Development of Autoantibodies before the Clinical Onset of Systemic Lupus Erythematosus

Arbuckle, Melissa R.; McClain, Micah T.; Rubertone, Mark V.; Scofield, R. Hal; Dennis, Glynn; James, Judith A.; Harley, John B.

doi:10.1056/nejmoa021933

Cited by 2,155 publications

(1,649 citation statements)

References 24 publications

Supporting

Mentioning

1,535

Contrasting

Unclassified

Order By: Relevance

“…Over 100 autoantibody targets are associated with SLE, and antinuclear antibodies are present in more than 95% of patients. Autoantibodies can be present years before the onset of clinical symptoms 17. Transfer of human autoantibodies from patients with SLE can cause glomerulonephritis and proteinuria in murine experimental systems,18, 19 emphasizing that they can be pathogenic.…”

Section: Slementioning

confidence: 99%

See 1 more Smart Citation

Antibody repertoire analysis in polygenic autoimmune diseases

2018

View full text Add to dashboard Cite

SummaryHigh‐throughput sequencing of the DNA/RNA encoding antibody heavy‐ and light‐chains is rapidly transforming the field of adaptive immunity. It can address key questions, including: (i) how the B‐cell repertoire differs in health and disease; and (ii) if it does differ, the point(s) in B‐cell development at which this occurs. The advent of technologies, such as whole‐genome sequencing, offers the chance to link abnormalities in the B‐cell antibody repertoire to specific genomic variants and polymorphisms. Here, we discuss the current research using B‐cell antibody repertoire sequencing in three polygenic autoimmune diseases where there is good evidence for a pathological role for B‐cells, namely systemic lupus erythematosus, multiple sclerosis and rheumatoid arthritis. These autoimmune diseases exhibit significantly skewed B‐cell receptor repertoires compared with healthy controls. Interestingly, some common repertoire defects are shared between diseases, such as elevated IGHV4‐34 gene usage. B‐cell clones have effectively been characterized and tracked between different tissues and blood in autoimmune disease. It has been hypothesized that these differences may signify differences in B‐cell tolerance; however, the mechanisms and implications of these defects are not clear.

show abstract

Section: Slementioning

confidence: 99%

“…This has been observed in multiple studies, suggesting differences in B‐cell selection and antigen‐specific B‐cell clonal expansion. All the BCR sequencing studies to date have shown an enrichment of IGHV4 gene family usages,17, 23, 35, 36 specifically IGHV4‐34 17, 36. IGHV4‐34 was the dominant serum autoantibody IGHV gene 17.…”

Section: Slementioning

confidence: 99%

Antibody repertoire analysis in polygenic autoimmune diseases

2018

View full text Add to dashboard Cite

show abstract

“…B cell hyperactivity, characteristic of SLE, results in excessive production of both polyclonal and autoreactive antibodies 19, even before the onset of clinical disease 20, 21, 22. Elevated levels of IgG anti–double‐stranded DNA (anti‐dsDNA) antibodies are characteristic of SLE and considered pathogenic, but may occur independently of hypergammaglobulinemia 23, 24.…”

Section: Introductionmentioning

confidence: 99%

Pragmatic Treatment of Patients With Systemic Lupus Erythematosus With Rituximab: Long‐Term Effects on Serum Immunoglobulins

Reddy

Martinez

Isenberg

et al. 2017

Arthritis Care & Research

View full text Add to dashboard Cite

ObjectiveB cell–depletion therapy based on rituximab is a therapeutic option for refractory disease in patients with systemic lupus erythematosus (SLE). The aim of this observational study was to document long‐term effects on B cell function by following serum immunoglobulin levels in patients with SLE treated with rituximab in routine clinical practice.MethodsWe included 57 consecutive patients with SLE treated with rituximab and concomitant/sequential immunosuppressants and measured serum total IgG, IgM, and IgA and IgG anti‐dsDNA antibodies, over a median of 48 months most recent followup. Flow cytometry was used prospectively to assess B cell phenotypes in 17 of 57 patients.ResultsTwelve patients (21%) had persistent IgM hypogammaglobulinemia (<0.4 gm/liter), and 4 of 57 (5%) had low IgG (<7 gm/liter) at the most recent followup (range 12–144 months). This was not associated with serious adverse events or high anti–double‐stranded DNA (anti‐dsDNA) antibodies (>1,000 IU/ml; normal <50 IU/ml). Factors predictive of low serum IgM included baseline serum IgM ≤0.8 gm/liter (receiver operator curve analysis) and subsequent therapy with mycophenolate mofetil (MMF; odds ratio 6.8, compared with other immunosuppressants). In patients maintaining normal IgM levels (9 of 17), the frequency of circulating IgD+CD27+ B cells was significantly higher (P = 0.05). At 12 months after rituximab, 7 of 30 SLE patients with baseline anti‐dsDNA ≤1,000 IU/ml had lost seropositivity.ConclusionLower baseline serum IgM levels and sequential therapy with MMF were predictive of IgM hypogammaglobulinemia after rituximab in SLE, but this was not associated with higher levels of anti‐dsDNA antibodies or an increased risk of infections. This provides useful directions for clinicians regarding rituximab and sequential immunosuppressive treatment for patients with SLE.

show abstract

“…Whether systemic immune alterations pre‐dating disease have an effect on pregnancy is not known. Autoantibodies associated with SLE, including antiphospholipid antibodies and SSA, both of which are known to be associated with pregnancy morbidity, are present up to 5 years before the clinical diagnosis of SLE 4, 5, 6. Furthermore, as the clinical diagnosis nears, the levels of many of these autoantibodies increase 4.…”

Section: Introductionmentioning

confidence: 99%

“…Autoantibodies associated with SLE, including antiphospholipid antibodies and SSA, both of which are known to be associated with pregnancy morbidity, are present up to 5 years before the clinical diagnosis of SLE 4, 5, 6. Furthermore, as the clinical diagnosis nears, the levels of many of these autoantibodies increase 4. These autoantibodies may directly impact the maternal immune system during pregnancy or may be manifestations of immune dysregulation, potentially even in a pre‐SLE state.…”

Section: Introductionmentioning

confidence: 99%

What to Expect When Expecting With Systemic Lupus Erythematosus (SLE): A Population‐Based Study of Maternal and Fetal Outcomes in SLE and Pre‐SLE

Arkema

Palmsten

Sjöwall

et al. 2016

Arthritis Care & Research

View full text Add to dashboard Cite

ObjectiveTo assess maternal and fetal outcomes associated with subclinical (pre‐systemic lupus erythematosus [SLE] and SLE presenting up to 5 years postpartum) and prevalent maternal SLE during pregnancy compared with the general population.MethodsThis prospective cohort study used population‐based Swedish registers to identify 13,598 women with first singleton pregnancies registered in the Medical Birth Register (551 prevalent SLE, 65 pre‐SLE within 0–2 years, 133 pre‐SLE within 2–5 years, and 12,847 general population). SLE was defined as ≥2 SLE‐coded discharge diagnoses in the patient register with ≥1 diagnosis from a specialist. Unadjusted risks of adverse pregnancy or birth outcomes were calculated by SLE status, and Cochran‐Armitage tests evaluated trend across exposure groups.ResultsMaternal outcomes such as preeclampsia, hypothyroidism, stroke, and infection were more common among women with SLE. Sixteen percent of prevalent‐SLE pregnancies were diagnosed with preeclampsia compared with 5% of those from the general population. Among the pre‐SLE women, preeclampsia was found in 26% of those with SLE within 2 years postpartum and 13% in those with SLE within 2–5 years postpartum. Similarly, infant outcomes, such as preterm birth, infection, and mortality, were worse among those born to mothers with prevalent SLE and pre‐SLE during pregnancy. The test for trend was significant for most outcomes.ConclusionOur data demonstrate that adverse maternal and fetal outcomes are more common in SLE pregnancies. Furthermore, these unfavorable outcomes are observed in pregnancies occurring prior to the diagnosis of SLE. Thus, the underlying immunologic profile of SLE and alterations preceding clinical SLE may contribute to these pregnancy complications.

show abstract

Development of Autoantibodies before the Clinical Onset of Systemic Lupus Erythematosus

Cited by 2,155 publications

References 24 publications

Antibody repertoire analysis in polygenic autoimmune diseases

Antibody repertoire analysis in polygenic autoimmune diseases

Pragmatic Treatment of Patients With Systemic Lupus Erythematosus With Rituximab: Long‐Term Effects on Serum Immunoglobulins

What to Expect When Expecting With Systemic Lupus Erythematosus (SLE): A Population‐Based Study of Maternal and Fetal Outcomes in SLE and Pre‐SLE

Contact Info

Product

Resources

About