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. 2024 Mar 20;31(1):77–86. doi: 10.1093/ibd/izae040

Clinical Pharmacist Counselling Improves Long-term Medication Safety and Patient-reported Outcomes in Anti-TNF-treated Patients With Inflammatory Bowel Diseases: The Prospective, Randomized AdPhaNCED Trial

Johannes Plechschmidt 1,✉, Konstantin Fietkau 2,3, Tobias Hepp 4, Peter Dietrich 5,6, Sarah Fischer 7,8, Sabine Krebs 9, Markus F Neurath 10,11, Frank Dörje 12, Raja Atreya 13,14
PMCID: PMC11700895  PMID: 38507608

Abstract

Background

Antitumor necrosis factor (anti-TNF) antibody treatment has led to marked improvements in the management of patients with inflammatory bowel diseases (IBDs). Nevertheless, anti-TNF therapy is associated with potential adverse drug reactions (ADRs). Our prospective, randomized trial investigated the effect of intensified clinical pharmacist counselling in a multidisciplinary team on medication safety in anti-TNF-treated IBD patients.

Methods

Patients with IBD with ongoing anti-TNF treatment were enrolled in our tertiary center AdPhaNCED trial and randomized to either receive conventional standard of care (control group) or additional clinical pharmacist counselling (intervention group) over 12 months. The primary end point consisted of the number and severity of ADRs associated with anti-TNF therapy. Secondary end points included patient satisfaction with medication information and medication safety.

Results

One hundred twenty-seven IBD patients were included in this study. Anti-TNF-related ADRs were significantly lower in the intervention compared with the control group (0.20 vs 0.32 [mean] ADR/patient/month, P = .006) after 12 months. The risk of more severe ADRs (Common Terminology Criteria for Adverse Events [CTCAE] grade ≥2) was significantly higher in the control compared with the intervention group (hazard ratio, 0.34; P = .001). The probability of ADR resolution (hazard ratio, 2.02; P < .001) and patient satisfaction with medication information (14.82 vs 11.60; P < .001) were significantly higher in the intervention group compared with the control group.

Conclusions

Our study results demonstrate that intensified pharmacist counselling significantly reduces the occurrence and severity of therapy-related ADRs and improves patient satisfaction. Clinical pharmacists should therefore be part of a holistic approach to IBD care delivered by a multidisciplinary team.

Keywords: inflammatory bowel diseases, patient reported outcomes, adverse drug reaction management, medication safety, patient support program

Key Messages.

What is already known?

Inflammatory bowel disease patients on anti-TNF therapy are at risk for occurrence of a broad spectrum of class-specific adverse drug reactions that can lead to impairment of patient’s quality of life and general well-being, therapy discontinuation, and increased economic burden.

What is new here?

Additional clinical pharmacist counselling in a multidisciplinary team reduces the number and severity of anti-TNF antibody-related adverse drug reactions and increases patient satisfaction with medication information.

How can this study help patient care?

Clinical pharmacists should ideally be part of a multidisciplinary team to improve holistic care of IBD patients.

Introduction

Inflammatory bowel diseases (IBDs) encompass immune-mediated inflammatory disorders of the gastrointestinal tract whose phenotypic entities mainly comprise Crohn’s disease (CD) and ulcerative colitis (UC).1,2 The clinical course of these chronic disorders is marked by unpredictable exacerbations and asymptomatic remission, causing lifelong morbidity. Clinical symptoms comprise diarrhea, rectal bleeding, abdominal pain, general malaise, weight loss, and fatigue. Both IBD subtypes are progressive conditions that can lead to bowel damage and disability, having a major impact on an individual’s quality of life. Occurring complications include anal fissures, abscesses, fistulas, structuring complications, and heightened risk for colorectal cancer. Optimized anti-inflammatory therapy is therefore indispensable in the rational management of IBD patients.1,2

Heightened understanding of underlying immunopathogenic mechanisms have led to the advent of targeted therapies, which selectively inhibit crucial mediators or pathways of the intestinal inflammatory process. They have made a major impact on existing therapeutic algorithms for the clinical benefit of the patient. The first classes of targeted therapy approved for the treatment of IBD patients were agents inhibiting the pro-inflammatory cytokine tumor necrosis factor (TNF). Inhibitors of TNF are applied for induction and maintenance therapy, and this substance class is still the most widely used targeted therapy in IBD patients.3 The initiation of anti-TNF therapy has led to fewer hospitalizations, higher remission rates, and fewer relapses,4 leading to their increased use in the management of IBD patients.5 However, not all treated patients benefit from commencing anti-TNF therapy. Depending on the duration of therapy and the clinical end points chosen, approximately a third of treated patients do not demonstrate adequate response to treatment (primary nonresponse).6 Additionally, 30% to 50% of treated patients eventually lose response during therapy (secondary nonresponse), resulting in exposure to potential side effects and toxicities without durable clinical benefit.6

The use of anti-TNF treatment can lead to potential adverse drug reactions (ADRs) like (opportunistic) infections, induction of autoimmune or demyelinating disorders, cardiac effects, skin reactions, fatigue, melanoma, and lymphoproliferative malignancies.7,8 The long-term (3 years) follow-up of the ACT-1 and ACT-2 trials demonstrated that approximately 10% of infliximab-treated patients discontinue therapy due to side effects.9 The Dutch Biologic Monitor, a prospective cohort model, revealed that patients contacted healthcare professionals only in 54% of the occurred ADRs.10 Moreover, a recent study among IBD patients on biological therapy (89.5% anti-TNF therapy) demonstrated that there is a significant gap between patient- and physician-reported ADRs.11 Here, the most burdensome patient-reported ADRs were fatigue, skin conditions, and musculoskeletal conditions.11 Furthermore, patients on biological therapy are interested in information on the probability of ADR occurrence and the self-limiting properties of ADRs.12 The occurrence of ADRs also leads to a substantial economic burden. It was estimated for Canada that the annual economic burden for severe ADRs related to use of the anti-TNF antibody infliximab are in a range from $10 to $20 million and in the case of the anti-TNF antibody adalimumab from $6 to $19 million.13 Most recommendations for the management of ADRs are based on retrospective observations and reviews, as prospective randomized trials are lacking.14,15

Due to the complexity of biological therapies and the necessity for ongoing monitoring, acute interventions to prevent occurrence of anti-TNF-related ADRs are required at multiple levels of the healthcare system by a variety of healthcare providers. Coordinated care and structured follow-up is indispensable for the optimal management of IBD patients. Integrated models of care, involving a multidisciplinary team (MDT) that consists of a group of healthcare professionals from different specialities working together, have been implemented with the goal of providing more comprehensive and holistic care to IBD patients.16 These gastroenterologist-led MDTs often include colorectal surgeons, an IBD nurse specialist, dietician, psychologists and sometimes pathologists, IBD-experienced endoscopists, and radiologists.17 It has already been shown that utilization of a gastroenterologist-lead MDTs is becoming a preferred model of care in comparison with a more traditional patient-physician model.18,39 Integration of a clinical pharmacist with a special interest in IBD as core member of the team might further improve continuous monitoring of medication outcomes to reduce ADRs and medication errors. Furthermore, the clinical pharmacist can also enhance patient education and counselling regarding the medication, improving patient adherence and satisfaction, and also communicate present issues with the whole MDT to improve quality of patient care.16,18

We therefore conducted a prospective, single-center, randomized controlled clinical trial at our academic tertiary care center in patients with IBD under ongoing anti-TNF antibody therapy to investigate whether standard of care with an additional intensified concomitant clinical pharmacist counselling is able to improve patient-reported outcomes, medication safety (ADR and medication errors), and patient’s treatment satisfaction with medication information about anti-TNF therapy in comparison with a conventional standard of care approach.

Materials and Methods

Study Design and Patients

The AdPhaNCED (medication safety with biologicals in IBD patients) trial was an open-label, randomized, single-center study, which was conducted at the tertiary IBD University Hospital Outpatient Clinic in Erlangen (First Department of Medicine). The study protocol was approved by the ethics committee of the Friedrich-Alexander-University Erlangen-Nürnberg. The trial was registered in the German Clinical Trials Register (DRKS00020374). All patients gave written informed consent prior to study inclusion.

Inflammatory bowel disease patients 18 years and older, treated continuously with an anti-TNF monoclonal antibody (infliximab or adalimumab originator; no switching to biosimilars) for at least 3 months and in clinical remission or with mild clinical disease activity were eligible to be included in this trial. Disease activity was determined by the partial Mayo Score19 for UC and IBD-unclassified and the Harvey-Bradshaw Index20 for CD by the treating physician. Patients with the partial Mayo Score ≤4 or Harvey-Bradshaw Index ≤7 were eligible for this study.21 Patients in the need of newly initiated systemic corticosteroid therapy for an acute IBD flare, discontinuation of anti-TNF treatment during the follow-up time of 12 months, or withdrawal of patient’s consent were excluded from the study. Patients were recruited between July 2019 and August 2020.

Patients were randomized 1:1 to the control group (standard of clinical care) or the intervention group (standard of clinical care and additional clinical pharmacist counselling). Randomization was performed via Microsoft Excel-generated lists, with anti-TNF therapy as stratification factor. For each anti-TNF inhibitor, predefined blocks (10 patients per block) were generated. Patients had contact with the clinical pharmacist after the treating physician evaluated the patient eligible for this study beforehand (month 0, baseline). At this time, all baseline parameters and sociodemographic data were collected via a patient interview and the medical record.

The control group received medical standard of care, which was provided by physicians specialized in IBD/gastroenterology with a minimum level of 3 years of IBD/gastroenterology experience. Patients treated with infliximab had standard of care visits during each intravenous infliximab administration (eg, monthly or bimonthly; Table 1). Patients treated with adalimumab were seen every 3 months. The control and intervention group received counselling by the physician as part of the standard of care on the initiation of anti-TNF therapy. This includes counselling regarding the elevated risk of infections, the need for vaccination, need for skin protection regarding sun exposure, possible heightened risk for neurological disorders, skin melanoma occurrence, and allergic reactions (infliximab) or skin reactions (adalimumab). Furthermore, the necessity to postpone anti-TNF administration in case of an infection was reinforced. A figure of the study design is shown in the Supplemental Material online. (Figure S1).

Table 1.

Patient characteristics at baseline.

No. (%) P
Characteristics Intervention
(n = 63)		 Control
(n = 64)
Age, years (mean, range) 37.6 (18-72) 37.1 (18-77) 0.925d
Female 34 (54.0) 35 (54.7) 1.000e
Male 29 (46.0) 29 (45.3) 1.000e
IBD Crohn’s disease (CD) 40 (63.5) 45 (70.3) 0.678f
Ulcerative colitis (UC) 20 (31.7) 17 (26.6) 0.678f
IBD-unclassifieda 3 (4.8) 2 (3.1) 0.678f
Montreal Classification UC
E1 3 (4.8) 4 (6.3) 0.368f
E2 4 (6.3) 6 (9.4) 0.368f
E3 13 (20.6) 7 (10.9) 0.368f
Montreal Classification CD
A1 13 (20.6) 8 (12.5) 0.295f
A2 25 (39.7) 35 (54.7) 0.295f
A3 2 (3.2) 2 (3.1) 0.295f
L1 13 (20.6) 16 (25.0) 0.622f
L2 5 (7.9) 2 (3.1) 0.622f
L3 21 (33.3) 25 (39.1) 0.622f
L1 + 4 1 (1.6) 2 (3.1) 0.622f
B1 15 (23.8) 16 (25.0) 0.942f
B2 11 (17.5) 13 (20.3) 0.942f
B3 7 (11.1) 10 (15.6) 0.942f
p 7 (11.1) 6 (9.4) 0.942f
Current smoker 7 (11.1) 14 (21.9) 0.151f
First biological therapy 44 (69.8) 43 (67.2) 0.896e
Current anti-TNF therapy infliximab (IFX) 59 (93.7) 60 (93.8) 1.000e
adalimumab 4 (6.3) 4 (6.2) 1.000e
Mean duration of current anti-TNF treatment in months (range) 34.9 (3-137) 35.9 (3-129) 0.914d
Anti-TNF dose 0.552f
10.0 mg/kg BW (IFX) 26 (41.3) 27 (42.2)
7.5 mg/kg BW (IFX) 10 (15.9) 5 (7.8)
5.0 mg/kg BW (IFX) 23 (36.5) 28 (43.8)
40 mg (adalimumab) 4 (6.3) 4 (6.3)
Anti-TNF interval 0.789d
Every 8 weeks (IFX) 24 (38.1) 25 (39.1)
Every 7 weeks (IFX) 7 (11.1) 7 (10.9)
Every 6 weeks (IFX) 10 (15.8) 7 (10.9)
Every 5 weeks (IFX) 9 (14.3) 7 (10.9)
Every 4 weeks (IFX) 9 (14.3) 14 (21.9)
Every other week (adalimumab) 3 (4.8) 3 (4.7)
Every week (adalimumab) 1 (1.6) 1 (1.6)
Concomitant immunosuppressive medication 7 (11.1) 3 (4.7) 0.206f
methotrexate 4 (6.3) 1 (1.6)
azathioprine 2 (3.2) 1 (1.6)
prednisolone (7,5 mg/d) 1 (1.6) 1 (1.6)
Harvey-Bradshaw Index (HBI) b
0-4 (clinical remission) 33 (52.3) 40 (62.5) 1.000f
5-8 (mild disease) 6 (9.5) 6 (9.4) 1.000f
Partial Mayo Score (pMS) c
<2 (clinical remission) 18 (28.6) 14 (21.9) 1.000f
2-4 (mild disease) 5 (7.9) 4 (6.3) 1.000f
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aIBD-unclassified was not classified via Montreal classification.

bOne patient of the intervention group hasn’t been scored by the physician at baseline. The physician documented “patient in clinical remission.”

cIBD-unclassified patients were scored via the pMS.

dWilcoxon rank sum test.

ePearson’s χ2 test.

fFisher’s exact Test.

Additional Clinical Pharmacist Counselling (Intervention Group)

Patients in the intervention group received a structured patient support program by a clinical pharmacist additional to the conventional standard of care medical counselling during the predefined clinical visits. Patient counselling was performed by a single clinical pharmacist (specialized in medication management) at 4 predefined time points: month 0, 3 ± 1, 6, and 12. Each counselling session required a mean time of 30 minutes and was carried out by the clinical pharmacist at the tertiary care center. The main topics of the structured counselling with the individual patient were management and prevention of ADRs, medication management, fatigue management, and nutritional information (for details see Supplemental Methods). The ADR counselling focused on 2 major side effect groups: skin reactions and infectious complications. In case of skin reactions, patients received information about skin care to reduce dry skin as a frequent side effect of infliximab. Patients received information about skin care products, factors which can irritate the skin and should be avoided. Patients with suspected inflammatory skin manifestation (eg, infliximab induced psoriasis) were early referred to a dermatologist to receive verification.

The immunocompromising effect of anti-TNF treatment was explained to every patient. Additionally, patients received information about routes of infections, how infections can spread, and how to avoid infections through hygienic rules and vaccinations.

Patients received self-designed standardized written patient information materials (Supplemental Figure S2 and S3) at month 0 about common side effects of the anti-TNF biological therapy and factsheets about the applied therapy (infliximab, adalimumab). In addition, patients received self-designed brochures about fatigue and nutrition. The handouts were standardized and understandable for laypersons. Medication management was performed according to international pharmaceutical standards.22 More specified information about medication management is provided in the supplement.

Study End Points and Assessment

Primary study end points were (1) the number (CTCAE, any grade), severity (CTCAE ≥2), and complete ADR resolution (CTCAE, any grade) related to the anti-TNF therapy during months 0 to 12 and (2) patient-reported health-related quality of life, measured with the IBDQ (German version)23 after 12 months. A post hoc analysis was out in patients with an IBDQ score <170 points at baseline, which indicated a reduced quality of life.24,25

Secondary end points included the patient-reported level of fatigue, measured with the German version of Functional Assessment of Chronic Illness Therapy—Fatigue (FACIT-F)26 questionnaire, satisfaction with knowledge about the anti-TNF therapy, measured with the German version of Satisfaction with Information about Medicines Scales (SIMS-D)27 after 12 months. Furthermore, all unsolved medication errors within month 0 and month 12 were evaluated.

Assessment and Tools

Patient demographics were collected at baseline (month 0). Clinical disease activity (Harvey-Bradshaw Index for CD and partial Mayo Score for UC and IBD-unclassified), medication (ATC Code), quality of life (IBDQ), fatigue (FACIT-F), and patient knowledge (SIMS-D) were collected at baseline and after 6 and 12 months. Adverse drug reactions (CTCAE, v5.0) were determined at baseline and subsequently at every outpatient appointment via patient interview (structured patient-reported documentation sheet, Supplemental Figure S4) and physician routine documentation.

Drug-related problems (medication errors and ADRs) were classified by the Pharmaceutical Care Network Europe “PCNE classification V 9.0” system.28 All drug-related problems were labelled unsolved after 12 months if they were coded as “O3, Not solved” or “O2, Partially solved.”28

Adverse drug reactions were coded using the Common Terminology Criteria for Adverse Events (CTCAE v5.0).29 Causality of ADRs was analyzed according to the WHO-UMC-Scheme,30 and association of ADRs with the biological therapy was given, if they were classified as “certain” or “probable/likely.”

The potential harm of medication errors was categorized according to the National Coordinating Council for Medication Error Reporting and Prevention (NCC-MERP).31Supplemental Table S1 depicts all tools and time points of data collection.

Statistical Analysis

Statistical analysis was performed using R version 4.1.1.32 For all hypothesis tests applied, a P value below 0.05 was considered to indicate statistical significance of the corresponding effect.

All analyses are based on the intention-to-treat principle. Occurring ADRs or medication errors with the potential to seriously harm patients of the control group could be intervened by the clinical pharmacist. Patients of the control group, which had an intervention for ethical reasons, were analyzed in accordance with their randomization to the control group.

As all measured continuous outcomes exhibit some form of non-normality (eg, asymmetry), differences between the randomized groups with respect to these variables were investigated using Wilcoxon rank-sum tests. Differences in categorical variables and ordered variables with less than 5 categories were evaluated using Pearson’s χ2 test or Fisher’s exact test, with the latter being used in cases of low cell counts in the contingency table. Ordered variables with at least 5 categories were again analyzed using Wilcoxon rank-sum tests.

For survival analysis, slightly different approaches were taken depending on the outcome. Since multiple ADRs with CTCAE grade ≥2 may occur for a single participant, the Nelson cumulative hazard estimate for repeated events was used to compare the number of ADRs (with CTCAE grade ≥2) to be expected for a patient after being observed for a given amount of time. The hazard ratio along with the corresponding P value is based on the results of a Cox proportional hazard model. Additionally, all ADRs occurring after study entry were compared between the groups with respect to their duration. Here, the Kaplan-Meier estimates were computed to estimate the probability of an ADR being resolved after persisting for a given amount of time. Hazard ratio and P value are based on a Cox mixed effects model with random intercept to account for several ADRs belonging to the same participants. It has to be taken into account that the Kaplan-Meier estimator for this calculation is based on ADR (that occurred before month 12) and not on an individual patient level. Thus, we calculated with the following numbers of risk: 206 (control group) and 140 (intervention group). The Kaplan-Meier estimator of ADR resolution with a total of 346 ADR seems appropriate, as the missing 11 ADRs (10 control group and 1 intervention group) are favoring the control group.

Finally, the average scores for IBDQ, SIMS-D, and FACIT-F were compared using linear mixed-effects models with random intercept to account for repeated measurements.

Data Availability

All data sets, patient-reported outcomes, and statistical analysis methods supporting the results are published in this article and the online Supplemental Material. The study protocol and all written patient fact sheets can be obtained from the corresponding author via reasonable request.

Results

A CONSORT flow chart is shown in Figure 1. Between July 2019 and August 2020, 159 patients were screened, 127 were enrolled and randomly assigned to receive standard of care (n = 64) or additional intensified pharmaceutical care (n = 63). Treatment groups at baseline were similar with respect to age, Montreal classification, anti-TNF treatment duration, and disease characteristics (Table 1). During the 12-month study period, there were no significant differences in respective clinical disease activity scores between the 2 studied groups (see Supplemental Table S2).

Figure 1.

Figure 1.

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CONSORT Flow Diagram. Study end points were analyzed according to the intention-to-treat (ITT) principle. All 64 patients (control group) and 63 patients (intervention group) were included for the evaluation of primary and secondary study end points.

Primary End Points

A total of 392 ADRs were observed within the study time, 357 of these were associated with the anti-TNF antibody treatment. The number of anti-TNF-related ADRs at the time point of patient recruitment were similar between both groups (median 1 ADR/patient in both groups; P = .779). Regarding the primary study end point, the number of ADRs with reference to anti-TNF therapy was significantly lower in the intervention compared with the control group (0.20 ± 0.14 vs 0.32 ± 0.26 [mean ± standard deviation] ADR/patient/month; P = .006; Figure 2A). Detailed tables on the type, time point, and severity of all ADRs with reference to anti-TNF treatment are provided in the Supplement (Table S3-S5). Even fewer ADRs related to the anti-TNF therapy occurred in the intervention group after month 0, leading to a highly significant result favoring the intervention group (0.08 ± 0.10 vs 0.19 ± 0.19 [mean ± standard deviation] ADR/patient/month; P < .001; Figure 2B). Correspondingly, the risk of more severe anti-TNF antibody-associated ADRs (CTCAE grade ≥2) within 12 months was significantly higher in the control than in the intervention group (hazard ratio, 0.34; 95% CI, 0.17-0.65; P = .001; Figure 3A). During the study period, 12 severe ADRs (CTCAE ≥3) were detected (8 control group and 4 intervention group). Investigating the characteristics of the severe ADRs, 8 occurred as skin manifestations (5 in control group and 3 in intervention group), and 4 were infectious complications (3 control group and 1 intervention group). The probability of complete ADR resolution was significantly higher in the intervention group (hazard ratio, 2.02; 95% CI, 1.41-2.90; P < .001; Figure 3B). The worsening of ADRs after 12 months only occurred in the control group (0 ADRs in the intervention group vs 13 ADRs in the control group).

Figure 2.

Figure 2.

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Primary study end point (A) Number of Adverse Drug Reactions per month and per patient with reference to the anti-TNF therapy between month 0 and month 12. B, Number of Adverse Drug Reactions per month and per patient with reference to the anti-TNF therapy between after month 0 till month 12. Box plot: grey dots, data for individual patients; black square, mean. ADRs, Adverse Drug Reactions

Figure 3. A,

Figure 3. A,

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Cumulative hazard ratio for patients to suffer from more severe adverse drug reactions (≥grade 2) with reference to anti-TNF therapy within 12 months. Shaded areas represent 95% CIs. Dropouts were censored according to the time point of dropout. B, Kaplan-Meier curves for the probability of complete anti-TNF therapy associated ADR resolution. Shaded areas represent 95% CIs. This Kaplan-Meier model is based on ADR (and not on patients). Thus, the number at risk are all ADR with reference to the biological that were observed before month 12. Dropouts were censored according to the time point of dropout.

Regarding the skin, 148 ADRs could be identified in both groups (63 in the intervention group and 85 in the control group). The complete healing of skin ADRs could be obtained with 46 (73.0 %) skin ADRs in the intervention group and 24 (28.2 %) in the control group. Analyzing the occurrence of infectious ADRs, the intervention group did significantly better than the control group (38 vs 73 infectious ADRs)

There was no significant difference between both groups at month 0, 6, and 12 regarding patient-reported health-related quality of life (184.19 ± 21.79 vs 183.08 ± 27.19; P = .607; Figure 4A). We analyzed the subgroup of patients (n = 33) with an IBDQ-Score <170 points at month 0, which indicated reduced quality of life.24,25 At month 6, clinically significant differences favoring the intervention group can be seen (170.89 ± 24.53 vs 142.30 ± 27.32 [mean ± SD]; P = .003). After 12 months, this significant difference was no longer observable (168.40 ± 23.20 vs 150.14 ± 34.80 [mean ± SD]; P = .054; Figure 4B).

Figure 4. A,

Figure 4. A,

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Average IBDQ Score as mean with standard deviation within 12 months of all patients. B, Average IBDQ Score as mean with standard deviation within 12 months of patients with an IBDQ Score ≤170 at month 0. Abbreviation: IBDQ, inflammatory bowel disease questionnaire.

Secondary End Points

Satisfaction with information about anti-TNF therapy (SIMS-D) was significantly higher in the intervention group compared with the control group at month 6 (14.27 ± 1.50 vs 10.93 ± 1.78 [mean ± SD]; P < .001) and 12 (14.82 ± 1.16 vs 11.60 ± 1.83 [mean ± SD]; P < .001; Supplemental Figure S5). There was no significant difference in the level of fatigue (FACIT-F) between both groups at month 0, 6, and 12 (38.51 ± 9.92 vs 38.74 ± 9.12; P = .982; Supplemental Figure S5).

The number of medication errors after 12 months was similar between both groups (57 vs 58 medication errors). The number of patients with unsolved medication errors during the study period was significantly lower in the intervention group (9 vs 35 patients; P < .001). The Supplemental Material online contains details of the status and types of medication errors (Supplemental Table S6 + S7, Figure S6).

Discussion

This is the first randomized controlled trial that has studied the impact of integrating a clinical pharmacist in the care of IBD patients undergoing anti-TNF therapy. The prospective, randomized open AdPhaNCED trial demonstrated a significant improvement in medication safety and the patient’s reported outcome of patient satisfaction with anti-TNF therapy during ongoing anti-TNF therapy in IBD patients.

In our study, 88.2% of the participants developed at least one anti-TNF-associated ADR, demonstrating the need of optimized side effect management. The rate of ADRs associated to anti-TNF therapy over the time period of 12 months was remarkably reduced by ADR monitoring and management within the intensified care group. Furthermore, the ADRs of the intervention group after initiation of the pharmaceutical care program were less severe in comparison with the standard of care.

Severe ADRs (CTCAE grade ≥3) are rather rare in the course of anti-TNF therapy, especially in patients who had already been exposed to therapy for over 3 months. Twelve severe ADRs were detected in this study (4 in the intervention group and 8 in the control group). It was evaluated that less burdensome ADRs are not frequently reported in postmarketing pharmacovigilance databases.13 In clinical trials, 13% of the reported ADRs were severe ADRs, whereas 97% of postmarket data were classified as severe ADRs.13

Worsening of ADRs solely occurred in the control group (0 intervention group and 13 control group). Moreover, we could demonstrate that the probability of ADR complete resolution was significantly higher in the intervention group.

D’Haens mentioned an underreporting of ADRs regarding skin manifestations,33 and the label of infliximab compounds mentions dry skin as a common ADR of infliximab.34 A recent meta-analysis including 29 776 IBD patients on anti-TNF treatment investigating skin ADRs only mentions psoriasis, eczema, and skin infections as commonly reported skin ADRs.35 Nigam et al included 11 530 infliximab-treated IBD patients in the meta-analysis, but dry skin was not reported as an ADR at all.35 In our trial, 67.7% of all patients reported dry skin during the course of infliximab treatment. Thus, this side effect should be addressed in comprehensive patient care. Pepijn et al showed that skin conditions are one of the most burdensome ADRs from the perspective of IBD patients on biological therapy.11 In all, 147 anti-TNF-related ADRs regarding skin conditions were observed in our trial: 63 appeared in the intervention group and 85 in the control group. In the intervention group, 73.0% of the ADRs regarding the skin were fully resolved, whereas only 28.2% in the control group could be resolved. Andrade et al demonstrated a significantly increased odds ratio for dermatologic ADRs among smokers.38 In our study, the control group did not have significantly more smokers (Table 1) to explain the increased rate of skin ADRs in the control group.

The intervention group numerically included more patients with additional immunosuppressive medication (not significant, Table 1) in combination with anti-TNF antibody therapy. Notably, we demonstrated that patient counselling concerning the immunocompromising effect of anti-TNF therapy, the necessity of vaccination, and hygienic rules can lead to fewer infectious complications in favor of the intervention group (38 vs 73 infectious diseases).

These results underline the importance of patient support programs for the management of ADRs in IBD patients in clinical care.

The second primary end point, health-related quality of life as assessed by the IBDQ questionnaire, showed no significant difference after 6 and 12 months between groups. Both groups started with an average IBDQ score of 180 points, which indicates a good quality of life for IBD patients, as all patients were in clinical remission or had mild disease activity at most and were already under anti-TNF therapy for a minimum of 3 months. Inflammatory bowel disease patients in clinical remission are marked by an IBDQ score of >170 points.24,25 We therefore analyzed the subgroup of patients with less than 170 points at baseline. In this subgroup (n = 33; intervention group = 20 and control group = 13), we could demonstrate that the intervention group had a significant and clinically relevant improvement at 6 months in comparison with the control group. After 12 months, this significant difference could not be detected. Nevertheless, we think these results are important since this study was not powered for a subgroup analysis and still reached significance after 6 months. In addition, we demonstrate that patients with initially lower health-related quality of life were able to profit from the patient support program, reaching an average IBDQ score of 170 in comparison with the control group (150 points; P = .054) after 12 months.

The secondary patient relevant end point, satisfaction with information about anti-TNF therapy was significantly higher in the intervention group at months 6 and 12. This illustrates, that pharmacist-led medication education for IBD patients on anti-TNF therapy can considerably improve patient satisfaction with medication information.

Remarkably, significant results could be demonstrated for the secondary end point, unsolved medication errors in favor of the intervention group. Twenty-two medication errors related to anti-TNF therapy were detected. One anti-TNF related medication error in the intervention group and 9 in the control group remained unsolved. Furthermore, 27 (21.3%) patients with unselective nonsteroidal anti-inflammatory drugs (NSAID) in their medication history were identified. The use of unselective NSAID in IBD has been described to have the potential for worsening IBD, and its use is not recommended in IBD patients by respective guidelines.36 These data emphasize that intensified pharmaceutical care improves medication safety in IBD patients.

This study could not demonstrate an impact on patient-reported fatigue. The study patients showed an average score of 38 points in the FACIT-F questionnaire, which is in line with the current literature.26 The healthy population obtains a score of 42 to 43 points.26 Managing fatigue in IBD remains challenging for healthcare professionals. A recent Cochrane review emphasized that no evident conclusion about efficacy of interventions for fatigue in IBD can be drawn.37

This study has limitations that need to be considered. Blinding of patients and physicians to the study design was not possible. This single-center study was conducted at an outpatient academic tertiary care center, and patient counselling was performed by a single clinical pharmacist. The study duration of 12 months might be too short to fully address the impact on severe ADRs. The proactive management of therapy related ADRs may reduce the need for expensive healthcare utilization and productivity loss of patients, which results in costs savings. However, these data were not recorded in our trial. More than 90% of the patients received infliximab. Most of the eligible adalimumab patients denied the study participation because of the time needed for consultation. At therapy initiation, it is known that patients are prone to suffer from rapidly occurring ADRs depending on disease activity and comorbidity.8,14 In addition, approximately one-third of treated patients do not demonstrate adequate response to initiated treatment (primary nonresponse) in the first 3 months of therapy initiation.6 These patients would have resulted in a dropout in this trial, independently of the intensified patient support program, and were therefore not included.

Given that the armamentarium of approved targeted therapies is steadily increasing in the IBD field, embedding a clinical pharmacist in the MDT taking care of IBD patients should be a best practice consideration. A clinical pharmacist as an integral part of the MDT could take care of monitoring ongoing medication in IBD patients, which often consists of complex and costly targeted therapies. Beyond monitoring of medication and ADRs, the clinical pharmacist also provides medication education and information considering health maintenance.18This is strongly supported by the results of our study and also reflected by a study among experts in the field of IBD, where 94% agreed that an IBD unit should have a pharmacist with experience in the administration of all approved drugs for IBD.39 These recommendations also reflect the Canadian consensus for IBD quality indicators.40 Furthermore, the role of IBD pharmacists was defined in the recently published systematic review and consensus paper of Bhat et al.18 The expert panel determined, among others, medication education, medication monitoring, and health maintenance review as primary tasks of IBD pharmacists.18 One of the challenges for IBD centers in implementing the clinical pharmacist as integral part of the care team is the lack of data that support this initiative. To our knowledge, this is the first randomized clinical trial that has demonstrated that the integration of an IBD pharmacist in the MDT improves patient-reported outcomes and optimizes medication safety.

In conclusion, our randomized trial demonstrates that an additional intensified pharmaceutical patient support program is effective to substantially improve patient relevant ADR burden and patient satisfaction with information about anti-TNF therapy, and reduces medication errors. Clearly our data support the recommendation that the implementation of a clinical pharmacist in the MDT of a tertiary care center is an appropriate intervention to substantially improve the comprehensive management of IBD patients under anti-TNF therapy.

Supplementary Data

Supplementary data is available at Inflammatory Bowel Diseases online.

izae040_suppl_Supplementary_Material
izae040_suppl_supplementary_material.docx (4.9MB, docx)

Acknowledgments

The authors thank all patients for participating in this study and all physicians and nurses contributing to an effective patient recruitment, especially during the challenging times of the Covid-19 pandemic. The authors are grateful to the Department of General Practice and Health Services Research and Department of Internal Medicine VI, Clinical Pharmacology and Pharmacoepidemiology, University Hospital Heidelberg, Heidelberg, Germany for kindly providing the SIMS-D questionnaire.

Contributor Information

Johannes Plechschmidt, Pharmacy Department, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.

Konstantin Fietkau, First Department of Medicine, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Ulmenweg 18, 91054 Erlangen, Germany; Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany.

Tobias Hepp, Institute of Medical Informatics, Biometry and Epidemiology, Friedrich-Alexander-University Erlangen-Nürnberg, Waldstraße 6, 91054 Erlangen, Germany.

Peter Dietrich, First Department of Medicine, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Ulmenweg 18, 91054 Erlangen, Germany; Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany.

Sarah Fischer, First Department of Medicine, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Ulmenweg 18, 91054 Erlangen, Germany; Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany.

Sabine Krebs, Pharmacy Department, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.

Markus F Neurath, First Department of Medicine, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Ulmenweg 18, 91054 Erlangen, Germany; Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany.

Frank Dörje, Pharmacy Department, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.

Raja Atreya, First Department of Medicine, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Ulmenweg 18, 91054 Erlangen, Germany; Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany.

Funding

This work was supported by the Friedrich-Alexander-University Erlangen-Nürnberg and the Erlangen University Hospital (IIT—Investigator-initiated study).

Conflicts of Interest

J.P., T.H., K.F., P.D., and S.K. have no conflict of interest. S.F. has served as a speaker, or consultant, or received research grants from Lilly, Janssen, Biogen, MSD, and AbbVie. M.F.N. has served as a speaker, or consultant, or received research grants from AbbVie, MSD, Takeda Pharma, Boehringer, Roche, Pfizer, Janssen, Pentax, PPD. F.D. received an earmarked financial contribution for the first award of the MSD Germany Health Award 2021. F.D. has received consultancy fees from Lilly Deutschland and SANDOZ AG and has received lecture fees from E. Lilly. R.A. has served as a speaker, or consultant, or received research grants from AbbVie, Arena Pharmaceuticals, AstraZeneca, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Cellgene, Celltrion Healthcare, DrFalk Pharma, Galapagos, Gilead, InDex Pharmaceuticals, Janssen-Cilag, Lilly, MSD Sharp & Dohme, Roche Pharma, Samsung Bioepsis, Takeda Pharma. DFG-SFB/TRR241 Project No. C02 and IBDome (RA) are funded by the German Research Council (DFG).

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

izae040_suppl_Supplementary_Material
izae040_suppl_supplementary_material.docx (4.9MB, docx)

Data Availability Statement

All data sets, patient-reported outcomes, and statistical analysis methods supporting the results are published in this article and the online Supplemental Material. The study protocol and all written patient fact sheets can be obtained from the corresponding author via reasonable request.

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