Abstract The use of plasma exchanges (PLEX) in systemic necrotizing vasculitides (SNV) still need to be codified. To describe indications, efficacy and safety of PLEX for the treatment of SNV, we ...conducted a multicenter retrospective study on patients with ANCA-associated vasculitis (AAV) or non-viral polyarteritis nodosa (PAN) treated with PLEX. One hundred and fifty-two patients were included: GPA (n = 87), MPA (n = 56), EGPA (n = 4) and PAN (n = 5). PLEX were used for rapidly progressive glomerulonephritis (RPGN) in 126 cases (86%), alveolar hemorrhage in 64 cases (42%), and severe mononeuritis multiplex in 23 cases (15%). In patients with RPGN, there was a significant improvement in renal function compared to baseline value (P < 0.0001), the plateau being reached at month 3 after PLEX initiation, and estimated glomerular filtration rate improved especially as the number of PLEX increased. In patients with alveolar hemorrhage, mechanical ventilation was discontinued in all patients after a median time of 15 days. Patients treated for mononeuritis multiplex showed improvement of severe motor weakness. After a median follow of 22 months, 18 deaths (12%) were recorded, mainly in patients with RPGN and within the first 6 months. Incidence of end-stage renal disease and/or death was similar between groups of different baseline renal function, but was increased in MPO-ANCA compared to PR3-ANCA. Adverse events attributable to PLEX were recorded in 63%. No death occurred during PLEX. This large series describes indications, efficacy and safety of PLEX in daily practice. Randomized controlled studies are ongoing to define optimal indications, PLEX regimen and concomitant medications.
The combination of cyclophosphamide and glucocorticoids leads to remission in most patients with antineutrophil cytoplasm antibody (ANCA)-associated vasculitides. However, even when patients receive ...maintenance treatment with azathioprine or methotrexate, the relapse rate remains high. Rituximab may help to maintain remission.
Patients with newly diagnosed or relapsing granulomatosis with polyangiitis, microscopic polyangiitis, or renal-limited ANCA-associated vasculitis in complete remission after a cyclophosphamide-glucocorticoid regimen were randomly assigned to receive either 500 mg of rituximab on days 0 and 14 and at months 6, 12, and 18 after study entry or daily azathioprine until month 22. The primary end point at month 28 was the rate of major relapse (the reappearance of disease activity or worsening, with a Birmingham Vasculitis Activity Score >0, and involvement of one or more major organs, disease-related life-threatening events, or both).
The 115 enrolled patients (87 with granulomatosis with polyangiitis, 23 with microscopic polyangiitis, and 5 with renal-limited ANCA-associated vasculitis) received azathioprine (58 patients) or rituximab (57 patients). At month 28, major relapse had occurred in 17 patients in the azathioprine group (29%) and in 3 patients in the rituximab group (5%) (hazard ratio for relapse, 6.61; 95% confidence interval, 1.56 to 27.96; P=0.002). The frequencies of severe adverse events were similar in the two groups. Twenty-five patients in each group (P=0.92) had severe adverse events; there were 44 events in the azathioprine group and 45 in the rituximab group. Eight patients in the azathioprine group and 11 in the rituximab group had severe infections, and cancer developed in 2 patients in the azathioprine group and 1 in the rituximab group. Two patients in the azathioprine group died (1 from sepsis and 1 from pancreatic cancer).
More patients with ANCA-associated vasculitides had sustained remission at month 28 with rituximab than with azathioprine. (Funded by the French Ministry of Health; MAINRITSAN ClinicalTrials.gov number, NCT00748644; EudraCT number, 2008-002846-51.).
Fluorodesoxyglucose Positron Emission Tomography (PET/CT) has never been compared to Chest-Abdomen-Pelvis CT (CAPCT) in patients with a fever of unknown origin (FUO), inflammation of unknown origin ...(IUO) and episodic fever of unknown origin (EFUO) through a prospective and multicentre study. In this study, we investigated the diagnostic value of PET/CT compared to CAPCT in these patients. The trial was performed between 1 May 2008 through 28 February 2013 with 7 French University Hospital centres. Patients who fulfilled the FUO, IUO or EFUO criteria were included. Diagnostic orientation (DO), diagnostic contribution (DC) and time for diagnosis of both imaging resources were evaluated. One hundred and three patients were included with 35 FUO, 35 IUO and 33 EFUO patients. PET/CT showed both a higher DO (28.2% vs. 7.8%,
< 0.001) and DC (19.4% vs. 5.8%,
< 0.001) than CAPCT and reduced the time for diagnosis in patients (3.8 vs. 17.6 months,
= 0.02). Arthralgia (OR 4.90,
= 0.0012), DO of PET/CT (OR 4.09,
= 0.016), CRP > 30 mg/L (OR 3.70,
= 0.033), and chills (OR 3.06,
= 0.0248) were associated with the achievement of a diagnosis (Se: 89.1%, Sp: 56.8%). PET/CT both orients and contributes to diagnoses at a higher rate than CAPCT, especially in patients with FUO and IUO, and reduces the time for diagnosis.
Abstract Background Cardiac involvement is one of the most important prognostic factors in systemic AL amyloidosis. The aim of our study was to assess the role of cardiovascular magnetic resonance ...(CMR) imaging in prognosis evaluation in AL amyloidosis. Methods We retrospectively analyzed 29 consecutive patients with AL amyloidosis who had undergone CMR. Clinical, laboratory, echocardiographic, and CMR characteristics were compared between CMR-positive (ie, with CMR signs of cardiac localization of AL amyloidosis) and CMR-negative patients. Univariate and multivariate analyses were performed to assess the prognostic value of positive CMR in comparison with other prognostic factors. Results CMR was positive in 11 patients (38%). The overall survival rates for CMR-positive patients were 28%, 14%, and 14% versus 84%, 77%, and 45% at 1, 2, and 5 years, respectively, for CMR-negative patients ( P = .002). Late gadolinium enhancement patterns, biventricular hypertrophy, and pericardial effusion on CMR were more frequent in nonsurvivors. Congestive heart failure, abnormal echocardiography, Eastern Cooperative Oncology Group grade >1, brain natriuretic peptide, and left ventricular ejection fraction <55% also were associated with a decreased survival. The presence of congestive heart failure was the only significant variable associated with survival on multivariate analysis. Conclusion We found that the presence of a positive CMR in AL amyloidosis was associated with a significantly increased risk of death, in particular of cardiac origin, but was not independent of clinical congestive heart failure.
With recent advances in endovascular treatment, percutaneous endoluminal angioplasty has become particularly attractive for arterial lesions of Takayasu arteritis. However, data came from case ...reports or small series, and the long-term outcome has not been reported. The incidence of potential vascular complications after surgery or endovascular treatment is still to be determined.
This retrospective multicenter study analyzed the results and outcomes of 79 consecutive patients with Takayasu arteritis (median age, 39 years; interquartile range IQR, 25-50 years; 63 women 79.7%) who underwent 166 vascular procedures (surgery, 104 62.7%; endovascular repair, 62 37.3%) for the management of arterial complications. After a follow-up of 6.5 years (IQR, 2.2-11.5 years), 70 complications were observed, including restenosis (n=53), thrombosis (n=7), bleeding (n=6), and stroke (n=4). The overall 1-, 3-, 5-, and 10-year arterial complication-free survival rates were 78% (IQR, 69%-88%), 67% (IQR, 57%-78%), 56% (IQR, 46%-70%), and 45% (IQR, 34%-60%), respectively. Among the 104 surgical procedures, 39 (37.5%) presented a complication compared with 31 of the 62 (50%) with endovascular repair. In multivariate analysis, biological inflammation at the time of revascularization (odds ratio, 7.48; 95% confidence interval, 1.42-39.39; P=0.04) was independently associated with the occurrence of arterial complications after the vascular procedure. Patients who experienced complications had higher erythrocyte sedimentation rates (P<0.001) and C-reactive protein (P<0.001) and fibrinogen (P<0.005) serum levels compared with those without complications.
The overall 5-year arterial complication rate was 44%. Biological inflammation increased the likelihood of complications after revascularization in patients with Takayasu arteritis.
We investigated whether partitioning DLCO into membrane conductance for CO (DmCO) and pulmonary capillary blood volume (Vcap) was helpful in suspecting precapillary pulmonary (arterial) hypertension ...(P(A)H) in systemic sclerosis (SSc) patients with or without interstitial lung disease (ILD). We included 63 SSc patients with isolated PAH (n=6), isolated ILD (n=19), association of both (n=12) or without PAH and ILD (n=26). Partitioning of DLCO was performed by the combined DLNO/DLCO method. DLCO, DmCO and Vcap were equally reduced in patients with isolated PAH and patients with isolated ILD but Vcap/alveolar volume (VA) ratio was significantly lower in the isolated PAH group. In patients without ILD, DLCO, DmCO, Vcap and Vcap/VA ratio were reduced in patients with isolated PAH when compared to patients without PAH and both Vcap/VA and DLCO had the highest AUC to detect PAH. In patients with ILD, Vcap had the highest AUC and performed better than DLCO to detect PH in this subgroup. In conclusion, Vcap/VA was lower in PAH than in ILD in SSC whereas DLCO was not different. Vcap/VA ratio and DLCO had similar high performance to detect PAH in patients without ILD. Vcap had better AUC than DLCO, DmCO and FVC/DLCO ratio to detect PH in SSC patients with ILD. These results suggest that partitioning of DLCO might be of interest to detect P(A)H in SSC patients with or without ILD.
The only treatment available to restore normal cardiac output in patients with hereditary hemorrhagic telangiectasia (HHT) and cardiac failure is liver transplant. Anti-vascular endothelial growth ...factor treatments such as bevacizumab may be an effective treatment.
To test the efficacy of bevacizumab in reducing high cardiac output in severe hepatic forms of HHT and to assess improvement in epistaxis duration and quality of life.
Single-center, phase 2 trial with national recruitment from the French HHT Network. Patients were 18 to 70 years old and had confirmed HHT, severe liver involvement, and a high cardiac index related to HHT.
Bevacizumab, 5 mg per kg, every 14 days for a total of 6 injections. The total duration of the treatment was 2.5 months; patients were followed up for 6 months after the beginning of the treatment.
Decrease in cardiac output at 3 months after the first injection, evaluated by echocardiography.
A total of 25 patients were included between March 2009 and November 2010. Of the 24 patients who had echocardiograms available for reread, there was a response in 20 of 24 patients with normalization of cardiac index (complete response CR) in 3 of 24, partial response (PR) in 17 of 24, and no response in 4 cases. Median cardiac index at beginning of the treatment was 5.05 L/min/m(2) (range, 4.1-6.2) and significantly decreased at 3 months after the beginning of the treatment with a median cardiac index of 4.2 L/min/m(2) (range, 2.9-5.2; P < .001). Median cardiac index at 6 months was significantly lower than before treatment (4.1 L/min/m(2); range, 3.0-5.1). Among 23 patients with available data at 6 months, we observed CR in 5 cases, PR in 15 cases, and no response in 3 cases. Mean duration of epistaxis, which was 221 minutes per month (range, 0-947) at inclusion, had significantly decreased at 3 months (134 minutes; range, 0-656) and 6 months (43 minutes; range, 0-310) (P = .008). Quality of life had significantly improved. The most severe adverse events were 2 cases of grade 3 systemic hypertension, which were successfully treated.
In this preliminary study of patients with HHT associated with severe hepatic vascular malformations and high cardiac output, administration of bevacizumab was associated with a decrease in cardiac output and reduced duration and number of episodes of epistaxis.
clinicaltrials.gov Identifier: NCT00843440.
Systemic sclerosis per se should not be considered as an a priori contraindication for a pre-transplantation assessment in patients with advanced interstitial lung disease and/or pulmonary ...hypertension. For lung or heart-lung transplantation, a multidisciplinary approach, adapting the pre-transplant assessment to systemic sclerosis and optimizing systemic sclerosis patient management before, during and after surgery should improved the short- and long-term prognosis. Indications and contraindications for transplantation have to be adapted to the specificities of systemic sclerosis. A special focus on the digestive tract involvement and its thorough evaluation are mandatory before transplantation in systemic sclerosis. As the esophagus is almost always involved, isolated gastro-oesophageal reflux disease, pH metry and/or manometry abnormalities should not be a systematic per se contraindication for pre-transplantation assessment. Corticosteroids may be harmful in systemic sclerosis as they are associated with acute renal crisis. A low dose corticosteroids protocol for immunosuppression is therefore advisable in systemic sclerosis.
To assess the effect of sildenafil, a phosphodiesterase type 5 inhibitor, on digital ulcer (DU) healing in systemic sclerosis (SSc).
Randomised, placebo-controlled study in patients with SSc to ...assess the effect of sildenafil 20 mg or placebo, three times daily for 12 weeks, on ischaemic DU healing. The primary end point was the time to healing for each DU. Time to healing was compared between groups using Cox models for clustered data (two-sided tests, p=0.05).
Intention-to-treat analysis involved 83 patients with a total of 192 DUs (89 in the sildenafil group and 103 in the placebo group). The HR for DU healing was 1.33 (0.88 to 2.00) (p=0.18) and 1.27 (0.85 to 1.89) (p=0.25) when adjusted for the number of DUs at entry, in favour of sildenafil. In the per protocol population, the HRs were 1.49 (0.98 to 2.28) (p=0.06) and 1.43 (0.93 to 2.19) p=0.10. The mean number of DUs per patient was lower in the sildenafil group compared with the placebo group at week (W) 8 (1.23±1.61 vs 1.79±2.40 p=0.04) and W12 (0.86±1.62 vs 1.51±2.68, p=0.01) resulting from a greater healing rate (p=0.01 at W8 and p=0.03 at W12).
The primary end point was not reached in intention-to-treat, partly because of an unexpectedly high healing rate in the placebo group. We found a significant decrease in the number of DUs in favour of sildenafil compared with placebo at W8 and W12, confirming a sildenafil benefit.
NCT01295736.
Beyond the production of autoantibodies, B-cells are thought to play a role in systemic sclerosis (SSc) by secreting proinflammatory/profibrotic cytokines. B-cells are a heterogeneous population with ...different subsets distinguished by their phenotypes and cytokine production. Data about B-cell subsets, cytokine production and intracellular pathways leading to this production are scarce in SSc. The aim of our study was to describe B-cell homeostasis, activation, proliferation, cytokine production in B-cells and serum and B-cell intracellular signaling pathways in SSc. We hypothezided that B-cell homeostasis and cytokine production were altered in SSc and could be explained by serum cytokine as well as by intracellular signaling pathway abnormalities.
Forty SSc patients and 20 healthy controls (HC) were prospectively included. B-cell subsets were determined by flow cytometry using CD19, CD21, CD24, CD38, CD27, IgM and IgD. CD25, CD80, CD95, HLA-DR were used to assess B-cell activation. Intracellular production of IL-10 and IL-6 were assessed by flow cytometry after TLR9 and CD40 stimulation. IL-6, IL-10, Ki67, Bcl2 mRNA were quantified in B-cells. Cytokine production was also assessed in sera and supernatants of B-cell culture, using a multiplex approach. Signaling pathways were studied through phosphorylation of mTOR, ERK, STAT3, STAT5 using a flow cytometry approach.
We found that SSc patients exhibited an altered peripheral blood B-cell subset distribution, with decreased memory B-cells but increased proportion of naive and CD21LoCD38Lo B-cell subsets. We observed an increased expression of activation markers (CD80, CD95, HLA-DR) on some B-cell subsets, mainly the memory B-cells. Secretion of IL-6, BAFF and CXCL13 were increased in SSc sera. There was no correlation between the peripheral blood B-cell subsets and the serum concentrations of these cytokines. After stimulation, we observed a lower proportion of IL-10 and IL-6 producing B–cells in SSc. Finally, we observed a significant decrease of mTOR phosphorylation in SSc patient B-cells.
In conclusion, we observed an altered B-cell homeostasis in SSc patients compared to HC. Memory B-cells were both decreased and activated in patients. IL-10 producing B-cells were decreased in SSc. This decrease was associated with an alteration of mTOR phosphorylation in B-cells. Conversely, there was no correlation between serum cytokine profile and B-cell homeostasis alterations.
•In systemic sclerosis, memory B-cells are decreased but markedly activated.•There is a decrease in regulatory IL-10 producing B-cells in patients.•This decrease is associated with an alteration of mTOR phosphorylation in B-cells.•IL-6, BAFF and CXCL-13 are increased in patients sera.•However, they are not correlated with the altered B-cell subset distribution.
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