Immune thrombocytopenia and pregnancy: an exposed/nonexposed cohort study.

The risk of immune thrombocytopenia (ITP) worsening during pregnancy and neonatal ITP (NITP) have never been prospectively studied. We included 180 pregnant and 168 nonpregnant women with ITP in a prospective, multicenter, observational cohort study. A total of 131 pregnant women with ITP were matched to 131 nonpregnant women with ITP by history of splenectomy, ITP status (no response, response, complete response), and duration. Groups were followed for 15 months. The primary outcome was the first occurrence of ITP worsening defined by a composite end point including bleeding events and/or severe thrombocytopenia (<30 × 109/L) and/or ITP treatment modification. We also studied the recurrence of ITP worsening and the incidence of NITP and risk factors. The first occurrence of ITP worsening did not differ between pregnant and nonpregnant women with ITP (53.4 per 100 person-years [95% confidence interval {CI}, 40.8-69.9] vs 37.1 [95% CI, 27.5-50.0]; hazard ratio {HR}, 1.35 [95% CI, 0.89-2.03], P = .16). Pregnant women with ITP were more likely to have recurrence of severe thrombocytopenia and treatment modification (HR, 2.71 [95% CI, 1.41-5.23], P = .003; HR, 2.01 [95% CI, 1.14-3.57], P = .017, respectively). However, recurrence of severe bleeding events was not different between groups (P = .4). Nineteen (14%) neonates showed NITP <50 × 109/L. By multivariable analysis, NITP was associated with a previous offspring with NITP and maternal platelet count <50 × 109/L within 3 months before delivery (adjusted odds ratio, 5.55 [95% CI, 1.72-17.89], P = .004 and 4.07 [95% CI, 1.41-11.73], P = .009). To conclude, women with ITP do not increase their risk of severe bleeding during pregnancy. NITP is associated with NITP history and the severity of maternal ITP during pregnancy. These results will be useful for counseling women with ITP.

Characteristics and outcome of ANCA-associated vasculitides induced by anti-thyroid drugs: a multicentre retrospective case-control study.

OBJECTIVE: Data on ANCA-associated vasculitis (AAV) induced by anti-thyroid drugs (ATD) are scarce. We aimed to describe the characteristics and outcome of these patients in comparison to primary AAV. METHODS: We performed a retrospective multicentre study including patients with ATD-induced AAV. We focused on ATD-induced microscopic polyangiitis (MPA) and compared them with primary MPA by matching each case with four controls by gender and year of diagnosis. RESULTS: Forty-five patients with ATD-induced AAV of whom 24 MPA were included. ANCA were positive in 44 patients (98%), including myeloperoxidase (MPO)-ANCA in 21 (47%), proteinase 3 (PR3)-ANCA in six (13%), and double positive MPO- and PR3-ANCA in 15 (33%). Main clinical manifestations were skin involvement (64%), arthralgia (51%) and glomerulonephritis (20%). ATD was discontinued in 98% of cases, allowing vasculitis remission in seven (16%). All the remaining patients achieved remission after glucocorticoids, in combination with rituximab in 11 (30%) or cyclophosphamide in four (11%). ATD were reintroduced in seven cases (16%) without any subsequent relapse. Compared with 96 matched primary MPA, ATD-induced MPA were younger at diagnosis (48 vs 65 years, P < 0.001), had more frequent cutaneous involvement (54 vs 25%, P = 0.007), but less frequent kidney (38 vs 73%, P = 0.02), and a lower risk of relapse (adjusted HR 0.07; 95% CI 0.01, 0.65, P = 0.019). CONCLUSION: ATD-induced AAV were mainly MPA with MPO-ANCA, but double MPO- and PR3-ANCA positivity was frequent. The most common manifestations were skin and musculoskeletal manifestations. ATD-induced MPA were less severe and showed a lower risk of relapse than primary MPA.

Immunohistochemical expression of DnaJ homolog subfamily B member 9 in immunoglobulin G4-related disease: a pilot study.

OBJECTIVES: DnaJ homolog subfamily B member 9 (DNAJB9) is a co-chaperone protein that governs the functions and integrity of cells. In immunoglobulin G4-related disease (IgG4-RD), DNAJB9 was shown to be upregulated in plasma cells, but its immunohistochemical expression has never been explored. This pilot study aims to investigate the immunohistochemical distribution and intensity of DNAJB9 in IgG4-RD tissue specimens. METHODS: Patients with definite IgG4-RD and normal tissue controls were selected for anti-DNAJB9 immunohistochemistry, applying a semi-quantitative staining intensity score. RESULTS: We studied the tissue slides of 9 IgG4-RD patients and 15 controls, including salivary gland, pancreatic, pulmonary, pleural, and retroperitoneal fibrosis tissue. Median immunohistochemical intensity was 0 for IgG4-RD patients vs. 2 for controls for endothelial cells (ES=1.58, p<0.01), 2 in each group for glandular epithelial cells (ES 0.70, p=0.26), and 2 for IgG4-RD vs. 3 for controls for inflammatory cells regarding salivary glands alone (ES=0.90, p=0.11). Endothelial staining intensity was negatively correlated with serum IgG4 concentrations (r= -0.72, p=0.03) and the number of treatments required to achieve disease remission (r= -0.70, p=0.04). CONCLUSIONS: Our findings evidenced reduced immunohistochemical expression of DNAJB9 in IgG4-RD endothelial cells, and suggested loss of expression in other cell types, possibly correlating with disease severity and risk of relapse. Although DNAJB9 may not serve as a marker for IgG4-RD, it may be part of a pathophysiological pathway involved in the disease and the onset of fibrosis.

Eicosanoids and Oxylipin Signature in Hereditary Hemochromatosis Patients Are Similar to Dysmetabolic Iron Overload Syndrome Patients but Are Impacted by Dietary Iron Absorption.

INTRODUCTION: Oxylipins are mediators of oxidative stress. To characterize the underlying inflammatory processes and phenotype effect of iron metabolism disorders, we investigated the oxylipin profile in hereditary hemochromatosis (HH) and dysmetabolic iron overload syndrome (DIOS) patients. METHODS: An LC-MS/MS-based method was performed to quantify plasma oxylipins in 20 HH and 20 DIOS patients in fasting conditions and 3 h after an iron-rich meal in HH patients. RESULTS: Principal component analysis showed no separation between HH and DIOS, suggesting that the clinical phenotype has no direct impact on oxylipin metabolism. 20-HETE was higher in DIOS and correlated with hypertension (p = 0.03). Different oxylipin signatures were observed in HH before and after the iron-rich meal. Discriminant oxylipins include epoxy fatty acids derived from docosahexaenoic acid and arachidonic acid as well as 13-HODE and 9-HODE. Mediation analysis found no major contribution of dietary iron absorption for 16/22 oxylipins significantly affected by the meal. DISCUSSION: The oxylipin profiles of HH and DIOS seemed similar except for 20-HETE, possibly reflecting different hypertension prevalence between the two groups. Oxylipins were significantly affected by the iron-rich meal, but the specific contribution of iron was not clear. Although iron may contribute to oxidative stress and inflammation in HH and DIOS, this does not seem to directly affect oxylipin metabolism.

Combining thrombopoietin receptor agonists with immunosuppressive drugs in adult patients with multirefractory immune thrombocytopenia, an update on the French experience.

Combining drugs could be an effective option for treating multirefractory ITP, that is, patients not responding to rituximab, thrombopoietin receptor agonists (TPO-RA) and splenectomy. We conducted a retrospective, multicenter, observational study including multirefractory ITP patients who received a combination of a TPO-RA and an immunosuppressive drug. We included 39 patients (67% women, median age 59 years [range 21-96]), with a median ITP duration of 57 months [3-393] and a median platelet count at initiation of 10 × 109 /L [1-35]. The combination regimen was given for a median duration of 12 months [1-103] and included eltrombopag (51%) or romiplostim (49%), associated with mycophenolate mofetil (54%), azathioprine (36%), cyclophosphamide (5%), cyclosporin (3%) or everolimus (3%). Overall, 30 patients (77%) achieved at least a response (platelet count ≥30 × 109 /L and at least doubling baseline during at least 3 months), including 24 complete responses (platelet count >100 × 109 /L during at least 3 months) with a median time to response of 30 days [7-270] and a median duration of response of 15 months [4-63]. Severe adverse event related to ITP treatment was observed in 31%. In conclusion, this study confirms that some patients with multirefractory ITP can achieve long lasting response with this combination.

Dupilumab for relapsing or refractory sinonasal and/or asthma manifestations in eosinophilic granulomatosis with polyangiitis: a European retrospective study.

BACKGROUND: Eosinophilic granulomatosis with polyangiitis (EGPA) is often associated with glucocorticoid-dependent asthma and/or ear, nose and throat (ENT) manifestations. When immunosuppressants and/or mepolizumab are ineffective, dupilumab could be an option. We describe the safety and efficacy of off-label use of dupilumab in relapsing and/or refractory EGPA. PATIENTS AND METHODS: We conducted an observational multicentre study of EGPA patients treated with dupilumab. Complete response was defined by Birmingham Vasculitis Activity Score (BVAS)=0 and prednisone dose ≤4 mg/day, and partial response by BVAS=0 and prednisone dose >4 mg/day. Eosinophilia was defined as an eosinophil count >500/mm3. RESULTS: Fifty-one patients were included. The primary indication for dupilumab was disabling ENT symptoms in 92%. After a median follow-up of 13.1 months, 18 patients (35%) reported adverse events (AEs), including two serious AEs. Eosinophilia was reported in 34 patients (67%), with a peak of 2195/mm3 (IQR 1268-4501) occurring at 13 weeks (IQR 4-36) and was associated with relapse in 41%. Twenty-one patients (41%) achieved a complete response and 12 (24%) a partial response. Sixteen (31%) patients experienced an EGPA relapse while on dupilumab, which was associated with blood eosinophilia in 14/16 (88%) patients. The median eosinophil count at the start of dupilumab was significantly lower in relapsers than in non-relapsers, as was the median time between stopping anti-IL-5/IL-5R and switching to dupilumab. CONCLUSION: These results suggest that dupilumab may be effective in treating patients with EGPA-related ENT manifestations. However, EGPA flares occurred in one-third of patients and were preceded by eosinophilia in 88%, suggesting that caution is required.

Cardiac sarcoidosis: systematic review of the literature on corticosteroid and immunosuppressive therapies.

BACKGROUND: Cardiac sarcoidosis (CS) is a life-threatening condition in which clear recommendations are lacking. We aimed to systematically review the literature on cardiac sarcoidosis treated by corticosteroids and/or immunosuppressive agents in order to update the management of CS. METHODS: Using PubMed, Embase and Cochrane Library databases, we found original articles on corticosteroid and standard immunosuppressive therapies for CS that provided at least a fair Scottish Intercollegiate Guidelines Network (SIGN) overall assessment of quality and we analysed the relapse rate, major cardiac adverse events (MACEs) and adverse events. We based our methods on the PRISMA statement and checklist. RESULTS: We retrieved 21 studies. Mean quality provided by SIGN assessment was 6.8 out of 14 (range 5-9). Corticosteroids appeared to have a positive impact on left ventricular function, atrioventricular block and ventricular arrhythmias. For corticosteroids alone, nine studies (45%, n=351) provided data on relapses, representing an incidence of 34% (n=119). Three studies (14%, n=73) provided data on MACEs (n=33), representing 45% of MACEs in patients treated by corticosteroid alone. Nine studies provided data on adjunctive immunosuppressive therapy, of which four studies (n=78) provided data on CS relapse, representing an incidence of 33% (n=26). Limitations consisted of no randomised control trial retrieved and unclear data on MACEs in patients treated by combined immunosuppressive agents and corticosteroids. CONCLUSION: Corticosteroids should be started early after diagnosis but the exact scheme is still unclear. Studies concerning adjunctive conventional immunosuppressive therapies are lacking and benefits of adjunctive immunosuppressive therapies are unclear. Homogenous data on CS long-term outcomes under corticosteroids, immunosuppressive therapies and other adjunctive therapies are lacking.

Significance of eosinophilia in granulomatosis with polyangiitis: data from the French Vasculitis Study Group Registry.

OBJECTIVE: To describe disease presentation and long-term outcome of granulomatosis with polyangiitis (GPA) patients according to blood eosinophils count (Eos) at vasculitis diagnosis. METHODS: Data from newly diagnosed GPA patients registered in the French Vasculitis Study Group database with available eosinophil count at diagnosis were reviewed. Disease characteristics, rate and type of relapses, and overall survival were analysed according to Eos, categorized as normal (<500/mm3), mild-to-moderate hypereosinophilia (HE) (between 500 and 1500/mm3) and severe HE (>1500/mm3). RESULTS: Three hundred and fifty-four patients were included. At diagnosis, 90 (25.4%) patients had HE ≥500/mm3; they were more likely male (73% vs 56%, P = 0.006) and had more frequent cutaneous manifestations (49% vs 33%, P = 0.01), peripheral neuropathy (32% vs 17%, P = 0.004) and higher BVAS (21 vs 18, P = 0.01), compared with those with Eos <500/mm3. Patients with severe HE (n = 28; median Eos 2355, range 1500-9114) had more frequent renal function worsening at presentation (P = 0.008). After a median follow-up of 3.95 (interquartile range 1.95-6.76) years, no difference was found in overall relapse rates according to baseline Eos, but those with HE experienced more neurological (P = 0.013) and skin (P = 0.024) relapses and had more frequently peripheral neuropathy as damage at last follow-up (P = 0.02). Overall survival was not significantly different in patients with normal Eos or HE at diagnosis. (P = 0.08). CONCLUSIONS: Blood HE at diagnosis, observed in about one-quarter of GPA patients, identifies a subgroup of patients with a more severe disease and higher rate of skin and neurological involvement both at presentation and during follow-up.

Localized versus systemic granulomatosis with polyangiitis: data from the French Vasculitis Study Group Registry.

OBJECTIVE: To describe the main features at diagnosis and evolution over time of patients with localized granulomatosis with polyangiitis (L-GPA) compared with those of systemic GPA (S-GPA). METHODS: EULAR definitions of L-GPA, i.e. upper and/or lower respiratory tract involvement, and S-GPA were applied to patients from the French Vasculitis Study Group Registry. L-GPA and S-GPA patients' characteristics at diagnosis and long-term outcomes were analysed and compared. RESULTS: Among the 795 Registry patients, 79 (10%) had L-GPA. Their main clinical manifestations were rhinitis, lung nodules, sinusitis and otitis. L-GPA vs S-GPA patients at diagnosis, respectively, were younger, more frequently had saddle nose deformity or subglottic stenosis and were less often PR3-ANCA-positive. L-GPA vs S-GPA induction therapy less frequently included CYC but more often a combination of MTX and glucocorticoids; 64% of MTX-treated patients experienced disease progression within 18 months post-diagnosis. L- and S-GPA patients' estimated relapse-free-survival probabilities, relapse rates and refractory disease rates at each time point were comparable, but L-GPA patients had more frequent ENT and lung relapses, and higher overall survival rates (P<0.02). Over a median follow-up of 3.5 years, 18 (22.8%) L-GPA progressed to S-GPA, either as a relapse after a period in remission or more frequently in the context of refractory disease. L-GPA patients experienced more ENT-related damage. CONCLUSIONS: The relapse risks of L-GPA and S-GPA were similar, but relapse patterns differed and L-GPA overall survival rate was higher. About one-quarter of L-GPA patients developed S-GPA over time, but without end-stage organ involvement.

Splenectomy for primary immune thrombocytopenia revisited in the era of thrombopoietin receptor agonists: New insights for an old treatment.

Although splenectomy is still considered the most effective curative treatment for immune thrombocytopenia (ITP), its use has significantly declined in the last decade, especially since the approval of thrombopoietin receptor agonists (TPO-RAs). The main objective of the study was to determine whether splenectomy was still as effective nowadays, particularly for patients with failure to respond to TPO-RAs. Our secondary objective was to assess, among patients who relapsed after splenectomy, the pattern of response to treatments used before splenectomy. This multicenter retrospective study involved adults who underwent splenectomy for ITP in France from 2011 to 2020. Response status was defined according to international criteria. We included 185 patients, 100 (54.1%) and 135 (73.0%) patients had received TPO-RAs and/or rituximab before the splenectomy. The median follow-up after splenectomy was 39.2 months [16.5-63.0]. Overall, 144 (77.8%) patients had an initial response and 23 (12.4%) experienced relapse during follow-up, for an overall sustained response of 65.4%, similar to that observed in the pre-TPO-RA era. Among patients who received at least one TPO-RA or rituximab before splenectomy, 92/151 (60.9%) had a sustained response. Six of 13 (46%) patients with previous lack of response to both TPO-RAs and rituximab had a sustained response to splenectomy. Among patients with relapse after splenectomy, 13/21 (61.2%) patients responded to one TPO-RAs that failed before splenectomy. In conclusion, splenectomy is still a relevant option for treating adult primary ITP not responding to TPO-RAs and rituximab. Patients with lack of response or with relapse after splenectomy should be re-challenged with TPO-RAs.

Profile of patients with type 2 diabetes and glycated haemoglobin ≥ 10% followed in general practice.

OBJECTIVE: To determine whether profiles of patients with unbalanced type 2 diabetes (T2DM) and glycated haemoglobin (HbA1c) ≥ 10% could be identified on the basis of socio-demographic, behavioural, clinical, and biological characteristics. METHODS: Retrospective, cross-sectional, factorial analysis study of patients with T2DM treated for at least 1 year, with HbA1c ≥ 10%. Patients were recruited via medical analysis laboratories, France. Patients were followed up in general practice with possible recourse to specialist consultations. Data were collected by means of self-administered questionnaires sent by post. RESULTS: A total of 104 patients were included: 69 men and 35 women, with a median age of 66 ± 12 years, body mass index 30.7 ± 6.2kg/m2 and 47% in a vulnerable socio-economic situation. Fifty patients (48%) were followed exclusively by their general practitioners and only 30% had no compliance problems. Creatinuria was measured at least once during the year in 92% of patients, but microalbuminuria was measured in only 20%. Age, socio-economic precariousness, insulin treatment, and follow-up by several health professionals had a negative influence on quality of life (QoL). Two patient profiles were defined by factor analysis: (i) young, rural, smoker, socially isolated, precarious patient with poor compliance and QoL; and (ii) elderly, urban, regular physical activity, in a couple, without precariousness and with satisfactory QoL. CONCLUSIONS: Analysis of the characteristics of patients with T2DM and glycaemic imbalance reveals profiles that are useful in clinical practice for a personalized approach to treatment and active prevention of diabetes complications.

Microscopic polyangiitis: Clinical characteristics and long-term outcomes of 378 patients from the French Vasculitis Study Group Registry.

OBJECTIVE: To describe characteristics and long-term outcomes of patients with microscopic polyangiitis (MPA), an antineutrophil cytoplasm antibody (ANCA)-associated small-vessel necrotizing vasculitis. METHODS: MPA patients from the French Vasculitis Study Group Registry satisfying the European Medicines Agency algorithm were analyzed retrospectively. Characteristics at diagnosis, treatments, relapses and deaths were analyzed to identify factors predictive of death or relapse. RESULTS: Between 1966 and 2017, 378 MPA patients (median age 63.7 years) were diagnosed and followed for a mean of 5.5 years. At diagnosis, the main clinical manifestations included renal involvement (74%), arthralgias (45%), skin (41%), lung (40%) and mononeuritis multiplex (32%), with less frequent alveolar hemorrhage (16%), cardiomyopathy (5%) and severe gastrointestinal signs (4%); mean serum creatinine was 217 µmol/L. ANCA were detected in 298/347 (86%) patients by immunofluorescence and/or enzyme-linked immunosorbent assay (ELISA). Among the 293 patients with available ELISA specificities, 272 (92.8%) recognized myeloperoxidase and 13 (4.4%) proteinase-3. During follow-up, 131 (34.7%) patients relapsed and 78 (20.6%) died, mainly from infections. Respective 5-year overall and relapse-free survival rates were 84.2% and 60.4%. Multivariable analyses retained age >65 years, creatinine >130 µmol/L, severe gastrointestinal involvement and mononeuritis multiplex as independent risk factors for death. Renal impairment was associated with a lower risk of relapse. CONCLUSION: Non-renal manifestations and several risk factors for death or relapse were frequent in this nationwide cohort. While mortality was low, and mainly due to treatment-related complications, relapses remained frequent, suggesting that MPA management can be further improved.

Non-severe eosinophilic granulomatosis with polyangiitis: long-term outcomes after remission-induction trial.

OBJECTIVE: In a previous controlled trial, 1-year adjunction of AZA to glucocorticoids (GC) for patients with non-severe, newly diagnosed eosinophilic granulomatosis with polyangiitis (EGPA) failed to lower remission failure, vasculitis relapse and isolated asthma/rhinosinus exacerbation rates, or cumulative GC use at month (M) 24. The aim of this study was to analyse longer-term outcomes to determine whether subsequent vasculitis relapse or isolated asthma/rhinosinus exacerbation (IARE) rates differed. METHODS: After M24, patients were followed prospectively, being treated based on physicians' best judgment. Flares and reasons for increased GC dose or immunosuppressant use were recorded, and reviewed according to randomization group to distinguish vasculitis relapses from IAREs according to EGPA Task Force recommendations. RESULTS: Fifty EGPA trial participants were followed for a median (interquartile range) of 6.3 (5.4-7.6) years; two (4%) died 11 months post-inclusion. By M24, vasculitis had relapsed in 21/49 (43%) patients and 14/50 (28%) had IAREs. Another patient died 4.8 years post-inclusion (infection). Among nine patients with subsequent vasculitis relapses, three had a major relapse and three had their first relapse after M24; among 25 patients with later IAREs, 17 occurred after M24. At 5 years, respective vasculitis relapse and IARE rates were 48% (95% CI 34.0, 62.6) and 56% (95% CI 41.7, 70.8), with no between-arm differences (P = 0.32 and 0.13). No entry clinical or biological parameter was associated with these outcomes during follow-up. CONCLUSION: These results confirmed that 1-year AZA and GC induction obtained good overall survival but no long-term benefit for non-severe EGPA patients. Vasculitis relapses, occurring mostly during the first 2 years, and IAREs, occurring throughout follow-up, require other preventive treatments. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT00647166.

Clinical and biological features in PIEZO1-hereditary xerocytosis and Gardos channelopathy: a retrospective series of 126 patients.

We describe the clinical, hematologic and genetic characteristics of a retrospective series of 126 subjects from 64 families with hereditary xerocytosis. Twelve patients from six families carried a KCNN4 mutation, five had the recurrent p.Arg352His mutation and one had a new deletion at the exon 7-intron 7 junction. Forty-nine families carried a PIEZO1 mutation, which was a known recurrent mutation in only one-third of the cases and private sequence variation in others; 12 new probably pathogenic missense mutations were identified. The two dominant features leading to diagnosis were hemolysis that persisted after splenectomy and hyperferritinemia, with an inconstant correlation with liver iron content assessed by magnetic resonance imaging. PIEZO1-hereditary xerocytosis was characterized by compensated hemolysis in most cases, perinatal edema of heterogeneous severity in more than 20% of families and a major risk of post-splenectomy thrombotic events, including a high frequency of portal thrombosis. In KCNN4-related disease, the main symptoms were more severe anemia, hemolysis and iron overload, with no clear sign of red cell dehydration; therefore, this disorder would be better described as a 'Gardos channelopathy'. These data on the largest series to date indicate that PIEZO1-hereditary xerocytosis and Gardos channelopathy are not the same disease although they share hemolysis, a high rate of iron overload and inefficient splenectomy. They demonstrate the high variability in clinical expression as well as genetic bases of PIEZO1-hereditary xerocytosis. These results will help to improve the diagnosis of hereditary xerocytosis and to provide recommendations on the clinical management in terms of splenectomy, iron overload and pregnancy follow-up.

Characteristics, risk factors and management of venous thromboembolism in immune thrombocytopenia: a retrospective multicentre study.

BACKGROUND: An increased risk of thrombosis has been reported in immune thrombocytopenic purpura (ITP), but the characteristics, risk factors of occurrence, recurrence and management of venous thromboembolic events (VTE) have been poorly investigated. AIMS: To describe VTE and ITP characteristics, distribution of VTE risk factors and their impact on VTE features and recurrence. METHODS: A retrospective study of patients with ITP and VTE registered in databases of three reference French centres of ITP. RESULTS: Among 49 patients, 66 VTE were recorded. The platelet count at the time of the first VTE was <100 × 109 /L for 28/43 (65%) patients. In total, 19/48 (40%) patients had at least one positive antiphospholipid test result. For the 10 VTE occurring in eight patients with platelet count <50 × 109 /L, ITP treatment was efficient in 7. One haemorrhagic complication associated with anticoagulant (AC) therapy was recorded. For 31/49 (63%) patients, long-term AC therapy could have been discussed after the first VTE, but only 13 received it. A second VTE occurred in 13 (27%) patients. The risk of recurrence was increased in patients with unprovoked VTE before ITP diagnosis or active cancer. CONCLUSION: VTE in ITP mainly occurred in the presence of multiple risk factors of TE. A low platelet count does not protect against VTE. Management with AC therapy despite persistently low platelet count seems possible. Risk of VTE recurrence is high, particularly with a history of unprovoked VTE or active cancer. In this setting, indefinite AC therapy could be discussed.

Efficacy of tocilizumab in Takayasu arteritis: Multicenter retrospective study of 46 patients.

OBJECTIVES: To assess the efficacy of tocilizumab in patients with Takayasu arteritis (TA). METHODS: We conducted a retrospective multicenter study in 46 TA patients treated with tocilizumab. We analyzed factors associated with response to tocilizumab (assessed using NIH score). RESULTS: Forty-six patients with TA were included, with a median age of 43 years [29-54], and 35 (76%) females. We observed a decrease in the median NIH scale (from 3 [2-3] at baseline to 0 [0-1] and 0 at 3 and 6 months, respectively; p < 0.0001). The daily prednisone dose also decreased from 15 mg [8-19] at baseline to 4 mg [5-21] and 5 mg [4.5-9] at 3 and 6 months, respectively (p < 0.0001) under tocilizumab. The overall tocilizumab failure free survival was 81% [CI 95%; 0.7-0.95], 72% [CI 95%; 0.55-0.95] and 48% [CI 95%; 0.2-0.1] at 12, 24 and 48 months, respectively. The presence of constitutional symptoms (HR 5.6 [CI 95%; 1.08-29], p = 0.041), and C-reactive protein level (HR 1.16 [CI 95%; 1.01-1.31], P = 0.003) at the time of tocilizumab initiation were significantly associated with tocilizumab event-free survival. The event-free survival was significantly better under tocilizumab therapy in comparison to DMARDs (p = 0.02). CONCLUSION: This large multicenter study shows that tocilizumab is efficient and may reduce the incidence of relapses in TA.

Metabolic and hepatic effects of bloodletting in dysmetabolic iron overload syndrome: A randomized controlled study in 274 patients.

Dysmetabolic iron overload syndrome (DIOS) is a common cause of hyperferritinemia, accounting for a mild increase of iron stores in insulin-resistant subjects. Iron removal could improve insulin sensitivity. We performed a prospective, randomized, controlled trial (NCT01015525) in nondiabetic DIOS patients with hepatic iron >50 µmol/g at magnetic resonance imaging to compare the metabolic and hepatic outcomes of 1-year maintenance of serum ferritin levels <50 µg/L by bloodletting associated with lifestyle and diet advice (LFDA) to those of LFDA only. Patients were randomly assigned (1:1) with stratification by center (n = 8) and hyperglycemia (>5.6 mmol/L). Sample size was calculated to provide 90% power and a difference in fasting glycemia of 0.25 mmol/L. Analysis was done in an intention-to-treat population. In 2010-2014, 146 patients were randomly assigned to receive venesections with LFDA and 128 to LFDA only. At the end of the study, comparison of iron-depleted patients and controls showed ferritin levels 71 ± 48 µg/L after removal of 4.9 ± 1.6 L of blood versus 733 ± 277 µg/L (P < 0.0001), glycemia 5.44 ± 0.7 versus 5.49 ± 0.7 mmol/L (P = 0.57), body weight +0.5 ± 4.3% versus -0.6 ± 3.3% (P = 0.03), homeostasis model of assessment of insulin resistance 3.39 versus 2.40 (P = 0.002), alanine aminotransaminase 33 ± 22 versus 37 ± 21 IU/L (P = 0.10), aspartate aminotransaminase 27 ± 13 versus 27 ± 10 IU/L (P = 0.81), gamma-glutamyl transferase 54 ± 138 versus 49 ± 35 IU/L (P = 0.72), Fatty Liver Index 58.9 ± 24.6 versus 61.2 ± 22.9 (P = 0.37), and Fibrosis-4 score 1.5 ± 0.6 versus 1.30 ± 0.6 (P = 0.51). Fatigue occurred in 25.3% of venesected patients versus 2.3% of controls (P < 0.0001). In the subgroup of patients who lost weight, glycemia, homeostasis model of assessment of insulin resistance, serum ferritin, lipid profile, and liver function tests improved irrespective of bloodletting. CONCLUSION: In DIOS patients, iron depletion by bloodletting does not improve metabolic and hepatic features, is associated with weight gain, and is not as well tolerated as expected; sustained modification of diet and lifestyle habits remains the first therapeutic intervention in DIOS. (Hepatology 2017;65:465-474).

Efficacy of bortezomib in non-IgM type I cryoglobulinaemic vasculitis: a single-centre retrospective case series.

INTRODUCTION: Treatment of non-IgM type I cryoglobulinaemic vasculitis (CV) is challenging. Corticosteroids are first-line therapy, but relapses are frequent leading to therapeutic escalation. Bortezomib is a proteasome inhibitor with rapid effect on monoclonal component. However, its use in non-IgM type I CV has been barely reported. OBJECTIVE: To assess the efficacy of bortezomib in non-IgM type I CV. METHOD: Single-centre case series of four patients with non-IgM type I CV treated with bortezomib monotherapy. RESULTS: Two men and two women, 60-84 years old, received bortezomib monotherapy. Monoclonal component was IgG-λ (n = 2), IgA-λ and IgG-κ. Clinical features were necrotic rash (n = 3), synovitis (n = 3) and sensitive neuropathy (n = 2). CV was refractory to corticosteroids (n = 4), cyclophosphamide (n = 3) and rituximab (n = 2). Three patients experienced dramatic clinical improvement with undetectable cryoglobulin after three cycles (bortezomib 1.3 mg/m2 weekly). Each patient relapsed 4-18 months after treatment discontinuation. Bortezomib was unsuccessful after four cycles in one patient. Bortezomib toxicity included one pneumonia and 1 case of worsening neuropathic pain. CONCLUSION: Bortezomib in monotherapy should be considered as a valuable option in refractory non-IgM type I CV because of its swift efficacy and acceptable tolerance profile.

Microscopic polyangiitis and non-HBV polyarteritis nodosa with poor-prognosis factors: 10-year results of the prospective CHUSPAN trial.

OBJECTIVES: To analyse the 10-year outcomes of 64 patients with non-HBV polyarteritis nodosa (PAN) or microscopic polyangiitis (MPA) and Five-Factor Score-defined poor-prognosis factors enrolled (1994-2000) in the prospective, randomised, open-label CHUSPAN trial. METHODS: The 64 patients were randomised to receive 12 (33: 23 MPA, 10 PAN) or 6 (31: 17 MPA, 14 PAN) cyclophosphamide (CYC) pulses combined with glucocorticoids. Ten-year follow-up of these patients included times to relapse(s), failure(s) and/or deaths calculated from treatment onset. Data were censored after 120 months of follow-up. RESULTS: Eleven patients were lost to-follow-up (mean±SD follow-up: 61.9±35.2 months), with no between-group difference. As previously reported, baseline clinical characteristics and laboratory values were comparable for the 2 groups. After induction, 53/64 (83%) entered remission, with comparable percentages for both groups. The regimen was intensified for 11 initial non-responders: 4 achieved remission and 8 died before doing so. During extended follow-up, 26 patients experienced ≥1 relapse(s): 12 in the 12-pulse group and 14 in the 6-pulse group (p=0.47). At 10 years, overall and disease-free survival rates were 57.4% and 29.9%, with no between-group differences (p=0.185 and p=0.367, respectively). Factors associated with shorter disease-free survival were age ≥65 years and alveolar haemorrhage at diagnosis. CONCLUSIONS: Although the 3-year CHUSPAN trial results indicated the superiority of 12 vs. 6 CYC pulses, that early advantage progressively declined and became non-significant by 10 years.