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Background. Basic calcium phosphate (BCP) deposition disease is a frequent musculoskeletal problem characterized by the intraarticular or periarticular deposition of carbonate substituted hydroxyapatite, octacalcium phosphate and tricalcium phosphate. BCP and calcium pyrophosphate (CPP) crystals play an important role in the pathogenesis of osteoarthritis. Objectives. The primary aim was to evaluate the clinical and ultrasonographic characteristics of patients with BCP. The secondary aim was to compare the radiographic scores of patients with BCP, calcium pyrophosphate dihydrate (CPPD) deposition disease and degenerative disease (DD). Material and methods. 50 patients with BCP deposition disease diagnosed by imaging or by identification of BCP in synovial fluid (SF) were included in the study. The second part of the study included 20 patients with BCP crystals in SF, 20 patients with CPP crystals in SF and 20 patients with degenerative changes on radiography and without crystals in SF. Clinical, ultrasonographic and radiographic data were recorded. Results. The shoulder joint (56%), followed by the knee joint (36%) and the acute clinical presentation (84%) were the most common findings. The fragmented ultrasound appearance (54%) was the most frequent, followed by the arch-shaped (36%). The localization of the deposits was found most often in the tendons (68%), mainly in the supraspinatus tendon (55.88%). Higher K/L scores were found in patients with BCP and CPP crystals than in the patients with DD. K/L score ≥3, defining osteoarthritis was associated with the presence of BCP and CPP crystals. Conclusions. The shoulder and the fragmented ultrasound pattern are the most common findings in patients with BCP. Higher K/L scores are found in patients with BCP and CPP crystal associated disease than in the degenerative disease patients.

© Copyright Clinical and Experimental Rheumatology 2022, Objectives: The purpose of this study was to review the frequency and clinical presentation of the rarest clinical manifestations of systemic lupus erythematosus (SLE). Methods: A list of 6 rare SLE manifestations were defined: gastrointestinal, liver, pulmonary, cardiac, ocular and neurological manifestations. Each topic was assigned to a pair of authors to perform a literature search and article review. Results: In total, 149 articles were included in the literature review: 37 for gastrointestinal manifestations, 6 for liver manifestations, 27 for pulmonary manifestations, 50 for cardiac manifestations, 16 for ocular manifestations, 13 for neurological manifestations. Gastrointestinal disorders included several clinical presentations with variable frequency (from 0.5% to 10.7% of the cases); liver involvement included lupus-related hepatitis (9.3%) and autoimmune hepatitis (2.3%). The rarest pulmonary manifestations identified were shrinking lung syndrome, described in 1.5% of patients, while interstitial lung disease and lupus pneumonia were reported in 4% and 3% of patients respectively. Myocarditis and pulmonary hypertension were also rarely described in SLE patients although ranging from 0.4-16% and 1-14% respectively, depending on the methodology used for its identification. Ocular manifestations in SLE included some rare manifestations (reported in less than 5% of patients) and lupus retinopathy that is described in 1.2-28.8% of patients depending on methods of ascertainment. Aseptic meningitis and chorea were also confirmed as very rare manifestations being reported in less than 1% and in 0.3-2.4% of cases respectively. Conclusions: The results of this literature review provide the basis for a better understanding of some less-known manifestations of SLE and for stressing the need for a higher awareness in diagnostic and therapeutic protocols regarding these rare disease aspects.

Introduction. As oral mesenchymal stromal cells (MSCs) have not, to date, been isolated from systemic sclerosis (SSc) patients, the aim of this in vitro experiment was to characterize gingival MSCs (SScgMSCs) and granulation tissue MSCs (SScgtMSCs) from SSc and to evaluate their functionality in comparison to healthy MSCs (hMSCs), in normal or hyaluronic acid (HA) culture media. Materials and Methods. Isolated cells were described by immunophenotyping of surface antigen make-up and by trilineage mesenchymal differentiation capacity. Colony-Forming Unit-Fibroblast (CFU-F) test and migration potential evaluated MSC functionality. Results. All types of MSCs displayed positivity for the following surface markers: CD29, CD73, CD90, CD105, CD44, and CD79a. These cells did not express CD34, CD45, HL-DR, and CD14. Isolated MSCs differentiated into osteoblasts, adipocytes, and chondroblasts. The frequency of CFU-F for SScgtMSCs was significantly lower than that of hMSCs (p = 0.05) and SScgMSCs (p = 0.004) in normal medium, and also markedly lower than that of SScgMSCs (p = 0.09) in HA medium. Following HA exposure, both SScgMSCs and SScgtMSCs migrated significantly less (p = 0.033 and p = 0.005, respectively) than hMSCs. Conclusions. A reduced functionality of MSCs derived from SSc as compared to hMSCs was observed. HA in culture medium appeared to significantly stimulate the migration potential of hMSCs.

We aimed to investigate the prevalence of US findings in the hand joints and related tendons and explore clinical and laboratory associations in SLE patients of the typical lupus clinic.One hundred consecutive SLE patients were enrolled in the study. Using B-mode and Doppler US, bilateral wrist, metacarpophalangeal and proximal interphalangeal joints were examined for synovitis and erosions, as well as for signs of hand tenosynovitis.US detected synovitis (grade 1-3) in 75% and erosive changes in 25% of the cohort. We found that clinical examination underestimated grade ≥2 synovitis by 13%, while US detected SH grade ≥2 in 10% of asymptomatic patients. The overall inflammatory burden, reflected by the US score, was associated with disease activity (respectively with CPR, SELENA-2K, MS-BILAG, and hypocomplementemia), as well as the presence of bone erosions. Rhupus patients had higher inflammatory markers, significantly more synovial hypertrophy, more erosions, more grade 3 tenosynovitis, and were more likely to receive methotrexate (p0.001) than patients with SLE arthritis, while patients with Jaccoud's arthropathy were more likely to accumulate damage. The dominant hand exhibited more inflammatory changes (respectively synovial hypertrophy grade ≥2) at both the wrist and MCP joints; however, handedness was not associated with structural damage.In conclusion: 1. joint involvement in SLE is frequent and underacknowledged; 2. the overall inflammatory burden is associated with systemic disease activity and joint damage; (3) destructive arthritis is more likely to occur in the context of concomitant RA or within an "RA-like" subtype of SLE arthropathy; 4. hand dominance is associated with synovitis, but not structural changes; 5. US assessment may help tailor the management of joint involvement, thus preventing joint damage and disability in SLE patients.

The PI3K/AKT/mTOR signaling pathway is significantly activated in rheumatoid arthritis. In addition, somatic activating mutations of the PI3K/AKT/mTOR pathway may result in PIK3CA-related overgrowth spectrum diseases, including CLOVES (Congenital Lipomatous Overgrowth, Vascular malformation, Epidermal nevi, Skeletal abnormalities/Scoliosis) syndrome. We describe the case of a young female patient, with anti-citrullinated peptide antibodies-positive rheumatoid arthritis, referred for persistent finger pain and stiffness. Examination revealed discrete macrodactyly involving two fingers, scoliosis, asymmetrical calves, venectasias, a shoulder nevus and triangular feet with a “sandal gap” between two toes. These mild dysmorphic features with early-onset and the history of surgeries for thoracic lipoma and venous malformation were strongly suggestive of CLOVES syndrome. Confirmatory mutation analysis was not performed, as blood or saliva testing is not contributive for tissue-specific localized effects in the PIK3CA-related overgrowth spectrum. Nevertheless, lack of detection of a PIK3CA mutation does not exclude the diagnosis in patients fulfilling clinical criteria. Due to the patient’s wish to plan a pregnancy, therapy consisted in sulfasalazine and hydroxychloroquine, along with orthotic correction of leg length discrepancy. Overgrowth syndromes and arthritis may share common pathways. Mild macrodactyly should be differentiated from dactylitis. Diagnosing patients with minimal dysmorphic features within the PI3K-related overgrowth spectrum may help design better care strategies, in the quest for personalized medicine.

ObjectivesChronic renal impairment remains a feared complication of lupus nephritis (LN). The present work aimed at identifying mechanisms and markers of disease severity in renal tissue samples from patients with LN.MethodsWe performed high-throughput transcriptomic studies (Illumina HumanHT-12 v4 Expression BeadChip) on archived kidney biopsies from 32 patients with LN and eight controls (pretransplant donors). Histological staging (glomerular and tubular scores) and immunohistochemistry experiments were performed on the same and on a replication set of 37 LN kidney biopsy samples.ResultsA group of LN samples was identified by unsupervised clustering studies based on their gene expression features, that is, the overexpression of transcripts involved in antigen presentation, T and B cell activation. These samples were characterised by a significantly lower estimated glomerular filtration rate (eGFR) at the time of biopsy (T0) compared with the other systemic lupus erythematosus samples. Yet, apparent disease duration at T0, double-stranded DNA antibody titres at T0 and other relevant characteristics (serum C3, proteinuria, histological scores, numbers of previous flares) were not different between groups.Immunohistochemistry studies confirmed the association between interstitial infiltration by adaptive immune effectors and decreased renal function in the same and in a replication group of LN kidney biopsies. This was associated with transcriptomic, histological and immunohistochemical evidence of renal tubular cell involvement.ConclusionInterstitial infiltration of LN kidney biopsies by adaptive immune effectors is associated with impaired renal tubular cell function and decreased eGFR. These results open new perspectives in evaluating and treating patients with LN, focusing on intrarenal mechanisms of immune cell activation.

Background Delayed-enhancement magnetic resonance imaging (DE-MRI) is a noninvasive diagnostic tool able to identify myocardial fibrosis. In patients with scleroderma, its relationship with arrhythmias and conduction disorders has not been fully explored. Objectives The aim of this study was to evaluate the possible correlations between ventricular arrhythmias, conduction disorders, and myocardial fibrosis in patients with systemic sclerosis. Methods Thirty-six patients with diffuse or limited cutaneous scleroderma underwent 12-lead electrocardiogram (ECG), 24-hour Holter ECG monitoring, transthoracic echocardiography, and cardiac DE-MRI, with gadolinium administration in 33 patients. Results High-quality DE-MRI scans were obtained in 30 patients. Myocardial fibrosis was detected in 25 patients (83.3%). Eighteen patients (60%) had ventricular arrhythmias or conduction disorders. There was no significant difference in ventricular arrhythmia burden (the total number of premature ventricular contractions [PVCs]/24 hours) (48 ± 304 vs. 69 ± 236, P = 0.97), ventricular arrhythmia severity (couplets, triplets, runs) on Holter ECG, or in the presence of conduction disorders (36% vs. 40%, P = 0.86) between patients with and without myocardial fibrosis. In univariate analysis, diffuse fibrosis was weakly associated with the number of PVCs/24 hours (R = 0.157, P = 0.03). A number of at least 597 PVCs/24 hours had a sensitivity of 60% and a specificity of 92% in predicting the presence of diffuse fibrosis on DE-MRI (area under the curve = 0.640). Conclusions Delayed-enhancement magnetic resonance imaging can identify myocardial fibrosis in a high percentage of scleroderma patients. Its presence does not seem to influence the ventricular arrhythmia burden and severity or the presence of conduction disorders, with the exception of diffuse myocardial fibrosis, which modestly influences the total number of PVCs/24 hours.

Background Relapsing polychondritis (RP) is a rare condition defined by recurrent inflammation of cartilaginous tissue and systemic manifestations. Biomarkers for RP diagnosis and assessment of disease activity, damage and prognostic in clinical practice are currently lacking. Red blood cell distribution width (RDW) is an index of erythrocyte size variation depicting anizocytosis. RDW is routinely assessed, is not influenced by infections and its standard deviation (RDW-SD) does not depend on medium corpuscular volume. Recent studies showed an increased RDW in various autoimmune diseases (systemic lupus erythematosus, Sjogren’s syndrome, rheumatoid arthritis, systemic vasculitis), correlating with inflammatory markers and disease activity. Also, the RDW seen in solid tumors and hematological cancers has prognostic value. Objectives To asses the RDW-SD in RP patients, its relation with the disease activity and with the presence of neoplasia Methods We performed a retrospective study on the patients diagnosed with RP in a tertiary Rheumatology department between January 2017 and January 2019, using the Atlasmed data management system of the institution. The concomitant diseases and the inflammation parameters were recorded. The RP activity was measured using RPDAI (relapsing polychondritis disease activity index). The correlation between variables were calculated using GraphPad Prism. Results We identified 20 patients, median age 59.04 years (range 38-81), with a male-to-female ratio of 1: 5.66. An associated autoimune disease (Sjogren syndrome, Hashimoto thyroiditis, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis) was found in 85% of pacients. Moreover, 40% of the pacients had various types of solid or hematologic neoplasia, including myelodysplastic syndrome. An elevated RDW-SD was seen in 90% of RP patients. The average RPDAI was 10.6 points. RDW-SD significantly correlated to RPDAI (p=0.0012). Of the inflammatory parameters, RDW-SD was not found to be related to ESR and CRP. RDW-SD increased with age, but no correlation was found between RPDAI and age. All pacients with neoplasia had abnormally high RDW-SD. Nevertheless, RDW-SD was not significantly different in RP patients with or without neoplasia (Mann-Whitney test, p=0.56). Conclusion RP was frequently associated with other autoimune diseases, but also with neoplasia.The positive correlation of RDW-SD and RPDAI in RP suggests a possible new, clinically employable, biomarker of disease activity. References [1] Arnaud L et al, Autoimmun Rev 2012; 12(2):204-9. doi:10.1016/j.autrev.2012.06.005. [2] Hu ZD, JLPM 2016, doi: 10.21037/jlpm.2016.10.02 Disclosure of Interests None declared

Background: Rowell syndrome is a rather rare and highly debated entity, initially defined by Rowell et all as discoid lupus associated with erythema multiforme-like (EM) lesions, positive speckled ANA, RF and Anti-SJT antibody, later known as anti Ro/La antibodies. In 2000, Zeitouni et al extended the definition by including all types of systemic lupus erythematosus (SLE) and proposed major and minor criteria, while in 2012 Torchia et al proposed another set of criteria defining Rowell syndrome as a distinct subtype of chronic cutaneous lupus. To date, Rowell syndrome as a distinct entity remains in question. Objectives: To establish whether patients with clinically suggestive Rowell syndrome, meet the proposed criteria and form a distinct SLE subgroup. Methods: A retrospective study which included SLE patients who associated EM-like lesions was carried out in the Rheumatology Department Cluj-Napoca, between 2008 and 2019. Clinical, immunological and histopathological parameters were recorded. Results: Among 200 patients who fulfilled the 2012 SLICC criteria, 12 patients with target lesions, resembling EM, were identified. Four patients were excluded: 3 were not fully investigated and 1 was My. pneumoniae positive, thus 8 patients were studied. The majority of patients (87.5%) developed the cutaneous lesions after diagnosis. In all cases, the erythematous maculopapular rash with targetoid aspect was present, with poorly defined borders and a dusky center and a diameter between 2 to 6 cm. The lesions extended to the trunk and limbs, sparring the acral and mucosal areas. Five patients associated pruritus. The lesions could not be linked to any viral or bacterial infection in any of the cases. With regard to drug allergies, a link with AZA and HCQ was suspected in three patients – which was infirmed. The majority of patients (87.5%) had negative anti-ds DNA, 87.5% presented speckled pattern ANA, one patient exhibited ANA rods and rings pattern, with a negative serology for B and C hepatitis and no antiviral therapy. Of note, 25% had positive rheumatoid factor, 87.5% had positive anti-Ro antibody and 37.5% of patients exhibited chilblains. The first three classifications were tested on all patients: 25% met Rowell’s criteria, 12.5% met Lee’s criteria and 87.5% met Zeitouni’s criteria, with only 1 patient meeting all 3, and 1 patient meeting none of them. In the cases in which the SLE etiology of the lesion was in question from a clinical point of view, a biopsy was performed. In one case the histopathological examination described lymphocytic infiltrates and few eosinophils in the dermis, suggestive of drug allergy. Interestingly, this patient met all 3 classification criteria. Another report described thin epidermis, parakeratosis, dyskeratosis and spongiosis with dermis and perivascular lymphocytic infiltrate- findings highly suggestive for EM; this report belonged to the patient who met neither of the 3 classifications, but who associated a rods and rings ANA pattern. The third histopathological report was inconclusive. Conclusion: Our study shows that patients with suspected clinical, immunological or histological Rowell syndrome do not meet all studied classifications criteria. Furthermore, studied classifications are incongruent. Should Rowell syndrome be a distinct entity it would most certainly be a very rare one. Further study is needed to better frame LES and EM. References [1] ROWELL, N. R. (1963). Lupus Erythematosus and Erythema Multiforme-like Lesions. Archives of Dermatology, 88(2), 176. [2] Torchia, D., Romanelli, P., & Kerdel, F. A. (2012). Erythema multiforme and Stevens-Johnson syndrome/toxic epidermal necrolysis associated with lupus erythematosus. Journal of the American Academy of Dermatology, 67(3), 417–421. Disclosure of Interests: None declared

Background:The presence of anti-Ro antibodies in female patients diagnosed with systemic lupus erythematosus (SLE) and primary Sjögren syndrome (SS) in their fertile years raises concern among the medical team due to the risk of neonatal lupus in their newborns (NB).(1)Objectives:The aim of this study was to determine whether there are differences between the outcome of anti-Ro positive pregnancies in SLE and SS.Methods:This is a retrospective observational study carried out in a Rheumatology tertiary center. We included anti-Ro positive female SLE and SS patients, who were diagnosed before or during pregnancy and followed in our clinic between 2003-2020. The diagnosis of SLE or SS was established according to the 2012 SLICC criteria and the 2016 EULAR/ACR criteria, respectively. Clinical, immunological and pregnancy parameters were recorded before (where available), during and after pregnancy, as well as maternal risk factors (smoking, BMI, disease and medication history). Statistical analysis for continuous variables were performed with T-student test and categorical variables with Person Chi-square test, using IBM SPSS Statistics version 20.Results:Eleven out of 65 anti-Ro positive SLE patients and 10 out of 153 anti Ro-positive SS patients met the inclusion criteria and had 13 and 12 pregnancies, respectively. The mean age at diagnosis was 24,75 ± 5,19 years for SLE and 31,92 ± 4,05 years for SS, and the mean pregnancy age was 28,33 ± 4,05 years for SLE and 33,17 ± 3,63 years for SS. Nine (81,81%) SLE patients were diagnosed before pregnancy, while 6 (60%) of the SS patience were diagnosed during pregnancy.Two (18,18%) SLE and 1 (10%) SS were smokers, median BMI was 21 for both SLE and SS (1 SS patient was obese), 2 (18,18%) had a history of lupus nephritis, 6 (54.54%) LES patients had secondary antiphospholipid syndrome, out of which 1 had a previous miscarriage. In the SS group there were 3 previous miscarriages, one patient had a history of parotid lymphoma. The majority of both SLE and SS patients had moderate anti-Ro antibody titers (More preterm NB and stillbirths were encountered in SLE mothers, possibly due to the association of secondary antiphospholipid syndrome, both groups encountered 1 pregnancy loss, and cesarean delivery outweighed vaginal ones in both SLE and SS patients. (Table 1)Table 1.Gestational age and delivery type according to maternal diseaseGestational ageSLEnumber (%)SSnumber (%)Full-term pregnancy4 (30.76%)10 (83.33%)Late preterm births4 (30.76%)1 (8.33%)Very preterm births2 (15.38%)0Stillbirth2 (15.38%)0Pregnancy loss1 (7.69%)1 (8.33%)Delivery typeVaginal3 (25%)4 (36.36%)Cesarean9 (75%)7 (63.63%)Distribution of pregnancy outcome is exhibited in figure 1. There were 4 (33.33%) NB with cutaneous neonatal lupus all from SS mothers, 3 of whom used HCQ before and/or during pregnancy; and there were 5 NB with complete fetal atrioventricular block (AVB), 3 (25%) from SS mothers and 2 (15.38%) from SLE mothers. A history of HCQ usage was recorded in 3 out of these 5 mothers, and all 5 NB with complete fetal AVB were treated with dexamethasone, without success. Two NB died (both from SLE mothers) and 3 NB (all from SS mothers) needed pacemaker implantation. From the latter, 1 developed pacemaker cardiomyopathy and 1 developed sepsis.Conclusion:Neonatal lupus seems to be more prevalent in anti-Ro positive SS patients than SLE patients, even though no difference was seen in anti-Ro titer between the two diseases. Fetal cardiac arrhythmia may lead to SS diagnosis. Dexamethasone did not improve the outcome of the fetal AVB.References:[1]Mollerach FB, Scolnik M, Catoggio LJ, Rosa J, Soriano ER. Causes of fetal third-degree atrioventricular block and use of hydroxychloroquine in pregnant women with Ro/La antibodies. Clin Rheumatol. 2019 Aug;38(8):2211-2217.Disclosure of Interests:None declared

Background:Gastrointestinal involvement (GI) in systemic sclerosis (SSc) is one of the major disease burdens. Its consequences on the nutritional status of SSc patients and their quality of life is poorly evaluated during routine check-ups. Since malnutrition is an important cause of morbidity and mortality, addressing this issue seems necessary.Objectives:The aim of this study was to evaluate the risk of malnutrition in SSc patients and to identify potential associations between the risk of malnutrition and clinical features or laboratory parameters.Methods:All patients aged >18 years old with a definite diagnosis of SSc according to the 2013 ACR/EULAR classification criteria from the EUSTAR Center 16 and ERN ReCONNET cohort of the County Emergency Clinical Hospital Cluj-Napoca were included in the study. Patients with localized scleroderma, scleroderma sine scleroderma, overlap syndromes and mixed connective tissue disease were excluded. Clinical and laboratory data was collected from the EUSTAR database and medical charts. A telephone survey was conducted and patients were interviewed using the Malnutrition Universal Screening Tool (MUST) questionnaire.Results:75 patients were eligible for the study. Female to male ratio was 10:1 with an almost equal distribution among limited (57%) and diffuse (43%) SSc subtypes. The most prevalent autoantibodies were anti-TOPO-I and anti-centromere. GI symptoms were reported in 48.6% patients out of which 86% SSc patients underwent further evaluation by upper GI endoscopy. Abnormal endoscopic findings, such as esophagitis, Barret esophagus and gastritis were identified in 80% patients. Most patients had a low risk of malnutrition (93%) with only a minority carrying a medium (6%) or high (1%) risk. No significant association was demonstrated between MUST score and the extend of cutaneous involvement (limited SSc versus diffuse SSc; p=0.39), presence of GI symptoms (p=0.35), presence of abnormal endoscopic findings (p=0.45) or presence of anemia (p=0.83).Conclusion:The majority of SSc patients from this cohort exhibited a low risk of malnutrition. These results are contradictory to previous literature reports. A possible explanation is that the MUST score is a dynamic screening tool and therefore interviewing patients with a stable disease (outpatient care) versus patients with active disease (inpatient care) might lead to different results. Another limitation of this study is the small number of patients included. This is a pilot study. We aim to further extend the study population to the other EUSTAR cohorts and to prospectively evaluate these patients in an inpatient care setting.References:[1]Dupont R et al. Impact of micronutrient deficiency & malnutrition in systemic sclerosis: Cohort study and literature review. Autoimmun Rev. 2018 Nov;17(11):1081-1089;[2]Caimmi C et al. Malnutrition and sarcopenia in a large cohort of patients with systemic sclerosis. Clin Rheumatol. 2018 Apr;37(4):987-997;[3]Türk İ et al. Malnutrition, associated clinical factors, and depression in systemic sclerosis: a cross-sectional study. Clin Rheumatol. 2020 Jan;39(1):57-67.Disclosure of Interests:None declared

Background:Interstitial lung disease (ILD) is a common manifestation of connective tissue diseases (CTDs), and is associated with significant morbidity and mortality. Chest high-resolution computed tomography (HRCT) play an important role in the diagnosis of ILD and may provide prognostic information.Objectives:We aimed to characterize the clinical profile and chest HRCT abnormalities and patterns of patients diagnosed with CTDs and ILD.Methods:In this retrospective, observational study we included 80 consecutive patients with CTDs and ILD referred to a tertiary rheumatology center between 2015 and 2019. From hospital charts we collected clinical data, immunologic profile, chest HRCT findings. HRCT patterns were defined according to new international recommendations.Results:Out of 80 patients, 64 (80%) were women, with a mean age of 55 years old. The most common CTD associated with ILD was systemic sclerosis (38.8%), followed by polymyositis (22.5%) and rheumatoid arthritis (18.8%). The majority of patients had dyspnea on exertion (71.3%), bibasilar inspiratory crackles were present in 56.3% patients and 10% had clubbing fingers. Antinuclear antibodies (ANA) were present in 78.8% patients, and the most frequently detected autoantibodies against extractable nuclear antigen were anti-Scl 70 (28.8%), followed by anti-SSA (anti-Ro, 17.5%), anti-Ro52 (11.3%) and anti-Jo (7.5%). Intravenous cyclophosphamide therapy for 6-12 months was used in 35% of patients, while 5% of patients were treated with mycophenolate mofetil.The most frequent HRCT abnormalities were reticular abnormalities and ground glass opacity. Non-specific interstitial pneumonia (NSIP) was identified in 46.3% CTDs patients. A pattern suggestive of usual interstitial pneumonia (UIP) was present in 32.5% patients, mainly in patients with systemic sclerosis. In 21.3% patients the HRCT showed reticulo-nodular pattern, micronodules and other abnormalities, not diagnostic for UIP or NSIP pattern.Conclusion:Nonspecific interstitial pneumonia (NSIP) is the most common HRCT pattern associated with CTDs. Further prospective longitudinal studies are needed in order to determine the clinical and prognostic significance of various HRCT patterns encountered in CTD-associated ILD and for better patient management.References:[1]Ohno Y, Koyama H, Yoshikaua T, Seki S. State-of-the-Art Imaging of the Lung for Connective Tissue Disease (CTD). Curr Rheumatol Rep. 2015;17(12):69.[2]Walsh SLF, Devaraj A, Enghelmeyer JI, Kishi K, Silva RS, Patel N, et al. Role of imaging in progressive-fibrosing interstitial lung diseases. Eur Respir Rev. 2018;27(150)Disclosure of Interests:None declared

Pain is the most common symptom in rheumatic diseases. However, the severity of pain does not correlate with pathology. The lack of an objective test for pain results in clinicians consider pain in patients with fibromyalgia as psychological. Research over the last two decade using functional neuroimaging especially functional MRI scan have demonstrated objectively that patients with fibromyalgia were not malingering. Pain processing is complex and multiple regions of the brain are involved. One consistent finding is decrease activity in regions of the brain involved in pain inhibitory pathways suggesting this is one of the fundamental pathophysiology processes in fibromyalgia.

Introduction Nodular localised amyloidosis is a rare subtype of cutaneous amyloidosis, associated with various connective tissue diseases, mostly Sjogren’s syndrome. Progression to systemic amyloidosis was described in 7%–50% cases. Amyloid deposition was also noted in hypertrofic lupus lesions. Purpose To report a case of systemic lupus erythematosus (SLE) presenting with nodular localised cutaneous amyloidosis, followed up for 17 years. Methods A 55 year patient was addressed to our tertiary unit with pain and swollen in both hands and multiple soft nodular lesions pink to brown on the chest and back. Results Clinical examination and further investigations revealed inflammatory hand arthritis and polyserositis including pericarditis and pleural effusion. Laboratory showed antinuclear antibodies with low anti-dsDNA titer, positive anti-Ro antibodies, positive rheumatoid factor, C3 and C4 consumption. She had negative anti -cyclic citrullinated peptide antibodies and anti-LA antibodies, no sicca symptoms and no ultrasound modification of the salivary glands. The skin histopathology with Congo red staining revealed amyloid deposition in the dermis. A screening for multiple myeloma, including bone marrow biopsy, was negative. She was treated with hydroxychloroquine, and over the time with methotrexate, azathioprine (with loss of tolerance), acitretin (with no significant skin improvement), and topical glucocorticorticoids. New lesions appeared mostly upon cessation of SLE therapy, on traumatised areas and sun exposure, but were quite stable during sustained systemic therapy, suggesting some relation to disease activity. She developed new-onset cryoglobulinemia with increasing anti- Ro titers and rheumatoid factor, but has still normal immunoglobulins, complement fractions and LDH and no light chains on immunelectrophoresis. Conclusions Nodular localised amyloidosis is rare in SLE. The lesions evolve slowly, are minimally influenced by systemic therapy, but a close monitoring for systemic amyloidosis or plasma cell dyscrasia is required even in longstanding cases.

Background Among the clinical manifestation of systemic lupus erythematosus (SLE), neurolupus (NPSLE) is one of the hardest to identify. While active systemic diseases usually evolve with weight loss, the increase is generally associated with glucocorticoid therapy and immobilisation and rarely with hypothalamic inflammation. NMDA encephalitis, increasingly recognised, may be paraneoplastic or autoimmune. Material and methods We present the case of a 20 year female student, with an SLE with juvenile onset, at 16, mainly with renal features and malar rash. She was in a prolonged remission on azathioprine, hydroxychloroquine, low-dose aspirin and 5 mg prednisone/day. However, after the exam session, she came for a significant weight increment (over 12 kg in 2 weeks), despite allegedly normal eating, accompanied by day-time sleepiness and hyposmia. The BMI, initially 22.5, increased to 27.1, with a 29.3% of body fat by screening impedancemetry. The analyses revealed a high ESR (90 mm/h), an increased AAN titer (1/1280), with high anti-DNA (1055), and an anti-NMDA titer of 933 IU/mL. All other tests, including lupus anticoagulant, anti-cardiolipin, and beta-2 glicoprotein IgA, IgG, anti-Ro, anti-La, and ribosomal P anti-TPO, anti-thyreoglobulin antibodies, FT4 and TSH, were normal. Cerebral MRI was unremarkable, as well as the organ involvement screening, including genital examination and PAP smear. Olfactory function measurement revealed a threshold score of 6 (normal 7–12) and an identification score of 11 (normal 12–15). She received 3 courses of methylprednisolone and cyclophosphamide courses, with slow weight decrease and normalisation after two months and some correction of hyposmia in more than six months. Conclusion Rapid unexplicable weight gain and decreased olfactory perception in lupus may suggest neurolupus or NMDA encephalitis.

Recent genetic and genomics approaches have yielded novel insights in the pathogenesis of Systemic Lupus Erythematosus (SLE) but the diagnosis, monitoring and treatment still remain largely empirical1,2. We reasoned that molecular characterization of SLE by whole blood transcriptomics may facilitate early diagnosis and personalized therapy. To this end, we analyzed genotypes and RNA-seq in 142 patients and 58 matched healthy individuals to define the global transcriptional signature of SLE. By controlling for the estimated proportions of circulating immune cell types, we show that the Interferon (IFN) and p53 pathways are robustly expressed. We also report cell-specific, disease-dependent regulation of gene expression and define a core/susceptibility and a flare/activity disease expression signature, with oxidative phosphorylation, ribosome regulation and cell cycle pathways being enriched in lupus flares. Using these data, we define a novel index of disease activity/severity by combining the validated Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)1 with a new variable derived from principal component analysis (PCA) of RNA-seq data. We also delineate unique signatures across disease endo-phenotypes whereby active nephritis exhibits the most extensive changes in transcriptome, including prominent drugable signatures such as granulocyte and plasmablast/plasma cell activation. The substantial differences in gene expression between SLE and healthy individuals enables the classification of disease versus healthy status with median sensitivity and specificity of 83% and 100%, respectively. We explored the genetic regulation of blood transcriptome in SLE and found 3142 cis-expression quantitative trait loci (eQTLs). By integration of SLE genome-wide association study (GWAS) signals and eQTLs from 44 tissues from the Genotype-Tissue Expression (GTEx) consortium, we demonstrate that the genetic causality of SLE arises from multiple tissues with the top causal tissue being the liver, followed by brain basal ganglia, adrenal gland and whole blood. Collectively, our study defines distinct susceptibility and activity/severity signatures in SLE that may facilitate diagnosis, monitoring, and personalized therapy.

Sjögren's syndrome (SS) is a complex autoimmune rheumatic disease that specifically targets salivary and lachrymal glands. As such, patients typically had ocular and oral dryness and salivary gland swelling. Moreover, skin, nasal and vaginal dryness are frequently present. In addition to dryness, musculoskeletal pain and fatigue are the hallmarks of this disease and constitute the classic symptom triad presented by the vast majority of patients. Up to 30% to 50 % of patients with SS may present systemic disease; moreover, there is an increased risk for the development of non-Hodgkin's lymphoma that occurs in a minority of patients. The present work was developed in the framework of the European Reference Network (ERN) dedicated to Rare and Complex Connective Tissue and Musculoskeletal Diseases (ReCONNET). In line with its goals of aiming to improve early diagnosis, treatment and care of rare connective and musculoskeletal diseases, ERN-ReCONNET set to review the current state of clinical practice guidelines (CPGs) in the rare and complex connective tissue diseases of interest of the network. Therefore, the present work was aimed at providing a state of the art of CPGs for SS. info:eu-repo/semantics/publishedVersion

Systemic lupus erythematosus (SLE) is the paradigm of systemic autoimmune diseases characterised by a wide spectrum of clinical manifestations with an unpredictable relapsing-remitting course. The aim of the present work was to identify current available clinical practice guidelines (CPGs) for SLE, to provide their review and to identify physicians' and patients' unmet needs. Twenty-three original guidelines published between 2004 and 2017 were identified. Many aspects of disease management are covered, including global disease management, lupus nephritis and neuropsychiatric involvement, management of pregnancies, vaccinations and comorbidities monitoring. Unmet needs relate with disease management of some clinical manifestations and adherence to treatment. Many patient's unmet needs have been identified starting with faster diagnosis, need for more therapeutic options, guidelines on lifestyle issues, attention to quality of life and adequate education. info:eu-repo/semantics/publishedVersion

Purpose. Cardiac autonomic dysfunction is frequently encountered among patients with systemic sclerosis. Its presence correlates with potentially fatal ventricular arrhythmias, having a good positive predictive value for mortality. The aim of this paper was to identify cardiac autonomic dysfunction in patients with systemic sclerosis using Holter ECG monitoring and to assess the possible correlations between its presence and other disease characteristics. Material and methods. Forty nine patients with diffuse cutaneous and limited cutaneous scleroderma, diagnosed according to the American College of Rheumatology/EULAR 2013 criteria underwent ECG, transthoracic echocardiography, blood sample testing, chest X-ray and spirometry. Subsequently, all patients and a control group of 49 healthy subjects underwent Holter ECG monitoring with time and frequency domain heart rate variability (HRV) analysis. Results. Scleroderma patients had significantly lower HRV values compared to controls: SDNN (123 ± 39.4 vs. 143.2 ± 32, p =0.001), SDANN (137.2 ± 34.9 vs. 127.9 ± 25.7, p=0.001), TI (-) (30.6 ± 9.6 vs. 38.1 ± 8.9, p=0.01) and TINN (758.8 ± 208 vs. 815.1 ± 138, p=0.04). The LF/HF ratio was significantly higher among patients with diffuse scleroderma (1.18 ± 0.34 vs. 1.08 ± 0.43, p= 0.005). There was a positive correlation between the TI values, SDANN and the duration from the onset of Raynaud’s phenomenon (r=0.399, p=0.016) (r=0.419, p=0.011), between the SDANN values and systolic pulmonary arterial pressure (sPAP) values (0.032, p=0.034) and a negative correlation between the LF/HF values and the patients’ age (r=-0.442, p=0.001), the duration from the onset of non-Raynaud’s phenomenon (r=-0.395, p=0.034), echocardiographic value of sPAP(r=-0.330, p=0.035) and the total number of premature ventricular contractions (r=-0.0459, p=0.001). Conclusion. Patients with systemic sclerosis often have cardiac autonomic dysfunction, which can be diagnosed with Holter ECG monitoring.

Aim. To achieve extensive information (regional) in relation with the tuberculosis identified in current clinical practice in patients with inflammatory rheumatic diseases treated with biological agents. Patients and methods. Twenty seven rheumatologists from 11 Romanian medicale center agreed to participate voluntarily and provide required data on tuberculosis (TB) occurring between January 1999 and June 2011 in their patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthropathy (PsA) in relation with anti-TNFα agent. This observational research included 693 patients (RA n=492, SA n=137, AP n= 64). All patients were screen for latent Mycobacterium tuberculosis infection (LTBI) before they start anti-TNFα treatment. Chemoprophylaxis with isoniazid before anti-TNFα therapy is recommended if the diameter of tuberculin skin test reaction is more than 5 mm (before 2005 only if indurations was more than 10 mm). We recorded the demographic characteristics, and complex information about disease, treatment, tuberculosis diagnosis and the comorbidities. Incidence rate of TB are presented as events/1,000 person-years with associated 95% confidence interval [95%CI]. Results. Fifteen patients were diagnosed with TB, most (60%) were born in rural areas and 40% in areas with higher incidence (≥ 80%ooo) of TB. The incidence of TB was 1.65‰ (IC95% [11.54-34.63]). The extra pulmonary sites were present in 53.3% of the cases. Cultures were positive for Mycobacterium tuberculosis in 11 cases (73.3%). Suspicion of TB was confirmed histological in 6 cases (40%). The average duration of developing TB after initiation of TNF inhibitor was 23.26 months (range one month to 120 months). In 7/12 TB cases treated with IFX the incidence appeared in the first year of treatment. Any of known risk factors don’t have a significant influence in our cohort. Conclusions. The risk of reactivation of a latent TB during biologic therapy is greater in patients with rheumatic inflammatory diseases living in geographical areas with high endemicity of TB infection. Reduced compliance to chemoprophylaxis may be responsible for the occurrence of these cases.

Background SLE displays significant immunological and clinical heterogeneity. Understanding the molecular basis of this variability may facilitate early diagnosis, risk stratification and personalized therapy. Objectives To perform full transcriptome analysis in SLE patients in order to identify molecular sub-phenotypes and explore the genomic basis for the disease susceptibility and severity. Methods Whole blood mRNA and genomic DNA were extracted from 142 SLE patients with varying levels of disease activity/severity and 48 matched healthy volunteers. Paired-end RNA sequencing was performed using the Illumina HiSeq 2000 platform and genotyping with the Infinium CoreExome followed by imputation from the 1000 Genomes. To integrate blood transcriptome with genotype data we used the enrichment analysis of expression-quantitative trail loci (eQTLs). The CIBERSORT tool was used to provide an estimation of the abundancies of different circulating immune cell types. Results We found a large number (6730, 5% False Detection Rate [FDR]) of differentially expressed genes (DEGs) between SLE patients and controls. Interferon signaling was significantly upregulated in SLE with most of the DEGs (146 out of 281) being regulated by both type I and type II interferon. Analysis of the blood composition in different immune cell types revealed global upregulation of type I interferon and antiviral response genes as well as immune cell-specific alterations in gene expression in SLE patients. Comparison of the transcriptome in active/inactive SLE and healthy individuals identified distinct “disease susceptibility” and “disease activity” gene signatures encompassing 2738 and 377 DEGs, respectively. Analysis according to individual organ involvement revealed more widespread aberrancies in gene expression in SLE patients with active nephritis as compared to activity from other organs, corresponding to oxidative phosphorylation, granulocyte activation and antimicrobial humoral response pathways. By integration of genotyping data, we mapped a total 3142 (5% FDR) cis-eQTLs in SLE patients suggesting extensive genetic effects on whole blood gene expression. Importantly, linear discriminant analysis enabled the definition of a set of DEGs which discriminated SLE versus healthy state with median sensitivity 83% and specificity 100%. Design of gene expression panels and expression profile/clinical trait correlation matrices for improved diagnostics, stratification and personalized therapy is in progress. Conclusions Specific gene networks confer susceptibility to SLE as well as to severe forms of the disease. These results may facilitate the early diagnosis, monitoring and prognosis, and the molecular taxonomy of SLE patients into pathophysiologically and prognostically distinct subsets for personalized therapy. Disclosure of Interest None declared

Background Even during remission, the systemic lupus erythematosus (SLE) patients have reduced exercise performance and this contributes to impairment of their quality of life 1 . Several causes as depression and deconditioning, arthritis, anemia, cardiovascular and respiratory involvement are widely accepted; however the weight of each factor is less known in particular individuals. Objectives Our study aimed to assess through cardiopulmonary exercise testing (CPX) the exercise performance of a SLE cohort and to establish its main determinants. Methods Thirty-one SLE patients with low disease activity underwent a CPX on cycle ergometer; the main metabolic parameters and standard 12-leads ECG were recorded; before exercise testing, a cardiac Doppler ultrasound was performed. The patient9s characteristics, cumulative organ damage and laboratory data were retrieved by medical chart review. The control group consisted of 25 age and sex-matched healthy, non-trained individuals. Results Within the study group, 28 (90.3%) were female, the mean age was 42.7±10.6 years and disease median duration 7.9 years. The aerobic performance was decreased by 16.2% (17.6 vs 21.36 ml/kg/min, p=0.022); the main disease characteristics which correlated with maximum oxygen uptake (VO2Mx) were anemia (p=0.035), renal involvement (p=0.05) and antiphospholipid syndrome (APS) (p=0.042) but not disease duration, cumulative damage or the immunological tests (hypocomplementemia, anti-Ro, anti-Sm, anti-dsDNA, AAN or APL antibodies). One quarter of patients did not reach the ventilatory anaerobic threshold (VAT, expressed as a percentage of calculated VO2Mx), mainly due to musculoskeletal pain (5 patients), dyspnea (2 patients with history of pulmonary embolism) and sudden rise in blood pressure (1 patient). Among the rest of them (23 patients, 74%), the VAT was at the lower limit of normal range (41.03% vs 54.0% for controls, p=0.014) corresponding to a “training reserve” of 31%. Of particular importance from this point of view were the criteria for test termination: dyspnea in 4 patients (1 with anemia, 1 with pulmonary fibrosis and 2 by hyperventilation proved by mean VE/VCO2 =41.5), fatigue (9 patients) and arthralgia (7 patients). Notably, among patients with established diagnosis of mild pulmonary fibrosis, COPD, ischemic or valvular heart disease, not dyspnea but arthralgia or fatigue was the reason for test termination, even if the VO2Mx was lower than recorded in the rest of the group (15.8 vs 19.2 ml/kg/min, p=0.037). Conclusions The exercise aerobic capacity of SLE patients is diminished and correlates with anemia, renal involvement and with hystory of pulmonary embolism. Surprisingly, even in patients with mild cardiovascular or respiratory involvement, the decreasing of exercise performance is limited mainly from musculoskeletal symptoms and from deconditioning. References Carvalho MR, Sato EI, Tebexreni AS, et al. Effects of supervised cardiovascular training program on exercise tolerance, aerobic capacity, and quality of life in patients with systemic lupus erythematosus. Arthritis Rheum 2005;53(6):838–44. Disclosure of Interest None declared

Aim: To evaluate the relationship between epicardial adipose tissue (EAT) and arterial stiffness (AS) in patients with rheumatoid arthritis (RA), considering cardiovascular risk factors and disease characteristics.Material and methods: A total of 84 RA patients were included in this cross-sectional study. EAT and carotid intima-media thickness (cIMT) were measured ultrasonographically while aortic pulse wave velocity (aPWV), the main AS parameter, was determined using an oscillometric device.Results: Mean duration of RA was 12±9.5 years and disease activity score was 4.3±1.4, as assessed by Disease Activity Score-28 using C-reactive protein (DAS-28 CRP). The correlation analysis displayed a significant positive correlation between cIMT, aPWV and EAT (r= 0.037, p

Systemic lupus erythematosus (SLE) is a multiorgan disease with protean manifestations. Because SLE is uncommon and heterogeneous, its diagnosis can pose a considerable challenge, especially for clinicians with limited expertise of the disease. This is particularly true at the early stages of SLE, when an inadequate number of features to secure the diagnosis might be present, and for patients presenting with uncommon features, which can nonetheless be severe and require prompt treatment. Furthermore, the suboptimal performance of immunological testing in patients referred for possible SLE has been highlighted. As a result, SLE remains largely a clinical diagnosis that is made after excluding alternative diagnoses. Diagnostic criteria can expedite diagnosis and treatment, but are not available for SLE. Thus, SLE classification criteria are often used, but strict adherence to these criteria could delay diagnosis. Therefore, while eagerly awaiting diagnostic criteria for this disease, we propose interim potential solutions to facilitate its diagnosis.

Patients with lupus nephritis suffer from excessive morbidity and mortality compared with patients without renal involvement and the general population. Over the past few decades, early mortality in lupus nephritis due to uncontrolled renal disease activity and acute renal failure has decreased, whereas cardiovascular, metabolic, infectious comorbidities and malignancies have emerged as important long-term complications. Their pathogenesis involves chronic inflammatory burden, exposure to drugs with high toxicity potential (particularly glucocorticoids), and metabolic abnormalities due to impaired renal function. Although the lupus literature lacks controlled data for the management of most of the aforementioned disorders, there is evidence from other patients with chronic kidney disease to guide therapeutic decisions. Importantly, a multitargeted approach is recommended, which includes adequate control of disease activity with minimization of exposure to glucocorticoids, tight control of cardiovascular risk factors, and prompt identification and management of other chronic kidney disease comorbidities according to existing recommendations.

ObjectivesDevelop recommendations for women's health issues and family planning in systemic lupus erythematosus (SLE) and/or antiphospholipid syndrome (APS).MethodsSystematic review of evidence followed by modified Delphi method to compile questions, elicit expert opinions and reach consensus.ResultsFamily planning should be discussed as early as possible after diagnosis. Most women can have successful pregnancies and measures can be taken to reduce the risks of adverse maternal or fetal outcomes. Risk stratification includes disease activity, autoantibody profile, previous vascular and pregnancy morbidity, hypertension and the use of drugs (emphasis on benefits from hydroxychloroquine and antiplatelets/anticoagulants). Hormonal contraception and menopause replacement therapy can be used in patients with stable/inactive disease and low risk of thrombosis. Fertility preservation with gonadotropin-releasing hormone analogues should be considered prior to the use of alkylating agents. Assisted reproduction techniques can be safely used in patients with stable/inactive disease; patients with positive antiphospholipid antibodies/APS should receive anticoagulation and/or low-dose aspirin. Assessment of disease activity, renal function and serological markers is important for diagnosing disease flares and monitoring for obstetrical adverse outcomes. Fetal monitoring includes Doppler ultrasonography and fetal biometry, particularly in the third trimester, to screen for placental insufficiency and small for gestational age fetuses. Screening for gynaecological malignancies is similar to the general population, with increased vigilance for cervical premalignant lesions if exposed to immunosuppressive drugs. Human papillomavirus immunisation can be used in women with stable/inactive disease.ConclusionsRecommendations for women's health issues in SLE and/or APS were developed using an evidence-based approach followed by expert consensus.

Aims: Myocardial damage is frequent and often silent in systemic lupus erythematosus (SLE). The aim of the study was to determine the prevalence of myocardial damage by novel ultrasound techniques and to systematically assess the relationship between subclinical cardiac dysfunction and SLE-related clinical parameters. Material and methods: Seventy-five consecutive SLE patients without evidence of cardiac disease and seventy-three controls underwent standard transthoracic echocardiography using classical and novel ultrasound techniques: tissue Doppler imaging and speckle tracking echocardiography. Patient characteristics, cumulative organ damage and laboratory data were retrieved by medical chart review. Results: Within the cohort, 89.3% of the patients were female; mean±SD age and median (IQR) disease duration were 43.2±12.5 years and 8.03(6.3) years, respectively. SLE patients exhibited a significant decrement in endocardial longitudinal strain (-18.4% vs 19.3%, p=0.001) compared with controls. Diastolic dysfunction was detected in 34 (45.3%) of SLE patients. Major determinants of systolic and diastolic dysfunction were hypertension (p=0.023 and p

Systemic lupus erythematosus is the prototypic autoimmune disease with a broad range of clinical manifestations and a complex pathogenesis. B-cells hold a central role in its pathogenesis, not only as autoantibody producing cells, but also by producing other inflammatory mediators and by presenting autoantigens to autoreactive T cells. BlyS, a soluble ligand of the TNF cytokine family, is a key factor affecting B-cell homeostasis and survival and its blockade ameliorated the disease in animal models and preclinical studies of SLE. Following an unsuccessful phase II trial of belimumab, a monoclonal antibody targeting BlyS, two large phase III studies in patients with mild-to-moderate disease, BLISS-52 and BLISS-76, met their primary endpoints showing better efficacy of the drug over standard of care alone. To this end, development of a novel more sensitive responder index and improvements in study designs were crucial. As a result, belimumab became the first drug to get approval for the treatment of SLE after more than 50 years. In this paper we discuss the rationale, development, indications, lessons learned, pitfalls and challenges for this novel therapy and point-out to additional issues that need to be addressed in the future.http://dx.doi.org/10.7175/rhc.v3i3.206

Models for the attribution of neuropsychiatric manifestations to systemic lupus erythematosus (NPSLE) that incorporate timing and type of manifestation, exclusion/confounding or favouring factors have been proposed. We tested their diagnostic performance against expert physician judgment.SLE patients with neuropsychiatric manifestations were identified through retrospective chart review. Manifestations were classified according to physician judgment as attributed to SLE, not attributed or uncertain. Results were compared against the Systemic Lupus International Collaborating Clinics (SLICC) attribution models A and B, and one introduced by the Italian Study Group on NPSLE.191 patients experienced a total 242 neuropsychiatric manifestations, 136 of which were attributed to SLE according to physician. Both SLICC models showed high specificity (96.2% and 79.2% for model A and B, respectively) but low sensitivity (22.8% and 34.6%, respectively) against physician judgment. Exclusion of cases of headache, anxiety disorders, mild mood and cognitive disorders and polyneuropathy without electrophysiologic confirmation led to modest increases in sensitivity (27.7% and 42.0% for SLICC models A and B, respectively) and reductions in specificity (94.8% and 65.5%, respectively). The Italian Group model showed good accuracy in NPSLE attribution with an area under the curve of the receiver operating characteristics analysis of 0.862; values ≥7 showed the best combination of sensitivity and specificity (82.4% and 82.9%, respectively).Attribution models can be useful in NPSLE diagnosis in routine clinical practice and their performance is superior in major neuropsychiatric manifestations. The Italian Study Group model is accurate, with values ≥7 showing the best combination of sensitivity and specificity.

Cyclophosphamide (CYC) is used in severe neuropsychiatric systemic lupus erythematosus (NPSLE), but long-term data regarding its efficacy and safety are lacking. We identified NPSLE cases who received CYC from two centres during the period 1999–2013 and had regular follow-up. General and neuropsychiatric outcome at last follow-up visit were determined, and major complications were documented. CYC was administered in 50 neuropsychiatric events. Median age was 45.0 years and 46% of patients were positive for antiphospholipid antibodies. Most frequent indications were psychosis (11 cases), polyneuropathy (six cases), and cerebrovascular disease, seizure disorder and cranial neuropathy (five cases). CYC was mainly administered as monthly pulses (median number: 8.0 (range 3–26), median cumulative dose: 7.2 g (range 2.4–33.8)). Cases were followed for a median of 46.5 months (range 5–408). At last follow-up, partial or complete response of NPSLE was observed in 84% of events; 10% had stable disease, whereas the remaining 6% failed to improve or worsened and were rescued with rituximab. In events that responded to CYC, maintenance therapy consisted of azathioprine in 31 events (65.9%), bimonthly or quarterly pulses of intravenous CYC in nine (19.1%), and mycophenolate mofetil in five (10.6%). Relapses were observed in six events (12%) at median eight months after initial response. No malignancies were observed, yet there were three cases of severe infections. Amenorrhea was recorded in three patients, who had not received gonadal protection. In conclusion, cyclophosphamide was efficacious and led to sustained response of severe NPSLE in a cohort with long follow-up.

Autoimmune liver diseases may be associated with extrahepatic autoimmune pathology. We report the case of a 52-year old woman who initially presented to the gastroenterology department for extreme fatigue, pale stools, dark urine and pruritus. Laboratory tests showed significant cholestasis and elevation of aminotransferase levels. Immunological tests revealed positive antinuclear (ANA=1:320) and antimitochondrial antibodies (AMA=1:40) with negative anti-smooth muscle and liver kidney microsomal type 1 antibodies. The biopsy was compatible with overlap syndrome type 1. The patient was commenced on immunosuppressive therapy according to standard of care (azathioprine 50mg, ursodeoxycholic acid and prednisone 0.5mg/kg), with moderate biochemical improvement. She subsequently developed proximal symmetrical weakness and cutaneous involvement and was diagnosed with biopsy-proven dermatomyositis. The immunosuppressive regimen was intensified to 150 mg azathioprine. At the three-month follow-up, her symptoms subsided and aminotransferases and muscle enzymes normalized. Upon further investigation the patient was diagnosed with autoimmune thyroiditis and antiphospholipid syndrome. To our knowledge, this is the first case of primary biliary cirrhosis - autoimmune hepatitis overlap syndrome associated with dermatomyositis, autoimmune thyroiditis and antiphospholipid syndrome.

OBJECTIVE To compare the European League Against Rheumatism (EULAR) recommendations for the management of NPSLE with usual care in two tertiary centres and to detect potential pitfalls in their use for diagnosis and treatment. METHODS A chart-based review of NPSLE manifestations was conducted in two European centres. Diagnostic and treatment decisions were compared against the EULAR recommendations for general NPSLE and specific manifestations. RESULTS We studied a total of 94 patients who experienced 123 lupus-related neuropsychiatric events over 10 years. In 80% of the events, at least one EULAR-defined risk factor (previous NPSLE, generalized disease activity or aPL positivity) was present. Overall, there was good concordance between clinical care and recommendations for diagnosis and treatment (68.7% and 62.7% of events, respectively). Brain MRI was performed in the absence of a clear EULAR recommendation in 42.9% of events; therein, it was more frequently normal compared with imaging performed according to the recommendations (52.4% vs 18.5%, P = 0.008), and it did not influence management. Among patients reporting cognitive dysfunction, only 27.8% underwent the recommended neuropsychological assessment. In line with the recommendations, immunosuppressants were more frequently given in events suggestive of an inflammatory process (80.5% vs 47.6% in non-inflammatory events, P < 0.001). Notably, 52% of cerebrovascular events were managed with combined immunosuppressive/antithrombotic therapy due to either coexisting generalized lupus activity or recurrence despite prior antithrombotic treatment. CONCLUSION Despite good concordance between EULAR recommendations for NPSLE and usual clinical practice, we identified a number of issues (such as overutilization of brain MRI, suboptimal evaluation of cognitive dysfunction, and frequent use of immunosuppressives in cerebrovascular disease) that need to be investigated further.

With current advances in medical treatment, reproductive issues have become more important for women with chronic immune-mediated diseases. Most, if not all, patients report that their disease affects their personal relationships, their decision to have children, and the size of their family. These decisions are multi-factorial, influenced mainly by concerns over the effect of pregnancy on the rheumatic disease, the impact of disease activity during pregnancy on foetal health, the patient's ability to care for the child, and the possible harmful effects medication could have on the child, both pre- and post-natally during breastfeeding. Apart from that, women's health issues tend to be overlooked in favour of the management of the underlying rheumatic disease. To this end, we convened an expert panel to review the published literature on women's health and reproductive issues and provide evidence- and eminence-based points to consider for the treating physicians. We conclude that there is a need for a change in mind-set from one which 'cautions against pregnancy' to one which 'embraces pregnancy' through the practice of individualised, pre- and post-conceptual, multi-disciplinary care.

Systemic lupus erythematosus (SLE) is a multiorgan disease with protean manifestations. Because SLE is uncommon and heterogeneous, its diagnosis can pose a considerable challenge, especially for clinicians with limited expertise of the disease. This is particularly true at the early stages of SLE, when an inadequate number of features to secure the diagnosis might be present, and for patients presenting with uncommon features, which can nonetheless be severe and require prompt treatment. Furthermore, the suboptimal performance of immunological testing in patients referred for possible SLE has been highlighted. As a result, SLE remains largely a clinical diagnosis that is made after excluding alternative diagnoses. Diagnostic criteria can expedite diagnosis and treatment, but are not available for SLE. Thus, SLE classification criteria are often used, but strict adherence to these criteria could delay diagnosis. Therefore, while eagerly awaiting diagnostic criteria for this disease, we propose interim potential solutions to facilitate its diagnosis.

Objectives The coexistence of systemic lupus erythematosus (SLE) and multiple sclerosis (MS) in the same individual has rarely been described. Our objective was to report on the prevalence, clinical characteristics, and prognosis of cases fulfilling the criteria for both SLE and MS. Methods We utilized existing patient cohorts from the Departments of Rheumatology and Neurology, University of Crete, and screened patients diagnosed with either SLE ( n = 728) or MS ( n = 819) for features of both diseases. The clinical, laboratory, and neuroimaging findings were assessed. Results We identified nine patients who fulfilled the diagnostic criteria for both SLE and MS, corresponding to a prevalence rate of 1.0–1.2% in each cohort. All patients were women, with an average age at SLE diagnosis of 42.1 years (range: 34–56 years). The diagnosis of SLE preceded the development of MS in five patients, with a time lag ≤5 years in four of them. Initial presentation of MS included spinal symptoms in seven patients. All patients had features of mild SLE with predominantly cutaneous, mucosal, and musculoskeletal manifestations. Accordingly, therapeutic decisions were mainly guided by the severity of the neurological syndrome. During the median follow-up of 4 years (range: 1–10 years), three patients remained stable and the remaining experienced gradual deterioration in their neurological status. SLE remained quiescent in all patients while on standard immunomodulatory MS therapy. Conclusions Occurrence of both diseases in the same individual is rare, corroborating data that suggest distinct molecular signatures. SLE and MS coexistence was not associated with a severe phenotype for either entity.

Autoimmune hepatitis (AIH) is a chronic disorder characterized by persistent hepatocellular inflammation and necrosis. AIH overlap syndromes with other autoimmune diseases have been reported, including connective tissue diseases (CTD). Reports of AIH in systemic sclerosis (SSc), however, are scarce and have been particularly described in the limited SSc subtype. We report a case of systemic sclerosis-polymyositis overlap syndrome that developed AIH and subsequently, cerebral vasculitis. To our knowledge, this is the first report of such a complex mosaic of autoimmunity. We also review the literature regarding scleroderma-related AIH.