Inflammatory bowel disease BMJ Open Gastroenterol: first published as 10.1136/bmjgast-2019-000351 on 26 March 2020. Downloaded from http://bmjopengastro.bmj.com/ on October 27, 2023 at Univesity Impact of comorbidities on anti-­TNFα response and relapse in patients with inflammatory bowel disease: the VERNE study Ignacio Marin-­Jimenez ‍ ‍ ,1,2 Guillermo Bastida,3 Ana Forés,4 Esther Garcia-­Planella,5 Federico Argüelles-­Arias,6 Pilar Sarasa,7 Ignacio Tagarro,7 Alonso Fernández-­Nistal,7 Carmen Montoto,7 Mariam Aguas,3 Javier Santos-­Fernández,8 Marta Maia Bosca-­Watts,9 Rocio Ferreiro,10 Olga Merino,11 Xavier Aldeguer,12 Xavier Cortés,13 Beatriz Sicilia,14 Francisco Mesonero,15 Manuel Barreiro-­de Acosta16 To cite: Marin-­Jimenez I, Abstract Autonomous of Barcelona. Protected by copyright. Bastida G, Forés A, et al. Impact Summary box Objective To evaluate the impact of comorbidities and of comorbidities on anti-­ extraintestinal manifestations of inflammatory bowel TNFα response and relapse What is already known about this subject? in patients with inflammatory disease on the response of patients with inflammatory ►► Different real-­life studies have investigated factors bowel disease: the VERNE bowel disease to antitumour necrosis factor alpha (anti-­ that might predict response to antitumour necrosis study. BMJ Open Gastro TNFα) therapy. factor alpha (anti-­TNFα) drugs in patients with in- 2020;7:e000351. doi:10.1136/ Design Data from 310 patients (194 with Crohn’s flammatory bowel disease (IBD); however, none has bmjgast-2019-000351 disease and 116 with ulcerative colitis) treated specifically addressed the impact of comorbidities consecutively with the first anti-­TNFα in 24 Spanish and extraintestinal manifestation (EIM) profile on the Received 24 October 2019 hospitals were retrospectively analysed. Univariate and response to these therapies. Revised 13 January 2020 Accepted 19 January 2020 multivariate logistic regression analyses were performed to assess the associations between inflammatory bowel What are the new findings? ►► To the best of our knowledge, this is the first study to disease comorbidities and extraintestinal manifestations assess the association between comorbidities and with anti-­TNFα treatment outcomes. Key clinical EIM profile of patients with IBD and the response to features, such as type of inflammatory bowel disease and the first treatment with an anti-­TNFα. concomitant treatments, were included as fixed factors in the model. How might it impact on clinical practice in the Results Multivariate logistic regression analyses (OR, foreseeable future? 95% CI) showed that chronic obstructive pulmonary ►► These results may be useful in selecting those pa- disease (2.67, 1.33 to 5.35) and hepato-­pancreato-­biliary tients who most likely can benefit from anti-­TNFα diseases (1.87, 1.48 to 2.36) were significantly associated therapies. with primary non-­response to anti-­TNFα, as was the use ►► Specifically, the results suggest that chronic ob- of corticosteroids and the type of inflammatory bowel structive pulmonary disease, myocardial infarction, disease (ulcerative colitis vs Crohn’s disease). It was hepato-­pancreato-­biliary conditions and skin dis- also found that myocardial infarction (3.30, 1.48 to 7.35) eases may have a negative influence on anti-­TNFα and skin disease (2.73, 1.42 to 5.25) were significantly treatment outcomes. associated with loss of response, along with the use of corticosteroids and the type of inflammatory bowel disease (ulcerative colitis vs Crohn’s disease). Introduction © Author(s) (or their Conclusions Our results suggest that the presence of Inflammatory bowel disease (IBD) describes employer(s)) 2020. Re-­use some comorbidities in patients with inflammatory bowel a group of chronic, progressive disorders that permitted under CC BY-­NC. No disease, such as chronic obstructive pulmonary disease commercial re-­use. See rights predominantly affect the bowel. Although the and permissions. Published and myocardial infarction, and of certain extraintestinal pathophysiology is not fully known, it seems by BMJ. manifestations of inflammatory bowel disease, such as that environmental factors and an abnormal hepato-­pancreato-­biliary conditions and skin diseases, For numbered affiliations see immune response to enteric microbes play a end of article. appear to be related to failure to anti-­TNFα treatment. role in individuals with a genetic predispo- Therefore, their presence should be considered when Correspondence to sition.1 Crohn’s disease (CD) and ulcerative choosing a treatment. Dr Ignacio Marin-­Jimenez; colitis (UC) are the two main forms of IBD. Trial registration number NCT02861118. ​drnachomarin@​hotmail.​com The disease often has an onset during young Marin-­Jimenez I, et al. BMJ Open Gastro 2020;7:e000351. doi:10.1136/bmjgast-2019-000351 1 Open access BMJ Open Gastroenterol: first published as 10.1136/bmjgast-2019-000351 on 26 March 2020. Downloaded from http://bmjopengastro.bmj.com/ on October 27, 2023 at Univesity adulthood and a course characterised by remission and comorbidities was described, and the comorbidity profile relapse phases.2 The progressive organ damage results in at each level of IBD severity was determined. a negative impact on the patient’s health-­related quality of life (HRQoL) and in a major economic burden for both society and health services.3–7 Methods The Spanish incidence of IBD seems to have increased Study population in recent years, similarly to other countries,8 9 and ranges This study was a retrospective, non-­interventional, obser- between 8 and 11 cases per 100 000 inhabitants per vational, multicentre study involving 24 gastroenterology year.10–12 sites from Spain. The study included patients diagnosed IBD has been frequently associated with comorbidities with UC or CD who started their first anti-­TNFα between that, although not having a direct relationship with bowel June 2011 and June 2013. To minimise selection bias, inflammation, can modify the course and management patients were recruited consecutively. outcomes of the disease.13 The prevalence of comorbidi- Patients had to be diagnosed with UC or CD according ties in patients with IBD ranges between 30% and 70%.14–16 to the ‘World Gastroenterology Organization Practice The presence of comorbidities in patients with IBD has Guidelines for the Diagnosis and Management of IBD been shown to negatively affect patients’ HRQoL,16 and in 2010’.31 All patients must have been prescribed anti-­ importantly to prolong their length of hospital stay and TNFα treatment according to daily clinical practice and increase the risk of postsurgical mortality. Furthermore, have given written informed consent. immune-­ mediated inflammatory disorders associated Investigators collected data from medical charts, with IBD have been proven to incur higher healthcare including sociodemographic information (age, gender, costs.14 race, level of education, smoking habits and alcohol Autonomous of Barcelona. Protected by copyright. In addition, up to 50% of patients with IBD may intake) and clinical information (concomitant diseases, develop extraintestinal manifestations (EIMs) of the EIM of IBD, date of diagnosis, previous treatments, disease,17 involving multiple organ systems throughout current treatments, disease activity when starting treat- the body,17 18 and sometimes being even more debili- ment with anti-­ TNFα). When data were not properly tating than the intestinal disease itself.19 recorded in the medical charts, particularly demographic In recent decades, the objective of IBD treatment information, they were obtained directly from patients has evolved from a symptomatic relief to symptom- during a routine visit. atic and endoscopic deep remission.20 21 Conventional treatment with corticosteroids and immunosuppres- Clinical outcome evaluation sants has not been able to reduce the complications Disease activity at the beginning of the reference period of the disease or modify its course.22–24 Over the last and at the study visit was assessed through the following two decades, biologic treatments have been success- variables: (1) for patients with UC, the Partial Mayo Score fully used in patients with moderate to severe CD and (PMS)32 for general disease activity, disease anatomical UC who failed to respond to corticosteroids.25 Early extent, and endoscopy findings; (2) for patients with introduction of biologic agents in patients with more CD, the Harvey-­ Bradshaw Index (HBI)33 for general serious disease is probably the most widely accepted disease activity, disease behaviour, and disease location; management strategy.22–25 Antitumour necrosis factor and (3) for patients with UC and CD, stool frequency, alpha (anti-­TNFα) monoclonal antibodies, such as rectal bleeding, urgency, nocturnal stools, need for infliximab and adalimumab, have been rather effec- antidiarrhoeal drugs, constipation, abdominal tender- tive in inducing and maintaining mucosal healing and ness, abdominal pain or cramping, anorexia, nausea, reducing surgery and hospitalisation rates for over 15 vomiting, fever, appetite loss, weight loss, fatigue, night years. Nonetheless, since anti-­ TNFα therapy failures sweats, stunted growth, primary amenorrhoea, general are not uncommon,26 27 many studies have investigated well-­ being, physician’s global assessment, and other patient-­related, disease-­related and treatment-­related complications. factors predicting response to anti-­ TNFα agents in The reference period of the study was defined as the IBD. They have found associations among the response interval between the start of anti-­TNFα until either the to anti-­TNFα medications and disease duration, study visit or lack or loss of treatment response or until biomarker levels, genetic polymorphisms and immu- treatment discontinuation. To assess the main outcome, nopharmacological factors.27–30 However, there have non-­responders were defined as those patients not not been studies conducted to determine the impact of achieving either a reduction in HBI of at least two points comorbidities on anti-­TNFα treatment response. from baseline for CD,32 or a decrease in PMS of at least The primary objective of this study was to evaluate the two points for UC.33 In the cases where these indexes were impact of the comorbidity profile of patients with IBD not available, clinical response was evaluated according on treatment response to the first anti-­TNFα therapy. to physician criteria as recorded in medical charts. In Secondarily, the impact of the EIM profile in patients both cases, response was assessed after induction treat- with IBD on treatment response to the first anti-­TNFα was ment (10 weeks after starting anti-­ TNFα) and after assessed, the percentage of patients with IBD exhibiting maintenance treatment (at least 6 months after starting 2 Marin-­Jimenez I, et al. BMJ Open Gastro 2020;7:e000351. doi:10.1136/bmjgast-2019-000351 Open access BMJ Open Gastroenterol: first published as 10.1136/bmjgast-2019-000351 on 26 March 2020. Downloaded from http://bmjopengastro.bmj.com/ on October 27, 2023 at Univesity groups or categories and categorical variables, and with Table 1 Charlson index χ2 tests or Fisher’s exact tests when comparing categorical Comorbidity Weighted index variables. Myocardial infarction 1 To analyse the factors associated with PNR or LOR, a Congestive heart failure 1 univariate analysis was performed including the sociode- Peripheral vascular disease 1 mographic variables, comorbidities, EIM, and other clin- ical variables as factors. Afterwards, a stepwise (backward Cerebrovascular disease 1 and forward) multiple logistic regression analysis was Dementia 1 performed using as the dependent variable either PNR Chronic obstructive pulmonary 1 or LOR and as independent variables those considered disease potential factors in the univariate analysis (p<0.100). Connective tissue disease 1 In addition, given the potential relevance of the type of Peptic ulcer disease 1 IBD (CD or UC) and of concomitant treatments on the response to anti-­TNFα medications, the type of IBD and Diabetes mellitus 1 (mild), 2 (moderate to severe) the concomitant administration of immunosuppressants and corticosteroids were included as fixed factors in the Chronic renal disease 2 (moderate to severe) models. Hemiplegia 2 An additional analysis to evaluate the impact of the Leukaemia 2 EIM profile on treatment response to the first anti-­TNFα Lymphoma 2 therapy was conducted. It was based on two stepwise multiple logistic regression analyses with PNR or LOR Autonomous of Barcelona. Protected by copyright. Solid tumour 2 (tumour), 6 (metastatic) as dependent variables and all EIMs (arthropathy and Liver disease 1 (mild), 3 (moderate to arthritis, metabolic bone disease, eye disease, oral, aural severe) and nasal disease, skin disease, hepato-­pancreato-­biliary AIDS 6 disease, neurological disease, and cardiovascular, pulmo- nary and genitourinary manifestations) as independent anti-­TNFα). Primary non-­response (PNR) was defined as variables. Again, type of IBD, treatment with immuno- lack of response after induction treatment (weeks 0–10). suppressants, and treatment with corticosteroids were Loss of response (LOR) was defined as loss of the effect included as fixed factors in the models. of the drug along the follow-­up in a patient with an initial Additionally, we analysed the associations among response.34 Reasons to stop the drug were classified as comorbidities and IBD severity at baseline. Patients were PNR, LOR, side effect, remission or other.34 categorised as having a severe disease if HBI was >16 or IBD comorbidities in patients with UC and CD (defined PMS was 8–9. We performed a univariate analysis consid- as the coexistence of another medical condition along- ering severity as the dependent variable and type of side IBD that did not imply causation) at the time of diag- IBD and comorbidities as independent variables. After- nosis and at the study visit were listed according to the wards, a stepwise multiple logistic regression analysis was Charlson index35 (table 1). EIMs in patients with UC and performed using non-­severe disease as the dependent CD were chosen from a list from the European Crohn’s variable and as independent variables those that were and Colitis Organisation guidelines.18 significant at p<0.10 in the univariate analysis. All data analyses were performed using IBM SPSS Statistical analysis Statistics V.22.0 Statistical Package for Windows. With an estimated 50% of non-­responders to the first anti-­ TNFα treatment and considering a minimum sample of 10 patients who presented with the event of interest per Results independent variable included in the logistic regression Patient characteristics model and a maximum of 10 independent variables per A total of 357 patients with IBD were included in this model, a sample of 200 patients with UC and 200 patients study. Forty-­seven patients were eventually excluded from with CD were estimated. the analysis due to screening failure. Of the 310 anal- All patients participating in the study who fulfilled the ysed patients, 194 were diagnosed with CD and 116 were inclusion criteria and did not have a major deviation from diagnosed with UC. Subjects’ characteristics are shown the study protocol were included in the final analysis. in table 2. The mean age (SD) at the time of anti-­TNFα Continuous variables were described as the number of treatment initiation was 38.8 (12.7) years for CD and patients with valid/missing observations, mean, and SD, 41.8 (13.3) years for UC. Men comprised 53.5% of the or the median and IQR if required. Categorical variables whole analysed population. There was a higher preva- were described by absolute and relative frequencies. lence of non-­smokers among patients with UC (60.3%) Pairwise comparisons were performed by t-­tests, Mann-­ compared with patients with CD (44.3%). Likewise, Whitney tests, analyses of variance or Kruskal-­Wallis tests there was a higher prevalence of ex-­smokers in the UC when comparing quantitative variables between study subpopulation (32.0%) compared with patients with CD Marin-­Jimenez I, et al. BMJ Open Gastro 2020;7:e000351. doi:10.1136/bmjgast-2019-000351 3 Open access BMJ Open Gastroenterol: first published as 10.1136/bmjgast-2019-000351 on 26 March 2020. Downloaded from http://bmjopengastro.bmj.com/ on October 27, 2023 at Univesity Table 2 Demographics and clinical characteristics CD UC Total n % n % n % Gender  Male 103 53.10 63 54.30 166 53.50  Female 90 46.40 47 40.50 137 44.20  Not available 1 0.50 6 5.20 7 2.30  Total 194 100 116 100 310 100 Ethnicity  Caucasian 189 97.50 108 93 297 95.80  Latin 3 1.50 1 0.90 4 1.30  Gypsy 1 0.50 0 0 1 0.30  Arab 0 0 1 0.90 1 0.30  Not available 1 0.50 6 5.20 7 2.30  Total 194 100 116 100 310 100 Working status  Employed by self 115 59.30 51 44 166 53.50 Autonomous of Barcelona. Protected by copyright.  Self-­employed 15 7.70 17 14.50 32 10.30  Retired 16 8.20 16 13.80 32 10.30  Housework 12 6.20 11 9.50 23 7.50  Unemployed 17 8.80 4 3.40 21 6.80  Student 6 3.10 6 5.20 12 3.90  Permanently unable to work 6 3.10 3 2.60 9 2.90  Temporarily unable to work 4 2.10 1 0.90 5 1.60  Other 1 0.50 1 0.90 2 0.60  Not available 2 1 6 5.20 8 2.60  Total 194 100 116 100 310 100 Level of education  Secondary education 101 52.10 46 39.60 147 48.50  Primary education 45 23.20 30 25.90 75 24.50  University education 42 21.60 32 27.60 74 24.30  Uneducated 4 2.10 2 1.70 6 1.90  Not available 2 1 6 5.20 8 2.70  Total 194 100 116 100 310 100 Smoking habits  Non-­smoker 86 44.30 70 60.30 156 50.30  Ex-­smoker 52 26.80 37 32 89 28.70  Smoker 55 28.40 7 6 62 20  Not available 1 0.50 2 1.70 3 1  Total 194 100 116 100 310 100 Alcohol abuse  No 189 97.40 114 98.30 303 97.70  Yes 4 2.10 0 0 4 1.30  Not available 1 0.50 2 1.70 3 1  Total 194 100 116 100 310 100 Continued 4 Marin-­Jimenez I, et al. BMJ Open Gastro 2020;7:e000351. doi:10.1136/bmjgast-2019-000351 Open access BMJ Open Gastroenterol: first published as 10.1136/bmjgast-2019-000351 on 26 March 2020. Downloaded from http://bmjopengastro.bmj.com/ on October 27, 2023 at Univesity Table 2 Continued 25th 75th n Mean Median SD percentile percentile Age at signed informed consent (years)  CD 194 43.8 43 12.8 34.0 51.3  UC 116 46.8 46 13.3 38.0 57.8  Total 310 44.9 44 13 36.0 53.3 Time from diagnosis of IBD to anti-­TNFα treatment initiation (months)  CD 193* 89.5 45.5 97.8 11.6 156  UC 115* 77.6 43.8 82.1 10.8 143.8  Total 308 85.0 45.5 92.3 11.1 150.2 Follow-­up time from anti-­TNFα treatment initiation (months)  CD 92 59.5 59.8 7.9 53.2 65.8  UC 65 59.5 59.8 7.5 53.4 65.1  Total 157 59.5 59.8 7.7 53.3 65.6 *Not available: 1 patient. anti-­TNFα, antitumour necrosis factor alpha; CD, Crohn’s disease; IBD, inflammatory bowel disease; UC, ulcerative colitis. Autonomous of Barcelona. Protected by copyright. (26.8%). The median (IQR) time from diagnosis of IBD immunosuppressants, and 65% were still under immuno- to anti-­TNFα treatment initiation was 45.5 (11.6–156.0) suppressant therapy during the maintenance phase. and 43.8 (10.8–143.8) months for CD and UC, respec- tively. Eighty-­two per cent of patients reported having Comorbidities and EIMs been previously treated with corticosteroids, and 33.3% The Charlson comorbidity index mean values for CD were still receiving concomitant corticosteroid therapy were 0.21 (SD: 0.57), and 0.27 (SD: 0.72) for patients during the maintenance phase. In addition, 78.4% of with UC. The prevalence of all individual comorbidities the study patients had been previously treated with identified was below 6% (figure 1). Diabetes mellitus Figure 1 Prevalence of comorbidities. The following comorbidities presented a prevalence of 0%: dementia, hemiplegia, moderate-­severe chronic kidney disease, solid tumours with metastases, and AIDS. COPD, chronic obstructive pulmonary disease. Marin-­Jimenez I, et al. BMJ Open Gastro 2020;7:e000351. doi:10.1136/bmjgast-2019-000351 5 Open access BMJ Open Gastroenterol: first published as 10.1136/bmjgast-2019-000351 on 26 March 2020. Downloaded from http://bmjopengastro.bmj.com/ on October 27, 2023 at Univesity Table 3 Prevalence of extraintestinal manifestations of IBD CD UC Total n %* n %† n %‡ Arthropathy and arthritis 33 17.0 29 25.0 62 20.0 Metabolic bone disease 6 3.1 8 6.9 14 4.5 Eye disease 5 2.6 5 4.3 10 3.2 Oral, aural and nasal disease 3 1.5 2 1.7 5 1.6 Skin disease 17 8.8 7 6.0 24 7.7 Hepato-­pancreato-­biliary disease 0 0 1 0.9 1 0.3 Neurological disease 0 0 2 1.7 2 0.6 Cardiovascular manifestations of IBD 0 0 0 0 0 0 Pulmonary manifestations of IBD 0 0 0 0 0 0 Genitourinary manifestations 1 0.5 0 0 1 0.3 *Percentages calculated over 194 patients with CD. †Percentages calculated over 116 patients with UC. ‡Percentages calculated over 310 patients. CD, Crohn’s disease; IBD, inflammatory bowel disease; UC, ulcerative colitis. Autonomous of Barcelona. Protected by copyright. (5.3%) was the most prevalent comorbidity for UC, and significantly associated with more severe disease severity chronic obstructive pulmonary disease (COPD) was the (OR 18.26, 95% CI 2.32 to 143.62). most prevalent among patients with CD (3.2%). The prevalence of EIMs was higher in the UC subpop- Discussion ulation (32.8% vs 26.3%). The most frequent EIMs Although several studies have investigated the clinical (table 3) were arthropathy and arthritis (17% for CD and and demographic factors that might predict PNR or LOR 25% for UC), skin disease (8.8% for CD and 6% for UC), to anti-­TNFα drugs in IBD, to the best of our knowledge, and metabolic bone disease (6.9% for UC). this is the first study to assess the association between Factors associated with PNR and LOR to anti-TNFα the comorbidity profile in patients with IBD and PNR or In the univariate analysis of comorbidities, COPD and LOR to anti-­TNFα drugs. solid tumours were identified as potential factors (p<0.10) The advent of anti-­TNFα drugs supposed a substantial associated with PNR. Multivariate logistic regression anal- improvement in the management of IBD. However, up ysis showed that COPD (OR 2.67, 95% CI 1.33 to 5.35) to 30% of patients do not respond to anti-­TNFα therapy was significantly associated with PNR to anti-­TNFα, as was during the treatment induction phase (PNR), and the use of corticosteroids and the type of IBD (UC vs CD) 13%–20% lose the initial response over time (LOR).25 (table 4). Consequently, personalised medicine approaches need In the univariate analysis, myocardial infarction and to be developed to avoid the risk of non-­response to a skin disease were identified as potential factors (p<0.10) drug, identify those patients most likely to benefit from of LOR to anti-­TNFα during the maintenance phase. specific therapies and choose the best treatment for each Multivariate logistic regression analysis confirmed the individual patient either at the initiation of the therapy or association of myocardial infarction (OR 3.30, 95% CI at the eventual LOR.26 Some studies conducted in other 1.48 to 7.35) and skin disease (OR 2.73, 95% CI 1.42 to autoimmune diseases, such as rheumatoid arthritis, have 5.25), along with the use of corticosteroids and the type shown the negative impact of the presence of comorbidi- of IBD (UC vs CD) (table 4), with LOR. ties on therapeutic response to biologics.36 37 In contrast, The additional analysis to evaluate the impact of the even though there have been a number of epidemio- EIM profile in patients with IBD on treatment response logical studies assessing the prevalence of comorbidi- to the first anti-­TNFα therapy showed that the only EIM ties associated with IBD,14–16 31 none has addressed the significantly associated with PNR was hepato-­pancreato-­ impact of the entire clinical profile of comorbidities and biliary disease (OR 1.87, 95% CI 1.48 to 2.36), and the EIMs on the response to biologic therapy. only EIM associated with LOR was skin disease (OR 2.58, We found a statistically significant association among 95% CI 1.98 to 3.35) (table 4). a few comorbidities and EIMs and both PNR to anti-­ TNFα during the induction phase (COPD) and LOR Factors associated with IBD severity during the maintenance phase (myocardial infarction In the univariate analysis, IBD type, cerebrovascular and skin diseases). As COPD, myocardial infarction and disease, leukaemia, diabetes mellitus, and diabetes with some skin diseases can aetiopathogenically be connected injuries to target organs were potential factors associated with smoking, it is plausible that the true factor behind with IBD severity (p<0.1). UC, compared with CD, was the increased risk of PNR and LOR to anti-­ TNFα is 6 Marin-­Jimenez I, et al. BMJ Open Gastro 2020;7:e000351. doi:10.1136/bmjgast-2019-000351 Open access BMJ Open Gastroenterol: first published as 10.1136/bmjgast-2019-000351 on 26 March 2020. Downloaded from http://bmjopengastro.bmj.com/ on October 27, 2023 at Univesity Table 4 Multivariate logistic regression analysis of factors influencing efficacy 95% CI for OR B SE Wald df P value OR Lower Upper Primary efficacy analysis: comorbidities associated with primary non-­response during the induction phase*  IBD −0.54 0.24 5.09 1 0.024 0.59 0.37 0.93  Corticosteroids 0.77 0.28 7.66 1 0.006 2.16 1.25 3.73  Chronic obstructive pulmonary disease 0.98 0.35 7.70 1 0.006 2.67 1.33 5.35 Primary efficacy analysis: comorbidities associated with loss of response during the maintenance phase†  IBD −0.54 0.27 4.05 1 0.044 0.58 0.34 0.99  Corticosteroids 0.90 0.30 8.67 1 0.003 2.45 1.35 4.44  Myocardial infarction 1.20 0.41 8.57 1 0.003 3.30 1.48 7.35 Secondary efficacy analysis: EIMs associated with primary non-­response during the induction phase‡  Corticosteroids 0.73 0.27 7.32 1 0.007 2.08 1.22 3.54  Constant 0.83 0.40 4.21 1 0.04 2.29 Secondary efficacy analysis: EIMs associated with loss of response during the maintenance phase§  Corticosteroids 0.94 0.30 9.89 1 0.002 2.57 1.43 4.61  Skin disease 1.01 0.33 9.13 1 0.003 2.73 1.42 5.25 Autonomous of Barcelona. Protected by copyright. *Stepwise MLRA including as independent factors those comorbidities that were significant at p<0.1 in the univariate analysis, and as the dependent factor the primary non-­response during the induction phase. In addition, type of IBD, treatment with immunosuppressants, and treatment with corticosteroids were included as fixed factors in the model. †Stepwise MLRA including as independent factors those comorbidities that were significant at p<0.1 in the univariate analysis, and as the dependent factor the loss of response during the maintenance phase. In addition, type of IBD, treatment with immunosuppressants, and treatment with corticosteroids were included as fixed factors in the model. ‡Stepwise MLRA including as independent factors those EIMs that were significant at p<0.1 in the univariate analysis, and as the dependent factor the primary non-­response during the induction phase. In addition, type of IBD, treatment with immunosuppressant, and treatment with corticosteroids were included as fixed factors in the model. §Stepwise MLRA including as independent factors those EIMs that were significant at p<0.1 in the univariate analysis, and as the dependent factor the loss of response during the maintenance phase. In addition, type of IBD, treatment with immunosuppressants, and treatment with corticosteroids were included as fixed factors in the model. EIMs, extraintestinal manifestations; IBD, inflammatory bowel disease; MLRA, multivariate logistic regression analysis. smoking habit, in such a manner that COPD, myocar- with healthy controls, the risk of COPD in patients with dial infarction and skin diseases could be mere surro- CD was 2.7-­fold higher, and in UC it was 1.8-­fold higher.38 gates of smoking behaviour. However, this does not In our study, COPD was among the most frequently appear to be the case, as smoking habit was not identi- reported comorbidities in both patients with CD (3.2%) fied under univariate analysis as a potential predictor of and patients with UC (4.4%). Likewise, acute myocardial PNR (p=0.670) or LOR (p=0.677). In any case, in order infarction was found to be almost three times as likely in to test this hypothesis more in depth, additional multi- patients with IBD as in matched controls in a population-­ variate analyses were conducted, forcing three different based study.38 On the other hand, major skin involve- variables related with smoking behaviour as independent ment has also been described in 2%–34% of patients with variables: current smoker, ex-­smoker and ever smoker. IBD.39 However, it is difficult to diagnose these skin mani- Interestingly, whereas none of these three variables was festations as EIMs because they can also arise as paradox- identified as an independent predictor of PNR or LOR, ical reactions to anti-­TNFα drugs.40 For example, some COPD, myocardial infarction and skin diseases kept reports have suggested that inhibition of TNFα induces significance as independent predictors of PNR or LOR overexpression of cutaneous interferon-α, which in turn (data not shown). This reinforces that the determinants causes a predisposition to psoriasis.40 Hence, in light of of failure to anti-­TNFα therapy are the identified comor- the present results, when selecting an anti-­TNFα for the bidities/EIMs, rather than smoking habits. treatment of patients with IBD, the identified comorbidi- These comorbidities/EIMs had increased prevalence ties and EIMs predicting a possible drug response failure in many epidemiological IBD studies, and some aetio- should be taken into consideration. pathogenic explanations have been hypothesised.38–40 The prevalence of comorbidities in our study was Overexpression of inflammatory factors and abnormal relatively low compared with other studies.14–16 A plau- immune responses have been postulated as the common sible explanation might be that the median age of pathogenetic mechanisms underlying IBD and comor- study patients was relatively young (approximately 44 bidities. In some epidemiological studies, a strong asso- years old). Another reason could be that many IBD ciation between COPD and IBD was found. Compared specialists or even patients are reluctant to use biologic Marin-­Jimenez I, et al. BMJ Open Gastro 2020;7:e000351. doi:10.1136/bmjgast-2019-000351 7 Open access BMJ Open Gastroenterol: first published as 10.1136/bmjgast-2019-000351 on 26 March 2020. Downloaded from http://bmjopengastro.bmj.com/ on October 27, 2023 at Univesity therapy, and we cannot discard a possible overlap Nonetheless, larger prospective controlled and pref- between comorbidities and EIMs due to the retrospec- erably randomised studies are needed to confirm our tive study design. We also found an unusual distribu- results. In addition, a study assessing the impact of tion of comorbidities in the subpopulations of patients comorbidities on response to other biologics in the IBD with CD and UC. Unlike most of the epidemiological population should be conducted to compare the study data, we found higher prevalence of comorbidities and results with the results of the present study. EIMs in UC than in CD. Interestingly, patients with In conclusion, our results suggest that the presence UC in our study showed a significant association with of some comorbidities, such as COPD and myocardial a more severe disease compared with patients with CD, infarction, and of certain EIMs of IBD, such as hepato-­ and also showed a significant association with PNR or pancreato-­ biliary conditions and skin diseases, seems LOR compared with patients with CD. Therefore, the to be connected to the lower probability of therapeutic higher disease severity in patients with UC included in success with anti-­TNFα. Therefore, the presence of these our study may explain the higher occurrence of EIMs in conditions in patients with IBD should guide clinicians this group. These findings are nonetheless in line with when selecting the most appropriate treatment. other published results.41–43 Park et al found disease Author affiliations severity to be a strong predictor of non-­response to 1 Department of Gastroenterology, Hospital General Universitario Gregorio Marañón, infliximab in patients with UC.43 The authors hypoth- Madrid, Spain esised that, unlike CD, UC seems to result from an 2 Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain 3 immune response of type 2 helper T cells in the colonic Department of Gastroenterology, Hospital La Fe, Valencia, Spain 4 mucosa, suggesting that TNFα would play no important Department of Gastroenterology, Hospital General de Castellón, Castellón, Spain 5 Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Barcelona, Autonomous of Barcelona. Protected by copyright. role in the pathogenesis of UC. Spain We also found a significant association between the 6 Department of Gastroenterology, Hospital Universitario Virgen Macarena, Sevilla, use of corticosteroids and both PNR and LOR. Some Spain 7 published studies have reported the early use of corti- 8 Medical Department, Takeda Farmacéutica España SA, Madrid, Spain costeroids as an independent predictor of a disabling Department of Gastroenterology, Hospital Universitario Río Hortega, Valladolid, Spain disease,44 of the need for anti-­ TNFα treatment dose 9 IBD Unit, Gastroenterology Department, University Clinic Hospital of Valencia, intensification, and of an increased risk of anti-­TNFα Valencia, Spain treatment failure.45 All these findings together appear to 10 Department of Gastroenterology, Hospital Clínico Universitario de Santiago de suggest that the early need for corticosteroids may be a Compostela, Santiago de Compostela, Spain 11 Department of Gastroenterology, Hospital Universitario Cruces, Bilbao, Spain proxy for disease severity or hard-­to-­treat disease. 12 Department of Gastroenterology, Hospital Universitari de Girona Doctor Josep Some of the limitations of the present study were the Trueta, Girona, Spain retrospective design and the lack of a control group. On 13 IBD Unit, Gastroenterology Section, Internal Medicine, Hospital de Sagunto, the other hand, a requirement to a successful logistic Sagunto, Spain 14 regression model is to select appropriate variables to be Department of Gastroenterology, Hospital Universitario de Burgos, Burgos, Spain 15 Department of Gastroenterology, Hospital Ramon y Cajal, Madrid, Spain entered into the model. While it is tempting to include 16 Department of Gastroenterology, Hospital Clínico Universitario de Santiago de as many input variables as possible, this can dilute true Compostela, Madrid, Spain associations, or conversely identify spurious associations. In order to limit these risks, the conventional technique Acknowledgements We would like to thank Ana Sánchez-­Gabriel (Takeda was followed, meaning to first run the univariate analyses Farmacéutica España), Tamara Pozo (Takeda Farmacéutica España), Teresa Letosa (Takeda Farmacéutica España), Yaiza Gimeno (Takeda Farmacéutica España), Silvia to identify potential predictor variables, and then to use Vives (Takeda Farmacéutica España), Susana Vara (Apices) and Juan Luis Sanz only those variables which meet a preset cut-­off for signif- (Apices) for their support in design, set-­up, coordination, operation, monitoring, icance to run a multivariate model. statistical analysis and medical writing. The following investigators contributed to Another limitation was the low frequency of comor- patient recruitment and data collection: Dra Montserrat Rivero Tirado (H Marqués de Valdecilla), Dr Oscar Roncero (H La Mancha Centro), Dra Yolanda Ber (H San bidities and EIMs observed, which may have reduced the Jorge), Dr Fernando Bermejo (H Fuenlabrada), Dra Cristina Verdejo (H Ciudad Real), statistical power to detect some other comorbidities or Dra Cristina Rodríguez Gutierrez (H Navarra), Dra Belén Botella (H Infanta Cristina), EIMs as predictors of PNR or LOR to anti-­TNFα treat- Dra Pilar López Serrano (H Alcorcón), Dra Silvia Chacón (H Morales Meseguer), Dr Daniel Ceballos (H Dr Negrín) and Dra Pilar Varela (H Cabueñes). ment in patients with IBD. In any case, the fact that some comorbidities or EIMs were identified as predictors of Contributors All authors have contributed to and agreed on the content of the manuscript: IM-­J, GB, AF, EG-­P, FA-­A, MA, JS-­F, MMB-­W, RF, OM, XA, XC, BS, treatment failure, despite their low prevalence in the FM, and MB-­A contributed to study design, patient recruitment, data collection studied population, indicates that they show a strong and results interpretation. IT, AF-­N, PS, and CM contributed to data analysis and association with PNR or LOR to anti-­TNFα treatment. interpretation, drafting of the report, and reviewed it critically. All authors approved Furthermore, even though the UC patient sample was the final version of the manuscript. smaller than planned, which was probably because many Funding The VERNE study was funded by Takeda Farmacéutica España SA. patients with UC successfully responded to conventional Competing interests IM-­J has served as a consultant, advisory member, therapies, both the final study sample size and the patient speaker, or has received research funding from MSD, AbbVie, Takeda, Tillotts, Ferring, Falk Pharma, Faes Farma, UCB Pharma, Otsuka Pharmaceutical, Shire, distribution were appropriate for meeting the study Gebro Pharma, and Chiesi. GB has received a speaker honorarium from AbbVie, objectives. Pfizer, Janssen, FAES, Takeda, Tillotts and Abbott. Also, GB has participated in the 8 Marin-­Jimenez I, et al. BMJ Open Gastro 2020;7:e000351. doi:10.1136/bmjgast-2019-000351 Open access BMJ Open Gastroenterol: first published as 10.1136/bmjgast-2019-000351 on 26 March 2020. Downloaded from http://bmjopengastro.bmj.com/ on October 27, 2023 at Univesity scientific advisory committees of Takeda, Janssen and AbbVie. EG-­P has served 13 Román ALS, Muñoz F. Comorbidity in inflammatory bowel disease. as a speaker or received research or educational funding or advisory fees from World J Gastroenterol 2011;17:2723–33. MSD, AbbVie, Janssen, Ferring, Shire, Tillotts, and FAES. FA-­A has served as a 14 Bähler C, Schoepfer AM, Vavricka SR, et al. Chronic comorbidities speaker, a consultant and as an advisory member for or have received research associated with inflammatory bowel disease: prevalence and impact on healthcare costs in Switzerland. Eur J Gastroenterol Hepatol funding from Janssen, MSD, AbbVie, Pfizer, Kern Pharma, Biogen, Sandoz, Takeda, 2017;29:916–25. Ferring, Faes Farma, Shire Pharmaceuticals, Dr Falk Pharma, Tillotts Pharma, Gebro 15 Bernstein CN, Wajda A, Blanchard JF. The clustering of other chronic Pharma, Amgen and Vifor Pharma. IT, AF-­N, and CM are full employees of Takeda inflammatory diseases in inflammatory bowel disease: a population-­ Farmacéutica España. PS was a Takeda Farmacéutica España employee at the based study. Gastroenterology 2005;129:827–36. moment this work was conducted. MA has served as a speaker for MSD, AbbVie, 16 Haapamäki J, Roine RP, Turunen U, et al. Increased risk for Janssen, Takeda and Tillotts, and received educational grants from Janssen, coronary heart disease, asthma, and connective tissue diseases in MSD and AbbVie. JS-­F has nothing to declare. MMB-­W declares educational inflammatory bowel disease. J Crohns Colitis 2011;5:41–7. activities, research projects, scientific meetings and advisory boards sponsored 17 Olpin JD, Sjoberg BP, Stilwill SE, et al. Beyond the bowel: extraintestinal manifestations of inflammatory bowel disease. by MSD, Ferring, AbbVie, Janssen and Takeda. RF has served as a speaker for or Radiographics 2017;37:1135–60. has received research funding from Takeda, MSD, AbbVie, Janssen, Palex, Shire 18 Harbord M, Annese V, Vavricka SR, et al. The first European Pharmaceuticals, Tillotts Pharma and Casen Recordati. OM has nothing to declare. evidence-­based consensus on extra-­intestinal manifestations in MB-­A has served as a speaker, a consultant and advisory board member for, or inflammatory bowel disease. J Crohns Colitis 2016;10:239–54. has received research funding from, MSD, AbbVie, Janssen, Pfizer, Kern Pharma, 19 Vavricka SR, Schoepfer A, Scharl M, et al. Extraintestinal Biogen, Takeda, Ferring, Faes Farma, Shire Pharmaceuticals, Dr Falk Pharma, manifestations of inflammatory bowel disease. Inflamm Bowel Dis Tillotts Pharma, Chiesi, Gebro Pharma, Otsuka Pharmaceutical and Vifor Pharma. 2015;21:1982–92. 20 Renna S, Cottone M, Orlando A. Optimization of the treatment with Patient consent for publication Not required. immunosuppressants and biologics in inflammatory bowel disease. Ethics approval The study was reviewed and approved by the corresponding World J Gastroenterol 2014;20:9675–90. 21 Baert F, Moortgat L, Van Assche G, et al. Mucosal healing predicts ethics committees. sustained clinical remission in patients with early-­stage Crohn's Provenance and peer review Not commissioned; externally peer reviewed. disease. Gastroenterology 2010;138:463–8. 22 Zallot C, Peyrin-­Biroulet L. Deep remission in inflammatory bowel Data availability statement Data are available upon reasonable request. The data disease: looking beyond symptoms. Curr Gastroenterol Rep Autonomous of Barcelona. Protected by copyright. that support the findings of this study are available from the sponsor upon request. 2013;15:315. Open access This is an open access article distributed in accordance with the 23 Ordás I, Feagan BG, Sandborn WJ. Early use of immunosuppressives or TNF antagonists for the treatment of Creative Commons Attribution Non Commercial (CC BY-­NC 4.0) license, which Crohn's disease: time for a change. Gut 2011;60:1754–63. permits others to distribute, remix, adapt, build upon this work non-­commercially, 24 Ford AC, Sandborn WJ, Khan KJ, et al. Efficacy of biological and license their derivative works on different terms, provided the original work is therapies in inflammatory bowel disease: systematic review and properly cited, appropriate credit is given, any changes made indicated, and the meta-­analysis. Am J Gastroenterol 2011;106:644–59. use is non-­commercial. See: http://c​ reativecommons.​org/​licenses/​by-​nc/​4.​0/. 25 Martínez-­Montiel MP, Casis-­Herce B, Gómez-­Gómez GJ, et al. Pharmacologic therapy for inflammatory bowel disease refractory to ORCID iD steroids. Clin Exp Gastroenterol 2015;8:257–69. 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