Effectiveness of infliximab after adalimumab failure in Crohn's disease

Abstract

AIM: To evaluate the effectiveness of infliximab as a second-line therapy in Crohn’s disease patients after adalimumab failure.

METHODS: A historical cohort study in a community-based gastroenterology practice evaluated Crohn’s disease patients treated with infliximab (induction plus maintenance) after adalimumab failure. Patients were identified using a large Spanish database (ENEIDA).

RESULTS: We included 15 Crohn’s disease patients who received infliximab after adalimumab failure. Five patients discontinued adalimumab due to loss of response, 3 due to adverse events and 7 due to partial response. After infliximab therapy was started, all patients who had interrupted adalimumab due to loss of efficacy regained response. All patients who discontinued adalimumab due to adverse events responded to infliximab and maintained this response; one of these patients had an uneventful course on infliximab, but 2 developed adverse events. None of the 7 patients who interrupted adalimumab due to partial response reached remission with infliximab.

CONCLUSION: Switching from adalimumab to infliximab may be useful in patients who develop adverse effects or loss of response, however, the benefit of infliximab in primary nonresponders was not established.

Key Words: Adalimumab; Biologics; Crohn’s disease; Infliximab; Switch

INTRODUCTION

Crohn’s disease (CD) is a chronic, relapsing, transmural inflammation of the gastrointestinal tract that affects mainly young patients, and results in a considerably decreased quality of life[1]. There is no medical or surgical cure for CD, and the goal of the existing therapeutic modalities is to induce and maintain remission[2]. Since tumor necrosis factor (TNF)-α has a pivotal role in the pathogenesis of CD[3], the introduction of antibodies against TNF-α has created new perspectives for the management of this disease[4,5].

Infliximab is a murine, chimeric, monoclonal immunoglobulin G1 antibody against TNF-α which was approved for CD treatment ten years ago. Infliximab is effective in inducing and maintaining remission in patients with moderate to severe CD and in patients who have failed conventional non-biologic therapy[6]. However, one-third of these patients do not respond to induction therapy. In addition, a subset of patients who initially respond to infliximab will discontinue therapy due to loss of response or intolerance[7,8].

Adalimumab is a recombinant fully human immunoglobulin G1 monoclonal antibody against TNF-α. Randomized controlled trials have demonstrated the efficacy of adalimumab for induction and maintenance of remission in patients naïve to anti-TNF therapy[9-11]. There are also several studies providing data on the efficacy of adalimumab after infliximab failure[12-16]. The CHARM trial[9] evaluated adalimumab as a maintenance therapy in patients after infliximab failure as part of a subgroup analysis. The GAIN study[16], a randomized placebo-controlled trial, demonstrated that adalimumab therapy is effective in inducing remission in patients with active CD who initially responded to infliximab, but then lost response or became intolerant to the drug.

Since adalimumab was approved in 2007 for use in CD, it can be prescribed as a first-line therapy, and similar to infliximab, one-third of patients do not respond to this drug and a proportion of patients can lose efficacy or become intolerant over time[12,17,18]. In clinical practice, patients who do not respond to infliximab, who lose response, or become intolerant may be prescribed adalimumab in an attempt to regain response, but to the best of our knowledge, there are no published data on the effectiveness of infliximab after adalimumab failure. Therefore, the aim of this study was to evaluate the effectiveness and safety of infliximab after adalimumab failure in CD patients.

MATERIALS AND METHODS

Study subjects

Patients who received infliximab for CD after adalimumab failure at a community-based gastroenterology practice were evaluated in a historical cohort study. They were identified using a large Spanish database (ENEIDA), promoted by the Spanish Working Group in Crohn’s and Colitis (GETECCU), including patients with inflammatory bowel disease. The database prospectively records the use, effectiveness and adverse events of immunomodulators and anti-TNF therapy. The database at the time of the study included 10752 patients, of whom 5467 had CD. Patients were excluded from the study if adalimumab or infliximab was initiated for treatment of a disease other than CD.

Data collection

Data collected included: sex, age, smoking status, age at diagnosis, location of disease, disease behavior (inflammatory, stenosing or fistulizing), perianal disease, concurrent use of immunomodulators, indication of anti-TNF therapy, data regarding adalimumab therapy (start date for adalimumab therapy, initial response, loss of response, date of loss of response, dose escalation of adalimumab after loss of response, response to escalated dose, loss of response to escalated dose, date of loss of response to escalated dose, adverse events with standard and with escalated treatment), reasons for discontinuation of adalimumab therapy, data regarding infliximab therapy (start date for infliximab therapy, initial response, loss of response, date of loss of response, dose escalation of infliximab after loss of response, response to escalated dose, loss of response to escalated dose, date of loss of response to escalated dose, adverse events with standard and with escalated treatment) and reasons for discontinuation of infliximab treatment. Individual charts were reviewed to obtain all data.

Definitions

Dose escalation: Dose escalation of adalimumab was defined as a decrease in the interval of administration from every-other-week to every-week. In the case of infliximab, dose escalation was defined either as an increase in infliximab dose, e.g., from 5 to 10 mg/kg, or a decrease in infliximab infusion interval, e.g., from every 8-wk to every 4-wk, or both a dose increase and an interval decrease.

Evaluation of response: For luminal disease, response to adalimumab and infliximab was evaluated using the Harvey-Bradshaw index (HBI)[19] four weeks after the first dose. Partial response was defined as a decrease in the HBI of more than 3 points. Remission was defined as a HBI below or equal to 4 without steroids. In perianal CD, complete response was defined as closure of all fistulas and partial response as a 50% or more reduction in the number of draining fistulas.

Loss of efficacy: Loss of efficacy was defined as impairment in patient’s symptoms coupled with endoscopic, radiographic, and/or serologic (elevated C-reactive protein) evidence of inflammation that made the physician escalate the dose of treatment or change to other drug.

Disease behavior and location: Disease behavior was categorized based on the Montreal classification as: (1) inflammatory or CD without fistulizing or stricturing complications; (2) stricturing disease was defined as the presence of clinical symptoms of partial or complete obstruction with fixed narrowing and/or narrowing with proximal dilatation; and (3) fistulizing, which included the presence of enteric fistulas, intraabdominal abscesses, or bowel perforation. The location of disease was established by identifying macroscopic evidence of CD in any part of the gastrointestinal tract. Possible categories of disease location included the ileum, colon, ileum and colon, upper gastrointestinal tract, and perianal/perineal area.

Concomitant immunomodulators: Concomitant immunosuppressive treatment was considered if a patient had been on immunomodulators for at least the first 6 mo after starting the anti-TNF therapy.

Smoking history: Smoking was defined as the consumption of at least 1 cigarette daily for a period of at least 3 mo prior to study entry.

Statistical analysis

mean ± SD was calculated for continuous variables. Percentages and 95% confidence intervals were provided for categorical variables.

RESULTS

We included 15 CD patients who received infliximab after adalimumab failure. The main characteristics of the study population are summarized in Table 1. Mean time from diagnosis to adalimumab treatment was 69 mo and the median time of adalimumab treatment was 5 mo (range: 2-19 mo). Four patients had stricturing CD. Two of these patients discontinued treatment with adalimumab due to partial response, one patient had an initial partial response but lost this response, and the other patient was in remission but experienced adverse events which led to the interruption of adalimumab. The two patients who had a partial response achieved a partial response after switching to infliximab and the patient who lost the partial response achieved a partial response with infliximab. The patient who had adverse events tolerated infliximab without secondary effects. Four patients received immunosuppressants concomitantly with adalimumab and seven patients were on immunosuppressants previously and maintained this therapy when they started adalimumab.

Table 1 Characteristics of study patients n (%).

Gender (female %)	10 (67)
Median age (yr)	33
Time of evolution to adalimumab therapy (mo)	69
Location
L1	7 (47)
L2	1 (6)
L3	7 (47)
Behavior (%)
Inflammatory	10 (67)
Stricturing	4 (27)
Fistulizing	1 (6)
Perianal disease	4 (27)
Smoking habit	3 (21)
Previous surgical resection	7 (47)
Concomitant immunosuppressants	11 (71)
Reason for discontinuation of adalimumab
Partial response	7 (47)
Loss of efficacy	5 (33)
Adverse events	3 (20)

L1: Ileum; L2: Colon; L3: Ileum and colon.

Adalimumab discontinuation due to loss of efficacy

Five patients discontinued adalimumab due to loss of efficacy. Three were women, 3 had CD of the ileum, 4 showed inflammatory behavior and one perianal disease. Two of these patients had extraintestinal manifestations and 2 were on concomitant immunomodulators (azathioprine).

Median time to loss of efficacy of adalimumab was 6.2 mo (range: 3-9 mo). After loss of efficacy, the dose of adalimumab was escalated in 3 of these patients, but only 1 responded to this treatment strategy (Table 2).

Table 2 Responses to the switch from adalimumab to infliximab.

Reason for ADA discontinuation	Indication for anti-TNF	Initial response to ADA	Final response to ADA	ADA escalation	Initial response to ADA escalation	Final response to ADA escalation	Initial response to IFX	AE with IFX
Loss of response	Perianal	Partial response	No response	No	NA	NA	Remission	No
Loss of response	Luminal	Remission	No response	No	NA	NA	Remission	No
Loss of response	Luminal	Partial response	No response	Yes	Partial response	No response	Remission	No
Loss of response	Luminal	Partial response	Partial response	Yes	No response	NA	Partial response	No
Loss of response	Luminal	Partial response	No response	Yes	No response	NA	Partial response	No
Partial response	Luminal	Partial response	Partial response	No	NA	NA	Partial response	No
Partial response	Perianal	Partial response	No response	Yes	Partial response	Partial response	Partial response	No
Partial response	Luminal	Partial response	Partial response	No	NA	NA	Partial response	No
Partial response	Luminal	Partial response	Partial response	No	NA	NA	Partial response	No
Partial response	Luminal	Partial response	Partial response	Yes	Partial response	Partial response	No response	No
Partial response	Luminal	Partial response	Partial response	Yes	Partial response	Partial response	No response	No
Partial response	Perianal	Partial response	Partial response	No	NA	NA	Partial response	No
Adverse events	Luminal	Remission	Remission	No	NA	NA	Remission	No
Adverse events	Perianal	Partial response	Partial response	No	NA	NA	Partial response	Yes
Adverse events	Luminal	Remission	Remission	No	NA	NA	Remission	Yes

ADA: Adalimumab; TNF: Tumour necrosis factor; IFX: Infliximab; NA: Not applicable; AE: Adverse events.

All patients who discontinued adalimumab due to loss of efficacy regained response after switching to infliximab (3 reached remission and 2 had a partial response) (Table 2).

Adalimumab discontinuation due to lack of response

Seven patients discontinued adalimumab due to partial response. Four were women, 5 had CD of the ileocolic region, 6 showed inflammatory behavior and 2 perianal disease. The dose of adalimumab was escalated in 3 of these patients with the aim of reaching remission, but without improvement in response (Table 2).

None of the 7 patients who interrupted adalimumab due to partial response reached remission with infliximab: 5 (71%) maintained partial response and 2 (29%) lost partial response (Table 2).

Adalimumab discontinuation due to adverse events

Three patients discontinued adalimumab due to adverse events: 1 had facial edema, 1 an injection site reaction and 1 had dizziness. All of these patients were female, 2 had CD of the ileum, 2 showed stricturing behavior, 1 perianal disease and 2 were on concomitant immunomodulators (azathioprine). Two of these patients were in remission and 1 had a partial response at the time of adalimumab discontinuation due to adverse events. All patients maintained the response they had with adalimumab after switching to infliximab (patients in remission maintained remission with infliximab and the single patient with partial response had a partial response to infliximab). One of these patients received infliximab uneventfully, 1 had a delayed hypersensitivity reaction controlled by premedication with steroids before infliximab infusion, and the third patient interrupted infliximab due to facial edema (the same adverse event that forced the discontinuation of adalimumab).

DISCUSSION

The treatment of CD has evolved over the past decade with the introduction of anti-TNF agents. However, some patients do not respond or show suboptimal response to these drugs. Furthermore, patients who respond initially may lose efficacy over time or develop adverse events, which sometimes forces them to discontinue treatment. In these different scenarios, switching from one anti-TNF-α to another could represent an option for CD patients who fail the first anti-TNF drug.

The findings of the present observational study suggest that the probability of achieving clinical response after switching from adalimumab to infliximab may be higher in patients who discontinue adalimumab due to loss of efficacy or adverse events; as compared to those switching due to primary failure with adalimumab. In fact, patients who did not reach remission with adalimumab had no response to infliximab, whereas a relatively high proportion of patients showed a satisfactory response after discontinuing adalimumab due to loss of response or adverse events.

These observations seem to be in agreement with some of the published reports focusing on the effectiveness of adalimumab after infliximab failure[11,12,16,17]. In this respect, we have evidence that after loss of efficacy or intolerance to infliximab, adalimumab can be effective. However, to the best of our knowledge, this is the first study evaluating the effectiveness of infliximab after adalimumab failure.

Both infliximab and adalimumab are monoclonal antibodies and can be recognized by the human immune system as foreign antigens which respond by creating their own antibodies to different sites on the molecule[7,20,21]. In the case of infliximab, the development of antibodies to infliximab and, as a consequence, low trough concentration of the drug, have been implicated as predisposing factors for infliximab treatment failure[21-24]. The presence of antibodies to infliximab has been associated with the development of hypersensitivity reactions (infusional or delayed), while low trough concentration of infliximab has shown a high correlation with loss of response to treatment[7,21,24,25].

Although fully human, adalimumab is not devoid of immunogenicity. Antibodies to adalimumab have been reported in 2.6%-38% of patients treated for CD and rheumatoid arthritis[11,26,27]. In patients with rheumatoid arthritis, antibodies to adalimumab have been associated with low adalimumab trough serum concentration and decreased clinical response[26]. Karmiris et al[20] in a recently published study on CD patients treated with adalimumab after infliximab failure, found that 9% of patients developed antibodies to adalimumab, and that patients who developed antibodies to adalimumab frequently had low trough serum concentrations. They also reported that adalimumab trough serum concentration was lower throughout the follow-up period in patients who had to discontinue treatment due to loss of efficacy[20]. These findings suggest that the role of immunogenicity in the loss of response and in the development of adverse events following adalimumab treatment may be similar to that previously described with infliximab.

There is a lack of data on the development of adverse events with an anti-TNF drug in the subgroup of patients that had discontinued other anti-TNF drugs due to this reason, as the published studies provide this information globally irrespective of the type of failure (loss of efficacy or adverse events)[7,11,16]. The occurrence of immunoallergic reactions has been related to the formation of antibodies against the anti-TNF drug and, in this respect, Karmiris et al[20] found that the presence of antibodies to infliximab before initiation of adalimumab therapy was not associated with a higher incidence of antibodies against adalimumab. There are no data on the development of antibodies to infliximab in patients with previous antibodies to adalimumab, but we would expect that they were not increased based on the findings of the previously mentioned study[20]. In our study, among the 3 patients who discontinued adalimumab due to adverse events, 2 had adverse events with infliximab and 1 of them had to interrupt infliximab due to the same adverse event which had developed with adalimumab. Considering that antibodies to one anti-TNF drug do not seem to be increased in patients with antibodies to other anti-TNF drug, our findings could be explained by the existence of cross reactions between antibodies to adalimumab and infliximab molecules, but this hypothesis has not been proved.

Finally, we found no benefit after switching from adalimumab to infliximab in patients who discontinued treatment due to partial response to adalimumab. The lack of efficacy of the anti-TNF agent in these patients could be due to particular disease characteristics in which TNF-α does not play a pivotal role[23]. In the adjunctive catheter-directed thrombolysis trial performed in rheumatoid arthritis patients, the authors found that an incomplete response to anti-TNF therapy in the population included in the study was not related to an insufficient concentration of the drug or to the presence of antibodies against it, concluding that other pro-inflammatory molecules different from TNF-α could play a main role in these patients.

One limitation of our study is the small sample size. Although our results are original, since there are no published data on the efficacy and safety of infliximab after adalimumab failure in CD patients, studies with a larger sample size are needed to establish the benefit of switching to another anti-TNF agent after one anti-TNF agent has failed.

In conclusion, the results of the present study suggest that CD patients may be successfully treated with infliximab after adalimumab failure, specifically those withdrawing for loss of efficacy or adverse events. Conversely, in patients discontinuing adalimumab due to lack of response, the efficacy of infliximab was not established and other drugs with different targets might offer a greater chance of therapeutic success.

COMMENTS

Background

There is no medical or surgical cure for Crohn’s disease (CD), and the goal of the existing therapeutic modalities is to induce and maintain remission. Infliximab and adalimumab are monoclonal antibodies against tumor necrosis factor (TNF-α). However, one third of patients can lose response or become intolerant to these drugs.

Research frontiers

Studies are being performed in order to identify which are the factors responsible of the loss of efficacy or intolerance to anti-TNF drugs.

Innovations and breakthroughs

In clinical practice, patients who do not respond to infliximab, who lose response or become intolerant may be prescribed adalimumab in an attempt to regain response. Data regarding the outcome of patients who received infliximab after adalimumab failure are scarce. This study assesses the effectiveness of infliximab after adalimumab failure in CD patients.

Applications

The results of the present study suggest that CD patients may be successfully treated with infliximab after adalimumab failure, specifically those withdrawing due to loss of efficacy or adverse events. Conversely, in patients discontinuing adalimumab due to lack of response, the efficacy of infliximab has not been established and other drugs with different targets might offer a greater chance of therapeutic success.

Peer review

This is a good study in which the authors valuated the effectiveness of infliximab as a second-line therapy in CD patients after adalimumab failure. The result is interesting and suggested that CD patients may be successfully treated with infliximab after adalimumab failure.