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Six year adalimumab efficacy in steroid-dependent Crohn's disease patients: A prospective single-center real life study

Published:August 28, 2016DOI:https://doi.org/10.1016/j.dld.2016.07.019

      Abstract

      Background

      Adalimumab is effective in the treatment of Crohn's disease. We have already reported data on the efficacy of adalimumab in 110 steroid-dependent patients. At the end of the study 90 patients (64.5%) maintained clinical remission.

      Aims

      To assess efficacy and safety of adalimumab after 6 years in patients of the original cohort who responded to treatment.

      Methods

      The present study is an extension of the published paper on 90/110 patients. We report results on clinical remission and safety of 6 year maintenance therapy with adalimumab.

      Results

      Of the original cohort 90 patients completed the study, 17 were lost to follow-up and 3 died. At the end of follow-up (74.16 ± 10.3 months) 37/90 patients (41%) maintained clinical remission. Of these, 32 (86%) continued adalimumab and 5 (13%) discontinued treatment due to clinical remission and mucosal healing. Of the remaining 53/90 patients, 47 (52%) discontinued adalimumab due to clinical failure and 6 (7%) to adverse events.
      We obtained endoscopy data in 31/32 patients in clinical remission continuing adalimumab: 11 (36%) did not improve, 6 (19%) worsened, 14 (45%) improved. At univariable analysis no variables were related to treatment outcome.

      Conclusions

      This “real life” prospective study shows that adalimumab is a long-term effective and safe maintenance treatment in steroid-dependent Crohn's disease patients.

      Keywords

      1. Introduction

      According to the second European evidence-based consensus on diagnosis and management of Crohn's disease (CD) [
      • Van Assche G.
      • Dignass A.
      • Panes J.
      • et al.
      The second European evidence-based consensus on the diagnosis and management of Crohn's disease: definitions and diagnosis.
      ], steroid-dependent patients are defined as those ‘unable to reduce steroids below the equivalent of prednisolone 10 mg daily (or budesonide below 3 mg daily) within 3 months of starting steroids, without recurrent active disease’, and those who relapse within 3 months of stopping steroids. According to the Italian guidelines, patients treated with any dosage of steroids are considered steroid-dependent [
      • Orlando A.
      • Armuzzi A.
      • Papi C.
      • et al.
      Clinical Practice Guidelines: the use of tumor necrosis factor-alpha antagonist therapy in inflammatory bowel disease.
      ].
      Prolonged steroid response has been reported in 44% of patients with CD, steroid dependency in 36% and steroid refractory in 20% of patients [
      • Munkholm P.
      • Langholz E.
      • Davidsen M.
      • et al.
      Frequency of glucocorticoid resistance and dependency in Crohn's disease.
      ]. Despite the widespread use of immunosuppressive and biological treatment, corticosteroid dependency remains clinically challenging.
      Immunosuppressant [
      • Prefontaine E.
      • Sutherland L.R.
      • Macdonald J.K.
      • et al.
      Azathioprine or 6-mercaptopurine for maintenance of remission in Crohn's disease.
      ] and anti-TNFα therapies [
      • Hanauer S.B.
      • Feagan B.G.
      • Lichtenstein G.R.
      • et al.
      Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial.
      ,
      • Jilani N.Z.
      • Akobeng A.K.
      Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial. Colombel JF, Sandborn WJ, Rutgeerts P et al. Gastroenterology 2007;132:52–65.
      ,
      • Schreiber S.
      • Khaliq-Kareemi M.
      • Lawrance I.C.
      • et al.
      Maintenance therapy with certolizumab pegol for Crohn's disease.
      ] are effective in steroid-dependent CD patients to maintain the steroid-free clinical remission [
      • Orlando A.
      • Armuzzi A.
      • Papi C.
      • et al.
      Clinical Practice Guidelines: the use of tumor necrosis factor-alpha antagonist therapy in inflammatory bowel disease.
      ]. Adalimumab (ADA) is effective for induction [
      • Hanauer S.B.
      • Sandborn W.J.
      • Rutgeerts P.
      • et al.
      Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn's disease: the CLASSIC-I trial.
      ] and maintenance [
      • Jilani N.Z.
      • Akobeng A.K.
      Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial. Colombel JF, Sandborn WJ, Rutgeerts P et al. Gastroenterology 2007;132:52–65.
      ] therapy of patients with moderate to severe CD. In the CHARM study [
      • Jilani N.Z.
      • Akobeng A.K.
      Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial. Colombel JF, Sandborn WJ, Rutgeerts P et al. Gastroenterology 2007;132:52–65.
      ], the steroid-sparing effect of ADA was analyzed in a subgroup (44%) of patients treated with corticosteroids at the baseline visit. Lémann's study [
      • Lémann M.
      • Mary J.Y.
      • Duclos B.
      • et al.
      Infliximab plus azathioprine for steroid-dependent Crohn's disease patients: a randomized placebo-controlled trial.
      ] evaluated prospectively the efficacy of infliximab plus azathioprine in steroid-dependent CD patients, although it must be noted that the mean baseline Crohn's Disease Activity Index (CDAI) score of the trial population was 240, corresponding to a moderate disease activity despite steroids.
      We have previously published data on efficacy and prognostic factors for response to ADA (80/40 mg or 160/80 mg every other week followed by 40 mg every other week) in 110 steroid-dependent patients [
      • Orlando A.
      • Renna S.
      • Mocciaro F.
      • et al.
      Adalimumab in steroid-dependent Crohn's disease patients: prognostic factors for clinical benefit.
      ]. At week 6, 91% of patients had clinical benefit (remission 45.5%, response 45.5%). After a mean follow-up of 14.6 months, 80.9% of responder patients maintained a clinical benefit (remission 64.5%, response 16.4%). Multivariable analysis showed that the highest induction regimen was the only variable significantly correlated to remission at week 6. To date, long-term efficacy data of ADA in steroid-dependent patients was reported only in the ADHERE studies, as a subgroup analysis of the CHARM trial at 2 and 4 years [
      • Panaccione R.
      • Colombel J.F.
      • Sandborn W.J.
      • et al.
      Adalimumab sustains clinical remission and overall clinical benefit after 2 years of therapy for Crohn's disease.
      ,
      • Panaccione R.
      • Colombel J.F.
      • Sandborn W.J.
      • et al.
      Adalimumab maintains remission of Crohn's disease after up to 4 years of treatment: data from CHARM and ADHERE.
      ].
      In the current study, we report the results on efficacy and safety of a 6-year maintenance therapy with ADA in 90 out of the original 110 steroid-dependent CD patients, including statistical analysis of prognostic factors for remission.

      2. Materials and methods

      2.1 Patients’ characteristics

      In this prospective observational analysis, we extended the follow-up of the previous study [
      • Orlando A.
      • Renna S.
      • Mocciaro F.
      • et al.
      Adalimumab in steroid-dependent Crohn's disease patients: prognostic factors for clinical benefit.
      ] until November 2015. As previously described in detail [
      • Orlando A.
      • Renna S.
      • Mocciaro F.
      • et al.
      Adalimumab in steroid-dependent Crohn's disease patients: prognostic factors for clinical benefit.
      ], patients who achieved clinical response or remission after prednisone treatment but subsequently developed steroid-dependency, according to the definition of the second European evidence-based consensus [
      • Orlando A.
      • Armuzzi A.
      • Papi C.
      • et al.
      Clinical Practice Guidelines: the use of tumor necrosis factor-alpha antagonist therapy in inflammatory bowel disease.
      ], were treated with ADA in order to achieve and maintain a steroid-free clinical remission. Patients included in the original cohort were followed up prospectively in the outpatient clinic at 3–4 monthly intervals, to evaluate maintenance of steroid-free remission (CDAI score less than 150). At each visit, we recorded general wellbeing and physical examination. We did not evaluate the C-reactive protein as serologic marker because all included patients were steroid-dependant and most of them had normal CRP values under steroids.
      In the current study we collected data on 90 out of 110 patients. In patients with steroid-free maintained clinical remission, we reported data on endoscopic features in order to evaluate their relationship with clinical outcome. We defined endoscopic improvement or worsening according to the SES-CD score [
      • Daperno M.
      • D’Haens G.
      • Van Assche G.
      • et al.
      Development and validation of a new, simplified endoscopic activity score for Crohn's disease: the SES-CD.
      ], compared to baseline features at the beginning of the previous study. We also evaluated the long-term safety of ADA during and at the end of the follow-up period.

      2.2 Statistical analysis

      Data were analyzed using the software package SPSS 15 (SPSS Inc., Chicago, IL, USA). Continuous variables were summarized as means ± SD or range when appropriate. Categorical variables were summarized as frequency and percentage. Significant differences were calculated using a χ2 test for categorical variables. Demographic and disease variables were related to the main outcome (maintenance of steroid-free clinical remission) using a univariable analysis. We considered the following variables: sex, age, smoking habit, disease duration, family history, previous surgery, pattern of disease, dosage of steroids at baseline, induction regimen, site of disease, previous biological therapies, ADA discontinuation, ADA dose escalation, switch to another biologic, surgical treatment in ADA failure, and side effects.
      Differences were considered significant for p-value <0.05. We planned to carry out multivariable analysis if we obtained a p-value <0.05 at univariable analysis.

      3. Results

      Of the 110 patients included in the original study, we report long-term data on 90 patients, given that 17 (19%) were lost to follow up and 3 (0.3%) died for reasons not related to ADA treatment (myocardial infarction, car accident, post-surgical complication). Mean follow-up was 74.16 ± 10.3 months. Clinical characteristics of the evaluated patients are reported in Table 1. Patients who continued ADA were followed up every 3 months, the others every 4–6 months or according to clinical symptoms. At the end of follow-up, 37 patients (41%) maintained clinical remission, as showed in the Kaplan Meier curve (Fig. 1): 32 of these (87%) were still in maintenance treatment with ADA monotherapy, with 21 (66%) receiving ADA 40 mg every other week and 11 (34%) receiving ADA 40 mg weekly as maintenance treatment; 5 patients (13%) discontinued ADA due to clinical remission and mucosal healing, switching to immunosuppressants with clinical benefit until now. Of the remaining patients, 6 (7%) discontinued ADA due to adverse events and 47 (52%) due to clinical failure: 20 out of the latter 47 patients (43%) switched to other treatments (infliximab or immunosuppressants) while 27 (57%) underwent surgery. The flow chart of the evaluated patients is summarized in Fig. 2.
      Table 1Baseline characteristics of study population (N. 90).
      Male/female, N (%)47 (52.2)/43 (47.8)
      Mean age, years ± sd40 ± 13.1
      Disease duration, months ± sd10.3 ± 8.8
      Smoking habit, N (%)
       • Non-smokers40 (44.4)
       • Current smokers30 (33.3)
       • Ex-smokers20 (22.2)
      Luminal disease location, N (%)
       • Ileo-Colitis (L3)56 (62.2)
       • Jejuno-ileitis (L1)21 (23.3)
       • Colitis (L2)13 (14.4)
      Mean CDAI score ± sd165.8 ± 43.5
      Previous abdominal surgery, N (%)46 (51.1)
      Patients with concomitant perianal disease, N (%)5 (5.5)
      Previous biologics treatment, N (%)
       • Infliximab
        - Intolerant15 (16.7)
        - Non-responders12 (13.3)
        - End of treatment
       • Certolizumab pegol
        - Non-responders5 (5.6)
        - Intolerant1 (1.1)
      History of immunosuppressants, N (%)63 (70)
      Dosage of steroid at baseline, N (%)
       • 10–15 mg/die47 (52.2)
       • >15 mg/die43 (47.8)
      Figure thumbnail gr1
      Fig. 1Kaplan–Meier curve showing the probability of maintained clinical remission.
      We obtained data on endoscopy at 2 years in 31 out of the 32 patients in steroid-free clinical remission and still in maintenance treatment: 11 (36%) showed no endoscopic improvement, 6 (19%) had an endoscopic worsening (SES-CD score 9 ± 1.5 vs. 11.2 ± 1.8), while 14 patients (45%) improved the endoscopic lesions, with complete mucosal healing in 8 cases. Patients who discontinued ADA due to treatment failure were switched to another therapy, taking into consideration the clinical condition without endoscopic evaluation.
      At univariable analysis, we found no correlation between the evaluated variables and treatment outcomes at the end of follow-up.
      ADA was well tolerated in the long-term. At the end of the previous study, 7 patients (6.3%) had developed side effects with treatment discontinuation (1 pneumonia, 1 severe mycosis, 2 fever, 1 severe cutaneous reaction, 2 abdominal abscesses). In the current analysis, no other discontinuation of ADA, due to side effects, was recorded. As one of the 7 patients was lost to follow-up, we have data on the remaining 6 patients, as reported above.

      4. Discussion

      To our knowledge this is the study with the longest follow-up, with a mean length of 6 years, analysing outcomes of CD steroid-dependent patients treated with ADA as maintenance therapy. In our previous report [
      • Orlando A.
      • Renna S.
      • Mocciaro F.
      • et al.
      Adalimumab in steroid-dependent Crohn's disease patients: prognostic factors for clinical benefit.
      ], 91% of patients had clinical benefit at week 6 (remission 45.5%, response 45.5%) and at the end of follow-up 80.9% of responders maintained a clinical benefit (remission 64.5%, response 16.4%). We subsequently evaluated this cohort after over 3 years of follow-up, observing 54% of maintained steroid-free clinical remission [
      • Orlando A.
      • Renna S.
      • Mocciaro F.
      • et al.
      Long term adalimumab efficacy in steroid-dependent Crohn's disease patients.
      ], with an acceptable percentage of patients lost to follow-up.
      In the present study, at the end of follow-up, 41% of patients, who had obtained steroid-free clinical remission in the previous analysis, maintained clinical remission. This result is more reasonable than those reported in clinical trials. In the ADHERE study [
      • Panaccione R.
      • Colombel J.F.
      • Sandborn W.J.
      • et al.
      Adalimumab maintains remission of Crohn's disease after up to 4 years of treatment: data from CHARM and ADHERE.
      ], 16% of patients taking corticosteroids at baseline were in steroid-free remission after 4 years follow-up. However, the authors reported (in a table and not in the text) data on patients who achieved steroid-free clinical remission at the end of the CHARM study [
      • Jilani N.Z.
      • Akobeng A.K.
      Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial. Colombel JF, Sandborn WJ, Rutgeerts P et al. Gastroenterology 2007;132:52–65.
      ]. In these patients the maintenance clinical remission at 4 years was 51% (NRI analysis). The findings on the latter cohort of patients are similar to ours, which were obtained after a further two years of follow-up, representing a relevant percentage of clinical success.
      In the current analysis, 45% of patients, who maintained steroid-free clinical remission, showed an improvement of endoscopic lesions, with 26% reaching complete mucosal healing. This result is similar to data from the EXTEND study [
      • Rutgeerts P.
      • Van Assche G.
      • Sandborn W.J.
      • et al.
      Adalimumab induces and maintains mucosal healing in patients with Crohn's disease: data from the EXTEND trial.
      ] where 24% of patients treated with ADA reached mucosal healing after 52 weeks, considering that the final cohort did not discriminate the steroid-dependent population. Of note, our results on mucosal healing were obtained at 2 years, suggesting a stronger clinical value of these findings.
      Regarding the long-term ADA safety, we observed 6% of adverse events causing treatment discontinuation within the first year. As reported in the ADHERE study [
      • Panaccione R.
      • Colombel J.F.
      • Sandborn W.J.
      • et al.
      Adalimumab maintains remission of Crohn's disease after up to 4 years of treatment: data from CHARM and ADHERE.
      ], no increased risk of time-related adverse events was observed with long-term maintenance therapy.
      A key point of discussion remains the length of maintenance therapy with ADA, once clinical remission is obtained. Half of patients with CD in stable remission have been shown to undergo clinical relapse after anti-TNFα discontinuation [
      • Louis E.
      • Mary J.Y.
      • Vernier-Massouille G.
      • et al.
      Maintenance of remission among patients with Crohn's disease on antimetabolite therapy after infliximab therapy is stopped.
      ]. Rheumatologists continue anti-TNFα therapies for long periods to avoid clinical recurrence and subsequent joint damage and disability [
      • Kirwan J.R.
      Links between radiological change, disability, and pathology in rheumatoid arthritis.
      ,
      • Van der Heijde D.
      • Breban M.
      • Halter D.
      • et al.
      Maintenance of improvement in spinal mobility, physical function and quality of life in patients with ankylosing spondylitis after 5 years in a clinical trial of adalimumab.
      ,
      • Cantini F.
      • Niccoli L.
      • Cassarà E.
      • et al.
      Sustained maintenance of clinical remission after adalimumab dose reduction in patients with early psoriatic arthritis: a long-term follow-up study.
      ]. In clinical practice, it is often challenging to discontinue anti-TNFα treatment in patients with moderate to severe steroid-dependent CD who achieved steroid-free clinical remission after previous immunosuppressant failure or intolerance. In patients naive to immunosuppressants, switching to thiopurines or methotrexate is a suggested strategy after anti-TNFα discontinuation [
      • Dignass A.
      • Van Assche G.
      • Lindsay J.O.
      • et al.
      The second European evidence-based consensus on the diagnosis and management of Crohn's disease: current management.
      ]. In patients with previous immunosuppressant failure or intolerance, anti-TNFα therapy could be considered a valid maintaining treatment, considering also the safety of ADA reported above [
      • Panaccione R.
      • Colombel J.F.
      • Sandborn W.J.
      • et al.
      Adalimumab maintains remission of Crohn's disease after up to 4 years of treatment: data from CHARM and ADHERE.
      ]. Nevertheless, all therapeutic strategies should be considered in CD patients after achievement of deep remission.
      In conclusion, our study confirms long-term efficacy and safety of ADA in steroid-dependent CD patients. Once deep remission is achieved, ADA discontinuation should be considered only in the presence of a valid therapeutic alternative. In patients with previous immunosuppressant failure or intolerance, ADA could be maintained considering the observed long-term safety profile.

      Conflict of interest

      A. Orlando served as an advisory board member for AbbVie, MSD, Takeda Pharmaceuticals and received lecture grants for AbbVie, MSD, Sofar, Chiesi, and Takeda Pharmaceuticals.
      S. Renna served as an advisory board member for AbbVie and MSD Pharmaceuticals, and received lecture grants for AbbVie, MSD, and Takeda Pharmaceuticals.
      F. Mocciaro served as an advisory board member for AbbVie and MSD Pharmaceuticals, and received lecture grants for AbbVie, MSD, and Takeda Pharmaceuticals.
      M. Cappello served as an advisory board member for AbbVie, MSD, Takeda Pharmaceuticals and received lecture grants for AbbVie, MSD, Chiesi, and Takeda Pharmaceuticals.
      R. Dimitri served as an advisory board member for AbbVie Pharmaceuticals.
      The other authors have no conflict of interest.

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