Medical Treatment of UC
Men were significantly more likely than women to be prescribed medications used for maintenance therapy including biologic (12.43% vs 10.19%, p < 0.001), immunomodulatory (16.30% vs 14.86%, p < 0.001), and 5-aminosalicylate medications (66.96% vs 63.21%, p < 0.001) (Table 3). Men were significantly more likely than women to be treated with biologic (OR, 1.22; 95% CI, 1.14–1.30; p < 0.001), immunomodulatory (OR, 1.08; 95% CI, 1.02–1.14; p = 0.006), and 5-aminosalicylate medications (OR, 1.18; 95% CI, 1.13–1.23; p<0.001) in multivariate analysis (Appendix 4, Supplement Digital Content, http://links.lww.com/DCR/A947). Men started biologic, immunomodulatory, and 5-aminosalicylate medications significantly earlier than women (Figs. 3B–D).
Rescue and Palliative Medications
Women were significantly more likely to be prescribed corticosteroids (55.53% vs 53.99%, p = 0.002) as well as opioids (50.23% vs 45.86%, p < 0.001) (Table 3). After adjusting for covariates, male sex remained protective against treatment with corticosteroids (OR, 0.93; 95% CI, 0.90–0.98; p = 0.002) and opioids (OR, 0.85; 95% CI, 0.82–0.89; p<0.001) (Appendix 4, Supplement Digital Content, http://links.lww.com/DCR/A947). Mean number of opioid prescriptions for women was significantly higher than for men (3.73 prescriptions vs 2.73, p < 0.001).
Medical and Surgical Treatment of UC in Patients Past Usual Reproductive Age
Sex differences in surgical treatment persisted among women past the usual reproductive age. Compared with men ≥45 years old, women ≥45 years old were less likely to undergo surgical treatment for UC (1.82% vs 2.44%, p = 0.002). The positive effect of male sex persisted in this older age group in multivariate analysis (OR, 1.29; 95% CI, 1.04–1.58; p = 0.02) (Appendix 5, Supplement Digital Content, http://links.lww.com/DCR/A948). Women ≥45 years old progressed more slowly to surgery compared with their male peers in time-to-event analysis (Fig. 4).
Sex differences in maintenance medical treatment also persisted in an age-stratified analysis. Women past usual reproductive age underwent treatment with biologic medications less frequently than their male peers (6.19% vs 8.12%, p < 0.001) and were less likely to be treated with 5-aminosalicylates (57.40% vs 62.12%, p < 0.001). The positive effect of male sex persisted in multivariate analysis (biologics: OR, 1.35; 95% CI, 1.20–1.52; p < 0.001; 5-aminosalicylates: OR, 1.24; 95% CI, 1.17–1.32; p < 0.001) (Appendix 6, Supplemental Digital Content, http://links.lww.com/DCR/A949). Young men <45 years old used methotrexate at a rate equivalent to their female counterparts (2.13% vs 2.06%, p = 0.72).
Finally, differences in rescue medication treatment persisted in the age-stratified cohort. Women remained more likely to undergo treatment with corticosteroids than their male peers (51.34% vs 49.46%, p = 0.01). Male sex remained protective against corticosteroid treatment in multivariate analysis (OR, 0.92; 95% CI, 0.87–0.98; p = 0.02).
Health Care Utilization
In a post hoc analysis, we assessed sex differences in health care utilization. Women with UC were more likely to access the health care system for any reason compared with men. Women were more likely to visit the emergency department during their enrollment (50.2% vs 46.8%, p < 0.001; OR, 1.15; 95% CI, 1.10–1.20; p < 0.001) or to be hospitalized for any reason during their enrollment (33.2% vs 26.8%, p < 0.001; OR, 1.38; 95% CI, 1.31–1.44; p < 0.001). Women had a higher mean number of annual outpatient visits (12.2 vs 9.1 visits, p < 0.001). However, when we assessed health care utilization specific to UC, this pattern changed. Men had slightly higher mean annual UC-related outpatient visits (3.0 vs 2.7, p < 0.001), whereas women were very slightly more likely to visit the emergency department for UC (9.1% vs 8.6%, p = 0.12; OR, 1.08; 95% CI, 1.01–1.16; p = 0.04). Men and women were equally likely to be hospitalized for UC (15.4% vs 15.1%, p = 0.49; OR, 1.04; 95% CI, 0.98–1.10; p = 0.20).
Men and women sought care from specialist providers at different rates. Both men and women were very likely to seek care from internal medicine physicians and gastroenterologists. Women were very slightly more likely to see an internal medicine physician compared with men (88.7% vs 87.4%, p < 0.001; OR, 1.13; 95% CI, 1.06–1.20; p < 0.001). There were no differences in rates of gastroenterologist consultation after adjusting for covariates (80.6% vs 79.6%, p = 0.02; OR, 1.05; 95% CI, 0.99–1.11; p = 0.06). Although they underwent less surgical therapy for UC, women were more likely to seek consultation with a colorectal or general surgeon (27.3% vs 23.5%, p < 0.001; OR, 1.22; 95% CI, 1.16–1.28; p < 0.001). Women were also more likely to seek care from a psychiatrist than men (9.9% vs 6.1%, p < 0.001; OR, 1.39; 95% CI, 1.28–1.50; p < 0.001).
We found persistent differences in treatment patterns between men and women with UC. Men were more likely than women to undergo treatment aligned with longer-term disease maintenance or surgical cure. Men were more likely to undergo treatment to proactively manage disease, whereas women were more likely to undergo treatment to reactively manage symptoms, specifically, corticosteroids and narcotic pain medication.
It is particularly interesting that women undergo less surgical therapy for UC than men, even though they are more likely to undergo surgical consultation. The underlying reasons behind this discrepancy beg further investigation. Are female patients counseled by surgeons to defer or avoid surgery, or is it a patient-driven decision? Several factors may influence patient and provider choices regarding surgery. Prior studies have described a 20% to 30% increased risk of female infertility after restorative proctocolectomy and ileal pouch.19,20 It is possible that risk aversion toward postoperative infertility may drive female patients and providers away from proctocolectomy. However, a subgroup analysis of women ≥45 years showed that low rates of surgery persisted for women after usual reproductive age. Women may have increased concerns about postoperative body image related to stomas and scarring compared with men. A Dutch study showed that women undergoing open restorative proctocolectomy have a lower postoperative body image score than men.21
Sex-specific differences in UC medications are harder to explain, given that nearly all UC medications are considered safe even during pregnancy. In this study, the largest differences by sex included 1) biologic medications, 2) 5-aminosalicylates, and 3) opioids. Women were slower to start biologic medications than men, potentially indicating delay in initiation or reluctance in treatment. There is no evidence that biologic medications are teratogenic, so women are encouraged to continue biologic medications while pregnant or breast-feeding.22 For other medications considered in our analysis, 5-aminosalicylates have been shown to affect fertility in men but not women,23 yet men were more likely to take these drugs than women. Methotrexate has been associated with birth defects, pregnancy loss, and azoospermia,24 yet our analysis suggests that men and women <45 years take methotrexate at equivalent rates.
The difference in rates of opioid prescription is especially concerning, because this could serve as an indicator of poorly treated disease requiring more pain control. Differences in opioid prescription rates disappear for patients ≥45 years, suggesting that sex differences in opioid prescription exist primarily in younger patients. Prior studies have investigated sex differences in pain reporting and seeking pain relief, as well as the psychogenic attributions providers may make regarding pain in female but not male patients.25 It is possible that female patients’ reports of pain could result in an attempt by providers to deal with the symptom instead of prompting a more in-depth exploration of potentially inadequate disease control.26
The current study has limitations related to its retrospective nature and use of a commercial claims database. Databases built on billing codes rely on the accuracy of coding by physicians to obtain the correct diagnoses and procedures. For this reason, we required stringent enrollment criteria including ≥2 encounters with a primary diagnosis of UC, lower endoscopy, and lengthy pre- and postdiagnosis periods to ensure that those captured would represent a patient with newly diagnosed UC as accurately as possible. Despite this, the mean duration of follow-up is 3.3 years, with a maximum follow-up of 8 years. A longer duration of follow-up would provide additional information regarding long-term treatment choices and the consequences of the treatment differences noted here. In addition, the database used for this analysis contains no clinical or laboratory data to address questions of disease severity (such as frequency of bowel movements, bleeding, and nutritional status) that may influence patient and provider decisions regarding treatment strategy. The ability to statistically adjust for or match on clinical and laboratory markers of disease severity (including endoscopy reports, number of bloody bowel movements, hemoglobin, albumin, C-reactive protein, and fecal calprotectin) would strengthen our conclusion that sex alone is driving the treatment differences noted here. Thus, it is possible, albeit unlikely, that men described in this analysis may have more severe UC and thus undergo more medical and surgical treatment. This data set also does not reliably capture whether a surgery was completed on an elective or emergent basis; accordingly, we have refrained from commenting about sex differences in the urgency of surgical treatment.
The magnitude of treatment differences by sex noted here are small, and, if present for a single medication or treatment option, would likely bear little clinical significance despite strong statistical significance. However, the remarkable consistency across a variety of treatment classes in this large population study suggests a small but important sex-based treatment bias. Similar patterns exist for female patients with other diseases, including receiving less care consistent with guideline-indicated therapy and decreased likelihood of undergoing procedural interventions,7–13 which further strengthens this conclusion. It is critical for providers caring for patients with UC to recognize that sex-based treatment preferences exist, and to appropriately explore these preferences in their own patients. It is also important to remain vigilant to the possibility of misattribution of symptoms (for example, to gynecological issues). Providers and patients should engage in shared decision making to achieve satisfactory clinical outcomes using treatment methods acceptable to patients.
In summary, our study is the largest population-level study describing treatment differences by sex for patients with UC. We found that men are more likely than women to receive treatment consistent with long-term disease remission or cure. Further work is necessary to understand the implications of sex-driven treatment differences on UC outcomes and to identify the underlying reasons for these treatment differences. Understanding patient- and provider-level drivers of these differences requires a qualitative or mixed-methods approach. Exploring the decision-making process of male and female patients with UC choosing between different treatment options may provide additional insight. Interviewing providers who care for patients with UC may reveal different methods of counseling used for male versus female patients.
Data for this project were accessed using the Stanford Center for Population Health Sciences Data Core. The PHS Data Core is supported by a National Institutes of Health National Center for Advancing Translational Science Clinical and Translational Science Award (UL1 TR001085) and from internal Stanford funding. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This work was also supported by a National Institutes of Health National Center for Advancing Translational Science, Clinical and Translational Science Award (KL2TR001083 and UL1TR001085). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Additional support came from The Donna and Frederick Fleugel Colorectal Surgery Fund, and from a seed grant from Women & Sex Differences in Medicine (Stanford University).
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Sex differences; Inflammatory bowel disease; Medical therapy; Surgery; Ulcerative colitis
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