Hydroxychloroquine Suppresses Interferon-inducible Genes and B Cell Activating Factor in Patients With Incomplete and New-onset Systemic Lupus Erythematosus

OBJECTIVE: Hydroxychloroquine (HCQ) is commonly used as first-line treatment for systemic lupus erythematosus (SLE). Interferon (IFN)-inducible gene expression, IFN-γ-induced protein 10 (IP-10) and B cell activating factor (BAFF) are early mediators in SLE. The purpose of this study was to analyze the effects of HCQ on these factors. METHODS: Patients with incomplete SLE (iSLE; antinuclear antibody titer ≥ 1:80, symptoms < 5 years, ≥ 1 objectified clinical American College of Rheumatology or SLE International Collaborating Clinics criteria), or new-onset, mild SLE were included when HCQ treatment was started for clinical reasons. Blood samples were taken at start and after 16 weeks. Three SLE-related IFN-inducible genes were measured in whole blood by real-time PCR, and an IFN score was calculated. Serum levels of IP-10 and BAFF were measured using ELISA. RESULTS: In total, 9 patients were included: 7 with iSLE and 2 with new-onset SLE. The median SLE Disease Activity Index (SLEDAI) was 4. After 16 weeks of treatment with HCQ, the expression of IFN-inducible genes decreased in 8 of 9 patients, and the IFN-3 score decreased significantly (P = 0.012). There was a trend towards lower IP-10 levels (P = 0.055), and a significant decrease in BAFF levels (P = 0.023). CONCLUSION: HCQ suppresses IFN score and BAFF levels in patients with iSLE or new-onset SLE, and there is a trend towards lowering IP-10 levels. As these biomarkers are early mediators in SLE, this might support the hypothesis that HCQ could influence disease progression. However, prospective research with a larger sample size and longer follow-up is needed

From incomplete to complete systemic lupus erythematosus; A review of the predictive serological immune markers

Systemic lupus erythematosus (SLE) is a complex and heterogeneous autoimmune disease. A main challenge faced by clinicians is early identification of SLE, frequently resulting in diagnostic delay. Timely treatment, however, is important to limit disease progression, and prevent organ damage and mortality. Often, patients present with clinical symptoms and immunologic abnormalities suggestive of SLE, while not meeting classification criteria yet. This is referred to as incomplete SLE (iSLE). However, not all these patients will develop SLE. Therefore, there is need for predictive biomarkers that can distinguish patients at high risk of developing SLE, in order to allow early treatment. This article reviews the current literature on immunological changes in patients with stages preceding SLE, focusing on autoantibodies, type-I and -II interferons, and the complement system. We also provide an overview of possible predictive markers for progression to SLE that are applicable in daily clinical practice

Incomplete Systemic Lupus Erythematosus:What Remains After Application of American College of Rheumatology and Systemic Lupus International Collaborating Clinics criteria?

Incomplete systemic lupus (iSLE) is an acknowledged condition of patients with clinical signs of lupus who do not fulfill classification criteria for SLE. Some patients with iSLE have persistent mild disease, but others have serious organ involvement, and up to 55% progress to established SLE. Research on this subject could reveal predictive or diagnostic biomarkers for SLE. Ideally, it would become possible to discern those patients with critical organ involvement or a high risk for progression to SLE. This high-risk group might benefit from early treatment, which would preferably be confirmed in randomized controlled trials. This process would, however, require agreement on a definition of iSLE. The Systemic Lupus International Collaborating Clinics (SLICC) classification criteria was composed in order to diagnose SLE earlier. The present review outlines the clinical characteristics of iSLE after introduction of SLICC criteria and furthermore proposes a definition of iSLE with the aim of discriminating the high-risk group from those with a lower risk

Interferon score is increased in incomplete systemic lupus erythematosus and correlates with myxovirus-resistance protein A in blood and skin

OBJECTIVES: Patients with incomplete systemic lupus erythematosus (iSLE) have lupus features, but do not meet classification criteria for SLE. Type I interferons (IFN) are important early mediators in SLE, and IFN upregulation in incomplete SLE may be associated with progression to SLE. Since many patients present with skin symptoms, the aim of this study is to investigate IFN type I expression and IFN-related mediators in the blood and skin of iSLE patients.METHODS: Twenty-nine iSLE patients (ANA titer ≥ 1:80, symptoms &lt; 5 years, ≥ 1 objectified clinical criterion), 39 SLE patients with quiescent disease (fulfilling ACR or SLICC criteria, SLEDAI ≤4), and 22 healthy controls were included. IFN signature was measured in whole blood, based on 12 IFN-related genes, using RT-PCR, and IFN-score was calculated. IFN-related mediators myxovirus-resistance protein A (MxA), IFN-γ-induced protein 10 (IP-10), and monocyte chemoattractant protein (MCP-1) were measured using ELISA. IFN type I expression in the unaffected skin was analyzed by immunostaining with MxA.RESULTS: IFN-score was increased in 50% of iSLE patients and 46% of SLE patients and correlated positively with the number of autoantibodies, anti-SSA titer, ESR, and IgG and negatively with C4 in iSLE. Levels of MxA correlated strongly with IFN-score (r = 0.78, p &lt; 0.0001). Furthermore, MxA expression was found in 29% of unaffected skin biopsies of iSLE and 31% of SLE patients and also correlated with IFN-score (r = 0.54, p &lt; 0.0001).CONCLUSIONS: IFN-score was increased in half of the iSLE patients, and given the correlation with complement and autoantibody diversity, this suggests a higher risk for disease progression. MxA in the blood and unaffected skin correlated strongly with the IFN-score and is possibly an easily applicable marker for IFN upregulation.</p

Proportions of B-cell subsets are altered in incomplete systemic lupus erythematosus and correlate with interferon score and IgG levels

OBJECTIVES: Incomplete SLE (iSLE) patients display symptoms typical for SLE but have insufficient criteria to fulfil the diagnosis. Biomarkers are needed to identify iSLE patients that will progress to SLE. IFN type I activation, B-cell-activating factor (BAFF) and B-cell subset distortions play an important role in the pathogenesis of SLE. The aim of this cross-sectional study was to investigate whether B-cell subsets are altered in iSLE patients, and whether these alterations correlate with IFN scores and BAFF levels. METHODS: iSLE patients (n = 34), SLE patients (n = 41) with quiescent disease (SLEDAI ≤4) and healthy controls (n = 22) were included. Proportions of B-cell subsets were measured with flow cytometry, IFN scores with RT-PCR and BAFF levels with ELISA. RESULTS: Proportions of age-associated B-cells were elevated in iSLE patients compared with healthy controls and correlated with IgG levels. In iSLE patients, IFN scores and BAFF levels were significantly increased compared with healthy controls. Also, IFN scores correlated with proportions of switched memory B-cells, plasma cells and IgG levels, and correlated negatively with complement levels in iSLE patients. CONCLUSION: In this cross-sectional study, distortions in B-cell subsets were observed in iSLE patients and were correlated with IFN scores and IgG levels. Since these factors play an important role in the pathogenesis of SLE, iSLE patients with these distortions, high IFN scores, and high levels of IgG and BAFF may be at risk for progression to SLE

Response to: "A combination of complement activation products with autoantibodies predicts transition of probable lupus to systemic lupus erythematosus":comment on the article by Lambers et al Reply

We thank Dr Alexander and Dr Weinstein for their response to our review.1 We welcome the attempt to develop a diagnostic test that can predict progression to systemic lupus erythematosus (SLE). Early identification of SLE is one of the main challenges faced by clinicians, and is hindered by both the heterogeneous presenting symptoms of the disease, as well as overlap with other diseases.2,3 Timely treatment, however, is important in order to limit disease progression, and prevent organ damage and mortality.4