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Journal of Crohn's and Colitis: 10 (8)


Laurence J. Egan, Ireland

Associate Editors

Shomron Ben-Horin, IsraelSilvio Danese, ItalyPeter Lakatos, HungaryMiles Parkes, UKJesús Rivera-Nieves, USABritta Siegmund, GermanyGijs van den Brink, NLSéverine Vermeire, Belgium


Published on behalf of

Efficacy of Adalimumab as a long term maintenance therapy in ulcerative colitis

Edel McDermott, Seamus Murphy, Denise Keegan, Diarmuid O'Donoghue, Hugh Mulcahy, Glen Doherty
DOI: http://dx.doi.org/10.1016/j.crohns.2012.03.016 150-153 First published online: 1 March 2013


Introduction: Adalimumab is a recombinant human IgG1 monoclonal antibody to TNF-alpha. There are limited data with regard to its efficacy in ulcerative colitis. We report experience of adalimumab in ulcerative colitis in a single centre with a focus on the ability of this agent to maintain response and avoid colectomy in the medium to long-term.

Methods: Twenty-three ulcerative colitis patients (mean age 32 years; 7 female) who received adalimumab were identified from a prospectively maintained database of over 2700 IBD patients. The primary study endpoint was treatment failure defined as discontinuation of adalimumab due to lack of efficacy, as defined by requiring an alternative maintenance therapy or colectomy, or intolerance. Colectomy rate was recorded as a secondary endpoint.

Results: Most patients (96%) had received immunosuppressants prior to adalimumab therapy (infliximab 20/23 87%). Sixteen of 23 patients (70%) discontinued adalimumab. Six primary failures, 8 secondary loss of response, one had unacceptable side effects and one discontinued treatment after 6 months but remains in remission. Overall estimated cumulative treatment failure rates at 6, 12 and 24 months were 50%, 65% and 72% respectively. Median follow-up in patients continuing adalimumab is 23 months (IQR 17–31 months). Treatment failure was unrelated to patient age, gender, disease extent, smoking status or CRP. Colectomy free survival was 59% at 2 years. No patient experienced a major adverse event.

Conclusion: Adalimumab shows some efficacy as a maintenance strategy in Ulcerative Colitis, but only a limited proportion of patients remain well on continued treatment at 2 years.

  • Inflammatory Bowel Disease;
  • Ulcerative colitis;
  • Treatment;
  • Adalimumab;
  • Biologics

1 Introduction

Inflammatory Bowel Diseases are chronic inflammatory disorders of the gastrointestinal tract, which comprise two main disease types, Crohn's Disease and ulcerative colitis. While these are distinct disease entities, their pathogenesis and treatment show considerable overlap.1,2 Tumour necrosis factor (TNF-alpha) is an important pro-inflammatory cytokine involved in the pathogenesis of both disorders and has emerged as an important therapeutic target.3 Infliximab, a chimeric antibody to TNF-alpha, has demonstrated efficacy in the treatment of ulcerative colitis.4 Adalimumab is a recombinant human IgG1 monoclonal antibody to TNF-alpha that is licensed for use in Crohn's disease.5 Given the efficacy of infliximab for ulcerative colitis, there has been considerable interest in whether a subcutaneously delivered anti-TNF agent could be employed for maintenance therapy. A randomised controlled trial assessing the efficacy of adalimumab in ulcerative colitis has been completed and preliminary reports suggest adalimumab is effective for induction of remission in this disease.6 Although adalimumab has been used on an unlicensed basis as a treatment for ulcerative colitis, there are limited data on its long-term effectiveness as part of a maintenance strategy. We report a single centre experience of adalimumab in ulcerative colitis with a focus on the ability of this agent to maintain long-term clinical response and avoid colectomy in clinical practice.

2 Materials and methods

Thirty-nine patients with biopsy proven ulcerative colitis who received adalimumab were identified from a prospectively maintained database of over 2734 IBD patients. Sixteen patients were excluded as they were receiving adalimumab for an indication other than active ulcerative colitis (Pyoderma gangrenosum post colectomy (n = 4), Ankylosing Spondylitis with long-standing quiescent colitis (n = 2), Ankylosing Spondylitis post colectomy (n = 2), Subsequent diagnosis of Crohn's Disease (n = 7), Insufficient data (n = 1)). Patients with indeterminate colitis were excluded.

Twenty-three patients who received adalimumab for treatment of ulcerative colitis were included in the final analysis. Patient data were retrieved from a prospectively maintained IBD Database. In addition, all histopathology records, electronic laboratory, radiological and endoscopic databases were retrieved and were cross checked against both the patients' clinical notes and database to ensure accuracy. All patients received a standard induction protocol of 160 mg, 80 mg and 40 mg at weeks 0, 2 and 4 respectively. Patients were maintained on 40 mg every other week and dose escalation to 40 mg every week was used if deemed necessary, by the treating consultant gastroenterologist, to achieve clinical response, in a patient inadequately controlled on 40 mg every other week. The primary endpoint analysed was treatment failure defined as discontinuation of adalimumab due to i) intolerance, ii) requirement for additional therapies including systemic corticosteroids or an alternative maintenance therapy or iii) listing for colectomy. Secondary endpoints included median time to colectomy and colectomy-free survival. Data were recorded in Microsoft Excel and analysed using SPSS version 18.

3 Results

Patient characteristics are shown in Table 1. Median age at starting adalimumab was 35.4 years, with a median of 4.3 years from date of diagnosis to adalimumab treatment. Most patients had a pancolitis (74%) while the remainder (26%) had left sided disease. There were 17 (71%) non-smokers. Twenty-two patients (96%) had received prior immunomodulatory therapy. Most patients had received more than one immunosuppressive agent (mean 2.4; range 0–4) including azathioprine (n = 20), mercaptopurine (n = 6), ciclosporin (n = 6), and mycophenolate mofetil (n = 5). In addition, 20 patients (86%) had previously been treated with infliximab. Three of these patients were infliximab primary non-responders, 11 had secondary loss of response to infliximab and a further 6 discontinued infliximab due to side-effects.

View this table:
Table 1

Clinical features of 23 patients receiving Adalimumab (ada) for UC.

Age receiving ada (median [range])35.4 years [25–70]
Time from diagnosis to ada Rx4.3 years [0.5–12.4]
Gender: male16 (70%)
Disease extent: pancolitis16
Left sided7
Prior immunosuppression22 (96%)

The median follow up for all patients was 22 months, IQR 8–32 months. Overall estimated cumulative treatment failure rates (Fig. 1) at 6, 12 and 24 months respectively were 50%, 65% and 72%. Sixteen patients discontinued ADA during follow up of which 15/23 (65%) were classified as treatment failures. The indication for discontinuing adalimumab treatment was primary non-response in 6 patients (37%), secondary non-response in 8 patients (50%) and side-effects in 1 patient (6%). 1 patient stopped adalimumab at 6 months when well and remains in steroid free remission at 28 months follow-up. The patient who discontinued adalimumab secondary to side effects reported feeling systemically unwell and developed a rash and had also experienced a poor response to treatment. Two other patients experienced mild side effects that did not necessitate cessation of therapy. One had transient neurological symptoms, queried mononeuritis multiplex, which resolved spontaneously and the patient continued on adalimumab. The other had a mild injection site reaction. All three patients who were primary infliximab failures also failed to respond to adalimumab. Treatment failure was unrelated to patient age, gender, disease extent, smoking status, C Reactive Protein (CRP) or prior immunosuppressant exposure.

Figure 1

Proportion of UC patients continuing Adalimumab therapy without treatment failure.

Eight of 23 patients (35%) were deemed not to have failed adalimumab therapy after a median follow up of 23 months, of which seven continue treatment. Dose escalation was required in two of the seven. Endoscopic data available in 4 of the 8 responders confirms both clinical and endoscopic response. Colectomy free survival (Fig. 2) was 78% at 6 months, 70% at 12 months and 59% at 2 years. Nine of 15 patients (60%) who failed treatment required a colectomy with a median time to colectomy of 5 months from commencing adalimumab. Three of 15 patients (20%) were referred for surgery for active disease but refuse surgery. One patient improved while on chemotherapy for breast cancer and 1 patient is maintained on low dose oral steroid and azathioprine. A further patient was lost to follow-up (1 month) after failing adalimumab treatment.

Figure 2

Colectomy free survival for all UC patients treated with Adalimumab.

4 Discussion

Inhibition of TNF-alpha with infliximab has been shown to be effective for both induction and maintenance of remission in ulcerative colitis.4,7 There has also been considerable interest in the use of a subcutaneous TNF-alpha antagonist in this condition. The results of a recently published randomised controlled trial by Reinisch et al.6 show that adalimumab is superior to placebo for induction of remission in ulcerative colitis, with clinical response rates of 55% at 8 weeks. Smaller observational studies have also suggested that adalimumab may be an effective maintenance strategy (clinical response rates of 60% at 12 weeks in Taxonera et al.,8 50% at 24 weeks in Afif et al.9 and 60% at 24 weeks in Oussalah et al.10 Indeed, our data are remarkably similar to the Spanish data8 with regard to immunosuppressant exposure, extent of colitis and response rates at 12 weeks. Our data are also similar to the existing data up to 52 weeks from Sandborn et al.'s RCT11 who report a response rate of 30.2% at 52 weeks. Gies et al. reported a 56% 1 year maintenance response for a cohort of 25 patients treated with adalimumab,12 which is higher than our corresponding figure, but of note in the Gies population all patients were infliximab naive, thus significantly different from our patient cohort. However, overall, our 23 month follow-up has allowed us to identify a progressive increase in treatment failure over time, with an estimated cumulative treatment failure rate of 72% at 24 months.

The observation of a positive trend in terms of initial response reflects the patient population in which adalimumab has been employed. None of our patients had acute severe colitis; all were at least partially steroid responsive and most could probably be best characterised as steroid dependent, having failed conventional steroid sparing strategies with immunomodulators or infliximab. The gap between the rates of cumulative treatment failure and colectomy is also probably explained by the fact that many patients resumed corticosteroid therapy in order to further temporise a definitive surgical solution. The success of the use of adalimumab as a definitive steroid sparing maintenance strategy therefore requires long term follow up and our data adds to current knowledge about the real world clinical effectiveness of this strategy. With regard to prior infliximab use, our data replicate previous observations8 that primary non-response to infliximab is associated with failure to respond to adalimumab. Two of three infliximab naive patients demonstrated sustained clinical response and remain steroid free on adalimumab. Data from Sandborn's RCT11 suggests that patients previously exposed to an anti-tnf agent do not do as well on adalimumab as those who are anti-tnf naïve, but the study was underpowered to detect a statistically significant difference and they did not include primary infliximab nonresponders. Our numbers show a trend but are too small to detect a statistically significant difference between either infliximab primary non-responders versus secondary failures or infliximab naive patients versus prior infliximab use.

Our observed colectomy free survival was 78% at 6 months, which is comparable to Spanish data.8 As with the treatment failure data, there is a continued decline in colectomy free survival after this point to 59% at two years. Colectomy free survival is also falsely elevated as two patients who have ongoing active disease have declined surgery. Successful treatment at three months has previously been shown to be associated with a lower incidence of colectomy.8 Five of 9 patients (55%) who failed adalimumab within 3 months underwent colectomy, compared to a colectomy rate of 28% in the remainder. This difference was not statistically significant, and probably reflects disease severity. We did not identify this or any other factors that were significantly associated with either colectomy free survival or treatment failure.

Our study has significant limitations, including its retrospective design and small patient numbers. While data on outcomes such as surgery and changes to maintenance therapy were captured prospectively in our database, we lack universal documentation of disease activity scores such as mayo index and endoscopic data in order to comment on remission. However, our data do provide information on the effectiveness of adalimumab in day-to-day clinical practice that cannot be extrapolated from tightly structured controlled trials. Thus, when examining a maintenance strategy, outcomes such as treatment failure and colectomy serve well as useful ‘hard’ endpoints. While the results with adalimumab maintenance are disappointing, we also recognise that our patient cohort represents a relatively treatment refractory population with a median disease duration of greater than four years. Patient selection is important and it is possible that the use of adalimumab earlier in the course of disease, avoiding its use in patients with known history of primary non-response to other anti-TNF therapies and administration in combination with an immunomodulator13 might all improve longer term outcomes.

The economic implications of using multiple biologic agents in ulcerative colitis are significant,14 with potential opportunity costs for these and other patients. In most of our patient cohort, colectomy was merely postponed rather than avoided. Surgery is a definitive steroid sparing treatment strategy for these patients and represents the closest thing to a cure that we can offer at present. With an estimated treatment failure rate of 72% at 2 years adalimumab demonstrates limited long-term efficacy as a maintenance strategy. However, a sustained treatment response was observed in a minority of patients and if these individuals could be identified in advance, its use in this targeted group might offer a durable solution. Future prospective studies might reasonably focus on identifying patient factors and biomarkers that predict long-lasting treatment response in order to minimise risks of toxicity, cost and treatment futility.

Conflict of interest

There is no conflict of interest for any of the authors.


Author's contribution: SM, HM and GD designed the study. EMD, DK and DOD contributed to data collection. HM performed the statistical analysis. EMD wrote the manuscript. GD and HM revised critically the manuscript. All authors have read and approved the final version of the manuscript.


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