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ObjectiveTo characterize the molecular landscape of patients with Type 1 and Type 2 systemic SLE erythematosus (SLE) by analyzing gene expression profiles from peripheral blood.MethodsFull transcriptomic RNA sequencing was carried out on whole blood samples from 18 subjects with SLE selected by the presence of manifestations typical of Type 1 and Type 2 SLE. The top 5,000 row variance genes were analyzed by Multiscale Embedded Gene Co-expression Network Analysis (MEGENA) to generate gene co-expression modules, that were functionally annotated and correlated to various demographic traits, clinical features and laboratory measures.ResultsExpression of specific gene coexpression modules correlated with individual features of Type 1 and 2 SLE and also effectively segregated samples from Type 1 from Type 2 SLE patients. Unique Type 1 SLE enrichments included IFN, monocytes, T cells, cell cycle, and neurotransmitter pathways, whereas unique Type 2 SLE enrichments included B cells and metabolic and neuromuscular pathways. Gene co-expression modules of Type 2 SLE patients were identified in subsets of previously reported patients with inactive SLE and idiopathic fibromyalgia (FM) and also identified subsets of patients with active SLE with a greater frequency of severe fatigue.ConclusionGene co-expression analysis successfully identified unique transcriptional patterns that segregate Type 1 SLE from Type 2 SLE and further identified Type 2 molecular features in patients with inactive SLE or FM and with active SLE with severe fatigue.

Evobrutinib is a highly selective, orally administered Bruton's tyrosine kinase (BTK) inhibitor. The objective of this phase II, multicenter, randomized, double-blind, placebo-controlled trial was to evaluate the efficacy and safety of evobrutinib in patients with active autoantibody-positive systemic lupus erythematosus (SLE).Patients were diagnosed with SLE by either the Systemic Lupus International Collaborating Clinics criteria or at least four American College of Rheumatology criteria 6 months or more prior to screening, had an SLE Disease Activity Index-2000 score of 6 or more, were autoantibody-positive and on standard-of-care therapy. Randomization was 1:1:1:1 to oral evobrutinib 25 mg once daily (QD), 75 mg QD, 50 mg twice daily, or placebo. Primary efficacy endpoints were SLE responder index (SRI)-4 response at week 52 and SRI-6 response at week 52 in the high disease activity subpopulation. Safety endpoints included treatment-emergent adverse events (TEAEs).A total of 469 patients were randomized and received at least one dose of evobrutinib or placebo at the time of primary analysis. Mean (SD) age at baseline was 40.7 (±12.3) years; 94.9% of patients were female. Neither primary efficacy endpoint was met. All doses of evobrutinib were well tolerated, and there was no clear dose effect on the incidence of reported TEAEs, or serious TEAEs, including severe infections.This phase II, dose-ranging trial in SLE failed to show a treatment effect of evobrutinib versus placebo at any dose. Evobrutinib was generally well tolerated, with no dose effect observed for TEAEs. These results suggest that BTK inhibition does not appear to be an effective therapeutic intervention for patients with SLE.

Individuals with potential exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) do not necessarily develop PCR or antibody positivity, suggesting that some individuals may clear subclinical infection before seroconversion. T cells can contribute to the rapid clearance of SARS-CoV-2 and other coronavirus infections1–3. Here we hypothesize that pre-existing memory T cell responses, with cross-protective potential against SARS-CoV-2 (refs. 4–11), would expand in vivo to support rapid viral control, aborting infection. We measured SARS-CoV-2-reactive T cells, including those against the early transcribed replication–transcription complex (RTC)12,13, in intensively monitored healthcare workers (HCWs) who tested repeatedly negative according to PCR, antibody binding and neutralization assays (seronegative HCWs (SN-HCWs)). SN-HCWs had stronger, more multispecific memory T cells compared with a cohort of unexposed individuals from before the pandemic (prepandemic cohort), and these cells were more frequently directed against the RTC than the structural-protein-dominated responses observed after detectable infection (matched concurrent cohort). SN-HCWs with the strongest RTC-specific T cells had an increase in IFI27, a robust early innate signature of SARS-CoV-2 (ref. 14), suggesting abortive infection. RNA polymerase within RTC was the largest region of high sequence conservation across human seasonal coronaviruses (HCoV) and SARS-CoV-2 clades. RNA polymerase was preferentially targeted (among the regions tested) by T cells from prepandemic cohorts and SN-HCWs. RTC-epitope-specific T cells that cross-recognized HCoV variants were identified in SN-HCWs. Enriched pre-existing RNA-polymerase-specific T cells expanded in vivo to preferentially accumulate in the memory response after putative abortive compared to overt SARS-CoV-2 infection. Our data highlight RTC-specific T cells as targets for vaccines against endemic and emerging Coronaviridae., Seronegative healthcare workers with an innate signature of infection preferentially expand pre-existing T cells targeting the conserved replication transcription complex of SARS-CoV-2 in abortive infection.

Objectives To perform an exploratory study to identify a JDM serum metabolic profile that differs from healthy controls (HCs) and responds to immunosuppressive treatment. Methods Blood was collected from 9 HCs and 10 patients diagnosed with probable (n = 4) or definite (n = 6) JDM based on the criteria of Bohan and Peter for myositis, with 7 of the 10 providing longitudinal samples following initiation of treatment; these patients comprised the treatment-naïve cohort. Sera underwent mass spectroscopy–based measurements of targeted metabolic intermediates, including 15 amino acids, 45 acylcarnitines (ACs), 15 ceramides and 29 sphingomyelins. Principal components analysis reduced metabolites into smaller sets of factors each comprised of correlated metabolic intermediates. Factor scores and metabolite concentrations were compared with HCs using two-sample t-tests while treatment effects were evaluated using paired t-tests. Results Of eight principal components analysis–derived metabolite factors (one AC, two amino acids, three sphingosine and two ceramide), two were significantly associated with JDM: one AC factor containing mostly long-chain ACs (P = 0.049) and one ceramide factor (P Conclusion While additional validation is needed, these lipids have potential as JDM serum diagnostic and/or treatment biomarkers. Additionally, the significant association of long-chain ACs and ceramides with JDM offers insights regarding pathogenesis, implicating dysregulation of mitochondrial fatty acid β-oxidation.

Systemic lupus erythematous is a systemic autoimmune disease that can cause severe pain and impair quality of life. Pain in lupus can arise from a variety of mechanisms and is usually assessed in terms of activity and damage. In contrast, categorization of symptoms as type 1 and type 2 manifestations encompasses a broader array of symptoms, including widespread pain, fatigue, and depression that may track together. The categorization of symptoms as type 1 and type 2 manifestations can facilitate communication between patient and provider as well as provide a framework to address more fully the complex symptoms experienced by patients.

Objective The type 1 and type 2 systemic lupus erythematosus (SLE) categorization system was recently proposed to validate the patients' perspective of disease and to capture a more comprehensive spectrum of symptoms. The objective of this study was to characterize the clinical manifestations of SLE subtypes and to determine the correlation between the patient- and physician-reported measures used in the model. Methods This was a cross-sectional study of patients with SLE in a university clinic. Patients completed the Systemic Lupus Activity Questionnaire (SLAQ) and 2011 American College of Rheumatology fibromyalgia (FM) criteria. Active SLE was defined as Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score ≥6, clinical SLEDAI score ≥4, or active lupus nephritis. We identified 4 groups: type 1 SLE (active SLE without FM), type 2 SLE (inactive SLE with FM), mixed SLE (active SLE with FM), and minimal SLE (inactive SLE without FM). Results In this cohort of 212 patients (92% female, mean age 45 years), 30% had type 1 SLE, 8% had type 2 SLE, 13% had mixed SLE, and 49% had minimal SLE. Regardless of SLE disease activity, patients with FM (21%), reported higher SLAQ scores, patient global assessment scores, and self-reported lupus flare that resulted in discordance between patient- and physician-reported measures. Conclusion Fatigue, widespread pain, sleep dysfunction, and mood disorders are common symptoms in SLE. Identifying these symptoms as type 2 SLE may be a method to improve patient communication and understanding. The level of type 2 SLE impacts patients' perception of disease and self-reported symptoms. The SLAQ may need to be reinterpreted based on the FM severity scale.

Antibodies to DNA (anti-DNA) are the serological hallmark of systemic lupus erythematosus, a prototypic autoimmune disease. These antibodies bind to conserved sites on single-stranded and double-stranded DNA and display variable region somatic mutations consistent with antigen selection. Nevertheless, the interaction of anti-DNA with DNA has unconventional features. Anti-DNA antibodies bind by a mechanism called monogamous bivalency, in which stable interaction requires contact of both Fab sites with determinants on the same extended DNA molecule; the size of this DNA can be hundreds to thousands of bases, especially in solid phase assays. This binding also requires the presence of the Fc portion of IgG, a binding mechanism known as Fc-dependent monogamous bivalency. As shown by the effects of ionic strength in association and dissociation assays, anti-DNA binding is primarily electrostatic. Like anti-DNA autoantibodies, anti-DNA antibodies that bind specifically to non-conserved sites on bacterial DNA, a type of anti-DNA found in otherwise healthy individuals, also interact by monogamous bivalency. The unconventional features of anti-DNA antibodies may reflect the highly charged and polymeric nature of DNA and the need for molecular rearrangements to facilitate monogamous bivalency; the Fc portion contributes to binding in an as yet unknown way.

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by antinuclear antibodies (ANAs) that form immune complexes that mediate pathogenesis by tissue deposition or cytokine induction. Some ANAs bind DNA or associated nucleosome proteins, whereas other ANAs bind protein components of complexes of RNA and RNA-binding proteins (RBPs). Levels of anti-DNA antibodies can fluctuate widely, unlike those of anti-RBP antibodies, which tend to be stable. Because anti-DNA antibody levels can reflect disease activity, repeat testing is common; by contrast, a single anti-RBP antibody determination is thought to suffice for clinical purposes. Experience from clinical trials of novel therapies has provided a new perspective on ANA expression during disease, as many patients with SLE are ANA negative at screening despite previously testing positive. Because trial results suggest that patients who are ANA negative might not respond to certain agents, screening strategies now involve ANA and anti-DNA antibody testing to identify patients with so-called ‘active, autoantibody-positive SLE’. Evidence suggests that ANA responses can decrease over time because of the natural history of disease or the effects of therapy. Together, these findings suggest that, during established disease, more regular serological testing could illuminate changes relevant to pathogenesis and disease status. Antinuclear antibodies (ANAs), characteristic features of systemic lupus erythematosus (SLE), are a requirement for disease classification and trial enrolment. In this Review, the authors re-examine the role of ANAs in SLE and discuss changing attitudes towards using ANAs as biomarkers.

Personalized medicine is an important goal for the treatment of rheumatic disease that seeks to improve outcomes by matching therapy more precisely with the underlying pathogenetic disturbances in the individual patient. Realization of this goal requires actionable biomarkers to identify these disturbances as well as pathways that can be targeted for novel therapy. Among advances in characterizing pathogenesis, Big Data provides an unprecedented picture of pathogenesis, with analysis of tissue lesions revealing disturbances that may not be apparent in blood. Big Data approaches include single cell RNAseq (scRNAseq) which can elucidate patterns of gene expression by individual cells. Galvanized by the Accelerating Medicines Partnership, a public-private initiative of the NIH, investigative teams have analyzed gene expression in cells in the synovium for rheumatoid arthritis and kidney for systemic lupus erythematosus. A review of basic and translational research for 2018-2019 provides the progress in these areas. Thus, the studies on rheumatoid arthritis have identified subpopulations of immune cells and fibroblasts implicated in synovitis. For lupus, transcriptomic studies have provided evidence for widespread effects of type 1 interferon. Studies in progressive sclerosis have demonstrated changes associated with stem cell therapy as well as potential new targets for anti-fibrotic agents. Other studies using molecular approaches have defined new mechanisms for vasculitis as well as the potential role of the microbiome in inflammatory arthritis and systemic lupus erythematosus. Future studies with Big Data will incorporate the spatial relationships of cells in inflammation as well as changes in gene expression over time.

Objective We developed a model that categorizes systemic lupus erythematosus (SLE) activity into two dimensions: Type 1 SLE consists of inflammatory activity, including arthritis, nephritis, and rashes; Type 2 SLE includes fatigue, myalgia, mood disturbance, and cognitive dysfunction. Patient-reported outcome (PRO) measures have received attention as a way to capture symptomatology of SLE. The objective of this study was to explore the use of existing PRO measures to classify Type 1 and 2 SLE activity. Methods Systemic lupus erythematosus patients completed three questionnaires: Systemic Lupus Activity Questionnaire (SLAQ), Polysymptomatic Distress Scale (PSD), and Patient Health Questionnaire (PHQ-2). SLE Disease Activity Index (SLEDAI) and physician global assessments (PGA; 0–3) for Type 1 and Type 2 activity were also recorded. High Type 1 SLE activity was defined as cSLEDAI ≥4 (scored without labs), SLEDAI ≥6, active nephritis, or Type 1 PGA ≥1.0. High Type 2 SLE activity was defined as Type 2 PGA ≥1.0. Patients with both high Type 1 and 2 activity were defined as Mixed SLE, and patients with low Type 1 and 2 activity were defined as Minimal SLE. Data were reduced with a factor analysis. Using a reduced set of 13 variables, multinomial logistic regression models estimated the probability of Minimal, Type 1, Type 2, and Mixed SLE classification. Results The study included 208 patients with SLE. The model accurately predicted the clinician-based Type 1 and 2 SLE classification in 63% of patients; 73% of patients had their Type 1 SLE activity accurately predicted; and 83% had their Type 2 SLE activity accurately predicted. Performance varied by group: 87% of Minimal patients were correctly predicted to be in the Minimal SLE group, yet only about one-third of patients in the Type 1 group were correctly predicted to be in the Type 1 group. Conclusions Our findings indicate Type 2 SLE activity can be identified by patient-reported data. The use of PROs was not as accurate at predicting Type 1 activity. These findings highlight the challenges of using PROs to categorize and classify SLE symptoms since some manifestations of Type 1 activity (e.g., nephritis) may be essentially clinically silent while other Type 1 manifestations may cause severe symptoms.

Devauchelle-Pensec V, Carvajal-Alegria G, Dernis E, et al.

ObjectivesThe goals of these studies were to elucidate the inter-relationships of specific anti-nuclear antibody (ANA), complement, and the interferon gene signature (IGS) in the pathogenesis of systemic lupus erythematosus (SLE).MethodsData from the Illuminate trials were analysed for antibodies to dsDNA as well as RNA-binding proteins (RBP), levels of C3, C4 and various IGS. Statistical hypothesis testing, linear regression analyses and classification and regression trees analysis were employed to assess relationships between the laboratory features of SLE.ResultsInter-relationships of ANAs, complement and the IGS differed between patients of African Ancestry (AA) and European Ancestry (EA); anti-RNP and multiple autoantibodies were more common in AA patients and, although both related to the presence of the IGS, relationships between autoantibodies and complement differed. Whereas, anti-dsDNA had an inverse relationship to C3 and C4, levels of anti-RNP were not related to these markers. The IGS was only correlated with anti-dsDNA in EA SLE and complement was more correlated to the IGS in AA SLE. Finally, autoantibodies occurred in the presence and absence of the IGS, whereas the IGS was infrequent in anti-dsDNA/anti-RBP-negative SLE patients.ConclusionThere is a complex relationship between autoantibodies and the IGS, with anti-RNP associated in AA and both anti-dsDNA and RNP associated in EA. Moreover, there was a difference in the relationship between anti-dsDNA, but not anti-RBP, with complement levels. The lack of a relationship of anti-RNP with C3 and C4 suggests that anti-RNP immune complexes (ICs) may drive the IGS without complement fixation, whereas anti-dsDNA ICs involve complement consumption.

DNA is a polymeric macromolecule that can display a variety of backbone conformations. While the classical B-DNA is a right-handed double helix, Z-DNA is a left-handed helix with a zig-zag orientation. The Z conformation depends upon the base sequence, base modification and supercoiling and is considered to be transient. To determine whether the presence of Z-DNA can be detected immunochemically, the binding of monoclonal and polyclonal anti-Z-DNA antibodies to a panel of natural DNA antigens was assessed by an ELISA using brominated poly(dG-dC) as a control for Z-DNA. As these studies showed, among natural DNA tested (Micrococcus luteus, calf thymus, Escherichiacoli, salmon sperm, lambda phage), micrococcal (MC) DNA showed the highest binding with both anti-Z-DNA preparations, and E. coli DNA showed binding with the monoclonal anti-DNA preparation. The specificity for Z-DNA conformation in MC DNA was demonstrated by an inhibition binding assay. An algorithm to identify propensity to form Z-DNA indicated that DNA from Mycobacterium tuberculosis could form Z-DNA, a prediction confirmed by immunoassay. Together, these findings indicate that anti-Z-DNA antibodies can serve as probes for the presence of Z-DNA in DNA of various species origin and that the content of Z-DNA varies significantly among DNA sources.

Abs to DNA (anti-DNA) are a unique population of Abs that bind structural determinants on the DNA molecule. In systemic lupus erythematosus (SLE), anti-DNA Abs bind to conserved antigenic determinants, with the phosphodiester backbone being the most likely. In contrast, otherwise healthy subjects (HS) express anti-DNA that bind selectively to nonconserved sites on certain bacterial and viral DNA. As shown previously, SLE anti-DNA bind by a mechanism termed Fc-dependent monogamous bivalency. In this mechanism, both Fab sites interact with determinants on the same extended DNA molecule, reflecting the low affinity of each Fab site; the requirement for the Fc region suggests some contribution of the C region to increase avidity. In this study, we investigated whether anti-DNA from HS also bind to bacterial DNA by Fc-dependent monogamous bivalency. For this purpose, we compared the activity of intact IgG with Fab and F(ab′)2 fragments prepared from the plasmas of SLE patients and HS using ELISAs with DNA from calf thymus or Micrococcus luteus. These studies showed that Fab fragments from all plasmas tested, both SLE and HS, failed to bind significantly to DNA compared with intact IgG. By contrast, some, but not all, F(ab′)2 preparations from both SLE patients and HS showed binding to M. luteus DNA; F(ab′)2 fragments from SLE plasmas, however, did not bind significantly to calf thymus DNA. Together, these findings suggest that although anti-DNA Abs, whether from SLE or HS, bind by monogamous bivalency, binding to bacterial DNA does not require the Fc region.

BACKGROUND: Autoimmune diseases comprise a spectrum of illnesses and are on the rise worldwide. Although anti-nuclear antibodies (ANA) are detected in many autoimmune diseases, up to 20% of healthy women are ANA+ and most will never develop clinical symptoms. Further, disease transition is higher among ANA+ African Americans compared to European Americans. OBJECTIVE: To determine the immune features that might define and prevent transition to clinical autoimmunity in ANA+ healthy individuals. METHODS: We comprehensively phenotype immune profiles of African Americans and European Americans who are ANA- healthy, ANA+ healthy, or have systemic lupus erythematosus (SLE) using single cell mass cytometry, next-generation RNA sequencing, multiplex cytokine profiling, and phospho-signaling analyses. RESULTS: We found that SLE patients of both races displayed T cell expansion and elevated expression of Type I and II interferon pathways compared to both ANA- and ANA+ healthy individuals. We discovered a unique immune signature that suggests a suppressive immune phenotype and reduced CD11C+ autoimmunity-associated B cells in healthy ANA+ European Americans that is absent in their SLE or even healthy ANA- counterparts, or among African American cohorts. In contrast, ANA+ healthy African Americans exhibited elevated expression of T cell activation markers and higher plasma levels of IL-6 compared to healthy ANA+ European Americans. CONCLUSIONS: We propose that this novel immune signature identified in ANA+ healthy European Americans protects them from T cell expansion, heightened activation of interferon pathways, and disease transition.

Immune checkpoint inhibitors are novel biologic agents to treat cancer by inhibiting the regulatory interactions that limit T cell cytotoxicity to tumours. Current agents target either CTLA-4 or the PD-1/PD-L1 axis. Because checkpoints may also regulate autoreactivity, immune checkpoint inhibitor therapy is complicated by side effects known as immune-related adverse events (irAEs). The aim of this article is to review the mechanisms of these events. irAEs can involve different tissues and include arthritis and other rheumatic manifestations. The frequency of irAEs is related to the checkpoint inhibited, with the combination of agents more toxic. Because of their severity, irAEs can limit therapy and require immunosuppressive treatment. The mechanisms leading to irAEs are likely similar to those promoting anti-tumour responses and involve expansion of the T cell repertoire; furthermore, immune checkpoint inhibitors can affect B cell responses and induce autoantibody production. Better understanding of the mechanisms of irAEs will be important to improve patient outcome as well as quality of life during treatment.

Objective In the development of novel therapies for systemic lupus erythematosus, antinuclear antibody (ANA) positivity represents a criterion for trial eligibility. Since as many as 30% of patients enrolled in trials have been ANA negative, we evaluated the performance characteristics of immunofluorescence assays (IFAs) for ANA determinations for screening. Methods This study used 5 commercially available IFAs to assess the ANA status of 181 patients enrolled in a phase II clinical trial for an anti-interleukin-6 antibody. Enrollment included a detailed review of medical records to verify a historical ANA value. IFA results were related to various clinical and serologic features at enrollment. Results While the frequency of ANA negativity assessed by the central laboratory was 23.8% in a cohort of 181 patients, the evaluated IFA kits demonstrated frequencies of negativity from 0.6 to 27.6%. With 2 IFA kits showing a significant frequency of ANA negativity, positive and negative samples differed in levels of anti-double-stranded DNA, C3, and presence of other ANAs as well as the frequency of high interferon (IFN) expression. Conclusion These findings indicate that, when used for screening, IFAs can vary because of performance characteristics of kits and thus can affect determination of trial eligibility. With kits producing a significant frequency of ANA negativity, ANA status can be associated with other serologic measures as well as the presence of the IFN signature, potentially affecting responsiveness to a trial agent.

Pain is the most common symptom of patients with rheumatic disease, and its characteristics can be used to diagnose disease, assess disease activity, inform treatment decisions, and determine treatment response. Pain nevertheless remains one of the most difficult symptoms to evaluate and treat. Understanding the mechanisms of pain in the rheumatic diseases can provide a framework for a holistic approach to guide treatment decisions. In this article, we provide an overview on pain generation in rheumatologic disease, with a focus on rheumatoid arthritis, osteoarthritis, and fibromyalgia, and offer a perspective on treatment. Pain in rheumatic disease can be divided into three categories: inflammation, damage, and pain processing and perception. The contribution of these mechanisms can change during the course of disease and characteristics of different causes of pain can be present at any given time. In view of the diverse mechanisms of pain in the individual patient, a personalized approach of pharmacologic and non-pharmacologic interventions can be used to address symptomatology. The division of pain into the three categories of inflammation, damage, and pain processing and perception can provide a useful construct for pain assessment and management in patients with rheumatic disease. Given its complex nature, pain can be treated using a variety of pharmacologic and non-pharmacologic interventions. For patients with inflammatory arthritis, the underlying mechanism of pain should be frequently re-assessed and a holistic approach used to manage better this important symptom.

ObjectiveWe have developed a new conceptual model to characterise the signs and symptoms of SLE: the Type 1 and 2 SLE Model. Within the original model, Type 1 SLE consists of inflammatory manifestations like arthritis, nephritis and rashes; Type 2 SLE includes symptoms of fatigue, myalgia, mood disturbance and cognitive dysfunction. Through in-depth interviews, we explored how the Type 1 and 2 SLE Model fits within the lived experience of patients with SLE, with a focus on the connection between Type 1 and Type 2 SLE symptoms.MethodsSemistructured in-depth interviews were conducted among adult participants meeting 1997 American College of Rheumatology or Systemic Lupus International Collaborating Clinics criteria for SLE. Participants were purposefully selected for age, race, sex and nephritis history. All interviews were audio-recorded and transcribed. Data were analysed through episode profile and thematic analysis.ResultsThrough interviews with 42 patients with SLE, two patterns of Type 2 SLE emerged: Intermittent (n=18) and Persistent (n=24). Participants with Intermittent Type 2 SLE described feeling generally well when Type 1 is inactive; these participants were younger and had more internal SLE manifestations. Participants with Persistent Type 2 described always experiencing Type 2 symptoms despite inactive Type 1, although the severity may fluctuate. Participants with Persistent Type 2 SLE experienced traditional lupus symptoms of joint pain, hair loss and rash, but less often had severe organ system involvement.ConclusionsBy listening to the stories of our patients, we found two underlying patterns of Type 2 SLE: Intermittent Type 2 symptoms that resolve in synchrony with Type 1 inflammatory symptoms, and Persistent Type 2 symptoms that continue despite remission of Type 1 symptoms.

We have read with interest the reply by Klareskog et al , ‘ How to communicate in science ’,1 to our editorial, ‘ Pathogenic effector function of …

We have read with interest the comments by Dr Holmdahl1 on our editorial entitled ‘Pathogenic effector functions of ACPA: where do we stand?’2 and thank him for the additional information. We fully agree …

Rheumatic diseases are a diverse group of conditions in which the host and the environment interact to drive inflammation and autoreactivity. In this dyadic model, the strongest environmental influence is infection, with bacteria and viruses likely to trigger disease in a host predisposed by genetics; infection can either non-specifically stimulate the immune system to heighten the propensity for autoreactivity or specifically stimulate B and T cell autoreactivity by molecular mimicry. For many years, this venerable model has powerfully influenced the design of experiments in both the human and animal systems as well as their interpretation. While the ‘one organism, one disease’ mechanism may pertain to at least some rheumatic diseases (eg, rheumatic fever following Streptococcus infection), for most other conditions, pathogenesis is more complicated, at least in part because one of the major sources of foreign organisms—bacteria, viruses, fungi and others—resides in or around the host as the microbiome. The microbiome is a huge biomass, with the mammalian host containing as many prokaryotic as eukaryotic cells; the number is in the trillions. Many studies have therefore addressed whether the microbiome can influence the occurrence of not only rheumatic diseases but also metabolic, cardiovascular and neuropsychiatric conditions, among others.1 2 As shown recently in a provocative study by Rosshart et al 3, the host and the environment are not truly distinct, with data presented suggesting that the microbiome and the host have coevolved to produce an optimal balance of positive and negative effects. In their drive to study disease in a more reductionist way, investigators have likely disrupted this balance by breeding genetically inbred mice in very clean environments. Although a clean environment would seemingly reduce potential ‘contaminating’ influences of infection, it is very much unnatural and leads to a microbiome that itself can alter host responses and skew …

Antibodies to DNA (anti-DNA) are the serological hallmark of systemic lupus erythematosus. Previous studies have indicated that the phosphodiester backbone is the main antigenic target, with electrostatic interactions important for high avidity. To define further these interactions, the effects of ionic strength on anti-DNA binding of SLE plasmas were assessed in association and dissociation assays by ELISA. As these studies demonstrated, increasing ionic strength to a concentration of 1000 mM NaCl reduced antibody binding although the extent of the reduction varied among samples. In dissociation assays, differences among plasmas were also observed. For one of the plasmas, binding to DNA displayed resistance to dissociation by increasing ionic strength even though these concentrations limited binding in association assays. Time course studies showed a gradual change in binding interactions. These studies indicate that anti-DNA binding can involve both electrostatic and non-electrostatic interactions, with binding in some plasmas showing evidence of hysteresis.

SOURCE CITATION Yang W, Sun C, He SQ, et al. The efficacy and safety of disease-modifying osteoarthritis drugs for knee and hip osteoarthritis-a systematic review and network meta-analysis. J Gen Intern Med. 2021;36:2085-93. 33846938.

Antinuclear antibodies (ANAs) are a diverse group of autoantibodies that recognize nuclear macromolecules and their complexes. ANAs represent key biomarkers in the evaluation of rheumatic diseases, most prominently systemic lupus erythematosus (SLE), and ANA testing is commonly performed in the clinical setting. In addition, ANA testing is now used to assess eligibility for participation in clinical trials of new therapeutic agents for SLE. ANAs can be assayed by various techniques, with the fluorescent ANA assay often viewed as the gold standard. Whereas a positive ANA test represents a classification criterion for SLE, up to 20-30% of the healthy population, depending on the assay used, is positive for an ANA, complicating the use of this test for diagnosis or the detection of preclinical autoimmunity. Furthermore, ANAs might be expressed in SLE less commonly than often thought. This Perspectives article discusses important questions about the use of ANA testing in both the clinical and research settings.

The past two decades have witnessed remarkable advances in the treatment of inflammatory arthritis that have made remission in previously untreatable conditions a realistic goal for many patients. These advances derive from new insights into disease mechanisms; the advent of the biologics and other new therapies; the development of robust measures of disease activity; coherent treatment strategies to guide therapy (ie, treat to target or T2T); and a sufficient supply of rheumatologists to implement the new approaches.1 The advances in rheumatology have been unprecedented and, arguably, the treatment of inflammatory arthritis has progressed faster and further than that of any other serious chronic disease in all of medicine. Indeed, a patient with rheumatoid arthritis (RA) today can lead an essentially normal life, whereas, a few decades ago, such a patient would have a restricted existence and be easily recognised by the appearance of grave illness, wasting and deformity. Along with better outcomes have come challenges in the utilisation of the current armamentarium of disease modifying antirheumatic drugs or DMARDs (table 1). These challenges are, of course, welcome since they signify progress. In the face of literally hundreds to thousands of ways to treat arthritis and the continuing influx of novel agents, they also demand guidance for both providers and patients to establish a treatment plan, recognising potential risks, benefits and costs. The publication of three articles on European League Against Rheumatism (EULAR) recommendations for the treatment of early inflammatory arthritis, RA and axial spondyloarthritis (axSpA) is therefore an important event and provides a much needed perspective and framework for the delivery of best care.2–4 View this table: Table 1 Disease-modifying antirheumatic drugs (DMARDs) Each article represents a remarkable effort by panels of rheumatologists, health professionals and patient representatives to encompass an ever-expanding literature and provide overarching principles as well as specific recommendations. The work …

In a seminal paper published in Nature , Heinz et al provide important new information on the gene product of CXorf21 , an X-linked gene associated with systemic lupus erythematosus (SLE).1 Using an impressive array of molecular techniques, these investigators demonstrated that the protein encoded by a gene originally known as CXorf21 interacts with SLC15A4, an amino acid transporter in the endolysosomal compartment; the gene for SLC15A4 has also been genetically associated with SLE. While the role of CXorf21 in SLE had been investigated for many years, the function of its protein product was a mystery until Heinz et al identified it as an adaptor in TLR signalling. The name for this protein is now ‘TLR adaptor interacting with endolysosomal SLC15A4’ or TASL; the gene is designated as TASL (CXorf21 ). As the studies in THP1 and other human cells in the Nature paper illustrate, TASL is important for the recruitment and activation of the transcription factor IRF5 in downstream signalling by TLR 7, 8 and 9; as such, TASL has analogy with adaptor proteins like STING, MAVS and TRIF. These findings are relevant to the pathogenesis of SLE since, in this disease, DNA and RNA in the form of immune complexes can enter cells of the innate immune system to induce responses by TLR 7, 8 and 9 in the endosomes; the production of interferon and other proinflammatory cytokines is an outcome of this pathway. Interestingly, in its regulation of gene expression, TASL affects the IRF pathway but does not affect NF-κB or MAPK signalling.1 This pattern points to a unique role of TASL in the activation of innate immunity by the endosomal TLRs (figure 1). Figure 1 The role of TASL in TLR signalling. As the schematic indicates, TASL plays a key role in the activation of …