Objectives Adult-onset Still’s disease (AOSD) is a rare condition characterized by fevers, rash, and arthralgia/arthritis; most doctors treating AOSD in the Netherlands treat <5 patients per year. Currently, there is no internationally accepted treatment guideline for AOSD. The objectives of this study were to conduct a Delphi panel aimed at reaching consensus about diagnostic and treatment strategies for patients with AOSD and to use the outcomes as a basis for a treatment algorithm. Methods The Delphi panel brought together 18 AOSD experts: rheumatologists, internists and paediatricians. The Delphi process consisted of three rounds. In the first two rounds, online lists of questions and statements were completed. In the third round, final statements were discussed during a virtual meeting and a final vote took place. Consensus threshold was set at 80%. Two targeted literature searches were performed identifying the level of evidence of the consensus-based statements. Results Consensus was reached on 29 statements, including statements related to diagnosis and diagnostic tests, definition of response and remission, the therapy, the use of methotrexate and tapering of treatment. The panel consented on reduction of the use of glucocorticoids to avoid side effects, and preferred the use of biologics over conventional treatment. The role of IL-1 and IL-6 blocking agents was considered important in the treatment of AOSD. Conclusion In this Delphi panel, a high level of consensus was achieved on recommendations for diagnosis and therapy of AOSD that can serve as a basis for a treatment guideline.

Timing of vaccination and its relationship with concomitant immunosuppressive therapy has been a matter of debate in the field of AutoImmune Inflammatory Rheumatic Diseases (AIIRD). Vaccination is crucial in the prevention of infections, which, in the setting of AIIRD, are known risk factors for disease flare and expose patients to increase risk of complications and mortality. As evidenced from real-life studies, vaccines do not significantly affect disease activity. Conversely, disease activity (especially in Systemic Lupus Erythematosus) may predict for vaccine response: high disease activity correlates with decreased seroconversion. For this reason, according to the EULAR 2019 recommendation, vaccination should preferably be administered during quiescent AIIRD. Beside disease activity, background immunosuppressive therapy should be considered when performing vaccination, as different Disease Modifying Anti-Rheumatic Drugs (DMARDs) decrease vaccine immunogenicity. AIIRD patients should be vaccinated, independently from the vaccine type, before starting immunosuppression. If the patient is on active immunosuppressive therapy, the best window of opportunity to boost vaccine response is during AIIRD quiescence, as low disease activity increases seroconversion and allows safe immunosuppressant spacing. In conclusion, the majority of AIIRD patients should receive vaccination, preferably during quiescent disease and taking into consideration immunosuppressant spacing.

BackgroundRecurrence risk of systemic lupus erythematosus (SLE)-associated venous thromboembolism (VTE) is unclear. AimTo determine the recurrence risk of SLE-associated VTE overall and by presence of provoking factors and SLE flares. MethodsA multicenter, retrospective cohort study was conducted among patients with first SLE-associated VTE who discontinued anticoagulation. SLE flares were defined as Systemic Lupus Erythematosus Disease Activity Index 2000 greater than 4. The primary outcome was recurrent VTE. Incidence rates and cumulative incidences were calculated by presence of provoking factors and antiphospholipid syndrome (APS) at index VTE. The hazard ratio (HR) for recurrence after SLE flare-associated index VTE was estimated with Cox regression, adjusted for provoking factor presence and APS. ResultsEighty patients were included with 21 recurrent VTEs in median 8 years. For provoked index VTE, the recurrence rate in patients without APS was 1.1 per 100 person-years (PY; 95% confidence interval [CI], 0.1-3.1) and in the presence of APS 3.5 per 100 PY (95% CI, 0.9-8.9), yielding cumulative incidences of 7.5% (95% CI, 1.2%-21.7%) and 31.4% (95% CI, 6.3%-61.6%) respectively. For unprovoked index VTE, these analogous rates were 3.8 per 100 PY (95% CI, 1.2-9.0) and 16.7 per 100 PY (95% CI, 4.5-42.7), with cumulative incidences of 33.7% (95% CI, 10.7%-58.9%) and 54.2% (95% CI, 10.7%-84.5%), respectively. Forty-six index VTEs were flare associated, and the adjusted HR for recurrence was 0.4 (95% CI, 0.1-1.8) compared to those without flares at their index VTE. ConclusionAntiphospholipid syndrome is the main determinant for recurrence risk of SLE-associated VTE irrespective of presence of a provoking factor. Future research should attempt to confirm that flare-associated VTE has a lower recurrence risk.

OBJECTIVES Calcinosis cutis affects 20-40% of patients with systemic sclerosis (SSc). When calcinosis cutis becomes clinically apparent, it is irreversible in most cases. Detection of active calcification formation might allow early disease-modifying interventions. We assessed the feasibility of visualizing active calcifications using [18F]Sodium Fluoride ([18F]NaF) PET/low-dose CT (LDCT) in SSc patients with calcinosis cutis. METHODS In this cross-sectional, observational pilot study patients underwent a whole body [18F]NaF PET/LDCT. All patients met the 2013 ACR/EULAR SSc criteria and had clinically detectable calcinosis cutis. (Sub)cutaneous calcifications were described by three investigators. RESULTS Nine female patients were included (median age 59.0 years [IQR 51.5-70.5]). [18F]NaF uptake was mostly visible in the fingers (n=7) and knees (n=5). [18F]NaF PET showed calcifications in the fingers of 3 patients where calcifications were undetected on LDCT and in the clinic. Ninety-seven percent of [18F]NaF positive lesions was visible on LDCT. Of all lesions visible on LDCT, 70% was also visible on [18F]NaF PET. CONCLUSION Imaging of active calcifications in SSc is feasible using [18F]NaF PET/LDCT. Seventy percent of calcifications on LDCT were [18F]NaF PET positive. Although these findings require replication, [18F]NaF PET/LDCT may detect active calcification formation, being potentially suitable for early disease-modifying interventions.

Background:In 2011, the first European League Against Rheumatism (EULAR) vaccination recommendations for pediatric patients with autoimmune inflammatory rheumatic diseases (pedAIIRD) were published. The past decade numerous new studies were performed to assess the safety, efficacy and immunogenicity of vaccinations in pedAIIRD. A systematic literature review (SLR) was therefore performed to serve as the basis for the updated 2021 EULAR/PRES recommendations.Methods:An SLR was performed according to the standard operating procedures for EULAR-endorsed recommendations. Primary outcomes were efficacy, immunogenicity and safety of vaccination in pedAIIRD. The search was performed in Medline, Embase and the Cochrane Library and included studies published from November 2010 until July 2020.Results:The SLR yielded 57 studies which were included for critical appraisal and data extraction. Only 8 studies described the occurrence of vaccine-preventable infections after vaccination (efficacy), none of these studies were powered to assess efficacy. The majority of studies assessed (humoral) immune responses as surrogate endpoint for vaccine efficacy. Studies on non-live vaccines showed that these were safe and in general immunogenic. Biologic disease-modifying antirheumatic drugs (bDMARDs) in general did not significantly reduce seroprotection rates, except for B-cell depleting therapies which severely hampered humoral responses. Four new studies on human papilloma virus vaccination showed that this vaccine was safe and immunogenic in pedAIIRD. Regarding live-attenuated vaccinations, level 1 evidence of the measles mumps rubella (MMR) booster vaccination became available which showed the safety of this booster for patients treated with methotrexate. In addition, level 3 evidence became available that suggested that the MMR and varicella zoster virus (VZV) vaccination for patients on low dose glucocorticosteroids and bDMARDs might be safe as well.Conclusions:The past decade, knowledge on the safety and immunogenicity of (live-attenuated) vaccines in pedAIIRD significantly increased. Data on efficacy (infection prevention) remains scarce. The results from this SLR are the basis for the updated EULAR/PRES vaccination recommendations in pedAIIRD.

ObjectivesRecent insights supporting the safety of live-attenuated vaccines and novel studies on the immunogenicity of vaccinations in the era of biological disease-modifying antirheumatic drugs in paediatric patients with autoimmune/inflammatory rheumatic diseases (pedAIIRD) necessitated updating the EULAR recommendations.MethodsRecommendations were developed using the EULAR standard operating procedures. Two international expert committees were formed to update the vaccination recommendations for both paediatric and adult patients with AIIRD. After a systematic literature review, separate recommendations were formulated for paediatric and adult patients. For pedAIIRD, six overarching principles and seven recommendations were formulated and provided with the level of evidence, strength of recommendation and Task Force level of agreement.ResultsIn general, the National Immunisation Programmes (NIP) should be followed and assessed yearly by the treating specialist. If possible, vaccinations should be administered prior to immunosuppressive drugs, but necessary treatment should never be postponed. Non-live vaccines can be safely given to immunosuppressed pedAIIRD patients. Mainly, seroprotection is preserved in patients receiving vaccinations on immunosuppression, except for high-dose glucocorticoids and B-cell depleting therapies. Live-attenuated vaccines should be avoided in immunosuppressed patients. However, it is safe to administer the measles–mumps–rubella booster and varicella zoster virus vaccine to immunosuppressed patients under specific conditions. In addition to the NIP, the non-live seasonal influenza vaccination should be strongly considered for immunosuppressed pedAIIRD patients.ConclusionsThese recommendations are intended for paediatricians, paediatric rheumatologists, national immunisation agencies, general practitioners, patients and national rheumatology societies to attain safe and effective vaccination and optimal infection prevention in immunocompromised pedAIIRD patients.

Objectives. The aims were to gain insight into the care provided to patients with APS in The Netherlands and to identify areas for improvement from the perspective of both patients and medical specialists. Methods. APS care was evaluated using qualitative and quantitative methods. Perspectives on APS care were explored using semi-structured interviews with medical specialists, patient focus groups and a cross-sectional, online patient survey. In order to assess current practice, medical records were reviewed retrospectively to collect data on clinical and laboratory manifestations and pharmacological treatment in six Dutch hospitals. Results. Fourteen medical specialists were interviewed, 14 patients participated in the focus groups and 79 patients completed the survey. Medical records of 237 patients were reviewed. Medical record review showed that only one-third of patients were diagnosed with APS within 3 months after entering specialist care. The diagnostic approach and management varied between centres and specialists. Almost 10% of all patients and 7% of triple-positive patients with thrombotic APS were not receiving any anticoagulant treatment at the time of medical record review. Correspondingly, poor recognition and fragmentation of care were reported as the main problems by medical specialists. Additionally, patients reported the lack of accessible, reliable patient education, psychosocial support and trust in physicians as important points for improvement. Conclusion. Delayed diagnosis, variability in management strategies and fragmentation of care were important limitations of APS care identified in this study. A remarkable 10% of patients did not receive any anticoagulant treatment.

Periodontitis, a bacterial-induced infection of the supporting soft and hard tissues of the teeth (the periodontium), is common in patients with rheumatoid arthritis (RA). As RA and periodontitis underlie common inflammatory pathways, targeting the progression of RA might mediate both periodontitis and RA. On the other hand, patients with RA on immunosuppressive medication have an increased risk of infection. Therefore, the objective of this longitudinal observation study was to assess the effect of methotrexate (MTX) and anti-tumor necrosis factor-α (anti-TNF, etanercept) treatment on the periodontal condition of RA patients. Overall, 14 dentate treatment-naive RA patients starting with MTX and 12 dentate RA patients starting with anti-TNF therapy in addition to MTX were included. Follow-up was scheduled matching the routine protocol for the respective treatments. Prior to the anti-rheumatic treatment with MTX or the anti-TNF therapy in addition to MTX, and during follow-up, i.e., 2 months for MTX, and 3 and 6 months for the anti-TNF therapy in addition to MTX, the periodontal inflamed surface area (PISA) was measured. The efficacy of the anti-rheumatic treatment was assessed by determining the change in RA disease activity (DAS28-ESR). Furthermore, the erythrocyte sedimentation rates were determined and the levels of C-reactive protein, IgM-rheumatoid factor, anti-cyclic citrullinated protein antibodies, and antibodies to the periodontal pathogen Porphyromonas gingivalis, were measured. Subgingival sampling and microbiological characterization of the subgingival microflora was done at baseline. MTX or anti-TNF treatment did not result in an improvement of the periodontal condition, while both treatments significantly improved DAS28 scores (both p < 0.01), and reduced C-reactive protein levels and erythrocyte sedimentation rates (both p < 0.05). It is concluded that anti-rheumatic treatment (MTX and anti-TNF) has negligible influence on the periodontal condition of RA patients.

OBJECTIVES We aimed to determine the presence, amount and origin of microchimerism in peripheral blood of pregnant and non-pregnant parous women with systemic lupus erythematosus (SLE) as compared to control subjects. METHODS We performed a comparative study in which peripheral blood was drawn from eleven female non-pregnant SLE-patients and 22 control subjects, and from six pregnant SLE-patients and eleven control subjects during gestation and up to six months postpartum. Quantitative PCR for insertion-deletion polymorphisms and null alleles was used to detect microchimerism in peripheral blood mononuclear cells and granulocytes. RESULTS Microchimerism was detected more often in non-pregnant SLE-patients than control subjects (54.4% vs. 13.6%, respectively; p=0.03). When present, the median total number of foetal chimeric cells was 5 gEq/106 in patients and 2.5gEq/106 in control subjects (p=0.048). Microchimerism was mostly foetal in origin; maternal microchimerism was detected in one patient and one control subject. In control subjects, microchimerism was always derived from only one source whereas in 50% of patients it originated from multiple sources. The pregnant patients had a significantly higher median number of foetal chimeric cells in the granulocyte fraction just after delivery than control subjects (7.5 gEq/106 vs. 0 gEq/106, respectively; p=0.02). CONCLUSIONS Just after delivery, SLE-patients had more microchimerism than control subjects. Three months post-partum, microchimerism was no longer detectable, only to reappear many years after the last pregnancy, more often and at higher levels in SLE-patients than in control subjects. This suggests that these chimeric cells may originate from non-circulating foetal chimeric stem cells.

In view of the COVID-19 pandemic, there is an unmet clinical need for the guidelines on vaccination of patients with autoimmune inflammatory rheumatic diseases (AIIRD). This position paper summarises the current data on COVID-19 infection in patients with AIIRD and development of vaccines against COVID-19, discusses the aspects of efficacy and safety of vaccination, and proposes preliminary considerations on vaccination against COVID-19 in patients with AIIRD, mainly based on the expert opinion and knowledge on the use of other vaccines in this population of patients.

Calcinosis cutis is a major daily challenge to patients with longstanding systemic sclerosis (SSc), negatively affecting their quality of life. Unfortunately, treatment options are very limited due to lack of understanding of the pathogenetic process. Currently, calcinosis cutis is only detected at its irreversible end-stage. Early detection of calcinosis cutis could putatively allow early disease-modifying interventions and monitor treatment effects.The aim of the current study is to assess the feasibility of visualising “active” micro-calcifications with 18-F Sodium Fluoride (NaF) PET scanning, compared to low-dose CT in patients with clinically overt calcinosis cutis.This was a cross-sectional, observational, pilot study. All patients met 2013 ACR/EULAR criteria for SSc. Patients underwent a whole body NaF PET/low-dose CT scan, scanned 90 minutes post-injection. (Sub)cutaneous calcifications were described and assessed on NaF PET, which was compared to CT images by two independent investigators.A total of 10 female patients with limited cutaneous SSc [median age 56 years (IQR 52-66), median disease duration 17 years (8-19), PAH 10%, ILD 20%] were included, and compared to 10 controls [70 years (65-73)]. NaF uptake showed normal distribution throughout the skeletal bones, arterial tree, and visceral organs, which was comparable between patients and controls. Additionally, NaF uptake was visible in the skin of all SSc patients, but in none of the controls. Cutaneous NaF uptake largely correlated with clinical calcifications. Most common sites of cutaneous NaF uptake were fingers (6 patients) and knees (7 patients). Only 5% of the NaF positive lesions were not accompanied by visible calcifications on CT. Furthermore, of all calcified lesions seen on CT, 51% showed uptake on NaF PET. Small lesions (<1 cm), were generally only visible on CT, due to lower resolution of NaF PET.Imaging of “active” calcinosis cutis in limited cutaneous systemic sclerosis is feasible using NaF PET scanning. Most clinically overt calcifications and half of those seen on CT were positive for NaF uptake. Whether these “active” calcifications behave differently in terms of faster progression, clinical complaints, and infection risk, and whether these are potentially suitable for disease modifying interventions is subject to future study.None declared

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.

To update the European League Against Rheumatism (EULAR) recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases (AIIRD) published in 2011. Four systematic literature reviews were performed regarding the incidence/prevalence of vaccine-preventable infections among patients with AIIRD; efficacy, immunogenicity and safety of vaccines; effect of anti-rheumatic drugs on the response to vaccines; effect of vaccination of household of AIIRDs patients. Subsequently, recommendations were formulated based on the evidence and expert opinion. The updated recommendations comprise six overarching principles and nine recommendations. The former address the need for an annual vaccination status assessment, shared decision-making and timing of vaccination, favouring vaccination during quiescent disease, preferably prior to the initiation of immunosuppression. Non-live vaccines can be safely provided to AIIRD patients regardless of underlying therapy, whereas live-attenuated vaccines may be considered with caution. Influenza and pneumococcal vaccination should be strongly considered for the majority of patients with AIIRD. Tetanus toxoid and human papilloma virus vaccination should be provided to AIIRD patients as recommended for the general population. Hepatitis A, hepatitis B and herpes zoster vaccination should be administered to AIIRD patients at risk. Immunocompetent household members of patients with AIIRD should receive vaccines according to national guidelines, except for the oral poliomyelitis vaccine. Live-attenuated vaccines should be avoided during the first 6 months of life in newborns of mothers treated with biologics during the second half of pregnancy. These 2019 EULAR recommendations provide an up-to-date guidance on the management of vaccinations in patients with AIIRD.

Purpose This study aims to gain insight into the care provided to patients with antiphospholipid syndrome (APS) in The Netherlands and to identify areas for improvement from the perspective of both patients and clinicians. Methods APS care was evaluated using qualitative and quantitative methods. Perspectives on APS care were identified using semi-structured interviews with medical specialists, patient focus groups and a cross-sectional, online patient survey. In order to examine differences in medical practice, medical records were reviewed retrospectively regarding clinical and laboratory manifestations, pharmacological treatment and management of disease in six hospitals throughout The Netherlands. Results Fourteen interviewed medical specialists, fourteen focus group participants and 79 survey respondents participated in the study. 237 patients were included in medical record review. Only one-third of patients were diagnosed with APS within three months after entering specialist care. Diagnosis and management varied between centres and specialists. Almost 10% of triple positive patients did not receive any treatment at the time of medical record review. Major challenges according to specialists and patients were poor recognition of APS by health care professionals, fragmentation of care and lack of accessible, reliable patient education and psychosocial support. Conclusion This study describes delayed diagnosis, variability in management strategies and a burden placed on patients to orchestrate their own care in APS care in The Netherlands. Of note, almost 10% of triple positive patients did not receive any treatment, despite this group of patients being at the highest risk of recurrent thrombosis. Acknowledgements This work was supported by the Arthritis Research and Collaboration Hub (ARCH) Foundation.

Childhood‐onset systemic lupus erythematosus (SLE) is a severe, lifelong, multisystem autoimmune disease. Long‐term outcome data are limited. This study was undertaken to identify clinical characteristics and health‐related quality of life (HRQoL) of adults with childhood‐onset SLE.

INTRODUCTIONThe antiphospholipid syndrome (APS) is defined by the occurrence of venous and/or arterial thrombosis and/or pregnancy-related morbidity, combined with the presence of antiphospholipid antibodies (aPL) and/or a lupus anticoagulant (LAC). Large, controlled, intervention trials in APS are limited. This paper aims to provide clinicians with an expert consensus on the management of APS.METHODSRelevant papers were identified by literature search. Statements on diagnostics and treatment were extracted. During two consensus meetings, statements were discussed, followed by a Delphi procedure. Subsequently, a final paper was written.RESULTSDiagnosis of APS includes the combination of thrombotic events and presence of aPL. Risk stratification on an individual base remains challenging. 'Triple positive' patients have highest risk of recurrent thrombosis. aPL titres > 99th percentile should be considered positive. No gold standard exists for aPL testing; guidance on assay characteristics as formulated by the International Society on Thrombosis and Haemostasis should be followed. Treatment with vitamin K-antagonists (VKA) with INR 2.0-3.0 is first-line treatment for a first or recurrent APS-related venous thrombotic event. Patients with first arterial thrombosis should be treated with clopidogrel or VKA with target INR 2.0-3.0. Treatment with direct oral anticoagulants is not recommended. Patients with catastrophic APS, recurrent thrombotic events or recurrent pregnancy morbidity should be referred to an expert centre.CONCLUSIONThis consensus paper fills the gap between evidence-based medicine and daily clinical practice for the care of APS patients.

Objectives The aims of this study were to update the evidence on the incidence and prevalence rates of vaccine preventable infections (VPI) in patients with autoimmune inflammatory rheumatic diseases (AIIRD) and compare the data to the general population when available. Methods A literature search was performed using Medline, Embase and Cochrane library (October 2009 to August 2018). The primary outcome was the incidence or prevalence of VPI in the adult AIIRD population. Meta-analysis was performed when appropriate. Results Sixty-three publications out of 3876 identified records met the inclusion criteria: influenza (n=4), pneumococcal disease (n=7), hepatitis B (n=10), herpes zoster (HZ) (n=29), human papillomavirus (HPV) infection (n=13). An increased incidence of influenza and pneumococcal disease was reported in patients with AIIRD. HZ infection-pooled incidence rate ratio (IRR) was 2.9 (95% CI 2.4 to 3.3) in patients with AIIRD versus general population. Among AIIRD, inflammatory myositis conferred the highest incidence rate (IR) of HZ (pooled IRR 5.1, 95% CI 4.3 to 5.9), followed by systemic lupus erythematosus (SLE) (pooled IRR 4.0, 95% CI 2.3 to 5.7) and rheumatoid arthritis (pooled IRR 2.3, 95% CI 2.1 to 2.6). HPV infection-pooled prevalence ratio was 1.6, 95% CI 0.7 to 3.4 versus general population, based on studies mainly conducted in the SLE population in Latin America and Asia. Pooled prevalence of hepatitis B surface antigen and hepatitis B core antibody in patients with AIIRD was similar to the general population, 3%, 95% CI 1% to 5% and 15%, 95% CI 7% to 26%, respectively. Conclusion Current evidence shows an increased risk of VPI in patients with AIIRD, emphasising that prevention of infections is essential in these patients.