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BACKGROUND: Disease activity in systemic lupus erythematosus follows three different courses: long quiescent, relapsing remitting and persistently active. However, the patterns of disease course since diagnosis are not known. This study aimed to assess the prevalence and characteristics of such patterns over 10 years. PATIENTS AND METHODS: The inception cohort of the Toronto Lupus Clinic (≥10 year follow up, between visit interval ≤18 months) was investigated. Prolonged remission was defined as a clinical Systemic Lupus Erythematosus Disease Activity Index 2000 = 0 achieved within 5 years of enrolment and maintained for ≥10 years. The relapsing-remitting pattern was defined based on ≥2 remission periods (clinical Systemic Lupus Erythematosus Disease Activity Index 2000 = 0 for two consecutive visits). Patients with no remission were categorized as persistently active. Groups were compared for baseline characteristics, cumulative damage, flare rate, mortality and certain co-morbidities. RESULTS: Of 267 patients, 27 (10.1%) achieved prolonged remission, 180 (67.4%) relapsing-remitting and 25 (9.4%) persistently active. In total, 35 (13.1%) had only one remission period (hybrid). At enrollment, there were no differences regarding clinical and immunological variables. At 10 years, persistently active patients had accumulated significantly more damage than the prolonged remission and relapsing-remitting patients. Being of Black race and higher adjusted mean Systemic Lupus Erythematosus Disease Activity Index 2000 over the first 2 years were associated with a more severe disease course. Relapsing-remitting and persistently active patients had an increased flare rate and accrued more osteoporosis, osteonecrosis and cardiovascular events. CONCLUSIONS: Approximately 70% of systemic lupus erythematosus patients followed a relapsing-remitting course, whereas 10% displayed prolonged remission and another 10% a persistently active course. Early response to treatment was associated with a less severe course and better prognosis.

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Background Severe brady-arrhythmias, requiring a permanent pacemaker (PPM), have been sparsely reported in systemic lupus erythematosus (SLE). The aim of this study was to describe the characteristics of such arrhythmias in a defined lupus cohort. Patients and methods The database of the Toronto Lupus Clinic ( n = 1366) was searched for patients who received a PPM. Demographic, clinical, immunological and therapeutic variables along with electrocardiographic (ECG) and echocardiographic findings (based on the last available test prior to PPM) were analyzed. Patients with a PPM (cases) were compared with age-, sex- and disease duration-matched patients without a PPM (controls). Analysis was performed with SAS 9.0; p < 0.05 was considered significant. Results Eighteen patients were identified, 13 (0.95%) with complete atrioventricular block and 5 (0.37%) with sick sinus syndrome. Disease duration at PPM implantation was 22 ± 12 years. Compared to controls, cases had more frequently coronary artery disease, hypertension, dyslipidemia and longer antimalarial (AM) treatment duration. The prevalence of first-degree atrioventricular block, right bundle branch block, left anterior fascicular block and septal hypertrophy was also higher. AM treatment was significantly associated with brady-arrhythmias (OR = 1.128, 95% CI = 1.003-1.267, p = 0.044). Nine patients had prior heart disease and one received a PPM two years after renal transplantation. Eight patients did not have any potential risk factors; prolonged AM therapy (mean 22 years) might have been the cause. Conclusions Apart from known causes, prolonged AM treatment may be associated with severe brady-arrhythmias in SLE. Certain ECG and echocardiographic characteristics may represent indicators of an ongoing damage in the conduction system.

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Background Lupus myocarditis (LM) is reported in 3-9% of patients with systemic lupus erythematosus (SLE) but limited evidence exists regarding optimal treatment and prognosis. This study aims to describe LM in a defined lupus cohort as compared with the existing literature. Patients and methods Patients with LM were identified from the University of Toronto Lupus Clinic database. Diagnosis was based on clinical manifestations and electrocardiographic, imaging, and biochemical criteria. Demographic, clinical, diagnostic and therapeutic variables and outcomes were collected in a standardized data retrieval form. A literature review was performed to identify cohort studies reporting on LM treatment and outcome. A comparative analysis was conducted between our patients and the combined cohort of the existing studies. Results Thirty patients were diagnosed with LM (prevalence 1.6%) and compared with a cumulative cohort of 117 patients from five distinct studies. No significant differences were found regarding the age at diagnosis (32.6 ± 13.4 years) and SLE duration (2.5 years median). Concomitant lupus activity from other organ systems was observed in 97% of the patients. Chest pain was more frequently reported in our cohort whereas dyspnea was more prominent in the other studies. Diagnostic criteria were similar across studies. Therapeutic approach was comparable and consisted of glucocorticosteroids (96.6%) and immunosuppressives (70%). Mortality was approximately 20% whereas another 20% of the patients achieved partial and 60% complete recovery. Conclusions LM usually occurs early in the disease course and in the context of generalized lupus activity. Despite aggressive therapy, approximately 40% of the patients died or had residual heart damage.

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Background Antimalarials (AMs) are widely used in the treatment of connective tissue diseases. Their main side effect is retinal damage, while heart disease has been described in isolated cases. The aim of this study is to systematically review the existing literature on AM-induced cardiomyopathy (AMIC). Methods The PubMed database was searched for heart biopsy-confirmed AMIC cases. Information on demographics, clinical presentation, concomitant AM-related toxicity, cardiological investigations, treatment and outcome were collected. Descriptive statistics were used. Results Forty-seven cases (42 females) were identified with a mean age at diagnosis 56.4 ± 12.6 and mean AM treatment duration 12.7 ± 8.2 years. Systemic lupus erythematosus ( n = 19) and rheumatoid arthritis ( n = 18) were the most common primary diseases. Clinical presentation was that of congestive heart failure in 77%, while eight patients presented with syncope (17%). Complete atrioventricular block was reported in 17 patients; 24 received a permanent pacemaker (51%). Impaired systolic function was detected in 52.8%, bi-ventricular hypertrophy in 51.4% and restrictive filling pattern of the left ventricle in 18 patients. Cardiac magnetic resonance showed late gadolinium enhancement in seven cases, with a non-vascular pattern in the interventricular septum. Cardiomyocyte vacuolation was reported in all cases; intravacuolar lamellar and curvilinear bodies were observed in 46 (98%) and 42 (89.4%) respectively. Mortality rate was 45% (18/40). Conclusion AMIC is a rare, probably under-recognized, complication of prolonged AM treatment. It presents as a hypertrophic, restrictive cardiomyopathy with or without conduction abnormalities. Early recognition and drug withdrawal are critical with a survival rate of almost 55%.

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Introduction Shrinking lung syndrome (SLS) is a rare manifestation of systemic lupus erythematosus (SLE), characterized by decreased lung volumes and extra-pulmonary restriction. The aim of this study was to describe the characteristics of SLS in our lupus cohort with emphasis on prevalence, presentation, treatment and outcomes. Patients and methods Patients attending the Toronto Lupus Clinic since 1980 ( n = 1439) and who had pulmonary function tests (PFTs) performed during follow-up were enrolled ( n = 278). PFT records were reviewed to characterize the pattern of pulmonary disease. SLS definition was based on a restrictive ventilatory defect with normal or slightly reduced corrected diffusing lung capacity for carbon monoxide (DLCO) in the presence of suggestive clinical (dyspnea, chest pain) and radiological (elevated diaphragm) manifestations. Data on clinical symptoms, functional abnormalities, imaging, treatment and outcomes were extracted in a dedicated data retrieval form. Results Twenty-two patients (20 females) were identified with SLS for a prevalence of 1.53%. Their mean age was 29.5 ± 13.3 years at SLE and 35.7 ± 14.6 years at SLS diagnosis. Main clinical manifestations included dyspnea (21/22, 95.5%) and pleuritic chest pain (20/22, 90.9%). PFTs were available in 20 patients; 16 (80%) had decreased maximal inspiratory (MIP) and/or expiratory pressure (MEP). Elevated hemidiaphragm was demonstrated in 12 patients (60%). Treatment with prednisone and/or immunosuppressives led to clinical improvement in 19/20 cases (95%), while spirometrical improvement was observed in 14/16 patients and was mostly partial. Conclusions SLS prevalence in SLE was 1.53%. Treatment with glucocorticosteroids and immunosuppressives was generally effective. However, a chronic restrictive ventilatory defect usually persisted.

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OBJECTIVE: To investigate the relationship between antimalarials (AM) and elevated muscle enzymes in systemic lupus erythematosus (SLE). PATIENTSMETHODS: 325 lupus patients with abnormal creatine phosphokinase (CPK) for at least two consecutive clinic visits were enrolled; 54 patients on statins/fibrates (n = 43) and/or active myositis (n = 14) were excluded. The control group consisted of 1453 lupus patients with no CPK elevation during follow-up. Descriptive statistics and Cox regression analyses were performed, p < 0.05 was considered significant. RESULTS: Cases and controls did not differ regarding age at SLE diagnosis, gender ratio, or disease duration. AM use was more frequent in cases, which had more prolonged AM use. Total frequency of elevated CPK in AM users was 216/1322 (16.3%). Chloroquine was associated with a 3.3-fold, and hydroxychloroquine with a 3.1-fold, increased risk for CPK elevation. Black race was associated with higher CPK (HR = 2.941), whereas female gender was protective (HR = 0.697). 203 patients were followed for 7.3 ± 5.6 years; 49.8% had persistent and 14.8% intermittent CPK elevation, while in 35.4% CPK was normalized. Clinical proximal muscle weakness developed in 5/203 patients. CONCLUSIONS: Chronic AM use is a potential risk factor for muscle enzyme elevation in SLE patients. CPK abnormalities persist in almost two thirds of the patients, but this remains mainly a biochemical finding, evolving to clinical myopathy in about 2.5%.

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OBJECTIVES: Regulatory T cells (Tregs) are inversely correlated to disease activity in systemic lupus erythematosus (SLE). However, little is known concerning the influence of immunosuppressive agents on Tregs, which was the objective of this study. METHOD: Thirty-five patients with SLE (29 females, six males, mean age 42.4 ± 12.8 years) were included. CD4+CD25(high)FOXP3+ Tregs were prospectively assessed by flow cytometry every month for intravenous (iv) and quarterly for oral regimens. Clinical assessment was made with the SLE Disease Activity Index (SLEDAI). Statistical analysis was performed with a Student's t-test; p < 0.05 was considered significant. RESULTS: In total, 44 cases of SLE relapse were treated with iv cyclophosphamide (CYP, n = 10), iv methylprednisolone (MP, n = 7), iv immunoglobulins (IVIGs, n = 5), oral MP (n = 8), oral MP + azathioprine (AZA, n = 8), and hydroxychloroquine (HCQ, n = 6). CYP, iv MP, and IVIGs resulted in a significant increase in Tregs (4.2 ± 1.6 vs. 10.1 ± 5.7, 2.9 ± 1.3 vs. 10.6 ± 4.8, and 5.6 ± 2.7 vs. 15.2 ± 6.3 cells/mm(3), respectively, p < 0.05). Oral MP, alone or combined with AZA, led to a significant increase in Tregs (7.4 ± 2.5 vs. 11.8 ± 3.8 and 5.1 ± 2.4 vs. 9.4 ± 3.6 cells/mm(3), respectively, p < 0.05), as did HCQ (8.2 ± 2.4 vs. 12.8 ± 2.7 cells/mm(3), p < 0.05). Time to Tregs recovery was significantly shorter with iv MP and IVIGs compared to CYP (1.4 ± 0.5, 1.6 ± 0.9, and 4.0 ± 1.5 months, respectively, p < 0.05). CONCLUSIONS: Increase in Tregs during SLE remission is independent of the therapeutic regimen used and probably represents an epiphenomenon of disease remission. Time to Tregs restoration was significantly shorter in patients treated with iv MP and IVIGs compared to CYP pulse therapy.

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To clarify the role of ADAMTS-13 in the pathogenesis of thrombotic microangiopathy in systemic lupus erythematosus (SLE) we evaluated ADAMTS-13 profile (metalloprotease antigen levels, anti-ADAMTS-13 autoantibody levels, activity) in distinct patient groups according to disease activity, extent of cumulative tissue damage and history of antiphospholipid syndrome or end-organ damage. Forty-one lupus patients were analysed. ADAMTS-13 metalloprotease antigen levels and anti-ADAMTS-13 autoantibodies were evaluated by ELISA. ADAMTS-13 activity was measured by Fluorescence resonance energy transfer (FRET) technique. ADAMTS-13 metalloprotease antigen levels were significantly decreased in patients with Systemic Lupus International Collaborative Clinics/American College of Rheumatology (SLICC/ACR) >1 (p<0.05). ADAMTS-13 metalloprotease antigen levels also exhibited a significant inverse correlation with anti-dsDNA levels (r= -0.60, p<0.05). Anti-ADAMTS-13 autoantibodies were marginally higher in patients with positive anti-dsDNA (p=0.08). Additionally, patients with positive anti-ADAMTS-13 autoantibodies exhibited the lowest activity levels (p<0.05). To our knowledge ADAMTS-13 profile in SLE has not been studied in regard to composite structured indices. The results of this study suggest that in patients with active SLE or considerable cumulative tissue damage, ADAMTS-13 levels may be decreased and anti-ADAMTS-13 autoantibodies may partially mediate this reduction. Further evaluation of ADAMTS-13 profile may explain its role in the pathogenesis of thrombotic microangiopathy in lupus patients and reveal a potential prognostic marker of microthrombotic manifestations in SLE.

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A 43 year old female patient presented for recurrent bacterial lower respiratory infections. A research for immunodeficiency status revealed total hypogammaglobulinemia, reduced IgG1, IgG2, IgG3 subclass levels, and low number of B lymphocytes (CD19+). Common Variable Immunodeficiency (CVID) 11.2 category was diagnosed according to recent criteria of primary immunodeficiencies (PID). Further immunological study consisting of genetic polymorphism of genes relating to differentiation, activation and function of B cells (ICOS, BAFF receptor BCMA and TACI) was performed, which did not reveal any related mutations. T cell parameters and Th1/Th2 cytokine network did not show any disturbances. It is postulated that probable endstage B cell differentiation defects should be investigated. The patient receives IVIGs replacement thereafter and the rate and severity of infections have significantly improved.

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UNLABELLED: OBJECTIVE-METHODS: Adamantiades-Behcet disease (ABD) is a multi-systemic vasculitis of unknown origin, with a characteristic geographic distribution, that affects vessels of all kinds and sizes and is characterized by recurrent mucosal, skin and ocular lesions. In the present study, a series of 36 patients from Northern Greece is analyzed retrospectively in regard to the epidemiological, clinical and immunological parameters. RESULTS: All patients had recurrent oral ulcerations (36/36, 100%), while 23/36 (63.9%) experienced genital ulcerations and 22/36 (61.1%) developed ocular disease. Skin manifestations were observed in 23/36 patients (63.9%) and pathergy test was found positive in 14/36 patients (38.9%). Other manifestations included central nervous system involvement, recurrent genitourinary inflammations, arthralgias and superficial thrombophlebitis. Laboratory findings were not specific, partly reflecting the severity of inflammation. Ocular disease was more often observed in HLA-B51 (+) patients (20/31, 64.5%) than in HLA-B51 (-) patients. Standard of care (SOC) treatment consisted of cyclosporine A, azathioprine, methylprednisolone and aspirin, whereas refractory disease was treated with intravenous pulses of methylprednisolone and cyclophosphamide. Occasionally, anti-TNF agents (infliximab) were applied to treat refractory ocular disease. CONCLUSION: The findings of the present study come in agreement with those reported for other Mediterranean series. HLA-B51 seems to predispose to more severe disease, while early therapeutic intervention is beneficial for these patients.

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Adamantiades-Behçet disease (ABD) is characterised by oral and genital ulcerations, skin lesions and ocular manifestations and, rarely, by central nervous system (CNS) involvement. Neuro-Behçet disease (NBD) is categorised to parenchymal or non-parenchymal, while combined CNS disease is rarely reported in the literature. A case of NBD, with severe relapsing ocular and neurological disease of combined pattern is presented. Neurological complications included brainstem manifestations, as well as neurovascular involvement, while ocular involvement consisted of bilateral uveitis and branch retinal vein occlusion. Manifestations responded to corticosteroid plus cyclophosphamide pulse therapy. Maintenance therapy included cyclosporine A, azathioprine and corticosteroids. Case individualities are discussed, focusing on scepticism concerning treatment of NBD relapses in the long term.

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