Beyond the gut: Understanding gender disparities and ocular complications in inflammatory bowel disease

The umbrella term, inflammatory bowel disease (IBD), covers a group of conditions that cause tissue swelling and inflammation in the digestive tract.^1,2 

IBD is a chronic immune-mediated condition in which the immune system goes awry and attacks the flora in the gastrointestinal tract, resulting in persistent inflammation.¹ The disease is characterized by cycles of flare-ups and remissions.² 

The most common of these conditions under the umbrella are ulcerative colitis (UC) and Crohn’s disease (CD). The former causes inflammation and ulceration in the lining of the colon and rectum. The latter affects the lining of the digestive tract, often the deeper layers, which become inflamed, most commonly in the small intestine; however, the large intestine and, infrequently, the upper gastrointestinal tract can also be involved¹ as can the mouth.²

A third condition, indeterminate colitis inflammatory bowel disease, can be present that refers to IBD that has features of both UC and CD.²

The two disorders share the same symptoms, ie, abdominal pain, diarrhea, rectal bleeding, extreme tiredness, and weight loss. However, the effects are not limited to the digestive tract.¹ 

Who’s affected and how? 

Any ethnic or racial group can be affected; however, individuals of Jewish ancestry³ have a greater predisposition to development of IBD.

Venkateswaran and Sultan³ reported that “What has been clearer since the first descriptions of UC in the 1800s, followed by CD in the early 1900s, is the Northern Hemisphere and Caucasian predominance of IBD prevalence. This risk has been consistently observed to be greatest in the Ashkenazi Jewish population, which remains the highest risk cohort. However, the recent decades have observed that IBD is increasingly common in non-traditional populations. This phenomenon is occurring worldwide but also has been noted within the US population itself. Internationally, this has been attributed to increasing “westernization” through a variety of mechanisms such as diet, lifestyle, early access to antibiotics, improved sanitation, etc. In addition to these factors playing a role in the disease, there is also an increased recognition of IBD with the inclusion of different ethnicities in population-based studies.³ 

Currently, the triggers of IBD remain unknown, and researchers are investigating the disease mechanism as well as the impact of genetic, environmental, infectious, immune, and other factors, including the balance of bacteria in the gut.²

Abegunde et al. also observed that environmental influences are increasingly recognized as risk factors; cigarette smoking increases risk and severity of Crohn’s disease but may be protective in UC. Westernized diets high in processed foods, low fiber intake, and emulsifiers may disrupt microbial homeostasis. Early-life factors, such as antibiotic exposure, cesarean delivery, and reduced breastfeeding, are associated with altered microbiota and increased risk. Urban living and higher socioeconomic status correlate with increased incidence, supporting a hygiene-related hypothesis. Nonsteroidal anti-inflammatory drugs and infections may trigger disease onset or flares. Overall, IBD pathogenesis reflects a loss of tolerance to intestinal microbiota in genetically predisposed individuals exposed to modern environments. These investigators explore a range of environmental factors in their review.⁴ 

Danese and colleagues⁵ agree that “Environmental factors are essential components of the pathogenesis of IBD and primarily responsible for its growing incidence around the globe.” They list smoking, diet, drugs, geographical and social status, stress, microbial agents, intestinal permeability, and appendectomy. “Data supporting the involvement of each of these factors in predisposing to, triggering, or modulating the course or outcome of IBD vary from strong to tenuous. Smoking and the enteric bacterial flora are the ones for which the most solid evidence is currently available. Smoking increases the risk of CD and worsens its clinical course but has a protective effect in UC.”

A positive family history is one of the strongest risk factors, with numerous susceptibility loci identified (e.g., NOD2 variants).⁴ Studies have reported that from 5% to 20% of patients with IBD have a first-degree relative, such as a parent, child, or sibling, with the condition. However, random cases also can develop.^6,7 

According to a recent study, “The genetic background of IBD … has been known for more than 2 decades. In the last 20 years, genome-wide association studies have dramatically increased our knowledge of the genetics of IBD, with more than 200 risk genes having been identified. Paralleling this increasing knowledge, the armamentarium of IBD medications has been growing constantly.⁶ 

IBD is not limited to adults and can affect children, who can present with the classic symptoms of weight loss, abdominal pain, and bloody diarrhea; many present with nonclassic symptoms of isolated poor growth, anemia, or other extraintestinal manifestations. Once IBD is diagnosed, the goals of therapy consist of eliminating symptoms, normalizing quality of life, restoring growth, and preventing complications while minimizing the adverse effects of medications. Unique considerations when treating children and adolescents with IBD include attention to the effects of the disease on growth and development, bone health, and psychosocial functioning,⁸ according to Rosen and colleagues.

The systemic reach of IBD

IBD can cause other medical conditions in the gastrointestional tract and beyond, some of which are medical emergencies. These include colon cancer, perforated bowel, toxic megacolon, anal fistula, anemia, blood clots, kidney stones, cirrhosis and primary sclerosing cholangitis (PSC), malabsorption and malnutrition, rashes, osteoporosis, and last but not least, eye pain and irritation.⁶ Others include spondylolysis, sacroiliitis, arthritis, phlebitis, and steatosis.² 

IBD also has an impact on quality of life in the form of psychological distress, sleep disruption, and challenges with daily activities.⁷

Gender-based differences in IBD

Many studies have reported differences in IBD manifestations between men and women.

A large study by Severs and collegues⁹ from the Netherlands reported the results obtained from two prospective cohort studies. First, the IBD Biobank Study included 2,118 patients with CD and 1,269 with UC. Data analysis showed the following: “Female CD patients were more often current smokers, and male UC patients were more often previous smokers. Early-onset CD (<16 years of age) was more frequently encountered in males than in females (20% versus 12%, P < 0.01). Male CD patients were more often diagnosed with ileal disease (28% versus 20%, P < 0.01) and more often underwent small bowel and ileocecal resection. Extraintestinal manifestations were encountered more often in female IBD patients. In the COIN study, 1,139 CD patients and 1,213 UC patients were analyzed. Male CD patients used prednisone more often and suffered more often from osteopenia. IBD-specific healthcare costs did not differ between male and female IBD patients.”⁹

The authors emphasized the importance of understanding the gender differences because that understanding would facilitate the initiation of tailored treatment for individual patients.⁹

Although depression, fatigue, anxiety disorders, eating disorders, and sexual dysfunction also occur in male IBD patients, women seem to be affected much more frequently and severely in these areas.¹⁰

Adam C. Ehrlich, MD, a gastroenterologist from Temple University, Philadelphia, explained that men and women develop IBD at different ages. “Women are more likely to develop CD than men, but more men develop UC than women. Even though the average age of developing IBD is between 15 and 35, more men are diagnosed with UC in their 50s and 60s than women of the same age.”¹¹

He also noted differences in symptoms and complications. “Women can experience issues with menstruation and may experience anemia and osteoporosis. Abdominal tenderness/pain and diarrhea are hallmarks of IBD, but they’re also common symptoms of premenstrual syndrome. During menstruation, IBD symptoms may worsen for women. Blood loss during menstruation can also cause anemia, putting women with IBD at higher risk for iron-deficiency anemia than men.¹¹ 

Regarding fertility and pregnancy, women with IBD do not have decreased fertility, though it may increase the risk of complications during pregnancy. He advised that if pregnancy is a consideration, a gastroenterologist should be consulted to treat their IBD and get symptoms and inflammation under control before becoming pregnant.

While men are typically diagnosed later in life, Erhlich pointed out that they are more likely to develop PSC and colorectal cancer and also can experience sexual dysfunction. PSC can lead to cirrhosis, increased risk of liver cancer, and possible need for transplantation.

Studies are suggesting that the differences in disease manifestations between the sexes may be related to hormones, genetics, lifestyle, and environmental factors.¹¹

Rustqi and colleagues¹² cited the clear sex-based differences observed in the IBD pathogenesis, epidemiology, clinical course, and disease outcomes. “There are varying levels of evidence suggesting that the complex interaction between well-described factors of pathogenesis, including genetic predisposition, immune dysregulation, environmental exposures, and intestinal dysbiosis, might be modified by sex-dependent factors. Differences in incidence by sex and geography warrant further investigation and suggest there may be other mediating factors that have yet to be defined. In addition to these biologic factors, the impact of healthcare systems and differential access to care by sex on patient outcomes should not be underestimated. For instance, barriers to treatment with maintenance medications for female patients should be identified and addressed to improve patient outcomes. Further investigation on the impact of sex hormones on IBD is warranted and may result in better therapeutic response and disease course for our patients with IBD.”¹²

Treatment of IBD

Medications to treat IBD generally manage the inflammation and control the response of the immune system. The same types of medications can be used to treat CD and UC. These include antibiotics, antidiarrheal medication, biologics to prevent antibody release that triggers IBD, corticosteroids, and immunomodulators and immunosuppressants to quiet the immune system.⁷ 

Colectomy is a surgical option if the medications lose their effectiveness.7

Over and above medical treatment and surgery, changes in lifestyle and diet can help manage IBD. Patients are advised to avoid food triggers that can include high-fiber, fatty, spicy, or dairy foods during flares; avoid or reduce stress to manage symptoms; and practice smoking cessation, which is crucial, especially for patients with CD.⁷

Patients are also advised to seek mental health support to manage depression.⁷ 

IBD and the eye

Ocular complications occur in approximately 4% to 10% of patients with IBD. Females with IBD have a higher frequency of ocular manifestations.

The common ones are:

• Episcleritis, one of the most common, characterized by red, sore eyes, is usually correlated with active IBD flares.
• Uveitis/iritis, also common, causes painful inflammation, light sensitivity, and blurred vision and can occur independently of gut activity.
• Scleritis, which causes severe, deep pain, is rarer but more dangerous.

Dry eye syndrome can result from vitamin deficiencies or reduced tear production.¹³

The authors also pointed out the potential for development of iatrogenic eye issues that can result from steroid use to treat IBD; these include cataracts and glaucoma.¹³

Troncoso et al. cited numerous articles that reported ocular impairments related to IBD. Some of these were dacryoadenitis, palpebral ptosis, retinal vein occlusion, retinal pigment epithelial dystrophy, and retinal neovascularization, among others.¹³

Sharma and colleagues¹⁴ also noted that uveitis may be the presenting symptom during active bowel disease or dormant periods or may precede the diagnosis of IBD. Common presenting symptoms include pain, photophobia, and blurred vision. On examination, patients usually have diminishing visual acuity (VA), hyperemia, perikeratic injection, exudates in the anterior chamber, keratic precipitates, and iris involvement.”

Sharma et al. cited a case report in which they noted that Roth spots may be a rare manifestation of IBD, and these have not traditionally been associated with IBD. “To our knowledge, coexisting hyperacute, severe bilateral panuveitis and Roth’s spots are atypical presentations of CD.”¹⁴ 

The authors described a 17-year-old male who presented with bilateral red eyes, photophobia, and blurriness. The patient’s history reported a 5-day history of fever, chills, nausea, vomiting, and diarrhea. He also had a history of multiple sexual partners but no history of travel or sick contacts. The family history was unremarkable.

His examination revealed bilateral findings of VA of 20/70-2 and intraocular pressures of 9 mmHg, subconjunctival hemorrhages bilaterally, Descemet folds, and significant vitritis. Examination also showed a cup-to-disc ratio of 0.1, a flat retina with no lesions, and +3 vitreous cells bilaterally.

Treatment included Pred Forte every hour and homatropine 5% three times daily. A uveitic work-up was initiated. Two days later, the VAs in the right and left eyes were, respectively, 20/100 and 20/60. Roth’s spots, vitreous opacities, and bilateral optic nerve head edema were observed. An echocardiogram was normal. Testing for sarcoidosis, syphilis, tuberculosis, toxoplasmosis, herpetic, and connective tissue diseases was negative.

Five days later, numerous aphthous ulcers developed on the buccal mucosa. Colonoscopy and gastroscopy showed edematous mucosa and numerous aphthae in the gastrointestinal tract. The pathological reports revealed areas of varying inflammation, which confirmed CD. Treatment with oral prednisone 40 mg was started and tapered over 5 weeks.

Ultimately the VA improved to 20/20, retinal hemorrhages and optic nerve head edema resolved, and his other signs of panuveitis improved significantly.

The authors commented, “Although panuveitis has been reported as a secondary complication of IBD, it is difficult to understand the reasoning behind the presence of Roth’s spots. Considering its pathophysiology, there may be some underlying hemorrhage due to ruptured capillaries, and the subsequent formation of a fibrin thrombus.”

Treatment of ocular manifestations

Studies indicate that while some ocular manifestations of IBD improve with systemic treatment of the digestive tract, many require specialized, localized, or different therapeutic approaches.

The treatment for ocular IBD frequently involves interdisciplinary care between gastroenterologists and ophthalmologists because ocular symptoms, particularly uveitis, can occur independently of, or fail to respond to, the treatment for intestinal inflammation. Here are some treatment differences identified.

Rogler and colleagues¹⁵ explained that episcleritis, generally associated with active gut disease, often resolves with appropriate treatment of the underlying IBD. “Topical or oral non-steroidal anti-inflammatory drugs (NSAIDs) and topical corticosteroids can be used in refractory cases, although NSAIDs may predispose to IBD exacerbations and adverse gastrointestinal effects and are not currently recommended by the European Crohn’s and Colitis Organisation.

First-line therapy for episcleritis includes topical lubricants (artificial tears) and cool compresses.¹⁶ Since episcleritis is a self-limiting condition, the treatment focuses on providing symptomatic relief and conservative measures. In addition to artificial tears, additional topical NSAIDs or corticosteroids may be considered if symptoms persist or if achieving resolution of intestinal inflammation proves challenging.¹⁶

Regarding uveitis and systemic IBD treatment, Tronosco and colleagues¹³ said, “Treatment of anterior uveitis is based on topical steroids to reduce inflammation, and topical cycloplegics, to prevent ciliary body and pupillary spasms related to ocular pain. Also, cycloplegics prevent posterior synechiae because they dilate the pupil and stabilize the blood-aqueous barrier, avoiding protein leakage (flare). According to the gravity of the uveitis, periocular corticosteroid injections or systemic corticosteroids may also be necessary. Uveitis with a chronic course requires immunosuppressive therapy to spare the prolonged use of corticosteroids and their side effects. However, the choice of immunosuppressive therapy requires a multidisciplinary decision, especially if there is another associated EIM.”¹³

Scleritis and peripheral ulcerative keratitis are rare but severe. “This condition is potentially dangerous and can lead to retinal detachments and inflammation of the optic nerve. Therefore, it must be managed aggressively with systemic steroids, NSAIDs, and immunomodulators to prevent visual loss, and the patient must always be referred to an ophthalmologist.”¹⁷ 

The iatrogenic effects of IBD treatments include cataracts and glaucoma from steroids and irritation of the lids, cornea, and conjunctiva from methotrexate used to suppress gut inflammation. In some cases, the treatment of the digestive tract causes the ocular issues, requiring a reversal or change in strategy.

Duff et al.¹⁸ offered the following recommendations for non-pharmacologic treatments for IBD.

• Diet: Consumption of diets rich in vegetables, fruit, and soluble fiber may be beneficial in IBD. A trial of a low FODMAP diet¹⁹ can be considered in those patients with functional gastrointestinal symptoms. Restrictive diets are lacking in evidence and should be avoided. The Cleveland Clinic describes the FODMAP diet: “The low-FODMAP diet reduces certain kinds of carbohydrates that are hard for people to digest. It’s often prescribed as an elimination diet to identify food triggers in those who have functional gastrointestinal disorders, such as irritable bowel syndrome,” according to the Cleveland Clinic.

In line with diet, managing iron levels in women is important, in that anemia is the most frequent complication of IBD, but anemia, mostly due to iron deficiency, has long been neglected in these patients.²⁰ 

• Physical activity and exercise: Regular low-moderate intensity activity, including cardiovascular and resistance exercise, has been shown to improve quality of life and may improve inflammation¹⁸
• Psychotherapy: Therapies such as cognitive-behavioral interventions, mindfulness, hypnosis, and stress management have been shown to improve the quality of life, but evidence is limited on their impact on anxiety, depression, and disease activity.¹⁸ 

The caveat is that “Overall, these complementary therapies are promising and should be used to treat patients with IBD from a more holistic perspective.”¹⁷

References

1. Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/inflammatory-bowel-disease/symptoms-causes/syc-20353315#:~:text=Inflammatory%20bowel%20disease%2C%20also%20called,uncommonly%2C%20the%20upper%20gastrointestinal%20tract.

2. https://www.hopkinsmedicine.org/health/conditions-and-diseases/inflammatory-bowel-disease#:~:text=Inflammatory%20Bowel%20Disease%20Symptoms,that%20normally%20do%20not%20connect.

3. Venkateswaran N, Sultan K. Racial and ethnic disparities in clinical presentation, management, and outcomes of patients with inflammatory bowel disease: a narrative review. Trans Gastroenterol Hepatol. 2024;9. https://tgh.amegroups.org/article/view/8711/html#:~:text=What%20has%20been%20clearer%20since,ethnicities%20in%20population%2Dbased%20studies.

4. Abegunde AT, Muhammad BH, Bhatti O, Ali T. Environmental risk factors for inflammatory bowel diseases: Evidence based literature review. World J Gastroenterol. 2016;22:6296–317. doi: 10.3748/wjg.v22.i27.6296

5. Danese S, Sans M, Fiocchi C. Inflammatory bowel disease: the role of environmental factors. Autoimmun Rev. 2004;3:394-400. doi: 10.1016/j.autrev.2004.03.002.

6. El Hadad J, Schreiner P, Vavricka SR, et al. The genetics of inflammatory bowel disease. MolDiagn Ther . 2024;8:27–35. https://doi.org/10.1007/s40291-023-00678-7

7. Cleveland Clinic. https://my.clevelandclinic.org/health/diseases/15587-inflammatory-bowel-disease 

8. Rosen MJ, Dhawan A, Saeed SA. Inflammatory bowel disease in children and adolescents. JAMAPediatr. 2015;169:1053–60. doi: 10.1001/jamapediatrics.2015.1982

9. Severs M, Spekhorst LM, Mangen MJ, et al. Sex-related differences in patients with inflammatory bowel disease: results of 2 prospective cohort studies. Inflamm Bowel Dis. 2018;24:1298-306. doi: 10.1093/ibd/izy004.

10. Blumenstein I, Sonnenberg E. Sex- and gender-related differences in inflammatory bowel diseases. Front Gastroenterol. 2023;2. |https://doi.org/10.3389/fgstr.2023.1199687

11. Ehrlich AC. How women and men experience IBD differently. Temple Health. February 9, 2021. https://www.templehealth.org/about/blog/how-women-men-experience-ibd-differently

12. Rustqi SD, Kayal M, Shah SC. Sex-based differences in inflammatory bowel diseases: a review. Ther Adv Gastroenterol. 2020;13:1756284820915043. doi: 10.1177/1756284820915043

13. Troncoso LL, Biancardi, AL, Vieira de Morares Jr H, Zaltman C. Ophthalmic manifestations in patients with inflammatory bowel disease: A review. World J Gastroenterol. 2017;23:5836–48. doi: 10.3748/wjg.v23.i32.5836

14. Sharma SN, Qasemi F, Sharma V. A rare ocular manifestation of Crohn’s Disease. J Clin ExpOphthalmol. 2012,3:7. DOI: 10.4172/2155-9570.1000237.

15. Rogler G, Singh A, Kavanaugh A, Rubin DT. Extraintestinal manifestations of inflammatory bowel disease: current concepts, treatment, and implications for disease management. Gastroenterology. 2021;161:1118–32. doi: 10.1053/j.gastro.2021.07.042

16. Faggiani I, Fanizza J, D’Amico F, et al. Extraintestinal manifestations in inflammatory bowel disease: from pathophysiology to treatment. Biomedicines. 2024;12:1839. doi: 10.3390/biomedicines12081839

17. Vera EL, Betancur Vasquez C, Peinado Acevedo JS, Rivera Bustamante T, Redondo JMJ. Ocular manifestations of inflammatory bowel disease. Cureus. 2023;15:e40299. doi: 10.7759/cureus.40299

18. Duff W, Haskey N, Potter G, Alcorn J, Hunter P, Fowler S. Non-pharmacological therapies for inflammatory bowel disease: Recommendations for self-care and physician guidance. World J Gastroenterol. 2018;24:3055–70. doi: 10.3748/wjg.v24.i28.3055

19. Cleveland Clinic. https://my.clevelandclinic.org/health/treatments/22466-low-fodmap-diet

20. Nielsen OH, Ainsworth M, Coskun M, Weiss G. Management of iron-deficiency anemia in inflammatory bowel disease. Medicine (Baltimore).  2015;94:e963. doi: 10.1097/MD.0000000000000963