Giant cell arteritis associated with scalp, tongue or lip necrosis: A French multicenter case control study.

BACKGROUND: Scalp, tongue and/or lip necrosis are rare complications of GCA. OBJECTIVES: To describe characteristics and outcome of patients with giant cell arteritis (GCA) -related scalp, tongue and/or lip necrosis. METHODS: A retrospective nationwide multicenter study included 20 GCA patients with scalp, tongue, and/or lip necrosis diagnosed between 1998 and 2021 and 80 GCA control patients matched for age, sex and management period. Logistic regression analyses were conducted to identify baseline characteristics associated with scalp, tongue and/or lip necrosis. RESULTS: Compared to controls, patients with scalp, tongue and/or lip necrosis showed significantly more cranial manifestations (headache, p=0.045; scalp tenderness, p=0.006; jaw claudication, p=0.02). No differences were observed between both groups regarding the occurrence of visual symptoms or large vessel involvement. At diagnosis, GCA patients with necrosis more likely received IV methylprednisolone infusions and higher doses of oral prednisone. There were no differences regarding vascular complications during follow up. Compared to controls, survival was decreased in GCA patients with necrosis (p=0.003). In a multivariable logistic regression model, scalp tenderness [odds ratio (OR) 4.81(95 % CI: 1.57, 14.79), p = 0.006] and cognitive disorder [OR 6.42 (95 % CI: 1.01, 40.60), p=0.048] were identified as factors associated to scalp, tongue, and/or lip necrosis. CONCLUSION: Our results suggest that scalp, tongue, and/or lip necrosis is associated to higher mortality in GCA patients. Scalp tenderness and cognitive disorder were significant factors associated to this very rare complication of GCA.

Continuous positive airway pressure for respiratory support during COVID-19 pandemic: a frugal approach from bench to bedside.

BACKGROUND: We describe a frugal approach (focusing on needs, performance, and costs) to manage a massive influx of COVID-19 patients with acute hypoxemic respiratory failure (AHRF) using the Boussignac valve protected by a filter ("Filter Frugal CPAP", FF-CPAP) in and out the ICU. METHODS: (1) A bench study measured the impact of two filters with different mechanical properties on CPAP performances, and pressures were also measured in patients. (2) Non-ICU healthcare staff working in COVID-19 intermediate care units were trained with a video tutorial posted on a massive open online course. (3) A clinical study assessed the feasibility and safety of using FF-CPAP to maintain oxygenation and manage patients out of the ICU during a massive outbreak. RESULTS: Bench assessments showed that adding a filter did not affect the effective pressure delivered to the patient. The resistive load induced by the filter variably increased the simulated patient's work of breathing (6-34%) needed to sustain the tidal volume, depending on the filter's resistance, respiratory mechanics and basal inspiratory effort. In patients, FF-CPAP achieved pressures similar to those obtained on the bench. The massive training tool provided precious information on the use of Boussignac FF-CPAP on COVID-19 patients. Then 85 COVID-19 patients with ICU admission criteria over a 1-month period were studied upon FF-CPAP initiation for AHRF. FF-CPAP significantly decreased respiratory rate and increased SpO2. Thirty-six (43%) patients presented with respiratory indications for intubation prior to FF-CPAP initiation, and 13 (36%) of them improved without intubation. Overall, 31 patients (36%) improved with FF-CPAP alone and 17 patients (20%) did not require ICU admission. Patients with a respiratory rate > 32 breaths/min upon FF-CPAP initiation had a higher cumulative probability of intubation (p < 0.001 by log-rank test). CONCLUSION: Adding a filter to the Boussignac valve does not affect the delivered pressure but may variably increase the resistive load depending on the filter used. Clinical assessment suggests that FF-CPAP is a frugal solution to provide a ventilatory support and improve oxygenation to numerous patients suffering from AHRF in the context of a massive outbreak.

Efficacy, safety and immunological profile of combining rituximab with belimumab for adults with persistent or chronic immune thrombocytopenia: results from a prospective phase 2b trial.

B-cell activating factor may be involved in the failure of B-cell depleting therapy with rituximab in immune thrombocytopenia (ITP) by promoting the emergence of splenic long-lived plasma cells. From results obtained in mouse models, we hypothesized that combining rituximab with sequential injections of belimumab could increase the rate of response at one year in patients with persistent or chronic ITP by preventing the emergence of these long-lived plasma cells. The study was a single-center, single arm, prospective phase 2b trial (RITUX-PLUS, NCT03154385) investigating the safety and efficacy of rituximab given at a fixed dose of 1,000 mg, two weeks apart, combined with five infusions of belimumab, 10 mg/kg at week 0 (W0)+2 days, W2+2 days, W4, W8 and W12 for adults with primary persistent or chronic ITP. The primary endpoint was the total number of patients achieving an overall response (complete response + response) at W52 according to a standard definition. In total, 15 non-splenectomized adults, nine (60%) with persistent IPT and six (40%) with chronic ITP, were included. No severe adverse event, infection, or severe hypogammaglobulinemia was observed. Thirteen patients achieved an initial overall response. At W52, 12 (80%) patients achieved an overall response, including ten (66.7%) with complete response. When compared with a cohort of patients receiving rituximab alone, the kinetics of B-cell repopulation appeared similar, but the number of circulating T follicular helper cells was significantly decreased with belimumab combination therapy. Combining rituximab and belimumab seems a promising strategy in ITP, with high efficacy and acceptable safety.

Procalcitonin to Reduce Antibiotic Exposure during Acute Chest Syndrome in Adult Patients with Sickle-Cell Disease.

Acute chest syndrome (ACS) is a major complication of sickle-cell disease. Bacterial infection is one cause of ACS, so current guidelines recommend the routine use of antibiotics. We performed a prospective before-after study in medical wards and an intensive-care unit (ICU). During the control phase, clinicians were blinded to procalcitonin concentration results. We built an algorithm using the obtained measurements to hasten antibiotic cessation after three days of treatment if bacterial infection was not documented, and procalcitonin concentrations were all <0.5 µg/L. During the intervention period, the procalcitonin algorithm was suggested to physicians as a guide for antibiotic therapy. The primary endpoint was the number of days alive without antibiotics at Day 21. One-hundred patients were analyzed (103 ACS episodes, 60 in intervention phase). Possible or proven lung infection was diagnosed during 13% of all ACS episodes. The number of days alive without antibiotics at Day 21 was higher during the intervention phase: 15 [14-18] vs. 13 [13,14] days (p = 0.001). More patients had a short (≤3 days) antibiotic course during intervention phase: 31% vs 9% (p = 0.01). There was neither infection relapse nor pulmonary superinfection in the entire cohort. A procalcitonin-guided strategy to prescribe antibiotics in patients with ACS may reduce antibiotic exposure with no apparent adverse outcomes.

Different phenotypes in dermatomyositis associated with anti-MDA5 antibody: Study of 121 cases.

OBJECTIVES: The predominance of extramuscular manifestations (e.g., skin rash, arthralgia, interstitial lung disease [ILD]) as well as the low frequency of muscle signs in anti-melanoma differentiation-associated gene 5 antibody-positive (anti-MDA5+) dermatomyositis caused us to question the term myositis-specific antibody for the anti-MDA5 antibody, as well as the homogeneity of the disease. METHODS: To characterize the anti-MDA5+ phenotype, an unsupervised analysis was performed on anti-MDA5+ patients (n = 83/121) and compared to a group of patients with myositis without anti-MDA5 antibody (anti-MDA5-; n = 190/201) based on selected variables, collected retrospectively, without any missing data. RESULTS: Within anti-MDA5+ patients (n = 83), 3 subgroups were identified. One group (18.1%) corresponded to patients with a rapidly progressive ILD (93.3%; p < 0.0001 across all) and a very high mortality rate. The second subgroup (55.4%) corresponded to patients with pure dermato-rheumatologic symptoms (arthralgia; 82.6%; p < 0.01) and a good prognosis. The third corresponded to patients, mainly male (72.7%; p < 0.0001), with severe skin vasculopathy, frequent signs of myositis (proximal weakness: 68.2%; p < 0.0001), and an intermediate prognosis. Raynaud phenomenon, arthralgia/arthritis, and sex permit the cluster appurtenance (83.3% correct estimation). Nevertheless, an unsupervised analysis confirmed that anti-MDA5 antibody delineates an independent group of patients (e.g., dermatomyositis skin rash, skin ulcers, calcinosis, mechanic's hands, ILD, arthralgia/arthritis, and high mortality rate) distinct from anti-MDA5- patients with myositis. CONCLUSION: Anti-MDA5+ patients have a systemic syndrome distinct from other patients with myositis. Three subgroups with different prognosis exist.

Clinical efficacy of hydroxychloroquine in patients with covid-19 pneumonia who require oxygen: observational comparative study using routine care data.

OBJECTIVE: To assess the effectiveness of hydroxychloroquine in patients admitted to hospital with coronavirus disease 2019 (covid-19) pneumonia who require oxygen. DESIGN: Comparative observational study using data collected from routine care. SETTING: Four French tertiary care centres providing care to patients with covid-19 pneumonia between 12 March and 31 March 2020. PARTICIPANTS: 181 patients aged 18-80 years with documented severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia who required oxygen but not intensive care. INTERVENTIONS: Hydroxychloroquine at a dose of 600 mg/day within 48 hours of admission to hospital (treatment group) versus standard care without hydroxychloroquine (control group). MAIN OUTCOME MEASURES: The primary outcome was survival without transfer to the intensive care unit at day 21. Secondary outcomes were overall survival, survival without acute respiratory distress syndrome, weaning from oxygen, and discharge from hospital to home or rehabilitation (all at day 21). Analyses were adjusted for confounding factors by inverse probability of treatment weighting. RESULTS: In the main analysis, 84 patients who received hydroxychloroquine within 48 hours of admission to hospital (treatment group) were compared with 89 patients who did not receive hydroxychloroquine (control group). Eight additional patients received hydroxychloroquine more than 48 hours after admission. In the weighted analyses, the survival rate without transfer to the intensive care unit at day 21 was 76% in the treatment group and 75% in the control group (weighted hazard ratio 0.9, 95% confidence interval 0.4 to 2.1). Overall survival at day 21 was 89% in the treatment group and 91% in the control group (1.2, 0.4 to 3.3). Survival without acute respiratory distress syndrome at day 21 was 69% in the treatment group compared with 74% in the control group (1.3, 0.7 to 2.6). At day 21, 82% of patients in the treatment group had been weaned from oxygen compared with 76% in the control group (weighted risk ratio 1.1, 95% confidence interval 0.9 to 1.3). Eight patients in the treatment group (10%) experienced electrocardiographic modifications that required discontinuation of treatment. CONCLUSIONS: Hydroxychloroquine has received worldwide attention as a potential treatment for covid-19 because of positive results from small studies. However, the results of this study do not support its use in patients admitted to hospital with covid-19 who require oxygen.

Diffuse alveolar hemorrhage after gadolinium injection during a MRI.

Gadolinium is a frequently used contrast product for MRI exam. It is well known to be less immuno-reactive than iodine used in tomodensitometry but is safety is not completely exempt of secondary effect. Here we report one case of acute interstitial pulmonary toxicity due to gadolinium. After quick elimination of others possible diagnosis and broncho-alveolar lavage we establish the link between acute intra-alveolar hemorrhage and gadolinium injection.

Clinical presentation, treatment and outcome of IgG4-related pachymeningitis: From a national case registry and literature review.

Pachymeningitis is rare, either idiopathic or secondary to inflammatory disorders, after tumoral, surgical or infectious causes have been excluded. The fibroinflammatory IgG4-related disease is one of the etiologies of pachymeningitis with only few cases reported yet. From a single referral regional center, we evaluated the frequency of IgG4-related disease as the cause of inflammatory pachymeningitis in 10% of cases. From a National case registry of IgG4-related disease the pachymeningitis frequency was 4.1%. We report eight new cases with cranial, spinal or both involvements and a literature review of 46 pathological proven cases. We observed that IgG4-related pachymeningitis is in most cases not associated to extra-neurological manifestations of the disease. Only 27% of spinal and 40% of cranial IgG4-related pachymeningitis are associated with other disease localizations. First line treatment strategies included surgery and steroids. The use of immunosuppressants or rituximab was necessary in 18% of spinal and 54% of cranial localizations. Some patients remained with sequellae and clinical and/or radiological improvement can be difficult to obtain.

Long-term efficacy and safety of rituximab in IgG4-related disease: Data from a French nationwide study of thirty-three patients.

OBJECTIVES: To assess efficacy and safety of rituximab (RTX) as induction therapy, maintenance of remission and treatment of relapses in a cohort of IgG4-related disease (IgG4-RD) patients. METHODS: Nationwide retrospective multicenter study of IgG4-RD patients treated with at least one course of RTX. Clinical, biological and radiological response, relapse rate and drug tolerance were analyzed. Kaplan-Meier curves were plotted and risk factors for relapse studied with a Cox regression model. RESULTS: Among 156 IgG4-RD patients included in the French database, 33 received rituximab. Clinical response was noted in 29/31 (93.5%) symptomatic patients. Glucocorticoids withdrawal was achieved in 17 (51.5%) patients. During a mean follow-up of 24.8 ±21 months, 13/31 (41.9%) responder patients relapsed after a mean delay of 19 ±11 months after RTX. Active disease, as defined by an IgG4-RD Responder Index >9 before RTX, was significantly associated with relapse (HR = 3.68, 95% CI: 1.1, 12.6) (P = 0.04), whereas maintenance therapy with systematic (i.e. before occurrence of a relapse) RTX retreatment was associated with longer relapse-free survival (41 versus 21 months; P = 0.02). Eight severe infections occurred in 4 patients during follow-up (severe infections rate of 12.1/100 patient-years) and hypogammaglobulinemia ≤5 g/l in 3 patients. CONCLUSION: RTX is effective for both induction therapy and treatment of relapses in IgG4-RD, but relapses are frequent after B-cell reconstitution. Maintenance therapy with systematic RTX infusions is associated with longer relapse-free survival and might represent a novel treatment strategy. Yet, the high rate of infections and the temporary effect of RTX might be hindrances to such strategy.

Ophthalmic manifestations in IgG4-related disease: Clinical presentation and response to treatment in a French case-series.

IgG4-related disease (IgG4-RD) is characterized by variable tissue or organ involvements sharing common pathological findings. Orbital or orbital adnexa involvement of the disease has been reported in a few case series. The aim of our study was to characterize and analyze ophthalmic manifestations from a nationwide French case-series.Patients with IgG4-RD and orbital or orbital adnexa involvement included in the French multicentric IgG4-RD case-registry were identified. Only patients fulfilling "modified" comprehensive diagnostic criteria with pathological documentation were retained for the study. Clinical, biological, pathological, radiological findings and data regarding the response to treatment were retrospectively analyzed.According to our data registry, the frequency of IgG4-related ophthalmic disease (IgG4-ROD) was 17%. Mean age at diagnosis was 55.1 ±â€Š7.1 years with a male/female ratio of 2.2. The 19 cases of IgG4-ROD consisted of lacrimal gland (68.4%), soft tissue (57.9%), extra-ocular muscles (36.8%), palpebral (21.1%), optical nerve (10.5%), orbital bone (10.5%), and mononeuritis (V1 and/or V2, 10.5%) involvements. IgG4-ROD was bilateral in 57.9% of cases. Extra-ophthalmic manifestations were reported in 78.9% of cases. All patients responded to prednisone but two-thirds of patients relapsed within a mean (SD) of 9.8 (3.5) months and 72.2% required long-term glucocorticoids and/or immunosuppressive agents. Eight patients were treated by rituximab with a favorable response in 87.5% of cases.Lacrimal involvement is the most frequent ophthalmic manifestation of IgG4-RD and is frequently associated with extra-orbital manifestations. Despite initial favorable response to steroids, the long-term management of relapsing patients needs to be improved.

Delayed hemolytic transfusion reaction in adult sickle-cell disease: presentations, outcomes, and treatments of 99 referral center episodes.

Delayed hemolytic transfusion reaction (DHTR) is one of the most feared complications of sickle-cell disease (SCD). We retrospectively analyzed the clinical and biological features, treatments and outcomes of 99 DHTRs occurring in 69 referral center patients over 12 years. The first clinical signs appeared a median of 9.4 [IQR, 3-22] days after the triggering transfusion (TT). The most frequent DHTR-related clinical manifestation was dark urine/hemoglobinuria (94%). Most patients (89%) had a painful vaso-occlusive crisis and 50% developed a secondary acute chest syndrome (ACS). The median [IQR] hemoglobin-concentration nadir was 5.5 [4.5-6.3] g/dL and LDH peak was 1335 [798-2086] IU/L. Overall mortality was 6%. None of the patients had been receiving chronic transfusions. Among these DHTRs, 61% were developed in previously immunized patients, 28% in patients with prior DHTR. Among Abs detected after the TT in 62% of the episodes, half are classically considered potentially harmful. No association could be established between clinical severity and immunohematological profile and/or the type and specificity of Abs detected after the TT. Management consisted of supportive care alone (53%) or with adjunctive measures (47%), including recombinant erythropoietin and sometimes rituximab and/or immunosuppressants. Additional transfusions were either ineffective or worsened hemolysis. In some cases, severe intravascular hemolysis can be likely responsible for the vascular reaction and high rates of ACS, pulmonary hypertension and (multi)organ failure. In conclusion, clinicians and patients must recognize early DHTR signs to avoid additional transfusions. For patients with a history of RBC immunization or DHTR, transfusion indications should be restricted. Am. J. Hematol. 91:989-994, 2016. © 2016 Wiley Periodicals, Inc.

Sofosbuvir plus ribavirin for hepatitis C virus-associated cryoglobulinaemia vasculitis: VASCUVALDIC study.

BACKGROUND: Hepatitis C virus (HCV) is the aetiological agent for most cases of cryoglobulinaemia vasculitis. Interferon-containing regimens are associated with important side effects and may exacerbate the vasculitis. OBJECTIVE: To evaluate safety and efficacy of an oral interferon-free regimen, sofosbuvir plus ribavirin, in HCV-cryoglobulinaemia vasculitis. PATIENTS AND METHODS: We enrolled 24 consecutive patients (median age of 56.5 years and 46% of women) with HCV-cryoglobulinaemia vasculitis. Sofosbuvir (400 mg/day) was associated with ribavirin (200-1400 mg/day), for 24 weeks. The primary efficacy end point was a complete clinical response of the vasculitis at the end of treatment (week 24). RESULTS: Main features of HCV-cryoglobulinaemia vasculitis included purpura and peripheral neuropathy (67%), arthralgia (58%), glomerulonephritis (21%) and skin ulcers (12%). Twenty-one patients (87.5%) were complete clinical response at week 24. Complete clinical response was achieved in six (25%) patients at week 4, four (16.6%) at week 8, seven (29.2%) at week 12, three (12.5%) at week 16 and one (4.2%) at week 20. The cryoglobulin level decreased from 0.35 (0.16-0.83) at baseline to 0.15 (0.05-0.45) g/L at week 24. The C4 serum level increased from 0.10 (0.07-0.19) to 0.17 (0.09-0.23) g/L at week 24. Seventy-four per cent of patients had a sustained virological response at week 12 post treatment. The most common side effects were fatigue, insomnia and anaemia. Two serious adverse events were observed. CONCLUSIONS: Sofosbuvir plus ribavirin combination was associated with a high rate of complete clinical response and a low rate of serious adverse events in HCV-cryoglobulinaemia vasculitis.

Profound symptomatic hypogammaglobulinemia: a rare late complication after rituximab treatment for immune thrombocytopenia. Report of 3 cases and systematic review of the literature.

INTRODUCTION: B-cell depletion with rituximab (RTX) is widely used to treat autoimmune diseases, especially as second-line therapy for immune thrombocytopenia (ITP). The incidence of RTX-induced hypogammaglobulinemia is unknown because of heterogeneous follow-up and confounding factors such as concomitant immunosuppressive treatments in most patients. We describe 3 cases and attempted to determine the incidence of RTX-induced hypogammaglobulinemia by a systematic review of the literature. METHODS: We retrospectively analyzed 189 ITP patients receiving RTX in 3 referral centers in France and conducted a systematic review of 32 studies (results published 2001-2014) reporting the use of RTX for ITP, particularly searching for symptomatic secondary hypogammaglobulinemia. We also searched for case reports of hypogammaglobulinemia after RTX initiation for ITP. RESULTS: Of the 189 patients, 3 showed symptomatic hypogammaglobulinemia more than 2years after RTX infusion (initial immunoglobulin level was normal). All 3 presented recurrent severe infections. In 2, the outcome suggested common variable immunodeficiency. In patient 3, the peripheral blood lacked CD19(+)CD20(+) B cells and the bone-marrow B-cell precursor level was impaired. Among 1245 ITP patients in the literature who received RTX for ITP, gammaglobulin level was monitored before and after RTX initiation for 351 (28%). For 192 (55%), dosages were available and we identified 21 patients with secondary hypogammaglobulinemia, usually not symptomatic, 14 of whom had received concomitant dexamethasone. Finally, we found 4 case reports of ITP and symptomatic hypogammaglobulinemia possibly related to RTX according to the authors. CONCLUSIONS: This large analysis led us to recommend monitoring serum immunoglobulin level before and repeatedly after RTX initiation for ITP. Physicians should be aware of hypogammaglobulinemia as a rare but severe complication of RTX.

Characteristics and outcome of warm autoimmune hemolytic anemia in adults: New insights based on a single-center experience with 60 patients.

Warm autoimmune hemolytic anemia (wAIHA) is a rare autoimmune disease with poorly known natural history and management remaining mainly empirical. To better describe the characteristics and outcome of wAIHA in adults, we performed a single-center cohort study of patients diagnosed with wAIIHA from 2001 to 2012 in our center. Sixty patients (50% women) were included, the mean age at the time of wAIHA onset was 54 ± 23 years. wAIHA was considered "primary" for 21 patients (35%) and was associated with an underlying disorder in 39 (65%), including mainly lymphoproliferative disorders and systemic lupus. All patients but two needed treatment and received corticosteroids, with an overall initial response rate of 87%. However, 63% of the patients were corticosteroid-dependent and 56% required at least one second-line treatment including mainly rituximab (n = 19). At the time of analysis, after a mean follow-up of 46 months, 28 patients (47%) were in remission and off treatment and 5 (8%) had died. The presence of an underlying lymphoproliferative disorder was associated with reduced response to corticosteroids and increased need for second-line therapy. In conclusion, in the last decade and compared to a previous series from our center, the rate of secondary wAIHA has increased and the use of rituximab has emerged as the preferred second-line treatment and corticosteroid-sparing strategy; the overall mortality has significantly decreased (8 vs. 18%).

Hemolytic anemia in adults: main causes and diagnostic procedures.

Hemolytic anemia is not an exceptional situation in adults. Although establishing the hemolytic mechanism of an anemia is usually rather easy, finding the etiology may be quite difficult as both hereditary (corpuscular) and acquired causes of hemolytic anemia may occur during adulthood. The diagnosis of hemolytic anemia, therefore, requires a multistep procedure taking into account both the patient's and family history, a careful analysis of the blood smear and a direct antiglobulin test. Based on these first data, the diagnostic procedure may then require more specific tests whose indications are discussed in this review.

[Hemolytic anemia in adults: Main causes and diagnostic procedure]. / Anémie hémolytique chez l'adulte : principales causes et démarche diagnostique.

Hemolytic anemia (HA) is not an exceptional situation in adults. While establishing the hemolytic mechanism of an anemia is usually rather easy, finding the etiology may be quite difficult as both some hereditary (corpuscular) and acquired causes of HA may occur during adulthood. The diagnosis of HA therefore requires a multiple step procedure taking into account both patient's and family history, a careful analysis of the blood smear and a direct antiglobulin test. Based on these first data, the diagnosis procedure may then require more specific tests whose indications are discussed in this review.