Depressed serum IgM levels in SLE are restricted to defined subgroups

Grönwall, Caroline; Hardt, Uta; Gustafsson, Johanna; Elvin, Kerstin; Jensen‐Urstad, Kerstin; Kvarnström, Marika; Grosso, Giorgia; Rönnelid, Johan; Padykov, Leonid; Gunnarsson, Iva; Silverman, Gregg J.; Svenungsson, Elisabet

doi:10.1016/j.clim.2017.09.013

Cited by 20 publications

(13 citation statements)

References 62 publications

(92 reference statements)

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“…To shed light on the heterogeneity of SLE we built on previous observations [8, 9], we designed a simple and clinically useful subgroup definition based on autoantibody profiles. The SSA/SSB+ group was characterized by elevated levels of IgG and depressed levels of IgM, in line with a recent report from our group [22], and lower frequency of nephritis (21% vs. 48%). Others and we have previously noted that SSA/SSB antibodies are associated with a less severe SLE, with less renal manifestations and reduced risk for cardiovascular disease and mortality [7, 23, 24].…”

Section: Discussionsupporting

confidence: 91%

Two subgroups in systemic lupus erythematosus with features of antiphospholipid or Sjögren’s syndrome differ in molecular signatures and treatment perspectives

et al. 2019

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Background Previous studies and own clinical observations of patients with systemic lupus erythematosus (SLE) suggest that SLE harbors distinct immunophenotypes. This heterogeneity might result in differences in response to treatment in different subgroups and obstruct clinical trials. Our aim was to understand how SLE subgroups may differ regarding underlying pathophysiology and characteristic biomarkers. Methods In a cross-sectional study, including 378 well-characterized SLE patients and 316 individually matched population controls, we defined subgroups based on the patients’ autoantibody profile at inclusion. We selected a core of an antiphospholipid syndrome-like SLE (aPL+ group; positive in the lupus anticoagulant (LA) test and negative for all three of SSA (Ro52 and Ro60) and SSB antibodies) and a Sjögren’s syndrome-like SLE (SSA/SSB+ group; positive for all three of SSA (Ro52 and Ro60) and SSB antibodies but negative in the LA test). We applied affinity-based proteomics, targeting 281 proteins, together with well-established clinical biomarkers and complementary immunoassays to explore the difference between the two predefined SLE subgroups. Results The aPL+ group comprised 66 and the SSA/SSB+ group 63 patients. The protein with the highest prediction power (receiver operating characteristic (ROC) area under the curve = 0.89) for separating the aPL+ and SSA/SSB+ SLE subgroups was integrin beta-1 (ITGB1), with higher levels present in the SSA/SSB+ subgroup. Proteins with the lowest p values comparing the two SLE subgroups were ITGB1, SLC13A3, and CERS5. These three proteins, rheumatoid factor, and immunoglobulin G (IgG) were all increased in the SSA/SSB+ subgroup. This subgroup was also characterized by a possible activation of the interferon system as measured by high KRT7, TYK2, and ETV7 in plasma. In the aPL+ subgroup, complement activation was more pronounced together with several biomarkers associated with systemic inflammation (fibrinogen, α-1 antitrypsin, neutrophils, and triglycerides). Conclusions Our observations indicate underlying pathogenic differences between the SSA/SSB+ and the aPL+ SLE subgroups, suggesting that the SSA/SSB+ subgroup may benefit from IFN-blocking therapies while the aPL+ subgroup is more likely to have an effect from drugs targeting the complement system. Stratifying SLE patients based on an autoantibody profile could be a way forward to understand underlying pathophysiology and to improve selection of patients for clinical trials of targeted treatments. Electronic supplementary material The online version of this article (10.1186/s13075-019-1836-8) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 91%

Two subgroups in systemic lupus erythematosus with features of antiphospholipid or Sjögren’s syndrome differ in molecular signatures and treatment perspectives

et al. 2019

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“…(12,16) We observed that the prevalence of oral and ocular dryness was more pronounced in patients who are positive for each and all three SSA/Ro52 and Ro60 and SSB/La antibodies. Our study thus supports the presence of an autoantibody cluster related to the SLE-sSS subset (10,11,29).…”

Section: Accepted Articlesupporting

confidence: 87%

“…(28) Furthermore, hypergammaglobulinemia, a well-known feature of SS (29) was in our study consequently more common among SLE-sSS patients, although the levels of IgG were usually below 20 mg/ml. We previously reported that low total IgM levels were associated with an SSA/SSB positive profile in SLE (29), but using the AECC IgM levels were similar in SLE-sSS and SLE-nonsSS subgroups.…”

Section: Discussionmentioning

confidence: 81%

Sjögren Syndrome in Systemic Lupus Erythematosus: A Subset Characterized by a Systemic Inflammatory State

Ruacho

Kvarnström

Zickert³

et al. 2019

J Rheumatol

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Objective.An often-neglected subset of patients with systemic lupus erythematosus (SLE) is those with secondary Sjögren syndrome (SLE-sSS). Further, primary SS overlaps and can be difficult to delineate from SLE. To shed light on the SLE-sSS subset, we investigated a large and well-characterized SLE cohort, comparing patients with SLE-sSS and SLE patients without SS (SLE-nonsSS) and controls.Methods.We included 504 consecutive patients with SLE, fulfilling the 1982 revised American College of Rheumatology criteria, and 319 controls from the general population, matched for age and sex to the first 319 patients. SLE-sSS was defined according to the American-European Consensus Criteria (AECC). A thorough clinical examination, including subjective and objective quantifications of sicca symptoms, was performed in all participants. Autoantibodies and 20 selected cytokines were measured by luminex and multiplex analysis, respectively.Results.SLE-sSS, as defined by AECC, occurred in 23% of the patients with SLE. In comparison to SLE-nonsSS, the SLE-sSS group was older and more frequently female. Leukopenia and peripheral neuropathy were more frequent and nephritis less frequent. Circulating levels of 6/20 investigated proinflammatory cytokines [tumor necrosis factor-α, interleukin (IL) 6, monocyte chemoattractant protein 4, macrophage inflammatory protein 1β, IL-12/IL-23p40, and interferon γ–induced protein 10], total IgG, anti-SSA/Ro52, anti-SSA/Ro60, anti-SSB/La antibodies, and rheumatoid factor (IgM and IgA) were higher in the SLE-sSS group (p < 0.05 for all comparisons).Conclusion.The frequency of SLE-sSS increased with age and affected roughly one-quarter of all patients with SLE. Despite less internal organ involvement, a systemic inflammatory state with high levels of proinflammatory cytokines is present in the SLE-sSS subgroup. This is a novel observation that may affect future understanding and treatment of the SLE-sSS subset.

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“…Interestingly, the high anti-MDA patients were found to be more likely to have an antiphospholipid syndrome (APS) autoantibody profile (OR = 1.96; p = 0.02) and a history of cardiovascular events (OR = 1.74; p = 0.03). We have previously reported that patients with APS autoantibody profile that includes anti-CL/ β 2 GPI represent a distinct lupus subgroup associated with HLA DRB1 *04 and higher natural IgM levels [ 32 ]. IgG anti-MDA-positive patients also displayed lower frequency of skin manifestations and photosensitivity.…”

Section: Resultsmentioning

confidence: 99%

Autoimmune reactivity to malondialdehyde adducts in systemic lupus erythematosus is associated with disease activity and nephritis

et al. 2018

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BackgroundImmunoglobulin M (IgM) autoreactivity to malondialdehyde (MDA) protein modifications is part of the natural antibody repertoire in health and may have beneficial functions. In contrast, IgG anti-MDA are increased in chronic inflammation and autoimmunity and may instead have pathogenic properties.MethodsHerein, we investigated serum IgG anti-MDA levels by enzyme-linked immunosorbent assay (ELISA) in 398 systemic lupus erythematosus (SLE) patients in the Swedish Karolinska SLE cohort and compared these to findings in 225 US SLE patients from New York University and Johns Hopkins University.ResultsIn two independent cohorts, IgG anti-MDA levels correlated positively with disease activity by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI; p < 0.0001, Spearman R = 0.3). Meta-analysis found an odds ratio of 2.7 (confidence interval (CI) 1.9–3.9; p < 0.0001) for high anti-MDA IgG levels with active disease (SLEDAI ≥ 6). Furthermore, IgG anti-MDA correlated directly with erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), soluble tumor necrosis factor receptors (sTNFR-1, sTNFR-2), and vascular cell adhesion molecule 1 (VCAM-1) measurements, and inversely with complement factors (C1q, C2, C3, C4). Importantly, IgG anti-MDA levels were significantly elevated in SLE patients with active nephritis (p = 0.0005) and correlated with cystatin C estimated glomerular filtration rate and albuminuria.ConclusionsElevated IgG anti-MDA in SLE patients was associated with high disease activity, with active lupus nephritis, and with biomarkers of systemic inflammation. This natural antibody reactivity may have potential prognostic utility, and may also actively contribute to pathogenesis.Electronic supplementary materialThe online version of this article (10.1186/s13075-018-1530-2) contains supplementary material, which is available to authorized users.

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Depressed serum IgM levels in SLE are restricted to defined subgroups

Cited by 20 publications

References 62 publications

Two subgroups in systemic lupus erythematosus with features of antiphospholipid or Sjögren’s syndrome differ in molecular signatures and treatment perspectives

Two subgroups in systemic lupus erythematosus with features of antiphospholipid or Sjögren’s syndrome differ in molecular signatures and treatment perspectives

Sjögren Syndrome in Systemic Lupus Erythematosus: A Subset Characterized by a Systemic Inflammatory State

Autoimmune reactivity to malondialdehyde adducts in systemic lupus erythematosus is associated with disease activity and nephritis

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