR7. XIST levels were elevated in blood leukocytes from women with SLE compared with controls, correlated positively with disease activity and the IFN signature, and were enriched in extracellular vesicles released from dying cells in vitro. Importantly, XIST was not IFN inducible, suggesting that XIST is a driver, rather than a consequence, of IFN in SLE. Overall, our work elucidated a role for XIST RNA as a female sex-specific danger signal underlying the sex bias in SLE.

Affinity maturation generates pathogenic antibodies with dual reactivity to DNase1L3 and dsDNA in systemic lupus erythematosus.

Anti-dsDNA antibodies are pathogenically heterogeneous, implying distinct origins and antigenic properties. Unexpectedly, during the clinical and molecular characterization of autoantibodies to the endonuclease DNase1L3 in patients with systemic lupus erythematosus (SLE), we identified a subset of neutralizing anti-DNase1L3 antibodies previously catalogued as anti-dsDNA. Based on their variable heavy-chain (VH) gene usage, these antibodies can be divided in two groups. One group is encoded by the inherently autoreactive VH4-34 gene segment, derives from anti-DNase1L3 germline-encoded precursors, and gains cross-reactivity to dsDNA - and some additionally to cardiolipin - following somatic hypermutation. The second group, originally defined as nephritogenic anti-dsDNA antibodies, is encoded by diverse VH gene segments. Although affinity maturation results in dual reactivity to DNase1L3 and dsDNA, their binding efficiencies favor DNase1L3 as the primary antigen. Clinical, transcriptional and monoclonal antibody data support that cross-reactive anti-DNase1L3/dsDNA antibodies are more pathogenic than single reactive anti-dsDNA antibodies. These findings point to DNase1L3 as the primary target of a subset of antibodies classified as anti-dsDNA, shedding light on the origin and pathogenic heterogeneity of antibodies reactive to dsDNA in SLE.

Role of Platelet-Bound C4d (PC4d) in Predicting Risk of Future Thrombotic Events in Systemic Lupus Erythematosus.

OBJECTIVE: Platelet-bound complement activation product C4d (PC4d) levels correlate with history of thrombosis in patients with systemic lupus erythematosus (SLE). The present study evaluated whether PC4d levels could assess risk of future thrombosis events. METHODS: PC4d level was measured by flow cytometry. Thromboses were confirmed by electronic medical record data review. RESULTS: The study included 418 patients. Nineteen events (13 arterial and 6 venous) occurred in 15 subjects in the 3 years post-PC4d level measurement. PC4d levels above the optimum cutoff of 13 mean fluorescence intensity (MFI) predicted future arterial thrombosis with a hazard ratio of 4.34 (95% confidence interval [95% CI] 1.03-18.3) (P = 0.046) and a diagnostic odds ratio (OR) of 4.30 (95% CI 1.19-15.54). Negative predictive value of PC4d level of ≤13 MFI for arterial thrombosis was 99% (95% CI 97-100%). Although a PC4d level of >13 MFI did not reach statistical significance for prediction of total thrombosis (arterial and venous) (diagnostics OR 2.50 [95% CI 0.88-7.06]; P = 0.08), it was associated with all thrombosis (n = 70 historic and future arterial and venous events in the 5 years pre- to 3 years post-PC4d level measurement) with an OR of 2.45 (95% CI 1.37-4.32; P = 0.0016). In addition, the negative predictive value of PC4d level of ≤13 MFI for all future thrombosis events was 97% (95% CI 95-99%). CONCLUSIONS: A PC4d level of >13 MFI predicted future arterial thrombosis and was associated with all thrombosis. Patients with SLE presenting with a PC4d level of ≤13 MFI had high probability of not experiencing arterial or any thrombosis in the 3 years afterwards. Taken together, these findings indicate that PC4d levels may help predict the risk of future thrombosis events in SLE.

Effect of Systemic Lupus Erythematosus and Immunosuppressive Agents on COVID-19 Vaccination Antibody Response.

OBJECTIVE: The risk of COVID-19 infection is increased in patients with systemic lupus erythematosus (SLE) versus those without SLE. Some immunosuppressive medications increase COVID-19 infection and decrease the efficacy of vaccination. Consensus documents have suggested management strategies for handling immunosuppressive medications to increase vaccine efficacy, but the benefit of such strategies has not been proven. The current study was undertaken to determine the effect of immunosuppressive drugs on vaccine response in SLE. METHODS: We collected information on COVID-19 infection, vaccination history, and COVID-19 antibodies in the Hopkins Lupus Cohort. A cohort of health care workers was used for comparison. Outcome measures included SARS-CoV-2 antibody IgG levels after vaccination over time in both cohorts and effect of immunosuppressive medications on postvaccination IgG levels in SLE patients. RESULTS: The analysis was based on 365 observations from 334 different patients in the SLE cohort, and 2,235 observations from 1,887 different health care workers. SLE patients taking immunosuppressive medications had lower vaccine IgG levels than SLE patients who were not; but both groups had lower levels than health care workers. Holding mycophenolate for 1 week after vaccination increased postvaccine IgG levels significantly without leading to clinical flares. In multiple variable models, mycophenolate mofetil, tacrolimus, and belimumab all significantly reduced antibody response to vaccination. CONCLUSION: SLE patients, regardless of background immunosuppressive therapy, had lower vaccine IgG levels than health care workers. Mycophenolate, tacrolimus, and belimumab significantly reduced IgG response to vaccination. Holding mycophenolate for 1 week improved vaccine efficacy, providing clinical benefit on vaccine response without leading to clinical flares.

Coronary plaque progression is greater in systemic lupus erythematosus than rheumatoid arthritis.

BACKGROUND: Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are associated with a high incidence of cardiovascular disease. Coronary atherosclerosis, particularly total plaque and noncalcified plaque on coronary computed tomography angiography (CCTA) has been correlated with cardiovascular events. We compared baseline coronary plaque burden and progression by serial CCTA in SLE and RA patients. METHODS: We prospectively evaluated 44 patients who underwent serial CCTA examinations to quantify coronary plaque progression, 22 SLE patients, and 22 age- and sex-matched RA patients. Semiautomated plaque software was used for quantitative plaque assessment. Linear regression examined the effect of SLE diagnosis (versus RA) on annualized change in natural log-transformed total normalized atheroma volume (ln-TAV norm ) for low-attenuation, fibrofatty, fibrous, total noncalcified, densely calcified, and total plaque. RESULTS: No quantitative differences for any plaque types were observed at baseline between SLE and RA patients ( P = 0.330-0.990). After adjustment for baseline plaque and cardiovascular risk factors, the increase in ln-TAV norm was higher in SLE than RA patients for fibrous [Exp-ß: 0.202 (0.398), P = 0.0003], total noncalcified [Exp-ß: 0.179 (0.393), P = 0.0001], and total plaque volume [Exp-ß: 0.154 (0.501), P = 0.0007], but not for low-attenuation, fibrofatty, or densely calcified plaque ( P = 0.103-0.489). Patients with SLE had 80% more fibrous, 82% more noncalcified, and 85% more total plaque increase than those with RA. CONCLUSION: Coronary plaque volume was similar in RA and SLE at baseline. Progression was greater in SLE, which may explain the greater cardiovascular risk in this disease. Further research to evaluate screening and management strategies for cardiovascular disease in these high-risk patients is warranted.

Alternative exon usage in TRIM21 determines the antigenicity of Ro52/TRIM21 in systemic lupus erythematosus.

The origin and mechanisms of autoantigen generation in systemic lupus erythematosus (SLE) are poorly understood. Here, we identified SLE neutrophils activated in vivo by IFN as a prominent source of Ro52, also known as tripartite motif-containing protein 21 (TRIM21), a critical autoantigen historically thought to be primarily generated by keratinocytes in SLE. Different from mononuclear cells and keratinocytes, SLE neutrophils are enriched in several unique Ro52 species containing a core sequence encoded by exon 4 (Ro52Ex4) in TRIM21. Ro52Ex4 is the main target of anti-Ro52 antibodies and is found in 2 Ro52 variants (Ro52α and a potentially novel isoform termed Ro52γ) upregulated in SLE neutrophils. Further analysis of Ro52γ revealed a subset of autoantibodies against a unique C-terminal domain (Ro52γCT) generated from a frameshift due to the lack of exon 6 in Ro52γ. Antibodies to Ro52Ex4 and Ro52γCT distinguish SLE patient subsets characterized by distinct clinical, laboratory, treatment, and transcriptional profiles that are not discerned by the "classical" anti-Ro52 antibodies. These studies uncover IFN-activated neutrophils as a key source of unique immunogenic forms of Ro52 in SLE. Moreover, the finding of Ro52Ex4 and Ro52γCT as core targets of anti-Ro52 antibodies focus interest on Ro52γ as the potential isoform toward which immunological tolerance is initially lost in SLE.

Renal response at 2 years post biopsy to predict long-term renal survival in lupus nephritis: a retrospective analysis of the Hopkins Lupus Cohort.

OBJECTIVE: This retrospective analysis evaluated the prognostic value of renal response status 2 years after biopsy-proven lupus nephritis (LN) for the prediction of long-term renal outcomes. METHODS: Eligible patients with SLE as per American College of Rheumatology or Systemic Lupus International Collaborating Clinics criteria and biopsy-proven class III, IV, V or mixed LN were identified from the Hopkins Lupus Cohort, and categorised into binary renal response categories (modified primary efficacy renal response (mPERR) or no mPERR at 2 years post biopsy). These categories were defined by a modified version of the Belimumab International Lupus Nephritis Study (BLISS-LN) protocol using urine protein:creatinine ratio (≤0.7 g/day) and estimated glomerular filtration rate (≥60 mL/min/1.73 m2 or ≤20% below the baseline value) criteria. Long-term renal survival (defined as survival without end-stage renal disease (ESRD) or death) and chronic renal insufficiency-free survival were assessed in Kaplan-Meier plots with log-rank test and covariate-adjusted Cox proportional hazards models. RESULTS: Of the 173 eligible patients, 91.3% were female; the mean (SD) age at biopsy was 36.2 (11.8) years. At 2 years post biopsy, 114 (65.9%) patients achieved mPERR. These patients showed a lower risk of ESRD/death and chronic renal insufficiency in the follow-up period (HR (95% CI) 0.33 (0.13 to 0.87), p=0.0255; and HR (95% CI) 0.26 (0.14 to 0.47), p<0.0001, respectively). CONCLUSIONS: The 2-year post-biopsy renal response status, defined per 2019-updated BLISS-LN criteria, has prognostic value for long-term renal survival and lower risk of chronic renal insufficiency in patients with LN.

Trajectory of Damage Accrual in Systemic Lupus Erythematosus Based on Ethnicity and Socioeconomic Factors.

OBJECTIVE: The Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) is associated with increased healthcare costs and mortality. We compared the trajectory of total and individual damage items of the SDI in African American vs White ethnicities in a large prospective systemic lupus erythematosus (SLE) cohort. We also estimated the association between ethnicity and individual damage items after adjusting for several socioeconomic factors. METHODS: Poisson regression was used to calculate the rate of damage per year for each organ. Cox regression modeling was used to determine the association between time to the individual damage item and ethnicity. RESULTS: We included 2436 patients: 42.9% African American, 57.1% White, and 92% female. There was a linear relationship between time since diagnosis and mean SDI score, with no plateau. Compared to White patients, African American patients had a faster total, renal, pulmonary, and skin damage accrual rate even after adjustment for differences in socioeconomic variables. CONCLUSION: The linear increase in damage in both ethnicities over time is of particular concern. African American patients accrued more damage at a faster rate compared to White patients. For a few organs, higher rates of damage in African American patients was partially explained by socioeconomic differences, whereas for most organs, the difference persisted after adjustment for these factors.

The DNA sensors AIM2 and IFI16 are SLE autoantigens that bind neutrophil extracellular traps.

Background: Nucleic acid binding proteins are frequently targeted as autoantigens in systemic lupus erythematosus (SLE) and other interferon (IFN)-linked rheumatic diseases. The AIM-like receptors (ALRs) are IFN-inducible innate sensors that form supramolecular assemblies along double-stranded (ds)DNA of various origins. Here, we investigate the ALR absent in melanoma 2 (AIM2) as a novel autoantigen in SLE, with similar properties to the established ALR autoantigen interferon-inducible protein 16 (IFI16). We examined neutrophil extracellular traps (NETs) as DNA scaffolds on which these antigens might interact in a pro-immune context. Methods: AIM2 autoantibodies were measured by immunoprecipitation in SLE and control subjects. Neutrophil extracellular traps were induced in control neutrophils and combined with purified ALR proteins in immunofluorescence and DNase protection assays. SLE renal tissues were examined for ALR-containing NETs by confocal microscopy. Results: AIM2 autoantibodies were detected in 41/131 (31.3%) SLE patients and 2/49 (4.1%) controls. Our SLE cohort revealed a frequent co-occurrence of anti-AIM2, anti-IFI16, and anti-DNA antibodies, and higher clinical measures of disease activity in patients positive for antibodies against these ALRs. We found that both ALRs bind NETs in vitro and in SLE renal tissues. We demonstrate that ALR binding causes NETs to resist degradation by DNase I, suggesting a mechanism whereby extracellular ALR-NET interactions may promote sustained IFN signaling. Conclusions: Our work suggests that extracellular ALRs bind NETs, leading to DNase resistant nucleoprotein fibers that are targeted as autoantigens in SLE. Funding: These studies were funded by NIH R01 DE12354 (AR), P30 AR070254, R01 GM 129342 (JS), K23AR075898 (CM), K08AR077100 (BA), the Jerome L. Greene Foundation and the Rheumatology Research Foundation. Dr. Antiochos and Dr. Mecoli are Jerome L. Greene Scholars. The Hopkins Lupus Cohort is supported by NIH grant R01 AR069572. Confocal imaging performed at the Johns Hopkins Microscopy Facility was supported by NIH Grant S10 OD016374.

Systemic lupus erythematosus (SLE or lupus for short) is an autoimmune disease in which the immune system attacks healthy tissue in organs across the body. The cause is unknown, but people with the illness make antibodies that stick to proteins that are normally found inside the cell nucleus, where DNA is stored. To make these antibodies, the immune system must first 'see' these proteins and mistakenly recognise them as a threat. But how does the immune system recognise proteins that are normally hidden inside cells? During infection, a type of immune cell called a neutrophil releases DNA from its nucleus to form structures called neutrophil extracellular traps, or NETs for short. The role of these NETs is to capture and kill pathogens, but they also expose the neutrophil's DNA and the proteins attached to it to other immune cells. It is therefore possible that other immune cells interacting with NETs during infection may contribute to the development of lupus. Two proteins of interest are AIM2 and IFI16. These proteins form large, shield-like structures around strands of DNA, and previous work has shown that some people with lupus make antibodies against IFI16. Antiochos et al. wondered whether IFI16 and AIM2 might stick to NETs, exposing themselves to the immune system. Examining the blood of people with lupus revealed that one in three of them made antibodies that could stick to AIM2. Those people were also more likely to have antibodies that could stick to IFI16 and to strands of DNA. Using microscopy, Antiochos et al. also found AIM2 and IFI16 on NETs in the kidneys of some people with lupus. Further investigation showed that the presence of AIM2 and IFI16 prevents NETs from breaking down. If proteins like AIM2 and IFI16 can stop NETs from breaking down, they could allow the immune system more time to develop antibodies against them. Further investigation could reveal whether this is one of the causes of lupus. A clearer understanding of the antibodies could also boost research into diagnosis and treatment.

Autoantibodies targeting LINE-1-encoded ORF1p are associated with systemic lupus erythematosus diagnosis but not disease activity.

OBJECTIVES: Long Interspersed Element 1 (LINE-1) is an endogenous retroelement that constitutes a significant portion of the human genome and has been implicated in the pathogenesis of systemic lupus erythematosus (SLE). The LINE-1 RNA chaperone protein ORF1p was recently identified as an SLE autoantigen. Here we analyse ORF1p for qualities underlying SLE autoantigen status, compared anti-ORF1p antibodies to markers of SLE disease activity, and performed screening for antibodies against LINE-1 reverse transcriptase ORF2p. METHODS: ORF1p was examined in epithelial cell lines treated with cytotoxic lymphocyte granules and UV irradiation. Anti-ORF1p and anti-ORF2p antibodies were assayed by ELISA and analysed in two SLE cohorts. RESULTS: We found that ORF1p localises to cytoplasmic RNA-containing blebs in apoptotic cells, and is a substrate of the cytotoxic protease granzyme B (GrB). Anti-ORF1p antibodies were present in 4.2% of healthy controls, compared to 15.8% (p=0.0157) and 15.5% (p=0.036) of subjects in the two SLE cohorts. Anti-ORF1p antibodies were not associated with SLE disease activity nor peripheral blood markers of interferon (IFN) activation. Anti-ORF1p titres demonstrated stability over serial time points. Anti-ORF1p antibodies were not associated with anti-DNA, anti-RNP, or other SLE autoantibodies. There was no difference in anti-ORF2p ELISA results in controls versus SLE patients. CONCLUSIONS: LINE-1 ORF1p is a component of apoptotic blebs and a substrate for GrB. Anti-ORF1p antibodies are enriched in SLE subjects but are not associated with dynamic markers of disease activity. These data support a potential role for LINE-1 dysregulation in SLE pathogenesis.

Deconvoluting virome-wide antibody epitope reactivity profiles.

BACKGROUND: Comprehensive characterization of exposures and immune responses to viral infections is critical to a basic understanding of human health and disease. We previously developed the VirScan system, a programmable phage-display technology for profiling antibody binding to a library of peptides designed to span the human virome. Previous VirScan analytical approaches did not carefully account for antibody cross-reactivity among sequences shared by related viruses or for the disproportionate representation of individual viruses in the library. METHODS: Here we present the AntiViral Antibody Response Deconvolution Algorithm (AVARDA), a multi-module software package for analyzing VirScan datasets. AVARDA provides a probabilistic assessment of infection with species-level resolution by considering sequence alignment of all library peptides to each other and to all human viruses. We employed AVARDA to analyze VirScan data from a cohort of encephalitis patients with either known viral infections or undiagnosed etiologies. We further assessed AVARDA's utility in associating viral infection with type 1 diabetes and lupus. FINDINGS: By comparing acute and convalescent sera, AVARDA successfully confirmed or detected encephalitis-associated responses to human herpesviruses 1, 3, 4, 5, and 6, improving the rate of diagnosing viral encephalitis in this cohort by 44%. AVARDA analyses of VirScan data from the type 1 diabetes and lupus cohorts implicated enterovirus and herpesvirus infections, respectively. INTERPRETATION: AVARDA, in combination with VirScan and other pan-pathogen serological techniques, is likely to find broad utility in the epidemiology and diagnosis of infectious diseases. FUNDING: This work was made possible by support from the National Institutes of Health (NIH), the US Army Research Office, the Singapore Infectious Diseases Initiative (SIDI), the Singapore Ministry of Health's National Medical Research Council (NMRC) and the Singapore National Research Foundation (NRF).

Association of Higher Hydroxychloroquine Blood Levels With Reduced Thrombosis Risk in Systemic Lupus Erythematosus.

OBJECTIVE: Hydroxychloroquine (HCQ) has a primary role in the prophylaxis and treatment of systemic lupus erythematosus (SLE) and may be protective against thrombosis in SLE. Optimal weight-based dosing of HCQ is unknown. This study was undertaken to examine the usefulness of HCQ blood monitoring in predicting thrombosis risk in a longitudinal SLE cohort. METHODS: HCQ levels were serially quantified from EDTA whole blood by liquid chromatography-tandem mass spectrometry. The mean HCQ blood levels calculated prior to thrombosis or until the last visit were compared using t-tests between patients with and those without thrombosis. Pooled logistic regression was used to analyze the association between rates of thrombosis and HCQ blood level. Rate ratios (RRs) and 95% confidence intervals (95% CIs) were calculated. RESULTS: In 739 patients with SLE, thrombosis occurred in 38 patients (5.1%). The mean ± SD HCQ blood level was lower in patients who developed thrombosis versus those who did not develop thrombosis (720 ± 489 ng/ml versus 935 ± 580 ng/ml; P = 0.025). Thrombosis rates were reduced by 13% for every 200-ng/ml increase in the most recent HCQ blood level (RR 0.87 [95% CI 0.78-0.98], P = 0.025) and by 13% for mean HCQ blood level (RR 0.87 [95% CI 0.76-1.00], P = 0.056). Thrombotic events were reduced by 69% in patients with mean HCQ blood levels ≥1,068 ng/ml versus those with levels <648 ng/ml (RR 0.31 [95% CI 0.11-0.86], P = 0.024). This remained significant after adjustment for confounders (RR 0.34 [95% CI 0.12-0.94], P = 0.037). CONCLUSION: Low HCQ blood levels are associated with thrombotic events in SLE. Longitudinal measurement of HCQ levels may allow for personalized HCQ dosing strategies. Recommendations for empirical dose reduction may reduce or eliminate the benefits of HCQ in this high-risk population.

Comparison of the 2019 European Alliance of Associations for Rheumatology/American College of Rheumatology Systemic Lupus Erythematosus Classification Criteria With Two Sets of Earlier Systemic Lupus Erythematosus Classification Criteria.

OBJECTIVE: The Systemic Lupus International Collaborating Clinics (SLICC) 2012 systemic lupus erythematosus (SLE) classification criteria and the revised American College of Rheumatology (ACR) 1997 criteria are list based, counting each SLE manifestation equally. We derived a classification rule based on giving variable weights to the SLICC criteria and compared its performance to the revised ACR 1997, the unweighted SLICC 2012, and the newly reported European Alliance of Associations for Rheumatology (EULAR)/ACR 2019 criteria sets. METHODS: The physician-rated patient scenarios used to develop the SLICC 2012 classification criteria were reemployed to devise a new weighted classification rule using multiple linear regression. The performance of the rule was evaluated on an independent set of expert-diagnosed patient scenarios and compared to the performance of the previously reported classification rules. RESULTS: The weighted SLICC criteria and the EULAR/ACR 2019 criteria had less sensitivity but better specificity compared to the list-based revised ACR 1997 and SLICC 2012 classification criteria. There were no statistically significant differences between any pair of rules with respect to overall agreement with the physician diagnosis. CONCLUSION: The 2 new weighted classification rules did not perform better than the existing list-based rules in terms of overall agreement on a data set originally generated to assess the SLICC criteria. Given the added complexity of summing weights, researchers may prefer the unweighted SLICC criteria. However, the performance of a classification rule will always depend on the populations from which the cases and non-cases are derived and whether the goal is to prioritize sensitivity or specificity.