TLR3 mediates skin solar injury by binding nuclear material released from apoptotic keratinocytes, resulting in the production of pro-inflammatory cytokines. Because the TLR3 gene is located in 4q35, a known systemic lupus erythematosus (SLE) susceptibility locus, we wondered whether TLR3 single nucleotide polymorphisms (SNPs) were associated with inflammatory mechanisms relevant to the development of SLE, and disease susceptibility.Functional assays were carried out in TLR3-transfected HEK293 cells and in monocyte-derived dendritic cells (moDCs). TLR3 and IFNβ immunofluorescence studies were performed in skin samples from 7 SLE patients and 3 controls. We performed a SNP association study in a discovery cohort of 153 patients and 105 controls, followed by a confirmation study in an independent cohort of 1,380 patients and 2,104 controls.TLR3 and IFNβ are overexpressed in SLE skin lesions. TLR3 overexpression in HEK293 cells amplifies their sensitivity to a pro-apoptotic stimulus. Taking advantage of a naturally occurring polymorphic TLR3 variant (rs3775291) that weakly versus strongly responds to poly I:C stimulation, we found that TLR3 is associated with amplified apoptotic responses, production of the Ro/SSA autoantigen and increased maturation of myeloid-derived dendritic cells (moDC) after exposure to UV irradiation. However, TLR3 SNPs are not associated with susceptibility to SLE in a large population of patients and controls.TLR3 is overexpressed in SLE skin lesions and amplifies apoptotic and inflammatory responses to UV-irradiation in antigen-presenting cells in vitro. However, TLR3 SNPs do not impact susceptibility to the development of the disease.
Rituximab (RTX) is a biological treatment used off-label in patients with systemic lupus erythematosus (SLE). This survey aimed to investigate the off-label use of RTX in Europe and compare the characteristics of patients receiving RTX with those receiving conventional therapy.Data on patients with SLE receiving RTX were taken from the International Registry for Biologics in SLE retrospective registry and complemented with data on patients with SLE treated with conventional therapy. For nationwide estimates of RTX use in patients with SLE, investigators were asked to provide data through case report forms (CRFs). Countries for which no data were submitted through CRFs, published literature and/or personal communication were used, and for European countries where no data were available, estimates were made on the assumption of similarities with neighbouring countries.The estimated off-label use of RTX in Europe was 0.5%-1.5% of all patients with SLE. In comparison with patients with SLE on conventional therapy, patients treated with RTX had longer disease duration, higher disease activity and were more often treated with immunosuppressives. The most frequent organ manifestations for which either RTX or conventional therapy was initiated were lupus nephritis followed by musculoskeletal and haematological. The reason for treatment was, besides disease control, corticosteroid-sparing for patients treated with conventional therapy.RTX use for SLE in Europe is restrictive and appears to be used as a last resort in patients for whom other reasonable options have been exhausted.
Despite the low prevalence of each rare disease, the total burden is high. Patients with rare diseases encounter numerous barriers, including delayed diagnosis and limited access to high-quality treatments. In order to tackle these challenges, the European Commission launched the European Reference Networks (ERNs), cross-border networks of healthcare providers and patients representatives. In parallel, the aims and structure of these ERNs were translated at the federal and regional levels, resulting in the creation of the Flemish Network of Rare Diseases. In line with the mission of the ERNs and to ensure equal access to care, we describe as first patient pathways for systemic sclerosis (SSc), as a pilot model for other rare connective and musculoskeletal diseases. Consensus was reached on following key messages: 1. Patients with SSc should have multidisciplinary clinical and investigational evaluations in a tertiary reference expert centre at baseline, and subsequently every three to 5 years. Intermediately, a yearly clinical evaluation should be provided in the reference centre, whilst SSc technical evaluations are permissionably executed in a centre that follows SSc-specific clinical practice guidelines. In between, monitoring can take place in secondary care units, under the condition that qualitative examinations and care including interactive multidisciplinary consultations can be provided. 2. Patients with early diffuse cutaneous SSc, (progressive) interstitial lung disease and/or pulmonary arterial hypertension should undergo regular evaluations in specialised tertiary care reference institutions. 3. Monitoring of patients with progressive interstitial lung disease and/or pulmonary (arterial) hypertension will be done in agreement with experts of ERN LUNG.
Objective: To update the follow-up of the Euro-Lupus Nephritis Trial (ELNT), a randomised prospective trial comparing low-dose (LD) and high-dose (HD) intravenous (IV) cyclophosphamide (CY) followed by azathioprine (AZA) as treatment for proliferative lupus nephritis. Patients and methods: Data for survival and kidney function were prospectively collected during a 10-year period for the 90 patients randomised in the ELNT, except in 6 lost to follow-up. Results: Death, sustained doubling of serum creatinine and end-stage renal disease rates did not differ between the LD and HD group (5/44 (11%) vs 2/46 (4%), 6/44 (14%) vs 5/46 (11%) and 2/44 (5%) vs 4/46 (9%), respectively) nor did mean serum creatinine, 24 h proteinuria and damage score at last follow-up. Most patients in both groups were still treated with glucocorticoids, other immunosuppressant agents and blood pressure lowering drugs. After 10 years of follow-up, the positive predictive value for a good outcome of an early drop in proteinuria in response to initial immunosuppressive therapy was confirmed. Conclusion: The data confirm that a LD IVCY regimen followed by AZA—the “Euro-Lupus regimen”—achieves good clinical results in the very long term.
Additional file 1. MRM transitions used for the selected proteins analysis. This table shows the selected proteins/peptides for validation and the instrumental parameters used for peptide monitoring. Peptides highlighted in bold were used as the quantitative reference whereas the remaining peptides were used as qualitative references.
Abstract NK cell populations were derived from murine splenocytes stimulated by IL-2, IL-15, or the combination of IL-12 and IL-18. Whereas NK cells derived with the latter cytokines consisted of an homogeneous population of NK cells (DX5+CD3−), those derived with IL-2 or IL-15 belonged to two different populations, namely NK cells (DX5+CD3−) and T-NK cells (DX5+CD3+). Among NK cells, only those derived with IL-12/IL-18 produced detectable levels of cytokines, namely IFN-γ, IL-10, and IL-13 (with the exception of IL-13 production by NK cells derived with IL-2). As for T-NK cells, IL-2-stimulated cells produced a wide range of cytokines, including IL-4, IL-5, IL-9, IL-10, and IL-13, but no IFN-γ, whereas IL-15-derived T-NK cells failed to produce any cytokine. Switch-culture experiments indicated that T-NK cells derived in IL-2 and further stimulated with IL-12/IL-18 produced IFN-γ and higher IL-13 levels. Next, we observed that NK/T-NK cell populations exerted distinct effects on Ig production by autologous splenocytes according to the cytokines with which they were derived. Thus, addition of NK cells derived in IL-12/IL-18 inhibited Ig production and induced strong cytotoxicity against splenocytes, whereas addition of NK or T-NK cells grown in IL-2 or IL-15 did not. Experiments performed in IFN-γR knockout mice demonstrated that IFN-γ was not involved in the killer activity of IL-12/IL-18-derived NK cells. The hypothesis that their cytotoxic activity was related to the induction of target apoptosis was confirmed on murine A20 lymphoma cells. Experiments performed in MRL/lpr mice indicated that IL-12/IL-18-derived NK cells displayed their distinct killer activity through a Fas-independent pathway. Finally, perforin was much more expressed in IL-12/IL-18-derived NK cells as compared with IL-2- or IL-15-derived NK cells, an observation that might explain their unique cytotoxicity.
Lupus nephritis (LN) affects about a third of patients with systemic lupus erythematosus. Although the use of conventional therapy has significantly improved the prognosis of LN, the response to treatment remains suboptimal, with high rates of relapse and the occurrence of end-stage kidney disease. The implementation of new diagnostic and treatment strategies aimed at improving these outcomes represents a necessary paradigm shift in the management of LN.Herein, we discuss different points of view regarding these still unresolved issues; these comments represent a debate that took place during the virtual congress of the Pan American League of Associations for Rheumatology (PANLAR) and which was organized by the PANLAR Lupus Study Group, GLADEL (Grupo Latino Americano De Estudio del Lupus) on August 15, 2021.
Interferon-α-kinoid (IFN-K) elicits a polyclonal antibody response against IFNα in humans. In a previously reported study, we found that administration of IFN-K to SLE patients induces significant changes in biological markers of disease activity (IFN signature score, serum C3), which correlate with the anti-IFNα antibody (Ab) response. In the present study, we wanted to further explore the connections between serum type I IFN concentrations, IFN signature score and disease activity in IFN-K-treated patients.
Methods
28 patients (SLEDAI between 4 and 10) were included in the IFN-K trial, and received IFN-K or placebo. Whole blood transcriptome (GeneChip HGU133Plus 2.0 chips) and serum IFNα, IFNβ and IFNω concentrations (ELISA) were determined at day 0, 112 and 168. Whole blood transcriptomic profiles were also obtained in 46 healthy individuals, and in 18 of them after stimulation with IFNα. The IFN signature score was calculated according to the method described by Yao et al.
Results
IFNα was detected in the serum of 10 out of 28 patients. IFNβ and IFNω were detected in 18 and 26 different patients, respectively. Serum IFNβ and IFNω concentrations displayed a strong correlation (r =0.88, p<0.0001), indicating that the production of both cytokines is regulated by the same mechanisms in SLE. By contrast, there was no correlation between serum IFNα and serum IFNβ or IFNω concentrations. Interestingly, a mucocutaneous BILAG A/B was more frequently reported at times of positive serum IFNβ detection (p =0.006 by Chi-Square test). There was a significant, albeit weak, correlation between serum IFNα and SLEDAI scores (Spearman r =0.26, p =0.02). Strikingly, the IFN signature score displayed a strong and significant correlation with serum IFNα concentrations (Spearman r =0.54, p <0.0001), but not with serum IFNβ or IFNω. Out of the 54.675 probe sets analyzed in the whole blood transcriptomic studies, 349 correlated (r >0.4) with serum IFNα (including 19 out of the 21 probe sets included in the IFN signature score). By contrast, only 7 and 11 probe sets correlated with serum IFNβ and IFNω respectively. We finally calculated an IFNα score including probe sets up-regulated by IFNα in control whole blood cells, and up-regulated in SLE compared to controls. Not surprisingly, this new IFNα score strongly correlates with the IFN signature score by Yao et al. Re-analysis of the IFN-K trial data using the new score confirmed the initial observations: higher production of anti-IFNα Ab in patients with a positive score, diminution of the IFNα score after administration of IFN-K, correlating with anti-IFNα Ab titers.
Conclusions
IFNα, IFNβ and IFNω are detected in the sera of patients with SLE. IFNα and IFNβ/ω are not regulated similarly. Serum IFNβ is significantly associated with mucocutaneous involvement, while serum IFNα is higher in more active disease. The IFN signature score observed in SLE whole blood cells is driven by IFNα.
Disclosure of Interest
: B. Lauwerys Consultant for: Neovacs, F. Houssiau Consultant for: Neovacs, P. Vandepapeliere Shareholder of: Neovacs, Employee of: Neovacs, F. Colaone Shareholder of: Neovacs, Employee of: Neovacs, P. Blanco Consultant for: Neovacs, T. Defrance Consultant for: Neovacs, G. Grouard-Vogel Shareholder of: Neovacs, Employee of: Neovacs
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