What Is the Personal Experience of IBD Patients about Their Anti-TNF-Alpha Therapy?

AIM: To evaluate and compare the patients opinion on the two types of antiTNF-α therapies in a Hungarian cohort of IBD patients. METHODS: This was a prospective, multicentre, questionnaire-based observational study carried out in three Hungarian tertiary centres. From April to September 2014, an anonymous questionnaire was distributed to patients diagnosed with ulcerative colitis (UC) or Crohn’s disease (CD), who have received infliximab (IFX) and/or adalimumab (ADA). The survey focused on the preferences of the two anti-TNF-α therapies on the basis of the efficacy, the administration routes and the side-effects. RESULTS: 292 IBD patients, 216 CD, 75 UC and 1 indeterminate colitis patient completed the questionnaire. The mean duration of biological therapy was 1.7 (1 7) years. IFX treated patients noticed improvement of symptoms at 4 5 weeks while ADA treated patients noticed at 5 6 weeks. There was no difference between the patients’ satisfaction regarding the types of anti-TNF-α therapy if they received both. However, subcutaneous administration was preferred by ADA-treated patients previously receiving IFX (p = 0.007) compared to intravenous route and they did not intend to change the mode of therapy (p = 0.040). 90% of the patients, receiving only IFX or ADA were satisfied with their present therapy. The majority of patients (186/292, 63.7%) would not switch therapy. 63 of 291, 22% of the patients reported to have some concern with biological therapy—the majority (32/63, 50.8%) due to fear from side effects. CONCLUSION: Generally, patients preferred and would not change the present anti-TNF-α therapy, however, subcutaneous administration was preferred among those patients who had have experience with both. How to cite this paper: Milassin, Á., Rutka, M., Csontos, Á.A., Miheller, P., Palatka, K., Szűcs, M., Szepes, Z., Bálint, A., Bor, R., Fábián, A., Farkas, K., Nagy, F. and Molnár, T. (2017) What Is the Personal Experience of IBD Patients about Their AntiTNF-Alpha Therapy? Health, 9, 1007-1018. https://doi.org/10.4236/health.2017.97073 Received: February 27, 2017 Accepted: July 7, 2017 Published: July 10, 2017 Copyright © 2017 by authors and Scientific Research Publishing Inc. This work is licensed under the Creative Commons Attribution International License (CC BY 4.0). http://creativecommons.org/licenses/by/4.0/


Introduction
Inflammatory bowel disease (IBD) is a chronic inflammatory intestinal disorder defined clinically into two major entities: Crohn's disease (CD) and ulcerative colitis (UC).These diseases can affect the entire gastrointestinal tract [1].While the exact etiopathogenesis of the disease remains unknown, it is widely accepted that both CD and UC originate from an inappropriate immune response in genetically susceptible individuals as a result of complex interactions of genetic, environmental and microbial factors [2].These conditions usually require a lifelong treatment because of the complex, uncertain and chronic nature of the disease.The goal of the treatment in the management of IBD is not only to achieve clinical improvement but also to alter the course of disease and to restore a normal bowel function.This requires the suppression of inflammation and the induction of complete mucosal healing [3] [4].With the early use of biological agents, these treatment goals can now be achieved.Infliximab (IFX) and adalimumab (ADA) are the two firstly and most widely used anti-TNF-α biological therapies licensed for the treatment of IBD (CD and/or UC) in Europe.In 1997, IFX was the first biological agent used for the treatment of moderate to severe CD in patients with inadequate response to corticosteroid and/or immunosuppressant therapy, or who could not tolerate the side effects or had contraindications.Later IFX was subsequently used for the treatment of UC in similar indications.The recommended dose of IFX is 5 mg/kg given as an intravenous induction regimen at first, second and sixth week followed by a maintenance regimen of 5 mg/kg every eighth week.Patients have to spend time on treatment, because of waiting for blood test and for IFX infusion therapy at outpatient clinic.An infusion is given approximately over 2 hours, after that they have to stay for clinical observation in case of late infusion reactions occurred.ADA has been available in Hungary since 2007 and in contrast to IFX, and it is administered as a subcutaneous injection usually every other week, at dose of 160 mg, 80 mg for induction and subsequently 40 mg every other week for maintenance.This subcutaneous injection can be administered by general practitioner, nurse or by the patient after learning self-injection technique.Self-administration requires high cooperation and compliance from patients.Clinical indications of these two anti-TNF agents are similar.
On several occasions during IBD therapy can patient and doctor make decisions, but how they decide?The decision about which one of the two anti-TNF agents receive the patient depends on the specialist's recommendation and the patient's preference.Allen PB et al. found a trend towards patient preference for IFX (iv.) treatment as opposed to ADA (sc.) [5].They found the difference may be due to the frequency of administration, mode of administration or differing 'times in the market-place' [5].Contrary Vavricka et al. found that patients preferred anti-TNF medications that were administered by subcutaneous injection rather than by intravenous infusion [6].The two major factors influencing patient's decision were the ease of use and the time required for therapy [6].The aim of this study was to evaluate and compare the patients' opinion and satisfaction with the two types of anti-TNF-α therapies a Hungarian cohort of IBD patients.

Materials and Methods
This was a prospective, multicentre, questionnaire-based observational study carried out in three Hungarian tertiary centres.Adult patients diagnosed with UC or CD, who have administered at the time of the study or previously one or both of the two anti-TNF agents and performed anonymously questionnaire-based survey between April 2014 and September 2014, were enrolled in the study (Appendix 1).Patients who did not meet the above-mentioned inclusion criteria were excluded.The questionnaire contained questions for patient's demographic data (gender, age, smoking history and patients' highest educational level), IBD characteristics (year of diagnosis, disease phenotype, disease location, IBD related operations, concomitant medications), and further questions were about patients' preferences for anti-TNF drugs.Specifically, patients were asked about current and/or previous biological therapy, and the satisfaction in accordance with the current anti-TNF-α therapy.If they changed therapy, the reason and the satisfaction with previous or current therapy was also asked.Questions were about the price supposed of the biological agent they received, when and from who they heard first about biological treatment, their worst experience during biological therapy, the side effects they noticed and whether they were anxious of biological therapy.Further questions were about the time after they felt improvement of their symptoms, if they have ever observed that the efficacy of biological therapy decreased before the next maintenance therapy.Further questions were: "Which biological agent would you prefer based on your experience if you can choose"; "What was the most effective therapy you have ever received"; "Have you been operated during biological therapy?".Finally, patients were asked if they would participate in a new drug trial even though they would have to stop their current biological treatment or not.

Statistics
The collected data were analysed statistically.Data were analysed using Pearson's chi-square test, and Fisher exact test.P < 0.05 was considered statistically significant.For the statistical analysis, R statistical program (version 3.2.5)was used.

Ethical approval
The study was approved by the Regional and Institutional Human Medical Biological Research Ethics Committee of the University of Szeged.

Patients Characteristics
Two hundred and ninety-two IBD patients (133 women, 159 men, mean age 35 (15 -67) years) were prospectively enrolled.Table 1 gives an overview of the

Patients Satisfaction with Biological Therapy
The majority of the patients (259/292, 88%) treated with biological therapy were satisfied with their management (138/153, 90% of IFX; 90/106, 84% of ADA treated patients).33 of 292, 12% of the patients were unsatisfied with their therapy, they mentioned lack of efficacy, side effects (joint and bone pain), and 6 of them did not answer to the question.79 patients had experiences with both biological agent, majority of them (33/79, 42%) was more satisfied with ADA treatment, they mentioned that ADA is more effective, they were satisfied with the ease of use and less side effect of ADA. 15 of 79, 19% of the patients was content with IFX because of its effectiveness.According to the patients' decision biological therapy was the most effective treatment ever.181 of 292, 62% of them found biological therapy the most effective therapy ever received.Other treatment like steroid (32/292, 11%), thiopurine (15/292, 5.1%) was also found effective.Important to note, that 70 of 292, 24% of the patients did not fulfil this question.
Patients treated with IFX felt the effectiveness of the therapy at first time between the 4-5 th week, while patients on ADA therapy felt it between the 5-6 th week.More than half of the patients felt ever loss of effectiveness before the next would choose IFX again and they mentioned: "This treatment is effective for me"; "I have no experiences with other biological therapy"; " I prefer to take drug less often"; "I don't like the idea of self-injecting"; "fewer side effects"; "medical supervision during infusion".29 of 45 only ADA treated patients (note that 15 not responded) would choose ADA again and they mentioned: "This treatment is effective for me", "I have no other experiences with other biological agents"; "It is more comfortable for me to give the injection at home".The reasons cited for those patients who had experience with both anti-TNF-α agents and chose IFX (and the latest biological therapy was IFX), were: "This is more effective and I can feel the effect quicker than other biological agent" (n = 12), "I prefer to take drug less often" (n = 1).Significantly (p = 0.007) more from those patients, who had experiences with both anti-TNF-α agents and the latest biological therapy was ADA, chose ADA, and the reasons mentioned were: "I prefer the convenience of self-injecting at home and I don't have to wait so much."(n = 17), "This treatment is effective for me" (n = 15), fewer side effects (n = 10).
From them who chose IFX they mentioned "IFX was more effective" and they liked the infusion's frequency.

Mode of administration
Questions were about the patients' current treatment and about the mode of administration.In case of the current treatment was IFX (n = 179), the majority of the patients were satisfied with the infusion's time, and length of the therapy (150/179, 84%), while the mode of administration did not disturb them (163/ 179, 91%).They were asked whether they prefer the administration of IFX subcutaneously, like ADA, and 127 of 179, 71% were satisfied with the current intravenous mode of administration.In case of the current treatment was ADA (n = 113), the majority of the patients were satisfied with the subcutaneous mode of administration and with the therapy's frequency and did not disturb them (101 of 113, 89% -89%).Who gives the subcutaneous injection was also asked: the majority of the patients give the injection themselves (76/113, 67%), in other cases the injection is given by a family member or general practitioner (16/113, 14%; 14/113, 12%).The majority of the patients were satisfied with the mode of administration and they would not change it.There was no difference between the patients' satisfaction regarding the type of anti TNF-α therapy if they received both.However, subcutaneous administration was preferred by ADAtreated patients, previously receiving IFX (p = 0.007) compared to intravenous route and they do not intend to change the mode of administration of the ther-apy (p = 0.043).

Side effects and fears of biological therapy
Seventy-two patients (from 267 respondents) noticed side effect of biological therapy during their treatment period, 57 patients were on IFX, and 10 were on According to our survey 63 of 291 patients, 21.65% were anxious because of the biological therapy; adverse events may occur during treatment (n = 32), long term effects are unknown (n = 18), malignancies may develop (n = 2), infections can occur (n = 2), treatment can affect pregnancy (n = 1) were mentioned.
Patients were also asked about what they think about one therapies price.The mean price of IFX was supposed to be approximately 635,000 HUF, while the official price was approximately 153,000 HUF.The mean price of ADA was supposed to be approximately 446,000 HUF, while the official price was approximately 275,000 HUF at the time of the survey.

Discussion
In this prospective, multicentre observational study of the IBD patients' opinion and satisfaction about the currently available two anti-TNF drugs in Hungary were evaluated and a questionnaire based survey was used.Questionnaires were distributed between April 2014 and September 2014 among adult patients diagnosed with UC or CD and received separately IFX, ADA or both IFX and ADA after each other.Two-thirds of the patients included in the survey were on IFX therapy at the time of the study and 27% of the patients have been treated with both anti TNF agents.
Generally we found no significant differences in the patients' preferences for choosing one of the anti-TNF drugs (IFX or ADA).Our results showed that patients were satisfied with their current anti-TNF therapy; they found them effective therefore they did not want to change it to other anti-TNF medication with uncertain effect on their symptoms.Regarding those patients who were treated with both anti-TNF drugs, we found a tendency in preferring the currently used anti-TNF drugs.We found a tendency towards ADA treated patients like subcutaneous administration and they did not show a tendency to change it, while patients on IFX therapy, who were discontent with their therapy showed a tendency to change it to subcutaneous administration, and the time required for administration of IFX infusion was the main reason mentioned.
The majority of patients with IBD require long-term medication for disease control and maintenance of remission.Only limited data are available on the patients' knowledge and preference on biological therapy, although better cognition of the patients' opinion would improve the adherence to medications.Patient preference studies for anti TNF therapies are usually from the field of rheumatology.In rheumatoid arthritis studies, most patients prefer ADA to IFX because of the more convenient administration route of the drug [8] [9].The main differences between IFX and ADA are the route of administration (hospital vs. self administered infusion/injection), frequency of dosing and the time on market.Although IFX has been licensed for a greater time on the market than ADA, both drugs have been used for years and proved their efficacy in the treatment of IBD.Frequency of dosing and route of administration are potentially modifiable factors of nonadherence to maintenance medication for IBD which occurs in 30% -45% of patients [10] [11].Therefore adequately informing patients and considering their preference is important to improve adherence to therapy.The study by Selinger et al. revealed that patients on IFX were more adherent, than patients on ADA [11].
Several studies found that one anti-TNF drug is more preferred than other, but the results were controversial.Contrary to our data, in the study by Allen et al. nearly twice the number of patients chose IFX over ADA because of the lower frequency of dosing in 42% of the cases.The commonest reason cited for those who chose IFX (67%) was that they did not like 'self-injecting administration' [5].However, the study was not powered enough to draw significant conclusions and this difference did not reach statistical significance as well.In accordance with our results, they could not reveal any difference in preference for either anti-TNF therapy.Vavricka et al. evaluated the preferences of anti TNF naive CD patients for selecting one of the anti TNF drugs.Most patients preferred ADA and certolizumab pegol to IFX because of the ease of their subcutaneous administration and the reduced amount of time required to receive the therapy in comparison to anti-TNF drugs delivered by intravenous route [6].Our findings on patient preferences for subcutaneous administration are comparable to preferences of rheumatoid arthritis patients and CD patients in the Vavricka study.
However an important difference between our and Vavricka's study was that we included anti TNF experienced patients treated with either or both anti TNF drugs.Among patients who were treated with both agents, ADA was more preferred compared to IFX: patients found ADA to be more effective and they were satisfied with the ease of use and less side effects of the drug.Notably, patients treated with both agents were switched from IFX to ADA in 86% of the cases and the main reason of switching anti-TNF agents were loss of response and infusion reactions occurred during IFX therapy [6].
We found a tendency that patients treated with IFX felt the effectiveness of therapy earlier than patients treated with ADA but there were no significant differences between the two groups.
The limitation of the study was the relatively low response rates of certain parts of the survey despite the high number of enrolled patients.However, the study was able to demonstrate that the majority of the patients on biological therapy were satisfied with their management and found anti TNF therapy the most effective ever received.The majority of the patients received medical information from their physician suggesting an accurate knowledge about the therapies.60% of IFX and 64% of ADA treated patients would choose their therapy again because they found them effective and do not have experience with the other agent.However, interviewed patients who preferred IFX stated that "I prefer to take drug less often" and "I don't like the idea of self-injecting" that determined the choice of therapy.The patients preferring ADA identified the comfortable route of giving the injection at home as a factor influencing their treatment choice.
Route and frequency of drug administration and side effects may play role in decision making of IBD patients.According to our results Hungarian IBD patients prefer subcutaneous administration because of its convenience and time saving property, but they also find both IFX and ADA effective.Our result suggest that beside the route of administration and the therapy's effect the key factors influencing a decision to choose a therapy for patients were physician's recommendation.Further studies are required in IBD patients to investigate whether patients' decision affect their compliance, satisfaction and effectiveness of anti-TNF therapies.