Anti-KIF20B autoantibodies are associated with cranial neuropathy in systemic lupus erythematosus.

BACKGROUND: Cranial neuropathies (CN) are a rare neuropsychiatric SLE (NPSLE) manifestation. Previous studies reported that antibodies to the kinesin family member 20B (KIF20B) (anti-KIF20B) protein were associated with idiopathic ataxia and CN. We assessed anti-KIF20B as a potential biomarker for NPSLE in an international SLE inception cohort. METHODS: Individuals fulfilling the revised 1997 American College of Rheumatology (ACR) SLE classification criteria were enrolled from 31 centres from 1999 to 2011 and followed annually in the Systemic Lupus Erythematosus International Collaborating Clinics inception cohort. Anti-KIF20B testing was performed on baseline (within 15 months of diagnosis or first annual visit) samples using an addressable laser bead immunoassay. Logistic regression (penalised maximum likelihood and adjusting for confounding variables) examined the association between anti-KIF20B and NPSLE manifestations (1999 ACR case definitions), including CN, occurring over the first 5 years of follow-up. RESULTS: Of the 1827 enrolled cohort members, baseline serum and 5 years of follow-up data were available on 795 patients who were included in this study: 29.8% were anti-KIF20B-positive, 88.7% female, and 52.1% White. The frequency of anti-KIF20B positivity differed only for those with CN (n=10) versus without CN (n=785) (70.0% vs 29.3%; OR 5.2, 95% CI 1.4, 18.5). Compared with patients without CN, patients with CN were more likely to fulfil the ACR haematological (90.0% vs 66.1%; difference 23.9%, 95% CI 5.0%, 42.8%) and ANA (100% vs 95.7%; difference 4.3%, 95% CI 2.9%, 5.8%) criteria. In the multivariate analysis adjusting for age at baseline, female, White race and ethnicity, and ACR haematological and ANA criteria, anti-KIF20B positivity remained associated with CN (OR 5.2, 95% CI 1.4, 19.1). CONCLUSION: Anti-KIF20B is a potential biomarker for SLE-related CN. Further studies are needed to examine how autoantibodies against KIF20B, which is variably expressed in a variety of neurological cells, contribute to disease pathogenesis.

Can complement activation be the missing link in antiphospholipid syndrome?

APS is an autoimmune disorder with life-threatening complications that, despite therapeutic advantages, remains associated with thrombotic recurrences and treatment failure. The role of complement activation in APS pathogenesis is increasingly recognised, specifically in obstetric APS. However, its exact role in thrombotic APS and on the severity of the disease is not yet fully elucidated. Further mechanistic studies are needed to delineate the role of complement activation in the various APS clinical manifestations with aim to identify novel markers of disease severity, together with clinical trials to evaluate the efficacy of complement inhibition in APS. This could ultimately improve risk stratification in APS, patient tailored targeted therapy with complement inhibition identified as an adjunctive treatment. This article reviews current findings and challenges about complement activation in APS, discusses the potential role of platelet mediated complement activation in this setting and provides an overview on clinical implications and current therapeutics.

Thioredoxin is a metabolic rheostat controlling regulatory B cells.

Metabolic programming is important for B cell fate, but the bioenergetic requirement for regulatory B (Breg) cell differentiation and function is unknown. Here we show that Breg cell differentiation, unlike non-Breg cells, relies on mitochondrial electron transport and homeostatic levels of reactive oxygen species (ROS). Single-cell RNA sequencing analysis revealed that TXN, encoding the metabolic redox protein thioredoxin (Trx), is highly expressed by Breg cells, unlike Trx inhibitor TXNIP which was downregulated. Pharmacological inhibition or gene silencing of TXN resulted in mitochondrial membrane depolarization and increased ROS levels, selectively suppressing Breg cell differentiation and function while favoring pro-inflammatory B cell differentiation. Patients with systemic lupus erythematosus (SLE), characterized by Breg cell deficiencies, present with B cell mitochondrial membrane depolarization, elevated ROS and fewer Trx+ B cells. Exogenous Trx stimulation restored Breg cells and mitochondrial membrane polarization in SLE B cells to healthy B cell levels, indicating Trx insufficiency underlies Breg cell impairment in patients with SLE.

A large cohort comparison of very late-onset systemic lupus erythematosus with younger-onset patients.

OBJECTIVES: Age has a significant impact on systemic lupus erythematosus (SLE). However, data on very late-onset SLE (vlSLE) are scarce. We have compared the clinical and serological features of vlSLE patients with younger-onset patients. METHODS: We assessed the clinical and laboratory data of all patients fulfilling SLE classification criteria evaluated at a university hospital from 1978 to 2023. Patients were divided into 4 groups according to age at diagnosis: juvenile SLE (jSLE <8 years); adult SLE (aSLE 18-49 years); late SLE (lSLE 50-59 years); vlSLE (≥60 years). RESULTS: 845 patients were enrolled. The jSLE, aSLE, lSLE, and vlSLE groups included 153, 630, 47, and 15 patients, respectively. The vlSLE group tended to have a lower female-to-male ratio (4:1; p=0.282), was mainly Caucasian (93.3%; p<0.001), and had the lowest survival time (20.3 years; p<0.001). vlSLE patients had the lowest prevalence of positive anti-dsDNA antibodies (26.7%; p=0.010) and low C3 levels (13.3%; p<0.001). Although arthritis was less common among vlSLE patients (73.3%; p=0.043), they more commonly developed Sjögren's syndrome (SS 33.3%; p<0.001) and rheumatoid arthritis (RA 13.3%; p<0.001). Infections and malignancy were the main causes of death. CONCLUSIONS: Compared with younger patients, in vlSLE, female predominance is less pronounced. Arthritis, anti-dsDNA antibodies and low C3 levels are less frequent. SS and RA are more common. Despite lower disease activity, vlSLE patients have the lowest survival rate. While uncommon, SLE should not be excluded as a possible diagnosis in the elderly.

Collaborative research in myositis-related disorders: MIHRA, a global shared community model.

Myositis International Health and Research Collaborative Alliance (MIHRA) is a newly formed purpose-built non-profit charitable research organization dedicated to accelerating international clinical trial readiness, global professional and lay education, career development and rare disease advocacy in IIM-related disorders. In its long form, the name expresses the community's scope of engagement and intent. In its abbreviation, MIHRA, conveys linguistic roots across many languages, that reflects the IIM community's spirit with meanings such as kindness, community, goodness, and peace. MIHRA unites the global multi-disciplinary community of adult and pediatric healthcare professionals, researchers, patient advisors and networks focused on conducting research in and providing care for pediatric and adult IIM-related disorders to ultimately find a cure. MIHRA serves as a resourced platform for collaborative efforts in investigator-initiated projects, consensus guidelines for IIM assessment and treatment, and IIM-specific career development through connecting research networks.MIHRA's infrastructure, mission, programming and operations are designed to address challenges unique to rare disease communities and aspires to contribute toward transformative models of rare disease research such as global expansion and inclusivity, utilization of community resources, streamlining ethics and data-sharing policies to facilitate collaborative research. Herein, summarises MIHRA operational cores, missions, vision, programming and provision of community resources to sustain, accelerate and grow global collaborative research in myositis-related disorders.

The impact of antiphospholipid antibodies/antiphospholipid syndrome on systemic lupus erythematosus.

aPLs are a major determinant of the increased cardiovascular risk in patients with SLE. They adversely affect clinical manifestations, damage accrual and prognosis. Apart from the antibodies included in the 2006 revised classification criteria for APS, other non-classical aPLs might help in identifying SLE patients at increased risk of thrombotic events. The best studied are IgA anti-ß2-glycoprotein I, anti-domain I ß2-glycoprotein I and aPS-PT. Major organ involvement includes kidney and neuropsychiatric systems. aPL/APS severely impacts pregnancy outcomes. Due to increased thrombotic risk, these patients require aggressive cardiovascular risk factor control. Primary prophylaxis is based on low-dose aspirin in high-risk patients. Warfarin is the gold-standard drug for secondary prophylaxis.

Clinical patterns of disease: From early systemic lupus erythematosus to late-onset disease.

Systemic lupus erythematosus (SLE) is a complex disease with an insidious clinical presentation. In up to half of the cases, SLE onset is characterized by clinical and serological manifestations that, although specific, are insufficient to fulfill the classification criteria. This condition, called incomplete SLE, could be as challenging as the definite and classifiable SLE and requires to be treated according to the severity of clinical manifestations. In addition, an early SLE diagnosis and therapeutic intervention can positively influence the disease outcome, including remission rate and damage accrual. After diagnosis, the disease course is relapsing-remitting for most patients. Time in remission and cumulative glucocorticoid exposure are the most important factors for prognosis. Therefore, timely identification of SLE clinical patterns may help tailor the therapeutic intervention to the disease course. Late-onset SLE is rare but more often associated with delayed diagnosis and a higher incidence of comorbidities, including Sjogren's syndrome. This review focuses on the SLE disease course, providing actionable strategies for early diagnosis, an overview of the possible clinical patterns of SLE, and the clinical variation associated with the different age-at-onset SLE groups.

Where are we now in biological drugs for myositis?

Idiopathic inflammatory myopathies (IIM) are a rare and heterogeneous group of chronic autoimmune disorders. Up to 40% of IIM patients have long-term sequelae and significant functional disability. Its management can be challenging. New therapies are badly needed. The small number of cases with diverse presentations, and different diagnostic criteria interfere significantly with clinical trial results. Only intravenous immunoglobulin has been internationally approved for IIM patients. Most clinical trials of new biological therapies have failed to meet their primary endpoints in IIM, with only one biological drug recommended for refractory IIM treatment (rituximab), although not approved. We review several new emerging biological drugs including B cell depletion therapies, abatacept, janus-kinase inhibitors, and aldesleukin. Encouragingly, some phase II randomized controlled trials have evaluated the efficacy and safety of new biologics in IIM, demonstrating an improvement in clinical and laboratory measures.

Platelets and Thrombotic Antiphospholipid Syndrome.

Antiphospholipid antibody syndrome (APS) is an autoimmune disorder characterised by thrombosis and the presence of antiphospholipid antibodies (aPL): lupus anticoagulant and/or IgG/IgM anti-ß2-glycoprotein I and anticardiolipin antibodies. APS carries significant morbidity for a relatively young patient population from recurrent thrombosis in any vascular bed (arterial, venous, or microvascular), often despite current standard of care, which is anticoagulation with vitamin K antagonists (VKA). Platelets have established roles in thrombosis at any site, and platelet hyperreactivity is clearly demonstrated in the pathophysiology of APS. Together with excess thrombin generation, platelet activation and aggregation are the common end result of all the pathophysiological pathways leading to thrombosis in APS. However, antiplatelet therapies play little role in APS, reserved as a possible option of low dose aspirin in addition to VKA in arterial or refractory thrombosis. This review outlines the current evidence and mechanisms for excessive platelet activation in APS, how it plays a central role in APS-related thrombosis, what evidence for antiplatelets is available in clinical outcomes studies, and potential future avenues to define how to target platelet hyperreactivity better with minimal impact on haemostasis.

Bleeding events in thrombotic antiphospholipid syndrome: prevalence, severity, and associated damage accrual.

Background: Life-long anticoagulation increases bleeding risk in patients with antiphospholipid syndrome (APS). The Damage Index for Antiphospholipid Syndrome does not include bleeding events in damage accrual. Objectives: We aimed to characterize the prevalence, severity, and damage associated with bleeding events in patients with APS. Methods: This was a single-center retrospective analysis of patients with thrombotic APS (2006 Sydney criteria). Bleeding events were reviewed up to 43 years and classified according to the ISTH definitions into 2 groups: 1) major bleedings and 2) nonmajor bleedings (minor bleedings and clinically relevant nonmajor bleedings). Damage events were recorded as bleeding events a) resulting in permanent (>6 months) decrease in organ function and b) complicated by total/partial organ resection. Results: Among 197 patients (2412 patient-years [PYs] of follow-up), all of whom had been exposed to antithrombotic therapy, 40.6% experienced 167 bleedings (6.9 events per 100 PYs), of whom 61.3% had nonmajor bleedings (77.2% of bleedings: 42.6% minor, 57.4% clinically relevant nonmajor) and 38.8% had major bleedings (22.8% of bleedings; 1.6 events per 100 PYs). Soft/connective tissue was affected in 44.3% of bleedings, and 94.6% were nonmajor bleedings. Central nervous system was affected in 20.9% of bleedings, and 62.9% were major bleedings. Bleeding events were spontaneous in 90.4% of cases, and thrombocytopenia was likely involved in 62.2% of bleedings. Damage occurred in 11.4% of bleedings and affected 7.6% of patients. Most of the damage was associated with central nervous system events (8.4% of all bleedings). Conclusion: Approximately 40% of patients experienced at least 1 bleeding, and almost 8% of patients were left with organ damage not recognized by the current version of the Damage Index for Antiphospholipid Syndrome.

Management and treatment of children, young people and adults with systemic lupus erythematosus: British Society for Rheumatology guideline scope.

The objective of this guideline is to provide up-to-date, evidence-based recommendations for the management of SLE that builds upon the existing treatment guideline for adults living with SLE published in 2017. This will incorporate advances in the assessment, diagnosis, monitoring, non-pharmacological and pharmacological management of SLE. General approaches to management as well as organ-specific treatment, including lupus nephritis and cutaneous lupus, will be covered. This will be the first guideline in SLE using a whole life course approach from childhood through adolescence and adulthood. The guideline will be developed with people with SLE as an important target audience in addition to healthcare professionals. It will include guidance related to emerging approved therapies and account for National Institute for Health and Care Excellence Technology Appraisals, National Health Service England clinical commissioning policies and national guidance relevant to SLE. The guideline will be developed using the methods and rigorous processes outlined in 'Creating Clinical Guidelines: Our Protocol' by the British Society for Rheumatology.

Promising Experimental Treatments for Lupus Nephritis: Key Talking Points and Potential Opportunities.

Lupus nephritis (LN) is a frequent and serious complication of systemic lupus erythematosus (SLE), impairing patients' quality of life and significantly increasing mortality. Despite optimizing the use of conventional immunosuppressants and other biological drugs, its management remains unsatisfactory. This is mainly due to the heterogeneity of SLE, but also to insufficiently effective treatment regimens and clinical trial limitations (strict criteria, low number of patients included, and side effects). Most clinical trials of new biological therapies have failed to meet their primary endpoints in both general SLE and LN, with only two biological drugs (belimumab and anifrolumab) being approved by the Food and Drug Administration (FDA) for the treatment of SLE. Recently, several Phase II randomized controlled trials have evaluated the efficacy and safety of new biologics in LN, and some of them have demonstrated an improvement in clinical and laboratory measures. Multi-target therapies are also being successfully developed and encourage a belief that there will be an improvement in LN outcomes.

Predictors of British Isles Lupus Assessment Group-based outcomes in patients with systemic lupus erythematosus: Analysis from the Systemic Lupus International Collaborating Clinics Inception Cohort.

BACKGROUND: We aimed to identify factors associated with a significant reduction in SLE disease activity over 12 months assessed by the BILAG Index. METHODS: In an international SLE cohort, we studied patients from their 'inception enrolment' visit. We also defined an 'active disease' cohort of patients who had active disease similar to that needed for enrolment into clinical trials. Outcomes at 12 months were; Major Clinical Response (MCR: reduction to classic BILAG C in all domains, steroid dose of ≤7.5 mg and SLEDAI ≤ 4) and 'Improvement' (reduction to ≤1B score in previously active organs; no new BILAG A/B; stable or reduced steroid dose; no increase in SLEDAI). Univariate and multivariate logistic regression with Least Absolute Shrinkage and Selection Operator (LASSO) and cross-validation in randomly split samples were used to build prediction models. RESULTS: 'Inception enrolment' (n = 1492) and 'active disease' (n = 924) patients were studied. Models for MCR performed well (ROC AUC = .777 and .732 in the inception enrolment and active disease cohorts, respectively). Models for Improvement performed poorly (ROC AUC = .574 in the active disease cohort). MCR in both cohorts was associated with anti-malarial use and inversely associated with active disease at baseline (BILAG or SLEDAI) scores, BILAG haematological A/B scores, higher steroid dose and immunosuppressive use. CONCLUSION: Baseline predictors of response in SLE can help identify patients in clinic who are less likely to respond to standard therapy. They are also important as stratification factors when designing clinical trials in order to better standardize overall usual care response rates.

Association Between Severe Nonadherence to Hydroxychloroquine and Systemic Lupus Erythematosus Flares, Damage, and Mortality in 660 Patients From the SLICC Inception Cohort.

OBJECTIVE: The goals of this study were to assess the associations of severe nonadherence to hydroxychloroquine (HCQ), objectively assessed by HCQ serum levels, and risks of systemic lupus erythematosus (SLE) flares, damage, and mortality rates over five years of follow-up. METHODS: The Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort is an international multicenter initiative (33 centers throughout 11 countries). The serum of patients prescribed HCQ for at least three months at enrollment were analyzed. Severe nonadherence was defined by a serum HCQ level <106 ng/mL or <53 ng/mL for HCQ doses of 400 or 200 mg/day, respectively. Associations with the risk of a flare (defined as a Systemic Lupus Erythematosus Disease Activity Index 2000 increase ≥4 points, initiation of prednisone or immunosuppressive drugs, or new renal involvement) were studied with logistic regression, and associations with damage (first SLICC/American College of Rheumatology Damage Index [SDI] increase ≥1 point) and mortality with separate Cox proportional hazard models. RESULTS: Of the 1,849 cohort participants, 660 patients (88% women) were included. Median (interquartile range) serum HCQ was 388 ng/mL (244-566); 48 patients (7.3%) had severe HCQ nonadherence. No covariates were clearly associated with severe nonadherence, which was, however, independently associated with both flare (odds ratio 3.38; 95% confidence interval [CI] 1.80-6.42) and an increase in the SDI within each of the first three years (hazard ratio [HR] 1.92 at three years; 95% CI 1.05-3.50). Eleven patients died within five years, including 3 with severe nonadherence (crude HR 5.41; 95% CI 1.43-20.39). CONCLUSION: Severe nonadherence was independently associated with the risks of an SLE flare in the following year, early damage, and five-year mortality.

Survey on antiphospholipid syndrome diagnosis and antithrombotic treatment in patients with ischemic stroke, other brain ischemic injury, or arterial thromboembolism in other sites: communication from ISTH SSC Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibodies.

BACKGROUND: The optimal strategy for diagnosis and antithrombotic treatment of patients with antiphospholipid syndrome (APS)-associated acute ischemic stroke (AIS), transient ischemic attack (TIA), or other brain ischemic injury is poorly defined. OBJECTIVES: The survey goal was to capture variations in diagnosis and antithrombotic treatment of APS-associated ischemic stroke and related disorders to inform guidance and clinical trials to define optimal management. METHODS: Professional colleagues, including key opinion leaders, were invited to complete a REDCap survey questionnaire initiated by the International Society on Thrombosis and Haemostasis Scientific and Standardisation Committee Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibodies. The survey data were tallied using simple descriptive statistics. RESULTS: There was generally good agreement on several aspects, including which patients to test for antiphospholipid antibodies (aPL), use of a lifelong vitamin K antagonist for AIS or recurrent TIA, and formal cognitive assessment for suspected cognitive impairment. There was less agreement on other aspects, including aPL testing for brain ischemic injury other than AIS/TIA or if an alternative cause for AIS or TIA exists; choice of aPL tests, their timing, and age cutoff; the aPL phenotype to trigger antithrombotic treatment; management for patent foramen ovale; antithrombotic treatment for first TIA or white matter hyperintensities; head magnetic resonance imaging specifications; and low-molecular-weight heparin dosing/anti-Xa monitoring in pregnancy. The survey highlighted that approximately 25% practice at dedicated APS clinics and <50% have a multidisciplinary team structure for patients with APS. CONCLUSION: Much of the variation in practice reflects the lack of evidence-based recommendations. The survey results should inform the development of a more uniform multidisciplinary consensus approach to diagnosis and antithrombotic treatment.

Approach to vaccination in systemic lupus erythematosus on biological treatment.

In recent years, treat-to-target strategy and early intervention strategies with immunosuppressive agents have attempted to improve the prognosis and outcome in patients with autoimmune inflammatory rheumatic diseases. However, infectious complications due to side effects of medication remain a major concern in routine practice. In this regard, vaccine immunity and vaccination programmes are of the utmost importance in patients with systemic lupus erythematosus (SLE) in terms of morbidity and mortality. Encouragingly, research investigations have increased exponentially, both in monitoring the vaccines efficacy, and in determining the immune response while patients are on immunosuppression., However, in this biological era in rheumatology, relatively little data have been published investigating these parameters in those receiving biological agents, therefore, no definitive consensus about a vaccination policy for patients with SLE is currently available. In this review, we aim to address what is established about vaccinating patients with SLE on biological agents and discuss potential problems.

Targeted Therapy for SLE-What Works, What Doesn't, What's Next.

For many years, the failure of randomized controlled trials (RCTs) has prevented patients with systemic lupus erythematosus (SLE) from benefiting from biological drugs that have proved to be effective in other rheumatological diseases. Only two biologics are approved for SLE, however they can only be administered to a restricted proportion of patients. Recently, several phase II RCTs have evaluated the efficacy and safety of new biologics in extra-renal SLE and lupus nephritis. Six drug trials have reported encouraging results, with an improvement in multiple clinical and serological outcome measures. The possibility of combining B-cell depletion and anti-BLyS treatment has also been successfully explored.