Gene signature fingerprints stratify SLE patients in groups with similar biological disease profiles: a multicentre longitudinal study.

OBJECTIVES: Clinical phenotyping and predicting treatment responses in SLE patients is challenging. Extensive blood transcriptional profiling has identified various gene modules that are promising for stratification of SLE patients. We aimed to translate existing transcriptomic data into simpler gene signatures suitable for daily clinical practice. METHODS: Real-time PCR of multiple genes from the IFN M1.2, IFN M5.12, neutrophil (NPh) and plasma cell (PLC) modules, followed by a principle component analysis, was used to identify indicator genes per gene signature. Gene signatures were measured in longitudinal samples from two childhood-onset SLE cohorts (n = 101 and n = 34, respectively), and associations with clinical features were assessed. Disease activity was measured using Safety of Estrogen in Lupus National Assessment (SELENA)-SLEDAI. Cluster analysis subdivided patients into three mutually exclusive fingerprint-groups termed (1) all-signatures-low, (2) only IFN high (M1.2 and/or M5.12) and (3) high NPh and/or PLC. RESULTS: All gene signatures were significantly associated with disease activity in cross-sectionally collected samples. The PLC-signature showed the highest association with disease activity. Interestingly, in longitudinally collected samples, the PLC-signature was associated with disease activity and showed a decrease over time. When patients were divided into fingerprints, the highest disease activity was observed in the high NPh and/or PLC group. The lowest disease activity was observed in the all-signatures-low group. The same distribution was reproduced in samples from an independent SLE cohort. CONCLUSIONS: The identified gene signatures were associated with disease activity and were indicated to be suitable tools for stratifying SLE patients into groups with similar activated immune pathways that may guide future treatment choices.

Safety and immunogenicity of the quadrivalent human papillomavirus vaccine in patients with childhood systemic lupus erythematosus: a real-world interventional multi-centre study.

OBJECTIVE: This study aimed to assess the safety and immunogenicity of the quadrivalent human papillomavirus (qHPV) vaccination in childhood-onset systemic lupus erythematosus (cSLE) patients. METHODS: Volunteer cSLE patients aged 9-20 years and healthy controls (HC) were enrolled to receive a two- or three-dose qHPV vaccination schedule from March 2014 to March 2016. Study visits were performed before the first dose, one month after the second and third doses and one year after the first dose. In each study visit, disease activity and adverse events following vaccination were analyzed, and a serum sample was collected for testing antibody concentrations. Participant recruitment was conducted in 15 Brazilian paediatric rheumatology units. Of the 256 cSLE patients included, 210 completed the two- or three-dose schedules; 15 had previously received one dose, and 18 had received two doses of the vaccine. The analysis was based on intention-to-treat so that participants who did not complete the entire study protocol were also included. RESULTS: No severe adverse events were related to the vaccination. Disease activity was generally low and remained stable or even improved. The HC presented 100% seropositivity to HPV16 and HPV18, whereas the two- and three-dose cSLE groups presented 93% and 83% versus 97% and 91%, respectively. One year after the first dose, seropositivity of the three-dose cSLE group was 91% to HPV16 and 84% to HPV18. CONCLUSIONS: HPV vaccination in cSLE patients is safe and immunogenic. Since the seropositivity to HPV16 and HPV18 was higher for the three-dose schedule group, this regimen should be recommended for cSLE patients.

European consensus-based recommendations for diagnosis and treatment of immunoglobulin A vasculitis-the SHARE initiative.

OBJECTIVES: IgA vasculitis (IgAV, formerly known as Henoch-Schönlein purpura) is the most common cause of systemic vasculitis in childhood. To date, there are no internationally agreed, evidence-based guidelines concerning the appropriate diagnosis and treatment of IgAV in children. Accordingly, treatment regimens differ widely. The European initiative SHARE (Single Hub and Access point for paediatric Rheumatology in Europe) aims to optimize care for children with rheumatic diseases. The aim therefore was to provide internationally agreed consensus recommendations for diagnosis and treatment for children with IgAV. METHODS: Recommendations were developed by a consensus process in accordance with the EULAR standard operating procedures. An extensive systematic literature review was performed, and evidence-based recommendations were extrapolated from the included papers. These were evaluated by a panel of 16 international experts via online surveys and subsequent consensus meeting, using nominal group technique. Recommendations were accepted when ⩾80% of experts agreed. RESULTS: In total, 7 recommendations for diagnosis and 19 for treatment of paediatric IgAV were accepted. Diagnostic recommendations included: appropriate use of skin and renal biopsy, renal work-up and imaging. Treatment recommendations included: the importance of appropriate analgesia and angiotensin-converting enzyme inhibitor use and non-renal indications for CS use, as well as a structured approach to treating IgAV nephritis, including appropriate use of CS and second-line agents in mild, moderate and severe disease along with use of angiotensin-converting enzyme inhibitors and maintenance therapy. CONCLUSION: The SHARE initiative provides international, evidence-based recommendations for the diagnosis and treatment of IgAV that will facilitate improvement and uniformity of care.

European consensus-based recommendations for the diagnosis and treatment of rare paediatric vasculitides - the SHARE initiative.

OBJECTIVES: The European initiative Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) aimed to optimize care for children with rheumatic diseases. Systemic vasculitides are very rare in children. Consequently, despite recent advances, paediatric-specific information is sparse. The lack of evidence-based recommendations is an important, unmet need. This study aimed to provide recommendations for diagnosing and treating children with rare forms of childhood systemic vasculitis. METHODS: Recommendations were developed by a consensus process in accordance with the European League Against Rheumatism standard operating procedures. A systematic literature review informed the recommendations, which were devised and evaluated by a panel of experts via an online survey, and two consensus meetings using nominal group technique. Recommendations were accepted when ⩾ 80% of experts agreed. RESULTS: Ninety-three relevant articles were found, and 78 recommendations were accepted in the two consensus meetings. General, cross-cutting recommendations and disease-specific statements regarding the diagnosis and treatment of childhood-onset PAN, granulomatosis with polyangiitis, microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis, and Takayasu arteritis are provided. CONCLUSION: These Single Hub and Access point for paediatric Rheumatology in Europe recommendations were formulated through an evidence-based consensus process to support uniform, high-quality standard of care for children with rare forms of paediatric systemic vasculitis.

European consensus-based recommendations for the diagnosis and treatment of Kawasaki disease - the SHARE initiative.

OBJECTIVES: The European Single Hub and Access point for paediatric Rheumatology in Europe initiative aimed to optimize care for children with rheumatic diseases. Kawasaki disease (KD) is the most common cause of acquired heart disease in children and an important cause of long-term cardiac disease into adulthood. Prompt diagnosis and treatment of KD is difficult due to the heterogeneity of the disease but is crucial for improving outcome. To date, there are no European internationally agreed, evidence-based guidelines concerning the diagnosis and treatment of KD in children. Accordingly, treatment regimens differ widely. The aim of this study is to provide consensus-based, European-wide evidence-informed recommendations for diagnosis and treatment of children with KD. METHODS: Recommendations were developed using the EULAR's standard operating procedures. An extensive systematic literature search was performed, and evidence-based recommendations were extrapolated from the included papers. These were evaluated by a panel of international experts via online surveys and subsequently discussed in three consensus meetings, using nominal group technique. Recommendations were accepted when ⩾80% agreed. RESULTS: In total, 17 recommendations for diagnosis and 14 for treatment of KD in children were accepted. Diagnostic recommendations included laboratory and imaging workup for complete as well as incomplete KD. Treatment recommendations included the importance of early treatment in both complete and incomplete KD, use of intravenous immunoglobulin, aspirin, corticosteroids for high-risk cases, and other treatment options for those with resistant disease. CONCLUSION: The Single Hub and Access point for paediatric Rheumatology in Europe initiative provides international evidence-based recommendations for diagnosing and treating KD in children, facilitating improvement and uniformity of care.

TBK1: A key regulator and potential treatment target for interferon positive Sjögren's syndrome, systemic lupus erythematosus and systemic sclerosis.

OBJECTIVE: Upregulation of type I interferons (IFN-I) is a hallmark of systemic autoimmune diseases like primary Sjögren's syndrome (pSS), systemic lupus erythematosus (SLE) and systemic sclerosis (SSc). Expression of IFN-I is induced by three different receptor families: Toll-like receptors (TLRs), RIG-like receptors (RLRs) and DNA-sensing receptors (DSRs). TANK-binding kinase (TBK1) is an important signaling hub downstream of RLRs and DSRs. TBK1 activates IRF3 and IRF7, leading to IFN-I production and subsequent induction of interferon stimulated genes (ISGs). The objective of this study was to explore the potential of BX795, an inhibitor of TBK1, to downregulate IFN-I activation in pSS, SLE and SSc. METHODS: TBK1, IRF3, IRF7 and STAT1 were determined by RT-PCR in PAXgene samples and phosphorylated-TBK1 (pTBK1) was analyzed by flowcytometry in plasmacytoid dendritic cells (pDCs) from IFN-I positive (IFNpos) patients. Peripheral blood mononuclear cells (PBMCs) of pSS, SLE and SSc patients and TLR7 stimulated PBMCs of healthy controls (HCs) were cultured with the TBK1 inhibitor BX795, followed by analysis of ISGs. RESULTS: Increased gene expression of TBK1, IRF3, IRF7 and STAT1 in whole blood and pTBK1 in pDCs was observed in IFNpos pSS, SLE and SSc patients compared to HCs. Upon treatment with BX795, PBMCs from IFNpos pSS, SLE, SSc and TLR7-stimulated HCs downregulated the expression of the ISGs MxA, IFI44, IFI44L, IFIT1 and IFIT3. CONCLUSIONS: TBK1 inhibition reduced expression of ISGs in PBMCs from IFNpos patients with systemic autoimmune diseases indicating TBK1 as a potential treatment target.

European evidence-based recommendations for diagnosis and treatment of childhood-onset systemic lupus erythematosus: the SHARE initiative.

Childhood-onset systemic lupus erythematosus (cSLE) is a rare, multisystem and potentially life-threatening autoimmune disorder with significant associated morbidity. Evidence-based guidelines are sparse and management is often based on clinical expertise. SHARE (Single Hub and Access point for paediatric Rheumatology in Europe) was launched to optimise and disseminate management regimens for children and young adults with rheumatic diseases like cSLE. Here, we provide evidence-based recommendations for diagnosis and treatment of cSLE. In view of extent and complexity of cSLE and its various manifestations, recommendations for lupus nephritis and antiphospholipid syndrome will be published separately. Recommendations were generated using the EULAR (European League Against Rheumatism) standard operating procedure. An expert committee consisting of paediatric rheumatologists and representation of paediatric nephrology from across Europe discussed evidence-based recommendations during two consensus meetings. Recommendations were accepted if >80% agreement was reached. A total of 25 recommendations regarding key approaches to diagnosis and treatment of cSLE were made. The recommendations include 11 on diagnosis, 9 on disease monitoring and 5 on general treatment. Topics included: appropriate use of SLE classification criteria, disease activity and damage indices; adequate assessment of autoantibody profiles; secondary macrophage activation syndrome; use of hydroxychloroquine and corticosteroid-sparing regimens; and the importance of addressing poor adherence. Ten recommendations were accepted regarding general diagnostic strategies and treatment indications of neuropsychiatric cSLE. The SHARE recommendations for cSLE and neuropsychiatric manifestations of cSLE have been formulated by an evidence-based consensus process to support uniform, high-quality standards of care for children with cSLE.

European evidence-based recommendations for the diagnosis and treatment of childhood-onset lupus nephritis: the SHARE initiative.

Lupus nephritis (LN) occurs in 50%-60% of patients with childhood-onset systemic lupus erythematosus (cSLE), leading to significant morbidity. Timely recognition of renal involvement and appropriate treatment are essential to prevent renal damage. The Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) initiative aimed to generate diagnostic and management regimens for children and adolescents with rheumatic diseases including cSLE. Here, we provide evidence-based recommendations for diagnosis and treatment of childhood LN. Recommendations were developed using the European League Against Rheumatism standard operating procedures. A European-wide expert committee including paediatric nephrology representation formulated recommendations using a nominal group technique. Six recommendations regarding diagnosis and 20 recommendations covering treatment choices and goals were accepted, including each class of LN, described in the International Society of Nephrology/Renal Pathology Society 2003 classification system. Treatment goal should be complete renal response. Treatment of class I LN should mainly be guided by other symptoms. Class II LN should be treated initially with low-dose prednisone, only adding a disease-modifying antirheumatic drug after 3 months of persistent proteinuria or prednisone dependency. Induction treatment of class III/IV LN should be mycophenolate mofetil (MMF) or intravenous cyclophosphamide combined with corticosteroids; maintenance treatment should be MMF or azathioprine for at least 3 years. In pure class V LN, MMF with low-dose prednisone can be used as induction and MMF as maintenance treatment. The SHARE recommendations for diagnosis and treatment of LN have been generated to support uniform and high-quality care for all children with SLE.

European evidence-based recommendations for diagnosis and treatment of paediatric antiphospholipid syndrome: the SHARE initiative.

Antiphospholipid syndrome (APS) is rare in children, and evidence-based guidelines are sparse. Consequently, management is mostly based on observational studies and physician's experience, and treatment regimens differ widely. The Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) initiative was launched to develop diagnostic and management regimens for children and young adults with rheumatic diseases. Here, we developed evidence-based recommendations for diagnosis and treatment of paediatric APS. Evidence-based recommendations were developed using the European League Against Rheumatism standard operating procedure. Following a detailed systematic review of the literature, a committee of paediatric rheumatologists and representation of paediatric haematology with expertise in paediatric APS developed recommendations. The literature review yielded 1473 articles, of which 15 were valid and relevant. In total, four recommendations for diagnosis and eight for treatment of paediatric APS (including paediatric Catastrophic Antiphospholipid Syndrome) were accepted. Additionally, two recommendations for children born to mothers with APS were accepted. It was agreed that new classification criteria for paediatric APS are necessary, and APS in association with childhood-onset systemic lupus erythematosus should be identified by performing antiphospholipid antibody screening. Treatment recommendations included prevention of thrombotic events, and treatment recommendations for venous and/or arterial thrombotic events. Notably, due to the paucity of studies on paediatric APS, level of evidence and strength of the recommendations is relatively low. The SHARE initiative provides international, evidence-based recommendations for diagnosis and treatment for paediatric APS, facilitating improvement and uniformity of care.

Vaccinations in paediatric rheumatology: an update on current developments.

In 2011, the European League Against Rheumatism (EULAR) published recommendations regarding the vaccination of children with rheumatic diseases. These recommendations were based on a systematic literature review published in that same year. Since then, the evidence body on this topic has grown substantially. This review provides an update of the systematic literature study of 2011, summarizing all the available evidence on the safety and immunogenicity of vaccination in paediatric patients with rheumatic diseases. The current search yielded 21 articles, in addition to the 27 articles described in the 2011 review. In general, vaccines are immunogenic and safe in this patient population. The effect of immunosuppressive drugs on the immunogenicity of vaccines was not detrimental for glucocorticosteroids and methotrexate. Biologicals could accelerate a waning of antibody levels over time, although most patients were initially protected adequately. Overall, persistence of immunological memory may be reduced in children with rheumatic diseases, which shows the need for (booster) vaccination. This update of the 2011 systematic literature review strengthens the evidence base for the EULAR recommendations, and it must be concluded that vaccinations in patients with rheumatic diseases should be advocated.

Immunogenicity and safety of the bivalent HPV vaccine in female patients with juvenile idiopathic arthritis: a prospective controlled observational cohort study.

OBJECTIVES: To compare the immunogenicity and safety of the bivalent human papillomavirus (HPV)16/18 vaccine between female patients with juvenile idiopathic arthritis (JIA) and healthy female adolescents. METHODS: 68 patients and 55 healthy girls aged 12-18 years were included in a prospective controlled observational cohort and were vaccinated at 0, 1 and 6 months. Primary outcomes were immunogenicity expressed as seropositivity rate after three vaccine doses at 7 and 12 months and HPV-specific geometric mean antibody concentrations. Secondary outcomes were HPV16/18-specific memory B cell responses in a subset of participants and safety, defined as adverse events and the effect of vaccination on JIA disease activity. RESULTS: All participants were seropositive for HPV16 and HPV18 at 7 months. One patient turned seronegative at 12 months for HPV16/18. No significant differences were found between patients and controls in HPV-specific antibody concentrations; however, antibody concentrations were consistently lower in patients. No effect of methotrexate on HPV16 antibodies (p=0.79) or HPV18 antibodies (p=0.37) was detected. All patients on anti-TNFα treatment were seropositive after vaccination. The kinetics of HPV16/18 memory B cell responses was comparable between patients and controls, but the magnitude of B cell responses at 7 and 12 months appeared lower in patients. No relevant differences in adverse events were found. HPV vaccination did not aggravate JIA disease. CONCLUSIONS: The bivalent HPV16/18 vaccine is immunogenic and well tolerated in JIA patients. However, HPV-specific antibodies and B cell responses tended to be lower in patients compared with healthy controls. CLINICAL TRIAL LISTING: NCT00815282.

Effects of Childhood-onset Systemic Lupus Erythematosus on Academic Achievements and Employment in Adult Life.

OBJECTIVE: Long-term outcome data in adults with childhood-onset systemic lupus erythematosus (cSLE) are limited. Here, we report the effects of cSLE on education, vocation, and employment in a large cohort of adults with cSLE. METHODS: Patients were seen for a single study visit comprising a structured history and physical examination. Medical records were retrieved to supplement information obtained during the study visit. Education and employment status were assessed by questionnaires. Health-related quality of life (HRQOL) was measured with the 36-Item Short Form Health Survey (SF-36). RESULTS: One hundred six patients with cSLE (93% female, 73% White), with a median disease duration of 20 years, completed the visit and questionnaires. Almost all patients stated that cSLE had influenced their education, but the level of completed education was similar to the general Dutch population. Half of the patients had adjusted their vocational choice due to the disease. Still, 44% of patients who had finished education did not have a paid job. Of the employed patients, 61% worked part time. Disease damage was equally prevalent in patients with and without paid employment. A high percentage of patients (51%) were declared work disabled, due to disease damage. Patients who did not have paid employment were often work disabled. Both had a negative effect on HRQOL. CONCLUSION: The effect of cSLE on academic achievements and employment is substantial, despite patients adjusting their educational and vocational choices. To optimize participation in the community, ongoing support is necessary, not only to help patients find suitable education and vocations but also to offer guidance regarding potential adjustments during their career.

Safety and immunogenicity of the quadrivalent human papillomavirus vaccine in patients with juvenile dermatomyositis: a real-world multicentre study.

BACKGROUND: Concerns about the safety and efficacy of vaccines in patients with autoimmune diseases (AID) have led to contradictions and low vaccination coverage in this population, who are at a higher risk of infections, including by human papillomavirus (HPV). Although HPV vaccines have been recommended for immunocompromised patients, there is still a lack of data to support its use for AID patients, such as juvenile dermatomyositis (JDM) patients. The aim of this study was to assess the safety and immunogenicity of the quadrivalent HPV (qHPV) vaccine in a cohort of JDM patients. METHODS: JDM patients aged from 9 to 20 years and healthy controls (HC) were enrolled to receive a 3-dose schedule of qHPV vaccine from March/2014 to March/2016. Study visits were performed before the first dose, 1 month after the second and third doses, and 6 months after the third dose. Participants completed a diary of possible adverse events for 14 days following each dose of vaccination (AEFV). Disease activity and current therapy were analyzed at each visit for JDM patients. In addition, serum samples from all participants were collected to test antibody concentrations against HPV16 and 18 at each visit. Participant recruitment was conducted in ten Brazilian centres. From 47 eligible JDM patients and 41 HC, 42 and 35, respectively, completed the 3-dose schedule of the vaccine, given that five JDM patients and two HC had received doses prior to their inclusion in the study. RESULTS: The AEFVs presented by the participants were mild and in general did not differ between JDM and HC groups. No severe AEFVs were related to the vaccination. Disease activity was stable, or even improved during the follow-up. One month after the third dose of the vaccine the JDM group presented seropositivity of 100% for HPV16 and 97% for HPV18, similarly to the HC group, who presented 100% for both serotypes (p = 1.000). Six months after the third dose the seropositivity for the patient group was 94% for both HPV types. CONCLUSIONS: The HPV vaccination in this cohort of JDM patients was safe and immunogenic. Since the seropositivity against HPV16 and 18 was very high after the 3-dose schedule, this regimen should be recommended for JDM patients. TRIAL REGISTRATION: Brazilian Clinical Trials Registry, number: RBR-9ypbtf . Registered 20 March 2018 - Retrospectively registered.

Varicella vaccination elicits a humoral and cellular response in children with rheumatic diseases using immune suppressive treatment.

OBJECTIVE: To assess humoral and cellular responses to live-attenuated varicella zoster virus (VZV) vaccination of patients with juvenile idiopathic arthritis (JIA), juvenile dermatomyositis (JDM) or juvenile scleroderma (JScle) compared to those of healthy controls (HC). METHODS: Before, 4-6weeks and one year after VZV vaccination, blood samples of patients and HC were collected. VZV-specific antibody concentrations were measured by ELISA and multiplex immune-assay. IFN-γ ELISpot assays were performed to assess VZV-specific T-cell responses. Cytokine production upon VZV stimulation were measured with a Luminex-assay. RESULTS: 49 patients (39 JIA, 5 JDM, 5 JScle) and 18 HC were included. All patients used methotrexate (MTX), 16 also used corticosteroids, 3 patients used biologics. No disease flares were reported after vaccination. Antibody response to the vaccine was similar in patients and controls (p=0.139). Use of immunosuppressive drugs did not affect the response (p=0.203). A second vaccination (n=21) increased VZV-specific antibody concentrations (p=0.02). VZV-specific T-cells increased after vaccination (p=0.043), with a cytokine profile suggesting a VZV-specific Th1 and cytotoxic T-cell response. CONCLUSION: The humoral response to VZV vaccination in patients with pediatric rheumatic diseases (PRD) is similar to that of HC. Generally, patients are able to mount a VZV-specific cellular response. This study has been registered in the Brazilian Clinical Trials Registry under number U1111-1189-9837.

HPV infection and vaccination in Systemic Lupus Erythematosus patients: what we really should know.

Patients with Systemic Lupus Erythematosus (SLE) are at increased risk for infections. Vaccination is a powerful tool to prevent infections, even in immunocompromised patients. Most non-live vaccines are immunogenic and safe in patients with SLE, even if antibody titres are frequently lower than those of healthy controls. Human papillomavirus (HPV) infections are more prevalent in SLE patients when compared to the healthy population. Low-risk types of this virus cause anogenital warts, while high risk types are strongly related to pre-malignant cervical abnormalities and cervical cancer. HPV vaccines have been developed to prevent these conditions. Although little is known about HPV vaccination in SLE, few studies in patients with autoimmune rheumatic diseases (AIRDs) have shown that HPV vaccines are safe, and capable to induce an immunogenic response in this group of patients. To date, available data suggest that HPV vaccines can be given safely to SLE patients. Given the increased incidence of cervical abnormalities due to HPV in SLE patients, this vaccination should be encouraged.