Activating Killer-Cell Immunoglobulin-Like Receptors Are Associated With the Severity of Coronavirus Disease 2019.

BACKGROUND: Etiopathogenesis of the clinical variability of the coronavirus disease 2019 (COVID-19) remains mostly unknown. In this study, we investigate the role of killer cell immunoglobulin-like receptor (KIR)/human leukocyte antigen class-I (HLA-I) interactions in the susceptibility and severity of COVID-19. METHODS: We performed KIR and HLA-I genotyping and natural killer cell (NKc) receptors immunophenotyping in 201 symptomatic patients and 210 noninfected controls. RESULTS: The NKcs with a distinctive immunophenotype, suggestive of recent activation (KIR2DS4low CD16low CD226low CD56high TIGIThigh NKG2Ahigh), expanded in patients with severe COVID-19. This was associated with a higher frequency of the functional A-telomeric activating KIR2DS4 in severe versus mild and/or moderate patients and controls (83.7%, 55.7% and 36.2%, P < 7.7 × 10-9). In patients with mild and/or moderate infection, HLA-B*15:01 was associated with higher frequencies of activating B-telomeric KIR3DS1 compared with patients with other HLA-B*15 subtypes and noninfected controls (90.9%, 42.9%, and 47.3%; P < .002; Pc = 0.022). This strongly suggests that HLA-B*15:01 specifically presenting severe acute respiratory syndrome coronavirus 2 peptides could form a neoligand interacting with KIR3DS1. Likewise, a putative neoligand for KIR2DS4 could arise from other HLA-I molecules presenting severe acute respiratory syndrome coronavirus 2 peptides expressed on infected an/or activated lung antigen-presenting cells. CONCLUSIONS: Our results support a crucial role of NKcs in the clinical variability of COVID-19 with specific KIR/ligand interactions associated with disease severity.

Infliximab in ulcerative colitis: real-life analysis of factors predicting treatment discontinuation due to lack of response or colectomy: ECIA (ACAD Colitis and Infliximab Study).

OBJECTIVE: To describe clinical practice with infliximab (IFX) in ulcerative colitis (UC); identification of predictive factors for IFX treatment discontinuation due to insufficient response and for colectomy. MATERIAL AND METHODS: Retrospective, multicentric and observational study including every UC IFX-treated patient in 10 Spanish hospitals. Variables analyzed: epidemiological data; variables for poor prognosis; IFX prior treatments; characteristics of the IFX treatment; time from the UC diagnosis to induction with IFX; time from induction to colectomy or until data collection. Predictive and protective factors for IFX discontinuation due to lack of response and for colectomy were analyzed with binary logistic regression and Cox analysis. RESULTS: Follow-up time from induction with IFX to the collection of data or colectomy: 36.7 ± 25.7 months. Prior treatment with immunomodulator medications (IMM): 79%; IFX + immunosuppressant therapy: 77%; discontinuation of IFX: 26%, colectomy 16%. Independent predictive or protective factors for IFX discontinuation: IMM resistance (OR: 2.9, p = 0.022, 95% CI: 1.2-7.2), prior use of leukocytapheresis (OR: 3.3, p = 0.024, 95% CI: 1.1-9.4), IFX + IMM therapy (OR: 0.3, p = 0.022, 95% CI: 0.1-0.9, and HR: 0.4, p = 0.006, 95% CI: 0.2-0.8) and corticosteroid use in induction (HR: 1.9, p = 0.049, 95% CI: 1.0-3.8). Independent predictive or protective factors for colectomy: Use of leukocytapheresis (OR: 3.0, p = 0.036, 95% CI: 1.1-8.4), IFX + IMM therapy (OR: 0.3, p = 0.022, 95% CI: 0.1-0.8, and HR: 0.3, p = 0.011, 95% CI: 0.1-0.8) and severe cortico-resistant flare-up (HR: 2.5, p = 0.032, 95% CI: 1.1-5.9). CONCLUSIONS: Prior use of IMM and leukocytapheresis, the use of corticosteroids in induction and a severe cortico-resistant flare predict a worse response to IFX and the need for colectomy. Combination therapy is a protective factor for both.

Frequency, predictors, and consequences of maintenance infliximab therapy intensification in ulcerative colitis.

INTRODUCTION: Infliximab (IFX) therapy intensification in ulcerative colitis (UC) is more common than established in pivotal studies. OBJECTIVES: To establish the frequency and form of intensification for UC in clinical practice, as well as predictors, and to compare outcomes between intensified and non-intensified treatment. METHODS: A retrospective study of 10 hospitals and 144 patients with response to infliximab (IFX) induction. Predictive variables for intensification were analyzed using a Cox regression analysis. Outcome, loss of response to IFX, and colectomy were compared between intensified and non-intensified therapy. RESULTS: Follow-up time from induction to data collection: 38 months [interquartile range (IQR), 20-62]. Time on IFX therapy: 24 months (IQR, 10-44). In all, 37% of patients required intensification. Interval was shortened for 36 patients, dose was increased for 7, and 10 subjects received both. Concurrent thiopurine immunosuppressants (IMM) and IFX initiation was an independent predictor of intensification [Hazard ratio, 0.034; p, 0.006; CI, 0.003-0.371]. In patients on intensified therapy IFX discontinuation for loss of response (30.4% vs. 10.2%; p, 0.002), steroid reintroduction (35% vs. 18%; p, 0.018), and colectomy (22% vs. 6.4%; p, 0.011) were more common. Of patients on intensification, 17% returned to receiving 5 mg/kg every 8 weeks. CONCLUSIONS: Intensification is common and occasionally reversible. IMM initiation at the time of induction with IFX predictsnon-intensification. Intensification, while effective, is associated with poorer outcome.

Frecuencia, factores predictores y consecuencias de la intensificación del tratamiento de mantenimiento con infliximab en la colitis ulcerosa / Frequency, predictors, and consequences of maintenance infliximab therapy intensification in ulcerative colitis

INTRODUCCIÓN: la intensificación del tratamiento con infliximab (IFX) en la colitis ulcerosa (CU) es más frecuente de lo establecido en estudios pivotales. OBJETIVOS: establecer la frecuencia y forma con la que intensificamos en CU en práctica clínica, los factores predictores y comparar la evolución entre los pacientes con tratamiento intensificado y no intensificado. MÉTODOS: estudio retrospectivo de 10 hospitales y 144 pacientes con respuesta a la inducción con IFX. Se analizaron variables predictoras de la intensificación con análisis de regresión de Cox. Se comparó la evolución, pérdida de respuesta a IFX y colectomía según tratamiento intensificado o no intensificado. RESULTADOS: tiempo de seguimiento desde la inducción hasta la recogida de datos: 38 meses [rango intercuartil (RIC) 20-62]. Tiempo de tratamiento con IFX: 24 meses (RIC, 10-44). El 37% de los pacientes requirió intensificación. Se acortó el intervalo en 36 pacientes, se aumentó la dosis en 7, ambas en 10. La introducción simultánea de inmunosupresores tiopurínicos (INM) e IFX predijo la intensificación de forma independiente [Hazard ratio (HR) 0,034 p 0,006 IC 0,003-0,371]. En los pacientes con tratamiento intensificado fue más frecuente la suspensión de IFX por pérdida de respuesta (30,4% vs. 10,2% p 0,002), la reintroducción de corticoides (35% vs. 18%, p 0,018) y la colectomía (22% vs. 6,4% p 0,011). El 17% de los pacientes intensificados volvió a recibir 5 mg/kg cada 8 semanas. CONCLUSIONES: la intensificación es frecuente y en ocasiones reversible. La introducción del INM en el momento de la inducción con IFX predice la no intensificación. La intensificación, aunque eficaz, se asocia a una peor evolución

INTRODUCTION: Infliximab (IFX) therapy intensification in ulcerative colitis (UC) is more common than established in pivotal studies. OBJECTIVES: To establish the frequency and form of intensification for UC in clinical practice, as well as predictors, and to compare outcomes between intensified and non-intensified treatment. METHODS: A retrospective study of 10 hospitals and 144 patients with response to infliximab (IFX) induction. Predictive variables for intensification were analyzed using a Cox regression analysis. Outcome, loss of response to IFX, and colectomy were compared between intensified and non-intensified therapy. RESULTS: Follow-up time from induction to data collection: 38 months [interquartile range (IQR), 20-62]. Time on IFX therapy: 24 months (IQR, 10-44). In all, 37% of patients required intensification. Interval was shortened for 36 patients, dose was increased for 7, and 10 subjects received both. Concurrent thiopurine immunosuppressants (IMM) and IFX initiation was an independent predictor of intensification [Hazard ratio, 0.034; p, 0.006; CI, 0.003-0.371]. In patients on intensified therapy IFX discontinuation for loss of response (30.4% vs. 10.2%; p, 0.002), steroid reintroduction (35% vs. 18%; p, 0.018), and colectomy (22% vs. 6.4%; p, 0.011) were more common. Of patients on intensification, 17% returned to receiving 5 mg/kg every 8 weeks. CONCLUSIONS: Intensification is common and occasionally reversible. IMM initiation at the time of induction with IFX predicts non-intensification. Intensification, while effective, is associated with poorer outcome