Monocyte subsets and monocyte-related chemokines in Takayasu arteritis.

The pathogenesis of Takayasu arteritis (TAK) is poorly understood and no previous studies have analyzed monocytes in TAK. This study evaluated monocyte subsets and monocyte-related chemokines in the peripheral blood of TAK patients and healthy controls (HC). Monocyte subsets were identified as classical (CD14+CD16-), intermediate (CD14+CD16dim), and non-classical (CD14dimCD16high) in the peripheral blood. The chemokines CCL (C-C chemokine ligand)2, CCL3, CCL4, CCL5, CCL7, CXCL (C-X-C motif ligand)10, and CX3CL (C-X3-C motif ligand)1 were measured in the sera. Thirty-two TAK patients and 30 HC were evaluated. Intermediate monocytes were higher in TAK than HC [25.0 cells ×106/L (16.7-52.0) vs. 17.2 cells ×106/L (9.2-25.3); p = 0.014]. Active disease was associated with monocytosis (p = 0.004), increased classical (p = 0.003), and intermediate (p < 0.001) subsets than HC. Prednisone reduced the percentage of non-classical monocytes (p = 0.011). TAK patients had lower CCL3 (p = 0.033) and CCL4 (p = 0.023) levels than HC, whereas CCL22 levels were higher in active TAK compared to the remission state (p = 0.008). Glucocorticoids were associated with lower CXCL10 levels (p = 0.012). In TAK, CCL4 correlated with total (Rho = 0.489; p = 0.005), classical and intermediate monocytes (Rho = 0.448; p = 0.010 and Rho = 0.412; p = 0.019). In conclusion, TAK is associated with altered counts of monocyte subsets in the peripheral blood compared to HC and CCL22 is the chemokine with the strongest association with active disease in TAK.

Ramipril Improves Endothelial Function and Increases the Number of Endothelial Progenitor Cells in Patients With Systemic Lupus Erythematosus.

BACKGROUND/OBJECTIVES: Endothelial dysfunction and reduced number of endothelial progenitor cells (EPCs) in peripheral blood are contributing factors to cardiovascular disease in systemic lupus erythematosus (SLE) patients. Endothelial progenitor cell proliferation is regulated by vascular endothelial growth factor (VEGF). Angiotensin-converting enzyme inhibitors reduce cardiovascular mortality in patients with coronary heart disease. METHODS: This was a randomized trial including 37 female SLE patients without cardiovascular risk factors allocated into 2 groups: 19 patients received ramipril 10 mg/d for 12 weeks (IG) and 18 patients maintained without ramipril (CG). Endothelial function was assessed by brachial artery ultrasound measuring flow-mediated dilation, and EPCs were quantified by flow cytometry and cell culture, at baseline and after 12 weeks. Serum VEGF levels were measured by enzyme-linked immunosorbent assay. Statistical analysis was intention to treat. p < 0.05 was considered significant. RESULTS: After 12 weeks, higher flow-mediated dilation (6.17% vs. 11.14%, p < 0.001) was observed in IG, without change in CG (5.37% vs. 5.02%, p = 0.630). Higher number of EPC colony-forming units was also observed in IG (21.3 ± 10.4 vs. 31.6 ± 8.5, p < 0.001), without difference in CG ( p = 0.714). No difference was found in EPCs evaluated by flow cytometry. Vascular endothelial growth factor level increased after 12 weeks in IG ( p = 0.048), with no difference in CG ( p = 0.661). CONCLUSION: Ramipril improved endothelial function and increased the numbers of EPCs evaluated by cell culture and VEGF levels in SLE patients without cardiovascular risk factors. These data suggest that angiotensin-converting enzyme inhibitor bring an extra benefit beyond the hypotensive action and should be considered as a preferred antihypertensive drug in SLE patients.

Endothelial progenitor cells and vascular endothelial growth factor in patients with Takayasu's arteritis.

BACKGROUND: Endothelial progenitor cells (EPCs) are responsible for endothelial damage repair. Takayasu's arteritis (TA) is a chronic inflammatory disease that affects large vessels. The aim of the study was to evaluate the number of EPCs and the levels of vascular endothelial growth factor (VEGF) and the relationship of these variables in patients with TA. METHODS: Thirty women with TA and 30 healthy controls were included. EPCs were assessed by flow cytometry and cell culture and VEGF quantification was performed by commercial ELISA kits. RESULTS: Ages of patients and controls were similar. The number of EPCs in patients and controls (median (interquartile range) were 0.0073% (0.0081%) vs. 0.0062% (0.0089%), p = 0.779 by flow cytometry and 27.0 (42.3) colony forming units (CFUs) vs. 27.0 (20.5) CFUs, p = 0.473 by cells culture, respectively. VEGF levels in patients and controls was 274.5 (395.5) pg/ml vs. 243.5 (255.3) pg/ml, p = 0.460. There was no difference in the number of EPCs and VEGF level between patients with active and inactive disease. There was a tendency of the number of angioblast-like EPCs in patients taking anti-TNFs to be higher; and in patients using methotrexate to be lower. CONCLUSION: No significant difference was found in the quantification of EPCs and VEGF levels in TA patients compared to controls, and no difference was observed between patients with active and inactive disease.

Leflunomide in Takayasu arteritis - A long term observational study.

OBJECTIVE: To evaluate the extended follow-up data on efficacy and toxicity of leflunomide therapy in Takayasu arteritis (TA) patients previously enrolled in the original open-label study of short-term effects of leflunomide in TA. METHODS: An open-label long-term longitudinal study was performed in TA patients who fulfilled the 1990 American College of Rheumatology criteria for TA and had participated in a previous study that evaluated short-term efficacy of leflunomide in TA. Complete follow-up information could be retrieved from 12 out of 15 patients enrolled in the original study. Disease activity was evaluated by Kerr's criteria and by the Indian Takayasu Activity Score 2010 (ITAS2010). RESULTS: The mean follow up time was 43.0±7.6 months and 5 (41.6%) TA patients remained on leflunomide therapy while 7 (58.3%) TA patients had to change to another therapy due to failure to prevent relapses in 6 patients and toxicity in one patient. No significant differences were found between patients who remained on leflunomide therapy and those who changed to another agent regarding age at study entry, time since diagnosis, prednisone daily dose at study entry, baseline ITAS2010, mean or maximum ESR and CRP, and cumulative prednisone dose at study end. Among TA patients who had changed leflunomide to another agent, two had an additional clinical relapse and needed to change therapy. CONCLUSION: Leflunomide led to sustained remission in approximately half of patients at a mean time of 12 months and was well tolerated by TA patients.

Leflunomide in Takayasu arteritis - A long term observational study. / Leflunomida na arterite de Takayasu - Estudo observacional de longo prazo.

OBJECTIVE: To evaluate the extended follow-up data on efficacy and toxicity of leflunomide therapy in Takayasu arteritis (TA) patients previously enrolled in the original open-label study of short-term effects of leflunomide in TA. METHODS: An open-label long-term longitudinal study was performed in TA patients who fulfilled the 1990 American College of Rheumatology criteria for TA and had participated in a previous study that evaluated short-term efficacy of leflunomide in TA. Complete follow-up information could be retrieved from 12 out of 15 patients enrolled in the original study. Disease activity was evaluated by Kerr's criteria and by the Indian Takayasu Activity Score 2010 (ITAS2010). RESULTS: The mean follow up time was 43.0±7.6 months and 5 (41.6%) TA patients remained on leflunomide therapy while 7 (58.3%) TA patients had to change to another therapy due to failure to prevent relapses in 6 patients and toxicity in one patient. No significant differences were found between patients who remained on leflunomide therapy and those who changed to another agent regarding age at study entry, time since diagnosis, prednisone daily dose at study entry, baseline ITAS2010, mean or maximum ESR and CRP, and cumulative prednisone dose at study end. Among two TA patients who had changed laflunomide to another agent, two had a clinical relapse and needed to change therapy. CONCLUSION: Leflunomide led to sustained remission in approximately half of patients at a mean time of 12 months and was well tolerated by TA patients.

High mobility group box 1 levels in large vessel vasculitis are not associated with disease activity but are influenced by age and statins.

INTRODUCTION: Takayasu arteritis (TA) and giant cell arteritis (GCA) are large vessel vasculitides (LVV) that usually present as granulomatous inflammation in arterial walls. High mobility group box 1 (HMGB1) is a nuclear protein that acts as an alarmin when released by dying or activated cells. This study aims to evaluate whether serum HMGB1 can be used as a biomarker in LVV. METHODS: Twenty-nine consecutive TA patients with 29 healthy controls (HC) were evaluated in a cross-sectional study. Eighteen consecutive GCA patients with 16 HC were evaluated at the onset of disease and some of them during follow-up. Serum HMGB1 levels were measured by enzyme-linked immunosorbent assay. RESULTS: In GCA patients at disease onset mean serum HMGB1 levels did not differ from HC (5.74 ± 4.19 ng/ml vs. 4.17 ± 3.14 ng/ml; p = 0.230). No differences in HMGB1 levels were found between GCA patients with and without polymyalgia rheumatica (p = 0.167), ischemic manifestations (p = 0.873), systemic manifestations (p = 0.474) or relapsing disease (p = 0.608). During follow-up, no significant fluctuations on serum HMGB1 levels were observed from baseline to 3 months (n = 13) (p = 0.075), 12 months (n = 6) (p = 0.093) and at the first relapse (n = 4) (p = 0.202). Serum HMGB1 levels did not differ between TA patients and HC [1.19 (0.45-2.10) ng/ml vs. 1.46 (0.89-3.34) ng/ml; p = 0.181] and no difference was found between TA patients with active disease and in remission [1.31 (0.63-2.16) ng/ml vs. 0.75 (0.39-2.05) ng/ml; p = 0.281]. HMGB1 levels were significantly lower in 16 TA patients on statins compared with 13 patients without statins [0.59 (0.29-1.46) ng/ml vs. 1.93 (0.88-3.34) ng/ml; p = 0.019]. Age was independently associated with higher HMGB1 levels regardless of LVV or control status. CONCLUSIONS: Patients with TA and GCA present similar serum HMGB1 levels compared with HC. Serum HMGB1 is not useful to discriminate between active disease and remission. In TA, use of statins was associated with lower HMGB1 levels. HMGB1 is not a biomarker for LVV.

Testicular vasculitis: a rare manifestation of rheumatoid arthritis.

Testicular vasculitis is a very rare extra-articular manifestation of rheumatoid arthritis (RA). We describe the case of a 53-year-old man diagnosed with RA for eight years, who was poorly controlled and developed rheumatoid vasculitis, which manifested as leg ulcers and peripheral polyneuropathy. The patient also had acute neutrophilic meningitis and was treated with antibiotics and intravenous pulse therapy with methylprednisolone (500 mg daily) for three days, followed by oral cyclophosphamide (2 mg/kg daily) and prednisone. Overall improvement was observed, and the patient was discharged. But 15 days later, the meningitis recurred, and the patient was readmitted and treated again with antibiotics. Three days later, he developed pain and enlargement of his left testicle with gangrene. Unilateral orchiectomy was performed, revealing lymphocytic vasculitis. The patient died two days later due to aspiration pneumonia. This case illustrates a rare and severe manifestation of rheumatoid vasculitis.

Vasculite testicular: uma manifestação rara de artrite reumatoide / Testicular vasculitis: a rare manifestation of rheumatoid arthritis

A vasculite testicular é uma manifestação extra-articular muito rara da artrite reumatoide (AR). Descrevemos o caso de um homem de 53 anos com diagnóstico de AR por oito anos, sem controle adequado da doença. O paciente desenvolveu vasculite reumatoide, manifestada por úlceras de membros inferiores e neuropatia periférica. Apresentou ainda meningite neutrofílica aguda, tendo sido tratado com antibióticos e posterior pulsoterapia endovenosa com metilprednisolona (500 mg/dia) por três dias, seguida de ciclofosfamida (2 mg/kg/ dia) e prednisona orais. O paciente apresentou melhora do quadro, mas 15 dias após a alta hospitalar, houve reativação da meningite bacteriana. O paciente foi reinternado e tratado novamente com antibióticos. Três dias depois da segunda admissão hospitalar, o paciente apresentou dor, aumento de volume do testículo esquerdo e posteriormente gangrena. Foi realizada orquiectomia unilateral e o exame anatomopatológico revelou vasculite linfocítica. O paciente faleceu dois dias após a cirurgia devido a pneumonia aspirativa. Esse caso ilustra a vasculite testicular como uma manifestação rara e grave da vasculite reumatoide.

Testicular vasculitis is a very rare extra-articular manifestation of rheumatoid arthritis (RA). We describe the case of a 53-year-old man diagnosed with RA for eight years, who was poorly controlled and developed rheumatoid vasculitis, which manifested as leg ulcers and peripheral polyneuropathy. The patient also had acute neutrophilic meningitis and was treated with antibiotics and intravenous pulse therapy with methylprednisolone (500 mg daily) for three days, followed by oral cyclophosphamide (2 mg/kg daily) and prednisone. Overall improvement was observed, and the patient was discharged. But 15 days later, the meningitis recurred, and the patient was readmitted and treated again with antibiotics. Three days later, he developed pain and enlargement of his left testicle with gangrene. Unilateral orchiectomy was performed, revealing lymphocytic vasculitis. The patient died two days later due to aspiration pneumonia. This case illustrates a rare and severe manifestation of rheumatoid vasculitis.

Homocysteine levels in Takayasu arteritis -- a risk factor for arterial ischemic events.

OBJECTIVE: To evaluate homocysteine levels in patients with Takayasu arteritis (TA) and in controls, and to analyze associations between homocysteine levels and paraoxonase 1 (PON1) activity, cysteine levels, methotrexate use, disease activity, extent of arterial involvement, and ischemic events in patients with TA. METHODS: A cross-sectional study was performed with 29 patients with TA and 30 controls who underwent clinical evaluation and blood sample collection in the fasting state. RESULTS: Among patients with TA, active disease was observed in 9 (31.0%) and previous arterial ischemic events in 10 (34.5%). Therapy with methotrexate was prescribed to 9 (31.0%) patients and it was associated with folic acid in 8 cases. Median homocysteine level was higher in patients with TA [10.9 µmol/l, interquartile range (IQR) 9.6-14.8] than in controls (6.9 µmol/l, IQR 5.1-11.9; p < 0.001). No difference was found regarding mean homocysteine levels between those using methotrexate and those under other therapies (12.8 ± 5.3 µmol/l vs 12.1 ± 3.2 µmol/l, respectively; p = 0.662). TA patients with active disease presented lower homocysteine levels (10.4 ± 2.1 µmol/l) compared to TA patients in remission (13.1 ± 4.2 µmol/l) (p = 0.034). A significant correlation was found between cysteine and homocysteine levels in patients with TA (ρ = 0.676, p < 0.0001), while there was no correlation between homocysteine and PON1 activity (ρ = 0.214, p = 0.265). Median homocysteine levels were higher in patients with ischemic events (13.2 µmol/l, IQR 10.9-17.5) compared to patients with no ischemic events (9.8 µmol/l, IQR 8.7-14.7; p = 0.027) and were associated with arterial ischemia in patients with TA (OR 1.31, 95% CI 1.01-1.71, p = 0.041). CONCLUSION: Patients with TA presented higher homocysteine levels than controls and homocysteine was associated with an increased risk of arterial ischemic events in TA.

Behçet disease: clinical features and management in a Brazilian tertiary hospital.

BACKGROUND: Behçet disease (BD) is prevalent in Central and East Asia and in the Eastern Mediterranean area where most studies have been performed. Few studies have evaluated patients with BD in Brazil. OBJECTIVES: The objective of the study was to describe clinical manifestations of BD and their therapy in a single center in Brazil. METHODS: Sixty patients who met the International Study Group Criteria for BD and were under follow-up at the Vasculitis Unit of the Universidade Federal de São Paulo were evaluated in a retrospective observational study. RESULTS: Mean age at study was 40.0 (SD, 10.7) years, and the female-male ratio was 1.2:1.0. The frequency of disease manifestations was as follows: oral ulcers, 100%; genital ulcers, 93.3%; ocular manifestations, 63.3%; arthritis, 46.7%; cutaneous lesions, 71.7%; positive pathergy test, 22.7%; neurologic involvement, 28.3%; thrombosis, 13.3%; and gastrointestinal involvement, 3.3%. Arthritis and erythema nodosum were more prevalent among women, whereas papulopustular lesions were more common in men. The frequency of each treatment modality was as follows: colchicine, 78.3%; thalidomide, 26.7%; colchicine and penicillin, 21.7%; dapsone, 8.3%; and pentoxyphyline, 8.3%. These treatments were mainly used for mucocutaneous manifestations. Immunosuppressive drugs were prescribed for 70% of the patients, including azathioprine (35.0%), cyclophosphamide (28.3%), cyclosporin A (21.7%), methotrexate (18.3%), and chlorambucil (6.7%). Infliximab was used in 5.0% of refractory patients. No differences were observed between sexes related to severe manifestations of BD. CONCLUSIONS: Although reported elsewhere, Brazilian men with BD did not have a worse prognosis. Women had a higher frequency of arthritis manifestations.

Association of anti-glomerular basement membrane antibody disease with dermatomyositis and psoriasis: case report.

CONTEXT: anti-glomerular basement membrane (anti-GBM) antibody syndrome is characterized by deposition of anti-GBM antibodies on affected tissues, associated with glomerulonephritis and/or pulmonary involvement. This syndrome has been described in association with other autoimmune disorders, but as far as we know, it has not been described in association with dermatomyositis and psoriasis. CASE REPORT: a 51-year-old man with a history of dermatomyositis and vulgar psoriasis presented with a condition of sensitive-motor polyneuropathy of the hands and feet, weight loss of 4 kg, malaise and fever. On admission, he had been making chronic use of cyclosporin and antihypertensive drugs for three months because of mild arterial hypertension. Laboratory tests showed anemia and leukocytosis, elevated serum urea and creatinine and urine presenting proteinuria, hematuria, leukocyturia and granular casts. The 24-hour proteinuria was 2.3 g. Renal biopsy showed crescentic necrotizing glomerulonephritis with linear immunoglobulin G (IgG) deposits on the glomerular basement membrane by means of direct immunofluorescence, which were suggestive of anti-GBM antibodies. The patient was then treated initially with methylprednisolone and with monthly cyclophosphamide in the form of pulse therapy.

Association of anti-glomerular basement membrane antibody disease with dermatomyositis and psoriasis: case report / Associação de doença do anticorpo anti-membrana basal glomerular com dermatomiosite e psoríase: relato de caso

CONTEXT: Anti-glomerular basement membrane (anti-GBM) antibody syndrome is characterized by deposition of anti-GBM antibodies on affected tissues, associated with glomerulonephritis and/or pulmonary involvement. This syndrome has been described in association with other autoimmune disorders, but as far as we know, it has not been described in association with dermatomyositis and psoriasis. CASE REPORT: A 51-year-old man with a history of dermatomyositis and vulgar psoriasis presented with a condition of sensitive-motor polyneuropathy of the hands and feet, weight loss of 4 kg, malaise and fever. On admission, he had been making chronic use of cyclosporin and antihypertensive drugs for three months because of mild arterial hypertension. Laboratory tests showed anemia and leukocytosis, elevated serum urea and creatinine and urine presenting proteinuria, hematuria, leukocyturia and granular casts. The 24-hour proteinuria was 2.3 g. Renal biopsy showed crescentic necrotizing glomerulonephritis with linear immunoglobulin G (IgG) deposits on the glomerular basement membrane by means of direct immunofluorescence, which were suggestive of anti-GBM antibodies. The patient was then treated initially with methylprednisolone and with monthly cyclophosphamide in the form of pulse therapy.

CONTEXTO: A síndrome do anticorpo anti-membrana basal glomerular (anti-MBG) é caracterizada pela deposição de anticorpos anti-MBG em tecidos afetados, associada à glomerulonefrite e/ou ao envolvimento pulmonar. Essa síndrome já foi descrita em associação a outras doenças autoimunes, mas até onde conhecemos, não há relatos de sua associação com dermatomiosite e psoríase. RELATO DE CASO: Um homem de 51 anos com antecedentes de dermatomiosite e psoríase vulgar apresentou quadro de polineuropatia sensitivo-motora de mãos e pés, perda de 4 kg, adinamia e febre. À admissão estava em uso crônico de ciclosporina e de anti-hipertensivos há três meses devido a hipertensão arterial leve. Exames laboratoriais mostraram anemia e leucocitose, creatinina e ureia séricas elevadas e urina com proteinúria, hematúria, leucocitúria e cilindros granulosos. A proteinúria de 24 horas foi de 2,3 g. A biópsia renal revelou uma glomerulonefrite crescêntica necrotizante com depósitos lineares de imunoglobulina G (IgG) na MBG à imunofluorescência, sugestivos de anticorpos anti-MBG. O paciente foi então tratado inicialmente com metilprednisolona e com ciclofosfamida mensalmente na forma de pulsoterapia.