Australian inflammatory bowel disease consensus statements for preconception, pregnancy and breast feeding.

OBJECTIVE: Because pregnancy outcomes tend to be worse in women with inflammatory bowel disease (IBD) than in those without, we aimed to update consensus statements that guide the clinical management of pregnancy in patients with IBD. DESIGN: A multidisciplinary working group was established to formulate these consensus statements. A modified RAND/UCLA appropriateness method was used, consisting of a literature review, online voting, discussion meeting and a second round of voting. The overall agreement among the delegates and appropriateness of the statement are reported. RESULTS: Agreement was reached for 38/39 statements which provide guidance on management of pregnancy in patients with IBD. Most medications can and should be continued throughout pregnancy, except for methotrexate, allopurinol and new small molecules, such as tofacitinib. Due to limited data, no conclusion was reached on the use of tioguanine during pregnancy. Achieving and maintaining IBD remission before conception and throughout pregnancy is crucial to optimise maternofetal outcomes. This requires a multidisciplinary approach to engage patients, allay anxieties and maximise adherence tomedication. Intestinal ultrasound can be used for disease monitoring during pregnancy, and flexible sigmoidoscopy or MRI where clinically necessary. CONCLUSION: These consensus statements provide up-to-date, comprehensive recommendations for the management of pregnancy in patients with IBD. This will enable a high standard of care for patients with IBD across all clinical settings.

Characteristics and Effect of Anxiety and Depression Trajectories in Inflammatory Bowel Disease.

INTRODUCTION: Symptoms of common mental disorders, such as anxiety or depression, are associated with adverse clinical outcomes in inflammatory bowel disease (IBD). We report trajectories of these symptoms in IBD, patient characteristics associated with different trajectories, and effects on healthcare utilization and prognosis. METHODS: We collected demographic, symptom, psychological, and quality-of-life data, with questionnaires at 3-month intervals, over 12 months of follow-up. We collected healthcare utilization and IBD outcomes through notes review. We compared characteristics of those with persistently normal or improving anxiety or depression scores with those with persistently abnormal or worsening scores and the number of flares, glucocorticosteroid prescriptions, escalations of therapy, hospitalizations, or intestinal resections due to IBD activity. RESULTS: Among 771 and 777 patients, respectively, worsening or persistently abnormal anxiety or depression scores were associated with increased antidepressant (28.6% vs 12.3% anxiety, 35.8% vs 10.1% depression, P < 0.001) and opiate use (19.0% vs 7.8% anxiety, P = 0.001 and 34.0% vs 7.4% depression, P < 0.001), compared with those with persistently normal or improving scores. These individuals were also more likely to have been diagnosed with IBD in the last 12 months (16.3% vs 5.0% anxiety, P = 0.001, and 15.1% vs 5.5% depression, P = 0.006), to have clinically active disease at baseline (57.1% vs 26.6% anxiety and 71.7% vs 29.1% depression, P < 0.001) and lower quality-of-life scores ( P < 0.001). Individuals with worsening or persistently abnormal trajectories of anxiety or depression required significantly more outpatient appointments, radiological investigations, and endoscopic procedures for IBD-related symptoms. DISCUSSION: In this 12-month follow-up study, patients with IBD with worsening or persistently high anxiety or depression scores were higher utilizers of health care but were not at an increased risk of future adverse disease outcomes.

Anti-SARS-CoV-2 antibody responses are attenuated in patients with IBD treated with infliximab.

OBJECTIVE: Antitumour necrosis factor (anti-TNF) drugs impair protective immunity following pneumococcal, influenza and viral hepatitis vaccination and increase the risk of serious respiratory infections. We sought to determine whether infliximab-treated patients with IBD have attenuated serological responses to SARS-CoV-2 infections. DESIGN: Antibody responses in participants treated with infliximab were compared with a reference cohort treated with vedolizumab, a gut-selective anti-integrin α4ß7 monoclonal antibody that is not associated with impaired vaccine responses or increased susceptibility to systemic infections. 6935 patients were recruited from 92 UK hospitals between 22 September and 23 December 2020. RESULTS: Rates of symptomatic and proven SARS-CoV-2 infection were similar between groups. Seroprevalence was lower in infliximab-treated than vedolizumab-treated patients (3.4% (161/4685) vs 6.0% (134/2250), p<0.0001). Multivariable logistic regression analyses confirmed that infliximab (vs vedolizumab; OR 0.66 (95% CI 0.51 to 0.87), p=0.0027) and immunomodulator use (OR 0.70 (95% CI 0.53 to 0.92), p=0.012) were independently associated with lower seropositivity. In patients with confirmed SARS-CoV-2 infection, seroconversion was observed in fewer infliximab-treated than vedolizumab-treated patients (48% (39/81) vs 83% (30/36), p=0.00044) and the magnitude of anti-SARS-CoV-2 reactivity was lower (median 0.8 cut-off index (0.2-5.6) vs 37.0 (15.2-76.1), p<0.0001). CONCLUSIONS: Infliximab is associated with attenuated serological responses to SARS-CoV-2 that were further blunted by immunomodulators used as concomitant therapy. Impaired serological responses to SARS-CoV-2 infection might have important implications for global public health policy and individual anti-TNF-treated patients. Serological testing and virus surveillance should be considered to detect suboptimal vaccine responses, persistent infection and viral evolution to inform public health policy. TRIAL REGISTRATION NUMBER: ISRCTN45176516.

Efficacy and tolerability of initiating, or switching to, infliximab biosimilar CT-P13 in inflammatory bowel disease (IBD): a large single-centre experience.

OBJECTIVES: Recently, the infliximab biosimilar (CT-P13) received market authorisation for inflammatory bowel disease (IBD), allowing cost benefits when switching to CT-P13. We aim to assess the efficacy and safety of switching from originator infliximab to CT-P13 for new and existing patients. MATERIAL AND METHODS: Treatment response, remission, primary and secondary loss of response rates, and adverse events in patients who initiated infliximab originator in the 12 months pre-switch (n = 53) were compared with the patients who initiated CT-P13 in the 12 months post-switch (n = 69). Sustained responses were compared for existing infliximab originator patients who switched to CT-P13 (n = 191) and those who continued with the originator (n = 19). RESULTS: There was no difference in remission (58.1% vs. 47.4%, p = .37), response (12.6% vs. 10.5%, p = .80), secondary loss of response (24.6% vs. 42.1%, p = .10), or adverse events (4.7% vs. 0% p = 1.0) between those who switched to CT-P13 and those who continued infliximab originator. There was no difference in remission (42.0% vs. 26.4%, p = .074), response (21.7% vs. 22.6%, p = .91), primary non-response (5.8% vs. 15.1%, p = .09), secondary loss of response (21.7% vs. 22.6%, p = .91), or adverse events (8.7% vs. 11.3%, p = .63) in those who initiated CT-P13 compared with infliximab originator. CONCLUSIONS: There was no difference in the efficacy and safety of infliximab originator and CT-P13 during the first 12 months after switching.

When Your Pregnancy Echoes Your Illness: Transition to Motherhood With Inflammatory Bowel Disease.

Our aim is to provide an understanding of the experience of women with inflammatory bowel disease (IBD) who have made the transition to motherhood. A total of 22 mothers with IBD were recruited from around the United Kingdom. Semi-structured interviews were conducted and analyzed using thematic analysis. The central concept- Blurred Lines-offers a novel frame for understanding the transition to motherhood with IBD through identifying parallels between having IBD and becoming, and being, a mother. Parallels clustered into three main themes: Need for Readiness, Lifestyle Changes, and Monitoring Personal and Physical Development. Hence, women with IBD are in some ways well prepared for the challenges of motherhood even though, as a group, they tend to restrict their reproductive choices. We recommend health professionals initiate conversations about reproduction early and provide a multidisciplinary approach to pregnancy and IBD in which women have confidence that their ongoing treatment will be integrated successfully with their maternity care.

Long-term follow-up reveals low incidence of colorectal cancer, but frequent need for resection, among Australian patients with inflammatory bowel disease.

BACKGROUND & AIMS: Inflammatory bowel disease can require surgical resection and also lead to colorectal cancer (CRC). We investigated the cumulative incidence of resection surgeries and CRC among patients with ulcerative colitis (UC) or Crohn's disease (CD). METHODS: We analyzed data from a cohort of patients who participated in an inflammatory bowel disease study (504 with UC and 377 with CD) at 2 academic medical centers in Sydney, Australia from 1977 to 1992 (before the development of biologic therapies). We collected follow-up data on surgeries and development of CRC from hospital and community medical records or via direct contact with patients during a median time period of 14 years. Cumulative incidences of resection surgeries and CRC were calculated by competing risk survival analysis. RESULTS: Among patients with UC, CRC developed in 24, for a cumulative incidence of 1% at 10 years (95% confidence interval [CI], 0%-2%), 3% at 20 years (95% CI, 1%-5%), and 7% at 30 years (95% CI, 4%-10%). Their cumulative incidence of colectomy was 15% at 10 years (95% CI, 11%-19%), 26% at 20 years (95% CI, 21%-30%), and 31% at 30 years (95% CI, 25%-36%). Among patients with CD, 5 of 327 with colon disease developed CRC, with a cumulative incidence of CRC of 1% at 10 years (95% CI, 0%-2%), 1% at 20 years (95% CI, 0%-2%), and 2% at 30 years (95% CI, 0%-4%). Among all patients with CD, the cumulative incidence of resection was 32% at 5 years (95% CI, 27%-37%), 43% at 10 years (95% CI, 37%-49%), and 53% at 15 years (95% CI, 46%-58%). Of these 168 subjects, 42% required a second resection within 15 years of the first surgery (95% CI, 33%-50%). CONCLUSIONS: Patients with UC have a low incidence of CRC during a 30-year period (7% or less); the incidence among patients with CD is even lower. However, almost one-third of patients with UC and about 50% of those with CD will require surgery.

Considerations on Multimorbidity and Frailty in Inflammatory Bowel Diseases.

There are growing numbers of older people with inflammatory bowel diseases [IBD]. These older patients are more likely to have other comorbidities and polypharmacy, which can make recognizing and treating IBD complex. Frailty is a newer concept in the IBD field, and we are beginning to recognize the importance of this as a marker of biological age and its association with risk of adverse IBD-related outcomes. In this review article we aim to provide practical insight into the specific challenges facing older patients and their clinicians at each stage of the patient journey. We also discuss the latest understanding of the impact of frailty for these patients with IBD and highlight areas for future research.

Full title: "Hopes, worries and expectations" experiences of pregnancy with inflammatory bowel disease: An interpretative phenomenological analysis study.

Background and Aims: Inflammatory Bowel Disease (IBD) affects many women of childbearing age. High levels of voluntary childlessness and high levels of pregnancy-related fears have been reported amongst these patients in several quantitative studies. We investigated the lived experiences of pregnant patients to better understand decision-making processes around family planning. Methods: Nine participants between 7 and 34 weeks pregnant (6 Crohn's Disease/3 Ulcerative Colitis), with an age range of 22-39 were recruited prospectively from three United Kingdom hospitals. Semi-structured interviews were conducted, and audio recorded. Interpretative phenomenological analysis was used to interpret the data. Results: Two main themes emerged: 1) IBD is perceived as a threat to family planning; and 2) healthcare professional advice, support, and reassurance was important. IBD was viewed as a potential threat to fertility and reproductive health. Consequently, women's lived experience of pregnancy is shaped by anxiety and pregnancy-related worries for mother and baby. Mothers actively sought out expert medical assurances to alleviate some of the perceived fears. Conclusion: Previous research has repeatedly found that women with IBD exhibit high levels of pregnancy-related worries and anxieties. Our findings find that high levels of anxiety are due to patients' perceptions that IBD is a threat to their reproductive health and their offspring. Women relied on a medicalized discourse to understand their IBD experiences during pregnancy and actively sought biomedical resources for assistance before and during pregnancy. Consultants should be aware that when dealing with pregnant patients, some women may experience anxiety and require extra support.

Obstetric Considerations in Pregnant Women with Crohn's Disease.

Crohn's disease affects many women of childbearing age. Fecundity rates are often lower than in the general population due to reduced fertility during active inflammation, effects of pelvic surgery or voluntary childlessness. Many women have concerns regarding the effects of pregnancy on their Crohn's, any potential effect of medication on the fetus, and passing on Crohn's disease to the offspring. International guidelines on reproduction for women with Crohn's disease provide evidence-based advice to patients and health care professionals. There is an increasing literature on the safety of advanced medication for Crohn's disease during pregnancy. This review article therefore focuses on obstetric considerations beyond medication safety. We provide information on fertility, factors affecting pregnancy and fetal outcomes, obstetric complications, factors influencing mode of delivery, management of intestinal stomas during pregnancy and general considerations around breast feeding.

Anal High-risk Human Papillomavirus Infection, Squamous Intraepithelial Lesions, and Anal Cancer in Patients with Inflammatory Bowel Disease: A Systematic Review and Meta-analysis.

BACKGROUND: Ulcerative colitis [UC] and Crohn's disease [CD] can be associated with severe comorbidities, namely opportunistic infections and malignancies. We present the first systematic review and meta-analysis evaluating the burden of anal human papillomavirus disease in patients with UC and CD. METHODS: PubMed, Web of Science, and Scopus were searched until November 2022. Meta-analyses were performed using random effects models. The protocol was recorded at PROSPERO register with the number CRD42022356728. RESULTS: Six studies, including 78 711 patients with UC with a total follow-up of 518 969 person-years, described the anal cancer incidence rate. For anal cancer incidence rate in CD, six studies were selected, including 56 845 patients with a total follow-up of 671 899 person-years. The incidence of anal cancer was 10.2 [95% CI 4.3 - 23.7] per 100 000 person-years in UC and 7.7 [3.5 - 17.1] per 100 000 person-years in CD. A subgroup analysis of anal cancer in perianal CD, including 7105 patients, was calculated with incidence of 19.6 [12.2 - 31.6] per 100 000 person-years [three studies included]. Few studies described prevalence of anal cytological abnormalities [four studies including 349 patients] or high-risk human papillomavirus [three studies including 210 patients], with high heterogeneity. Prevalence of cytological abnormalities or high-risk human papillomavirus was not associated with pharmacological immunosuppression in the studies included. CONCLUSION: The incidence of anal cancer is higher in UC than in CD, with the exception of perianal CD. There are limited and heterogeneous data on anal high-risk human papillomavirus infection and squamous intraepithelial lesions prevalence in this population.

Factors Associated with Family Planning Status and Voluntary Childlessness in Women of Childbearing Age with Inflammatory Bowel Diseases.

BACKGROUND: Women with Inflammatory Bowel Diseases (IBD) have fewer children and stay childless more often. The decision-making process around family planning choices remains incompletely understood. METHODS: We examined family status in women who at recruitment to the UK IBD Bioresource had not had children yet via an electronic survey. The primary outcome was the proportion of women with voluntary childlessness. Secondary outcomes were factors associated with family planning status. RESULTS: Of 326 responders, 10.7% had either given birth, were currently pregnant or were currently trying to conceive; 12.6% were planning to conceive within 12 months; 54.4% were contemplating conception in the distant future (vague plans); and 22.3% were voluntarily childless. Factors associated with family planning status fell into three areas: general background (age, household income, perceived support to raise a child), relationship status (sexual orientation, being single, not cohabiting, perception of being 'in the right relationship to raise a child', perception of a good sex life) and the expression of having a child as a goal in life. On binary logistics regression analysis with voluntary childlessness versus vague family plans as the outcomes of choice, having a household income of <£30,000 (p = 0.046), not seeing a child as a life goal (p < 0.0001) and identifying as lesbian or bisexual (p = 0.047) were independent predictors of voluntary childlessness. CONCLUSIONS: Clinicians should consider sexual orientation, income, younger age, current relationship and lack of expression of having a child as a life goal as important factors for family planning when providing care. Pre-pregnancy advice should be made widely available for women with IBD.

Systematic review with network meta-analysis: Risk of Herpes zoster with biological therapies and small molecules in inflammatory bowel disease.

BACKGROUND: Biologics and small molecules for inflammatory bowel disease (IBD) may increase infection risk. Herpes zoster causes acute and long-term symptoms, but vaccination is not recommended in patients with IBD, unless >50 years of age. AIMS: To examine risk of Herpes zoster infection with all licensed biologics and small molecules for IBD using network meta-analysis. METHODS: We searched the literature to 4th October 2022, for randomised controlled trials of these drugs in luminal Crohn's disease or ulcerative colitis reporting data on occurrence of Herpes zoster infection during follow-up. We used a frequentist approach and a random effects model, pooling data as relative risks (RRs) with 95% confidence intervals (CIs). RESULTS: We identified 25 trials (9935 patients). Only tofacitinib 10 mg b.d. (RR = 6.90; 95% CI 1.56-30.63, number needed to harm (NNH) = 97; 95% CI 19-1022) and upadacitinib 45 mg o.d. (RR = 7.89; 95% CI 1.04-59.59, NNH = 83; 95% CI 10-14,305) were significantly more likely to increase risk of Herpes zoster infection. Janus kinase inhibitors were the most likely drug class to increase risk of infection, and risk increased with higher doses (RR with lowest dose = 3.16; 95% CI 1.02-9.84, NNH = 265; 95% CI 65-28,610, RR with higher dose = 5.91; 95% CI 2.21-15.82, NNH = 117; 95% CI 39-473). CONCLUSIONS: In a network meta-analysis, the janus kinase inhibitor tofacitinib, and all janus kinase inhibitors considered as a class, were most likely to increase risk of Herpes zoster infection. Risk increased with higher doses.

Reproductive Safety Issues of Novel Small Molecules for the Treatment of Inflammatory Bowel Disease: A Systematic Review.

Maintenance of remission during pregnancy is vital for women with inflammatory bowel disease (IBD). The antenatal safety of novel small molecules for IBD is yet to be ascertained. We aimed to describe the current evidence on reproductive data regarding small-molecule drugs. We performed a systematic review searching Embase Classic + Embase and Ovid MEDLINE for reproductive outcomes for tofacitinib, filgotinib, upadacitininb, and ozanimod. Additionally, we asked the manufacturers for available data on file regarding reproduction. We analysed data from 10 sources; six studies and four manufacturer reports were identified from our search. Significant malformation risks were reported for tofacitinib, filgotinib, upadacitininb, and ozanimod in animal studies. In 126 tofacitinib-exposed pregnancies, there were 55 live births with 2 congenital malformations and 1 serious infant infection, 14 terminations, 15 miscarriages, and 42 outcomes unknown. In 50 filgotinib-exposed pregnancies, there were 20 healthy babies, 1 congenital malformation, 9 terminations, 10 miscarriages, and 10 outcomes unknown. In 78 upadacitinib-exposed pregnancies, there were 30 healthy babies, 15 terminations, 15 miscarriages, and 18 outcomes unknown. In 60 ozanimod-exposed pregnancies, there were 31 live births with 1 congenital malformation, 1 case of intra-uterine growth restriction, 1 case of neonatal icterus, 13 terminations, 9 miscarriages, and 8 unknown outcomes. Animal data suggest significant risks of malformations for tofacitinib, filgotinib, upadacitininb, and ozanimod. Human data from clinical trials and real-world observations do not show concerning data so far, but these are very limited. Currently, alternative treatments should be used for IBD during pregnancy.

Planning to conceive within a year is associated with better pregnancy-specific disease-related patient knowledge and better medication adherence in women of childbearing age with inflammatory bowel disease.

Background: Adherence to inflammatory bowel disease (IBD) medication is crucial to maintain remission, especially during pregnancy. Objective: To examine the influence of family planning and pregnancy-related patient knowledge regarding IBD and pregnancy on adherence. Design: Cross-sectional survey study. Methods: We surveyed female patients with IBD aged 18-35 years, who at recruitment to the UK IBD BioResource had not had children. We elicited disease and treatment history, demographics and family planning status via an online questionnaire. Patient knowledge as assessed by the validated Crohn's and Colitis Pregnancy Knowledge Score (CCPKnow) and adherence by visual analogue scale (VAS). Results: In 326 responders (13.8% response rate), good adherence (VAS ⩾ 80) was found in only 38.35%. Disease- and treatment-related factors were not significantly associated with good adherence, except for methotrexate (70.0% adherent of 10 exposed patients versus 37.2% non-exposed; p = 0.036). Patients planning pregnancy for the next year were more often adherent (59.0% versus 35.5%; p = 0.019) and knowledgeable (median CCPKnow 8 versus 7; p = 0.035) compared to those in other family planning categories. Pregnancy-related patient knowledge was significantly associated with adherence (Pearson correlation 0.141; p = 0.015). Adherent patients had significantly higher CCPKnow scores than non-adherent patients (median 8 versus 6; p = 0.009). On binary regression analysis, only planning to conceive within 12 months was independently associated with better adherence (p = 0.016), but not methotrexate exposure (p = 0.076) and CCPKnow (p = 0.056). Conclusions: In a cohort of women of childbearing age with IBD overall medication, adherence was low. Planning to conceive within the next year was associated with better adherence and greater patient knowledge.

Impact of Opioid Use on the Natural History of Inflammatory Bowel Disease: Prospective Longitudinal Follow-up Study.

BACKGROUND: Opioid use is increasingly prevalent amongst patients with inflammatory bowel disease (IBD), but whether opioids have deleterious effects, or their use is merely linked with more severe disease, is unclear. We conducted a longitudinal follow-up study examining this issue. METHODS: Data on demographics, gastrointestinal and psychological symptoms, quality of life, and opioid use were recorded at baseline. Data on healthcare use and adverse disease outcomes were obtained from a review of electronic medical records at 12 months. Characteristics at baseline of those using opioids and those who were not were compared, in addition to occurrence of flare, prescription of glucocorticosteroids, treatment escalation, hospitalization, or intestinal resection during the 12 months of follow-up. RESULTS: Of 1029 eligible participants, 116 (11.3%) were taking opioids at baseline. Medium (odds ratio [OR], 4.67; 95% confidence interval [CI], 1.61-13.6) or high (OR, 8.03; 95% CI, 2.21-29.2) levels of somatoform symptom-reporting and use of antidepressants (OR, 2.54; 95% CI, 1.34-4.84) or glucocorticosteroids (OR, 6.63; 95% CI, 2.26-19.5; P < .01 for all analyses) were independently associated with opioid use. Following multivariate analysis, opioid users were significantly more likely to undergo intestinal resection (hazard ratio,  7.09; 95% CI, 1.63 to 30.9; P = .009), particularly when codeine or dihydrocodeine were excluded (hazard ratio, 42.9; 95% CI, 3.36 to 548; P = .004). CONCLUSIONS: Opioid use in IBD is associated with psychological comorbidity and increased risk of intestinal resection, particularly in stronger formulations. Future studies should stratify the risk of individual opioids, so that robust prescribing algorithms can be developed and assess whether addressing psychological factors in routine IBD care could be an effective opioid avoidance strategy.

Of the 1029 patients with IBD in this study, opioid use exceeded 10% and was associated with psychological comorbidity and an increased risk of intestinal resection during longitudinal follow-up, particularly when more potent formulations were used.