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Corresponding author at: Department of Biomedicine, Unit of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, Rua Plácido Costa, 4200-450, Porto, Portugal.
Department of Biomedicine, Unit of Pharmacology and Therapeutics, University of Porto, Porto, PortugalDepartment of Gastroenterology, São João University Hospital, Porto, PortugalMedInUP, Centre for Drug Discovery and Innovative Medicines, Porto, Portugal
The role of thiopurines in therapeutic algorithms of Crohn's disease (CD) and Ulcerative colitis (UC) is being questioned. This work aimed to investigate current practice and future perspectives of Inflammatory Bowel Disease (IBD) physicians regarding the efficacy, safety, and role of precision medicine with thiopurines in IBD.
Methods
A 29-questions web-based survey was developed and distributed to IBD physicians worldwide.
Results
We collected the complete answers of 408 physicians from 50 countries. Most participants were experienced physicians in IBD; 26.0% met our definition of “IBD expert”. Four physicians reported to not use thiopurines in clinical practice. Most respondents used thiopurines in monotherapy and in combination therapy, both in CD and UC. Respondents tended to consider thiopurines as drugs with a good safety profile, with the agreement of 61.5% of the overall cohort. A minority of physicians (~6%) considered that thiopurines will not be used in the future in IBD patients, while 57.8% believed that these drugs will still be used, in mono and combination therapy.
Conclusion
Despite the many emerging treatments in IBD, according to the beliefs of most physicians surveyed, thiopurines will still be an important part of the treatment algorithm of both CD and UC.
Inflammatory bowel disease (IBD), comprising Crohn's disease (CD) and ulcerative colitis (UC), are chronic disorders of the digestive tract with increasing incidence and prevalence worldwide [
]. With the approval of new agents, the role of thiopurines in the therapeutic algorithm of IBD is being questioned. Thiopurines were developed before the publication of international regulation on clinical research and before the adoption of objective outcomes in therapeutic trials of IBD [
Recommendations of the Spanish Working Group on Crohn’s Disease and Ulcerative Colitis (GETECCU) on the use of thiopurines in inflammatory bowel disease.
Recommendations of the Spanish Working Group on Crohn’s Disease and Ulcerative Colitis (GETECCU) on the use of thiopurines in inflammatory bowel disease.
. Nonetheless, thiopurines are recognized as an effective maintenance treatment, in both UC and CD, either as monotherapy or in combination with biologics [
Precision medicine tools are available in many countries to optimize treatment, including the evaluation of thiopurine S-methyltransferase (TPMT) activity and the measurement of 6-thioguanine nucleotides (6-TGN) and 6-methylmercaptopyrine ribonucleotides (6-MMPR) [
Recommendations of the Spanish Working Group on Crohn’s Disease and Ulcerative Colitis (GETECCU) on the use of thiopurines in inflammatory bowel disease.
. However, these tools may not be accessible to all IBD physicians globally or may not be adopted in the management of IBD patients, due to the uncertainties concerning their utility.
In this era of growing therapeutic diversity for IBD, physicians have been debating when and how to use thiopurines. The aim of this study was to investigate current practices with thiopurines in IBD, as well as future prescription perspectives and the role of precision medicine, along with physicians’ concerns on their efficacy and safety.
2. Materials and methods
2.1 Study design
We developed an investigator-initiated survey supported by the clinical committee of ECCO (ClinCom), through an independent review board. The first version of the survey was reviewed by ClinCom and by the members of the ECCO governing board. After one round of modifications, the final version of the survey was approved (Supplementary Document 1).
The survey consisted of 29 questions and was structured in three main sections: the first part gathered demographic data; the second part explored the current clinical practice regarding the use of thiopurines in IBD; the final part of the survey explored participants’ opinion concerning the efficacy, safety, role of precision medicine and future role of thiopurines in IBD.
All responses were anonymous. The survey was approved by the Ethical Committee of Tondela-Viseu Hospital Centre.
2.2 Survey population and administration
The inclusion criteria were physicians actively managing patients with IBD who completed the questionnaire. Not all questions were mandatory to all participants; in fact, negative answers in some questions led to a bypass in the survey form.
In the absence of a universal definition of “IBD expert”, we defined them as senior physicians observing more than 20 patients per week.
This survey was conducted through an online platform (SurveyMonkey®), between July 20 and December 27, 2020. In addition to the ECCO newsletter and website, the survey was distributed by several national Gastroenterology and IBD associations (Supplementary Document 2) and experts. Aiming to increase the size of our sample, the invitation letter sent to the physicians encouraged further distribution among colleagues.
2.3 Statistical analysis
Descriptive statistics of demographic data and overall responses were documented. Categorical variables were expressed as frequencies and percentages. Physicians’ opinions were evaluated with a five-point Likert-type scale, ranging from “strongly disagree” (1) to “strongly agree” (5). Results were displayed as percentages and medians. Categorical variables were compared with the use of the chi-square test [χ2 (degrees of freedom, N)]. All reported p values are two-tailed, with a p value of .05 indicating statistical significance. IBM SPSS Statistics 26® (IBM, New York, USA) was used for statistical analyses, and Microsoft Excel® (Microsoft Corporation, Washington, USA) was used for plot design.
3. Results
3.1 Demographics
465 physicians answered the survey, with a completion rate (questionnaires with no missing answers) of 87.7%. Table 1 presents the characteristics of the 408 physicians who completed the survey. Respondents were from 50 different countries distributed across 5 continents (Supplementary figure 1). Participants were mainly experienced physicians, with more than 10 years of practice, working in academic central hospitals or tertiary centres, and attending more than 20 patients per week. According to our definition, 106 physicians (26.0%) were considered “IBD experts”.
Table 1Demographic and clinical characteristics of the physicians.
3.2 Current use of thiopurines in clinical practice
One third (n=135/408) of the respondents declared that in their country failure or intolerance to thiopurines was generally mandatory before prescribing a biologic.
Most participants (404/408; 99.0%) were using thiopurines, with azathioprine as the preferred drug (Supplementary Table 1). Thioguanine was only used by 27 physicians (6.6%): 14 from Europe (Netherlands, n=7; Sweden, n=2; United Kingdom, n=2; France, Germany, Ireland, n=1 each), 11 from Oceania (New Zealand, n=8; Australia, n=3), and 2 from America (Brazil and USA n=1 each). In this group, most participants were senior physicians (15/27; 55.6%), consulting more than 20 patients/week (16/27; 59.3%), and working in an academic central hospital/ tertiary centre (21/27; 77.8%).
Most participants reported to use thiopurines both in monotherapy and in combination therapy, in CD and UC (Fig. 1a). Responses evidenced regional variations (Supplementary figure 2); for example, all respondents from Africa and Oceania used thiopurines both in mono and combination therapy in CD, as opposed to half of the participants from North America. There was a significant association between being an “IBD expert” and the use of thiopurines in both CD [χ2 (2, N=400) = 7.50; p=.02 - Supplementary table 2] and UC [χ2 (2, N=399) = 7.30; p=.03 - Supplementary table 3]. IBD experts were less likely than non-experts to only use thiopurines in monotherapy in CD and UC, and more likely to use thiopurines in both monotherapy and combination treatment in UC. Most physicians had less than half of their patients treated with thiopurines by the time of the survey (Fig. 1b). More CD patients were treated with these drugs than UC patients, as 28.2% of participants had more than half of their CD patients on treatment while 11.4% of participants had more than half of their UC patients on treatment. Of those patients on treatment with thiopurines, the majority was on combination therapy with biologics, as only 23.0% (for CD) and 23.5% (for UC) of the physicians reported having more than half of their total patients treated with thiopurines in monotherapy (Fig. 1c).
Fig. 1Current use of thiopurines in clinical practice
Two-thirds (274/404, 67.8%) of respondents usually check Epstein barr virus (EBV) status before prescribing a thiopurine, while 8.8% (36/404) only do so in specific situations, such as young males (n=21), young patients in general (n=7), and previous/active infection or immunodeficiency (n=5). When the analysis was restricted to paediatricians/paediatric gastroenterologists, 12.5% (3/24) declared to not screen for EBV status before introducing thiopurines.
Sixty-three percent (257/404) of respondents had access to TPMT activity assessment, by either genotype or phenotype. About 61% of physicians use these tools in clinical practice (Supplementary Figures 3a and b). Almost half of respondents (198/404) had access to thiopurine metabolites measurement and the majority (65.2%) resorted to this tool in clinical practice (Supplementary Figure 3c). The access to these tools varied between regions (Supplementary Figure 4); for example, while all participants from Oceania and most participants from Northern Europe, North America and Western Europe could use these tools in clinical practice, the access in Southern Europe, South America, Asia, and Africa was more limited.
Most participants started thiopurines with a low dose and gradually titrated it (Supplementary Table 1). Most participants that started treatment with the target dose had access to TPMT activity assessment by genotype and/or phenotype (87/111; 78.4%). Concerning thiopurines’ target dose, most respondents used lower target doses in combination therapy with biologics (49.5%), whereas 43.0% use the same target dose in monotherapy and in combination therapy.
Inefficacy, intolerance, and adverse events were the main reported reasons to stop treatment with thiopurines (Supplementary Table 1). About half (206/404; 51.0%) of the respondents stop treatment in elderly patients and twenty-five physicians (6.2%) mentioned they would stop treatment during pregnancy; one of the respondents specified that they only stop treatment with thiopurines in pregnant patients when used in combination therapy.
3.3 Current opinion on thiopurines use in IBD
3.3.1 Treatment efficacy and safety
In both CD and UC, most respondents agreed that thiopurines are an effective treatment in monotherapy (Fig. 2). Concerning the statement “Thiopurines should mainly be used in combination therapy”, the answers were divided, leading to an overall neutral opinion; experts’ opinion followed the same trend.
Respondents tended to consider that thiopurines have a good safety profile, (61.5% agreed; median score=4.00), mainly in patients aged between 30 and 50 years old (Fig. 3). Even though the experts’ overall opinion was similar, they did not agree with the sentence “Generally speaking, thiopurines have a good safety profile” in the same extent. Unlike the general cohort, more than half of the IBD experts agreed that they tend to prescribe less thiopurines in IBD due to the fear of adverse events.
Participants were also asked about the impact of thiopurine metabolites’ measurement and TPMT activity determination by genotype and phenotype on treatment efficacy and safety (Fig. 4). In relation to TPMT activity assessment, respondents were, in general, neutral about its utility in improving treatment efficacy. On the other hand, TPMT activity assessment was considered helpful in the prevention of adverse events. In line with these results, and despite a median result of 3.0, the general cohort agreed that “if they had easy access to TPMT activity determination they would feel more confident prescribing thiopurines”. In contrast, most experts did not consider that the access to these tools would improve confidence, with 48.1% of disagreement for genotype and 45.3% for phenotype. Nevertheless, most of the overall cohort and of the experts disagreed with the statements referring that TPMT activity determination by genotype or phenotype had no utility in the present clinical practice of IBD.
Concerning metabolites’ measurement, the overall results indicate that participants considered that this tool was helpful, both for improving treatment efficacy and to prevent adverse events (median agreement scores of 4.00, and agreement rates of 69.1% for efficacy and 61.5% for toxicity). Most participants agreed that the access to metabolites’ measurement increases the confidence while prescribing thiopurines; this tendency was less expressive in the expert group. The strongest disagreements were in relation to the statement “metabolites measurement has no utility in the present clinical practice of IBD”, with 65.9% of the total cohort disagreeing and half of the experts strongly disagreeing (with an additional 21.7% moderately disagreeing).
3.4 Future role of thiopurines in IBD
As far as the future positioning of thiopurines in treatment algorithms of CD and UC, most participants believed that these drugs will still be used in monotherapy and in combination treatment with biologics (Fig. 5). The opinion of the expert subgroup was similar for CD [χ2 (3, N=404) = 3.72; p=.29 - Supplementary table 4] and UC [χ2 (3, N=403) = 4.25; p=.24 - Supplementary table 5]. These opinions had also regional tendencies (Supplementary figure 5); for example, 28.0% of North American participants and 100% of African participants considered that thiopurines will be used both in monotherapy and in combination therapy in CD. A minority of participants, worldwide, believe that thiopurines will no longer be used in IBD in a near future.
Therapeutic options for IBD have expanded in the last decades, raising questions about the positioning of “old” drugs in the therapeutic algorithm of these disorders. This international web-based survey shed some light on current practice of thiopurines use in IBD as well as on the perspective of physicians and on the access to precision medicine tools for thiopurine treatment optimization.
Evidence from Cochrane systematic reviews and meta-analyses confirms that thiopurines in monotherapy are superior to placebo in maintaining steroid-free remission, in both CD and UC [
Recommendations of the Spanish Working Group on Crohn’s Disease and Ulcerative Colitis (GETECCU) on the use of thiopurines in inflammatory bowel disease.
. However, the quality of the evidence is only low to moderate, and the need of adequately powered comparison trials with other maintenance therapies is frequently quoted. Recently, a retrospective study from the United Kingdom including 11928 patients with IBD treated with thiopurine monotherapy, with 68132 patient-years of exposure, raised some questions concerning the efficacy of thiopurines in CD [
Thiopurine monotherapy is effective in ulcerative colitis but significantly less so in Crohn’s disease: long-term outcomes for 11 928 patients in the UK inflammatory bowel disease bioresource.
]. Thiopurines in monotherapy were an effective long-term treatment for 52.5% of UC patients, whereas the percentage or CD was lower (34.2%). Accordingly, intolerance to thiopurines was correlated with an increased risk of colectomy in UC patients, with a hazard ratio (HR) of 2.44 (p<0.0001). The impact on the risk of surgery of CD patients was smaller (HR of 1.23; p=0.0015). Similar data was reported from Leuven, where only 33.2% of CD patients treated with thiopurine monotherapy benefited from this treatment on the long term [
]. This led to the recommendation by these authors that thiopurines should mainly be used as adjuncts of anti-TNF agents in CD patients with moderate to severe disease. In our survey, surprisingly, most physicians stated that they still resort to thiopurines for the treatment of IBD in a significant percentage of patients. The majority also agreed that thiopurines are effective in monotherapy in CD and UC. The results evidenced that more CD patients were being treated with thiopurines. This may result from the existence of an effective non-immunosuppressive treatment for mild to moderate UC, (mesalamine), while a similar oral drug in terms of costs and efficacy is not yet available for CD. In addition, in UC there is a potential surgical cure with proctocolectomy available, when medical treatments are failing, which is usually not an option for the majority of CD patients.
In this survey, thiopurines were mainly being used in combination therapy. The combination of a thiopurine with an anti-TNF agent is a recognized strategy for IBD treatment [
Effects of concomitant immunomodulators on the pharmacokinetics, efficacy and safety of adalimumab in patients with Crohn’s disease or ulcerative colitis who had failed conventional therapy.
Postinduction serum infliximab trough level and decrease of C-reactive protein level are associated with durable sustained response to infliximab: a retrospective analysis of the ACCENT I trial.
Addition of azathioprine to the switch of anti-TNF in patients with IBD in clinical relapse with undetectable anti-TNF trough levels and antidrug antibodies: a prospective randomised trial.
]. A recent UK-wide multicentre prospective study (PANTS) demonstrated that the concomitant use of an immunomodulator in patients treated with infliximab was associated with higher remission rates at week 54, when compared with a strategy without immunomodulator [
]. The optimal dosage of thiopurines when used in combination therapy is still debated. In our survey, most physicians used lower target doses of thiopurines in combination treatment. In a French study, patients whose dose of azathioprine was reduced to half had similar through levels of infliximab as those with full doses; a level of 6-TGN below 105 pmol/8 × 108 RBC was associated with unfavourable evolution of infliximab pharmacokinetics [
Concentrations of 6-thioguanine nucleotide correlate with trough levels of infliximab in patients with inflammatory bowel disease on combination therapy.
]. Differently, in the PANTS study, the effect of thiopurines on the immunogenicity of infliximab was dose-dependent, with the lowest immunogenicity perceived in patients treated with higher doses of thiopurines [
]. While the US Food and Drug Administration (FDA) and the Clinical Pharmacogenetics Implementation Consortium recommend genotyping or phenotyping for TPMT deficiency prior to starting thiopurines [
American Gastroenterological association institute technical review on the role of therapeutic drug monitoring in the management of inflammatory bowel diseases.
state that the benefits of routine TPMT testing are still uncertain. While 63% of respondents have the possibility to determine TPMT activity (most by genotype), only about 2/3 of these physicians use these tools in clinical practice. Participants agreed that TPMT activity determination has some utility in current clinical practice of IBD, specifically in the prevention of adverse events, but it does not appear to increase confidence in the prescription of thiopurines.
About half of respondents have access to metabolites’ measurement, but from these only 65% measure them in clinical practice. Most participants agreed on the utility of measuring thiopurine metabolites’ levels in clinical practice, both for efficacy optimisation and prevention of toxicity. Although a weight-based regimen is usually advocated in clinical practice, the relationship between 6-TGN concentrations and thiopurine dose is weak, due to a high interindividual variation in thiopurine metabolism [
Respondents tend to stop thiopurines for intolerance, inefficacy, adverse events and in elderly patients (likely due to safety concerns). In our survey, 25 respondents claimed to stop thiopurines treatment during pregnancy. Thiopurines are considered a safe treatment in pregnant IBD patients and should be continued during this period, as a disease flare during gestation is associated with adverse foetal outcomes [
. More than half of the respondents stop thiopurines in patients in combination treatment in remission. The question of stopping one of the agents in patients treated with combination treatment is often debated [
]. Still, recent CD ECCO guidelines recommend maintaining infliximab or adalimumab in monotherapy in patients who achieved long-term remission with the combination of these drugs with immunosuppressants [
The toxicity profile of thiopurines is well studied due to their use in numerous disorders since the 1960s. Despite the fact that most participants considered that thiopurines have a good safety profile, mainly in patients aged between 30 and 50 years old, experts tend to have a lower degree of agreement with this statement and admitted prescribing less thiopurines than they did in the past due to toxicity concerns. Access to new drugs with novel mechanisms of action and seemingly better safety profiles may have contributed to this trend among experts. Nevertheless, when asked about the future role of thiopurines in the treatment algorithm of CD and UC, most participants, including experts, agreed that thiopurines will still be used, both in monotherapy and in combination treatment.
The results of this survey reflect regional differences that can be related to distinct access to new drugs, precision medicine tools, and different reimbursement rules. For example, in Australia, the restrictions related to the prescription of anti-TNF drugs (only after immunomodulators’ failure and/or intolerance) increased the reliance on thiopurines, with earlier introduction of these drugs after diagnosis [
]. Economic reasons are also on the basis of these differences; even if the safety profile of thiopurines may not be ideal, they can be a cost-effective treatment, more accessible than biologics [
This study has some limitations, the first of which is selection bias. Some world regions are overrepresented while in others the smaller number of answers might not be representative of the overall physicians’ opinion. The language barrier might have hindered the participation of some physicians, as we received none or few responses from non-native English-speaking countries whose IBD organizations had agreed to participate. In addition, concerning the topic of precision medicine evaluation, the study focused only on TPMT and metabolites’ assessment. However, TPMT deficiency is rare in South and East Asian populations [
], as opposed to polymorphism in nucleoside diphosphate-linked moiety X-type motif 15 (NUDT15), which is strongly associated with the occurrence of thiopurine induced-leukopenia in Asian populations [
On the other hand, this study has several strengths; it included a large number of responses, with a high completion rate. Most participants were experienced physicians, with several years of IBD practice, and a significant portion of the sample met our definition of “IBD experts”.
In summary, despite the emerging treatments in IBD, thiopurines will still be part of the treatment algorithm of both CD and UC in the future, according to the beliefs of most participants of this survey. Access to tools of precision medicine varies around the globe, and wider implementation of these instruments, especially metabolites measurement, may improve confidence on thiopurines prescription, improving safety and efficacy.
Funding
This research was supported by a Doctoral Scholarship from the Portuguese Group for the Study of Inflammatory Bowel Disease (Grupo de Estudo de Doença Inflamatória Intestinal—GEDII) to P.S. in 2018.
Conflict of interest statement
P.S. and M.L.H report no conflicts of interest.
P.M. is a consultant for Abbvie, Ferring, Hospira, Janssen, MSD, Pfizer, Takeda.
A.A. received consulting and/or advisory board fees from AbbVie, Allergan, Amgen, Arena, Biogen, Bristol-Myers Squibb, Celgene, Celltrion, Eli-Lilly, Ferring, Gilead, Janssen, MSD, Mylan, Pfizer, Roche, Samsung Bioepis, Sandoz and Takeda; lecture and/or speaker bureau fees from AbbVie, Amgen, Biogen, Bristol-Myers Squibb, Ferring, Gilead, Janssen, MSD, Novartis, Pfizer, Roche, Sandoz, Samsung Bioepis, Takeda and Tigenix; and research grants from MSD, Pfizer and Takeda.
A.D. has received research support or acted as a principal investigator for Abbvie, Dr. Falk Pharma, Celgene, Gilead, Janssen and Takeda; has acted as a consultant for AbbVie, Amgen, BMS, Boehringer Ingelheim, Celgene, Dr Falk Pharma, Ferring, Fresenius Kabi, Celltrion, Janssen, MSD, Pfizer, Roche, Takeda, Tillotts, Galapagos, Gilead, Pharmacosmos and Vifor; and has participated in speaker bureaus for AbbVie, Falk Foundation, Ferring, Janssen, Med Update, MSD, Pfizer, Roche, Takeda, Tillotts, and Vifor.
M.B.A. has served as a speaker, consultant and advisory member for or has received research funding from MSD, AbbVie, Janssen, Kern Pharma, Celltrion, Takeda, Gillead, Celgene, Pfizer, Sandoz, Biogen, Fresenius, Ferring, Faes Farma, Dr. Falk Pharma, Chiesi, Gebro Pharma, Adacyte and Vifor Pharma.
S.V. received consultant fees and unrestricted research grants from Abbott, Celtrion, Ferring, MSD, Pfizer, Sanofi-Aventis, Takeda, Tillots, UCB, Vifor and Falk Pharma.
R.S.H. has received speaker fees from AbbVie, Janssen, Pfizer and Takeda.
P.G.K has served as speaker and consultant for Abbvie, Janssen, Takeda, Pfizer, Novartis, and has received scientific grants from Takeda and Pfizer.
L.P.-B. reports personal fees from Merck, Abbvie, Janssen, Ferring, Tillots, Celltrion, Takeda, Pfizer, Amgen, Biogen, Samsung Bioepis, Genentech, Vifor, Pharmacosmos, Biogaran, Boerhinger-Ingelheim, Lilly, Index Pharmaceuticals, Sandoz, Celgene, Alma, Sterna, Nestlé and Enterome.
F.M. has served as a speaker and received honoraria from Merck Sharp & Dohme, Abbvie, Vifor, Falk, Laboratorios Vitoria, Ferring, Hospira, and Biogen.
Acknowledgments
We gratefully thank all participants in this project, as well as all organizations who agreed to distribute the survey to their members. We would particularly like to thank Sandra Dias and GEDII for the support provided.
The authors thank Paula Pinto, PharmD, PhD (PMA – Pharmaceutical Medicine Academy) for providing medical writing and editorial assistance.
Country of practice of physicians participating the survey. Countries participating are shown coloured and grouped by regions (European countries are grouped by subregions as defined by EuroVoc - https://op.europa.eu/en/web/eu-vocabularies).
TPMT activity and metabolites’ measurement – access and use by regionA: TPMT activity by Genotype ; B: TPMT activity by Phenotype ; C: TPMT activity by Genotype and/or Phenotype D: Metabolites’ measurement.
Recommendations of the Spanish Working Group on Crohn’s Disease and Ulcerative Colitis (GETECCU) on the use of thiopurines in inflammatory bowel disease.
Thiopurine monotherapy is effective in ulcerative colitis but significantly less so in Crohn’s disease: long-term outcomes for 11 928 patients in the UK inflammatory bowel disease bioresource.
Effects of concomitant immunomodulators on the pharmacokinetics, efficacy and safety of adalimumab in patients with Crohn’s disease or ulcerative colitis who had failed conventional therapy.
Postinduction serum infliximab trough level and decrease of C-reactive protein level are associated with durable sustained response to infliximab: a retrospective analysis of the ACCENT I trial.
Addition of azathioprine to the switch of anti-TNF in patients with IBD in clinical relapse with undetectable anti-TNF trough levels and antidrug antibodies: a prospective randomised trial.
Concentrations of 6-thioguanine nucleotide correlate with trough levels of infliximab in patients with inflammatory bowel disease on combination therapy.
American Gastroenterological association institute technical review on the role of therapeutic drug monitoring in the management of inflammatory bowel diseases.
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