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doi:10.1111/jgh.12803
GASTROENTEROLOGY
Predictive value of early restoration of quality of life in Crohn’s disease patients receiving antitumor necrosis factor agents Claudia Herrera-deGuise, Francesc Casellas, Virginia Robles, Ester Navarro and Natalia Borruel Unitat Atenció Crohn-Colitis (UACC), Hospital Universitari Vall d’Hebron, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Barcelona, Spain
Key words anti-TNF agents, Crohn’s disease, quality of life, restoration of health. Accepted for publication 25 September 2014. Correspondence Dr Francesc Casellas, Digestive System Research Unit, Hospital Universitari Vall d’Hebron, Pso. Vall d’Hebron 119, Barcelona 08035, Spain. Email: [email protected] This work was partially supported with grants from the Generalitat de Catalunya (RE: 2001SGR00389) and the Biomedical Investigation Centre in Network of Hepatic and Digestive Diseases (Ciberehd, Spain). Authors do not have financial or other conflicts of interests with the study.
Abstract Background and Aim: Crohn’s disease (CD) impairs patients’ health-related quality of life (HRQoL), therefore a goal of treatment is to improve their health. Recently, a more ambitious therapeutic target has been proposed, to reestablish patients’ HRQoL to normal standards. There is no information on long-term prognostic value of restoring the health of patients with CD. Our aim was to determine if early restoration of HRQoL with antitumor necrosis factor (anti-TNF) agents is associated with long-term clinical remission. Methods: Retrospective longitudinal study in patients with active CD treated with antiTNF agents. Patients completed the Inflammatory Bowel Disease Questionnaire (IBDQ)-36 at baseline and weeks 2, 6, 14, 28, and 52. Early restoration of health was defined as an IBDQ-36 score > 209 at week14, and long-term clinical remission as a Cohn’s disease activity index (CDAI) score < 150 maintained through week 52. Results: Ninety-four patients were included. Sixty-three patients maintained long-term remission, with 47 (75%) of them achieving early restoration of HRQoL. Of the 31 patients who did not maintain long-term remission, only 4 (13%) restored their HRQoL early (P < 0.01). There was a strong negative correlation between the IBDQ-36 at week14 and CDAI values at week 52 (rs = − 0.64, P < 0.01). Ninety-two percent of patients with early restoration of HRQoL maintained long-term remission versus 37% who did not restore their HRQoL (P < 0.01). To predict long-term remission, the cutoff point of 209 of the early IBDQ-36 had an area under the receiver operating characteristic (AUROC) curve of 0.87. Conclusion: Achieving early restoration of HRQoL with anti-TNF agents is associated with sustained long-term remission. This could be a therapeutic goal of treatment in clinical trials and daily practice.
Introduction Crohn’s disease (CD) is an inflammatory gastrointestinal disease that due to its chronicity, symptoms, complications, need for continuous treatment, potential drug adverse effects, surgical interventions, among others, causes a profound impact on the health of affected patients.1 The impact of CD is felt physically, socially, and emotionally, thus it can be considered as a disabling disease that affects all aspects of a patient’s life,2,3 and it considerably impairs health-related quality of life (HRQoL).4 HRQoL is a multidimensional construct comprised of physical, social, and psychological functioning, overall satisfaction and well-being, and subjective perceptions of health status, and also includes neuropsychological functioning, personal productivity, intimacy and sexual functioning, sleep disturbance, pain, symptoms, and spirituality.5 It has been shown that effective treatment of CD, regardless that it is medical or surgical, is capable of improving HRQoL6–8 and this 286
improvement in HRQoL remains in parallel with effective clinical treatment.9 However, due to the subjective nature of HRQoL, patients may achieve clinical remission, but the score in questionnaires assessing HRQoL may be less than the score obtained in the general population.10 There are multiple inflammatory bowel disease (IBD)-specific scales available to assess HRQoL in CD patients; however, the IBD Questionnaire (IBDQ) is the most commonly used instrument.11 The 36-question version of the IBDQ (IBDQ-36) was developed to assess the quality of life in outpatients.12 A normality cutoff value of the IBDQ-36 has been calculated.13 A score greater than or equal to 209 corresponds to a normal perception of quality of life equivalent to that of the general population of reference. During the last decade, biological agents directed against tumor necrosis factor alpha (anti-TNFα) have been introduced for patients with CD. These biological agents are not only effective in reducing signs and symptoms and inducing remission in CD, but
Journal of Gastroenterology and Hepatology 30 (2015) 286–291 © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
C Herrera-deGuise et al.
have also shown benefits on HRQoL.14 In controlled clinical trials, improvement was found in all domains of the IBDQ questionnaire as early as week 2 after starting treatment with an anti-TNF agent.15 It has also been shown that, in parallel to clinical remission, it is possible to obtain a normalized perceived health of patients treated with an anti-TNF agent.16 It has been shown that even if patients achieve clinical and endoscopic remission, sometimes they don’t normalize their quality of life.17 This suggests that response criteria based on patient-reported outcomes could be very discriminating. It would be of great interest in clinical practice to know whether a selective criterion as restoration of health and the improvement in the perceived health of patients has a prognostic value. Therefore, the aim of this study was to determine whether early normalization of the quality of life achieved with anti-TNF agents in a group of patients with CD could predict the maintenance of a long-term clinical response.
Materials and methods Patients. A retrospective, observational, longitudinal study was conducted in adult patients with active CD that were scheduled to receive anti-TNF agents. Diagnosis of CD was established by conventional clinical, endoscopic, radiological, and histological criteria. To be included in the study, patients had to be naïve to anti-TNF agents and have an active CD. Active disease was defined by a Crohn’s Disease Activity Index (CDAI) score greater than 150 points.18 Patients were excluded if the indication for anti-TNF was for prevention of surgical recurrence, if patient had other chronic diseases or if they were older than 70 years of age. The reason to exclude patients with other chronic diseases was to minimize other influences that could alter the HRQoL and that were not necessarily related to the disease itself, and patients older than 70 years were excluded because the cut-off value of normality of the IBDQ-36 used in our study has not been validated specifically for elderly patients. Patients receiving either adalimumab or infliximab were included, since both anti-TNF agents share similar mechanisms of action, safety profile, and therapeutic efficacy19 differing in origin and administration. Thus, infliximab is administered intravenously every 8 weeks, while adalimumab is administered subcutaneously every 2 weeks. The choice of infliximab or adalimumab was based on patient’s preference after a specific educational program visit. All patients were evaluated at baseline prior to initiation of treatment and at weeks 2, 6, 14, 28, and 52 after starting treatment with anti-TNF. Demographic and clinical data were collected. All patients completed the specific questionnaire of quality of life IBDQ-36, and the CDAI at each visit and blood samples were obtained for quantification of C-reactive protein (CRP). Assessment of quality of life. HRQoL of patients was assessed using the questionnaire IBDQ-36. This is a diseasespecific self-administered questionnaire that has been translated and validated for its use in Spain.20 This version12 includes 36 items that are grouped into five domains of health (bowel symptoms, systemic symptoms, functional impairment, social impairment, and emotional function). Responses are scored on a 7-point Likert scale, in which seven corresponds to the highest level of
Quality of life restoration in Crohn’s disease
functioning. The instrument produces five dimension scores and an overall IBDQ score ranging from 36 to 252, where a higher score reflects better HRQoL. According to previously validated criteria, perceived health was considered restored to normal when the overall score of IBDQ-36 was equal or greater than 209.13 We defined early restoration of quality of life if the overall score of the IBDQ-36 was equal or greater than 209 points at week 14 from the start of anti-TNF treatment. Evaluation of clinical response. The CDAI was used to assess the clinical response of patients. The CDAI is a tool designed to define the state of remission and response to treatment in patients with CD. It is based on eight clinical variables, three derived from a one-week patient diary. Each independent variable is coded so that 0 corresponds to good health, and increasing positive values correspond to greater degrees of sickness. CDAI values less than 150 generally mean quiescent disease, and those greater than 450 generally mean extremely severe disease.21 We considered patients to be in long-term clinical remission if the CDAI was less than 150 through week 52 from the start of anti-TNFα. Statistical analysis. Statistical analysis was carried out by the computerized program SPSS v20 (IBM Corp. Released 2011. IBM SPSS Statistics for Macintosh Version 20.0. Armonk, NY). According to the Kolmogorov–Smirnov Test, variables were not normally distributed. Thus, results are expressed as percentages or medians, and percentiles. The correlation between the IBDQ-36 values at week 14 and CDAI at week 52 was evaluated by using the Spearman’s Correlation Coefficient. The receiver operating characteristic (ROC) curves analysis was used to explore the predictive value of early restoration of HRQoL for long-term clinical remission.
Results Characteristics of patients. A total of 206 records of CD patients who received anti-TNFα treatment in our unit in clinical practice conditions were evaluated. Of these, 94 patients met the inclusion criteria so the final analysis was done with these patients. Sixty-three percent were female. Sixty patients received adalimumab and 34 received infliximab. Eighty-four patients were also receiving an immunomodulator (thiopurines in 66 cases, methotrexate in eight, and mycophenolate mofetil in 11 patients). Median baseline CDAI was 206 and IBDQ-36 was 175. (Table 1) Early restoration of HRQoL. Fifty-one patients achieved an early restoration of HRQoL according to previously defined criteria and forty-three did not restore it. All patients that achieved early restoration were on clinical remission at the time (CDAI < 150), whereas only 46% of patients who did not restore their quality of life were on clinical remission at week 14 (P < 0.01). As shown in Table 2, baseline characteristics of both groups were similar, however the value of basal IBDQ-36 was higher in patients who restored their quality of life (194 [156–206] vs 156 [130–175] P < 0.01 95% CI 19–45), also the CRP was lower in patients with early restoration (9.2 [2.52–11.86] vs 12.3 [5.61–15.22] P = 0.01 95% CI 0.93–2.38).
Journal of Gastroenterology and Hepatology 30 (2015) 286–291 © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
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Table 1 Baseline demographic and clinical characteristics of the 94 patients. Results expressed as medians and (25th percentile—75th percentile) Age at week 0 of anti-TNFα treatment Sex (male/female) Smoking status Current smoker Former smoker Never smoked Months since CD diagnosis Age at diagnosis A1: < 16 A2: 17–40 A3: > 40 Location of disease L1: Ileal L2: Colonic L3: Ileocolonic L2 + L4: Colonic + upper disease Behavior of disease B1: Non-stricturing, non-penetrating B2: Stricturing B3: Penetrating B1 + p† B2 + p† B3 + p† Treatment Infliximab/Adalimumab Immunomodulator (yes/no) CDAI IBDQ-36 Hemoglobin (g/dL) Leucocyte count (x103/mm3) Platelet count (x 109/L) CRP (mg/L) Ferritin (ng/mL)
34 [27.5–42] 35/59
33 21 40 86 [28–142.5] 12 67 15 32 19 42 1
Correlation between IBDQ-36 and clinical activity by CDAI. The Spearman correlation coefficient was used to determine the relationship between the values of the overall IBDQ-36 and the CDAI, as shown in Figure 3. We found a strong negative correlation between the values of the IBDQ-36 at week 14 and the CDAI values at week 52, and it was statistically significant (rs = − 0.64, P < 0.01, 95% CI − 0.79–− 0.38), this suggests that the higher the score on the early IBDQ-36 in response to anti-TNF treatment, the better the long-term clinical response, with lower activity (CDAI) scores.
Discussion
25 15 10 20 15 9 34/60 84/10 206 [163.75–251.25] 170.5 [142–199] 12.2 [11–13.1] 7.7 [5.4–9.8] 316.5 [255.4–401.2] 12.8 [3.8–45.7] 55 [23–126]
†
p is added to B1–B3 when concomitant perianal disease is present. TNFα, tumor necrosis factor-alpha.
Early restoration of HRQoL and long-term clinical remission. Sixty-three patients maintained a long-term clinical remission (CDAI < 150 at week 52), forty-seven (75%) of them achieved an early restoration of quality of life. Of the 31 patients who did not maintain long-term clinical remission, only four (13%) had an early restoration of their quality of life (P < 0.01, OR: 8.95, 95% CI 5.51–86). We also found that achieving restoration of HRQoL at week 2, after the first dose of anti-TNF, is also related with long termclinical remission (P < 0.01, OR: 6.96, 95% CI 2.04–30). (Table 3) Figure 1 shows that in patients who restore their HRQoL at week 14, clinical remission was achieved more frequently than in patients who did not restore their HRQoL, and this is maintained in follow-up visits (P < 0.01). This suggests that a very early restoration of HRQoL is an important and lasting favorable clinical outcome. To predict long-term remission, the area obtained underneath the ROC curve in early IBDQ-36 for the cutoff point of 209 was 288
0.87 (Fig. 2), with a sensitivity and specificity of 0.75 and 0.87, respectively, a positive likelihood ratio of 3.43 and a negative likelihood ratio of 0.17.
The results of our study demonstrate that the early restoration of the quality of life after induction with anti-TNF treatment in patients with CD is associated with clinical remission at one year. The need to examine subjective aspects of the health of patients with inflammatory bowel disease, basically HRQoL, has been recognized. In the vast majority of controlled clinical trials, the improvement of quality of life is defined as statistically significant when the questionnaires score increases. This measurement of improvement may not be clinically relevant and should be supplemented by additional information, such as the threshold of normality for the quality of life. Although some outcomes of treatment response in patients with CD, such as mucosal healing, have a prognostic value, this aspect has not been specifically designed for HRQoL. Results of our study showed that achieving higher scores in the IBDQ-36 at week 14 in response to biological treatment was associated with lower scores in the CDAI in subsequent visits. With these results, it can be concluded that patients who had an early restoration of their HRQoL not only had a clinical remission and overall lower activity scores but also that this was maintained in subsequent visits. The strong negative correlation between longterm CDAI and early IBDQ-36 may not be unexpected because some elements of the clinical assessment are similar in both instruments. It is interesting that achieving restoration of HRQoL as early as 2 weeks after the first dose of anti-TNF was also associated with long-term clinical remission. There are CD-related factors that could be involved in achieving and restoring HRQoL. Among them, a significant factor might be to have less severe disease. In the case of our patients, we found that baseline CRP was slightly lower in those who restored their HRQoL early, which might suggest that they had lower inflammatory activity than patients who did not restore their HRQoL. We found no differences in other variables such as disease behavior, location, or age at diagnosis. An interesting question is how a questionnaire that was designed to assess the quality of life can be a forecast tool to evaluate the activity of the disease in the long term. One possible answer is that alterations in quality of life often reflect the general welfare almost unconsciously, possibly even before the appearance of overt symptoms. Since the general welfare and quality of life are closely related, the quality of life scores have shown to be
Journal of Gastroenterology and Hepatology 30 (2015) 286–291 © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
C Herrera-deGuise et al.
Quality of life restoration in Crohn’s disease
Table 2 Baseline demographic and clinical characteristics of patients distributed according to early restoration of HRQoL to treatment. Results expressed as medians and (25th percentile—75th percentile) Early restoration of HRQoL (IBDQ-36 > 209 at week 14) Yes n Sex (male/female) Smoking status Smoker/Former smoker Never smoked Age at diagnosis A1: < 16 A2: 17–40 A3: > 40 Location of disease L1: Ileal L2: Colonic L3: Ileocolonic L2 + L4: Colonic + upper disease Behavior of disease B1: Non-stricturing, non-penetrating B2: Stricturing B3: Penetrating B1 + p† B2 + p† B3 + p† Infliximab/Adalimumab Immunomodulator CDAI IBDQ-36 global score CRP (mg/L)
P
No
51 21/30
43 14/29
29 22
25 18
7 38 6
5 29 9
17 9 24 1
15 10 18 0
ns ns
ns
ns
ns 13 11 6 9 8 4 14/37 46 179 [163–248] 194 [156–206] 9.2 [2.52–11.86]
12 4 4 11 7 5 20/23 38 230 [167–258] 156 [130–175] 12.3 [5.61–15.22]
ns ns ns P < 0.01 P = 0.01
†
p is added to B1–B3 when concomitant perianal disease is present. HRQoL, health-related quality of life; not significant (ns).
Table 3 Percentage of patients in long-term clinical remission according to restoration of HRQoL (IBDQ-36 >209) at week 2, 6 & 14 Long-term clinical remission (%)
Week 2 Week 6 Week 14
IBDQ-36 > 209
IBDQ-36 < 209
89% 88% 92%
53% 44.4% 37.2%
OR (95%CI)
P
6.96 (2.04–30) 8.2 (2.96–30.3) 8.95 (5.51–86)
P < 0.01 P < 0.01 P < 0.01
CI, confidence interval; HRQoL, health-related quality of life; IBDQ, Inflammatory Bowel Disease Questionnaire: OR, odds ratio.
very sensitive to detect early stages of disease exacerbation. Therefore, when patients are engaged in their daily activities, evaluation of quality of life can be a tool to raise awareness of changes in the course of the disease. Other authors have also observed this.22,23 From the results of this study, we observed stability of clinical response at one year, but we cannot determine whether this early restoration of HRQoL can predict clinical remission for longer periods of time. In addition, due to the retrospective design of the
Figure 1 Clinical remission per visit, arranged according to early restoration of health-related quality of life (HRQoL) at week 14. (*P < 0.01). ■, Early restoration HRQoL; , No early restoration HRQoL.
study, some data on clinical and endoscopic activity were not available in all patients. The results of our study should be evaluated in prospective studies and correlated with other objective markers such as fecal calprotectin or endoscopy and mucosal healing.
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References
Figure 2 Receiver operating characteristic (ROC) curve for the cutoff point of 209 at week 14 of the global IBDQ-36 to predict long-term clinical remission.
Figure 3 Inflammatory Bowel Disease Questionnaire (IBDQ)-36 global scores at week 14 was inversely correlated with clinical activity score at week 52 (rs = −0.64 (P < 0.01, 95% CI −0.79–0.38).
In conclusion, the results of our study show that early restoration of quality of life after induction with anti-TNFα treatment is associated with clinical remission one year after starting treatment. Quality of life is a well-established measure for the evaluation of effective treatment, and results of this study suggest that the restoration of a normal HRQoL in patients with CD has a significant predictive value of clinical remission. This could be a therapeutic goal of treatment both in clinical trials and in daily practice.
Acknowledgment The study was supported by grants from the CIBERehd, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación, Spain. 290
1 Peyrin-Biroulet L, Loftus EV Jr, Colombel JF, Sandborn WJ. The natural history of adult Crohn’s disease in population-based cohorts. Am. J. Gastroenterol. 2010; 105: 289–97. 2 Casellas F, Arenas JI, Baudet JS et al. Impairment of health-related quality of life in patients with inflammatory bowel disease: a Spanish multicenter study. Inflamm. Bowel Dis. 2005; 11: 488–96. 3 Vergara M, Montserrat A, Casellas F et al. A new validation of the Spanish Work Productivity and Activity Impairment Questionnaire—Crohn’s disease version. Value Health 2011; 14: 859–61. 4 Sorensen VZ, Olsen BG, Binder V. Life prospects and quality of life in patients with Crohn’s disease. Gut 1987; 28: 382–5. 5 Wolfe BJ, Sirois FM. Beyond standard quality of life measures: the subjective experiences of living with inflammatory bowel disease. Qual. Life Res. 2008; 17: 877–86. 6 Casellas F, Lopez-Vivancos J, Badia X, Vilaseca J, Malagelada JR. Impact of surgery for Crohn’s disease on health-related quality of life. Am. J. Gastroenterol. 2000; 95: 177–82. 7 Feagan BG, Yan S, Bala M, Bao W, Lichtenstein GR. The effects of infliximab maintenance therapy on health-related quality of life. Am. J. Gastroenterol. 2003; 98: 2232–8. 8 Loftus EV, Feagan BG, Colombel JF et al. Effects of adalimumab maintenance therapy on health-related quality of life of patients with Crohn’s disease: patient-reported outcomes of the CHARM trial. Am. J. Gastroenterol. 2008; 103: 3132–41. 9 Casellas F, Rodrigo L, Nino P, Pantiga C, Riestra S, Malagelada JR. Sustained improvement of health-related quality of life in Crohn’s disease patients treated with infliximab and azathioprine for 4 years. Inflamm. Bowel Dis. 2007; 13: 1395–400. 10 Iglesias M, Vazquez I, Barreiro-de Acosta M et al. Health related quality of life in patients with Cohn s disease in remission. Rev. Esp. Enferm. Dig. 2010; 102: 624–30. 11 Guyatt G, Mitchell A, Irvine EJ et al. A new measure of health status for clinical trials in inflammatory bowel disease. Gastroenterology 1989; 96: 804–10. 12 Love JR, Irvine EJ, Fedorak RN. Quality of life in inflammatory bowel disease. J. Clin. Gastroenterol. 1992; 14: 15–19. 13 Huaman JW, Casellas F, Borruel N et al. Cutoff values of the Inflammatory Bowel Disease Questionnaire to predict a normal health related quality of life. J. Crohns Colitis. 2010; 4: 637–41. 14 Zisman TL, Cohen RD. Pharmacoeconomics and quality of life of current and emerging biologic therapies for inflammatory bowel disease. Curr. Treat. Options Gastroenterol. 2007; 10: 185–94. 15 van Balkom BP, Schoon EJ, Stockbrugger RW et al. Effects of anti-tumour necrosis factor-alpha therapy on the quality of life in Crohn’s disease. Aliment. Pharmacol. Ther. 2002; 16: 1101–7. 16 Casellas F, Robles V, Borruel N et al. Restoration of quality of life of patients with inflammatory bowel disease after one year with antiTNFα treatment. J. Crohns Colitis. 2012; 6: 881–6. 17 Casellas F, Barreiro de Acosta M, Iglesias M et al. Mucosal healing restores normal health and quality of life in patients with inflammatory bowel disease. Eur. J. Gastroenterol. Hepatol. 2012; 24: 762–9. 18 Sandborn WJ, Feagan BG, Hanauer SB et al. A review of activity indices and efficacy endpoints for clinical trials of medical therapy in adults with Crohn’s disease. Gastroenterology 2002; 122: 512–30. 19 Peyrin-Biroulet L, Deltenre P, de Suray N, Branche J, Sandborn WJ, Colombel JF. Efficacy and safety of tumor necrosis factor antagonists in Crohn’s disease: meta-analysis of placebo-controlled trials. Clin. Gastroenterol. Hepatol. 2008; 6: 644–53.
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20 Lopez-Vivancos J, Casellas F, Badia X, Vilaseca J, Malagelada JR. Validation of the Spanish version of the inflammatory bowel disease questionnaire on ulcerative colitis and Crohn’s disease. Digestion 1999; 60: 274–80. 21 Best WR. Predicting the Crohn’s disease activity index from the Harvey–Bradshaw Index. Inflamm. Bowel Dis. 2006; 12: 304–10.
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22 Camara RJ, Juillerat P, Pittet V et al. Quality of life: a potentially useful measure to indicate subclinical flares in Crohn disease. Intern. Med. J. 2012; 42: e145–51. 23 Mittermaier C, Dejaco C, Waldhoer T et al. Impact of depressive mood on relapse in patients with inflammatory bowel disease: a prospective 18-month follow-up study. Psychosom. Med. 2004; 66: 79–84.
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doi:10.1111/jgh.12803
GASTROENTEROLOGY
Predictive value of early restoration of quality of life in Crohn’s disease patients receiving antitumor necrosis factor agents Claudia Herrera-deGuise, Francesc Casellas, Virginia Robles, Ester Navarro and Natalia Borruel Unitat Atenció Crohn-Colitis (UACC), Hospital Universitari Vall d’Hebron, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Barcelona, Spain
Key words anti-TNF agents, Crohn’s disease, quality of life, restoration of health. Accepted for publication 25 September 2014. Correspondence Dr Francesc Casellas, Digestive System Research Unit, Hospital Universitari Vall d’Hebron, Pso. Vall d’Hebron 119, Barcelona 08035, Spain. Email: [email protected] This work was partially supported with grants from the Generalitat de Catalunya (RE: 2001SGR00389) and the Biomedical Investigation Centre in Network of Hepatic and Digestive Diseases (Ciberehd, Spain). Authors do not have financial or other conflicts of interests with the study.
Abstract Background and Aim: Crohn’s disease (CD) impairs patients’ health-related quality of life (HRQoL), therefore a goal of treatment is to improve their health. Recently, a more ambitious therapeutic target has been proposed, to reestablish patients’ HRQoL to normal standards. There is no information on long-term prognostic value of restoring the health of patients with CD. Our aim was to determine if early restoration of HRQoL with antitumor necrosis factor (anti-TNF) agents is associated with long-term clinical remission. Methods: Retrospective longitudinal study in patients with active CD treated with antiTNF agents. Patients completed the Inflammatory Bowel Disease Questionnaire (IBDQ)-36 at baseline and weeks 2, 6, 14, 28, and 52. Early restoration of health was defined as an IBDQ-36 score > 209 at week14, and long-term clinical remission as a Cohn’s disease activity index (CDAI) score < 150 maintained through week 52. Results: Ninety-four patients were included. Sixty-three patients maintained long-term remission, with 47 (75%) of them achieving early restoration of HRQoL. Of the 31 patients who did not maintain long-term remission, only 4 (13%) restored their HRQoL early (P < 0.01). There was a strong negative correlation between the IBDQ-36 at week14 and CDAI values at week 52 (rs = − 0.64, P < 0.01). Ninety-two percent of patients with early restoration of HRQoL maintained long-term remission versus 37% who did not restore their HRQoL (P < 0.01). To predict long-term remission, the cutoff point of 209 of the early IBDQ-36 had an area under the receiver operating characteristic (AUROC) curve of 0.87. Conclusion: Achieving early restoration of HRQoL with anti-TNF agents is associated with sustained long-term remission. This could be a therapeutic goal of treatment in clinical trials and daily practice.
Introduction Crohn’s disease (CD) is an inflammatory gastrointestinal disease that due to its chronicity, symptoms, complications, need for continuous treatment, potential drug adverse effects, surgical interventions, among others, causes a profound impact on the health of affected patients.1 The impact of CD is felt physically, socially, and emotionally, thus it can be considered as a disabling disease that affects all aspects of a patient’s life,2,3 and it considerably impairs health-related quality of life (HRQoL).4 HRQoL is a multidimensional construct comprised of physical, social, and psychological functioning, overall satisfaction and well-being, and subjective perceptions of health status, and also includes neuropsychological functioning, personal productivity, intimacy and sexual functioning, sleep disturbance, pain, symptoms, and spirituality.5 It has been shown that effective treatment of CD, regardless that it is medical or surgical, is capable of improving HRQoL6–8 and this 286
improvement in HRQoL remains in parallel with effective clinical treatment.9 However, due to the subjective nature of HRQoL, patients may achieve clinical remission, but the score in questionnaires assessing HRQoL may be less than the score obtained in the general population.10 There are multiple inflammatory bowel disease (IBD)-specific scales available to assess HRQoL in CD patients; however, the IBD Questionnaire (IBDQ) is the most commonly used instrument.11 The 36-question version of the IBDQ (IBDQ-36) was developed to assess the quality of life in outpatients.12 A normality cutoff value of the IBDQ-36 has been calculated.13 A score greater than or equal to 209 corresponds to a normal perception of quality of life equivalent to that of the general population of reference. During the last decade, biological agents directed against tumor necrosis factor alpha (anti-TNFα) have been introduced for patients with CD. These biological agents are not only effective in reducing signs and symptoms and inducing remission in CD, but
Journal of Gastroenterology and Hepatology 30 (2015) 286–291 © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
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have also shown benefits on HRQoL.14 In controlled clinical trials, improvement was found in all domains of the IBDQ questionnaire as early as week 2 after starting treatment with an anti-TNF agent.15 It has also been shown that, in parallel to clinical remission, it is possible to obtain a normalized perceived health of patients treated with an anti-TNF agent.16 It has been shown that even if patients achieve clinical and endoscopic remission, sometimes they don’t normalize their quality of life.17 This suggests that response criteria based on patient-reported outcomes could be very discriminating. It would be of great interest in clinical practice to know whether a selective criterion as restoration of health and the improvement in the perceived health of patients has a prognostic value. Therefore, the aim of this study was to determine whether early normalization of the quality of life achieved with anti-TNF agents in a group of patients with CD could predict the maintenance of a long-term clinical response.
Materials and methods Patients. A retrospective, observational, longitudinal study was conducted in adult patients with active CD that were scheduled to receive anti-TNF agents. Diagnosis of CD was established by conventional clinical, endoscopic, radiological, and histological criteria. To be included in the study, patients had to be naïve to anti-TNF agents and have an active CD. Active disease was defined by a Crohn’s Disease Activity Index (CDAI) score greater than 150 points.18 Patients were excluded if the indication for anti-TNF was for prevention of surgical recurrence, if patient had other chronic diseases or if they were older than 70 years of age. The reason to exclude patients with other chronic diseases was to minimize other influences that could alter the HRQoL and that were not necessarily related to the disease itself, and patients older than 70 years were excluded because the cut-off value of normality of the IBDQ-36 used in our study has not been validated specifically for elderly patients. Patients receiving either adalimumab or infliximab were included, since both anti-TNF agents share similar mechanisms of action, safety profile, and therapeutic efficacy19 differing in origin and administration. Thus, infliximab is administered intravenously every 8 weeks, while adalimumab is administered subcutaneously every 2 weeks. The choice of infliximab or adalimumab was based on patient’s preference after a specific educational program visit. All patients were evaluated at baseline prior to initiation of treatment and at weeks 2, 6, 14, 28, and 52 after starting treatment with anti-TNF. Demographic and clinical data were collected. All patients completed the specific questionnaire of quality of life IBDQ-36, and the CDAI at each visit and blood samples were obtained for quantification of C-reactive protein (CRP). Assessment of quality of life. HRQoL of patients was assessed using the questionnaire IBDQ-36. This is a diseasespecific self-administered questionnaire that has been translated and validated for its use in Spain.20 This version12 includes 36 items that are grouped into five domains of health (bowel symptoms, systemic symptoms, functional impairment, social impairment, and emotional function). Responses are scored on a 7-point Likert scale, in which seven corresponds to the highest level of
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functioning. The instrument produces five dimension scores and an overall IBDQ score ranging from 36 to 252, where a higher score reflects better HRQoL. According to previously validated criteria, perceived health was considered restored to normal when the overall score of IBDQ-36 was equal or greater than 209.13 We defined early restoration of quality of life if the overall score of the IBDQ-36 was equal or greater than 209 points at week 14 from the start of anti-TNF treatment. Evaluation of clinical response. The CDAI was used to assess the clinical response of patients. The CDAI is a tool designed to define the state of remission and response to treatment in patients with CD. It is based on eight clinical variables, three derived from a one-week patient diary. Each independent variable is coded so that 0 corresponds to good health, and increasing positive values correspond to greater degrees of sickness. CDAI values less than 150 generally mean quiescent disease, and those greater than 450 generally mean extremely severe disease.21 We considered patients to be in long-term clinical remission if the CDAI was less than 150 through week 52 from the start of anti-TNFα. Statistical analysis. Statistical analysis was carried out by the computerized program SPSS v20 (IBM Corp. Released 2011. IBM SPSS Statistics for Macintosh Version 20.0. Armonk, NY). According to the Kolmogorov–Smirnov Test, variables were not normally distributed. Thus, results are expressed as percentages or medians, and percentiles. The correlation between the IBDQ-36 values at week 14 and CDAI at week 52 was evaluated by using the Spearman’s Correlation Coefficient. The receiver operating characteristic (ROC) curves analysis was used to explore the predictive value of early restoration of HRQoL for long-term clinical remission.
Results Characteristics of patients. A total of 206 records of CD patients who received anti-TNFα treatment in our unit in clinical practice conditions were evaluated. Of these, 94 patients met the inclusion criteria so the final analysis was done with these patients. Sixty-three percent were female. Sixty patients received adalimumab and 34 received infliximab. Eighty-four patients were also receiving an immunomodulator (thiopurines in 66 cases, methotrexate in eight, and mycophenolate mofetil in 11 patients). Median baseline CDAI was 206 and IBDQ-36 was 175. (Table 1) Early restoration of HRQoL. Fifty-one patients achieved an early restoration of HRQoL according to previously defined criteria and forty-three did not restore it. All patients that achieved early restoration were on clinical remission at the time (CDAI < 150), whereas only 46% of patients who did not restore their quality of life were on clinical remission at week 14 (P < 0.01). As shown in Table 2, baseline characteristics of both groups were similar, however the value of basal IBDQ-36 was higher in patients who restored their quality of life (194 [156–206] vs 156 [130–175] P < 0.01 95% CI 19–45), also the CRP was lower in patients with early restoration (9.2 [2.52–11.86] vs 12.3 [5.61–15.22] P = 0.01 95% CI 0.93–2.38).
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Table 1 Baseline demographic and clinical characteristics of the 94 patients. Results expressed as medians and (25th percentile—75th percentile) Age at week 0 of anti-TNFα treatment Sex (male/female) Smoking status Current smoker Former smoker Never smoked Months since CD diagnosis Age at diagnosis A1: < 16 A2: 17–40 A3: > 40 Location of disease L1: Ileal L2: Colonic L3: Ileocolonic L2 + L4: Colonic + upper disease Behavior of disease B1: Non-stricturing, non-penetrating B2: Stricturing B3: Penetrating B1 + p† B2 + p† B3 + p† Treatment Infliximab/Adalimumab Immunomodulator (yes/no) CDAI IBDQ-36 Hemoglobin (g/dL) Leucocyte count (x103/mm3) Platelet count (x 109/L) CRP (mg/L) Ferritin (ng/mL)
34 [27.5–42] 35/59
33 21 40 86 [28–142.5] 12 67 15 32 19 42 1
Correlation between IBDQ-36 and clinical activity by CDAI. The Spearman correlation coefficient was used to determine the relationship between the values of the overall IBDQ-36 and the CDAI, as shown in Figure 3. We found a strong negative correlation between the values of the IBDQ-36 at week 14 and the CDAI values at week 52, and it was statistically significant (rs = − 0.64, P < 0.01, 95% CI − 0.79–− 0.38), this suggests that the higher the score on the early IBDQ-36 in response to anti-TNF treatment, the better the long-term clinical response, with lower activity (CDAI) scores.
Discussion
25 15 10 20 15 9 34/60 84/10 206 [163.75–251.25] 170.5 [142–199] 12.2 [11–13.1] 7.7 [5.4–9.8] 316.5 [255.4–401.2] 12.8 [3.8–45.7] 55 [23–126]
†
p is added to B1–B3 when concomitant perianal disease is present. TNFα, tumor necrosis factor-alpha.
Early restoration of HRQoL and long-term clinical remission. Sixty-three patients maintained a long-term clinical remission (CDAI < 150 at week 52), forty-seven (75%) of them achieved an early restoration of quality of life. Of the 31 patients who did not maintain long-term clinical remission, only four (13%) had an early restoration of their quality of life (P < 0.01, OR: 8.95, 95% CI 5.51–86). We also found that achieving restoration of HRQoL at week 2, after the first dose of anti-TNF, is also related with long termclinical remission (P < 0.01, OR: 6.96, 95% CI 2.04–30). (Table 3) Figure 1 shows that in patients who restore their HRQoL at week 14, clinical remission was achieved more frequently than in patients who did not restore their HRQoL, and this is maintained in follow-up visits (P < 0.01). This suggests that a very early restoration of HRQoL is an important and lasting favorable clinical outcome. To predict long-term remission, the area obtained underneath the ROC curve in early IBDQ-36 for the cutoff point of 209 was 288
0.87 (Fig. 2), with a sensitivity and specificity of 0.75 and 0.87, respectively, a positive likelihood ratio of 3.43 and a negative likelihood ratio of 0.17.
The results of our study demonstrate that the early restoration of the quality of life after induction with anti-TNF treatment in patients with CD is associated with clinical remission at one year. The need to examine subjective aspects of the health of patients with inflammatory bowel disease, basically HRQoL, has been recognized. In the vast majority of controlled clinical trials, the improvement of quality of life is defined as statistically significant when the questionnaires score increases. This measurement of improvement may not be clinically relevant and should be supplemented by additional information, such as the threshold of normality for the quality of life. Although some outcomes of treatment response in patients with CD, such as mucosal healing, have a prognostic value, this aspect has not been specifically designed for HRQoL. Results of our study showed that achieving higher scores in the IBDQ-36 at week 14 in response to biological treatment was associated with lower scores in the CDAI in subsequent visits. With these results, it can be concluded that patients who had an early restoration of their HRQoL not only had a clinical remission and overall lower activity scores but also that this was maintained in subsequent visits. The strong negative correlation between longterm CDAI and early IBDQ-36 may not be unexpected because some elements of the clinical assessment are similar in both instruments. It is interesting that achieving restoration of HRQoL as early as 2 weeks after the first dose of anti-TNF was also associated with long-term clinical remission. There are CD-related factors that could be involved in achieving and restoring HRQoL. Among them, a significant factor might be to have less severe disease. In the case of our patients, we found that baseline CRP was slightly lower in those who restored their HRQoL early, which might suggest that they had lower inflammatory activity than patients who did not restore their HRQoL. We found no differences in other variables such as disease behavior, location, or age at diagnosis. An interesting question is how a questionnaire that was designed to assess the quality of life can be a forecast tool to evaluate the activity of the disease in the long term. One possible answer is that alterations in quality of life often reflect the general welfare almost unconsciously, possibly even before the appearance of overt symptoms. Since the general welfare and quality of life are closely related, the quality of life scores have shown to be
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Table 2 Baseline demographic and clinical characteristics of patients distributed according to early restoration of HRQoL to treatment. Results expressed as medians and (25th percentile—75th percentile) Early restoration of HRQoL (IBDQ-36 > 209 at week 14) Yes n Sex (male/female) Smoking status Smoker/Former smoker Never smoked Age at diagnosis A1: < 16 A2: 17–40 A3: > 40 Location of disease L1: Ileal L2: Colonic L3: Ileocolonic L2 + L4: Colonic + upper disease Behavior of disease B1: Non-stricturing, non-penetrating B2: Stricturing B3: Penetrating B1 + p† B2 + p† B3 + p† Infliximab/Adalimumab Immunomodulator CDAI IBDQ-36 global score CRP (mg/L)
P
No
51 21/30
43 14/29
29 22
25 18
7 38 6
5 29 9
17 9 24 1
15 10 18 0
ns ns
ns
ns
ns 13 11 6 9 8 4 14/37 46 179 [163–248] 194 [156–206] 9.2 [2.52–11.86]
12 4 4 11 7 5 20/23 38 230 [167–258] 156 [130–175] 12.3 [5.61–15.22]
ns ns ns P < 0.01 P = 0.01
†
p is added to B1–B3 when concomitant perianal disease is present. HRQoL, health-related quality of life; not significant (ns).
Table 3 Percentage of patients in long-term clinical remission according to restoration of HRQoL (IBDQ-36 >209) at week 2, 6 & 14 Long-term clinical remission (%)
Week 2 Week 6 Week 14
IBDQ-36 > 209
IBDQ-36 < 209
89% 88% 92%
53% 44.4% 37.2%
OR (95%CI)
P
6.96 (2.04–30) 8.2 (2.96–30.3) 8.95 (5.51–86)
P < 0.01 P < 0.01 P < 0.01
CI, confidence interval; HRQoL, health-related quality of life; IBDQ, Inflammatory Bowel Disease Questionnaire: OR, odds ratio.
very sensitive to detect early stages of disease exacerbation. Therefore, when patients are engaged in their daily activities, evaluation of quality of life can be a tool to raise awareness of changes in the course of the disease. Other authors have also observed this.22,23 From the results of this study, we observed stability of clinical response at one year, but we cannot determine whether this early restoration of HRQoL can predict clinical remission for longer periods of time. In addition, due to the retrospective design of the
Figure 1 Clinical remission per visit, arranged according to early restoration of health-related quality of life (HRQoL) at week 14. (*P < 0.01). ■, Early restoration HRQoL; , No early restoration HRQoL.
study, some data on clinical and endoscopic activity were not available in all patients. The results of our study should be evaluated in prospective studies and correlated with other objective markers such as fecal calprotectin or endoscopy and mucosal healing.
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References
Figure 2 Receiver operating characteristic (ROC) curve for the cutoff point of 209 at week 14 of the global IBDQ-36 to predict long-term clinical remission.
Figure 3 Inflammatory Bowel Disease Questionnaire (IBDQ)-36 global scores at week 14 was inversely correlated with clinical activity score at week 52 (rs = −0.64 (P < 0.01, 95% CI −0.79–0.38).
In conclusion, the results of our study show that early restoration of quality of life after induction with anti-TNFα treatment is associated with clinical remission one year after starting treatment. Quality of life is a well-established measure for the evaluation of effective treatment, and results of this study suggest that the restoration of a normal HRQoL in patients with CD has a significant predictive value of clinical remission. This could be a therapeutic goal of treatment both in clinical trials and in daily practice.
Acknowledgment The study was supported by grants from the CIBERehd, Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación, Spain. 290
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