key: cord-0922317-mpag80um
authors: Chaparro, María; Garre, Ana; Iborra, Marisa; Sierra, Mónica; Barreiro-de Acosta, Manuel; Fernández-Clotet, Agnés; de Castro, Luisa; Boscá-Watts, Maia; Casanova, María José; López-García, Alicia; Lorente, Rufo; Rodríguez, Cristina; Carbajo, Ana Y; Arroyo, Maria Teresa; Gutiérrez, Ana; Hinojosa, Joaquín; Martínez-Pérez, Teresa; Villoria, Albert; Bermejo, Fernando; Busquets, David; Camps, Blau; Cañete, Fiorella; Manceñido, Noemí; Monfort, David; Navarro-Llavat, Mercè; Pérez-Calle, José Lázaro; Ramos, Laura; Rivero, Montserrat; Angueira, Teresa; Camo, Patricia; Carpio, Daniel; García-de-la-Filia, Irene; González-Muñoza, Carlos; Hernández, Luis; Huguet, José M; Morales, Víctor J; Sicilia, Beatriz; Vega, Pablo; Vera, Isabel; Zabana, Yamile; Nos, Pilar; Suárez Álvarez, Patricia; Calviño-Suarez, Cristina; Ricart, Elena; Hernández, Vicent; Mínguez, Miguel; Márquez, Lucía; Hervías Cruz, Daniel; Rubio Iturria, Saioa; Barrio, Jesús; Gargayo-Puyuelo, Carla; Francés, Rubén; Hinojosa, Esther; del Moral, María; Calvet, Xavier; Algaba, Alicia; Aldeguer, Xavier; Guardiola, Jordi; Mañosa, Miriam; Pajares, Ramón; Piqueras, Marta; García-Bosch, Orlando; Lopez Serrano, Pilar; Castro, Beatriz; Lucendo, Alfredo J; Montoro, Miguel; Castro Ortiz, Elena; Mesonero, Francisco; García-Planella, Esther; Fuentes, David A; Bort, Inmaculada; Delgado-Guillena, Pedro; Arias, Lara; Iglesias, Agueda; Calvo, Marta; Esteve, Maria; Domènech, Eugeni; Gisbert, Javier P
title: Effectiveness and safety of ustekinumab in ulcerative colitis: Real-world evidence from the ENEIDA registry
date: 2021-04-16
journal: J Crohns Colitis
DOI: 10.1093/ecco-jcc/jjab070
sha: f4ef8941505da83b72b4652048fb8671193fc7a9
doc_id: 922317
cord_uid: mpag80um

BACKGROUND: The development program (UNIFI) has shown promising results of ustekinumab in ulcerative colitis (UC) treatment that should be confirmed in clinical practice. AIMS: To evaluate the durability, effectiveness and safety of ustekinumab in UC in real-life. METHODS: Patients included in the prospectively maintained ENEIDA registry who received at least one intravenous dose of ustekinumab due to active UC [Partial Mayo Score (PMS) >2] were included. Clinical activity and effectiveness were defined based on PMS. Short-term response was assessed at week 16. RESULTS: A total of 95 patients were included. At week 16, 53% of patients had response (including 35% of patients in remission). In the multivariate analysis, elevated serum C-reactive protein was the only variable significantly associated with lower likelihood of achieving remission. Remission was achieved in 39% and 33% of patients at weeks 24 and 52, respectively. Thirty-six percent of patients discontinued the treatment with ustekinumab during a median follow-up of 31 weeks. The probability of maintaining ustekinumab treatment was 87% at week 16, 63% at week 56, and 59% at week 72; primary failure was the main reason for ustekinumab discontinuation. No variable was associated with risk of discontinuation. Three patients reported adverse events; one of them had a fatal severe SARS-CoV-2 infection. CONCLUSIONS: Ustekinumab is effective both in the short and the long-term in real-life, even in a highly refractory cohort. Higher inflammatory burden at baseline correlated with lower probability of achieving remission. Safety was consistent with the known profile of ustekinumab.

M a n u s c r i p t M a n u s c r i p t

The UNIFI trial has demonstrated the superiority of ustekinumab over placebo in inducing and maintaining remission in patients with active ulcerative colitis (UC), not only in naïve patients but also in those who failed previous biological agents with a good safety profile 1 .

These promising results should be confirmed in clinical practice, where the experience with ustekinumab in clinical practice, in terms of both effectiveness and safety, is still limited 2,3 .

We performed the present study aiming to evaluate the durability of ustekinumab treatment in UC patients in clinical practice. Our secondary aims were to assess the shortterm response (at week 16) and the long-term effectiveness (at maximum follow-up), to identify predictive factors of response, to describe the schedules of ustekinumab administration in UC in real-life and the need for dose adjustments, and finally, to assess the safety of ustekinumab in clinical practice.

This was an observational multicentre study carried out with data from ENEIDA project 4 .

Patients 18 years of age or older, who received at least one intravenous dose of ustekinumab at least 16 weeks before data analysis due to active UC [Partial Mayo Score (PMS)>2] were included. Patients who received ustekinumab for an indication other than UC while in remission or with a previous colonic resection were excluded. Patients were followed-up until last ustekinumab administration or last visit, whichever came first. Data were remotely monitored to assess data quality. 

The assessment of ustekinumab effectiveness was based on the PMS. For the short-term efficacy analysis, the proportion of patients achieving remission or response after the induction (week 16) was calculated. In the long-term, the proportion of patients in remission and steroid-free remission at weeks 24 and 52 were calculated. Patients who discontinued ustekinumab owing to lack of therapeutic effect, an adverse event or worsening of UC before their last visit were considered as not having achieved the endpoint (remission or response) at subsequent time points, and therefore, they were considered failures. Dose adjustment was considered to be part of the treatment regimen (i.e., not included in treatment failure rules) unless otherwise indicated for dichotomous endpoints (remission vs. no remission at a certain time point).

The statistical analysis is described in Annex 3 in Supplementary Material. At baseline, the proportion of patients with elevated CRP (above the normal range limit) and the proportion of patients with severe endoscopic activity were significantly lower in patients who achieved remission at week 16 than in those who did not achieve remission, (52% vs. 75% p<0.05) and (50 vs. 74%, p<0.05), respectively (table 2). In the multivariate analysis, CRP above the normal range limit at baseline was the only variable associated with lower probability of achieving remission at week 16 [odds ratio (OR)=0.3, 95%CI=0.1-0.7].

A total of 34 patients (36%) discontinued ustekinumab over time; median time of exposure to ustekinumab was 31 weeks (IQR=18-59). The probability of maintaining ustekinumab treatment was 87% at week 16, 63% at week 56, and 59% at week 72 ( Figure   2 ). The reasons for ustekinumab discontinuation were: primary non-response in 21 patients (22%), loss of response in 12 patients (13%) and adverse event in 1 patient (1%). Neither 10 the univariate nor the multivariate analysis found any variable associated with ustekinumab discontinuation. Fifty-three patients were under steroids at baseline, and 35 (66%) were able to stop them.

Of 83 patients who started ustekinumab at least 24 weeks before data analysis, 32 (39%) were in remission at week 24, and 25 (30%) in steroid-free remission. Fifty-four patients started ustekinumab at least 52 weeks before data analysis; at week 52, 18 (33%) of them were in remission, and 17 (32%) in steroid-free remission ( Figure 3 ).

Eighty-one patients started the maintenance phase (at week 16). Thirty patients were in remission at that moment. Three patients (10%) started the maintenance phase with every-12-week schedule, 24 patients (80%) with every-8-weeks schedule, and 3 (10%) with intensified schedule (every-6-weeks or every-4-weeks). Two patients had to interrupt the treatment due to loss of response and one patient due to clinician's choice during follow-up. A total of 9 patients (9.5%) needed to undergo colectomy due to ustekinumab failure.

Median time from ustekinumab start to surgery was 14 weeks (IQR=7.5-18).

Three adverse events were reported in our cohort. A patient developed dry skin and itching probably related with ustekinumab. The symptoms were mild and did not lead to treatment discontinuation. Another patient had pneumonia probably not related to ustekinumab treatment which did not cause treatment discontinuation. Finally, a 54-year-old male with extensive UC and no comorbidities, who had been exposed to ustekinumab for 43 weeks, developed severe SARS-Cov-2 pneumonia and died. At the time of infection, the patient had been treated with ustekinumab 90 mg every-6-weeks for 43 weeks without steroids or immunomodulators, after previously failing infliximab, adalimumab, golimumab, vedolizumab and tofacitinib.

To our knowledge this is the largest study to date providing real-life evidence on the longterm benefit of ustekinumab treatment in UC patients. In our cohort, one-third of patients were able to achieve remission after the induction (week 16), despite being highly refractory patients (80% had failed both anti-TNF agents and vedolizumab, and 30% anti-TNF agents, vedolizumab and tofacitinib). In addition, one third of patients achieved steroid-free remission during follow-up (week 24 and week 52). Our study provides some relevant findings on the long-term real-life effectiveness of ustekinumab treatment in UC. With respect to drug survival, we observed that the proportion of patients maintained under ustekinumab treatment was over 60% at 12 months, being primary failure the main reason for ustekinumab discontinuation. These results are similar to those reported for other drugs in particularly refractory patient populations [5] [6] [7] . We acknowledge that ustekinumab might have been maintained in some patients, despite not reaching clinical remission, as the last medical option to avoid surgery. However, ustekinumab might have exerted some effect even in those patients avoiding colectomy (less than 10% of our patients ended-up undergoing surgery).

Approximately one-third of patients who were in remission at week 16 in our cohort, relapsed during follow-up (median time of exposure to ustekinumab was 31 weeks). Dose A c c e p t e d M a n u s c r i p t Manuscript Doi: 10.1093/ecco-jcc/jjab070 13 was optimized in 4 patients, and 2 of them regained remission. Ustekinumab dose intensification seems to be useful to regain remission in CD patients 8, 9 ; however, data in UC patients are lacking. The role of dose intensification in UC patients losing response to ustekinumab needs to be further studied.

Finally, the potential role of concomitant therapy with immunomodulators is of great interest to optimize the treatment in clinical practice. Evidence from CD studies supports that combo treatment with thiopurines does not increase either the short or the long-term effectiveness of ustekinumab 10 . In our cohort, combo treatment was not associated either with the probability of achieving short-term remission or with the durability of ustekinumab treatment in the long-term.

With respect to the safety profile, our results are consistent with those previously reported for ustekinumab 11 .

In conclusion, ustekinumab is effective in inducing remission in up to one-third of UC patients, even in a highly refractory population. Patients with higher inflammatory burden are less likely to achieve short-term remission. Over 60% of patients maintained ustekinumab treatment at 12 months, suggesting that it also provides benefit in the long-term. The safety profile is similar to the previously described for ustekinumab. 

Ustekinumab as Induction and Maintenance Therapy for Ulcerative Colitis

Effectiveness and safety of ustekinumab induction therapy for 103 patients with ulcerative colitis: a GETAID multicentre real-world cohort study

Clinical outcomes with ustekinumab as rescue treatment in therapy-refractory or therapy-intolerant ulcerative colitis

The ENEIDA registry (Nationwide study on genetic and environmental determinants of inflammatory bowel disease) by GETECCU: Design, monitoring and functions

Tofacitinib in Ulcerative Colitis: Real-world Evidence From the ENEIDA Registry

Short and long-term effectiveness and safety of vedolizumab in inflammatory bowel disease: results from the ENEIDA registry

Use of a third anti-TNF after failure of two previous anti-TNFs in patients with inflammatory bowel disease: is it worth it?

Effectiveness and Safety of Ustekinumab Intensification at 90 mg Every 4 Weeks in Crohn's Disease: A Multicentre Study

Effectiveness of ustekinumab dose escalation in Crohn's disease patients with insufficient response to standard-dose subcutaneous maintenance therapy

No Benefit of Concomitant Immunomodulator Therapy on Efficacy of Biologics That Are Not Tumor Necrosis Factor Antagonists in Patients With Inflammatory Bowel Diseases: A Meta-Analysis

Safety of Ustekinumab in Inflammatory Bowel Disease: Pooled Safety Analysis of Results from Phase 2/3 Studies

Steroids during induction, n (%) 36 (58) 17 (52) n.s

Standard deviation, SD: interquartile range, IQR; C-reactive protein, CRP; tumour necrosis factor

A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t A c c e p t e d M a n u s c r i p t