Incidence and prevalence of major central nervous system involvement in Systemic Lupus Erythematosus: A 3-year prospective study of 370 patients

Background: The incidence and prevalence of CNS involvement in SLE remains unclear owing to conflicting results in the published studies. The aim of the study was to evaluate the incidence and prevalence of major definite CNS events in SLE patients. Methods: 370 SLE patients with no previous history of CNS involvement were prospectively evaluated in a tertiary hospital referral center for 3 years. Major CNS manifestations were codified according to ACR definitions, including chorea, aseptic meningitis, psychosis, seizures, myelopathy, demyelinating syndrome, acute confusional state and strokes. Minor CNS events were excluded. ECLAM and SLEDAI-SELENA Modification scores were used to evaluate disease activity and SLICC/ACR Damage Index was used to assess accumulated damage. Results: 16/370 (4.3%) patients presented with a total of 23 major CNS events. These included seizures (35%), strokes (26%), myelopathy (22%), optic neuritis (8.7%), aseptic meningitis (4.3%) and acute psychosis (4.3%). Incidence was 7.8/100 person years. Among hospitalizations for SLE, 13% were due to CNS manifestations. Epileptic seizures were associated with high disease activity, while myelopathy correlated with lower disease activity and NMO-IgG antibodies (P#0.05). Stroke incidence correlated with APS coexistence (P = 0.06). Overall, CNS involvement correlated with high ECLAM and SLEDAI scores (P,0.001). Conclusions: Clinically severe CNS involvement is rare in SLE patients, accounting for 7.8/100 person years. CNS involvement correlates with high disease activity and coexistence of specific features that define the respective CNS syndromes

Disease interception with interleukin-17 inhibition in high-risk psoriasis patients with subclinical joint inflammation—data from the prospective IVEPSA study

Background A specific subset of psoriasis patients is characterized by subclinical inflammatory changes. These patients frequently present with arthralgia and have a higher risk to develop psoriatic arthritis (PsA). We hypothesized that IL-17A inhibition in this subset of patients can intercept the link between skin and joint disease and resolves pain and inflammatory changes. Methods Psoriasis, but no PsA, patients were included in the open prospective exploratory Interception in very early PsA (IVEPSA) study. Patients had to have nail or scalp involvement or a high psoriasis area severity index (PASI) (> 6) as well as inflammatory or erosive changes in MRI or CT. Patients received treatment with the anti-interleukin (IL)-17A antibody secukinumab over 24 weeks. Clinical assessments of skin and joint disease were done at baseline and after 12 and 24 weeks, MRI and CT at baseline and after 24 weeks. Results Twenty patients were included, 85% of them reporting arthralgia and 40% had tender joints at the examination. Eighty-three percent had at least one inflammatory lesion in the MRI, most of them synovitis/enthesitis. Skin disease (PASI: p < 0.002; BSA: p < 0.003) and arthralgia (VAS pain: p < 0.003) significantly improved after 24 weeks. Total PsAMRIS (p = 0.005) and synovitis subscore (p = 0.008) also significantly improved. Erosions and enthesiophytes did not progress, while bone mass in the distal radius significantly (p = 0.020) increased after 24 weeks. Conclusions These data suggest that very early disease interception in PsA is possible leading to a comprehensive decline in skin symptoms, pain, and subclinical inflammation. IVEPSA therefore provides rationale for future early interventions with the concept to prevent the onset of PsA in high-risk individuals. Trial registration Trial registry name PSARTROS; trial registry number: NCT02483234; June 26, 2015

Effect of disease-modifying anti-rheumatic drugs on bone structure and strength in psoriatic arthritis patients

Objectives To address whether the use of methotrexate (MTX) and biological disease-modifying anti-rheumatic drugs (bDMARDs) impacts bone structure and biomechanical properties in patients with psoriatic arthritis (PsA). Methods This is a cross-sectional study in PsA patients receiving no DMARDs, MTX, or bDMARDs. Volumetric bone mineral densities (vBMDs), microstructural parameters, and biomechanical properties (stiffness/failure load) were determined by high-resolution peripheral quantitative CT and micro-finite element analysis in the respective groups. Bone parameters were compared between PsA patients with no DMARDs and those receiving any DMARDs, MTX, or bDMARDs, respectively. Results One hundred sixty-five PsA patients were analyzed, 79 received no DMARDs, 86 received DMARDs, of them 52 bDMARDs (TNF, IL-17- or IL-12/23 inhibitors) and 34 MTX. Groups were balanced for age, sex, comorbidities, functional index, and bone-active therapy, while disease duration was longest in the bDMARD group (7.8 ± 7.4 years), followed by the MTX group (4.6 ± 7.4) and the no-DMARD group (2.9 ± 5.2). No difference in bone parameters was found between the no-DMARD group and the MTX group. In contrast, the bDMARD group revealed significantly higher total (p = 0.001) and trabecular vBMD (p = 0.005) as well as failure load (p = 0.012) and stiffness (p = 0.012). In regression models, age and bDMARDs influenced total vBMD, while age, sex, and bDMARDs influenced failure load and stiffness. Conclusion Despite longer disease duration, bDMARD-treated PsA patients benefit from higher bone mass and better bone strength than PsA patients receiving MTX or no DMARDs. These data support the concept of better control of PsA-related bone disease by bDMARDs

Central nervous system involvement in autoimmune diseases: a clinical and neuroimaging study: a study of autoantibodies and prognostic factors

The aim of the study was to evaluate the incidence and prevalence of major definite CNS events in SLE patients. 370 SLE patients with no previous history of CNS involvement were prospectively evaluated for 3 years. Major CNS manifestations were codified according to the American College of Rheumatology (ACR) definitions, including chorea, aseptic meningitis, psychosis, seizures, myelopathy, demyelinating syndrome, acute confusional state and strokes. Minor CNS events were excluded. Sixteen out of 370 (4.3%) patients presented with a total of 23 major CNS events. These included seizures (35%), strokes (26%), myelopathy (22%), optic neuritis (8.7%), aseptic meningitis (4.3%) and acute psychosis (4.3%). Incidence was 7.8 cases/ 100 person years. Among hospitalizations for SLE, 13% were due to CNS manifestations. Epileptic seizures were associated with high disease activity, while myelopathy correlated with lower disease activity and NMO-IgG antibodies (P≤0.05). Stroke incidence correlated with APS coexistence (P=0.06). Overall, CNS involvement correlated with high ECLAM and SLEDAI scores (P<0.001).The second part of the study evaluated the specificity of the autoantibodies against aquaporin-4 (AQP4), a marker and a pathogenetic factor in Neuromyelitis Optica (NMO, Devic’s syndrome). The aim of the study was to identify B-cell antigenic linear epitopes of the AQP4 protein. Sera from 21 patients positive for anti-AQP4 antibodies, 23 SLE and 23 pSS patients without neurologic involvement, 58 Multiple Sclerosis patients and from 28 healthy individuals were used. Eleven peptides, spanning the entire intracellular and extracellular domains of the AQP4 molecule, were synthesized, and all sera were screened for anti-peptide antibodies by ELISA. Specificity was evaluated by homologous inhibition assays.NMO-positive sera exhibited reactivity against 3 different peptides spanning the sequences aa1-22 (AQPpep1) (42.9% of patients), aa88-113 (AQPpep4) (33%) and aa252-275 (AQPpep8) (23.8%). All epitopes were localized in the intracellular domains of AQP4. Homologous inhibition rates were ranging from 71.1% to 84.3%. A 73% sequence homology was observed between AQPpep8 aa257-271 and the aa219-233 domain of the Tax1-HTLV-1 binding protein (TAX1BP1), a host protein associated with replication of the HTLV-1 virus. Antibodies against the AQP4 and the TAX1BP1 15-mer peptides were detected in 26.3% (N=5) and 31.6% (N=6) of NMO-positive sera, respectively (rs=0.81, P<0.0001). When the RRMS sera were evaluated, they all tested negative for anti-AQP4 antibodies using Cell Based Assays (CBA), but surprisingly 13% of them reacted with the peptide AQPpep8 (aa252-275). PMS sera showed no specific reactivity.Στόχος του κλινικού σκέλους της παρούσας διδακτορικής διατριβής ήταν η εκτίμηση του επιπολασμού και της επίπτωσης των μείζονων συμβαμάτων από το ΚΝΣ σε ασθενείς με ΣΕΛ, τα οποία να αποδίδονται με σαφήνεια στη νόσο. 370 ασθενείς με ΣΕΛ, χωρίς ιστορικό προηγούμενης προσβολής του ΚΝΣ, παρακολουθήθηκαν προοπτικά για 3 έτη. Οι μείζονες εκδηλώσεις από το ΚΝΣ καθορίστηκαν βάσει των ορισμών του American College of Rheumatology (ACR), και περιελάμβαναν τη χορεία, την άσηπτη μηνιγγίτιδα, την ψύχωση, τις επιληπτικές κρίσεις, τη μυελοπάθεια, το απομυελινωτικό σύνδρομο, την οξεία συγχυτική κατάσταση και τα αγγειακά εγκεφαλικά επεισόδια (ΑΕΕ). Τα ελάσσονα νευρολογικά συμβάματα αποκλείστηκαν. Δεκαέξι από τους 370 ασθενείς (4.3%) εμφάνισαν συνολικά 23 μείζονα συμβάματα από το ΚΝΣ. Αυτά περιελάμβαναν επιληπτικές κρίσεις (35%), ΑΕΕ (26%), μυελοπάθεια (22%), οπτική νευρίτιδα (8.7%), άσηπτη μηνιγγίτιδα (4.3%) και οξεία ψύχωση (4.3%). Η επίπτωση ήταν 7.8 περιπτώσεις/ 100 ανθρωποέτη. Μεταξύ των νοσηλειών των ασθενών με ΣΕΛ, το 13% οφειλόταν σε εκδηλώσεις του ΚΝΣ. Οι επιληπτικές κρίσεις συσχετίστηκαν με υψηλή ενεργότητα νόσου, ενώ η μυελοπάθεια με χαμηλότερη ενεργότητα και με τα NMO-IgG αντισώματα (P≤0.05). Η εμφάνιση ΑΕΕ σχετίστηκε με συνύπαρξη Αντιφωσφολιπιδικού Συνδρόμου (P=0.06). Συνολικά, η προσβολή του ΚΝΣ συσχετίστηκε με υψηλούς δείκτες ενεργότητας ECLAM και SLEDAI (P<0.001).Στο δεύτερο τμήμα της διδακτορικής διατριβής αξιολογήθηκε η ειδικότητα των αντισωμάτων έναντι της ακουαπορίνης-4 (AQP4), διαγνωστικού δείκτη και παθογενετικού παράγοντα της Οπτικής Νευρομυελίτιδας (NMO, Σύνδρομο Devic’s). Στόχος της μελέτης ήταν ο εντοπισμός των γραμμικών Β κυτταρικών επιτόπων του μορίου της AQP4. Χρησιμοποιήθηκαν οροί από 21 ασθενείς θετικούς για anti-AQP4 αντισώματα, 23 ασθενείς με ΣΕΛ και 23 με Σύνδρομο Sjögren's χωρίς νευρολογική προσβολή, 58 ασθενείς με Πολλαπλή Σκλήρυνση, καθώς και οροί από 28 υγιή άτομα. Συντέθηκαν 11 πεπτίδια, τα οποία κάλυπταν όλες τις ενδοκυττάριες και εξωκυττάριες δομές του μορίου της AQP4, και όλοι οι οροί ελέγχθηκαν για αντισώματα έναντι των πεπτιδίων με τη μέθοδο ELISA. Η ειδικότητα των αντιδράσεων αξιολογήθηκε με δοκιμασίες ομόλογης αναστολής.Οι NMO θετικοί οροί εμφάνισαν δραστικότητα έναντι 3 διαφορετικών πεπτιδίων , τα οποία αντιστοιχούσαν στις αλληλουχίες aa1-22 (AQPpep1) (42.9% των ασθενών), aa88-113 (AQPpep4) (33%) και aa252-275 (AQPpep8) (23.8%). Όλοι οι επίτοποι ήταν ενδοκυττάριοι. Τα επίπεδα ομόλογης αναστολής κυμαίνονταν από 71.1% έως 84.3%. Ακόμα, παρατηρήθηκε ομολογία της τάξης του 73% μεταξύ τμήματος του AQPpep8 (aa257-271) και της αλληλουχίας aa219-233 της πρωτεΐνης TAX1BP1 (Tax1-HTLV-1 binding protein), μιας ανθρώπινης πρωτεΐνης, εμπλεκόμενης στον αναδιπλασιασμό του ιού HTLV-1. Αντισώματα έναντι των 15-μερών πεπτιδίων της AQP4 και της TAX1BP1 ανιχνεύθηκαν στο 26.3% (N=5) και στο 31.6% (N=6) των ΝΜΟ θετικών ορών, αντίστοιχα (rs=0.81, P<0.0001). Τέλος, οι οροί ασθενών με RRMS εμφάνισαν στο 13% του συνόλου τους δραστικότητα για το πεπτίδιο AQPpep8. Οι οροί των ασθενών με PMS δεν εμφάνισαν ειδικότητα κατά των πεπτιδίων

Resolution of synovitis and arrest of catabolic and anabolic bone changes in patients with psoriatic arthritis by IL-17A blockade with secukinumab: results from the prospective PSARTROS study

Abstract Background Although the effects of interleukin-17A (IL-17A) inhibition on the signs and symptoms of psoriatic arthritis (PsA) are well defined, little is known about its impact of local inflammatory and structural changes in the joints. The PSARTROS study was designed to elucidate the effects of IL-17A inhibition on inflammation and bone changes in joints affected by PsA. Methods This was a prospective open-label study in 20 patients with active PsA receiving 24 weeks of treatment with the IL-17A inhibitor secukinumab. Magnetic resonance imaging (MRI), power Doppler ultrasound (PDUS), and high-resolution peripheral quantitative computer tomography (HR-pQCT) of the hands were performed at baseline and after 24 weeks to assess synovitis, periarticular inflammation, bone erosion, enthesiophyte formation, and bone structure. Demographic and clinical measures of joint disease (DAPSA and DAS28-ESR), skin disease (PASI and BSA), and composite measures (minimal disease activity, or MDA) were also recorded. Results Treatment with secukinumab led to significant improvement of signs and symptoms of PsA; 46% reached MDA and 52% DAPSA low disease activity. MRI synovitis (P = 0.034) and signal in PDUS (P = 0.030) significantly decreased after 24 weeks of treatment. Bone erosions in MRI and HR-pQCT and enthesiophytes in the HR-pQCT did not show any progression, and structural integrity and functional bone strength remained stable. Conclusions IL-17 inhibition by secukinumab over 24 weeks led to a significant decrease of synovial inflammation and no progression of catabolic and anabolic bone changes in the joints of patients with PsA. Trial registration ClinicalTrials.gov Identifier: NCT02483234, June 26, 2015; retrospectively registered

Secukinumab leads to shifts from stage-based towards response-based disease clusters—comparative data from very early and established psoriatic arthritis

Background!#!Limited information exists about the very early forms of psoriatic arthritis. In particular, differences and responsiveness of patient-reported outcomes (PROs) in very early as compared to established PsA have not been investigated to date.!##!Methods!#!Cross-sectional and prospective longitudinal evaluation of PROs related to pain (VAS), physical function (HAQ-DI, SF-36 physical), mental function (SF-36 mental), impact of psoriatic skin (DLQI), joint (PsAID), and global disease (VAS) in two small prospective observational studies on secukinumab 300 mg over 6 months in very early disease patients (IVEPSA study, N = 20) and established PsA (PSARTROS study, N = 20). Cluster analysis was performed at baseline and 24-weeks of follow-up.!##!Results!#!While responses in pain and physical activity-related PROs to secukinumab were more pronounced in established PsA than a very early disease, effects on PROs related to general health perception, as well as those related to emotional and mental well-being, were modified in a similar way in very early disease and established PsA. Cluster analysis based on global disease activity and PROs showed that baseline clusters reflected very early disease and established PsA, while after secukinumab treatment these clusters were abolished and new clusters based on differential responses to physically and mentally oriented PROs formed.!##!Conclusions!#!Inhibition of IL-17A by secukinumab leads to comprehensive improvement of general health perception and mental well-being in very early and established PsA, while overall responses in pain and physical activity are more pronounced in established disease. Most importantly, treatment restructures the original patients' clusters based on disease stage and leads to the formation of new clusters that reflect their response in physical and mental-orientated PROs.!##!Trial registration!#!NCT02483234 , registered 26 June 2015, retrospectively registered

Hospitalization causes of SLE patients during the 3 year follow up period.

**<p>Relapse manifestations can coexist during the same hospitalization.</p

Numbers of patients with the respective antibodies within each CNS subgroup.

<p>Each column group refers to the respective CNS subgroup. Each column represents a discrete autoantibody, while Y axes displays the number of patients presenting with the respective autoantibody.</p

Demographic and clinical characteristics of the SLE patients.

<p>Demographic and clinical characteristics of the SLE patients.</p

Additional file 1: of Resolution of synovitis and arrest of catabolic and anabolic bone changes in patients with psoriatic arthritis by IL-17A blockade with secukinumab: results from the prospective PSARTROS study

Figure S1. Examples of baseline and follow-up MRI and HR-pQCT images. Figure S2. Single patient analysis of MRI and PDUS changes. Table S1. Pattern of joint involvement at baseline. Table S2. Imaging data in PsA patients with and without pre-exposure to TNF inhibitors. Table S3. Imaging data in PsA patients with respect to concomitant and previous csDMARD treatments. Table S4. Imaging data in PsA patients with respect to concomitant methotrexate treatment. Table S5. Proportion of patients with improvement in MRI, PDUS, and clinical outcome. (DOCX 3094 kb