L. Guillevin

Evaluation of cardiac abnormalities by Doppler echocardiography in a large nationwide multicentric cohort of patients with systemic sclerosis

Objectives: There is increasing concern about heart and pulmonary vascular involvement in systemic sclerosis (SSc). One of the most severe complications of SSc is pulmonary arterial hypertension (PAH). There has been an increased awareness of left ventricular (LV) diastolic abnormalities in SSc patients. However, previous studies have generally been conducted in small populations. The aims of this study were to prospectively screen for PAH and to describe echocardiographic parameters in a large group of SSc patients. Methods: This prospective study was conducted in 21 centres for SSc in France. Patients without severe pulmonary function abnormalities, severe cardiac disease and known PAH underwent Doppler echocardiography performed by a reference cardiologist. Results: Of the 570 patients evaluated, PAH was suspected in 33 patients and was confirmed in 18 by right heart catheterisation. LV systolic dysfunction was rare (1.4%). LV hypertrophy was found in 22.6%, with LV diastolic dysfunction in 17.7%. These LV abnormalities were influenced by age, gender and blood pressure. We identified a small group of 21 patients with a restrictive mitral flow pattern in the absence of any other cardiopulmonary diseases, suggesting a specific cardiac involvement in SSc. Conclusions: Left and right heart diseases, including PAH, LV hypertrophy and diastolic dysfunction, are common in SSc. However, a small subset of patients without any cardiac or pulmonary diseases have a restrictive mitral flow pattern that could be due to primary cardiac involvement of SSc. The prognostic implications of the LV abnormalities will be evaluated in the 3-year follow-up of this cohort.

Scleroderma renal crisis: a retrospective multicentre study on 91 patients and 427 controls

OBJECTIVE Scleroderma renal crisis (SRC) is a severe manifestation of SSc, whose prognosis remains severe, despite treatment with angiotensin-converting-enzyme inhibitor and dialysis. This study was undertaken to describe SRC characteristics, prognosis and outcome, and evaluate the responsibility of CSs in its occurrence. METHODS Analysis concerned 91 SSc patients with SRC who were compared with 427 non-SRC-SSc patients taken as controls. RESULTS Among the 91 SRC patients, 71 (78.0%) had high blood pressure, 53 (58.2%) hypertensive encephalopathy and 51 (56.0%) thrombotic microangiopathy; 64 (70.3%) had received CSs before or concomitantly with SRC vs 156 (36.5%) non-SRC-SSc patients (P < 0.001). Treated SRC patients also received more prednisone 29.3 (28.4) vs 3.6 (9.9) mg than controls (P < 0.001). SRC clinical outcomes were poor: 49 (53.8%) patients required dialysis, which was definitive for 38. Thirty-seven (40.7%) SRC patients died vs 10.8% of the controls (P < 0.001). Death was most frequent among dialysed patients who never recovered renal function (22 vs 2) and 13 never-dialysed SRC patients died. CONCLUSIONS Although SRC prognosis has improved markedly, SRC remains a severe manifestation of SSc, despite treatment with angiotensin-converting enzyme inhibitor and dialysis. CSs contributed significantly to SRC occurrence.

Radical oxygen species production induced by advanced oxidation protein products predicts clinical evolution and response to treatment in systemic sclerosis

Objectives: To investigate the role of reactive oxygen species (ROS) in the development of the various patterns of systemic sclerosis (SSc) and the mechanisms of ROS production by endothelial cells and fibroblasts. Methods: Production of hydrogen peroxide (H2O2), nitric oxide (NO) and cellular proliferation were determined following incubation of endothelial cells and fibroblasts with 56 SSc and 30 healthy sera. Correlations were established between those markers, the type and the severity of the clinical involvements, and the response to treatment. The factors leading to ROS production were determined. Results: H2O2 production by endothelial cells and fibroblasts was higher after incubation with SSc sera than with normal sera (p<0.001) and with sera from SSc patients with severe complications than sera from other patients (p<0.05). Sera from patients with lung fibrosis triggered the proliferation of fibroblasts more than other SSc sera (p<0.001), whereas sera from patients with vascular complications exerted no proliferative effect on fibroblasts, but inhibited endothelial cell growth (p<0.05) and induced NO overproduction (p<0.05). Bosentan reduced NO release by 32%, whereas N-acetylcystein potentiated 5-fluorouracil (5FU) to inhibit fibroblast proliferation by 78%. Those serum-mediated effects did not involve antibodies but advanced oxidation protein products that selectively triggered cells to produce H2O2 or NO. Conclusions: SSc sera induce the production of different types of ROS that selectively activate endothelial cells or fibroblasts, leading to vascular or fibrotic complications. Assaying serum-induced ROS production allows clinical activity of the disease to be followed and appropriate treatments to be selected.

Low influenza-vaccination rate among adults receiving immunosuppressive therapy for systemic inflammatory disease

Although annual influenza vaccination is recommended for adults taking immunosuppressant drugs,1–3 the vaccination rate is suboptimal in these patients.4–6 We undertook a study to assess the flu-vaccination uptake of patients treated for systemic inflammatory diseases and to explore the factors that influence it. The study was approved by the Paris Ile de France III Ethics Committee (“Comite de Protection des Personnes Ile de France III”) Paris, France. We collected information about flu shots with a standardised form completed by the doctors of patients with systemic inflammatory diseases taking corticosteroids and/or immunosuppressant drugs, followed up in our internal medicine department during January 2006. One hundred and thirty-seven consecutive …

Pulmonary fibrosis associated with ANCA-positive vasculitides. Retrospective study of 12 cases and review of the literature

Objective: To describe the clinical presentation of the association between pulmonary fibrosis (PF) and systemic vasculitis related to antineutrophil cytoplasmic antibodies (ANCA-V). Methods: 12 patients (three female, mean age 70.7 years) with ANCA-V associated with “idiopathic” PF were studied retrospectively. Results: ANCA-V and PF were diagnosed simultaneously in eight cases; PF occurred earlier in three cases and during ANCA-V follow-up in one. No patient had intra-alveolar haemorrhage (IAH). ANCA were myeloperoxidase (MPO)-ANCA in all cases. Seven patients had blood eosinophilia at diagnosis. Two patients died during ANCA-V induction therapy. The respiratory status of five patients worsened and three of them died from exacerbation of end-stage respiratory failure. The five remaining patients had a stable respiratory status. Conclusion: The association of PF and ANCA-V does not seem to be fortuitous, even though their clinical evolutions are clearly not related. PF was the major cause of death.

Sialylation levels of anti–proteinase 3 antibodies are associated with the activity of granulomatosis with polyangiitis (Wegener's)

OBJECTIVE To investigate whether the glycosylation and sialylation levels of anti-proteinase 3 (anti-PR3) antibodies could affect their pathogenicity, and whether these levels could be correlated with the activity of granulomatosis with polyangiitis (Wegeners) (GPA). METHODS Forty-two serum samples positive for anti-PR3 antibodies from 42 patients with active or weakly active/inactive GPA were included. Anti-PR3 antibodies were assayed by enzyme-linked immunosorbent assay, and their levels of glycosylation and sialylation were assessed by enzyme-linked lectin assay. The glycosylation and sialylation levels of IgG purified from the serum of healthy donors and patients with active, remitted, or weakly active disease were assessed by permethylation and mass spectrometry analysis of glycans, following neuraminidase digestion. The neutrophil oxidative burst induced by purified IgG was assayed by spectrofluorimetry. RESULTS The mean sialylation ratio of anti-PR3 antibodies was significantly lower in patients with active disease than in patients with weakly active or inactive disease, and this was inversely correlated with the Birmingham Vasculitis Activity Score (BVAS) (P < 0.0001). Similar results were obtained using the BVAS/GPA. The area under the receiver operating characteristic curve for the sialylation ratio of anti-PR3 antibodies, as a test to determine the activity of GPA, was 0.82 (P = 0.0006). The characterization of N-glycans showed a decrease in 2,6-linked sialylated N-glycans and an increase in dHex₁ Hex₃ HexNAc₄ (mass/charge 1,836) agalactosylated structures in purified IgG from patients with active disease compared with controls. The anti-PR3 antibody-induced oxidative burst of neutrophils was inversely correlated with the sialylation levels of anti-PR3 IgG. CONCLUSION The sialylation level of anti-PR3 antibodies contributes to the clinical activity of GPA, by modulating the oxidative burst of neutrophils induced by these autoantibodies.

Dysregulated expression of CXCR4/CXCL12 in subsets of patients with systemic lupus erythematosus.

OBJECTIVE CXCR4 is a chemokine with multiple effects on the immune system. In murine lupus models, we demonstrated that monocytes, neutrophils, and B cells overexpressed CXCR4 and that its ligand, CXCL12, was up-regulated in diseased kidneys. We undertook this study to determine whether CXCR4 expression was increased in peripheral blood leukocytes from patients with systemic lupus erythematosus (SLE) and whether CXCL12 expression was increased in kidneys from patients with SLE. METHODS Peripheral blood leukocytes from 31 SLE patients, 8 normal controls, and 9 patients with rheumatoid arthritis were prospectively analyzed by flow cytometry for CXCR4 expression. Biopsy samples (n = 14) from patients with lupus nephritis (LN) were immunostained with anti-CXCL12 antibody. RESULTS CD19+ B cells and CD4+ T cells from SLE patients displayed a >2-fold increase (P = 0.0001) and >3-fold increase (P < 0.0001), respectively, in median CXCR4 expression compared with that in controls (n = 7-8). Moreover, CXCR4 expression on B cells was 1.61-fold higher in patients with SLE Disease Activity Index (SLEDAI) scores >10 (n = 8) than in patients with SLEDAI scores ≤10 (n = 16) (P = 0.0008), 1.71-fold higher in patients with class IV LN (n = 5) than in patients with other classes of LN (n = 7) (P = 0.02), and 1.40-fold higher in patients with active neuropsychiatric SLE (NPSLE) (n = 6) than in patients with inactive NPSLE (n = 18) (P = 0.01). CXCL12 was significantly up-regulated in the tubules and glomeruli of kidneys in patients with LN (n = 14), with the percentage of positive cells correlating positively with the severity of LN. CONCLUSION CXCR4 appears to be up-regulated in multiple leukocyte subsets in SLE patients. The heightened expression of CXCR4 on B cells in active NPSLE and of CXCL12 in nephritic kidneys suggests that the CXCR4/CXCL12 axis might be a potential therapeutic target for SLE patients with kidney and/or central nervous system involvement.

Pulmonary arterial hypertension: an autoimmune disease?

Pulmonary arterial hypertension (PAH) is a rare condition that occurs as a consequence of chronic obstruction of small pulmonary arteries due to endothelial cell, vascular smooth muscle cell and fibroblast dysfunction and proliferation 1. In recent years, major advances have been achieved in the understanding of PAH pathophysiology 1–7. It has been firmly demonstrated that pulmonary artery endothelial dysfunction leads to chronically impaired production of vasodilators, such as nitric oxide and prostacyclin, along with overexpression of vasoconstrictors such as endothelin-1 8–10. Moreover, genetic studies have shown that germline mutations in the gene coding for bone morphogenetic protein receptor type II (BMPR2) certainly play a critical role in a proportion of patients with familial and idiopathic PAH 2, 3. Immune disturbances are also believed to contribute to PAH 5. This is particularly clear in PAH related to connective tissue diseases 5, 11. In addition, there is a long standing association between autoimmunity and PAH of various origins including idiopathic PAH. However, it remains uncertain how autoimmune mechanisms contribute to the pathogenesis of PAH. In the current issue of the European Respiratory Journal , Nicolls et al. 7 review available data documenting the association of autoimmunity and PAH and speculate on the possible role of autoimmune injury in the pathogenesis of the disease. PAH is a common …

Severe bronchospasm associated with rituximab for refractory Churg–Strauss syndrome

Rituximab is now used to control antineutrophil cytoplasm antibody (ANCA)-associated vasculitides, eg, Wegener’s granulomatosis.1 2 In Churg–Strauss syndrome (CSS), a small-vessel systemic vasculitis with asthma and eosinophilia, 39% of patients have ANCA.3 4 Rituximab could be effective in ANCA-associated vasculitides, even if ANCA are not present at the time of prescription, because B lymphocytes also play a role as antigen-presenting cells and can modulate the immune response in another way than targeting antibody production. Therapy-refractory CSS5 was successfully treated with rituximab in three patients.6–8 We would like to draw attention to the potential risk of rituximab-associated bronchospasm, by reporting …

Protective effect of A/H1N1 vaccination in immune-mediated disease—a prospectively controlled vaccination study

OBJECTIVES To assess the 2009 influenza vaccine A/H1N1 on antibody response, side effects and disease activity in patients with immune-mediated diseases. METHODS Patients with RA, SpA, vasculitis (VAS) or CTD (n = 149) and healthy individuals (n = 40) received a single dose of adjuvanted A/H1N1 influenza vaccine. Sera were obtained before vaccination, and 3 weeks, 6 weeks and 6 months thereafter. A/H1N1 antibody titres were measured by haemagglutination inhibition (HAI) assay. Seroprotection was defined as specific antibody titre ≥ 1 : 40, seroconversion as 4-fold increase in antibody titre. RESULTS Titres increased significantly in patients and controls with a maximum at Week 3, declining to levels below protection at Month 6 (P < 0.001). Seroprotection was more frequently reached in SpA and CTD than in RA and VAS (80 and 82% and 57 and 47%, respectively). There was a significantly negative impact by MTX (P < 0.001), rituximab (P = 0.0031) and abatacept (P = 0.045). Other DMARDs, glucocorticoids and TNF blockers did not significantly suppress response (P = 0.06, 0.11 and 0.81, respectively). A linear decline in response was noted in patients with increasing age (P < 0.001). Disease reactivation possibly related to vaccination was suspected in 8/149 patients. No prolonged side effects or A/H1N1 infections were noted. CONCLUSIONS The results show that vaccination response is a function of disease type, intensity and character of medication and age. A single injection of adjuvanted influenza vaccine is sufficient to protect a high percentage of patients. Therefore, differential vaccination recommendations might in the future reduce costs and increase vaccination acceptance.