ObjectivesThe central nervous system disorder in systemic lupus erythematosus (SLE), called neuropsychiatric lupus (NPSLE), is one of the most severe phenotypes with various clinical symptoms, including mood disorder, psychosis and delirium as diffuse neuropsychological manifestations (dNPSLE). Although stress is one of the aggravating factors for neuropsychiatric symptoms, its role in the pathogenesis of dNPSLE remains to be elucidated. We aimed to investigate stress effects on the neuropsychiatric pathophysiology in SLE using lupus-prone mice and patients’ data.MethodsSleep disturbance stress (SDS) for 2 weeks was placed on 6–8-week-old female MRL/lpr and control mice. Behavioural phenotyping, histopathological analyses and gene and protein expression analyses were performed to assess SDS-induced neuroimmunological alterations. We also evaluated cytokines of the cerebrospinal fluid and brain regional volumes in patients with dNPSLE and patients with non-dNPSLE.ResultsSDS-subjected MRL/lpr mice exhibited less anxiety-like behaviour, whereas stressed control mice showed increased anxiety. Furthermore, stress strongly activated the medial prefrontal cortex (mPFC) in SDS-subjected MRL/lpr. A transcriptome analysis of the PFC revealed the upregulation of microglial activation-related genes, including Il12b. We confirmed that stress-induced microglial activation and the upregulation of interleukin (IL) 12/23p40 proteins and increased dendritic spines in the mPFC of stressed MRL/lpr mice. IL-12/23p40 neutralisation and tyrosine kinase 2 inhibition mitigated the stress-induced neuropsychiatric phenotypes of MRL/lpr mice. We also found a higher level of cerebrospinal fluid IL-12/23p40 and more atrophy in the mPFC of patients with dNPSLE than those with non-dNPSLE.ConclusionsThe microglial IL-12/23 axis in the mPFC might be associated with the pathogenesis and a promising therapeutic target for dNPSLE.

ObjectiveWe aimed to evaluate whether gadolinium-enhanced magnetic resonance imaging (MRI) in shoulders can contribute to more accurate diagnosis and prediction of recurrence in patients with polymyalgia rheumatica (PMR). Methods Gadolinium-enhanced MRI and ultrasonography (US) in shoulders were performed in the patients who had bilateral shoulders pain and fulfilled the Bird's Classification Criteria between June 2012 and June 2018. PMR was clinically diagnosed by at least two rheumatologists. MRI and US findings assessed by independent radiologists were comparedbetween the PMR or non-PMR patients. PMR patients were treated with 20 mg/day of prednisolone and were followed-up until June 2019 to determine any recurrences of the disease. Results PMR was diagnosed in 58 of 137 patients received gadolinium-enhanced MRI and US examinations. Enhancement of joint capsule, enhancement of rotator cuff tendon and focal bone oedema in humerus headswere frequently found in the PMR patients. If the three findings were used in combination to diagnose PMR, MRI had 76% sensitivity and 85% specificity, higher compared to US findings, which had 50% sensitivity and 72% specificity. During follow-up, PMR recurred in 24 patients. Patients with recurrent PMR were younger in age, had less enhancement of rotator cuff tendon and more synovial hypertrophy findings on their MRI. Conclusion Gadolinium-enhanced MRI could display capsulitis, rotator cuff tendonitis and focal bone oedema in humerus headsthat was sensitive and specific to patients with PMR, improving diagnostic accuracy in PMR. Rotator cuff tendonitis and synovial hypertrophy on MRI could help predict recurrence in PMR.

Multicentric Castleman disease-thrombocytopenia, anasarca, reticulin fibrosis of bone marrow, renal dysfunction and organomegaly (MCD-TAFRO) -is an emergent phenotype characterized by lymphoproliferation, fluid collection, hemocytopenia and multiple organopathy. Although studies have demonstrated an aberrant blood cytokine/chemokine profile referred to as "chemokine storm", the pathogenesis remains unclear. We aimed to identify pathogenic key molecules, potential diagnostic targets and therapeutic markers in MCD-TAFRO using serum cytokine/chemokine profiles. We performed the targeted cytokine/chemokine multiplex analysis in six cases of MCD-TAFRO with remission or non-remission status. We observed significant changes in serum concentrations of CCL2, CCL5, and Chitinase-3-like-1 in the MCD-TAFRO patients with active state compared to inactive state. Ingenuity pathway analysis revealed that glycogen synthase kinase 3 (GSK3) and CCR6, which is expressed in megakaryocytes, were detected as upstream positive regulators for activating MCD-TAFRO status. More GSK3b + CCR6 + cells like megakaryocytes were detected in the bone marrow of patients with MCD-TAFRO than in those with systemic lupus erythematosus, MCD-not otherwise specified or autoimmune haemophagocytic lymphohistiocytosis. The cellularity of GSK3b + CCR6 + cells was correlated with disease activity, including thrombocytopenia and anaemia. In conclusion, GSK3b and CCR6 of bone marrow cells were potentially involved in the pathogenesis of MCD-TAFRO and may act as diagnostic targets and therapeutic markers.

BackgroundAdult-onset Still’s disease (AOSD) is a systemic inflammatory disorder generally responsive to corticosteroid (CS) therapy, whereas cases not responding CS monotherapy are frequently found in clinical practice. In such cases, methotrexate and/or biologics including TNF-α, IL-1, or IL-6 inhibitors are used [1]. However, further treatment options are required for refractory AOSD patients who are intolerant to methotrexate and/or biologics. Calcineurin inhibitors (CNI) downregulate T cell activation through inhibiting IL-2 transcription and signal transduction. Therefore, they are reasonable therapeutic medication for AOSD considering T cells and subsequently activated macrophages play a pathophysiological role in AOSD [2]. Nevertheless, only a few case series have indicated effects of CNI for difficult AOSD.ObjectivesTo evaluate the efficacy of CNI in patients with AOSD.MethodsThis is a multi-centre historical cohort study comprised the consecutive patients with AOSD in accordance with Yamaguchi classification criteria. The primary endpoint was set as the time from the initiation of treatment to event defined as death of any causes or relapse of AOSD requiring an increase of CS dose. Secondary endpoints were set as persistency rate of CNI and safety. Based on the recurrent event data analysis, these endpoints were evaluated for each event. We compared the frequency of events between two groups according to the treatment that included calcineurin inhibitors (CNI+) or conventional therapy without calcineurin inhibitors (CNI-).ResultsOne hundred seventy-eight patients were enrolled in this study. Mean age was 46 year-old, and median follow-up period 36 months. Seventy-one events in 56 patients were treated with therapeutic regimen including CNI (CNI+, cyclosporine: 14, tacrolimus: 60), and 176 events in 138 patients were treated with the conventional therapy excluding CNI (CNI-). CNI were used in AOSD patients with recurrent history, high ferritin level, serositis, hemophagocytic syndrome (HPS) and/or disseminated intravascular coagulation (DIC). The CNI+ group had longer event-free survival than the CNI- group (83% versus 75% at 5th year). The hazard ratio (HR) was 0.57 (95% CI, 0.32-0.99) after adjustment of initial dose of CS and other concomitant medications. Subgroup analysis showed that CNI were more effective for AOSD patients with high ALT levels (≥ 80 IU/L) and/or severe complications such as HPS and DIC. The persistency rate of CNI was 71% at 5th year. Adverse events occurred more frequently in the CNI+ group than in the CNI- group (18% versus 8%, p = 0.04); however, serious adverse events did not increase in the CNI+ group (3% versus 2%). AOSD-related mortality had never been found in the observation period. One patient had a fatal course due to septic shock in the CNI+ group.ConclusionOur retrospective analysis suggested that CNI could be an additional option for treating AOSD with acceptable safety.References[1] Efthimiou P, et al. Diagnosis and management of adult onset Still’s disease. Ann Rheu...

BackgroundThe use of molecular targeted therapies has improved the clinical course and quality of life of patients with rheumatoid arthritis (RA); however, a percentage of patients experience treatment failure (non-responders), which is a particular challenge for clinicians. Diet and nutrients are potential environmental factors that are likely to influence the course and the response to pharmacological therapies in RA. The Mediterranean diet or omega-3 polyunsaturated fatty acids (n-3 PUFAs) supplementation have been shown to have a favorable effect on the reduction of RA symptom. A higher intake of fish, the main source of PUFAs, was associated with lower disease activity in RA patients. Several factors have been identified that may affect treatment response in RA; however, the effect of fish consumption on treatment response in RA patients has not been clarified.ObjectivesTo explore the relationship between fish consumption and response to targeted therapies in RA patients with two dietary patterns characterized by high fish consumption.MethodsThe study is a collaborative international cross-sectional retrospective study involving RA patients on treatment with biologics or Janus kinase inhibitors (JAKi) attending Hokkaido University Hospital (Japan) or Hospital Virgen de las Nieves (Spain). Patients complete a brief-type self-administered diet history questionnaire (BDHQ) and a detailed food frequency questionnaire (DFFQ) to assess fish consumption in the previous month. At study entry, qualified rheumatologists assessed RA disease activity. Demographic, clinical/laboratory data were collected retrospectively from the medical records. Descriptive analysis was performed in each cohort.ResultsOne-hundred-twenty-four Japanese RA patients, 100 females, median age at entry 66 yrs [IQR 54-72], median disease duration 12 yrs [IQR 7-20] were included. One-hundred-seven (86%) patients were on biologics and 17 (14%) on JAKi, median treatment duration of 4 yrs [IQR 1-7]. Concomitant treatment with conventional synthetic disease modifying anti rheumatic drugs (csDMARDs) and glucocorticoids were reported in 84% and 53% of patients, respectively. Ninety-six (77%) patients were responders to treatment defined as disease activity score 28 (DAS28)-ESR <3.2 and DAS28-CRP <2.7. All patients had fish consumption in the last month and 82% reported intake of n-3 PUFA rich fish (fatty fish) (<1 time/week 33%, ≧1 time/week 49%). A higher estimated daily intake of n-3 PUFAs from fish was found in the responder group compared to the non-responder group [median grams, 1.01 (IQR 0.47-1.44) vs 0.51 (IQR 0.34-1.14), p=0.044]. The Spanish cohort comprised of 62 RA patients, 47 females, median age at entry 58 yrs [IQR 49-66], median disease duration 12 yrs [IQR 5-21]. Fifty-nine (95%) patients were on biologic therapies and three (5%) on JAKi, median treatment duration of 3 yrs [IQR 1-8]. Concomitant treatment with csDMARDs and glucocorticoids were reported in 38% and 42% of patients, respectively. Thirty-four (55%) patients were responders to treatment. All patients had consumption of fish in the last month and 77% had consumed fatty fish (<1 time/week 31%, ≧1 time/week 46%). No difference in estimated intake of n-3 PUFAs from fish was observed in this cohort.ConclusionFish consumption may have a positive effect on the response to treatment of Japanese RA patients receiving targeted therapy.ReferencesNIL.AcknowledgementsAcknowledgements to Ms. Y. Ikea and S. Kumagai for their enriching support on the nutritional properties of fish. Supported by the Kakenhi C grant number 20K11597 from the Japan Society for the Promotion of Science.Disclosure of InterestsNone Declared.