Long-term outcome of kidney function in patients with ANCA-associated vasculitis.

BACKGROUND: Kidney involvement is common in ANCA associated vasculitis (AAV) and prognosis determined by the severity of kidney damage. This study focused on long-term kidney outcomes, defining possible risk factors and comparing the performance of three different histological classifications to predict outcomes for patients with AAV. METHODS: The dataset included 848 patients with newly diagnosed AAV who participated in 7 RCTs (1995-2012). Follow up information obtained from questionnaires sent to the principal investigators of the original RCTs. RESULTS: The cumulative incidence of end-stage kidney disease (ESKD) at 5 and 10 years was 17% and 22%, respectively. Patients who developed ESKD had reduced patient survival compared to those with preserved kidney function (HR: 2.8, P-value < 0.001). Comparing patients with AAV and kidney involvement to a matched general population, patients with AAV had poor survival outcomes, even in early stages of CKD. The main cause of death was infection followed by cardiovascular disease in patients developing ESKD and malignancy in those who did not. 34% of patients with initial need for dialysis recovered kidney function after treatment. 35 out of 175 in need of kidney replacement therapy (KRT) during follow up received a kidney transplant with good outcome; 86% patient survival at 10 years.In the subcohort of 214 patients with available kidney biopsies, three scoring systems were tested: the Berden classification, the Renal Risk Score (RRS), and the Mayo Clinic Score (MCCS). The scores highlighted the importance of normal glomeruli and severe glomerulosclerosis on kidney survival (P < 0.001 and P = 0.001, respectively). The RRS demonstrated a moderate prediction of kidney survival (AUC: 0.79; SE: 0.03, 95% CI: 0.71-0.83). CONCLUSIONS: Early diagnosis is extremely important. Even milder forms of kidney involvement have an impact on the prognosis. Patients in need of KRT had the lowest survival rates, but kidney transplantation has shown favorable outcomes for eligible AAV patients. The three histologic scoring systems were all identified as independent prognostic factors for kidney outcome.

Polyarteritis Nodosa: Old Disease, New Etiologies.

Polyarteritis nodosa (PAN), also known as panarteritis nodosa, represents a form of necrotizing vasculitis that predominantly affects medium-sized vessels, although it is not restricted to them and can also involve smaller vessels. The clinical presentation is heterogeneous and characterized by a significant number of patients exhibiting general symptoms, including asthenia, fever, and unintended weight loss. Although PAN can involve virtually any organ, it preferentially affects the skin, nervous system, and the gastrointestinal tract. Orchitis is a rare but specific manifestation of PAN. The absence of granulomas, glomerulonephritis, and anti-neutrophil cytoplasmic antibodies serves to distinguish PAN from other types of vasculitis. Major complications consist of hemorrhagic and thrombotic events occurring in mesenteric, cardiac, cerebral, and renal systems. Historically, PAN was frequently linked to hepatitis B virus (HBV) infection, but this association has dramatically changed in recent years due to declining HBV prevalence. Current epidemiological research often identifies a connection between PAN and genetic syndromes as well as neoplasia. This article provides a comprehensive review of PAN, specifically focusing on the progression of its clinical manifestations over time.

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.

Eosinophilic Granulomatosis with Polyangiitis after mRNA-1273 SARS-CoV-2 Vaccine.

During one of the worst global health crises, millions of people were vaccinated against SARS-CoV-2. In rare cases, new onset systemic inflammatory diseases were reported with temporal coincidence to the vaccination. We describe a case of severe Eosinophilic Granulomatosis with Polyangiitis (EGPA) in a young asthmatic woman, occurring after a second dose of the mRNA-1273 vaccine. She presented with multisystem EGPA with cardiac and central nervous system involvement, complicated by secondary immune thrombocytopenia (ITP). We review the reported cases of EGPA coinciding with SARS-CoV-2 mRNA vaccination. All potentially vaccine-related EGPA cases reported so far occurred within 14 days from immunization. EGPA is very rare with an incidence of 1:1,000,000 inhabitants, and the number of reported post-vaccination EGPA cases lies within the expected incidence rate for the period. While we cannot prove a causal relationship between the vaccine and EGPA onset, the temporal relationship with the vaccine immune stimulation is intriguing, in a disease occurring almost always in adults with asthma and/or chronic rhinosinusitis and driven by an aberrant Th2 lymphocyte activation with hypereosinophilia; nevertheless, cases of inflammatory diseases (IMIDs) emerging in the context of vaccination remain rare and the benefits of preventing severe COVID presentations with SARS-CoV-2 mRNA vaccines remain unquestionable.

Long-term outcomes and prognostic factors for survival of patients with ANCA-associated vasculitis.

BACKGROUND: Despite newer treatments with immunosuppressive agents, there still exists a considerable morbidity and mortality risk among patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Since 1994 the European Vasculitis Society (EUVAS) has aimed for an improved outcome for patients with AAV, conducting several prospective randomized controlled trials (RCTs). The aim for the present study was to further evaluate the long-term survival of patients with AAV included in seven RCTs conducted by the EUVAS as well as to identify potential prognostic factors. METHODS: Long-term follow-up data were collected from questionnaires sent to the principal investigators of the original RCTs (1995-2012): MEPEX, NORAM, CYCAZAREM, CYCLOPS, IMPROVE, RITUXVAS and MYCYC, comprising 848 patients, all newly diagnosed with AAV. Relative survival estimates are presented for the study cohorts. Demographic, clinical and laboratory characteristics at trial entry were studied as potential prognostic factors in multivariable models. RESULTS: A total of 478 (56%) patients had granulomatosis with polyangiitis (GPA) and 370 (44%) had microscopic polyangiitis (MPA) with a mean age at diagnosis of 58 ± 14 years. The median follow-up time was 8 years (interquartile range 2.9-13.6). During the observation period there were 305 deaths and the main causes were infections (26%), cardiovascular disease (14%) and malignancies (13%). When compared with a matched cohort (regarding country, age group and sex) from the background population there were 14.2% more deaths among our cohort of AAV patients at 5 years, 19.9% at 10 years, 28.8% at 15 years and 36.3% at 20 years. The excess mortality occurred in all age groups. The estimated median survival time (from diagnosis) was 17.8 years (95% confidence interval 15.7-20). Among variables measured at baseline, advanced age, male sex, low estimated glomerular filtration rate and low platelet count were identified as predictors of death in a multivariate Cox model. CONCLUSIONS: Patients with AAV still have an increased risk of mortality compared with the general population despite newer therapeutic regimens. Treatment complications and organ damage are the main causes of limited survival and infections remain the leading cause of mortality among patients with AAV.

Benralizumab for eosinophilic granulomatosis with polyangiitis: a retrospective, multicentre, cohort study.

BACKGROUND: Interleukin-5 (IL-5) inhibitors represent novel therapies for eosinophilic granulomatosis with polyangiitis (EGPA). This study assessed the effectiveness and safety of the IL-5 receptor inhibitor benralizumab in a European cohort of patients with EGPA. METHODS: This retrospective cohort study included patients with EGPA from 28 European referral centres of the European EGPA Study Group across six countries (Italy, France, UK, Russia, Spain, and Switzerland) who received benralizumab as any line of treatment between Jan 1, 2019, and Sep 30, 2022. We assessed the rates of complete response, defined as no disease activity (Birmingham Vasculitis Activity Score [BVAS] of 0) and a prednisone dose of up to 4 mg/day, in contrast to partial response, defined as a BVAS of 0 and a prednisone dose greater than 4 mg/day. Active disease manifestations, pulmonary function, variation in glucocorticoid dose, and safety outcomes were also assessed over a 12-month follow-up. FINDINGS: 121 patients with relapsing-refractory EGPA treated with benralizumab at the dose approved for eosinophilic asthma were included (64 [53%] women and 57 [47%] men; median age at the time of beginning benralizumab treatment 54·1 years [IQR 44·2-62·2]). Complete response was reported in 15 (12·4%, 95% CI 7·1-19·6) of 121 patients at month 3, 25 (28·7%, 19·5-39·4) of 87 patients at month 6, and 32 (46·4%, 34·3-58·8) of 69 patients at month 12; partial response was observed in an additional 43 (35·5%, 27·0-44·8) patients at month 3, 23 (26·4%, 17·6-37·0) at month 6, and 13 (18·8%, 10·4-30·1) at month 12. BVAS dropped from 3·0 (IQR 2·0-8·0) at baseline to 0·0 (0·0-2·0) at months 3 and 6, and to 0·0 (0·0-1·0) at month 12. The proportion of patients with systemic manifestations, active peripheral neurological disease, ear, nose, and throat involvement, and pulmonary involvement decreased, with an improvement in lung function tests. Six patients relapsed after having a complete response. The oral prednisone (or equivalent) dose decreased from 10·0 mg/day (5·0-12·5) at baseline to 5·0 mg/day (3·6-8·5) at month 3 (p<0·01), to 5·0 mg/day (2·5-6·3) at month 6, and to 2·5 mg/day (0·0-5·0) at month 12 (p<0·0001). 19 (16%) of 121 patients had adverse events and 16 (13%) discontinued benralizumab. INTERPRETATION: These data suggest that benralizumab could be an effective treatment for EGPA in real-life clinical practice. Further clinical trials are required to confirm the efficacy of benralizumab in patients with a higher baseline disease activity. FUNDING: None.

[Hypersensitivity reactions to intravenous iron: an allergist' perspective]. / Réactions d'hypersensibilité au fer intraveineux : le point de vue de l'allergologue.

Intravenous iron infusions rarely result in severe hypersensitivity reactions. The primary suspected hypersensitivity mechanism is an abnormal complement activation by non-IgE antibodies to the carbohydrate moieties stabilizing iron formulations. A major risk factor for hypersensitivity reactions is related to the infusion speed. Fishbane-like reactions usually resolve after pausing the infusion, which can be resumed under medical surveillance and at a lower infusion rate. Yet, anaphylactic reactions require emergency first aid and subsequent strict avoidance of intravenous iron. Desensitization protocols can be implemented in selected cases and under strict medical surveillance to reduce the risks of severe reactions upon re-exposure.

L'administration de fer intraveineux (IV) peut rarement se compliquer de réactions d'hypersensibilités sévères, parfois fatales. Le mécanisme supposé est celui d'une activation anormale du complément, possiblement liée à des anticorps non-IgE (immunoglobuline E) dirigés contre les groupements carbohydrates qui stabilisent la formulation de fer. Un débit de perfusion trop rapide est un facteur important de réaction d'hypersensibilité. En effet, les réactions légères se résolvent généralement après mise en pause de la perfusion, qui peut ensuite être reprise à un débit réduit. Les réactions anaphylactiques nécessitent en revanche un traitement d'urgence et une éviction stricte. Le recours à un protocole de désensibilisation sous surveillance médicale étroite permet, dans certaines situations, de limiter le risque de réaction lors d'une réadministration de fer IV.

[Adenosine deaminase 2 deficiency: a disease with multiple presentations]. / Déficit en adénosine désaminase 2 : une maladie aux présentations multiples.

Adenosine deaminase 2 deficiency (DADA2) is a genetic auto- inflammatory disease that most often presents in childhood, but that can also have a late onset in adulthood. It is characterized by vasculitis, mainly of the skin and nervous system most often in the form of a stroke, associated to immunodeficiency and cytopenias. The diagnosis is made by measuring adenosine deaminase 2 (ADA2) enzymatic activity and confirming the presence of mutations in the ADA2 gene by genetic testing. The treatment of choice for the inflammatory phenotype is the early administration of anti-TNFa to avoid the risk of major neurological disabilities. In the case of severe hematological involvement, hematopoietic stem cell transplantation is the only curative treatment currently available.

Le déficit en adénosine désaminase 2 (DADA2) est une maladie génétique auto-inflammatoire qui se manifeste le plus souvent à l'âge pédiatrique mais qui peut également débuter à l'âge adulte. Il se caractérise par une atteinte vasculitique responsable d'altérations cutanées et d'AVC associée à une immunodéficience et des cytopénies. Le diagnostic de DADA2 est posé par le dosage de l'activité de l'adénosine désaminase 2 (ADA2) et la confirmation par un test génétique d'une mutation dans le gène ADA2. Le traitement de choix du phénotype inflammatoire repose sur l'administration précoce d'anti-TNFα pour éviter la survenue d'un handicap neurologique majeur. En cas d'atteinte hématologique sévère, la greffe de cellules souches hématopoïétiques est le seul traitement curatif actuellement disponible.

Long-term outcomes in corticosteroid-refractory Graves' orbitopathy treated with tocilizumab.

BACKGROUND: Up to 20% of patients with moderate to severe Graves' orbitopathy (GO) do not respond to high-dose glucocorticoids (GC). A few studies, including a randomized trial, have demonstrated the efficacy of interleukin-6 (IL-6) blockade with tocilizumab (TCZ) in GC-refractory GO. However, data on predictors of response to TCZ and long-term outcomes are lacking. METHODS: Observational single-center study on ten consecutive patients treated with TCZ for GC-refractory GO, between 2016 and 2020. Median (interquartile range) follow-up was 24 (12-36) months. RESULTS: Inflammation and exophthalmos improved dramatically in all patients within months after starting TCZ. Mean Clinical Activity Score decreased from 4.80 ± 1.13 to 0.70 ± 0.82 points at 6 months (mean change: -4.10 ± 1.52; p < .0001). Proptosis improved from 23.2 ± 2.1 to 20.6 ± 2.0 mm at 6 months (mean change: -2.9 ± 1.4 mm; p < .0001). Diplopia resolved in 7 patients. Thyroid receptor antibodies decreased markedly during TCZ treatment. Baseline serum IL-6 levels did not predict clinical response. TCZ was well-tolerated. During follow-up, 3 patients were diagnosed with cancer (breast cancer in 2 and urothelial cancer in 1). CONCLUSIONS: TCZ was rapidly effective and well-tolerated in our patients with GC-refractory GO. Four patients experienced mild/moderate adverse events as neutropenia, hyperlipidemia, and infections; nearly a third developed cancer during the follow-up. The increased incidence observed could be explained by the high prevalence of smokers, that are at higher risk for Graves' orbitopathy and solid malignancies as breast cancer. Thus, regular cancer screening could be proposed to this vulnerable population receiving high doses of immunosuppressants.

Personalized Cytokine-Directed Therapy With Tocilizumab for Refractory Immune Checkpoint Inhibitor-Related Cholangiohepatitis.

INTRODUCTION: For patients with corticosteroid (CS)-refractory immune checkpoint inhibitor-related cholangiohepatitis (irCH), no consensus exists regarding treatment, and outcomes remain poor. We evaluated the possibility of personalized treatment according to the patient's cytokine profile and the immunohistopathologic assessment of the predominant immune infiltrate type of liver tissue. METHODS: NSCLCs with CS-refractory irCH were analyzed by immunohistochemistry of liver biopsy specimen, serum cytokine panel, and assessment of peripheral blood mononuclear cell immune cell monitoring by mass cytometry. RESULTS: A total of three consecutive patients with irCH were identified. We found a predominant T-cell infiltrate and an interferon-gamma or T helper 1 proinflammatory cytokine profile. Here, we report for the first time that a T-cell-targeted therapy with the interleukin (IL)-6 receptor-neutralizing antibody tocilizumab, which inhibits signaling downstream of interferon-gamma and several other Janus kinase-dependent cytokines, is an effective single cytokine-directed therapy for CS-refractory irCH. Three patients with severe, CS-refractory irCH who were treated with tocilizumab were found to have persistent clinical and biological remission. CONCLUSIONS: Dysregulation of the IL-6/T-cell axis may contribute to the pathogenesis of CS-refractory irCH. Our observations suggest that IL-6 blockade seems to have promise in the treatment of CS-refractory irCH. The results from our three patients need to be confirmed in a larger patient population.

[Allergy to human seminal plasma]. / Allergie au liquide séminal.

Hypersensitivity to human seminal plasma is rare, but probably under-diagnosed. It should be suspected in women with unexplained anaphylaxis, vulvo-vaginitis, pelvic pain and dyspareunia. The diagnosis relies on the clinical presentation, the exclusion of other causes, a positive skin test result to seminal plasma and the detection of IgE directed to allergenic proteins (such as prostate specific antigen). Use of condoms is the best preventive measure. Premedication with antihistamines or anti-inflammatory agents is often unreliable. Some patients may benefit from intra-vaginal or subcutaneous desensitization procedures to seminal plasma, which then require to measures to uphold tolerance. In case of pregnancy wish, artificial insemination or in-vitro fertilization with spermatozoids is an alternative to desensitization.

L'hypersensibilité au liquide séminal (LS) humain est rare, mais probablement sous-diagnostiquée. Il faut l'évoquer devant une anaphylaxie, vulvo-vaginite, douleur pelvienne ou dyspareunie d'origine peu claire. Le diagnostic repose sur l'anamnèse, l'exclusion d'autres causes, les tests cutanés au LS et la recherche d'IgE spécifiques (par exemple contre l'antigène prostatique spécifique). Le traitement dépend de la sévérité du tableau. Le préservatif est un moyen de prévention efficace. La prémédication par antihistaminiques ou anti-inflammatoires est souvent insuffisante. La désensibilisation au LS par voie sous-cutanée ou vaginale peut s'avérer efficace, mais nécessite un maintien de la tolérance. En cas de désir de procréation, le recours à l'insémination ou la fécondation in vitro avec des spermatozoïdes lavés constitue une alternative à la désensibilisation.