Ustekinumab en la enfermedad de Crohn: resultados en la vida real y posibles factores de respuesta / Ustekinumab in Crohn's disease: real-world outcomes and predictors of response

Antecedentes: ustekinumab es un anticuerpo monoclonal que inhibe las interleucinas IL-12 e IL-23, y está aprobado para el tratamiento de la enfermedad de Crohn (EC) y, más recientemente, también de la colitis ulcerosa (CU). El objetivo de este estudio fue evaluar la eficacia y seguridad de ustekinumab, así como identificar posibles factores predictivos de respuesta en un entorno de la vida real.Métodos: se realizó un estudio observacional, retrospectivo y multicéntrico en 4 hospitales de Andalucía. Se incluyeron pacientes adultos con diagnóstico confirmado de EC tratados con ustekinumab entre 2017 y 2019. Se analizó la respuesta clínica a los 3, 6 y 12 meses de tratamiento. La actividad clínica de la enfermedad se evaluó con el índice de Harvey-Bradshaw (HBI) y el índice de actividad de la enfermedad de Crohn (CDAI); La respuesta bioquímica se evaluó con parámetros de laboratorio como CRP y ESR. Se analizó la supervivencia al fármaco ustekinumab a un año.Resultados: Se analizaron un total de 98 pacientes (edad media, 43 años; el 52 % eran hombres); El 56 % había fracasado con ≥ 2 terapias biológicas previas. A los 3 meses, el 69 % de los pacientes estaban en respuesta y el 40,8 % en remisión. A los 6 meses, el 56 % estaba en remisión clínica. A los 12 meses, el 73,7 % estaba en respuesta clínica y el 60,5 % en remisión. La remisión sin corticosteroides fue del 32,4 %, 44 % y 47,4 % a los 3, 6 y 12 meses, respectivamente. La supervivencia acumulada tras un año de tratamiento con ustekinumab fue del 85,3 %. Los parámetros bioquímicos como CRP y ESR mostraron una disminución estadísticamente significativa entre los niveles de referencia y de control a los 3, 6 y 12 meses. Un HBI más bajo al inicio y el sexo femenino fueron predictores de remisión clínica libre de corticosteroides en un análisis univariante. (AU)

Ustekinumab in Crohn's disease: real-world outcomes and predictors of response.

BACKGROUND: ustekinumab is a monoclonal antibody that inhibits interleukins IL-12 and IL-23, and is approved for the treatment of Crohn's disease (CD) and, more recently, also ulcerative colitis (UC). The aim of this study was to evaluate the effectiveness and safety of ustekinumab, as well as to identify possible predictive factors of response in a real-life setting. METHODS: an observational, retrospective, multicenter study was carried out in 4 hospitals in Andalusia. Adult patients with a confirmed diagnosis of CD treated with ustekinumab from 2017 to 2019 were included. Clinical response was analyzed at 3, 6 and 12 months of treatment. Clinical disease activity was assessed with the Harvey-Bradshaw index (HBI) and the Crohn's Disease Activity Index (CDAI); biochemical response was assessed with lab parameters such as CRP and ESR. One-year ustekinumab drug-survival was analyzed. RESULTS: a total of 98 patients were analyzed (mean age, 43 years; 52 % were male); 56 % had failed with ≥ 2 previous biologicals therapies. At 3 months, 69 % of the patients were in response and 40.8 % in remission. At 6 months, 56 % were in clinical remission. At 12 months, 73.7 % were in clinical response and 60.5 % in remission. Corticosteroid-free remission was 32.4 %, 44 %, and 47.4 % at 3, 6, and 12 months, respectively. Cumulative survival after one year of treatment with ustekinumab was 85.3 %. Biochemical parameters such as CRP and ESR showed a statistically significant decrease between baseline and control levels at 3, 6, and 12 months. A lower HBI at baseline and female sex were predictors of corticosteroid-free clinical remission in a univariate analysis. In the multivariate analysis no variables were found as predictors of corticosteroid-free clinical remission. CONCLUSION: ustekinumab therapy is safe and useful, inducing clinical response in more than 50 % of patients, including patients who failed with other biological therapies.

Debut de colitis ulcerosa en contexto de tratamiento con secukinumab: ¿los anti-IL-17A pueden ser un factor desencadenante para la aparición de la enfermedad inflamatoria intestinal? / The onset of ulcerative colitis during treatment with secukinumab: can anti-IL-17A be a trigger for inflammatory bowel disease?

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Reinducción intravenosa de ustekinumab tras pérdida de respuesta secundaria como estrategia de rescate en la enfermedad de Crohn / Intravenous ustekinumab reinduction as a Crohn's disease rescue strategy following a secondary non-response

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Intravenous ustekinumab reinduction as a Crohn's disease rescue strategy following a secondary non-response.

Secondary non-response to biological treatments tends to occur in a high number of patients who undergo treatment with antiTNF, and it has also been observed in patients treated with vedolizumab or ustekinumab. The initial rescue guideline recommends intensifying the treatment by reducing the interval or increasing maintenance dosage. In the case of ustekinumab, the patients who began this treatment prior to its approval for treatment of Crohn's disease, were given a subcutaneous induction with no defined guideline and a maintenance dosage of 90 mg every eight weeks. Following secondary non-response in these patients, it was proposed that rescue be undertaken via intravenous reinduction adjusted for weight. We present a case of a patient with Crohn's disease with failure to respond to infliximab, adalimumab and vedolizumab who began treatment with ustekinumab prior to official approval. There was non-response at eight months but remission was achieved after reinduction with ustekinumab, adjusted for weight. This rescue guideline could be a cost-effective way to reinduce remission in this group of patients.

The onset of ulcerative colitis during treatment with secukinumab: can anti-IL-17A be a trigger for inflammatory bowel disease?

In recent months, cases of IBD have been reported in the context of treatment with secukinumab, a monoclonal antibody that blocks IL-17A and which is used in the treatment of certain rheumatic disorders. We present a case of a patient with psoriatic arthritis, with a first-degree relative who had suffered ulcerative colitis, who presented with onset ulcerative colitis in the weeks following treatment initiation with this drug.

Switching from reference infliximab to CT-P13 in patients with inflammatory bowel disease: results of a multicenter study after 12 months

Background and aims: infliximab has changed the natural history of inflammatory bowel disease (IBD). The advent of biosimilar treatments such as CT-P13 will hopefully improve the availability of biological therapies. Data with regard to drug switching are currently limited. The objective of the study was to assess the effectiveness and safety of switching from the reference product (RP), infliximab, to CT-P13 in patients with IBD. Methods: this was a multicenter prospective observational study in patients with Crohn's disease (CD) and ulcerative colitis (UC). All patients had switched from infliximab RP (Remicade(R)) to CT-P13 treatment and were followed up for 12 months. The efficacy endpoint was the change in clinical remission assessed at 0 and 12 months, according to the Harvey-Bradshaw score and partial Mayo score for patients with CD and UC, respectively. Adverse events were monitored and recorded throughout the study. Results: a total of 167 patients (116 CD/51 UC) were included; 88.8% (103/116) of patients with CD were in remission at the time of the drug switch and 69.7% were in remission at 12 months. The Harvey-Bradshaw (HB) score significantly changed at 12 months (p = 0.001); 84.3% (43/51) of patients with UC were in remission at the time of the drug switch and 76.7% were in remission at 12 months. No significant changes in the median partial Mayo score (p = 0.87) were observed at 12 months. Serious adverse events related to medication were reported in 12/167 (7.2%) cases. Conclusion: switching from infliximab RP to CT-P13 is safe and effective at 12 months. The loss of efficacy at 12 months was 15.7%

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Switching from reference infliximab to CT-P13 in patients with inflammatory bowel disease: results of a multicenter study after 12 months.

BACKGROUND AND AIMS: infliximab has changed the natural history of inflammatory bowel disease (IBD). The advent of biosimilar treatments such as CT-P13 will hopefully improve the availability of biological therapies. Data with regard to drug switching are currently limited. The objective of the study was to assess the effectiveness and safety of switching from the reference product (RP), infliximab, to CT-P13 in patients with IBD. METHODS: this was a multicenter prospective observational study in patients with Crohn's disease (CD) and ulcerative colitis (UC). All patients had switched from infliximab RP (Remicade®) to CT-P13 treatment and were followed up for 12 months. The efficacy endpoint was the change in clinical remission assessed at 0 and 12 months, according to the Harvey-Bradshaw score and partial Mayo score for patients with CD and UC, respectively. Adverse events were monitored and recorded throughout the study. RESULTS: a total of 167 patients (116 CD/51 UC) were included; 88.8% (103/116) of patients with CD were in remission at the time of the drug switch and 69.7% were in remission at 12 months. The Harvey-Bradshaw (HB) score significantly changed at 12 months (p = 0.001); 84.3% (43/51) of patients with UC were in remission at the time of the drug switch and 76.7% were in remission at 12 months. No significant changes in the median partial Mayo score (p = 0.87) were observed at 12 months. Serious adverse events related to medication were reported in 12/167 (7.2%) cases. CONCLUSION: switching from infliximab RP to CT-P13 is safe and effective at 12 months. The loss of efficacy at 12 months was 15.7%.

Accurate cut-offs for predicting endoscopic activity and mucosal healing in Crohn’s disease with fecal calprotectin

Background: Fecal biomarkers, especially fecal calprotectin, are useful for predicting endoscopic activity in Crohn’s disease; however, the cut-off point remains unclear. The aim of this paper was to analyze whether faecal calprotectin and M2 pyruvate kinase are good tools for generating highly accurate scores for the prediction of the state of endoscopic activity and mucosal healing. Methods: The simple endoscopic score for Crohn’s disease and the Crohn’s disease activity index was calculated for 71 patients diagnosed with Crohn’s. Fecal calprotectin and M2-PK were measured by the enzyme-linked immunosorbent assay test. Results: A fecal calprotectin cut-off concentration of ≥ 170 μg/g (sensitivity 77.6%, specificity 95.5% and likelihood ratio +17.06) predicts a high probability of endoscopic activity, and a fecal calprotectin cut-off of ≤ 71 μg/g (sensitivity 95.9%, specificity 52.3% and likelihood ratio -0.08) predicts a high probability of mucosal healing. Three clinical groups were identified according to the data obtained: endoscopic activity (calprotectin ≥ 170), mucosal healing (calprotectin ≤ 71) and uncertainty (71 > calprotectin < 170), with significant differences in endoscopic values (F = 26.407, p < 0.01). Clinical activity or remission modified the probabilities of presenting endoscopic activity (100% vs 89%) or mucosal healing (75% vs 87%) in the diagnostic scores generated. M2-PK was insufficiently accurate to determine scores. Conclusions: The highly accurate scores for fecal calprotectin provide a useful tool for interpreting the probabilities of presenting endoscopic activity or mucosal healing, and are valuable in the specific clinical context (AU)

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Accurate cut-offs for predicting endoscopic activity and mucosal healing in Crohn's disease with fecal calprotectin.

BACKGROUND: Fecal biomarkers, especially fecal calprotectin, are useful for predicting endoscopic activity in Crohn's disease; however, the cut-off point remains unclear. The aim of this paper was to analyze whether faecal calprotectin and M2 pyruvate kinase are good tools for generating highly accurate scores for the prediction of the state of endoscopic activity and mucosal healing. METHODS: The simple endoscopic score for Crohn's disease and the Crohn's disease activity index was calculated for 71 patients diagnosed with Crohn's. Fecal calprotectin and M2-PK were measured by the enzyme-linked immunosorbent assay test. RESULTS: A fecal calprotectin cut-off concentration of ≥ 170 µg/g (sensitivity 77.6%, specificity 95.5% and likelihood ratio +17.06) predicts a high probability of endoscopic activity, and a fecal calprotectin cut-off of ≤ 71 µg/g (sensitivity 95.9%, specificity 52.3% and likelihood ratio -0.08) predicts a high probability of mucosal healing. Three clinical groups were identified according to the data obtained: endoscopic activity (calprotectin ≥ 170), mucosal healing (calprotectin ≤ 71) and uncertainty (71 > calprotectin < 170), with significant differences in endoscopic values (F = 26.407, p < 0.01). Clinical activity or remission modified the probabilities of presenting endoscopic activity (100% vs 89%) or mucosal healing (75% vs 87%) in the diagnostic scores generated. M2-PK was insufficiently accurate to determine scores. CONCLUSIONS: The highly accurate scores for fecal calprotectin provide a useful tool for interpreting the probabilities of presenting endoscopic activity or mucosal healing, and are valuable in the specific clinical context.

Initial experience with golimumab in clinical practice for ulcerative colitis

Background: Golimumab is a TNF-blocking agent indicated as a second-line therapy in ulcerative colitis. Purpose: To research the effectiveness and safety of golimumab in patients with ulcerative colitis in clinical practice. Methods: Retrospective study of the effectiveness and safety of golimumab in patients with ulcerative colitis. All patients received golimumab 200 mg subcutaneously at week 0, and golimumab 100 mg subcutaneously at week 2. After the induction treatment, each patient received 50 mg sc. every 4 weeks in patients with body weight less than 80 kg, and 100 mg every 4 weeks in patients with body weight greater than or equal to 80 kg. Results: Study of a group of 23 ulcerative colitis patients, 7 of whom were naive to any anti-TNF therapy, and 16 patients who had previously been treated with an anti-TNF agent other than golimumab (non-naive patients). The average treatment time with golimumab was 14.3 weeks. Globally, withdrawal of corticosteroids was observed in 74% of cases. Clinical response was observed in 85.5% of patients who had not received biological treatment previously, and in patients who had previously received biological treatment the response rate was 75%. Conclusions: In this short study, golimumab seems to be an alternative treatment in naive and non-naive anti-TNF ulcerative colitis patients. It is also a safe therapy, given that there were no adverse effects in the patients studied (AU)

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Initial experience with golimumab in clinical practice for ulcerative colitis.

BACKGROUND: Golimumab is a TNF-blocking agent indicated as a second-line therapy in ulcerative colitis. PURPOSE: To research the effectiveness and safety of golimumab in patients with ulcerative colitis in clinical practice. METHODS: Retrospective study of the effectiveness and safety of golimumab in patients with ulcerative colitis. All patients received golimumab 200 mg subcutaneously at week 0, and golimumab 100 mg subcutaneously at week 2. After the induction treatment, each patient received 50 mg sc. every 4 weeks in patients with body weight less than 80 kg, and 100 mg every 4 weeks in patients with body weight greater than or equal to 80 kg. RESULTS: Study of a group of 23 ulcerative colitis patients, 7 of whom were naive to any anti-TNF therapy, and 16 patients who had previously been treated with an anti-TNF agent other than golimumab (non-naive patients). The average treatment time with golimumab was 14.3 weeks. Globally, withdrawal of corticosteroids was observed in 74% of cases. Clinical response was observed in 85.5% of patients who had not received biological treatment previously, and in patients who had previously received biological treatment the response rate was 75%. CONCLUSIONS: In this short study, golimumab seems to be an alternative treatment in naive and non-naive anti-TNF ulcerative colitis patients. It is also a safe therapy, given that there were no adverse effects in the patients studied.

Prevalence of Primary Resistance of Helicobacter pylori to Clarithromycin and Levofloxacin in Southern Spain.

BACKGROUND: The eradication of Helicobacter pylori (HP) using clarithromycin (CLA)-based triple therapy depends on the resistance of HP to antibiotics. The Maastricht III conference recommends the implementation of locoregional surveillance programmes for primary resistance of HP to CLA. In Andalusia, there are no previous data in this respect. The aim of this study was to determine the prevalence of the primary resistance of HP to CLA and levofloxacin (LF) in southern Spain. METHODS: Multicentre cross sectional study was carried out in 6 hospitals in Andalusia. Patients of both sexes numbering 401 were included (male 48%), aged 18-80 years and naïve to HP eradication. Resistance of HP to CLA (CLAr) and LF (LFr) was assessed by determining mutations by PCR: mutations of the 23S rRNA gene define CLAr and mutations of the gene gyrA define LFr. Four hundred one gastric samples were collected. CLAr was detected in 72 patients (17.9%) and LFr was detected in 56 patients (13.9%). Heteroresistance was detected for both antibiotics: CLA 37/72 (51.3%) and LF 28/56 (50%). Variability for CLAr was detected among the centres, ranging from 11.5% to 24.7% without statistical significance (p = 0.12). Female sex was related to CLAr. CONCLUSIONS: In Andalusia, there is a high rate of primary CLAr and LFr. CLA-based triple therapy should be avoided as the primary eradication regimen in this region. There is a wide variability in the rate of CLAr among centres.

Prognosis of Patients with Ulcerative Colitis in Sustained Remission After Thiopurines Withdrawal.

BACKGROUND: The ideal length of treatment with thiopurines in patients with ulcerative colitis (UC) in sustained remission remains unknown. It is widely accepted that the drug withdrawal is associated with a worse outcome. The aim of this study was to analyze the outcome after this withdrawal and to identify predictors of relapse. METHODS: A multicenter and retrospective study was designed. A total of 102 patients with UC who discontinued thiopurines in a situation of sustained remission were included. All the patients were followed up until last revision or until relapse (understood as the occurrence of signs and symptoms of UC that required a rescue treatment). RESULTS: After thiopurines withdrawal, overall relapse was recorded in 32.35% of the patients: 18.88% in the first year, 36.48% in the third, and 43.04% in the fifth year after withdrawal. On multivariate analysis, predictors of relapse were the time from diagnosis of UC until the starting of thiopurines (hazard ratio [HR], 1.01; 95% confidence interval [CI], 1.01-1.02; P = 0.039), the number of relapses before the withdrawal (HR, 1.3; 95% CI, 1.01-1.66; P = 0.029), pancolitis (HR, 5.01; 95% CI, 1.95-26.43; P = 0.028), the duration of treatment with thiopurines (HR, 0.15; 95% CI, 0.03-0.66; P = 0.013) and the situation of biological remission at withdrawal (HR, 0.004; 95% CI, 0.0001-0.14; P = 0.002). CONCLUSIONS: The withdrawal of thiopurines in patients with UC, although in sustained remission, is related to a high relapse rate. Clinical variables such as the extent of the disease, the duration of treatment or time from diagnosis to the start of thiopurines should be considered before stopping these drugs.

Crohn's-like disease in a patient with common variable immunodeficiency treated with azathioprine and adalimumab.

Common variable immunodeficiency (CVID) is the most frequent primary antibody deficiency. It is characterized by recurrent bacterial infections, and occurrence of autoimmune and neoplastic diseases is also frequent; there is also a high prevalence of gastrointestinal diseases. There are reports of inflammatory bowel disease in this entity, but incidence is low (2-4 %). We present the case of a patient with common variable immunodeficiency suffering a chronic diarrhea episode and who was diagnosed with ileocaecal Crohn s-like disease after performing intestinal transit, CT abdomen and colonoscopy with biopsy. It was first treated with prednisone but on showing cortisone dependency, treatment with azathioprine and adalimumab was started, with good results.

Enfermedad de Crohn-like en un paciente con inmunodeficiencia común variable tratada con azatioprina y adalimumab / Crohn’s-like disease in a patient with common variable immunodeficiency treated with azathioprine and adalimumab

La inmunodeficiencia común variable (IDCV) es la deficiencia primaria de anticuerpos más frecuente. Se caracteriza por infecciones bacterianas recurrentes, siendo también habitual la aparición de enfermedades autoinmunes y neoplásicas. Existe una alta prevalencia de enfermedades gastrointestinales. Se han descrito casos de enfermedad inflamatoria intestinal en esta entidad, pero con baja incidencia (2-4 %). Presentamos el caso de un paciente con inmunodeficiencia común variable que presenta un episodio de diarrea crónica, siendo diagnosticado de enfermedad de Crohn-like ileocecal tras realizar tránsito intestinal, TC de abdomen y colonoscopia con toma de biopsias. Se inició tratamiento con prednisona, pero presentó corticodependencia, por lo que se inicio tratamiento con azatioprina y adalimumab, presentando buena respuesta (AU)

Common variable immunodeficiency (CVID) is the most frequent primary antibody deficiency. It is characterized by recurrent bacterial infections, and occurrence of autoimmune and neoplastic diseases is also frequent; there is also a high prevalence of gastrointestinal diseases. There are reports of inflammatory bowel disease in this entity, but incidence is low (2-4 %). We present the case of a patient with common variable immunodeficiency suffering a chronic diar - rhoea episode and who was diagnosed with ileocaecal Crohn s-like disease after performing intestinal transit, CT abdomen and colonoscopy with biopsy. It was first treated with prednisone but on showing cortisone dependency, treatment with azathioprine and adalimumab was started, with good results (AU)