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The treatment of systemic lupus erythematosus involves a balance between control of disease activity and prevention of therapeutic harm that requires careful optimization. In this Review, the authors discuss available and emerging therapeutic strategies that exploit the current drug armamentarium.

Case 1. A young female with SLE and relapsing-remitting arthritisA 14-year-old Caucasian girl presented to her physician with malar and trunk photosensitivity rashes in Summer 2010. In October 2010, she developed fever, pleurisy, polyarthritis and mild proteinuria (<0.5 g/day). Laboratory tests showed positive antinuclear antibodies (ANA), anti-double-stranded DNA (anti-dsDNA, anti-U1RNP, anti-Sm and decreased C3. A diagnosis of systemic lupus erythematosus (SLE) was made and she was treated with IV pulses of methylprednisolone (MPN), 500 mg x 3, then oral prednisone starting from 25 mg/day, then tapered to 5 mg per day plus hydroxychloroquine (HCQ) 400 mg/day. After almost one-year prednisone was withdrawn due to clinical remission1; unfortunately, in 2017–2018, she experienced three episodes of SLE articular and skin flares; thus, prednisone was reintroduced (25 mg/day than tapered to 15 mg/day always plus HCQ). It must be mentioned that she experienced recurrent genital herpes simplex, 1–2 episodes/year, starting from 2015. In June 2018, she had a new hospital admission due to polyarthritis (DAS28 7.16), fever, malar rash, fatigue and lymphadenopathy, and muscular weakness. She had high C-reactive protein (CRP) 18.3 mg/l, lymphopenia 700/mm3, C3 0.83 mg/dl, increased anti-dsDNA 1.096 KIU/L and creatin kinase (CK) 965 U/L. Muscular MRI showed mild oedema at proximal muscle of the limbs. At that time, she was on prednisone 25 mg/day and HCQ 400 mg/day. [The best therapeutic options in this case will be discussed with the participants at the workshop.] However, we increased the daily dosage of prednisone and we added belimumab.2 3 After belimumab initiation we observed a progressive decline in SLEDAI-2K score and in DAS-28 score, a decrease in the prednisone dose taken by the patient, a decrease in anti-dsDNA serum levels and an increase in C3 and C4 serum levels. Regarding safety, we did not observe infusion reactions.ReferencesZen M, et al. Defining the targets in SLE management: insights and unmet gaps. Ann Rheum Dis. 2022 Nov;81(11):1483–1485. doi: 10.1136/ard-2022-222991. Epub 2022 Aug 25. PMID: 36008131.Zen M, et al. Early and late response and glucocorticoid-sparing effect of belimumab in patients with systemic lupus erythematosus with joint and skin manifestations: results from the belimumab in real life setting study-joint and skin (BeRLiSS-JS). J Pers Med. 2023 Apr 20;13(4):691. doi: 10.3390/jpm13040691.Gatto M, et al. Early disease and low baseline damage as predictors of response to belimumab in patients with systemic lupus erythematosus in a real-life setting. Arthritis Rheumatol. 2020 Aug;72(8):1314–1324. doi: 10.1002/art.41253. Epub 2020 Jun 12.Case 2. A patient with persistent arthritis leading to Jaccoud’s arthropathyA 32-year-old Caucasian female started to complain fever and headache in July 2010. In August 2010, she developed subacute lupus on upper arms, leukopenia and thrombocytopenia, arthritis, with mild arthritis at hands and wrists. Blood tests showed leukopenia (WBC 3,467/mm3), low C3 (0.79 g/L), increase gamma-globulins (24.2%), positive ANA, anti-dsDNA, anti-SSA, anti-P-ribosomal, and rheumatoid factor. The diagnosis of SLE was made and she was treated with prednisone 25 mg per day, progressively tapered to 5 mg/day, and HCQ 400 mg with improvement of her clinical manifestations. She went well until 2014, with the exception of mild but persistent inflammatory arthralgias.1 In May 2015 she developed skin and joint flares with subacute cutaneous lupus and arthritis at hands and wrists with mild Jaccoud’s deformities, leukopenia (WBC 2.320/mm3), increase in anti-dsDNA (199 KIU/L), decrease in C3. Notably, she had SLEDAI-2K: 7, CLASI activity: 10, DAS28: 4.58, SLICC-DI: 1. At that time she was on prednisone 25 mg and HCQ 400 mg. The best therapeutic options in this case will be discussed with the participants at the workshop. We increased the prednisone dose and started belimumab in June 2015. In May 2017 she developed a new flare with diffuse subacute lupus on upper arms, chest and back after sun exposition and persistent arthritis, leukopenia (WBC 3.722/mm3), increased anti-dsDNA (134 KIU/L), decreased complement levels (C3 0.79 g/l). She had SLEDAI-2K: 10, CLASIa: 11, DAS28: 4.52, SLEDAS:2 5.96, SLICC-DI: 0, PGA: 1.3. We continued belimumab and added mycophenolate mofetil (2 g/day) and this approach was effective. In august 2020 at the time of the 70th belimumab administration she presented mild skin involvement (few little red lesions on left arm), a worsening of Jaccoud’s joint deformities with inflammatory arthralgias and right wrist arthritis, positive anti-dsDNA (96 KUI/L), and leukopenia (WBC 2900 mm3); C3 and C4 within normal range; SLEDAI-2K 5; SLEDAS 8.05; CLASIa 2; DAS28 3.56; SLICC-DI 1 (no new damage). She was on prednisone 5 mg/day, belimumab 640 mg IV every 4 weeks, chloroquine 250 mg/day, MMF 2 g/day. Since she was not at target according to the treat-to-target strategy,1 3 in September 2020 we administered rituximab with a good result and in February 2021 we restarted belimumab.ReferencesGatto M, et al. New therapeutic strategies in systemic lupus erythematosus management. Nat Rev Rheumatol. 2019 Jan;15(1):30–48. doi: 10.1038/s41584-018-0133-2.Jesus D, et al. Derivation and validation of the SLE disease activity score (SLE-DAS): a new SLE continuous measure with high sensitivity for changes in disease activity. Ann Rheum Dis. 2019 Mar;78(3):365–371. doi: 10.1136/annrheumdis-2018-214502. Epub 2019 Jan 9.Jesus D, et al. Systemic lupus erythematosus disease activity score (SLE-DAS) enables accurate and user-friendly definitions of clinical remission and categories of disease activity. Ann Rheum Dis. 2021 Dec;80(12):1568–1574. doi: 10.1136/annrheumdis-2021-220363. Epub 2021 Aug 18.Learning ObjectivesDiscuss the different treatment approach in SLE patients with relapsing-remitting or persistent arthritisDiscuss how to treat patients with arthritis to the target and how to manage biologic treatment in SLE

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.

The present work analyses a hybrid free electron laser (FEL) scheme where the oscillator is based on a radiation source operating with a slow-wave guiding structure as, for instance, a Cerenkov FEL or a Smith–Purcell FEL. Such devices, often running in transverse magnetic (TM) modes, present a longitudinal electric field which can easily affect the longitudinal electrons’ velocities, inducing an energy modulation on the beam. Such a modulation, properly controlled, can induce a strong radiation emission in a magnetic undulator properly designed to operate as a radiator. General considerations will be exposed together with a practical numerical example in the far infrared region of the spectrum.

A precise definition of low disease activity (LDA) in systemic lupus erythematosus (SLE) is crucial for managing patients according to a T2T strategy.1 Lupus low disease activity state (LLDAS) was proven to be a valid outcome measure,2 since its achievement is associated with a significant decrease in disease flares and damage accrual, as well as with improved HR-QoL.Some pitfalls, however, may affect the definition of LLDAS:LLDAS is not aligned with the DORIS definition of remission, particularly in the most important item - SLEDAI. Indeed, SLEDAI≤4 (including serology) is considered in the definition of LLDAS, by contrast clinical SLEDAI=0 is included in the DORIS definition. We know that a significant proportion of patients with SLEDAI≤4 has a clinical SLEDAI=0, since they are patients with serologically active clinical quiescent disease (SACQ). As a consequence, there is a great overlap between LLDAS and DORIS remission, i.e. the majority of patients in LLDAS are also in remission on therapy, according to the DORIS definition of remission.3 Thus, LLDAS cannot discriminate between patients in LDA and those in remission.4The item that could theoretically distinguish between remission and LLDAS is physician global assessment (PGA), which has a cut-off of ≤0.5 for remission and ≤1.0 for LLDAS. It is, however, very difficult to predict the phenotype of patients with a PGA in between 0.5 and 1.0, and a poor inter-rater and intra-rater reliability of PGA has been recently confirmed in a meta-analysis, which highlighted the need for PGA standardisation.5 Notably, in a recent paper testing different definitions of remission, PGA did not increase the performance of clinical SLEDAI=0 in predicting damage progression.6Thus, the remaining item able to distinguish patients in remission from those in LLDAS is glucocorticoid intake: ≤5 mg in remission according to the DORIS definition and ≤7.5 mg in LLDAS. It has, however, been shown that the great majority of patients in LLDAS receive a dosage of prednisone ≤5 mg/day; moreover, the habit of prescribing prednisone largely varies among rheumatologists,7 and cannot be easily standardised.In addition, the major reason why LLDAS cannot capture patients in ‘true’ LDA is that it is based on the SLEDAI score, i.e. a binomial disease activity index that measures disease activity in each organ domain in terms of ‘present’ or ‘absent’, but it is not able to discriminate the level of disease activity within any single organ domain.A new disease activity index named SLE-DAS (http://sle-das.eu) has recently been proposed and validated,8 which measures disease activity in a continuous fashion and, thus, is more sensitive to clinical changes compared with the SLEDAI. The SLE-DAS includes some items that are not considered in the SLEDAI, namely lupus enteritis, cardiac and pulmonary manifestations and haemolytic anaemia. In addition, some items that are binomial in the SLEDAI were turned into continuous in the SLE-DAS, including arthritis, proteinuria, thrombocytopenia, and leukopenia. The SLE-DAS cut-offs for defining remission and LDA have recently been derived and validated.9 10Learning ObjectivesDiscuss the hurdles in defining low disease activity in SLE and the pitfalls of LLDASDiscuss why LLDAS does not capture patients with ‘true’ LDAExplain lupus LDA in clinical practice, and discuss other instruments that might identify patients in LDA better than LLDASReferencesGatto M, et al. New therapeutic strategies in systemic lupus erythematosus management. Nat Rev Rheumatol 2019 Jan;15(1):30–48.Franklyn K, et al. Definition and initial validation of a Lupus Low Disease Activity State (LLDAS). Ann Rheum Dis 2016 Sep;75(9):1615–1621.Golder V, Tsang-A-Sjoe MWP. Treatment targets in SLE: remission and low disease activity state. Rheumatology (Oxford). 2020 Dec 5;59(Suppl5):v19–v28.Zen M, et al. Lupus low disease activity state is associated with a decrease in damage progression in Caucasian patients with SLE, but overlaps with remission. Ann Rheum Dis 2018 Jan;77(1):104–110.Chessa E, et al. Use of Physician Global Assessment in systemic lupus erythematosus: a systematic review of its psychometric properties. Rheumatology (Oxford). 2020 Dec 1;59(12):3622–3632.Saccon F, et al. Remission in systemic lupus erythematosus: testing different definitions in a large multicentre cohort. Ann Rheum Dis 2020 Jul;79(7):943–950.Chen HL, et al. Cumulative Burden of Glucocorticoid-related Adverse Events in Patients with Systemic Lupus Erythematosus: Findings from a 12-year Longitudinal Study. J Rheumatol 2018 Jan;45(1):83–89.Jesus D, et al. Derivation and validation of the SLE Disease Activity Score (SLE-DAS): a new SLE continuous measure with high sensitivity for changes in disease activity. Ann Rheum Dis 2019 Mar;78(3):365–371.Jesus D, et al. Systemic Lupus Erythematosus Disease Activity Score (SLE-DAS) enables accurate and user-friendly definitions of clinical remission and categories of disease activity. Ann Rheum Dis 2021 Dec;80(12):1568–1574.Assunção H, et al. Definition of Low Disease Activity State based on the SLE-DAS: Derivation and validation in a multicentre real-life cohort. Rheumatology (Oxford). 2021 Dec 3:keab895.

Contrast-enhanced magnetic resonance imaging (MRI) is considered the diagnostic standard for identifying involvement of the temporomandibular joint by juvenile idiopathic arthritis. Early or active arthritis is shown as bone marrow oedema, joint effusion, synovial thickening and increased joint enhancement. Subsequent joint damage includes characteristic deformity of the mandibular condyle, bone erosion, disk abnormalities and short mandibular ramus due to impaired growth. In this pictorial essay, we illustrate normal MRI findings and growth-related changes of the temporomandibular joint in children. The rationale and practical application of semiquantitative MRI assessment of joint inflammation and damage are discussed and presented. This atlas can serve as a reference for grading temporomandibular joint arthritis according to the scoring systems proposed by working groups of OMERACT (Outcome Measures in Rheumatology and Clinical Trials) and the EuroTMjoint research network. Systematic assessment of the level of inflammation, degree of osteochondral deformation, and growth of the mandibular ramus by MRI may aid in monitoring the course of temporomandibular joint arthritis and evaluating treatment options.

We aimed to investigate the methodologies on image acquisition of normative data of high-resolution peripheral quantitative computed tomography (HR-pQCT) in children, adolescents and/or young adults (up to 25 years) and to determine their normative data based on available literature. A literature search was conducted in MEDLINE, EMBASE and Web of Science from 1947 to July 2019. Quality of articles was assessed using Standards for Reporting of Diagnostic Accuracy (STARD) scoring system and Modified Newcastle-Ottawa scale (NOS). Articles which fitted the following criteria were combined to meta-analysis: age range (15 to 22.6 years), references at tibia (22.5mm) and/or radius (9.0 to 9.5mm). Eight articles were ultimately included in the systematic review and 4 of them that filled the criteria were summarised in meta-analysis. The results of random effects model of HR-pQCT parameters of the 4 articles were as follows: 1)Radius: bone volume fraction (BT/BV) [estimate 0.17:0.1229(lower)-0.2115 (upper); trabecular number (Tb_N):2.08(2.03-2.12); trabecular thickness (Tb.Th):0.07 (0.07-0.0.08); trabecular separation (Tb.Sp):0.41 (0.38-0.42); cortical thickness (Ct.Th):0.85 (0.76-0.94); cortical porosity (Ct.Po):1.53 (0.63-2.44); total area (Tt.Ar):263.66(-385.3-912.6); total bone density (Tt-vBMD):280.5 (73.1-487.7); Trabecular density (Tb-vBMD):223.6 (47.1-400.09), and cortical density (CT.vBMD):765.9 (389.1-1142.8). 2)Tibia: BT/BV:0.18 (0.17-0.19); Tb_N:2.02 (1.83-2.2); Tb.Th:0.08 (0.80-0.09); Tb.Sp:0.40(0.36-0.44); Ct.Th:1.32(1.26-1.38); Ct.Po:3.15 (1.1-5.2); Tt.Ar:693.1(150.2-1235.8); Tt-vBMD:343.76 (335.5-352.1); Tb-vBMD:223.6 (213.37 (193.5-233.2), and CT.vBMD:894.3 (857.6-931.1). There is overall 'fair' evidence on reporting of results of normative data of HR-pQCT parameters in children, adolescents and/or young adults. However, data are scarce pointing out to the urgent need for standardization of acquisition parameters and guidelines on the use of HR-PQCT in these populations.

Remission and low disease activity (LDA) are the most important targets to achieve in systemic lupus erythematosus (SLE) management.1–4 Belimumab is the only biologic drug approved for SLE and whether or not it can help lupus patients to achieve these targets is a critical question.In a post-hoc analysis carried out in patients enrolled in BLISS-52 and BLISS-76, remission and LDA were able to discriminate response to belimumab 10 mg/kg from placebo.5 6 Notably, clinical (c) SLEDAI-2K=0 was the best discriminator6 and, importantly, in a recent multicentre cohort study including 646 patients, cSLEDAI=0 had the best performance in predicting damage accrual compared with all other definitions of remission.7 In real-life the proportion of patients who can achieve a stable low lupus disease activity state (LLDAS) and remission was higher than that obtained in randomised controlled trials, as shown in two recent studies.8 9 A recent Italian multicentre cohort study of 466 patients on the use of belimumab in clinical practice settings, with a median follow-up of 18 months (range 1–60 months), showed that 71.7% of patients achieved LDA, 61.3% SRI-4, and 41.1% remission at 12 months, with these figures being maintained over time.10 The most important independent predictors of SRI-4 response were baseline SLEDAI2K≥10, SLE duration ≤2 years and a baseline SLICC damage index=0. Independent predictors of remission and LDA were baseline SLEDAI-2K <10, baseline SLICC damage index=0 and prednisone intake ≤7.5 mg, and negative predictors of remission and LDA were number of flares in the 3 years before belimumab treatment initiation and baseline renal involvement. Notably, patients spending at least 50% of follow-up in LDA (66%) or at least 25% of follow-up in remission (42.9%) accumulated less damage at the end of the follow-up.Consequently, this study provided novel evidence that an earlier use of belimumab in patients with active SLE and low damage may maximise its efficacy in clinical practice.Learning ObjectivesExplain the importance of achieving remission or LDA in SLE managementDescribe the role of belimumab in achieving remission or LDA in post-hoc analysis of the randomised control trialsDiscuss the best use of belimumab in clinical practice settingsReferencesGatto M, Zen M, Iaccarino L, et al. New therapeutic strategies in systemic lupus erythematosus management. Nat Rev Rheumatol 2019;15(1):30–48.Zen M, Iaccarino L, Gatto M, et al. Prolonged remission in Caucasian patients with SLE: prevalence and outcomes. Ann Rheum Dis 2015;74(12):2117–22.Zen M, Iaccarino L, Gatto M, et al. The effect of different durations of remission on damage accrual: results from a prospective monocentric cohort of Caucasian patients. Ann Rheum Dis 2017;76(3):562–65.Zen M, Iaccarino L, Gatto M, et al. Lupus low disease activity state is associated with a decrease in damage progression in Caucasian patients with SLE, but overlaps with remission. Ann Rheum Dis 2018;77(1):104–10.Oon S, Huq M, Golder V, et al. Lupus Low Disease Activity State (LLDAS) discriminates responders in the BLISS-52 and BLISS-76 phase III trials of belimumab in systemic lupus erythematosus. Ann Rheum Dis 2019;78(5):629–33.Parodis I, Emamikia S, Gomez A, et al. Clinical SLEDAI-2K zero may be a pragmatic outcome measure in SLE studies. Expert opinion on biological therapy 2019;19(2):157–68.Saccon F, Zen M, Gatto M, et al. Remission in systemic lupus erythematosus: testing different definitions in a large multicentre cohort. Ann Rheum Dis 2020;79(7):943–50.Fanouriakis A, Adamichou C, Koutsoviti S, et al. Low disease activity-irrespective of serologic status at baseline-associated with reduction of corticosteroid dose and number of flares in patients with systemic lupus erythematosus treated with belimumab: A real-life observational study. Semin Arthritis Rheum 2018;48(3):467–74.Sbeih N, Mathian A, Pineton de Chambrun M, et al. Achieving lupus low-disease activity and remission states under belimumab in refractory systemic lupus erythematosus: time and organ involvement matter. Ann Rheum Dis 2019:annrheumdis-2019-215732.Gatto M, Saccon F, Zen M, et al. Early disease and low baseline damage predict response to belimumab in patients with systemic lupus erythematosus. Arthritis Rheumatol 2020 doi: 10.1002/art.41253 [published Online First: 2020/04/11]

PurposesTo review the uses of AI for magnetic resonance (MR) imaging assessment of primary pediatric cancer and identify common literature topics and knowledge gaps. To assess the adherence of the existing literature to the Checklist for Artificial Intelligence in Medical Imaging (CLAIM) guidelines.Materials and methodsA scoping literature search using MEDLINE, EMBASE and Cochrane databases was performed, including studies of > 10 subjects with a mean age of < 21 years. Relevant data were summarized into three categories based on AI application: detection, characterization, treatment and monitoring. Readers independently scored each study using CLAIM guidelines, and inter-rater reproducibility was assessed using intraclass correlation coefficients.ResultsTwenty-one studies were included. The most common AI application for pediatric cancer MR imaging was pediatric tumor diagnosis and detection (13/21 [62%] studies). The most commonly studied tumor was posterior fossa tumors (14 [67%] studies). Knowledge gaps included a lack of research in AI-driven tumor staging (0/21 [0%] studies), imaging genomics (1/21 [5%] studies), and tumor segmentation (2/21 [10%] studies). Adherence to CLAIM guidelines was moderate in primary studies, with an average (range) of 55% (34%–73%) CLAIM items reported. Adherence has improved over time based on publication year.ConclusionThe literature surrounding AI applications of MR imaging in pediatric cancers is limited. The existing literature shows moderate adherence to CLAIM guidelines, suggesting that better adherence is required for future studies.

BackgroundDr Andrea Doria is Professor and Vice-Chair of Radiology (Clinical Practice Improvement) at the University of Toronto, Research Director, Senior Scientist and Imaging Lead of Personalised Child Health, The Hospital for Sick Children (SickKids), Toronto, Canada. Over the past few decades, Dr Doria has established a track record of healthcare leadership. Based on Dr Doria’s extensive leadership experience, she believes it is essential for established healthcare leaders to be involved in cultivating emerging healthcare leaders.MethodsAn interview was conducted with Dr Doria to learn about key lessons she believes are essential for healthcare leaders to help develop the next generation. Dr Doria reflected on her leadership style and experiences, sharing what has worked to improve the effectiveness of her teams.ResultsKey messages were reflected upon, including practical ways for senior leaders to support the next generation; leadership insights gained from the pandemic; the importance of building diversity in teams and nurturing leaders from underrepresented minorities; challenges to be aware of for the future of healthcare leadership; finding inspiration from team members and essential traits for healthcare leaders.ConclusionThrough cultivating the next generation of healthcare leaders, established leaders can be involved in establishing a brighter future for healthcare. This article describes reflections and practical takeaways that can help established leaders support emerging leaders and build their leadership skills.