Rheumatology and IBD: What you should know about extra-intestinal manifestations of IBD

April 15, 2025

Introduction

The objectives of this presentation were to explore treatment for concomitant extra-intestinal manifestations (EIM) of inflammatory bowel disease (IBD), especially those affecting the joints (inflammatory arthritis) and also other commonly associated diseases such as psoriasis, and to consider how these manifestations influence treatment choices. Collaboration between specialists was also discussed with a focus on rheumatologists, who see a range of patients with inflammatory disease including rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), and IBD.

Shared Concepts in Inflammatory Rheumatologic & Gastroenterological Conditions

One important concept across inflammatory diseases is that they change over time. Specifically, in RA, circulating cytokine levels, particularly IL-6 and TNF, vary across the pre-disease state, establishment of RA, transition to chronic disease and, where relevant, remission. This likely occurs in IBD as well.^1,2 These changes could also lead to secondary failure of drugs in some patients.

Another important concept relevant to both therapeutic areas is the window of opportunity to treat patients. For instance, early treatment in RA is associated with a higher likelihood of remission, and treatment is considered urgent.³ Furthermore, the predictors of remission in RA are similar to those identified in IBD including early disease, rapid deep remission when treatment is initiated, and sustained remission. In addition, studies have shown that female sex is associated with worse treatment responses in RA, axial spondyloarthritis (axSpA), and IBD.^4-6 Another predictor of remission is the use of more aggressive therapy. For example, to increase the likelihood of remission in RA, triple treatment is better than double disease-modifying antirheumatic drug (DMARD) treatment, which in turn is better than single DMARD treatment.^7,8

The practice barriers to achieving treatment targets are also similar between IBD and rheumatic disease (RD), and can include comorbidities, psychological factors, low adherence to treatment, delayed referrals, access limitations to specialists and optimal treatment, and misdiagnosis.^9-11

Rheumatic Diseases (RD) & IBD: Shared Pathogenic Mechanisms

Common pathogenic mechanisms have been shown to link gut and joint inflammation.¹² Specifically, gut inflammation has been shown to be strongly associated with axSpA, with the prevalence of IBD in individuals with SpA estimated to range from 4% to 12% and subclinical gut inflammation in up to 50%.^13,14

Lifestyle accounts for a large proportion of autoimmune diseases in terms of both susceptibility and severity of illness. Environmental factors that have been shown to affect both RD and IBD, include poor diet, high BMI, smoking, antibiotic use (or possibly infections that lead to antibiotic treatment), and pollution.^15-24 A study of 1219 incident cases of RA found that an increasingly heathier lifestyle was associated with an incrementally reduced risk of developing both seropositive and seronegative RA.²⁵

The pathogenesis of Crohn’s disease (CD)-associated SpA is not well understood, but preclinical and clinical data suggest that the underlying mechanism may involve the microbiome.²⁶ Emerging evidence suggests that subclinical gut inflammation in patients with SpA may be involved in the pathogenesis of the disease. Intestinal dysbiosis is thought to modulate local and systemic inflammation in many diseases including SpA.²⁷

Furthermore, many drugs affect the gut-joint axis including non-steroidal anti-inflammatory drugs (NSAIDs), DMARDs, biologics, and steroids. While it is known that gut dysbiosis can be present prior to development of inflammatory arthritis, it may get worse as disease worsens or vice versa (worsening dysbiosis can precipitate flares or worse disease), and individuals with RD have fewer ‘healthy strains’ of intestinal flora and less diversity. How to define and treat gut dysbiosis is not yet known, so further research is needed.

Treating IBD and Rheumatologic Manifestations

In patients with both IBD and RD it is important to consider the impact of medications on the two diseases, as some drugs are helpful for RD but not IBD, some are helpful for IBD but not specific RDs, and importantly, there are some that are potentially beneficial for both diseases (see Table 1).

With respect to treatments that are helpful only for RD, one important class to consider is IL-17 inhibitors (e.g., secukinumab, ixekizumab, bimekizumab, brodalumab). While these have proven beneficial for PsO and three are approved in PsA, they may increase the incidence or exacerbate IBD. Specifically, in a study of the incidence of IBD following secukinumab use in PsO (n=3993 patients), the incidence of IBD was 0.33/100 patient/years.²⁸ Similarly, studies with ixekizumab based on data from 7 randomized controlled and uncontrolled trials in plaque PsO (n=4209 patients) found that <1% of patients developed or experienced exacerbated IBD. The IBD incidence rate was 0.30/100 patient-exposure years and 12 of 16 patients with a history of IBD did not report an exacerbation.²⁹

In addition, there are other drugs used in RD that are either ineffective or understudied in IBD such as etanercept, baricitinib, IL-6 inhibitors, rituximab, abatacept, and hydroxychloroquine. These treatments may still have a role in IBD patients with concomitant rheumatologic EIMs but not to treat the bowel manifestations and so would not be preferred options.

Unmet Needs

Unmet needs exist across inflammatory diseases and include definition of treatment goals, consideration of patient-reported outcomes, and the need for a more precision-medicine approach (see Figure 1).

For example, further research is needed to support the emerging trend of treating with two different advanced therapies, one for IBD combined with one for the rheumatologic or dermatologic condition. Furthermore, therapeutic drug monitoring is not used in rheumatology but may be important to consider in patients with EIMs if using a drug that could have rapid clearance and/or neutralizing antibodies such as anti-TNFs.

Conclusions

In conclusion, there are many parallels in the evolving knowledge of best practices in RD and IBD, but there are also differences with respect to the treatments used and their doses. Importantly, some drugs that work well for IBD are not great for RD. Anti-TNF and JAK inhibitors are likely the best option when both IBD and RD are present, while IL-23 inhibitors are preferred for psoriasis and IBD. Overall, rheumatology and gastroenterology patients have more in common than previously thought, and ongoing collaboration and co-management between specialists is important.

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Clinical Case

Erica is a 26-year-old female with a 3-year history of colonic Crohn’s disease (CD). She has 2 to 3 formed bowel movements per day with no bleeding and no abdominal pain. Her last colonoscopy 1 year ago showed that her disease was in endoscopic remission. She has only been on corticosteroids once previously and is currently on an infliximab biosimilar.

She has developed mild psoriasis while on infliximab, but this has been controlled with topical treatments. During the last 2 months she has experienced right lower back stiffness and pain. She sees you in the office and complains of a painful right knee. On physical exam there is no abdominal tenderness. You are not sure how to examine the joints and back, but you think there may be some mild swelling of the knee.

Commentary

• Some gastroenterologists will start an NSAID, and the majority would refer to rheumatology.
• Given that speed of access to referral varies, some would choose to treat in the meantime.
  • To help ensure rapid response to referral, it is important to note the presence of swollen joints and any impact on mobility.
  • NSAIDs are appropriate for transient use, with the goal of patients taking them for the shortest possible duration. To this end, it may be helpful to not include a refill to ensure a return visit if symptoms persist until the patient is seen by a rheumatologist.
• Gastroenterologists can order an HLA-B27 test, however, if it is negative that does not rule out axSpA (axial spondyloarthritis).
  • A positive result can be helpful, so the test may be worthwhile to order while awaiting the consult from rheumatology.
  • X-rays such as sacroiliac (SI) joint radiographs may also be helpful if there is a suspicion of sacroiliitis to help speed up the process but are often normal in early axSpA, which does not rule out the diagnosis.
  • The rheumatologist will order MRI T1, T2 STIR (Short Tau Inversion Recovery) sequence images of SI joints if warranted.
• For one problematic joint, one can consider short-term steroids orally on intra-articularly or alternate options for local injections if they can be obtained quickly (e.g., sports medicine clinics).
• Some gastroenterologists would scope to confirm if there is any underlying IBD disease activity, which can also serve as a baseline before using an NSAID. However, for patients is in clinical remission, NSAIDs are not contraindicated in IBD.
  • There may be benefits of doing a colonoscopy early as a joint flair may indicate that IBD is intensifying. Patients rarely get a rheumatologic EIM when their IBD is completely silent. However, in some patients EIM flares are not concordant with their IBD activity.
  • A fecal calprotectin may also be helpful if scopes can be performed quickly.

Case Evolution

You refer the patient to your rheumatologist colleague and in the meantime decide to start an NSAID although you are slightly concerned about the possibility of exacerbating her CD. She contacts your office 2 weeks later and reports an increase in stool frequency with 3 to 5 soft stools per day and mild abdominal cramping. Laboratory tests reveal hemoglobin (Hbg)112, C-reactive protein (CRP) 8, fecal calprotectin (FCP) 800.

A colonoscopy shows medium-sized ulcers in the sigmoid colon with a few scattered small ulcers in the transverse colon. She also sees the rheumatologist who makes the diagnosis of sacroiliitis with peripheral inflammatory arthritis. With the rheumatologist, you discuss what would be the most effective therapy at present.

Commentary

• Most gastroenterologists would do TDM at this point. In contrast, TDM is not used in rheumatology, despite some data on the effectiveness of reactive TDM for anti-TNFs.
  • Based on the results of TDM, they could potentially optimize the dose of infliximab, since it is effective for axSpA and IBD.
• If there is solely peripheral joint involvement, rheumatologists would consider adding SSZ or MTX or increasing infliximab or changing to another anti-TNF. They would also consider switching to a different mechanism of action as the IBD is active, including upadacitinib (UPA) or possibly tofacitinib if the patient has UC, either of which are also effective for axial involvement. This would be a joint decision between rheumatology and gastroenterology, and the doses may with higher doses used in IBD compared to inflammatory arthritis conditions.
  • Given the recent SEQUENCE trial results, consider the potential benefits of risankizumab over ustekinumab, unless cost is a factor.
  • Rheumatologists would be less likely to choose IL-12/23i (ustekinumab) or an IL-23i (risankizumab and guselkumab) given their lack of efficacy for axial involvement.

Case Evolution

TDM levels show no detectable infliximab and high anti-infliximab levels. The patient tells you that the main issues affecting her quality of life are her back and joint symptoms. You discuss several therapeutic options with her. She wants to get better quickly as she is newly married and wishes to get pregnant. Her preference is for an oral drug rather than intravenous or subcutaneous.

Commentary

• Some gastroenterologists would try another anti-TNF since she previously responded to infliximab, while others would switch to UPA.
• The decision would depend on her pregnancy plans, with some preference for anti-TNFs in case pregnancy happens soon, as currently UPA is contraindicated in pregnancy.
• Rheumatologists still use a lot of MTX, in part because of access requirements, and at higher doses than used in GI, but as with UPA, she would need to stop it before pregnancy.
• The impact of RD on pregnancy outcomes depends on the rheumatologic condition, but active IBD is more likely to negatively impact growth of the fetus with intrauterine growth restriction and prematurity.

Case Evolution

Following discussion of therapeutic options with her, adalimumab (ADA) is initiated. After 3 months, her back pain and joint pain have improved significantly. However, her GI symptoms are worse. She now experiences 5 to 6 loose stools per day including nocturnal bowel movements and mild to moderate abdominal cramps.

Laboratory tests reveal Hbg 102, CRP 16, FCP >2100. Adalimumab levels are 12.

You dose escalate to weekly adalimumab. You see her in the office 8 weeks later and despite the increase in adalimumab her GI symptoms have not improved.

Commentary

• Most gastroenterologists would switch or add another biologic. Assuming ADA is helping somewhat, they would add an IL-12/23i or IL-23i due to the favorable safety profiles.
• Some gastroenterologists would try to further push the ADA dose (e.g., 80 mg weekly). Given anti-TNFs are safe for pregnancy and effective for IBD and joints it is important to fully optimize that class of therapy if a woman is desiring to conceive. To that end, golimumab is also an option and can be dose optimized; whereas certolizumab pegol, which is safe in pregnancy, is not approved in Canada for IBD.
• They would also counsel her on the benefits of delaying pregnancy given her active disease.

Case Evolution

After discussion with the patient and rheumatologist you decide to maintain the adalimumab, as it has controlled her joint and back disease, and to add ustekinumab—noting this is off label for arthritis but is approved for CD. You see the patient in follow-up and at 6 months she is very now doing well. She has no joint or back pain, and her stool frequency is back to baseline with no abdominal pain.

CRP and FCP are now normal. The patient is concerned about becoming pregnant on dual biologic therapy as well as potential long-term side effects. She wishes to stop one of the biologics.

Commentary

• The majority of gastroenterologists would continue dual therapy, as they do not want to “rock the boat” and feel that the data with UST and anti-TNF suggest they can be safely continued through pregnancy.
• UST is not approved in combination with adalimumab, but there are some data and clinical experience to back up this decision. Also, ustekinumab appears to be safe in pregnancy based on large real-world experience in IBD and psoriasis.
• There may be room for discussion around de-escalation, either stopping or decreasing the anti-TNF dose before pregnancy.
  • The longer patients are in remission the more comfortable gastroenterologists feel with de-escalation.
  • However, it is not always predictable who will relapse, thus patient counselling is important.
  • In this case, given the arthritis likely developed because of the increase in CD activity, now that the CD is under control, long-term monotherapy with UST may be feasible.
  • No matter what choice is made between the patient and the gastroenterologist, the patient would be followed carefully, as if she becomes pregnant, having her IBD under excellent control will help ensure the best outcomes for the baby.

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Editor-in-Chief

John K. Marshall, MD MSc FRCPC CAGF AGAF
Professor, Department of Medicine
Director, Division of Gastroenterology
McMaster University
Hamilton, ON

Contributing Author

Janet Pope, MD MPH FRCPC
Professor of Medicine
Schulich School of Medicine & Dentistry
University of Western Ontario
St. Joseph’s Health Care
London, ON

Mentoring in IBD Curriculum Steering Committee

Alain Bitton, MD FRCPC, McGill University, Montreal, QC
Karen I. Kroeker, MD MSc FRCPC, University of Alberta, Edmonton, AB
Cynthia Seow, MBBS (Hons) MSc FRACP, University of Calgary, Calgary, AB
Jennifer Stretton, ACNP MN BScN, St. Joseph’s Healthcare, Hamilton, ON
Eytan Wine, MD PhD FRCPC, University of Alberta, Edmonton, AB

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