TY - JOUR
AU - Ulrich, Meinzer,
AB - Abstract Background Crohn’s disease (CD) is a chronic relapsing inflammatory disease. To optimize therapeutic decision making, it is essential to identify parameters that allow early prediction of a severe disease course. The aim of this study was to assess the link between arthritis and medium-term therapeutic failure in pediatric CD. Methods We conducted a population-based cohort study with prospectively collected electronic data. To be included, patients must be younger than 17 years and have a confirmed CD diagnosed between 2005 and 2014. The primary outcome was the percentage of patients with at least 1 therapeutic failure of immunosuppressive drugs during the 2 years after the CD diagnosis, with a propensity score analysis. Results We included 272 patients with CD. The median age was 12.1 years (interquartile [10.1–14.2]). Sixty-five patients (23.9%) developed arthritis, which predominantly occurred during the first year after CD diagnosis. We found a highly significant association between arthritis and therapeutic failure of immunosuppressive drugs after 2 years (OR = 6.9; 95% confidence interval [CI], 2.7–18.0; P < 0.0001; propensity score matching analysis). Arthritis was also significantly associated with introduction of biotherapy due to luminal disease 2 years after diagnosis (OR = 3.2, 95% CI, 1.8–6.0; P = 0.0001). Similar results were obtained after 4 years, and arthritis was significantly associated with a higher number of hospitalizations for luminal flare-up or complications after 4 years (OR = 2.2; 95% CI, 1.2–3.9; P = 0.007). Conclusions Arthritis was strongly associated with medium-term therapeutic failure of pediatric CD. Occurrence of arthritis early in the disease may justify closer follow-up visits or specific therapeutic management. arthritis, inflammatory bowel disease, pediatrics, propensity score INTRODUCTION Crohn’s disease (CD) is a chronic relapsing inflammatory bowel disease with a significant impairment of quality of life. Between 23,000 and 41,000 new cases are diagnosed annually in Europe.1 Disease onset occurs at pediatric age in up to 20% of the cases.2 The prevalence in people younger than 20 is about 43 per 100,000 in the United States.3 The use of intensified treatment approaches for patients with severe disease has been proposed previously,4 and the benefit of so-called “top-down” strategies to improve initial therapeutic management of severe CD is subject of a current debate.5 These approaches rely on early identification of severe disease.4 In adults, disease location, age at diagnosis, and behavior of the disease have been identified as prognostic factors of CD evolution.6, 7 Furthermore, pediatric onset and young age have been reported as risk factors for severe disease.8–10 The use of early aggressive treatment may therefore be of interest especially in pediatric patients. However, the course of CD is highly variable, and it remains difficult to reliably predict a severe disease course.6 Therefore, it is essential to identify new parameters that allow early prediction of a severe disease course.6, 7, 11 Extra-intestinal manifestations (EIM) are frequent in CD and may occur before or after diagnosis.12 Arthropahies, an umbrella term for inflammatory joint manifestations and noninflammatory peripheral joint pain, are the most common extra-intestinal manifestation in patients with inflammatory bowel disease (IBD).13 Peripheral arthropathies in inflammatory bowel disease (IBD) include arthritis, enthesitis, dactylitis, and arthralgia. Articular manifestations occur in approximately 10%–30% of adult patients with CD13–15 and in 16%–33% of pediatric CD patients.16 Arthralgia, or noninflammatory joint pain, is diagnosed clinically. Physical examination, which involves palpation of the joints, reveals pain but no swelling or effusion. Arthralgia in patients with IBD can have several causes that are not directly linked to CD.13 Peripheral arthritis in IBD is diagnosed clinically by the presence of pain and swelling in 1 or more joints. During physical examination, stiffness, tenderness, and a decreased range of motion may be present.13 Either aspiration of synovial fluid or imageries is necessary when alternative diagnoses are suspected.13 Peripheral arthritis in patients with IBD may be classified as type 1 and type 2 arthritis.14 Type 1 is a pauciarticular peripheral arthritis affecting 4 or fewer joints and usually resolves within weeks. In contrast, type 2 is a polyarticular arthritis affecting 5 or more joints with persistent symptoms for months to years and occurs independently of IBD activity. The type 1 and type 2 subdivision of arthritis associated with IBD is commonly used in gastroenterological studies17, 18 but not widely known in rheumatology literature. The onset of peripheral arthritis is generally believed to occur during exacerbations of IBD; though data on the interrelation between CD activity and occurrence of arthritis remains limited with respect to adult patients14, 17, 18 and are even less documented in pediatric patients.16 A recent systematic review19 analyzed the current evidence on prognostic factor in CD severity and highlighted that data about the role of extra intestinal manifestation to predict severe CD are currently very limited.19 In particular, arthritis is generally studied together with other EIM,8 and little specific data about arthritis have been reported.19 A recent study suggested that patients with arthritis are more likely to be treated with biologic therapy.20 It remains largely unknown whether arthritis can contribute to the identification of patients with severe disease evolution, especially in pediatric patients.8 The objective of this study was to assess the association between arthritis and medium-term therapeutic failure in pediatric CD with a propensity score analysis. METHODS Study Design We conducted a prospective and retrospective cohort study over 11 years. The retrospective period occurred from January 1, 2005, to September 30, 2014. The prospective period started on October 1, 2014, and ended on September 30, 2016. During this study period, data were prospectively recorded using the hospital medical software (PCS technology). The data were collected following the same procedure for the entire study period, ensuring a same data quality during the whole study period. We included all patients with CD diagnosis from January 1, 2005, to September 30, 2014, confirmed by endoscopy and histology at Robert Debré University Hospital. The accurate CD diagnosis was based on current international recommendations.21 The reporting of the study was based on Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) recommendations22 and on European Heart Journal (EHE) recommendations for studies using propensity score.23 Study Data and Setting The study was performed in a reference center for pediatric inflammatory bowel disease at the Robert Debré University Hospital in Paris, France. Data collection was based on a prospective recording allowed by the medical software of the hospital. The recording was performed by the medical specialist, who cared for the patients according to international guidelines for CD management during the entire period of the study.24 Data on demographic characteristics, clinical feature over time, endoscopic findings, therapeutic management over time, hospitalizations, and need for surgery were available in this cohort. Definitions According to previously described definitions, peripheral arthritis was defined as articular pain with inflammatory schedule and functional impotence, with articular swelling, tenderness ,or effusion.13 Inflammatory back pain was defined according to ASAS criteria.25 Patients receiving either azathioprine, 6-mercaptopurine, or methotrexate were considered as receiving immunosuppressive drugs.27 Treatment with immunosuppressive drugs was initiated within the first 3 months after CD diagnosis. The definition of therapeutic failure of immunosuppressive drugs was considered according to the previously established definition of nonsurgical recurrence6, 26 as any new treatment used to control luminal CD (excepted antibiotics) or any increase of a preexistent immunosuppressive treatment to control luminal CD.6, 26 To avoid confusion bias, we only considered treatments introduced due to luminal disease and not due to joint involvement. Thiopurine S-methyltransferase activity and thiopurine metabolite levels were explored systematically.28 A dose adjusted to reach or to maintain therapeutic metabolite levels were not considered as therapeutic failure. For biotherapy treatment, we reported the treatment indication grouped in 4 categories: failure of previous treatment, intolerance of previous treatment, perineal disease, and articular manifestations. Given that arthritis may represent an indication for biotherapy, we only considered introduction of biotherapy due to luminal disease flare-up or luminal disease complication to avoid confusion bias. Similarly, we only considered hospitalizations due to digestive CD flare-up and did not consider hospitalizations due to arthritis or joint-related CD flares or complications—or for reasons not related to CD (eg, acute infections, trauma). Outcome Measure The primary outcome was the percentage of patients with therapeutic failure of at least 1 immunosuppressive drug due to luminal disease during the 2 years after CD diagnosis. The first 3 months after CD diagnosis were considered as the therapeutic-adjustment and dose-finding period. Therefore, all therapeutic initiations or changes occurring during this period were not recorded as therapeutic failure. The secondary outcomes were 1) the percentage of patients with at least 1 biotherapy initiated to control luminal disease during the 2 years after the CD diagnosis; 2) the ercentage of patients with at least 1 therapeutic failure of immunosuppressive drugs within the 4 years after CD diagnosis; 3) the percentage of patients with at least 1 biotherapy initiated to control luminal disease during the 4 years after CD diagnosis; 4) the number of hospitalizations for CD flare-up or complication during the 4 years after CD diagnosis; and 5) the percentage of patients with surgery for CD flare-up or complication during the 4 years after CD diagnosis. In a post hoc analysis, we assessed the link between the precocity of arthritis and the number of therapeutic failures. Statistical Analysis Following guidelines on propensity score (PS) analysis reporting23 for each outcome, we presented results from a classic multivariate logistic regression, adjusted on baseline covariates (PARIS classification,29 including disease localization, behavior, growth impairment, and perineal disease modifier; year of diagnosis, age, and first-line drug used), and we also presented results from the propensity score analysis. The PS method30 attempts to balance the exposed and non-exposed groups to reduce selection bias in observational designs, thereby creating a quasi-randomized experiment.31–33 For each patient, we produced a score modeling the conditional probability of having a treatment or an exposition (arthritis), given the observed covariates of the patient.34 In this method, the number of potential confounders to be used in creating the score is not limited by the number of clinical outcome events, as opposed to the conventional regression approach.35 We included all baseline covariates presented in Appendix 1 of the supplementary data in the PS model. We chose all variables a priori based on previous work or clinical reasoning.36, 37 To avoid bias due to eventual modification of therapeutic management following the emergence of new treatments, the year of diagnosis was included into the PS. Distributions of PS in the matched and unmatched patients are displayed in Appendix 2 of the supplementary data. First, the PS was calculated with a nonparsimonious multivariate logistic regression model including the baseline covariates. Then, patients with arthritis were matched with patients without with a 1:2 ratio, given that joint involvement was present in only 24% of the population, to maximize the number of patients matched. We used a nearest-neighbor matching method that matched pairs of subjects with the 2 nearest PS values, with a minimum caliper of 0.25 of the PS,37 and with no replacement of the control patients. Finally, we performed a conditional logistic regression analysis with the matched cohort to test the association between the presence of arthritis and the therapeutic failure. The same process was performed for all the secondary outcomes. We also performed a post hoc subgroup analysis to assess the link between the precocity of joint involvement and the number of therapeutic failures for patients who experienced arthritis, using a linear regression adjusted on PARIS score, age, and first-line drug used. All comparisons were made using 2-sided significance level of P < 0.05. Statistical analyses were performed R software, version 3.3.0 (http://www.R-project.org). Ethical Considerations The study was approved by the Robert Debré Hospital ethics committee. RESULTS We identified 355 patients with suspected CD. We excluded 39 patients because disease was diagnosed before 2005, 26 patients because CD was not confirmed, and 18 patients who were not diagnosed and regularly followed up in our reference center. The remaining 272 patients were included in the study. The flow chart is shown in Fig. 1. Median age at CD diagnosis was 12.1 years (interquartile 10.1–14.2). Of the 272 patients, 65 (23.9%) developed arthritis. The general characteristics of the population are described in Table 1. FIGURE 1. View largeDownload slide Flow chart. FIGURE 1. View largeDownload slide Flow chart. TABLE 1: General Characteristics of the Population General population n = 272 Patients without arthritis n = 207 (76%) Patients with arthritis n = 65 (24%) Median age (years, [Q1-Q3]) 12.1 (10.1–14.2) 12.7 (10.4–14.2) 11.1 (8.5–13.8) Female gender 119 (44%) 87 (42%) 32 (49%) Localization*  L1 48 (18%) 39 (19%) 9 (14%)  L2 81 (30%) 61 (29%) 20 (31%)  L3 139 (51%) 104 (50%) 35 (54%)  L4 61 (22%) 47 (23%) 14 (22%) Behavior*  B1 195 (72%) 154 (74%) 41 (63%)  B2 57 (21%) 41 (20%) 16 (25%)  B3 12 (4%) 7 (3%) 5 (8%)  B2B3 8 (3%) 5 (2%) 3 (5%)  Perineal disease modifier* 105 (39%) 83 (40%) 22 (34%) Growth impairment* 59 (22%) 38 (18%) 21 (32%) Year of diagnosis 2009 (2007–2012) 2009 (2007–2012) 2010 (2007–2012) Length of follow up (years) 4.4 [3.2–6.4] 4.4 [3.2–6.3] 4.7 [3.2–6.8] Initial treatment  Corticosteroids + Azathioprine 60 (22.0%) 43 (20.8%) 17 (26.2%)  Enteral nutrition + Azathioprine 60 (22.0%) 46 (22.2%) 14 (21.5%)  Corticosteroids + Aminosalicylate 45 (16.5%) 35 (16.9%) 10 (15.4%)  Corticosteroids + Azathioprine + Aminosalicylate 52 (19.1%) 40 (19.3%) 12 (18.5%)  Corticosteroids + 6-mercaptopurine 13 (4.8%) 12 (5.8%) 1 (1.5%)  Corticosteroids + Methotrexate 8 (2.9%) 6 (2.9%) 2 (3.1%)  Enteral Nutrition + Methotrexate 7 (2.6%) 4 (1.9%) 3 (4.6%)  Infliximab 21 (7.7%) 15 (7.2%) 6 (9.2%)  Other treatment combination 6 (2.2%) 6 (2.9%) 0 (0%) General population n = 272 Patients without arthritis n = 207 (76%) Patients with arthritis n = 65 (24%) Median age (years, [Q1-Q3]) 12.1 (10.1–14.2) 12.7 (10.4–14.2) 11.1 (8.5–13.8) Female gender 119 (44%) 87 (42%) 32 (49%) Localization*  L1 48 (18%) 39 (19%) 9 (14%)  L2 81 (30%) 61 (29%) 20 (31%)  L3 139 (51%) 104 (50%) 35 (54%)  L4 61 (22%) 47 (23%) 14 (22%) Behavior*  B1 195 (72%) 154 (74%) 41 (63%)  B2 57 (21%) 41 (20%) 16 (25%)  B3 12 (4%) 7 (3%) 5 (8%)  B2B3 8 (3%) 5 (2%) 3 (5%)  Perineal disease modifier* 105 (39%) 83 (40%) 22 (34%) Growth impairment* 59 (22%) 38 (18%) 21 (32%) Year of diagnosis 2009 (2007–2012) 2009 (2007–2012) 2010 (2007–2012) Length of follow up (years) 4.4 [3.2–6.4] 4.4 [3.2–6.3] 4.7 [3.2–6.8] Initial treatment  Corticosteroids + Azathioprine 60 (22.0%) 43 (20.8%) 17 (26.2%)  Enteral nutrition + Azathioprine 60 (22.0%) 46 (22.2%) 14 (21.5%)  Corticosteroids + Aminosalicylate 45 (16.5%) 35 (16.9%) 10 (15.4%)  Corticosteroids + Azathioprine + Aminosalicylate 52 (19.1%) 40 (19.3%) 12 (18.5%)  Corticosteroids + 6-mercaptopurine 13 (4.8%) 12 (5.8%) 1 (1.5%)  Corticosteroids + Methotrexate 8 (2.9%) 6 (2.9%) 2 (3.1%)  Enteral Nutrition + Methotrexate 7 (2.6%) 4 (1.9%) 3 (4.6%)  Infliximab 21 (7.7%) 15 (7.2%) 6 (9.2%)  Other treatment combination 6 (2.2%) 6 (2.9%) 0 (0%) Quantitative characteristics (age, years of follow-up, year of diagnosis, length of follow-up) are given as median and interquartile, qualitative characteristics (localization, behavior, perineal disease modifier, growth impairment, initial treatment) are given as number and percentage. *Following the PARIS classification. View Large TABLE 1: General Characteristics of the Population General population n = 272 Patients without arthritis n = 207 (76%) Patients with arthritis n = 65 (24%) Median age (years, [Q1-Q3]) 12.1 (10.1–14.2) 12.7 (10.4–14.2) 11.1 (8.5–13.8) Female gender 119 (44%) 87 (42%) 32 (49%) Localization*  L1 48 (18%) 39 (19%) 9 (14%)  L2 81 (30%) 61 (29%) 20 (31%)  L3 139 (51%) 104 (50%) 35 (54%)  L4 61 (22%) 47 (23%) 14 (22%) Behavior*  B1 195 (72%) 154 (74%) 41 (63%)  B2 57 (21%) 41 (20%) 16 (25%)  B3 12 (4%) 7 (3%) 5 (8%)  B2B3 8 (3%) 5 (2%) 3 (5%)  Perineal disease modifier* 105 (39%) 83 (40%) 22 (34%) Growth impairment* 59 (22%) 38 (18%) 21 (32%) Year of diagnosis 2009 (2007–2012) 2009 (2007–2012) 2010 (2007–2012) Length of follow up (years) 4.4 [3.2–6.4] 4.4 [3.2–6.3] 4.7 [3.2–6.8] Initial treatment  Corticosteroids + Azathioprine 60 (22.0%) 43 (20.8%) 17 (26.2%)  Enteral nutrition + Azathioprine 60 (22.0%) 46 (22.2%) 14 (21.5%)  Corticosteroids + Aminosalicylate 45 (16.5%) 35 (16.9%) 10 (15.4%)  Corticosteroids + Azathioprine + Aminosalicylate 52 (19.1%) 40 (19.3%) 12 (18.5%)  Corticosteroids + 6-mercaptopurine 13 (4.8%) 12 (5.8%) 1 (1.5%)  Corticosteroids + Methotrexate 8 (2.9%) 6 (2.9%) 2 (3.1%)  Enteral Nutrition + Methotrexate 7 (2.6%) 4 (1.9%) 3 (4.6%)  Infliximab 21 (7.7%) 15 (7.2%) 6 (9.2%)  Other treatment combination 6 (2.2%) 6 (2.9%) 0 (0%) General population n = 272 Patients without arthritis n = 207 (76%) Patients with arthritis n = 65 (24%) Median age (years, [Q1-Q3]) 12.1 (10.1–14.2) 12.7 (10.4–14.2) 11.1 (8.5–13.8) Female gender 119 (44%) 87 (42%) 32 (49%) Localization*  L1 48 (18%) 39 (19%) 9 (14%)  L2 81 (30%) 61 (29%) 20 (31%)  L3 139 (51%) 104 (50%) 35 (54%)  L4 61 (22%) 47 (23%) 14 (22%) Behavior*  B1 195 (72%) 154 (74%) 41 (63%)  B2 57 (21%) 41 (20%) 16 (25%)  B3 12 (4%) 7 (3%) 5 (8%)  B2B3 8 (3%) 5 (2%) 3 (5%)  Perineal disease modifier* 105 (39%) 83 (40%) 22 (34%) Growth impairment* 59 (22%) 38 (18%) 21 (32%) Year of diagnosis 2009 (2007–2012) 2009 (2007–2012) 2010 (2007–2012) Length of follow up (years) 4.4 [3.2–6.4] 4.4 [3.2–6.3] 4.7 [3.2–6.8] Initial treatment  Corticosteroids + Azathioprine 60 (22.0%) 43 (20.8%) 17 (26.2%)  Enteral nutrition + Azathioprine 60 (22.0%) 46 (22.2%) 14 (21.5%)  Corticosteroids + Aminosalicylate 45 (16.5%) 35 (16.9%) 10 (15.4%)  Corticosteroids + Azathioprine + Aminosalicylate 52 (19.1%) 40 (19.3%) 12 (18.5%)  Corticosteroids + 6-mercaptopurine 13 (4.8%) 12 (5.8%) 1 (1.5%)  Corticosteroids + Methotrexate 8 (2.9%) 6 (2.9%) 2 (3.1%)  Enteral Nutrition + Methotrexate 7 (2.6%) 4 (1.9%) 3 (4.6%)  Infliximab 21 (7.7%) 15 (7.2%) 6 (9.2%)  Other treatment combination 6 (2.2%) 6 (2.9%) 0 (0%) Quantitative characteristics (age, years of follow-up, year of diagnosis, length of follow-up) are given as median and interquartile, qualitative characteristics (localization, behavior, perineal disease modifier, growth impairment, initial treatment) are given as number and percentage. *Following the PARIS classification. View Large The most frequent type of articular involvement was peripheral oligo-articular arthritis of large joints (86% of the patients with joint involvement), followed by inflammatory back pain (26% of the patients with joint involvement), and then peripheral polyarticular arthritis of small articulations (15% of the patients with joint involvement). Four patients (6%) had inaugural joint disease. Interestingly, the median delay between CD diagnosis and arthritis was 9 months, and 75% of the arthritis occurred during the first year after CD diagnosis. We concluded that joint involvement occurred early in CD evolution in the majority of pediatric cases. Therapeutic Failure of Immunosuppressive Drugs First, we studied the link between arthritis and therapeutic failure of immunosuppressive drugs due to luminal disease during the first 2 years of follow-up after diagnosis. Among the 272 included patients, 2 were lost during the follow-up 2 years after diagnosis, and 270 achieved at least 2 years of follow-up (99.3%). Two hundred fifty-one patients were initially treated by immunosuppressive drugs, and 21 received biotherapy as a first-line drug. During the 2 years after CD diagnosis, therapeutic failure of immunosuppressive drugs occurred in 55 of 59 patients with arthritis (93%) and in 123 of 192 patients without arthritis (64%) (Fig. 2A). FIGURE 2. View largeDownload slide Crohn’s disease (CD) evolution and treatment escalations for patients with or without ioint Involvement (JI). CD evolution and treatment escalation 2 years (A) and 4 years (B) after diagnosis. *Therapeutic failure of immunosuppressive drugs. **Enteral Nutrition. ***Other therapeutics: aminosalicylates, 6-mercaptopurine, methotrexate. C, survival curve without therapeutic failure in patients with or without arthritis. D, survival curve without biotherapy in patients with or without arthritis. FIGURE 2. View largeDownload slide Crohn’s disease (CD) evolution and treatment escalations for patients with or without ioint Involvement (JI). CD evolution and treatment escalation 2 years (A) and 4 years (B) after diagnosis. *Therapeutic failure of immunosuppressive drugs. **Enteral Nutrition. ***Other therapeutics: aminosalicylates, 6-mercaptopurine, methotrexate. C, survival curve without therapeutic failure in patients with or without arthritis. D, survival curve without biotherapy in patients with or without arthritis. Classic multivariate logistic regression without PS showed that arthritis was significantly associated with therapeutic failure of immunosuppressive drugs during the 2 years after CD diagnosis (odds ratio [OR] = 9.3; 95% CI, 3.1–34.9; P = 0.0001). Using PS matching, we also found a strongly significant association between arthritis and therapeutic failure 2 years after CD diagnosis (OR = 6.9; 95% CI, 2.7 to 18.0; P < 0.0001). Table 2 and Fig. 2A, C illustrate these results. Table 2: Association Between Arthritis and Severity of CD Evolution Patients with arthritis n = 65 Patients without arthritis n = 207 classic multi-variate logistic regression OR [CI 95%] PS matching analysis OR [CI 95%] PS matching analysis P Failure of immune-suppressive drugs:  after 2 years 55/59 (93%) 123/192 (64%) 9.3 IC (3.1–34.9) 6.9 (2.7–18.0) <0.0001  after 4 years 55/59 (93%) 136/192 (71%) 6.3 (2.3–22.5) 4.8 (1.8–12.6) 0.001 Biotherapy use:  after 2 years 35/59 (59%) 43/192 (22%) 4.3 (2.2–8.3) 3.2 (1.8–6.0) 0.0001  after 4 years 45/59 (76%) 62/192 (32%) 5.6 (2.9–11.3) 4.3 (2.2–8.4) <0.0001 N hospitalizations (mean, sd) 2.0 (2.5) 0.9 (1.3) 2.3 (1.5–3.7) 2.2 (1.2–3.9) 0.007 Surgery (%) 11/65 (17%) 27/207 (13%) 1.1 (0.9–1.2) 1.0 (0.4–2.4) 1.0 Patients with arthritis n = 65 Patients without arthritis n = 207 classic multi-variate logistic regression OR [CI 95%] PS matching analysis OR [CI 95%] PS matching analysis P Failure of immune-suppressive drugs:  after 2 years 55/59 (93%) 123/192 (64%) 9.3 IC (3.1–34.9) 6.9 (2.7–18.0) <0.0001  after 4 years 55/59 (93%) 136/192 (71%) 6.3 (2.3–22.5) 4.8 (1.8–12.6) 0.001 Biotherapy use:  after 2 years 35/59 (59%) 43/192 (22%) 4.3 (2.2–8.3) 3.2 (1.8–6.0) 0.0001  after 4 years 45/59 (76%) 62/192 (32%) 5.6 (2.9–11.3) 4.3 (2.2–8.4) <0.0001 N hospitalizations (mean, sd) 2.0 (2.5) 0.9 (1.3) 2.3 (1.5–3.7) 2.2 (1.2–3.9) 0.007 Surgery (%) 11/65 (17%) 27/207 (13%) 1.1 (0.9–1.2) 1.0 (0.4–2.4) 1.0 Abbreviations: JI, Joint involvement. Number of hospitalization is presented as mean and standard deviation to be more informative. View Large Table 2: Association Between Arthritis and Severity of CD Evolution Patients with arthritis n = 65 Patients without arthritis n = 207 classic multi-variate logistic regression OR [CI 95%] PS matching analysis OR [CI 95%] PS matching analysis P Failure of immune-suppressive drugs:  after 2 years 55/59 (93%) 123/192 (64%) 9.3 IC (3.1–34.9) 6.9 (2.7–18.0) <0.0001  after 4 years 55/59 (93%) 136/192 (71%) 6.3 (2.3–22.5) 4.8 (1.8–12.6) 0.001 Biotherapy use:  after 2 years 35/59 (59%) 43/192 (22%) 4.3 (2.2–8.3) 3.2 (1.8–6.0) 0.0001  after 4 years 45/59 (76%) 62/192 (32%) 5.6 (2.9–11.3) 4.3 (2.2–8.4) <0.0001 N hospitalizations (mean, sd) 2.0 (2.5) 0.9 (1.3) 2.3 (1.5–3.7) 2.2 (1.2–3.9) 0.007 Surgery (%) 11/65 (17%) 27/207 (13%) 1.1 (0.9–1.2) 1.0 (0.4–2.4) 1.0 Patients with arthritis n = 65 Patients without arthritis n = 207 classic multi-variate logistic regression OR [CI 95%] PS matching analysis OR [CI 95%] PS matching analysis P Failure of immune-suppressive drugs:  after 2 years 55/59 (93%) 123/192 (64%) 9.3 IC (3.1–34.9) 6.9 (2.7–18.0) <0.0001  after 4 years 55/59 (93%) 136/192 (71%) 6.3 (2.3–22.5) 4.8 (1.8–12.6) 0.001 Biotherapy use:  after 2 years 35/59 (59%) 43/192 (22%) 4.3 (2.2–8.3) 3.2 (1.8–6.0) 0.0001  after 4 years 45/59 (76%) 62/192 (32%) 5.6 (2.9–11.3) 4.3 (2.2–8.4) <0.0001 N hospitalizations (mean, sd) 2.0 (2.5) 0.9 (1.3) 2.3 (1.5–3.7) 2.2 (1.2–3.9) 0.007 Surgery (%) 11/65 (17%) 27/207 (13%) 1.1 (0.9–1.2) 1.0 (0.4–2.4) 1.0 Abbreviations: JI, Joint involvement. Number of hospitalization is presented as mean and standard deviation to be more informative. View Large In the same way, PS matching analysis showed a strong association between arthritis and therapeutic failure of immunosuppressive drugs during the 4 years after the diagnosis (OR = 4.8; 95% CI, 1.8–12.6; P = 0.001) (Table 2andFig. 2B, C). These data showed that the presence of arthritis was strongly associated with therapeutic failure of immunosuppressive drugs within the first 2 years after CD diagnosis. Biotherapy Use Second, we studied the link between arthritis and introduction of a biotherapy for luminal disease. We differentiated biotherapy introduced for control of luminal disease (72% of cases), for perineal modifier (21%), for treatment intolerance (5%), or for arthropathies (2%). Only biotherapies introduced to control luminal disease were considered. Two years after CD diagnosis, a biotherapy was introduced to control luminal disease for 35 of 59 (59%) patients with arthritis and for 43 of 192 (22%) without arthritis. Infliximab was used as the first-line biotherapy in 97% of cases and adalimumab in 3% of cases. Classic multivariate logistic regression without PS showed that arthritis was significantly associated with introduction of biotherapy for luminal disease during the two years after CD diagnosis (OR = 4.3; 95% CI, 2.2–8.3; P < 0.0001). Using PS matching, we also found a highly significant association between arthritis and introduction of biotherapy during the 2 years after diagnosis (OR = 3.2; 95% CI, 1.8–6.0; P = 0.0001) (Table 2). This association was also observed when analyzing the period of 4 years after CD diagnosis (OR = 4.3; 95% CI, 2.2–8.4; P < 0.0001, PS matching analysis) (Table 2 and Fig. 2D). These data showed that the presence of arthritis was strongly associated with introduction of a biotherapy for luminal disease. Number of Hospitalizations, Surgery, and Growth Impairment Third, we studied the link between arthritis and the number of hospitalizations for luminal flare-ups and the need for surgery caused by flare-ups of luminal disease or complications. The average number of hospitalizations 4 years after the CD diagnosis was 2.0 (standard deviation 2.5) for patients with arthritis and was 0.9 (standard deviation 1.3) for patients without joint involvement. PS matching analysis showed that arthritis was significantly associated with the number of hospitalization after 4 years (OR = 2.2; 95% CI, 1.2–3.9; P = 0.007) (Table 2). No association was found between joint involvement and the need for surgery for CD flare-up or complication within 4 years after diagnosis (OR = 1.0; 95% CI, 0.4–2.4; P = 1, PS matching analysis). We concluded that arthritis was associated to multiple and severe luminal disease flares. Precocity of Arthritis In a post hoc subgroup analysis, we assessed the link between precocity of arthritis and the number of therapeutic failures of immunosuppressive drugs within the 2 years after CD diagnosis. A shorter delay between CD diagnosis and arthritis was significantly associated with a higher number of therapeutic failure (P = 0.02, linear regression analysis). Among patients with arthritis, experiencing arthritis 1 year earlier in CD evolution was associated with a 35.6% increase of the number of therapeutic failures. These findings suggested that within 2 years after CD diagnosis, the earlier the occurrence of arthritis, the higher the risk of treatment failure of immunosuppressive drugs. DISCUSSION The main finding of this study was that the presence of arthritis in pediatric CD is associated with a highly significant increased risk of therapeutic failure of immunosuppressive drugs after 2 years of follow-up (OR = 6.9, P < 0.0001) and with a major risk of biotherapy use during the first 2 years after diagnosis for luminal disease. These findings were also confirmed after 4 years of follow-up. Additionally, we found that arthritis was strongly associated to increased risk of hospitalization for luminal disease flare-ups or complications. Together, these findings further strengthen the idea that occurrence of early arthritis is related to a higher level of luminal pediatric CD activity over time. To the best of our knowledge, this is the first study comprehensively reporting a link between arthritis and the medium-term evolution of CD. However, several studies suggested that peripheral arthritis occurs more often in the context of active luminal disease.13, 18, 38 Thus, data of the literature support the interrelation between activity of intestinal CD and the occurrence of arthritis. A recent study39 reviewed the current evidence on the clinical risk factors predictive of CD complications, surgery, and disabling disease in adult CD patients. The authors highlighted that an early intensive therapy may avoid complications of CD and disabling disease. Similarly, a recent study in pediatric CD patients showed that early use of anti-TNFα within 90 days after the CD diagnosis decreases penetrating complications.4 These intensified treatment approaches rely on early identification of patients with severe disease. A systematic review19 conducted in 2016 assessed the clinical, biological, genetic, endoscopic, histologic, serologic, and fecal markers to predict clinical course of CD—both in adult and pediatrics. The authors concluded that no single marker might predict flare. Notable in this study, the only extra-intestinal manifestation analyzed was the presence of erythema nodosum and pyoderma gangrenosum.19 Our findings that arthritis occurred in the majority of patients (75%) during the first year after diagnosis and that it is associated to a more severe CD phenotype over time may, therefore, have some relevance for clinical management. Indeed, our data suggest that, at least in pediatric patients, occurrence of arthritis at an early disease state may be used as an additional parameter to identify patients who may benefit from closer follow-up visits or intensified treatment regimens. In our cohort, the proportion of patients with arthritis was 24%. In the literature, several studies12, 16, 40–42 reported that arthritis was observed in 13%–33% of the patients with pediatric CD. Moreover, in a large American pediatric CD cohort,40 the proportion of female gender was 42.5% (against 44% in our cohort), and the mean age was 11.7 years (median 12.1 years in our cohort). Thus, patients’ characteristics in our cohort were similar to other pediatric CD cohorts. Our study was conducted in a pediatric cohort. Despite a large number of excellent large cohort studies searching for risk factors19, 39 no comparable data is currently available for adult patients. However, it should be noted that most studies consider arthritis together with other EIM of CD, which may hinder interpretation on the use of arthritis as a single marker. The interpretation of current data is further complicated by the use of umbrella terms such as “joint manifestations,” “musculoskeletal manifestations,” or “arthropathies” that comprise several different clinical entities. Therefore, studies in adult CD cohorts are now required to confirm or to infirm the validity of our findings in adults. The strengths of this study include a large population-based pediatric CD cohort with high-quality follow-up (only 2 patients were lost during follow up after 2 years), the strength of the association (OR = 6.2, P < 0.0001) with regard to the primary outcome, with similar results from 2 methods of analysis (propensity score and multivariate regression) and finally a finding that might impact clinical practice in the foreseeable future. However, our studies also had several limitations: While the monocentric design allowed for more robustness of the results due to homogeneity of data collection and patients’ management, it limited its external validation. Additionally, we cannot rule out a recruitment bias as our study only included patients from a tertiary reference hospital. We did not assess the Pediatric Crohn’s Disease Activity Index (PCDAI) score43 in our findings. Assessment of therapeutic failure occurring at any time during the 2 years of follow-up required a continuous evaluation and thus rendered the use of punctual evaluations by established disease activity scores (such as the PCDAI score43) less appropriate. Moreover, the PCDAI and Crohn’s Disease Activity Index (CDAI) have recently been criticized for several reasons,7, 44 particularly because they are affected by considerable interobserver variability.45 The large period of inclusion and follow-up provided a large cohort with high-quality longitudinal data on evolution of CD many years after diagnosis. However, the emergence of new treatments during this period may have modified therapeutic management for patients. To reduce this risk of bias, we also included the year of diagnosis as an adjustment factor in statistical analysis. Our study was performed in a relative small cohort, which reduces the possibility of covariate adjustment. From a methodological point of view, the use of propensity score in our study increased the robustness of the findings and allowed the inclusion of a higher number of potential confounders for which one can adjust than the classical regression model.46 Thus, the statistical method used in our study strongly limited the risk of selection bias for observational designs. However, despite the large number of cofactors included in PS analysis, we cannot completely exclude other hidden factors that could play the role of confusion, such as microbiologic or genetic factors, which were not recorded in this study. CONCLUSION Arthritis was strongly associated with an increased risk of medium-term therapeutic failure in pediatric CD. The observations of this study may impact therapeutic decision-making. Indeed, this study suggests that, in pediatric patients, occurrence of arthritis may contribute to the identification of patients with severe CD. From a clinical point of view, it indicates that patients with arthritis should be managed with particular attention, which may justify closer follow-up visits. When arthritis occurs during the first year after CD diagnosis, it may allow for selection of patients that could benefit from early aggressive treatment algorithms. ACKNOWLEDGEMENTS We thank the pediatric gastroenterology department of the Robert Debré Hospital for inclusion of patients followed in this setting. We also thank the clinical research unit of the Robert Debré Hospital for its technical assistance. Author contributions: NO, UM, CMV, and JPH contributed to the design of the study. NO and UM performed data extraction. NO and DM wrote the statistical programs, NO and UM wrote the first draft of the manuscript. All authors contributed to further drafts and approved the final manuscript. Supported by a grant to UM by the Agence Nationale de la Recherche project “GUT-JIA” ANR-16-CE17-0009. 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TI - Early Arthritis Is Associated With Failure of Immunosuppressive Drugs and Severe Pediatric Crohn’s Disease Evolution
JF - Inflammatory Bowel Diseases
DO - 10.1093/ibd/izy137
DA - 2018-10-12
UR - https://www.deepdyve.com/lp/oxford-university-press/early-arthritis-is-associated-with-failure-of-immunosuppressive-drugs-sG7HAvJtqd
SP - 2423
VL - 24
IS - 11
DP - DeepDyve
ER -