Angioedema due to acquired C1-inhibitor deficiency associated with monoclonal gammopathies of undetermined significance.

BACKGROUND: No specific description of monoclonal gammopathies of undetermined significance (MGUS)-associated angioedema due to acquired C1 inhibitor deficiency (AAE-C1-INH) has been reported yet. OBJECTIVE: Describe the biological and clinical characteristics, evolution and response to treatment of MGUS-associated AAE-C1-INH. MATERIAL AND METHODS: We conducted a French national retrospective observational study on MGUS-associated acquired angioedema spanning a 30-year period. RESULTS: Forty-one patients with MGUS-associated AAE-C1-INH at diagnosis were included; 68% displayed anti-C1INH antibodies. The monoclonal component was an IgM in 24 patients, IgG in 11 and IgA in 6 patients. Mean age at first angioedema attack was 63 years (SD = 13) and at diagnosis 66 years (SD = 11). 88 % of patients benefited from acute attack treatments, and 77% from long-term prophylaxis, either danazol, tranexamic acid or lanadelumab. Median follow-up was 7 years, during which 14 patients (33%) evolved into well-defined malignant hemopathies. 50 % of patients were given a hematological treatment, either rituximab alone, indicated by recurrent attacks of angioedema in patients with AAE-C1-INH with anti-C1-INH antibodies, or validated combinations of chemotherapies, indicated by evolution into a lymphoma in 7 patients and a myeloma in 3 patients. Fifteen patients (35%) were in clinical complete remission of angioedema at last visit, of which 60% had an undetectable serum monoclonal immunoglobulin. CONCLUSION: Complete remission of AAE-C1-INH is correlated to complete remission of the underlying hematological malignancy, as defined by an undetectable serum monoclonal immunoglobulin. In our MGUS-associated acquired angioedema cohort, we recorded an incidence of evolution into hematological malignancy of 4% per patient-year. It is therefore crucial to conduct full hematological workup during follow-up at an annual rate, and earlier if AAE relapses or if acute attacks frequency increases.

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.

Drug-induced meningitis: A review of the literature and comparison with an historical cohort of viral meningitis cases.

BACKGROUND: Drug-induced aseptic meningitis (DIAM) is potentially insufficiently considered by clinician, being of rare etiology, with there being no previously published exhaustive study describing its clinical and biological features. METHODS: Two independent academic clinicians searched all the case reports of DIAM from 1995 until 15th April, 2017. The search was limited to studies performed in humans, published in English or French. Clinical and biological data of subjects were compared with those of patients with documented viral meningitis. RESULTS: One hundred and fifty-one case reports fulfilled our inclusion criteria. Non-steroidal anti-inflammatory drugs were the commonest drug cause of AM n=49, followed by antibiotics n=46, biotherapy n=19 and finally immunomodulators n=15. The clinical and biological presentation of DIAM varies according to the causative etiological drug, especially with respect to the interval between exposure and presentation and cerebrospinal fluid (CSF) pleiocytosis. Clinical symptoms associated with meningitis were more prevalent in viral meningitis than in DIAM, except for fever and signs of encephalitis. Cerebrospinal fluid examination in DIAM reveals an increased CSF white cell count and an increased proportion of neutrophils and protein, compared with viral meningitis. DISCUSSION: We present an extensive review of the DIAM case reports, and highlight their clinical and biological characteristics according to the drugs involved. While comparing for the first time their characteristics with those of viral meningitis, this review hopes in facilitate earlier diagnosis and management of DIAM in clinical practice.

Visceral leishmaniasis in patients with lymphoma: Case reports and review of the literature.

INTRODUCTION: Non-HIV-related visceral leishmaniasis (VL) is becoming increasingly prevalent in nontropical countries because of the increasing number of patients with chronic diseases and the development of immune-modulating drugs. PATIENT CONCERNS: Case 1 is a 60-year-old male patient of Senegalese origin presented with weight loss, lymphadenopathy, anemia, and elevated lactate dehydrogenases. Case 2 is a 46-year-old male patient of Algerian origin, with a negative HIV serology presented with cutaneous lesions. DIAGNOSIS: Patient 1: The diagnosis of stage IV lymphocytic lymphoma (LL) was confirmed by an inguinal nodal biopsy in 2013. Patient 2: The diagnosis of T-cell lymphoma was made in 2003. INTERVENTIONS: Patient 1 received 5 cycles of bendamustine and rituximab followed by a complete remission. Patient 2 was initially treated with >10 different treatments followed by 8 different chemotherapy regimens due to the disease progression. OUTCOMES: Patient 1: In 2017, after a follow-up of 4 years, the patient presented with fever, lymphadenopathy, splenomegaly, and pancytopenia in the setting of hemophagocytic syndrome. The initial diagnosis was a relapse of lymphoma and the patient was treated with ibrutinib. His status worsened, and Leishmania DNA was detected by polymerase chain reaction (PCR) on the blood and bone marrow aspirates. Ibrutinib was stopped. Amphotericin B treatment induced a complete clinical remission and clearance of Leishmania DNA from the blood.Patient 2: In 2017, after a follow-up of 14 years, the patient presented with fever, lymphadenopathy, hepatosplenomegaly, pancytopenia with hemophagocytic syndrome, and an increase in the tumor skin lesions. A skin biopsy was taken from the face and the patient. A careful reexamination of the skin biopsy revealed the presence of Leishmania bodies. He was treated with 40 mg/kg liposomal amphotericin B leading to a regression of the clinical symptoms and negativation of the blood PCR. CONCLUSIONS: This case study shows that VL may be a diagnostic challenge in patients with lymphoma. Reactivation or primary infection should be considered in the differential diagnosis. The purpose of this study is to remind clinicians to think of VL in patients with systemic symptoms that could be misdiagnosed as a progression of the underlying lymphoma.