Therapeutic Approaches in Microscopic Colitis – Where do we Stand?

Microscopic Colitis (MC) is an inflammatory bowel disease with complex pathophysiology that is characterized by watery, non-bloody diarrhea [1]. Further symptoms include fecal urgency, fecal incontinence, nocturnal bowel movements, abdominal pain and weight loss that often result in decreased quality of life [2]. While in most cases endoscopic examination displays unremarkable intestinal mucosa of the colon, there are distinct histological aberrations detectable that classify MC into three phenotypical subtypes. These histological findings include an increase in intraepithelial lymphocytes (>20 per 100 surface epithelial cells) in Lymphocytic Colitis (LC) whereas a thickened subepithelial collagen band (>10μm) is characteristic for Collagenous Colitis (CC). The third subtype, incomplete MC, refers to patient colon specimen that do not reach the thresholds for LC and CC [3]. However, the diagnosis of incomplete MC remains challenging given an overlap in intestinal mucosal histology in normal (i.e., immune response) as well as in mucosa of patients with irritable bowel syndrome and diarrhea where an intermittent lymphocyte infiltration can occur. To date, several risk factors including older age [4], female gender [5], other autoimmune diseases [6], previous gastrointestinal infections (e.g., Norovirus, Clostridium difficile, Campylobacter concisius and Escherichia species) [7,8], smoking Niccum B et al. [9] and alcohol ingestion Niccum B et al. [10] have been identified. People of Asian, Hispanic/Latino, and African American descent as well as women with a BMI >30kg/m2 appear to have a lower risk for MC development [11,12]..

Different medications including non-steroidal antiinflammatory drugs, proton pump inhibitors and selective serotonin reuptake inhibitors have been associated with MC [13- 15]. However, given a recent study some of these associations have become less clear and further studies might therefore be essential [2].

Avoid risk factors

Before initiation of a medical therapy, one of the first and pivotal steps in the MC management is a thorough reviewing of abovementioned lifestyle factors, patient history and medications [1]. In case a (temporal) association between potentially modifiable factors can be found, terminating or adjusting the suspected risk should not unnecessarily be delayed by further investigations. In addition, smoking cessation is highly recommended in all patients.

First-line therapy

If MC symptoms persist subsequent to the elimination of any potentially modifiable exacerbating risk factors, oral budesonide 9 mg daily for six to eight weeks is safe and often efficacious for remission induction. Its superiority over placebo was shown in multiple controlled trials [16], and it is therefore considered first line therapy by the United European Gastroenterology (UEG) Miehlke S et al. [17] as well as the American Gastroenterological Association (AGA) Nguyen GC [18] in their current guidelines on MC. Furthermore, long-term budesonide administration has little, if any at all, side effects due to its high first-pass hepatic metabolism and low systemic bioavailability [19].

Clinical response should be assessed six to eight weeks after therapy initiation. If patients display clinical remission without relapse, no maintenance therapy is indicated [18]. Although response rates to budesonide induction therapy can be considered very high, so are relapses (50-80%) after discontinuation of budesonide [20,21]. Therefore, the UEG and the AGA suggest indeterminate oral budesonide administration (3 to 6mg per day) to maintain remission in MC if remission had occurred. Other drugs like loperamide may also be considered reasonable for maintenance therapy [22]. Recent studies suggest the effectiveness for bile acid sequestrants in MC either as monotherapy or in combination with budesonide since bile acid diarrhea coexists in a substantial number of patients [22,23]. To date, no consensus has been found whether budesonide tapering outperforms the risk of a MC relapse upon initial successful disease remission. Nevertheless, patients with severe symptoms (necessitating a high budesonide dose for remission) may benefit from tapering to the lowest dose possible maintaining clinical remission. Notably, vitamin D and calcium supplementation should be considered in every long-term steroid treatment despite the extremely limited systemic exposure. In case of doubt, presence of multiple risk factors or simply as a baseline in view of potential upcoming prolonged budesonide exposure a bone mineral density measurement can be considered [17,18].

Second-line therapies (biologics, immunomodulators and small molecules)

As of today, the cornerstone of MC treatment remains budesonide. Failure to first line treatment often significantly impairs quality of life, the ability to work as well as mental health issues due to the severity of symptoms [3]. Therefore, second line therapeutic options are pivotal. Yet, despite high budesonide doses about 4.9% and 13.6% of MC patients are primary non- or partial responders to budesonide, respectively, demonstrating persistent clinical MC activity with disease typical symptoms [22]. Even though very rare, side effects such as Cushing’s syndrome, palpitations, depression or dyspepsia of budesonide may require alternative therapeutic options. Importantly, prior to MC therapy escalation in MC management, another clinical work up including the reassessment and search for different diarrhea causes such as coeliac disease, bile acid diarrhea or infectious causes as well as a medication review is prerequisite [17,24]. Furthermore, smoking cessation is also strongly advised since it is associated with a reduced treatment response [21].
Immunomodulators (azathioprine, mercaptopurine): Several retrospective case studies evaluated the immunomodulators Azathioprine (AZA) and mercaptopurine (6-MP) and their treatment effect in steroid-dependent or refractory MC. Long-term response without concomitant steroid therapy ranged from 28% to 89% [25-27]. Therefore, the EUG recommends their use in MC patients who failed budesonide induction or clinical remission maintenance [17].
Anti-TNFα antibodies (infliximab, adalimumab): TNFα targeting immunoglobulins such as infliximab and adalimumab are the most often used as second-line therapeutics. A pooled analysis of 76 patients revealed a clinical remission rate of 57.8% and 39.3%, and a remission rate of 45.3% and 32.5% for infliximab and adalimumab, respectively [27]. However, discontinuation of these agents is frequent due to lack/loss of efficacy or adverse effects (32.9%, and 23.0% for infliximab, and adalimumab, respectively) [27].
α4β7-integrin antagonist (vedolizumab): A recent metaanalysis which was based on multiple studies including a total of 88 patients with budesonide refractory MC receiving vedolizumab revealed a clinical remission rate of 63.5% and a maintenance of remission rate of 65.9% (median duration of 13 months) [27]. Furthermore, therapy-related adverse events leading to discontinuation of vedolizumab therapy was 12.2% [27]. Therefore, vedolizumab appears to be a favorable and promising second-line therapy in MC. Nevertheless, further randomized controlled trials are needed.
Anti-IL12/IL-23 antibody (ustekinumab): Data on the use of ustekinumab in MC is scarce. In the retrospective series called ‘CONFER project’, ten patients who received ustekinumab in budesonide refractory MC were analyzed. 50% of these patients displayed clinical disease response whereas about 40% of study individuals reached clinical remission upon induction [28]. On the other hand, around 60% were discontinued due to lack/loss of efficacy or side effects.
JAK inhibitors (tofacitinib, filgotinib, upadacitinib): Promising results from the CONFER project were presented at the Digestive Disease Weeks 2024 [28]. Here, in a retrospective study 14 patients with refractory MC were treated with JAK inhibitors such as tofacitinib, filgotinib and upadacitinib leading to a clinical response and clinical remission upon induction of around 90% and 80%, respectively. Further studies with larger statistical power and higher patient numbers are urgently awaited in the field to confirm these encouraging and promising findings.
Surgical procedures: The clinical role of surgical procedures has not yet been established in the treatment of MC but can be considered and discussed on an individual basis as ultimo ratio option in case the majority of current MC-approved therapeutics fail [17].

Treatments not endorsed by current guidelines

Multiple agents have been studied in inducing and/or maintaining remission in MC without a relevant clinical impact. A placebo-controlled, randomized study showed that mesalamine lacks efficacy and is inferior to budesonide [29,30]. Based on these findings, the UEG advises against its use for MC induction of remission. The use of anti-infective agents such as antibiotics for inducing and maintaining remission in MC has not systematically been investigated. Smaller case series reported response rates up to 60% after treating with various antibiotics, no information on the response definition or treatment dosing were made available [31].

A large retrospective cohort study reported a significant (subjective) effect of loperamide treatment in MC. As of today, there is not enough evidence to recommend the use of loperamide alone in MC. Given its positive effect on diarrhea, it may be considered in mild disease [17]. Probiotics, namely Lactobacillus acidophilus and Bifidobacterium animalis subsp. Lactis were studied for their potential in inducing MC remission in a placebo-controlled trial. These agents did not display superiority compared to the placebo group though [32].

In this review, we summarize the evidence of efficacy for current treatment options in MC. Over the last years, the advances in pre- and clinical trials as well as an increased understanding of MC pathophysiology led to significantly more therapeutic options (i.e., immunomodulators, biologics and small molecules) in active MC in addition to ‘gold standard’ budesonide therapy. Given a large increase in rather novel anti-inflammatory therapeutics and combinatory possibilities, together with the lack of clinical studies are possible reasons why patient management of non- and partial responders still remains challenging. Hence, further studies are needed to clarify the role of second-line treatment options in tenacious disease.

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