Efficacy and Safety of Rituximab-Based Treatments in Angioedema With Acquired C1-Inhibitor Deficiency.

BACKGROUND: Angioedema (AE) due to acquired C1-inhibitor (C1-INH) deficiency (AAE-C1-INH) is related to excessive consumption of C1-INH or to anti-C1-INH antibodies, and is frequently associated with lymphoproliferative syndromes or monoclonal gammopathies. Standard of care for prophylactic treatment in this condition is not established. Rituximab may be effective to prevent attacks, especially if the lymphoid hemopathy is controlled, but data are scarce. OBJECTIVE: To evaluate efficacy of rituximab in AAE-C1-INH. METHODS: A retrospective multicenter study was carried out in France, including patients with AAE-C1-INH treated with rituximab between April 2005 and July 2019. RESULTS: Fifty-five patients with AAE-C1-INH were included in the study, and 23 of them had an anti-C1-INH antibody. A lymphoid malignancy was identified in 39 patients, and a monoclonal gammopathy in 9. There was no associated condition in 7 cases. Thirty patients received rituximab alone or in association with chemotherapy (n = 25). Among 51 patients with available follow-up, 34 patients were in clinical remission and 17 patients had active AE after a median follow-up of 3.9 years (interquartile range, 1.5-7.7). Three patients died. The presence of anti-C1-INH antibodies was associated with a lower probability of AE remission (hazard ratio, 0.29 [95% CI, 0.12-0.67]; P = .004). Relapse was less frequent in patients with lymphoma (risk ratio, 0.27 [95% CI, 0.09-0.80]; P = .019) and in patients treated with rituximab and chemotherapy (risk ratio, 0.31 [95% CI, 0.12-0.79]; P = .014). CONCLUSIONS: Rituximab is an efficient and well-tolerated therapeutic option in AE, especially in lymphoid malignancies and in the absence of detectable anti-C1-INH antibodies.

Validation of an anti-α-Gal IgE fluoroenzyme-immunoassay for the screening of patients at risk of severe anaphylaxis to cetuximab.

BACKGROUND: The link between immediate hypersensitivity reactions (HSR) following the first cetuximab infusion and the IgE sensitization against anti-galactose-α-1,3-galactose (α-Gal) is now well-established. An automated Fluoroenzyme-Immunoassay (FEIA) is available and may facilitate the screening of patients with anti-α-Gal IgE before treatment. METHODS: This study aimed to evaluate its performances as compared to a previously validated anti-cetuximab IgE ELISA, using 185 samples from two previously studied cohorts. RESULTS: Despite 21.1% of discrepancies between the two techniques, FEIA discriminated better positive patients and similarly negative ones with a ≥ 0.525 kUA/L threshold. Sensitivity was 87.5% for both tests, specificity was better for FEIA (96.3% vs ELISA: 82.1%). FEIA had a higher positive likelihood ratio (23.9 vs ELISA: 4.89) and a similar negative likelihood ratio (0.13 vs ELISA: 0.15). In our population, the risk of severe HSR following a positive test was higher with FEIA (56.7% vs ELISA: 19.6%) and similar following a negative test (0.7% vs ELISA: 0.8%). CONCLUSION: Although the predictive value of the IgE screening before cetuximab infusion remains discussed, this automated commercial test can identify high-risk patients and is suitable for routine use in laboratories. It could help avoiding cetuximab-induced HSR by a systematic anti-α-Gal IgE screening before treatment.

Long-term prophylaxis in hereditary angioedema management: Current practices in France and unmet needs.

Background: Hereditary angioedema (HAE) is characterized by unpredictable and potentially life-threatening attacks of cutaneous and submucosal swelling. Over the past decade, new agents, based on a better understanding of the underlying biologic mechanisms of HAE, have changed the face of long-term prophylaxis (LTP). Objective: The objective was to describe current practices and unmet needs with regard to LTP for HAE in expert centers in France. Methods: The study was conducted in France in 2020. Based on their experience with patients with HAE who had visited their center at least once in the past 3 years, physicians from 25 centers who are expert in the management of HAE were requested to fill in a questionnaire that encapsulated their active patient list, criteria for prescribing LTP, and medications used. They were asked about potential unmet needs with currently available therapies. They were asked to express their expectations with regard to the future of HAE management. Results: Analysis was restricted to 20 centers that had an active patient file and agreed to participate. There were 714 patients with C1 inhibitor (C1-INH) deficiency, of whom 423 (59.2%) were treated with LTP. Altered quality of life triggered the decision to start LTP, as did the frequency and severity of attacks. Ongoing LTP included androgens (28.4%), progestins (25.8%), lanadelumab (25.3%), tranexamic acid (14.2%), intravenous C1-INHs (5.6%), and recombinant C1-INH (0.7%). Twenty-nine percent of the patents with LTP were considered to still have unmet needs. Physicians' concerns varied among therapies: poor tolerability for androgens and progestins, a lack of efficacy for tranexamic acid and progestins, dosage form, and high costs for C1-INHs and lanadelumab. Physicians' expectations encompassed more-efficacious and better-tolerated medications, easier treatment administration for the sake of improved quality of life of patients, and less-expensive therapies. Conclusion: Despite the recent enrichment of the therapeutic armamentarium for LTP, physicians still expressed unmet needs with currently available therapies.

Impact of pharmacist interventions on clinical outcome and cost avoidance in a university teaching hospital.

Background A significant number of clinical pharmacy services have shown to improve in-hospital medication safety and patient outcome. Prescription review and pharmacist interventions are a fundamental part of hospital clinical pharmacy activities. In a context of restricted financial resources, proving the economic and clinical impact of this activity seems necessary. Objective The aim of this study was to assess the clinical impact on patient outcomes and economic benefit of prescription review by pharmacists. Setting 1624-bed tertiary French university teaching hospital. Method Prospective single center study evaluating prescriptions for which a pharmacist intervention was issued over a 6-month period. The clinical impact of every pharmacist intervention was evaluated by a multidisciplinary experts committee. Economic benefit was evaluated from the public health care system spending standpoint. Main outcome measures Number of avoided hospitalization days and associated public health care system cost-avoidance. Results Prescription review and interventions by pharmacists prevented 73 intensive care unit hospitalization days, 74 continuous monitoring unit hospitalization days and 66 days of conventional hospitalization. €252,294.00 in public health expenditure were thus prevented. For every Euro invested in the prescription review activity, €5.09 of public health spending were potentially saved. Conclusion Our study shows that prescription review and clinical pharmacists' interventions had an impact on clinical outcomes which translated into prevented hospitalization days. Prescription optimization through pharmacist interventions allows significant health care cost savings which makes this service highly efficient.

Oxaliplatin-induced bronchiolitis obliterans organizing pneumonia following hyperthermic intraperitoneal chemotherapy.

Oxaliplatin given systemically is associated with pneumonitis in less than 1% of cases. This case report describes acute respiratory failure, due to bronchiolitis organising pneumonia, in a patient with colorectal carcinoma being treated with hyperthermic intraperitoneal chemotherapy which included oxaliplatin and CPT-11 (irinotecan). The clinical course, the lack of an identifiable infectious agent and the complete response to corticosteroids suggested a drug-induced cause. After ruling out CPT-11, oxaliplatin was considered to be the causal agent. The unusual feature of this case was that pneumonitis developed after intraperitoneal administration of oxaliplatin. Oxaliplatin-associated respiratory complications can occur whatever route the drug is administered.

In Vivo Cysteinyl Leukotriene Release in Allergic and Nonallergic Immediate Hypersensitivity Reactions during Anesthesia.

BACKGROUND: Immediate hypersensitivity reactions occurring during anesthesia are classified as allergic when skin tests and mast cell tryptase are positive and as nonallergic when negative results are obtained. Cysteinyl leukotrienes (cysLTs) are potent mediators synthesized by mast cell and eosinophil that induce bronchial constriction. They could play a role in hypersensitivity reactions. METHODS: cysLT C4, D4, and E4 concentrations were measured by a competition immunoassay in serial plasma samples obtained prospectively from 21 anesthetized controls and retrospectively from 34 patients who reacted at induction of anesthesia (24 with allergic and 10 with nonallergic reactions). RESULTS: In controls, the median (interquartile range) cysLT concentration was 0.83 (0.69 to 1.02) µg/l before anesthesia and was unchanged 30 min, 6 h, and 24 h afterward. In the patients with allergic reactions, the values were highly increased 30 to 60 min after the reaction (17.9 [7.8 to 36.0] µg/l), while the patients with nonallergic reactions had less increased values (7.3 [3.0 to 11.5] µg/l). The difference between the three groups was significant (P < 0.0001). Increased values persisted during the 24 h of observation. Concentrations were significantly higher in patients with bronchospasm (P = 0.016). CONCLUSIONS: cysLTs appear to be an important mediator of allergic and nonallergic immediate hypersensitivity reactions. These findings might open a new field for management of patients with hypersensitivity reactions, especially nonallergic ones.

Diagnosis and treatment of upper airway oedema caused by acute angio-oedema in the emergency department: a French consensus statement.

Angio-oedema is a transitory, localized, noninflammatory oedema of subcutaneous tissue or mucous. When the oedema affects the mouth, lips, tongue or larynx, it can result in fatal asphyxiation in the absence of specific treatment. Oedema secondary to plasma extravasation is usually mediated by either histamine or bradykinin. As laboratory tests are not available in an emergency setting, the implicated mediator cannot be readily determined. The challenge for the emergency physician is to determine the aetiological type, evaluate severity and initiate adapted treatment by means of a structured approach. A team of experts from the French Reference Centre for Angio-oedema reached a consensus for recommendations for the diagnostic and therapeutic strategy to be adopted by emergency departments faced with angio-oedema of the upper airways in adults. The experts defined 11 important questions. Responses were rated using a two-round Delphi methodology. The 11 recommendations were related to triage on admission, a step-by-step diagnostic protocol, definition of attack severity, discouragement of instrumental examination, prioritization of treatment for severe attacks according to clinical signs and anticipation of access to specific treatments by the hospital. Angio-oedema of the upper airways can be fatal and requires anticipation by the emergency department. A search for the aetiology, an evaluation of clinical symptoms and the availability of the treatments are challenges justifying these recommendations.

Giant-cell arteritis without cranial manifestations: Working diagnosis of a distinct disease pattern.

Diagnosis of giant-cell arteritis (GCA) is challenging in the absence of cardinal cranial symptoms/signs. We aimed to describe the clinical presentation, diagnostic process, and disease course of GCA patients without cranial symptoms, and to compare them to those of patients with typical cranial presentation. In this retrospective multicenter study, we enrolled patients with GCA who satisfied at least 3 of the 5 American College of Rheumatology criteria for GCA, or 2 criteria associated with contributory vascular biopsy other than temporal artery biopsy or with demonstration of large-vessel involvement; underwent iconographic evaluation of large arterial vessels (aortic CT scan or a positron emission tomography with F-fluorodeoxyglucose combined with computed tomography (FDG-PET/CT) scan or cardiac echography combined with a large-vessel Doppler) at diagnosis. We divided the cohort into 2 groups, distinguishing between patients without cranial symptoms/signs (i.e., headaches, clinical temporal artery anomaly, jaw claudication, ophthalmologic symptoms) and those with cranial symptoms/signs. In the entire cohort of 143 patients, all of whom underwent vascular biopsy and vascular imaging, we detected 31 (22%) patients with no cranial symptoms/signs. In the latter, diagnosis was biopsy proven in an arterial sample in 23 cases (74% of patients, on a temporal site in 20 cases and on an extratemporal site in 3). One-third of these 31 patients displayed extracranial symptoms/signs whereas the remaining two-thirds presented only with constitutional symptoms and/or inflammatory laboratory test results. Compared to the 112 patients with cardinal cranial clinical symptoms/signs, patients without cranial manifestations displayed lower levels of inflammatory laboratory parameters (C-reactive level: 68 [9-250] mg/L vs 120 [3-120] mg/L; P < 0.01), highest rate of aorta and aortic branch involvement identified (19/31 (61%) vs 42/112 (38%); P = 0.02) and also a lower rate of disease relapse (12/31 (39%) vs 67/112 (60%); P = 0.04). Our results suggest that patients without cranial symptoms/signs are prone to lower inflammatory laboratory parameters, fewer relapses, and more large-vessel involvement than those displaying cardinal cranial manifestations. Further studies are therefore required in order to determine whether these 2 subgroups of patients have a different prognosis, and therefore warrant different therapeutic and monitoring regimens.

18F-fluorodeoxyglucose positron emission tomography and the risk of subsequent aortic complications in giant-cell arteritis: A multicenter cohort of 130 patients.

Previous studies reported a 2- to 17-fold higher risk of aortic complications (dilation or dissection) in patients with giant-cell arteritis (GCA). We aimed to determine whether or not GCA patients with large-vessel involvement demonstrated by positron emission tomography with F-fluorodeoxyglucose combined with computed tomography (FDG-PET/CT) have a higher risk of aortic complications. We conducted a retrospective multicenter study between 1995 and 2014. Patients were included if they fulfilled at least 3 American College of Rheumatology criteria for GCA, or 2 criteria associated with extratemporal biopsy-proven giant-cell vasculitis; they underwent at least 1 FDG-PET/CT scan at diagnosis or during follow-up; and the morphology of the aorta was assessed by medical imaging at diagnosis. Patients with an aortic complication at the time of diagnosis were excluded. Of the 130 patients included [85 women (65%), median age 70 (50-86)], GCA was biopsy proven in 77 (59%). FDG-PET/CT was performed at diagnosis in 63 (48%) patients and during the follow-up period in the 67 (52%) remaining patients. FDG-PET/CT was positive in 38/63 (60%) patients at diagnosis and in 31/67 (46%) patients when performed during follow-up (P = NS). One hundred four patients (80%) underwent at least 1 morphological assessment of the aorta during follow-up. Nine (9%) patients developed aortic complications (dilation in all and dissection in 1) at a median time of 33 (6-129) months after diagnosis. All of them displayed large-vessel inflammation on previous FDG-PET/CT. A positive FDG-PET/CT was significantly associated with a higher risk of aortic complications (P = 0.004).In our study, a positive FDG-PET/CT was associated with an increased risk of aortic complications at 5 years.

Bradykinin-mediated angioedema: factors associated with admission to an intensive care unit, a multicenter study.

OBJECTIVE: Bradykinin-mediated angioedema is characterized by transient attacks of localized edema of subcutaneous or submucosal tissues and can be life-threatening when involving the upper airways. The aim of this study was to determine the features of acute attacks that might be associated with admission to an ICU. PATIENTS AND METHODS: We carried out a retrospective, multicenter, observational study in consecutive patients attending one of six reference centers in France for acute bradykinin-mediated angioedema attacks. Patients had been hospitalized for an acute episode at least once previously. Acute attacks requiring ICU admission were compared with acute attacks that had not required ICU admission. RESULTS: Overall, 118 acute attacks in 31 patients were analyzed (10 patients with hereditary angioedema, 19 patients with angiotensin-converting enzyme inhibitor-induced angioedema, and two patients with acquired C1-inhibitor deficiency angioedema). In multivariate analysis, upper airway involvement, corticosteroid, and C1-inhibitor concentrate administration were associated with ICU admission. Seven episodes (18%) needed airway protection. The evolution was favorable in 38 of 39 attacks warranting ICU admission: patients were able to get out of the service (mean ICU stay 4±5 days). One death was observed by asphyxiation because of laryngeal swelling. CONCLUSION: Upper airway involvement is an independent risk factor for ICU admission. Corticosteroid use, which is an ineffective treatment, and C1-inhibitor concentrate use are factors for ICU admission. The presence of upper airway involvement should be a warning signal that the attack may be severe.

Intravenous Immunoglobulin as an Immunomodulating Agent in Antineutrophil Cytoplasmic Antibody-Associated Vasculitides: A French Nationwide Study of Ninety-Two Patients.

OBJECTIVE: Intravenous immunoglobulin (IVIG) represents a therapeutic alternative in antineutrophil cytoplasmic antibody-associated vasculitides (AAV), but its efficacy has been evaluated in only 2 small prospective trials. The aim of this study was to evaluate the efficacy and safety of IVIG in patients with AAV. METHODS: We conducted a nationwide retrospective study of patients who received IVIG as immunomodulatory therapy for AAV. RESULTS: A total of 92 patients (mean age 51 years) presenting with either granulomatosis with polyangiitis (Wegener's) (68%), eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (22%), or microscopic polyangiitis (10%) received at least 1 course of IVIG. Antineutrophil cytoplasmic antibodies were present in 72% during the flare that required IVIG, as determined by immunofluorescence assay. IVIG was initiated because of relapsing disease in 83% of cases. IVIG was given for a median of 6 months (range 1-156 months) and in combination with corticosteroids in 21% of the patients or with other immunosuppressive agents in 77%. Efficacy of IVIG was assessed in the entire population and in a subset of 34 patients with unmodified background therapy. Remission rates at 6 months were 56% in the entire population and 58% in the unmodified background therapy group. Refractory disease and treatment failure at 6 months were observed in 7% and 18% in the whole population and 3% and 21% in the unmodified background therapy group, respectively. Adverse events (AEs) occurred in 33%, including serious AEs in 12% and AEs leading to discontinuation of IVIG in 7%. CONCLUSION: This large study shows the clinical benefit of IVIG as adjunctive therapy, with an acceptable tolerance profile, and thus supports its use in AAV patients with refractory or relapsing disease.

Is there a place for cyclophosphamide in the treatment of giant-cell arteritis? A case series and systematic review.

OBJECTIVE: To report on the effectiveness of cyclophosphamide (CYC) to treat glucocorticoid (GC)-dependent giant-cell arteritis (GCA) and/or severe GC-related side effects. METHODS: Fifteen patients with GCA and treated with CYC were retrieved from the computerized patient-record system. Glucocorticoid dependence was defined as a prednisone dose of >20mg/day for 6 months or >10mg/day for 1 year in order not to relapse. Response to CYC was defined as improved clinical and biological findings. Remission was defined as a sustained absence (>12 months) of active signs of vasculitis at a daily GC dose of <7.5mg. A literature review searched PubMed for all patients diagnosed with GCA and who received CYC. RESULTS: Our 15 patients responded to monthly pulses of CYC, and all experienced a GC-sparing effect, including five patients who discontinued GC long term. At a median follow-up of 43 (range: 14-75) months after CYC, nine (53%) patients were still in remission and six (40%) had relapsed at 6 (3-36) months after the last CYC infusion. Twelve (80%) patients experienced side effects, leading to discontinuation of CYC in two (13%). A literature review retrieved 88 patients who received CYC: 66 for GC-dependent disease, 53 for GC toxicity, and 14 for severe organ involvement. Their median follow-up time was 24 (4-60) months. Among the 88 patients, 74 (84%) were responsive to CYC and 17 (19%) relapsed, although all were receiving a maintenance therapy with immunosuppressive agents (such as methotrexate). Twenty-nine (33%) patients experienced side effects and 11 (12.5%) discontinued treatment. CONCLUSION: Cyclophosphamide is an interesting option for GCA patients with GC-dependent disease or with severe GC-related side effects, especially when conventional immunosuppressive agents have failed.

Acquired C1-inhibitor deficiency: 7 patients treated with rituximab.

BACKGROUND: Acquired C1-inhibitor deficiency can occur secondary to excessive C1-inhibitor consumption (type I) and be associated with a lymphoid hemopathy, or linked to the presence of anti-C1-inhibitor autoantibodies (type II) in a context of an isolated monoclonal gammopathy, sometimes associated with lymphoproliferation. Efficacy of danazol, tranexamic acid and/or corticosteroids is inconstant. Rituximab efficacy against type II angioedema has been reported. METHODS: Description of 7 rituximab-treated patients, 6 with type II acquired angioedema and 1 with type I. RESULTS: Clinical efficacy (only for type II) was complete for 3, partial for 2 and 2 were therapeutic failures. Only 2 patients had improved biological parameters, with normalization of their C1-inhibitor levels and diminished anti-C1-inhibitor autoantibodies, observed 1-9 months after the last infusion of the second rituximab cycle. An associated lymphoproliferation did not affect the response to treatment. CONCLUSION: Rituximab efficacy in the treatment of acquired angioedema is inconstant and might require repeated cycles.

Early 2'-deoxy-2'-[18F]fluoro-D-glucose PET metabolic response after corticosteroid therapy to differentiate cancer from sarcoidosis and sarcoid-like lesions.

PURPOSE: We aimed at investigating whether early metabolic response to corticosteroid therapy may be used as a diagnostic tool to discriminate between cancer and sarcoidosis, a well-known cause of false-positive 2-deoxy-2-[F-18]fluoro-D: -glucose-positron emission tomography (FDG-PET) findings in oncology. PROCEDURE: Two cancer patients with biopsy-proven sarcoidosis or sarcoid-like reaction had multiple thoracic FDG foci. After infectious disease had been excluded, patients received oral corticosteroids for 16 and 14 days, respectively, and underwent posttherapeutic FDG-PET examination. RESULTS: Posttreatment PET revealed a complete metabolic response in both patients, and clinical and imaging follow-up showed no sign of cancer progression. CONCLUSION: Early metabolic response to systemic corticosteroid treatment may be used as a tool in the establishment of final diagnosis when sarcoidosis is suspected in a cancer patient and could be capable of differentiating cancer from sarcoidosis in the case of coexisting diseases.

Anti-thyroperoxidase antibodies from patients with Hashimoto's encephalopathy bind to cerebellar astrocytes.

A cohort of 10 Hashimoto's encephalopathy (HE) patients, 33 patients with unrelated neurological symptoms, 12 Hashimoto's thyroiditis patients and 4 healthy adult donors was studied to explore the neurological targets of anti-thyroperoxidase (TPO) autoantibodies (aAb) in HE. High levels of anti-TPO aAb were only detected in HE group's cerebrospinal fluids. In immunofluorescence assays on monkey brain cerebellum sections, both HE patients' sera and anti-TPO monoclonal antibodies (mAb) were able to bind cerebellar cells expressing glial fibrillary acid protein. Normal human astrocytes from primary cultures also reacted with anti-TPO mAb. Specific astrocyte binding of anti-TPO aAb suggests a role of these aAb in the HE pathogenesis.