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The European Reference Networks (ERNs) were launched by the European Commission in 2017 with the mission to improve quality, safety and access to highly specialised and sustainable healthcare to European patients with rare, low-prevalence and complex diseases.1ERN ReCONNET is the European Reference Network on Connective Tissue and Musculoskeletal Diseases and covers 10 musculoskeletal and connective tissue diseases (rCTDs): antiphospholipid syndrome (APS), Ehlers-Danlos syndromes (EDS), idiopathic inflammatory myopathies (IIM), IgG4-related diseases (IgG4), mixed connective tissue diseases (MCTD), relapsing polychondritis (RP), Sjögren’s syndrome (SS), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and undifferentiated connective tissue diseases (UCTD). ERN ReCONNET currently has 55 Full Members and 9 Affiliated Partners (APs) from over 23 European countries.ERN ReCONNET can be viewed as an infrastructure where all the stakeholders (health care professionals, patients, families, health care systems, hospital managers, private sectors, etc.) meet and work together to achieve common goals. One major objective of ReCONNET is to promote a partnership with patients (patients’ advocates – ePAGs). Since 2017 this objective has been pursued by starting to ensure and promote patients’ representation and their active involvement in all the ERN activities. In fact, the ePAG advocates have been involved in different levels of the network’s governance: the Steering Committee, the respective Disease Groups where they collaborate to plan and implement activities, and more recently in the Working Groups (WG) where they act as co-chairs in three WGs. ePAG representatives provide patients’ opinions and input in the different ERN activities, collaborate in the evaluation of the ERN actions, contribute to research, participate to dissemination activities, and ensure that patient’s rights and choices are considered in decision-making.Thanks to this collaboration, the opinions, needs and priorities of the ePAG advocates and of their communities have been integrated into the activities of ERN ReCONNET. ePAG advocates and patients’ representatives have participated to research activities, co-authored many ReCONNET publications, participated actively as speakers to ERN meetings and in the first ERN ReCONNET congress held in Brussels in 2023, and have disseminated ERN ReCONNET activities at international meetings including EULAR.All these activities are promoting the culture of an effective and solid patient-clinician partnership and are triggering a cultural change in the healthcare ecosystem at international level. European Reference Network on Rare and Complex Connective Tissue and Musculoskeletal Diseases Website. https://reconnet.ern-net.eu . Accessed July 2023.Learning ObjectivesExplain the value of ERN ReCONNET’s infrastructure in supporting patients, their families and healthcare professionals in working together to achieve common goalsDiscuss the value of patient representation and their active involvement in all the ERN activities to ensure patients’ rights and choices are considered in clinical decision making.

Health related quality of life (HRQOL) improvement in patients with SLE is defined as one of the treatment goals in the Treat to Target (T2T) recommendations and the 2019 EULAR recommendations for the management of SLE.1 2 However, the definitions of remission and low disease activity (LLDAS) do not address the health-related quality of life or disease burden. In fact, the physicians’ view on lupus dominated the development of remission criteria and it was postulated that a control of disease activity would improve QOL in patients with SLE.The relationship between activity, organ damage, and HRQOL, however, remains complex and controversial, and the value of activity and damage indices as predictors of patient quality of life continues to be debated.3 The attainment of remission in SLE represents the main treatment target, but QOL and fatigue are still insufficiently controlled in the state of remission and, despite improvement of disease activity, QOL can remain unchanged over several years.A patient’s perspective is still not accepted as equivalent to the physician’s perspective in treatment decisions. HRQOL is neither directly nor indirectly captured by disease activity instruments. Therefore, a better understanding of the patients’ experiences with the disease is crucial.4Looking at the evidence of patient reported outcomes (PROs) as treatment targets for SLE, it is important to consider that, in clinical trials, the target response is mostly defined by changes in disease activity instruments and physician global assessments, while PROs were never used as the primary endpoint. Studies to integrate the patient’s perspective with the physician’s definition of remission and low disease activity are needed.ReferencesFanouriakis A, et al. 2019 update of the EULAR recommendations for the management of systemic lupus erythematosus. Ann Rheum Dis 2019 Jun;78(6):736–745.Morand EF, Mosca M. Treat to target, remission and low disease activity in SLE. Best Pract Res Clin Rheumatol 2017 Jun;31(3):342–350.Shi Y, Li M, et al. Relationship between disease activity, organ damage and health-related quality of life in patients with systemic lupus erythematosus: a systemic review and meta-analysis. Autoimmun Rev 2021 Jan;20(1):102691.Kernder A, et al. The patient’s perspective: are quality of life and disease burden a possible treatment target in systemic lupus erythematosus? Rheumatology (Oxford) 2020 Dec 5;59(Suppl5):v63-v68.Learning ObjectivesDiscuss quality of life in SLE, its determinants, discordance between physician’s outcomes measures and PROs and the significance of PROs in clinical trials

Our objective was to update the EULAR recommendations for the management of systemic lupus erythematosus (SLE), based on emerging new evidence. We performed a systematic literature review (01/2007–12/2017), followed by modified Delphi method, to form questions, elicit expert opinions and reach consensus. Treatment in SLE aims at remission or low disease activity and prevention of flares. Hydroxychloroquine is recommended in all patients with lupus, at a dose not exceeding 5 mg/kg real body weight. During chronic maintenance treatment, glucocorticoids (GC) should be minimised to less than 7.5 mg/day (prednisone equivalent) and, when possible, withdrawn. Appropriate initiation of immunomodulatory agents (methotrexate, azathioprine, mycophenolate) can expedite the tapering/discontinuation of GC. In persistently active or flaring extrarenal disease, add-on belimumab should be considered; rituximab (RTX) may be considered in organ-threatening, refractory disease. Updated specific recommendations are also provided for cutaneous, neuropsychiatric, haematological and renal disease. Patients with SLE should be assessed for their antiphospholipid antibody status, infectious and cardiovascular diseases risk profile and preventative strategies be tailored accordingly. The updated recommendations provide physicians and patients with updated consensus guidance on the management of SLE, combining evidence-base and expert-opinion.

ObjectiveTo update the 2012 EULAR/ERA–EDTA recommendations for the management of lupus nephritis (LN).MethodsFollowing the EULAR standardised operating procedures, a systematic literature review was performed. Members of a multidisciplinary Task Force voted independently on their level of agreeement with the formed statements.ResultsThe changes include recommendations for treatment targets, use of glucocorticoids and calcineurin inhibitors (CNIs) and management of end-stage kidney disease (ESKD). The target of therapy is complete response (proteinuria <0.5–0.7 g/24 hours with (near-)normal glomerular filtration rate) by 12 months, but this can be extended in patients with baseline nephrotic-range proteinuria. Hydroxychloroquine is recommended with regular ophthalmological monitoring. In active proliferative LN, initial (induction) treatment with mycophenolate mofetil (MMF 2–3 g/day or mycophenolic acid (MPA) at equivalent dose) or low-dose intravenous cyclophosphamide (CY; 500 mg × 6 biweekly doses), both combined with glucocorticoids (pulses of intravenous methylprednisolone, then oral prednisone 0.3–0.5 mg/kg/day) is recommended. MMF/CNI (especially tacrolimus) combination and high-dose CY are alternatives, for patients with nephrotic-range proteinuria and adverse prognostic factors. Subsequent long-term maintenance treatment with MMF or azathioprine should follow, with no or low-dose (<7.5 mg/day) glucocorticoids. The choice of agent depends on the initial regimen and plans for pregnancy. In non-responding disease, switch of induction regimens or rituximab are recommended. In pure membranous LN with nephrotic-range proteinuria or proteinuria >1 g/24 hours despite renin–angiotensin–aldosterone blockade, MMF in combination with glucocorticoids is preferred. Assessment for kidney and extra-renal disease activity, and management of comorbidities is lifelong with repeat kidney biopsy in cases of incomplete response or nephritic flares. In ESKD, transplantation is the preferred kidney replacement option with immunosuppression guided by transplant protocols and/or extra-renal manifestations. Treatment of LN in children follows the same principles as adult disease.ConclusionsWe have updated the EULAR recommendations for the management of LN to facilitate homogenization of patient care.

The objective was to develop evidence-based recommendations for the management of antiphospholipid syndrome (APS) in adults. Based on evidence from a systematic literature review and expert opinion, overarching principles and recommendations were formulated and voted. High-risk antiphospholipid antibody (aPL) profile is associated with greater risk for thrombotic and obstetric APS. Risk modification includes screening for and management of cardiovascular and venous thrombosis risk factors, patient education about treatment adherence, and lifestyle counselling. Low-dose aspirin (LDA) is recommended for asymptomatic aPL carriers, patients with systemic lupus erythematosus without prior thrombotic or obstetric APS, and non-pregnant women with a history of obstetric APS only, all with high-risk aPL profiles. Patients with APS and first unprovoked venous thrombosis should receive long-term treatment with vitamin K antagonists (VKA) with a target international normalised ratio (INR) of 2–3. In patients with APS with first arterial thrombosis, treatment with VKA with INR 2–3 or INR 3–4 is recommended, considering the individual’s bleeding/thrombosis risk. Rivaroxaban should not be used in patients with APS with triple aPL positivity. For patients with recurrent arterial or venous thrombosis despite adequate treatment, addition of LDA, increase of INR target to 3–4 or switch to low molecular weight heparin may be considered. In women with prior obstetric APS, combination treatment with LDA and prophylactic dosage heparin during pregnancy is recommended. In patients with recurrent pregnancy complications, increase of heparin to therapeutic dose, addition of hydroxychloroquine or addition of low-dose prednisolone in the first trimester may be considered. These recommendations aim to guide treatment in adults with APS. High-quality evidence is limited, indicating a need for more research.

Background Remission or the lowest possible disease activity is the main target in the management of systemic lupus erythematosus (SLE). Anyway, conflicting data are present in the literature regarding the correlation between physician-driven definitions and patient perception of the disease. The objective of this study is to evaluate the relationship between the definition of lupus low disease activity state (LLDAS) and patient’s health-related quality of life (HRQoL). Methods This is a cross-sectional, monocentric study. Adult SLE patients were included. For each patient, demographics, disease duration, medications, comorbidities, organ damage, active disease manifestations and SELENA-SLEDAI were assessed. Patients have been categorised as follows: LLDAS, remission and active disease. Each patient completed the following patient-reported outcomes (PROs): SF-36, LIT, FACIT-Fatigue and SLAQ. A SLAQ score < 6 (25° percentile of our cohort) was used as the cut-off value to define a low disease activity state according to patient self-evaluation. Results We enrolled 259 consecutive SLE patients (mainly female and Caucasian, mean age 45.33 ± 13.14 years, median disease duration 14 years). 80.3% were in LLDAS, of whom 82.2% were in remission; 19.7% were active. No differences emerged for any of the PROs used between the LLDAS and the active group. Considering the LLDAS subgroup, we identified 56 patients with a subjective low disease activity (SLAQ < 6) and we defined them as “concordant”; the remaining 152 patients in LLDAS presented a subjective active disease (SLAQ ≥ 6) and were defined “discordant”. Discordant patients presented more frequently ongoing and past joint involvement ( p  < 0.05) and a diagnosis of fibromyalgia ( p  < 0.01); furthermore, they were more likely to be on glucocorticoid therapy ( p  < 0.01). Discordant patients showed a significantly poorer HRQoL, assessed by all PROs ( p  < 0.0001). Conclusions Joint involvement, glucocorticoid therapy and comorbid fibromyalgia resulted to be the most important variables determining the poor concordance between patient and physician perspective on the disease.

Behçet's syndrome (BS) is a rare systemic vasculitis. Clinical manifestations in BS are frequently clustered rather than discrete, and the concept that distinct clinical phenotypes may exist in BS has recently emerged. The aim of the present work was to identify and analyze the disease phenotypes in a monocentric historical cohort of patients with BS. A total of 202 patients with BS diagnosis followed up at the Behçet Clinic of the Azienda Ospedaliero-Universitaria Pisana were identified, and demographics, clinical, and therapeutic data were retrospectively collected. Pairwise correlation among variables was evaluated by means of Pearson or Spearman correlation coefficient. A multiple correspondence analysis was performed to investigate the possible phenotypes resulting from the different patterns of associations among the demographic and clinical variables. Most of the patients were female (67%), Caucasian (92%), and HLA-B51 carriers (65.5%). Mean age at disease onset was 30.06 ± 11.39 years, and oral ulcers (OU) and genital ulcers (GU) were the most common manifestations (96% and 61%, respectively). According to bivariate correlation analysis, significant positive correlations were observed between skin lesions and both OU ( = 0.005) and arthritis ( = 0.014), as well as pathergy ( = 0.001), gastrointestinal (GI) symptoms ( = 0.001), and other involvement (fever and serositis) ( = 0.015). Neurological involvement was significantly and positively associated with ocular lesions ( = 0.0114), GI symptoms ( = 0.030), pathergy (rho = 0.147, p = 0.037) and vein thromboses ( = 0.037). Despite the high heterogeneity, four disease phenotypes emerged from the MCA: (A) male Caucasians with greater age at onset and at diagnosis than the median values, with OU and GU, skin lesions, erythema nodosum (EN), arthritis, and GI symptoms; (B) co-existence of benign subset and pathergy; (C) orchitis/epididymitis associated with neurological involvement and ocular lesions; and (D) GI symptoms plus endoscopic lesions, large vessel disease (both arterial and venous), and other involvement. This study provides valuable insights into the possible BS clinical phenotypes, and the results partially agree with previous association studies on European and extra-European cohorts. Observational comparative studies are warranted to assess the response of tailored phenotype-based therapeutic approaches.

Infliximab (IFX) is an immunosuppressive drug widely used for the treatment of patients with Behçet's syndrome (BS) with severe or refractory organ involvements. The aim of this study was to evaluate IFX survival, clinical response and safety profile in a monocentric cohort of BS patients. Patients with BS treated with IFX intravenously across a 20-year period were retrospectively-prospectively examined. Total duration of therapy and drug retention until the end of follow-up were calculated, as well as the reasons of discontinuation, including adverse events. Clinical response, expressed as changes in BDCAF (Behçet's Disease Current Activity Form) indexacross the follow-up period, were evaluated and compared among patients. Sixty patients with BS were treated with IFX over a 20-year period. Overall drug retention was 45%, with survival rates of 78.3% at 1 year, 63.3% at 2 years, and 35% at 5 years (median duration 37 months, IQR 17-72). Most discontinuations occurred after 24 months and were mainly due to loss of efficacy (25%), de novo manifestations (21%), or allergic reactions (18%). Clinical activity improved markedly, with a mean BDCAF reduction of 4 points, ranging from -3.0 in mild to -5.7 in highly active disease. Continuers showed lower BDCAF scores at last follow-up and achieved higher remission and major response rates compared with discontinuers. Younger age and female sex were associated with higher discontinuation risk. Over the two decades, IFX indications shifted from major-organ involvement to predominantly refractory muco-cutaneous disease. IFX showed good safety profile and excellent clinical response in this real-world BS cohort, with a drug survival of 45% within a median treatment duration of 37 months.

The aim of this study was to investigate the incidence and clinical presentation of SARS-CoV-2 infections in a Systemic Lupus Erythematosus (SLE) cohort; to assess correlations with disease characteristics and rheumatic therapy; and to evaluate the occurrence of treatment discontinuation and its impact on disease activity. SLE patients monitored by a single Italian centre were interviewed between February and July 2020. Patients were considered to be positive for SARS-CoV-2 infections in case of 1) positive nasopharyngeal swab; 2) positive serology associated with COVID19 suggesting symptoms. The following data were also recorded: clinical symptoms, adoption of social distancing measures, disease activity and treatment discontinuation. 332 patients were enrolled in the study. Six patients (1.8%) tested positive for SARS-CoV-2 infection, with the incidence being significantly higher in the subgroup of patients treated with biological Disease-Modifying Anti-Rheumatic Drugs (p = 0.005), while no difference was observed for other therapies, age at enrollment, disease duration, type of cumulative organ involvement or adoption of social isolation. The course of the disease was mild. Thirty-six patients (11.1%) discontinued at least part of their therapy during this time period, and 27 (8.1%) cases of disease flare were recorded. Correlation between flare and discontinuation of therapy was statistically significant (p<0.001). No significant increase of rate of flare in a subgroup of the same patients during 2020 was observed. Treatment discontinuation seems to be an important cause of disease flare. Our findings suggest that abrupt drug withdrawal should be avoided or evaluated with caution on the basis of individual infection risk and comorbidities.

European League Against Rheumatism and are jointly supporting multiphase development of systemic lupus erythematosus (SLE) classification criteria based on weighted criteria and a continuous probability scale. Prior steps included item generation, item reduction and hierarchical organisation of candidate criteria using an evidence-based approach. Our objectives were to determine relative weights using multicriteria decision analysis (MCDA) and to set a provisional threshold score for SLE classification. An SLE Expert Panel (8 European, 9 North American) submitted 164 real, unique cases with a wide range of SLE probability in a standardised format. Using the candidate criteria, experts scored and rank-ordered 20 representative cases. At an in-person meeting, experts reviewed inter-rater reliability of scoring, further refined criteria definitions and participated in an MCDA exercise. Based on expert consensus decisions on pairwise comparisons of criteria, 1000minds software calculated criteria weights and rank-ordered the remaining 144 cases based on their additive scores. The score of the lowest-ranked case for which complete expert consensus was achieved defined the provisional threshold classification score. Inter-rater reliability of scoring cases with the candidate criteria was good. MCDA involved 74 pairwise decisions and was repeated for the arthritis and mucocutaneous domains when the initial ranking of some cases did not match expert opinion. After criteria weights and additive scores were recalculated once, experts reached consensus for SLE classification for all cases scoring>83. Using an iterative process, the candidate criteria definitions were refined, preliminary weights were calculated and a provisional threshold score for SLE classification was determined.