Introduction

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the intestine, which is characterized by periods of remission and relapses [1]. The incidence, prevalence, and overall burden of IBD are increasing in India, and as per recent reports, India has very high disease burdens of IBD in the world [2, 3]. It affects patients’ quality of life (QOL) and poses  substantial financial burden [4]. Maintaining the disease in remission, preventing relapses, and motivating patient to continue treatment and appropriate education are essential in managing IBD [5, 6]. Adalimumab is a tumor necrosis factor-alpha (TNFα) antagonist, a biological agent, which has been found to be effective in treating IBD [7]. In spite of its proven efficacy in IBD around the world [8, 9], doctors in Asia Pacific countries in general and in India, in particular, are reluctant to use the biological agents due to its high cost. Biosimilar has been recently introduced but sparse data exist on its  use in real life for managing IBD. There has been only one study available over the years in India since its availability [10]. Hence, this multicenter data analysis was carried out to study the effectiveness and safety of adalimumab biosimilar (Exemptia) in Indian patients with IBD.

Methods

Study setting and population

This study included patients with IBD seen at four medical institutes  in northern India (Department of Gastroenterology, All India Institute of Medical Sciences [AIIMS] New Delhi, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Fortis Memorial Research Institute [FMRI], Gurugram and Dayanand Medical College and Hospital, Ludhiana) from October 2015 to February 2018. This study was conducted in accordance with Good Clinical Practice and in a manner to conform with the Helsinki Declaration of 1975, as revised in 2000 and 2008 concerning human rights. The study protocol was approved by the institutional ethics committee of the coordinating center.

Study design and data extraction

This was a retrospective analysis of patients with IBD who had received adalimumab biosimilar at least once during their visit from October 2015 to February 2018. Patient details were extracted into a standard proforma. The following parameters were extracted from the database: demographic features, disease characteristics including location, extent, severity and behavior, presence and number of extraintestinal manifestations (EIMs), complete blood count and liver and renal functions prior to adalimumab, history of smoking or alcohol intake, past history of tuberculosis (TB), any history of receiving anti-tuberculosis therapy (ATT) prior to the diagnosis of Crohn’s disease, prior steroids and immunomodulator use, indication for the use of adalimumab, information on screening and presence of latent TB, dose, duration, period of follow up from the initiation of adalimumab biosimilar treatment, reason for loss to follow up, response, loss of response, and adverse events (AE) related to adalimumab biosimilar therapy. The frequency of development of active TB after adalimumab biosimilar treatment and its site was also recorded. Any missing data was confirmed by interviewing the patient in person. Patients’ data were entered from the date of first dose of adalimumab biosimilar at the study center till the date of switching to therapy or February 28, 2018, whichever was earlier.

Diagnosis and management

Subtypes of IBD were diagnosed on the basis of standard European Crohn’s and Colitis Organization (ECCO) guidelines [11, 12]. Disease extent was classified on the basis of the Montreal classification [13]. Except for one center (FMRI, Gurugram) which had used American College of Gastroenterology guidelines for definition of remission and relapse, other centers used simple clinical colitis activity index (SCCAI) for UC and Crohn’s disease activity index (CDAI) for CD [14, 15]. At baseline and at each visit, patients were clinically assessed according to above criteria. All patients were screened for latent TB at entry, and those positive received chemoprophylaxis with isoniazid (5 mg/kg) for 9 months. Patients were started on adalimumab (Exemptia, Zydus Cadila, India) injection (four injections of 40 mg each, total of 160 mg at baseline, 80 mg [40 mg each × 2] at 14 days, and then 40 mg every other week). The steroids were tapered, and the dose of other concomitant medications remained constant. The patients were evaluated at weeks 8, 26, and 52 for clinical response and remission. Patients with anemia received iron supplements, antihypertensive and antidiabetic were used in patients who had these comorbid illnesses. AE, if any, were recorded. Treatment-related AE was defined as new events that began during or following the first and within 2 months after the last dose of adalimumab biosimilar. Patients who had previously failed infliximab and were switched over to adalimumab biosimilar were also included in the analysis.

Definitions

The treatment with adalimumab biosimilar was considered efficacious if patients had clinical remission at 8 weeks, while maintenance was assessed at 26 and 52 weeks.

Remission

Remission for UC was defined as SCCAI < 2. For CD, remission was defined as CDAI < 150 [16].

Response

Response for UC was defined as decrease in SCCAI by 3 points. Response in CD was defined as decrease in CDAI by 100 points [16].

Relapse

Disease associated with need for steroids and/or hospitalization for flares of disease despite optimal treatment with biologics.

Primary non-response

Lack of response to induction dose of adalimumab.

Secondary loss of response

Loss of response with maintenance dose of adalimumab (after an initial response to induction dose).

  • Partial: Overcome by increasing the dose/frequency of adalimumab

  • Complete: No response to increasing the dose/frequency of the drug needing switching of the therapy

Steroid-refractory disease

As per ECCO guidelines, active disease despite prednisolone medication up to 0.75 mg/kg/day over a period of 4 weeks was defined steroid-refractory disease [11, 12].

Steroid-dependent disease

Patients who were unable to reduce steroids below the equivalent of prednisolone 10 mg/day within 3 months of starting without recurrent active disease or who had a relapse within 3 months of stopping steroids [11, 12].

Partial healing can be “endoscopic improvement” or “absence of ulcerations” to a more quantified endoscopic Mayo score of 1 or a prespecified decrease in Simple Endoscopic Score for CD or Crohn’s Disease Endoscopic Index of Severity [17].

Latent tuberculosis

Diagnosed on the basis of positive Mantoux (> 10 mm) or interferon gamma release assay (IGRA) [18, 19]. Evidence of healed tuberculosis on chest X-ray or computed tomography (pleural thickening, fibrotic scarring, calcified nodules, and calcified hilar or mediastinal lymphadenopathy) was also considered as latent TB [20].

Active tuberculosis

Pulmonary TB was diagnosed in the presence of clinical symptoms (e.g. fever, cough, anorexia, weight loss) and evidence of fresh lesions suggestive of TB on the chest-X-ray/contrast-enhanced computerized tomography scan of the  chest with or without demonstration of acid-fast bacillus (AFB) on the sputum smear examination [21]. Extra-pulmonary TB was diagnosed on the basis of clinical features, suggestive radiologic findings, and demonstration of AFB on culture or caseating or non-caseating granulomas on biopsy specimens. Diagnosis of pleural TB/peritoneal TB was based on biochemical evaluation of pleural/peritoneal fluid showing a high levels of protein along with a adenosine deaminase (> 40 IU/mL) and lymphocytic predominance [21]. Patients with evidence of TB at more than one sites were diagnosed as disseminated disease.

Statistics

Statistical analysis was done by SPSS (v.20) for Windows. Descriptive statistics were used. The median and interquartile ranges are given. Wherever appropriate, frequency, number, and percentage are mentioned. Categorical data were analyzed using the Chi-square test. Kaplan–Meier survival analysis was performed, and the log-rank test was used to compare remission and response rates among CD and UC patients; p values < 0.05 were  considered significant.

Results

Baseline demographic and clinical features

A total of 70 patients (49 CD; 21 UC) who received adalimumab biosimilar were included. The age of onset was comparable between patients with UC and CD (28 years, IQR 21–51 vs. 35 years, 23–51, p < 0.727). At study entry, 42 (85.7%) patients with CD had moderate disease, while 7 (14.3%) had severe disease. Among patients with UC, 19 (90.4%) had moderate disease while 2 (9.5%) had severe disease. Baseline characteristics and clinical details of the patients are given in Table 1.

Table 1 Baseline clinical, demographic features and disease characteristics of patients treated with adalumimab
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Remission and response in CD

Four patients with CD had a primary non-response. At 8 weeks, 23 (46.9%) patients with CD went into remission, and 5 had partial response (Fig. 1). At 26 and 52 weeks, 20 (40.8%) and 16 (32.6%) patients, respectively maintained clinical remission. Therefore, of 49 patients with CD who received adalumimab at baseline, 32.6% maintained clinical remission at end of 1 year (Table 2). The details on discontinuation due to loss of response and adverse events have been mentioned in Fig. 1.

Fig. 1
figure 1

Follow up of patients with Crohn’s disease treated with adalimumab biosimilar

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Table 2 Response and remission to treatment with adalimumab during follow up
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Remission and response in UC

Five patients with UC had a primary non-response. At 8 weeks, 11 (52.4%) with UC went into clinical remission, and 2 had partial response (Fig. 2). At 26 and 52 weeks, nine (42.8%) and seven (33.3%) patients respectively maintained clinical remission. Therefore, of 21 patients with UC who received adalumimab at baseline, 33.3% maintained clinical remission at the end of 1 year. The details on discontinuation due to loss of response and adverse events are mentioned in Fig. 2. Probability of short-term and long-term responses at 8, 26, and 52 weeks was not different between patients with CD and UC (Fig. 3a–c).

Fig. 2
figure 2

Ulcerative colitis patients on adalimumab biosimilar in remission and reasons for discontinuation

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Fig. 3
figure 3

a Kaplan–Meier curve showing clinical remission in UC and CD patients treated with adalimumab at 8 weeks. Log rank test, P = 0.62. b Kaplan–Meier curve showing clinical remission in UC and CD patients treated with adalimumab at 26 weeks. Log rank test, P = 0.56. c Kaplan–Meier curve showing clinical remission in UC and CD patients treated with adalimumab at 52 weeks. Log rank test, P = 0.62

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Only one center accessed mucosal healing during adalimumab biosimilar therapy. Three of 11 (27.3%) patients each with CD had partial and complete mucosal healing at 26 weeks while 4/11 (36.4%) had partial mucosal healing at 52 weeks.

Nine patients had previously received infliximab out of whom  one third responded to adalimumab biosimilar therapy, one third lost response after 26 weeks, and the data of remaining were unavailable.

Adverse events of  adalimumab

Characteristics of selected patients who developed AE during adalimumab biosimilar therapy are given in Table 3. Twelve (17.1%) patients underwent surgery, ten (14.2%) discontinued drug due to financial constraints, and seven (10%) had serious AE. Patients who had a low BMI (≤ 18.5) tended  to develop AE though the difference was not statistically significant. Three patients developed pulmonary TB after starting adalimumab biosimilar, although all were negative for latent TB on  appropriate screening; TB developed 8 months (median) later. Two of these patients (UC) received 6 months and one (CD) received 9 months ATT, and all of them responded. Two patients (CD), positive for latent TB on screening, received INH prophylaxis, none of whom developed TB.

Table 3 Characteristics of patients who developed serious adverse drug reaction on adalumimab
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Discussion

With the increasing disease burden of IBD in the developing world [22, 23] and with improving economy in these regions, more patients will receive anti-TNF agents; hence, we need information on their efficacy and side effects, especially TB (as these areas are endemic for TB). We recently analyzed our data on the efficacy and side effects of infliximab [24] and reported a primary non-response at 8 weeks and secondary loss of response at 26 and 52 weeks as 14.5%, 6%, and 15%, respectively and TB reactivation rate of 11.6%. We similarly evaluated the efficacy and side effect profile of adalimumab biosimilar Exemptia in 70 patients in a multicenter study in northern India.

The clinical remission rates at 8 weeks in patients with UC and CD were 52.4% and 46.9%, respectively. The results for patients with CD are almost similar to that seen in the CHARM trial (40%) [7] but slightly higher than CLASSIC trial (36%) [25]. However, for patients with UC, the remission rates at 8 weeks are considerably higher than that seen in ULTRA 1 and 2 trials (16.5% and 18.5%) [26, 27], the only available recent Indian study (response 24.1%; remission 3.5%) [10], and a Japanese study (10%) [28]. The response rates at 8 weeks were similar between the present study and the Japanese study (59% vs. 50%). However, the real-world studies from Europe and North America [29], Belgium [30], and Brazil [31] reported 8-week remission rates of 48%, 44%, and 41.7%, respectively, which were quite similar to the present study. Better response rates in the present study, as compared to the other Indian study, could be because of difference in disease severity between the two studies, as patients in the other study were refractory to 5 days of intravenous corticosteroids [10].

The efficacy of adalimumab in the present study are lower than that seen with infliximab at our center where at 8 weeks, the remission rates in patients with CD and UC were 80.8% and 77.3%, respectively [24]. Although there is no head to head comparison, these results are significant and are concordant with recent network meta-analyses, which reported better induction rates with infliximab than adalimumab [32]. Comparing the landmark registration trials of infliximab (IFX) (ACT 1 and ACT 2) [33] and adalumimab  (ULTRA 1 and ULTRA 2) for UC, the 8-week induction rates for clinical remission, response, and mucosal healing were approximately 16%, 18%, and 19% higher for infliximab  than adalumimab. The results of retrospective cohort studies comparing adalumimab  and infliximab are heterogeneous with a few reporting superiorities of infliximab over adalumimab and others reporting similar efficacy for both. Overall, the evidence supports similar efficacy of adalumimab  and infliximab  for CD, but for UC, infliximab  may be slightly better than adalumimab  for induction of remission.

Of patients who were in remission at 8 weeks, three quarter sustained remission by 52 weeks, which for CD was similar to the CLASSIC II trial (79%) and for UC was higher than the ULTRA 2 trial (17%). On comparing results of infliximab from our center, almost similar proportion of remitters maintained remission at 52 weeks. Similarly, most of the network meta-analyses have also reported similar efficacy of infliximab and adalimumab in the maintenance of remission. Comparison of registration (ACT 1 and ACT 2 [33] vs. ULTRA 2) trials revealed that for maintenance of remission, the differences between infliximab and adalimumab were less dramatic than that for induction of remission.

Patients with IBD who lose response or are intolerant to infliximab may benefit from switching to adalimumab. Of patients (n = 9) who lost response to infliximab and were switched to adalimumab, 44% (4/9) patients responded while one achieved remission by week 4. Although the numbers are small for any comparison, the literature suggests similar or lower response rates on adalimumab in infliximab-experienced patients [34]. In the study by Taxonera et al. [35], clinical response and remission at week 12 were achieved in 60% and 27% patients, respectively. In the ULTRA 2 trial, 9% and 10% of infliximab experienced patients with UC achieved clinical remission at week 8 and 52, respectively. In the GAIN trial, 21% infliximab experienced patients with CD achieved clinical remission at week 4 [36]. In patients who did not respond to adalimumab, there is an unmet need to do trough levels. If trough levels are low then dose needs to be optimized. If trough levels are adequate and autoantibodies are developed, then one needs to switch to the other drugs [37].

Patients on anti-TNF are at an increased risk of AE and opportunistic infections [38]. Twenty (28.6%) patients in our study experienced some form of AE during the treatment, of which 7 (10%) were serious AE. Though adalimumab is a humanized antibody (expected to be less immunogenic than infliximab), several studies reported varying rates of AE over a period of time. Of 70 patients, 3 (4.3%) developed pulmonary TB after adalimumab, and this risk was lower than that on infliximab as reported from a three-center Indian study (7.9%) and a recent report from our center (11.6%). However, the only Indian study [10] on adalimumab in UC reported a TB reactivation rate of 13.8% which is almost equal to that of TB reactivation on infliximab as reported from our center. Hence, the literature on TB reactivation risk between infliximab and adalimumab remains heterogeneous with the evidence suggesting possible higher risk associated with  infliximab. In our study, 14.3% discontinued drug due to financial constraints due  to high cost of therapy [39]. 

The relatively small sample size limits the generalizability of our findings. In patients showing loss of response to adalimumab, measurement of trough levels of the drug and autoantibodies could be useful. Other  limitations include retrospective, uncontrolled, observational nature of the study. As only the initial few doses were administered at the hospital, it may not be surprising if patients would have missed a few doses. Due to retrospective design, QOL and patient-reported outcome could not be assessed. We assessed for clinical response and remission while mucosal healing was not assessed routinely in all the patients. Despite these shortcomings, this study indeed provides vital information on usefulness, safety, and effectiveness of adalimumab biosimilar in IBD in India.

To summarize, for a chronic, frequently fluctuating disease like IBD, adalimumab biosimilar appears as an effective drug in inducing and maintaining remission. Early response to adalimumab is a good predictor of long-term response. In a subset of patients who do not respond to adalimumab might need appropriate dose optimization prior to switching to the other  drugs. This study has highlighted many important facts which might prove useful in clinical decision making for adalimumab in IBD.