Category: 8. Health

Coconut water is widely celebrated as a natural, hydrating drink rich in electrolytes, vitamins, and minerals. Many people consider drinking it straight from the coconut as the purest and safest way to enjoy its benefits. However, research and medical case studies reveal that this common belief may be dangerously misleading. Coconuts are not sterile once harvested, and under warm, humid conditions, they can harbour harmful bacteria, fungi, and toxins without visible signs of spoilage. A tragic case in Denmark demonstrated how fungal contamination in coconut water can turn fatal. Recognising these hidden risks is essential for safe and responsible consumption.

A seemingly fresh coconut turns deadly: Study insights

Coconuts are not sterile once harvested. When stored in warm and humid conditions, they become vulnerable to microbial contamination. Bacteria and fungi can infiltrate through cracks in the shell or during handling, leading to hidden spoilage that isn’t always visible from the outside.One of the most alarming cases is documented in the study Fatal 3-Nitropropionic Acid Poisoning after Consuming Coconut Water. The incident involved a 69-year-old man in Denmark who died after drinking coconut water contaminated by a toxin-producing fungus inside the shell. Around three hours after consumption, he began experiencing excessive sweating, nausea, and vomiting. When emergency responders arrived, they found him pale, clammy, confused, and struggling with poor balance and abnormal muscle movements. Within 26 hours, the man developed multi-organ failure caused by 3-nitropropionic acid (3-NPA), a toxin known to severely damage the nervous system and vital organs. This tragic case demonstrates that even a fresh-looking coconut can harbour lethal contaminants.

Health risks of contaminated coconut water

1. Gastrointestinal issuesStale or contaminated coconut water may harbour harmful bacteria that trigger digestive problems. Common symptoms include nausea, diarrhoea, and abdominal cramps, which often appear within just a few hours of consumption. Because these signs resemble ordinary food poisoning, many people may not realise the cause is contaminated coconut water.2. Neurological symptomsCertain toxins, such as 3-nitropropionic acid (3-NPA) produced by fungi, can directly affect the nervous system. This may lead to confusion, dizziness, abnormal muscle contractions, and even seizures. Neurological symptoms typically progress rapidly and require immediate hospital care to prevent worsening complications.3. Respiratory distressIn more severe cases, coconut water contaminated with fungal toxins can cause respiratory difficulties. Shortness of breath, chest tightness, or fluid build-up in the lungs may occur as the body reacts to toxin-induced damage. These symptoms are medical emergencies that demand urgent treatment.4. Fatal complicationsThe most dangerous risk linked to contaminated coconut water is death. As documented in the 2021 Danish case study, a man died within 26 hours of drinking water from a fungus-contaminated coconut. Such incidents highlight how quickly toxin-producing fungi can cause irreversible organ failure and fatal outcomes.

Safe consumption tips and preventive measures

Related FAQs

Q1. Is packaged coconut water safe?

• Yes, packaged coconut water is generally safer than drinking directly from the shell because it undergoes pasteurisation and quality checks to remove harmful microbes.

Q2. How can I tell if a coconut has gone bad?

Q3. Can refrigerated coconuts still get contaminated?

Q4. What should I do if I feel sick after drinking coconut water?

Q5. Who should avoid raw coconut water?

Disclaimer: This article is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional before making any changes to your health routine or treatment.Also read | Peanuts vs. Makhanas: Which one should you choose for blood sugar control and weight loss

Sleep disorders are increasingly recognised as a public health crisis. Among them, obstructive sleep apnoea (OSA) stands out for both its prevalence and its under-treatment.

Affecting nearly one billion individuals worldwide, OSA contributes to daytime fatigue, impaired cognition and elevated risks of cardiovascular disease, diabetes and premature mortality.

Despite the burden, current treatments remain insufficient. Continuous positive airway pressure (CPAP) devices (such as the mask shown below) are considered to be the gold standard; yet, adherence is poor, with up to half of patients abandoning therapy within the first year because of discomfort, nasal congestion and the inconvenience of nightly use.

Alternatives such as oral appliances or surgical interventions are not universally applicable. This gap has spurred growing interest in pharmaceutical approaches that target the underlying mechanisms of OSA rather than relying solely on mechanical solutions. 

The Democratic Republic of Congo (DRC) on September 4 declared its 16th Ebola outbreak after health authorities confirmed 28 suspected cases and 15 deaths, including four healthcare workers, in Kasai Province. The outbreak is centred in the Bulapé and Mweka health zones, near the Angolan border.

Laboratory analysis identified the Zaire strain of the virus, the first recorded in Kasai since 2008. The country’s most recent epidemic occurred in 2022 in Équateur Province and was contained within two months.

The World Health Organization (WHO) warned that case numbers are likely to rise and has dispatched a rapid response team to support Congolese health workers.

“We’re acting with determination to rapidly halt the spread of the virus and protect communities,” said Mohamed Yakub Janabi, WHO’s Regional Director for Africa. 

“Banking on the country’s long-standing expertise in controlling viral disease outbreaks, we’re working closely with the health authorities to quickly scale up key response measures to end the outbreak as soon as possible.”

WHO has deployed treatment stockpiles and transferred 2,000 doses of the Ervebo vaccine from Kinshasa to Kasai to protect frontline staff. Additional laboratory equipment and protective gear have also been delivered. Ebola carries an average case fatality rate of around 50%.

Kasai, which endured ethnic conflict and mass displacement in 2017, faces renewed pressure as health authorities confront the outbreak. Neighbouring Angola is monitoring potential cross-border transmission, while regional trade and movement through the Kasai corridor could be disrupted if the outbreak spreads.

Previous crises highlight the potential economic toll: the 2014–16 West African epidemic cost an estimated $53bn, while the 2018–20 Ebola outbreak in eastern DRC drained more than $1bn in emergency spending and trade losses.

The 2022 Équateur outbreak was contained within weeks, but the 2018–20 crisis lasted nearly two years, underscoring the risks if the Kasai outbreak extends beyond its epicentre.

Martha’s Rule rolled out across England

Families of patients at all acute hospitals in England can now seek a second opinion if they’re concerned about the care their relatives are receiving, after Martha’s Rule was rolled out nationwide.   

The patient safety scheme is named after Martha Mills, who died of sepsis in 2021, aged 13. Her mother Merope campaigned for patients and their loved ones to be given the right to request an urgent review of their care, after her concerns were ignored. 

The National Health Service said that between September 2024 and June 2025, 4,906 calls were made to Martha’s Rule helplines at hospitals trialling the scheme, leading to 241 “potentially life-saving interventions”. This week, it announced that it had been rolled out across England. 

“Families often know their loved ones better than anyone – they can spot when something isn’t right in ways that even experienced doctors might miss,” said Dr Ronny Cheung, consultant general paediatrician at Evelina London Children’s Hospital. 

“I’ve had Martha’s Rule invoked under my care, and while it can feel challenging initially, it’s ultimately about creating a culture where everyone… has a voice to raise concerns. This can only make the care we provide better.”

Image: Akram Huseyn

Introduction

Depression is one of the most common mental disorders worldwide. According to the World Health Organization, 3.8% of the global population suffers from this condition. It is more prevalent among individuals who have experienced abuse, severe loss, or prolonged intense stress, making them more susceptible to developing it.¹

In Ecuador, in 2015, approximately 2.088 people received medical care for depression in healthcare facilities. However, many cases of depression in the country continue to go unnoticed, leading to underreporting. Those who suffer from it often become accustomed to living in a state of persistent sadness and hopelessness, alternating with brief relatively calm periods. A significant percentage, however, ultimately end up in suicide. According to national statistics by 2023, 4.9% of deaths among young people aged 18 to 29 in Ecuador were due to self-inflicted injuries.²

However, the studies carried out so far in Ecuador have focused on determining the frequency of depression or its correlation with other variables such as anxiety and suicide risk in particular. Very few studies have been carried out on university students, and even fewer have established a correlation between elevated levels of proinflammatory cytokines and depression in university students of healthcare careers, a population group that is known to experience continuous and mounting stress levels due to the academic demands and emotional burdens inherent to these careers.

Despite being one of the most significant mental health disorders worldwide, the causes of this condition are still under investigation. In recent years, new theories have emerged that provide a better understanding of its complex pathophysiology; one of these is the neuroinflammation theory, which has proposed an alternate explanation of the role of systemic inflammatory processes, triggered by either an innate or acquired immune response, in the development of disorders such as depression.

Clearly understanding the causes of this disease will help down the road to develop effective prevention and treatment strategies, allowing for timely interventions and potential full recoveries. Taking all these facts into account, the objective of this study was proposed as finding if there is a correlation between elevated levels of circulating proinflammatory cytokines such as interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-α) and depression.

Materials and Methods

A cross sectional analytical correlational study was conducted. The study population consisted of 1200 medical and nursing students from a university in Loja – Ecuador.

Sample: the sample size was calculated using the finite population formula with a 95% confidence interval, a Z value of 1.96 and a margin of error of 5%, alpha significance level (α) of 0.05 and a statistical power of 80%. The total calculated sample was 291 participants, with an additional 9 participants included to account for potential losses, resulting in a final sample of 300 participants (150 from medical school and 150 from nursing school).

Inclusion criteria were applied: presently being a regularly enrolled student in the medical or nursing schools and duly signing of an informed consent. Exclusion criteria included students undergoing medical treatment with corticosteroids at the time of the study, also those with an immunosuppressive medical condition, and individuals belonging to vulnerable groups (elderly adults, children and adolescents, pregnant women, people with disabilities, individuals deprived of liberty, or those suffering from catastrophic or highly complex diseases).

The Project was approved by the Ethics Committee of the San Francisco General Hospital of the IESS (Ecuadorian Social Security Institute) under approval number N°18, following the ethical guidelines of the WHO (World Health Organization) and the Declaration of Helsinki as ethical principles for medical research. Prior to sample collection, informed consent was obtained from each participant.

To assess the presence of depression, the Beck Depression Inventory II was used. This is a self-report questionnaire consisting of 21 Likert type items. The original version was developed by Aaron Beck and has since become one of the most widely used instruments for detecting and assessing the severity of depression. Its items describe the most common clinical symptoms experienced by individuals with depression. This clinical tool is designed to evaluate both the presence and severity of depression in adults and adolescents aged 13 and older, with a sensitivity of 94% and a specificity of 92%.³

It is a self-administered inventory consisting of 21 items. In each item, the respondent must choose from four alternatives, rated from 0 to 3 points, ordered from least to greatest severity, based on the statement that best describes their mood over the past two weeks. The test evaluates symptoms associated with depression, such as mood variations, changes in habits, and somatic conditions. Once completed, the total score ranges from 0 to 63, with interpretation based on the following categories: 0–13 (no depression), 14–19 (mild depression), 20–28 (moderate depression), and 29–63 (severe depression).

After administering the Beck Depression Inventory II, blood samples were collected to assess inflammatory cytokines IL-6 and TNF– α in serum using the ELISA technique, following the instructions of the DIAsource IL-6-ELISA Kit and DIAsource TNF-α- ELISA Kit. The reference values for these cytokines were as follows: TNF-α: 0–7,2 pg/mL; IL-6: 0–5 pg/mL.^4,5

Statistical Analysis: Data normalization was performed using the Kolmogorov–Smirnov test. Levene’s test was used to assess homoscedasticity. Spearman correlation test and the Chi-square test were applied for the analysis of non parametric data, respectively. A p value <0.05 was considered statistically significant. The statistical analysis was conducted using IBM SPSS Statistics, Version 20.0.⁶

Results

The study population consisted of 300 university students from medical school and nursing school. The average age was 21.19 years among the participants, 71.66% were women while 28.33% were men (In nursing school, 81.3% of the students were of female gender, while in medicine, only 61.3% of the students were of female gender).

Depression was reported in 65% of participants (Table 1). A statistically significant correlation was found between elevated levels of proinflammatory cytokines and depression in the nursing student group, but it was not found in the medical student group (Tables 2 and 3).

Table 1 Beck Depression Inventory-II

Table 2 Correlation Between Inflammatory Cytokines IL-6 and TNF-α and Depression in Nursing Students

Table 3 Correlation Between Inflammatory Cytokines IL-6 and TNF-α and Depression in Medical Students

Discussion

High levels of depression (mild, moderate and severe) were observed in more than half of the study population. This finding is consistent with the results of studies conducted by Ngin et al,⁷ who reported similar percentages of depression among university students in Cambodia (2018). Their study also found an association between persistent depression and poor academic performance, unhealthy eating habits, limited physical activity, among other factors.

Similarly, the findings align with a study conducted on university students at the University of Santiago de Compostela by Blanco et al, where considering various types of depression from mild to very severe, the prevalence reached 48%, along with equally alarming levels of anxiety (2021). Additionally, Volken et al reported that the prevalence of depression was 43% among French students and 53.7% among Bangladeshi students.⁸

The high percentage of depression reported in this study is noteworthy not only due to the prevalence of this condition itself but also, as indicated by Anbesaw et al,⁹ because of the consequences that mental health issues have on university students. These consequences range from poor academic performance and an increased risk of dropping out of the university to higher consumption of alcohol, tobacco, and other drugs, engagement in risky sexual behaviors, physical inactivity, deterioration of physical health, self-harming behaviors and a greater risk of suicide, among others. These challenges are not uncommon in our context, particularly in healthcare career training, where high academic demands, combined with the emotional strain of interacting with ill patients in stressful hospital environments, exposure to frankly hostile treatment from patients, patient’s relatives and even peers, and highly competitive atmospheres, contribute to the onset and persistence of conditions such as depression. Additionally, the very limited hours of rest and proper night sleep required to meet academic demands, further exacerbate the stress building situations.¹⁰

A similar setting is explained by Zhang et al, who reported that academic stress is one of the most significant sources of chronic stress among university students. Academic stress is a psychological state experienced by students as a result of continuous social and self-imposed pressure in a school environment, leading to depletion of their psychological reserves (2020). This condition often results in feelings of frustration and hopelessness, which are particularly common among students in healthcare careers such as medicine and nursing.¹⁰

However, these results contrast with the study conducted by Anbesaw et al, where the depression rates in both studies are around 28%⁹ It is important to note that the first study used the PHQ-2 (Patient Health Questionnaire), which identifies depressive symptoms, while the second study is a systematic review. In our study, we applied the Beck Depression Inventory II, which allows for detecting and assessing the severity of depression. This difference in methodology may have influenced the variation in results between the studies. Additionally, our study only included medical and nursing students, whereas Anbesaw’s study included university students in general from Germany and Ethiopia, covering all academic fields. As explained by Milicet al, (2024), healthcare career students tend to exhibit higher levels of depression compared to the general population as these fields are academically, psychologically and emotionally demanding,¹¹ due to multiple risk factors such as an adverse academic environment, the competitive nature of the field, academic overload and increasing exposure to suffering and the reality of death, also certain neurotransmitters like serotonin can be affected potentially leading to depression in students pursuing health related careers as indicated in the study by Dhanoa et al.¹²

Nevertheless, the objective of this study was not only to determine the prevalence of depression in the study group but also to explore its origins. In this regard, previous research has shown that monoamine depletion such as serotonin depletion is not sufficient to cause depression in a healthy individual. Likewise, sustained serotonin depletion does not necessarily worsen depressive symptoms in untreated patients. This suggests that other mechanisms are involved in the pathophysiology of depression, including the GABAergic and glutamatergic systems, increased levels of pro-inflammatory cytokines and adrenal glucocorticoids, to hippocampal volume reduction and a chronic low-grade inflammatory state mediated by elevated levels of inflammatory interleukins such as IL-6 and TNF-α.¹³ This aligns with the findings of our study, which demonstrated a statistically significant correlation between elevated serum levels of IL-6 and TNF-α, and depression among nursing students (Table 2). We believe this can be explained by the high levels of chronic stress experienced by students of healthcare careers, which lead to an increase in pro-inflammatory cytokines and the presence of conditions such as depression.

Authors such as Kim et al, who state that inflammatory cytokines play a role in depression by triggering an inflammatory response in the brain, explain this. This response interferes with the activity of neurotransmitters such as adrenaline, serotonin and dopamine, affecting the functions of the hypothalamic-pituitary-adrenal (HPA) axis. As a result, early physical symptoms of depression may appear, including generalized and nonspecific pain, fatigue, appetite disturbances, reduced physical activity, sleep disorders, decreased academic performance and lower work productivity. Furthermore, they demonstrated statistical significance of the findings observed in their study. (Table 2).^14–16

In this regard, Beurel et al state that in the central nervous system, microglial cells function as immune cells and depending on stimuli can induce neuroinflammation. This process is mediated by cytokines produced not only by microglial cells but also by other immune system cells, including inflammatory cytokines such as interleukin-6, tumor necrosis factor-alpha, interferons, and interleukin-10, among others. This inflammatory response disrupts neuronal functions, leading to impaired neurotransmitter signaling, as well as interference with the synthesis and reuptake of serotonin, contributing to the development of depression.¹⁷ In fact, this inflammatory state also induces cellular apoptosis, increases oxidative stress, and causes metabolic disorders that impact neuroplasticity and neuronal function.^18–21 Regarding to this, researchers such as Li et al and Ruiz et al state that the brain contains two types of microglial cells: type 1 (M1), which produce inflammatory cytokines, and type 2 (M2), which produce anti-inflammatory cytokines. Therefore, the imbalance in M1/M2 activity not only influences brain inflammation but the persistence of the depressive disorders.^22,23

This link between depression and inflammatory processes is also highlighted by other researches, such as Zhan et al, who reported elevated IL-6 and TNF-α level in major depressive disorders. These elevations are associated with hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis, leading to increased corticosteroid secretion and subsequent dysfunction of immunocompetent cells. This dysfunction primarily affects brain function, particularly the turnover of 5-hydroxy-tryptamine (serotonin), reducing its availability in synaptic clefts, impairing neuroplasticity and contributing to depression.²⁴

Nevertheless, as explained by researchers such as Harsanyi et al, while elevated levels of pro-inflammatory cytokines can be found in depression, individuals with additional clinical conditions may, on the contrary, exhibit decreased levels of these cytokines. This occurs due to the activation and subsequent suppression of the immune response, which normally functions as part of the body’s homeostatic process. This phenomenon may explain the findings of the present study (Tables 2 and 3) where nursing students showed a statistically significant correlation between elevated IL-6 and TNF-α levels and depression, whereas this correlation was not observed in medical students.²⁵ Furthermore, as indicated by Paganin et al and Baurel et al, it is the persistence of the inflammatory process mediated by these cytokines that contributes to the continuation of depressive symptoms, failure of the antidepressant response and the emergence of atypical depression symptoms.^17,26,27

This variability in the results between the two study groups could be explained by the fact that the participants were university students in health sciences who were apparently healthy. However, the study reported not only the presence of depression but also elevated levels of pro-inflammatory cytokines.²⁷ This leads us to consider the possibility that unidentified health issues in this population may be primarily a response to sustained psychological stress rather than stress of organic origin, particularly in the case of nursing students (Table 2). Meanwhile, medical students may exhibit a compensatory homeostatic response (Table 3).

We also considered the interesting fact that in our study group, in nursing students there is a predominant feminine population (81.3%) compared to medical students (61.3%), and according to the study of Milić J, et al;¹¹ they also found an increased level of depression in women compared to men.

It should also be noted that one of the limitations of this study is its cross-sectional design, which did not include other variables that could affect the stress response, such as the development of a greater degree of resilience in female medical students compared to male medical students, which would also explain the difference observed between the two groups. Likewise, other variables such as sleep or stress levels, which can also influence elevated levels of proinflammatory cytokines and depression, were not included in this study.

Finally comparing the activities related to nursing and medical training, we considered that the much more intimate relationship at the human level that nursing students tend to have with their patients compared to medical students, could perhaps lead to higher chronic stress levels which could account for the higher levels of elevated cytokines and depression in this group.

Based on the findings presented, the relationship between the inflammatory process driven by the production of pro-inflammatory cytokines such as IL-6 and TNF-α and the onset and persistence of depression is evident, as demonstrated in this study among nursing students. Nevertheless, the results of this study are not conclusive, highlighting the need for further research on this topic in larger populations while considering a broader range of variables.

Conclusions

The prevalence of depression found in this research study was 65% of the study population, categorized into mild depression (23%), moderate depression (20.3%), and severe depression (21.7%).

A statistically significant correlation was observed between elevated levels of IL6 y TNF-α and depression among nursing students. However, no such correlation was found in the group of medical students.

Therefore, the correlation between elevated levels of inflammatory cytokines and depression remains inconclusive.

Studies are Required with a Larger Population and a Similar Proportion of Men and Women in the Study Groups.

Ethics

The authors confirm that the research presented in this article met the ethical guidelines, including adherence to the legal requirements, of Ecuador and received approval from the Ethics Committee of the San Francisco General Hospital of the IESS (Ecuadorian Social Security Institute) under approval number N°18.

Funding

The Vice-Rectorate for Research of Universidad Técnica Particular de Loja funded the purchase of reagents and supplies for the determination of Interleukin-6 and tumor necrosis factor-alpha cytokines.

Disclosure

The authors have no conflicts of interest to report.

References

1. Organización Mundial de la Salud (OMS). Depresión. 2023.

2. Instituto Nacional de Estadísticas y Censos (INEC). Boletín Técnico Registro Estadístico de Defunciones Generales; 2024.

3. JPALVC S. Adaptación española del Inventario para la Depresión de Beck-II (BDI-II): 2. Propiedades psicométricas en población general. Clin Salud. 2003;14(1130–5274):249–280.

4. Nara H, Watanabe R. Anti-inflammatory effect of muscle-derived interleukin-6 and its involvement in lipid metabolism. Inter J Mole Sci MDPI. 2021;22.

5. Molano Franco D, Arevalo-Rodriguez I, Roqué i Figuls M, Montero Oleas NG, Nuvials X, Zamora J Plasma interleukin-6 concentration for the diagnosis of sepsis in critically ill adults. Cochrane Database Syst Rev. 2019;4(4):CD011811. doi:10.1002/14651858.CD011811.pub2

6. Manterola C, Otzen T. Estudios observacionales. los diseños utilizados con mayor frecuencia en investigación clínica observational studies. The most commonly used designs in clinical research. Int J Morphol. 2014;32(2):634–645. doi:10.4067/S0717-95022014000200042

7. Ngin C, Pal K, Tuot S, Chhoun P, Yi R, Yi S. Social and behavioural factors associated with depressive symptoms among university students in Cambodia: a cross-sectional study. BMJ Open. 2018;8(9):e019918. doi:10.1136/bmjopen-2017-019918

8. Volken T, Zysset A, Amendola S, et al. Depressive symptoms in Swiss university students during the covid-19 pandemic and its correlates. Int J Environ Res Public Health. 2021;18(4):1–15. doi:10.3390/ijerph18041458

9. Anbesaw T, Zenebe Y, Necho M, et al. Prevalence of depression among students at Ethiopian universities and associated factors: a systematic review and meta-analysis. PLoS One. 2023;18(10):e0288597. doi:10.1371/journal.pone.0288597

10. Zhang J, Lin W, Tang M, et al. Inhibition of JNK ameliorates depressive-like behaviors and reduces the activation of pro-inflammatory cytokines and the phosphorylation of glucocorticoid receptors at serine 246 induced by neuroinflammation. Psychoneuroendocrinology. 2020;113.

11. Milić J, Skitarelić N, Majstorović D, et al. Levels of depression, anxiety and subjective happiness among health sciences students in Croatia: a multi-centric cross-sectional study. BMC Psychiatry. 2024;24(1). doi:10.1186/s12888-024-05498-5.

12. Dhanoa S, Oluwasina F, Shalaby R, et al. Prevalence and correlates of likely major depressive disorder among medical students in alberta, canada. Int J Environ Res Public Health. 2022;19(18):11496. doi:10.3390/ijerph191811496

13. Jazvinšćak Jembrek M, Oršolić N, Karlović D, Peitl V. Flavonols in action: targeting oxidative stress and neuroinflammation in major depressive disorder. Inter J Molecular Sci Multidisciplin Digital Publish Instit. 2023;24.

14. Kim Y, Pang Y, Park H, Kim O, Lee H. Cytokine associated with severity of depressive symptoms in female nurses in Korea. Front Public Health. 2023;11.

15. Cui L, Li S, Wang S, et al. Major Depressive Disorder: Hypothesis, Mechanism, Prevention and Treatment. Vol. 9. Signal Transduction and Targeted Therapy. Springer Nature; 2024.

16. Chan KL, Cathomas F, Russo SJ. Central and Peripheral Inflammation link Metabolic Syndrome and Major Depressive Disorder. Vol. 34. Physiology. American Physiological Society; 2019:123–133.

17. Beurel E, Toups M, Nemeroff CB. The Bidirectional Relationship of Depression and Inflammation: Double Trouble. Vol. 107. Neuron. Cell Press; 2020:234–256.

18. Rahimian R, Belliveau C, Chen R, Mechawar N. Microglial inflammatory-metabolic pathways and their potential therapeutic implication in major depressive disorder. Frontiers in Psychiatry. 2022;13.

19. Kouba BR, de Araujo Borba L, Borges de Souza P, Gil-Mohapel J, Rodrigues ALS. Role of Inflammatory Mechanisms in Major Depressive Disorder: From Etiology to Potential Pharmacological Targets. Vol. 13. Cells. Multidisciplinary Digital Publishing Institute (MDPI); 2024.

20. Poletti S, Mazza MG, Benedetti F. Inflammatory Mediators in Major Depression and Bipolar Disorder. Vol. 14. Translational Psychiatry. Springer Nature; 2024.

21. Roohi E, Jaafari N, Hashemian F. On inflammatory hypothesis of depression: what is the role of IL-6 in the middle of the chaos? J Neuroinflamm BioMed Central Ltd. 2021;18.

22. Ruiz NAL, Del Ángel DS, Brizuela NO, et al. Inflammatory Process and Immune System in Major Depressive Disorder. Vol. 25. International Journal of Neuropsychopharmacology. Oxford University Press; 2022:46–53

23. Li Z, Ruan M, Chen J, Fang Y. Major Depressive Disorder: Advances in Neuroscience Research and Translational Applications. Vol. 37. Neuroscience Bulletin. Springer; 2021:863–880.

24. Malik S, Singh R, Arora G, Dangol A, Goyal S. Biomarkers of major depressive disorder: knowing is half the battle. Clin Psychopharmacol Neurosci Korean College Neuropsychopharmacol. 2021;19(1):12–25. doi:10.9758/cpn.2021.19.1.12

25. Harsanyi S, Kupcova I, Danisovic L, Klein M. Selected biomarkers of depression: what are the effects of cytokines and inflammation? Inter J Mole Sci MDPI. 2023;24.

26. Paganin W, Signorini S. Inflammatory biomarkers in depression: scoping review. BJPsych Open. 2024;10(5):e165.

27. Islam MR, Sohan M, Daria S, et al. Evaluation of inflammatory cytokines in drug-naïve major depressive disorder: a systematic review and meta-analysis. Int J Immunopathol Pharmacol. 2023;37. doi:10.1177/03946320231198828

Introduction

Chronic low back pain (cLBP), pain affecting the lower region of the spine, is one of the most commonly reported locations for chronic pain, with prevalence estimates as high as 577 million individuals globally.^1,2 It has been estimated that up to 20% of adults have back pain within a single year and up to 80% of people experience at least one episode of back pain at some points in their lifetime.³ It has been a leading cause of disability and one of the major reasons for missing workdays worldwide.⁴ Recent analyses have demonstrated that individuals with cLBP have a high number of years lived with disability that peak in midlife (45–49 years of age) and are higher for females with cLBP.¹ The impact of cLBP on individuals, healthcare systems, and the economy is significant.

Previous studies have shown that treatment for low back pain depends on the underlying cause and the severity of symptoms. It often involves a combination of self-care measures, over-the-counter pain medications, physical therapy, chiropractic care, prescription medications, injections, or surgery.⁵ However, patients with cLBP respond very differently to these treatment methods in clinical practice.^6,7 Stratified care for acute and cLBP, which involves dividing patients into subgroups based on their specific factors to develop targeted treatment, has been proposed as an effective method to maximize treatment responses.^8,9 However, the subgroup factors most predictive of cLBP treatment outcomes have not been well established.

Therefore, the current study focused on statistically identifying subgroups of individuals who are clustered together based on their baseline pain profiles or related factors that may influence treatment outcomes. Specifically, the primary aims of this secondary analysis were to 1) examine baseline characteristics with latent class analysis to identify phenotypic subgroups of individuals with cLBP and 2) explore whether auricular point acupressure (APA) treatment responses differed between the pain phenotyping groups identified. Latent class analysis may be particularly useful for identifying clinical phenotypes that can build toward a precision medicine approach.¹⁰ In the current study, we focused on groupings of factors that may be modifiable; and how these groupings (ie, classes) were related to treatment outcomes.

Materials and Methods

Study Design and Sample

A total of 272 individuals with chronic low back pain were recruited for the parent study, 9 patients were excluded from the pain phenotyping analyses because of missing baseline pain profile data. The parent study, “Management of chronic low back pain (cLBP) in older adults using auricular point acupressure (APA)” (NIH/NIA R01AG056587; Clinicaltrails.gov Trial ID: NCT03589703), was a 3-arm, randomized clinical trial (RCT). The study protocol was approved by the Institutional Review Board of the Johns Hopkins School of Medicine and this study complies with the Declaration of Helsinki. All participants provided informed consent before participation; full protocol details were previously published.^11–13 See Supplementary Figure 1 for the CONSORT Diagram of Study Participation in the Parent Study. Adults, 60 years or older with cLBP for at least 3 months or caused pain for at least half of the days over the previous 6 months, were recruited. To be included, individuals were required to have average pain intensity over the past week of ≥4 on an 11-point scale, intact cognition, the ability to apply the APA study materials to their ears, and be willing to commit to the study procedures and timeline. Individuals were excluded if they had malignant or autoimmune disease, acute compression fractures, or hearing aid use that would obstruct application of study materials to the ear. Prior to recruitment initiation, the study statistician used a random-number generator to create group assignment lists. Participants were randomized (1:1:1) in blocks of 3 or 6 to APA ear points targeted to cLBP (T-APA, n = 92), APA ear points non-targeted to cLBP (NT-APA, n = 91), or education control (n = 89). Given evidence of APA as a safe and non-invasive treatment option, education control group participants were rerandomized to T-APA or NT-APA at 1 month follow-up. Participants were followed up to 6 months; and parent study outcomes were assessed at baseline, immediately post-intervention, and 1, 3, and 6 month follow-ups. Participants in the APA groups received 4 weekly APA sessions and were instructed to self-stimulate ear points at home; the education control group received 4 weekly educational sessions. The current analyses focus on baseline data for identifying latent classes. The primary treatment outcomes for the parent study included changes in pain (Numerical Rating Scale) and function (Roland and Morris Disability Questionnaire). Pain-related secondary outcomes were included. Data collection took place at 9 time points.

Indicators for Latent Class Model

The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) recommendations on patient phenotyping of chronic pain treatments⁶ were used to select the following indicators used to build the model:

1. Neuropathic pain was assessed from the painDETECT questionnaire,¹⁴ which includes seven items to identify the neuropathic components in patients with lower back pain.
2. Pain intensity was measured by a numeric scale. Participants were asked to rate their usual pain in the past week from 0 (no pain) to 10 (worst pain imaginable).
3. Sleep quality was assessed from PROMIS Sleep Disturbance – Short Form 4a.¹⁵ Participants were asked to answer four sleep-related questions based on their sleep quality in the past week. Lower scores indicate better sleep.
4. Depression and anxiety were measured with the PROMIS Depression and Anxiety – Short Form 4a.¹⁶ Each short version of the questionnaires contains four items evaluating depression and anxiety symptoms. All questions have 5-point scales and were scored 1 to 5, with higher scores indicating higher frequency of symptoms in the past seven days.
5. Fatigue was assessed from the 4-item PROMIS Fatigue – Short Form 4a.¹⁷ Participants scaled their fatigue levels from 1 to 5, where higher score represents higher fatigue level in the past one week.
6. Pain catastrophizing was measured with the Pain Catastrophizing Scale (PCS).¹⁸ The 13-item PCS instrument asked participants to measure their catastrophizing when experiencing pain on a numeric scale from 0 (not at all) to 4 (all the time). Higher total scores indicate worse pain catastrophizing.

Covariates – Baseline Characteristics

In addition to sociodemographic characteristics (sex, age, body mass index (BMI), and work status), the following baseline characteristics were included as covariates:

1. Comorbidity was measured by the Charlson Comorbidity index,¹⁹ which is a valid method to estimate the mortality risk of comorbid diseases.
2. Self-reported functional limitation for low-back pain was assessed by the 24-item Roland Morris Disability Questionnaire (RMDQ).²⁰ Patients were asked to check a statement if it was applicable for them. The RMDQ score is the total number of the checked items, with the range from 0 (no disability) to 24 (maximum disability).
3. Physical function was measured with PROMIS Physical Function – Short Form 4a.²¹ Participants answered this 4-item questionnaire by scoring numerically from 1 (without any difficulty) to 5 (unable to do).
4. Fear of physical activity was evaluated by the first 5 items in the Fear-Avoidance Beliefs Questionnaire (FABQ).²² Patients answered each question by scoring from 0 (completely disagree) to 6 (completely agree).

Raw scores were standardized to PROMIS T-scores for all PROMIS instruments.²³

Treatment Outcome Measures

For the current analyses, two variables, pain and disability reduction, were created to examine possible treatment latent class outcomes. The pain reduction variable refers to the change of worst pain from baseline to 1-month post-intervention. Disability reduction was calculated by the difference of the RMDQ score from baseline to 1-month post-intervention.

Statistical Analyses

Latent class analysis (LCA) is a statistical modeling method that is used to find clusters or subgroups of cases in multivariate data. These subgroups are called “latent classes”.²⁴ It is a widely used tool to investigate if there are unobserved or unmeasured subgroups within a population. To better understand cLBP, latent class analysis (LCA) was performed to cluster individuals into different classes based on their pain severity and pain impact at baseline (first visit). The IMMPACT recommendations⁶ were used to explore the pain phenotypes and select the indicators for the LCA model. The Bayesian Information Criterion (BIC) was used for model selection. A lower BIC indicates better model fit. Additionally, following prior recommendations, a restriction criterion was established that deemed classes <5% of the sample size as inadequate.²⁵ R package mclust5²⁶ was used to perform LCA. According to package documents, model-based clustering were based on parameterized finite Gaussian mixture models. Models are estimated by EM algorithm initialized by hierarchical model-based agglomerative clustering. The optimal model is then selected according to BIC. The LCA modeling approach allowed covariates to emerge during the classification process, they were then treated as predictors within the LCA regression framework. R² between each pair of indicators was calculated and no significant collinearity was found. After identifying participants into different latent classes, ANOVA and Fisher’s exact tests were conducted on continuous and categorical covariates, respectively, to see if there are any differences between the subgroups.

The parent study found that APA treatments significantly improved pain and functioning relative to the control group, with improvements lasting to the 6-month follow-up time period.¹³ The current study expanded on these analyses by incorporating phenotyping indicators from the LCA models. To assess the treatment effect, we calculated the difference of the worst pain and the RMDQ score between baseline and 1-month post-intervention. Patients without worst pain or RMDQ records were excluded, 199 patients with complete pain intensity and RMDQ data were included in the treatment effect evaluation. Two-way ANOVA was performed to examine the influence of treatment groups and latent classes.

Results

Patient Demographics and Baseline Characteristics

Of the 263 participants that had complete data for inclusion in the latent class analyses, 88 (33.46%) were in the T-APA treatment group, 88 (33.46%) in the NT-APA group, and 87 (33.08%) in the control group. See Table 1 for full demographic and clinical information.

Table 1 Demographic and Clinical Characteristics of the Sample (N = 263)

Clustering Results Based on the Latent Class Analysis (LCA)

Model Selection

Using the mclust5 package in R, all possible LCA models (a total of 126 different LCA models) were evaluated. The top three models with the lowest BIC, indicating better model fit, are provided in Table 2. Table 2 also gives an overview of the number of participants in each latent class for these models. Of these models, the VEI-7 and VEI-8 models (with 7 and 8 latent clusters respectively) contain small clusters with less than 5% of total subjects), which are not good for downstream analysis and interpretation. Thus, we consider the 3-class ellipsoidal and equal shape model (VEV-3) as the best due to relatively low BIC, good participant distributions across the latent classes, and model interpretation.

Table 2 BIC for the Three Best Fitted Models and Number of Participants in Each Class for Each Model (N = 263)

Identification of Latent Classes

Based on the best model (VEV-3), seven baseline characteristics emerged: anxiety, depression, fatigue, pain intensity, neuropathic pain, sleep, and pain catastrophizing. A breakdown of the pain severity and pain impact characteristics for each latent class are provided in Table 3. Results indicated that Latent class 2 had high pain severity (intensity, neuropathic pain) and high pain impact (anxiety, depression, pain catastrophizing, fatigue, sleep disturbance), Latent class 1 had moderate pain severity and pain impact, and Latent class 3 had low pain severity and pain impact. Based on the identified latent classes, demographic and clinical characteristics were subsequently examined (Table 4). Of the total participants (N = 263), Latent class 1 had 79 (30.04%), Latent class 2 had 109 (41.44%), and Latent class 3 had 75 (28.52%) subjects. No significant differences between these three latent classes were seen for age, BMI, or sex. However, significant differences by latent class were observed for baseline physical function, fear of physical activity, disability, comorbidity, and work status. Specifically, latent class 3 had the highest physical functioning, lowest fear of physical activity, and disability, and significantly lower unemployment rate compared to the other two classes.

Table 3 Indicator Characteristics at Baseline in Each Latent Class for the Best Model (VEV-3)

Table 4 Demographic and Clinical Characteristics at Baseline in Each Latent Class for the Best Model (VEV-3)

APA Treatment Responses for the Three Identified Latent Classes

Note that 64 subjects without worst pain score and/or RMDQ records were excluded for APA treatment response analysis, resulting in n = 199 subjects for APA treatment response analysis for different latent phenotyping classes. Results from the two-way ANOVA allowed us to examine how the three latent classes mapped to differences in pain reduction and disability reduction by treatment group. As seen in Table 5, the APA treatment was significant in pain reduction, but not significant in disability (RMDQ) reduction; however, pain phenotyping latent class was not significant in both pain reduction and disability reduction. For each of the latent classes, we further examined the APA treatment effects by one-way ANOVA and the results are reported in Table 6. Interestingly, the APA treatment effect in pain intensity reduction and disability reduction was not significant for Latent Class 1, however, in Latent Class 2, the APA treatment effect in disability reduction was significant, while the APA treatment effect in pain intensity reduction was significant in Latent Class 3.

Table 5 Reduction in Pain and Disability by Treatment Group and Latent Class Based on Two-Way ANOVA (N =199)

Table 6 Reduction in Pain and Disability by Group in Each Latent Class for the Best Model (VEV-3) (N=199)

Discussion

The current study used latent class analysis to identify phenotypic indicators within individuals with chronic low back pain and explored whether these subgroups were related to auricular point acupressure (APA) treatment outcomes. Three clusters were identified, where latent class 1 had moderate pain severity (intensity, neuropathic pain) and moderate pain impact (anxiety, depression, pain catastrophizing, fatigue, sleep disturbance), latent class 2 had high pain severity and pain impact, and latent class 3 had low pain severity and pain impact. When baseline demographic and clinical characteristics were examined, no significant differences were seen between the three classes for age, sex, or BMI. However, those with low pain severity and impact (latent class 3) had the highest physical functioning, lowest fear of physical activity, and disability, and significantly lower unemployment compared to the other two classes. Although follow-up analyses failed to detect significant differences in APA treatment responses among the three latent classes in general, the APA treatment effect in pain intensity reduction and disability reduction was different in different latent classes. The APA treatment effect in both pain intensity reduction and disability reduction was not significant for those with moderate pain severity and impact (latent class 1); however, the APA treatment effect in disability reduction was significant for those with high pain severity and impact (latent class 2); and the APA treatment effect in pain intensity reduction was significant for those with low pain severity and impact (latent class 3).

Latent class analysis is a specialized statistical approach that allows us to look at factor clustering that are indicative of phenotypic characteristics, and in the context of this study, factors that group together for individuals with chronic low back pain. Latent class analysis may be particularly useful for identifying clinical phenotypes that can build toward a precision medicine approach.¹⁰ In the context of chronic pain, there is hope that these phenotypes may be connected to treatment outcomes and lead to improved treatment efficacy.²⁷ These phenotypic analyses provide an important and novel opportunity to look at how pain and emotional factors may overlap and could indicate how these modifiable factors can be approached.

The variables examined in the current study represent potentially modifiable factors, including pain intensity, neuropathic pain, catastrophizing, anxiety, depression, fatigue, and sleep difficulty. In our exploratory analyses, we expected the three latent classes related to low, moderate, and high pain severity and pain impact to map onto APA treatment outcomes. However, these groupings (ie, classes) were not related to treatment outcomes in general, but the APA treatment effect is different in different latent classes. Although we only found a weak relationship between the latent classes and the treatment groups in the current APA study, we do propose that these classes may be related to other treatment types or indicate clinical characteristics that are especially important for physicians to consider.²⁸ It may seem intuitive that the factors that represented pain severity and pain impact clustered together, as these factors often co-occur and can exacerbate each other. For example, those with pain and sleep difficulties tend to have higher depression symptoms, pain catastrophizing, and anxiety.^29,30 This co-occurrence and potential amplification between the variables identified as clustering factors in the current analyses is especially relevant, as it provides further support for the interrelationship between these variables for people with chronic low back pain.

The potential compounding effect of the overlapping pain and pain impact variables highlighted in these clusters may be important in the clinical context, as they could be used to indicate those who may be in greater need of intervention or it may indicate alternative interventions that may be useful. For example, if an individual with high pain intensity seeks care and their pain is the sole focus of care, leaving their depression, anxiety, and catastrophizing untreated, they are unlikely to meaningfully improve. This lends support that a biopsychosocial treatment approach may have greater efficacy for this patient population.^31,32

The current findings are similar to previous studies,^7,33 as our pain phenotyping latent class analysis successfully clustered patients into classes presenting different pain profiles and emotional burden. Like previous studies, we can also see the relationship between physical and mental health among classes: the higher pain severity, the higher pain impact, which provides us a comprehensive understanding of the chronic low back pain population. Additionally, in line with previous work,⁷ we also found a significant difference of comorbidity among pain profiling groups. The current study expanded on these findings by demonstrating for the first time that the three pain profiling groups differed in physical function, fear of physical activity, disability, and work status. Lastly, related previous work that established similar pain and pain impact clustering did not explore the relationship between pain profiling classes and the treatment effect. Although we failed to find this association, these analyses were an important addition to the chronic low back pain phenotyping literature.

The current work sheds light on modifiable factors that appear to be phenotypic clusters in chronic low back pain; however, the limitations of the current study must be taken into account. Although the current study was powered to allow identification of latent classes, the parent study had higher than expected attrition due to halt of in-person assessments caused by COVID-19. The primary study endpoint of 1 month follow-up may have limited the ability to see therapeutic changes over time and may indicate a need for longer follow-up assessment. This study was conducted in the Baltimore area at an academic medical center which may limit generalizability to other regions. In the parent study, although most participants indicated that they believed they were in the T-APA group, it should be noted that the interventionist were not blinded to APA group assignment. Latent class analysis provides a unique opportunity to examine pain phenotypes; however, it should be noted that this type of analysis is based on probabilities and may underestimate or misestimate the number of individuals in each class.³⁴ Moreover, the majority of the pain severity and pain impact variables included in the current study were assessed over a brief period of time (eg, pain intensity over the past 7 days). This represents a relatively short window of time and is likely not reflective of longer-term pain and psychological burden. Future work should consider variables that reflect a greater time span (eg, chronic pain stage)³⁵ and are therefore more indicative of the patient experience.

Conclusion

Although the classes identified in the current analyses did not map onto APA treatment responses, they may still be useful for other interventions and should be explored in other clinical trials. The overlap in the clusters identified in the current analysis with previous work highlights the importance of co-occurring pain and pain impact factors. The relationship between those with the lowest pain and psychological distress with high physical functioning and higher employment status is a novel addition to the literature. It may be that the identified classes could be used in a clinical context to highlight those most in need of critical pain care and the importance of a personalized approach to pain management. They may also indicate the type of intervention that may be most useful, as a multidisciplinary approach to lessen pain with a focus on psychological distress may be warranted most for those in the high pain severity and pain impact class.

Data Sharing Statement

The deidentified datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

Acknowledgments

We would like to acknowledge Dr Chao Hsing Yeh for conceptualizing the parent study and for her enduring dedication to this work. She passed away after study recruitment was completed for this study, and it is our hope that we have honored her memory.

Funding

This work was funded by the National Institutes of Health NIA R01AG056587 (PI: Yeh), NINDS T32NS070201 (KRH), and K24AR081143 (CMC). Please note that the funders were not involved in the development of this research project or in the dissemination of results.

Disclosure

The authors report no conflicts of interest in this work.

References

1. Wu A, March L, Zheng X, et al. Global low back pain prevalence and years lived with disability from 1990 to 2017: estimates from the Global Burden of Disease Study 2017. Ann Translat Med. 2020;8(6):299. doi:10.21037/atm.2020.02.175

2. Yong RJ, Mullins PM, Bhattacharyya N. Prevalence of chronic pain among adults in the United States. Pain. 2022;163(2):e328–e332. doi:10.1097/j.pain.0000000000002291

3. Rubin DI. Epidemiology and risk factors for spine pain. Neurol Clin. 2007;25(2):353–371. doi:10.1016/j.ncl.2007.01.004

4. Hoy D, March L, Brooks P, et al. Measuring the global burden of low back pain. Best Pract Res Clin Rheumatol. 2010;24(2):155–165. doi:10.1016/j.berh.2009.11.002

5. Dale R, Stacey B. Multimodal treatment of chronic pain. Med Clin North Am. 2016;100(1):55–64. doi:10.1016/j.mcna.2015.08.012

6. Edwards RR, Dworkin RH, Turk DC, et al. Patient phenotyping in clinical trials of chronic pain treatments: IMMPACT recommendations. Pain Rep. 2021;6(1):e899. doi:10.1097/PR9.0000000000000896

7. Obbarius A, Fischer F, Liegl G, et al. A step towards a better understanding of pain phenotypes: latent class analysis in chronic pain patients receiving multimodal inpatient treatment. JPR. 2020;13:1023–1038. doi:10.2147/JPR.S223092

8. Foster NE, Hill JC, O’Sullivan P, Hancock M. Stratified models of care. Best Pract Res Clin Rheumatol. 2013;27(5):649–661. doi:10.1016/j.berh.2013.10.005

9. Sowden G, Hill JC, Morso L, Louw Q, Foster NE. Advancing practice for back pain through stratified care (STarT Back). Braz J Phys Ther. 2018;22(4):255–264. doi:10.1016/j.bjpt.2018.06.003

10. Mori M, Krumholz HM, Allore HG. Using latent class analysis to identify hidden clinical phenotypes. JAMA. 2020;324(7):700–701. doi:10.1001/jama.2020.2278

11. Yeh CH, Li C, Glick R, et al. A prospective randomized controlled study of auricular point acupressure to manage chronic low back pain in older adults: study protocol. Trials. 2020;21(1):99. doi:10.1186/s13063-019-4016-x

12. Lukkahatai N, Chen W, Kawi J, et al. Baseline predictors of responders to auricular point acupressure in chronic low back pain. Clin Trad Med Pharm. 2025;6(2):200215. doi:10.1016/j.ctmp.2025.200215

13. Kawi J, Yeh CH, Lukkahatai N, et al. Auricular point acupressure for older adults with chronic low back pain: a randomized controlled trial. Pain Med. 2025:pnaf035. doi:10.1093/pm/pnaf035

14. Freynhagen R, Baron R, Gockel U, Tölle TR. painDETECT: a new screening questionnaire to identify neuropathic components in patients with back pain. Curr Med Res Opin. 2006;22(10):1911–1920. doi:10.1185/030079906X132488

15. Hanish AE, Lin-Dyken DC, Han JC. PROMIS sleep disturbance and sleep-related impairment in adolescents: examining psychometrics using self-report and actigraphy. Nurs Res. 2017;66(3):246–251. doi:10.1097/NNR.0000000000000217

16. Pilkonis PA, Choi SW, Reise SP, Stover AM, Riley WT, Cella D. Item banks for measuring emotional distress from the patient-reported outcomes measurement information system (PROMIS^®): depression, anxiety, and anger. Assessment. 2011;18(3):263–283. doi:10.1177/1073191111411667

17. Cella D, Lai JS, Jensen SE, et al. PROMIS Fatigue item bank had clinical validity across diverse chronic conditions. J Clin Epidemiol. 2016;73:128–134. doi:10.1016/j.jclinepi.2015.08.037

18. Sullivan MJL, Bishop SR, Pivik J. The pain catastrophizing scale: development and validation. Psychol Assess. 1995;7(4):524–532. doi:10.1037/1040-3590.7.4.524

19. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373–383. doi:10.1016/0021-9681(87)90171-8

20. Roland M, Morris R. A study of the natural history of back pain: part I: development of a reliable and sensitive measure of disability in low-back pain. Spine. 1983;8(2):141. doi:10.1097/00007632-198303000-00004

21. Jensen RE, Potosky AL, Reeve BB, et al. Validation of the PROMIS physical function measures in a diverse U.S. population-based cohort of cancer patients. Qual Life Res. 2015;24(10):2333–2344. doi:10.1007/s11136-015-0992-9

22. Waddell G, Newton M, Henderson I, Somerville D, Main CJ. A Fear-Avoidance Beliefs Questionnaire (FABQ) and the role of fear-avoidance beliefs in chronic low back pain and disability. Pain. 1993;52(2):157–168. doi:10.1016/0304-3959(93)90127-B

23. Cella D, Riley W, Stone A, et al. The Patient-Reported Outcomes Measurement Information System (PROMIS) developed and tested its first wave of adult self-reported health outcome item banks: 2005–2008. J Clin Epidemiol. 2010;63(11):1179–1194. doi:10.1016/j.jclinepi.2010.04.011

24. Lazarsfeld PF, Henry NW. Latent Structure Analysis. Houghton, Mifflin; 1968. Available from: http://www.gbv.de/dms/hbz/toc/ht000685628.pdf. Accessed September 21, 2023.

25. Nasserinejad K, van Rosmalen J, de Kort W, Lesaffre E. Comparison of criteria for choosing the number of classes in Bayesian finite mixture models. PLoS One. 2017;12(1):e0168838. doi:10.1371/journal.pone.0168838

26. Scrucca L, Fop M, Murphy TB, Raftery AE. mclust 5: Clustering, classification and density estimation using Gaussian finite mixture models. R J. 2016;8(1):289–317. doi:10.32614/RJ-2016-021

27. Meisingset I, Vasseljen O, Vøllestad NK, et al. Novel approach towards musculoskeletal phenotypes. Eur J Pain. 2020;24(5):921–932. doi:10.1002/ejp.1541

28. Grant RW, McCloskey J, Hatfield M, et al. Use of latent class analysis and k-means clustering to identify complex patient profiles. JAMA Network Open. 2020;3(12):e2029068. doi:10.1001/jamanetworkopen.2020.29068

29. Husak AJ, Bair MJ. Chronic pain and sleep disturbances: a pragmatic review of their relationships, comorbidities, and treatments. Pain Med. 2020;21(6):1142–1152. doi:10.1093/pm/pnz343

30. Fullen B, Morlion B, Linton SJ, et al. Management of chronic low back pain and the impact on patients’ personal and professional lives: results from an international patient survey. Pain Pract. 2022;22(4):463–477. doi:10.1111/papr.13103

31. Jurak I, Delaš K, Erjavec L, Stare J, Locatelli I. Effects of multidisciplinary biopsychosocial rehabilitation on short-term pain and disability in chronic low back pain: a systematic review with network meta-analysis. J Clin Med. 2023;12(23):7489. doi:10.3390/jcm12237489

32. Ochsenkuehn FR, Crispin A, Weigl MB. Chronic low back pain: a prospective study with 4 to 15 years follow-up after a multidisciplinary biopsychosocial rehabilitation program. BMC Musculoskelet Disord. 2022;23(1):977. doi:10.1186/s12891-022-05963-w

33. Carlesso LC, Tousignant-Laflamme Y, Shaw W, Larivière C, Choinière M. Exploring pain phenotypes in workers with chronic low back pain: application of IMMPACT recommendations. Can J Pain. 2021;5(1):43–55. doi:10.1080/24740527.2020.1870103

34. Weller BE, Bowen NK, Faubert SJ. Latent class analysis: a guide to best practice. J Black Psychol. 2020;46(4):287–311. doi:10.1177/0095798420930932

35. Tanner JJ, Hanchate S, Price CC, et al. Relationships between chronic pain stage, cognition, temporal lobe cortex, and sociodemographic variables. J Alzheimers Dis. 2021;80:24. doi:10.3233/JAD-201345

Introduction

Ulcerative colitis (UC), a form of inflammatory bowel disease (IBD), is characterized by inflammation and ulceration predominantly affecting the rectum and colon, although in extensive disease, backwash ileitis may involve the terminal ileum.¹ The clinical manifestation often includes bloody diarrhea, which may be accompanied by additional gastrointestinal symptoms, signs of systemic inflammation, and extra-intestinal complications like sclerosing cholangitis or arthritis. In the past twenty years, UC has increasingly posed a global health concern worldwide, reflecting dynamic changes in its epidemiological landscape.² From 2010 to 2019, Japan experienced a notable rise in the annual prevalence per 100,000 individuals, climbing from 5 to 98. Simultaneously, the prevalence in the US rose from 158 to 233. Although the incidence of UC seems to have plateaued among various age groups in the United States, incidence rates among pediatrics and adolescents are still rising.³

The causes of UC are multifaceted, involving a diverse interplay among environmental, genetic, immune, and microbial contributions.¹ Numerous loci tied to a heightened susceptibility to UC have been pinpointed via genome-wide association research, indicating the involvement of genes related to cytokine signaling, microbial recognition, lymphocyte signaling, and autophagy.⁴ The consumption of a diet and specific lifestyle factors are related to a greater risk of developing UC, possibly mediated by affecting the microbiome and triggering immune responses to antigens. Although the specific cause is yet to be determined, critical pathogenic mechanisms encompass abnormalities in the intestinal barrier, abnormal immune activity, the secretion of inflammatory mediators, and imbalances within the gut microbiota.⁵ In this review, the term “intestinal barrier” is used to broadly refer to the epithelial lining, mucus layer, and immune-microbiota interface. “Epithelial barrier” or “mucosal barrier” are reserved for specific structural or functional contexts to ensure terminological clarity. Individuals with UC frequently exhibit disruptions in their intestinal barrier, notably with a lack of colonic goblet cells and an augmented permeability of the mucus layer. In UC, the immune system may be overactive, leading to an intensified inflammatory response. Chronic inflammation associated with UC may be attributed to immune dysregulation caused by T-cell-mediated processes, cytokines, and additional inflammatory cell populations.⁶ In UC, the inflamed mucosal tissue releases elevated levels of inflammatory mediators, like chemokines and cytokines, further aiding in the recruitment and stimulation of immune cells. These mediators potentiate the inflammatory response, thereby exacerbating mucosal injury and sustaining disease activity. Individuals suffering from UC frequently exhibit changes in their gut microbiome, marked by diminished microbial diversity and an overrepresentation of pro-inflammatory bacterial populations.⁷

The therapeutic options for UC have advanced significantly, providing a variety of treatments customized to the severity of the disease, its location, and the distinct responses.⁸ Conventional medications for UC, including corticosteroids, aminosalicylates, and immunosuppressants, are vital for alleviating symptoms and minimizing inflammation.⁹ Despite their benefits, these treatments frequently have restricted effectiveness and can lead to adverse effects, especially when used over extended periods. Therapies such as those targeting TNF, interleukins, and integrins represent biologics that have brought precision to UC treatment by selectively targeting immune pathways that drive inflammation.¹⁰ S1P receptor modulators and JAK inhibitors, as small molecule agents, have expanded treatment options, offering innovative solutions for those not responding to conventional approaches. Furthermore, FMT is considered a promising new treatment designed to restore the microbial balance within the gut, representing a forward-looking approach to managing UC that remains under rigorous investigation.¹¹

This review endeavors to provide a thorough assessment of UC by synthesizing recent progress in understanding its pathogenesis, diagnostic biomarkers, and therapeutic interventions. By systematically distinguishing conventional and emerging management strategies—including biologics, small molecules, and microbiota-directed therapies—we aim to clarify their mechanistic underpinnings and clinical implications. By analyzing both conventional and cutting-edge methods for managing UC, this review aims to provide insights for clinical practice and inform future research, ultimately enhancing outcomes for affected individuals. Special attention is given to combination approaches and precision strategies, addressing ongoing unmet needs in treatment resistance and disease monitoring. Recent mechanistic advances have highlighted critical issues such as anti-TNF treatment resistance, with emerging insights into immune dysregulation and adaptive immune response mechanisms contributing to therapeutic failure. Additionally, the use of biomarkers for long-term disease monitoring remains limited by challenges in specificity, sensitivity, and their inability to predict treatment outcomes over extended periods. Beyond the gut lumen, UC frequently presents with extra-intestinal manifestations (EIM) that significantly impact patient quality of life. Musculoskeletal involvement is the most common EIM, manifesting as peripheral arthritis, axial spondyloarthropathy, or enthesitis. Enteropathic arthritis affects an estimated 10–25% of IBD patients and often parallels intestinal disease activity. A recent single-center study reported that 20% of IBD cases developed arthritis, underscoring the need to integrate rheumatologic management into comprehensive care strategies.¹² These gaps underscore the need for comprehensive research into more effective strategies for managing UC and tailoring personalized therapies.

In summary, the onset of UC involves the interplay of environmental, genetic, immunological, and microbial factors. Unlike previous reviews that summarize treatment mechanisms, our manuscript offers a translational synthesis with clinical decision tools integrating multi-omics stratification and phenotypic tailoring for UC. The next section will contextualize these factors within a unified conceptual framework, highlighting how barrier dysfunction and immune dysregulation sustain chronic mucosal inflammation.

Pathogenesis of UC: Barrier Disruption, Immune Dysregulation, Cytokine Networks, and Microbiome Imbalance

UC arises from a self-amplifying inflammatory loop comprising epithelial barrier defects, immune cell infiltration, dysregulated cytokine networks, and gut microbiota imbalance. These interconnected processes form the conceptual backbone for understanding disease onset, progression, and therapeutic targeting. UC is characterized by a complex pathogenesis, making it difficult to grasp.¹³ Epithelial barrier defects, immune dysfunction, and microbial imbalance are fundamental in the onset and continuation of inflammation.⁴

Intestinal Barriers Defects

The compromise of the intestinal barrier is fundamental to the onset of UC, which results in immune imbalance and prolonged inflammation.⁵ Under healthy conditions, epithelial cells in the gut establish a shield against antigens and pathogens, which is upheld by mucin and tight junctions. In UC, the weakened barrier, resulting from epithelial cell damage, allows more antigens and pathogens to breach the lamina propria, where they engage with immune cells, triggering their activation.¹⁴ The activated immune cells subsequently secrete pro-inflammatory cytokines, further aggravating inflammation and inducing damage to epithelial cells. The damaged epithelial barrier allows antigens to infiltrate and further intensifies inflammation, creating a destructive cycle.⁶ In individuals with UC, impaired goblet cell function results in lower mucin-2 production, causing a weakened mucus layer with decreased protective function. The diminished mucus layer results in enhanced bacterial translocation, initiating immune responses and aggravating inflammation. In UC, tight junction modifications, particularly involving the claudin-2 upregulation, heighten paracellular permeability, promoting the infiltration of antigens, toxins, and bacteria into the lamina propria.¹⁵ The disrupted expression of claudin and other tight junction proteins result in a compromised barrier function in UC. Heightened permeability, driven by epithelial barrier damage, reduced mucus protection, and disrupted tight junctions, permits pathogens to breach the gut epithelium. This provokes an immune reaction, stimulating the liberation of pro-inflammatory cytokines and the initiation of inflammatory processes.

Dysregulated Immune Responses

In UC, immune cell infiltration within the colonic mucosa is a key factor in maintaining inflammation.⁶ In the course of UC, neutrophils are drawn to the injured regions of the colonic mucosa by chemotactic signals like chemokines and cytokines.¹⁶ Once recruited, these neutrophils secrete proteolytic enzymes, reactive oxygen species, and cytotoxic molecules that can intensify mucosal damage. In addition, neutrophils also produce neutrophil extracellular traps that assist in entrapping and eliminating pathogens in inflamed tissues, but these neutrophil extracellular traps may worsen tissue damage and trigger further inflammation.¹⁷ In a well-functioning gut, dendritic cells and macrophages can facilitate the production of Tregs, which are crucial for sustaining immune balance and controlling inflammation. The impairment of antigen-presenting cells in UC hampers Treg differentiation, causing a decrease in Treg levels and weaker inflammatory control. In UC, T cell migration to the gut is driven by the interaction between α4β7 integrin on T cells and MAdCAM-1, and targeting this binding can lessen lymphocyte trafficking. In UC, Th2 cells within the gut can facilitate NKT cell activation, boosting inflammation.¹⁸ The disruption of regulatory and effector T cells fuels chronic inflammation, causing sustained epithelial damage.

Release of Inflammatory Mediators

In UC, the chronic inflammation and tissue damage are largely attributed to the discharge of inflammatory molecules like chemokines, cytokines, and proteases. These molecules boost the recruitment of immune cells, sustain the inflammatory process, and weaken the intestinal mucosal structure. In individuals with UC, the intestinal tissues exhibit elevated levels of IL-1β, IL-6, TNF-α, and cytokines linked to Th1, Th2, and Th17 cells.¹⁹ Among these subsets, Th17 cells and the upstream IL-23 signaling axis play a pathogenic role in sustaining mucosal inflammation. IL-23 drives the expansion and activation of Th17 cells, which secrete IL-17A, IL-21, and IL-22, thereby amplifying epithelial barrier disruption and neutrophil recruitment. Targeted biologics such as mirikizumab and risankizumab have demonstrated clinical benefit by interrupting this IL-23/Th17 pathway, reducing cytokine output and promoting mucosal healing in refractory UC cases. TNF-α can attract immune cells, trigger cytokine activation, and cause epithelial cell apoptosis and tight junction disruption. Its high levels in the colonic mucosa cause mucosal injury and increased permeability. Cytokines like IL-13 and IL-17 impair the repair processes of epithelial cells, leading to persistent mucosal damage.²⁰ IL-13 promotes epithelial cell apoptosis and disrupts tight junction integrity, thereby weakening the intestinal barrier and intensifying mucosal inflammation. IL-6 and IL-1β are pivotal mediators that drive the stimulation of macrophages and T cells, while also triggering the acute inflammatory response that intensifies inflammatory reactions.²¹ IL-8 draws lymphocytes and neutrophils into the inflamed mucosal tissue, where their presence perpetuates the inflammation by producing chemokines and cytokines. The infiltrating leukocytes cause further damage to the intestinal barrier, driving inflammation and heightening the immune reaction. Protease-mediated enzymatic breakdown of tissue weakens the intestinal barrier, enabling further antigen penetration and prolonging inflammation. In addition to injuring the mucosa, protease activity can disrupt the stability of the intestinal barrier.¹³ Moreover, the degradation of tight junction proteins and the extracellular matrix raises permeability, allowing additional antigens to infiltrate the intestinal barrier. By triggering signaling cascades like NF-κB and JAK/STAT, pro-inflammatory cytokines induce further release of inflammatory molecules, fueling immune cell activity and intensifying colonic tissue damage. Recent studies have demonstrated that excessive ROS accumulation in inflamed intestinal regions disrupts epithelial tight junctions and compromises barrier integrity, thereby exacerbating mucosal injury in UC. Innovative redox-responsive nanomaterials—such as boronate esters, polydopamine, and metal nanozymes—have shown promise in selectively neutralizing ROS and delivering anti-inflammatory agents to affected sites. Wan et al proposed a layered programmable delivery strategy combining ROS-, pH-, and membrane-targeted nanoparticles, offering enhanced precision and multifunctionality for localized UC therapy.²²

Imbalance in the Gut Microbiota

Maintaining intestinal homeostasis fundamentally depends on a properly functioning gut microbiota. Its disturbance significantly contributes to the onset of UC by altering immune balance, impairing nutrient digestion, and compromising the intestinal barrier’s protective function.²³ UC may advance as a result of shifts in gut microbiota that undermine the gut’s defenses and enhance inflammatory processes. The stability of the intestinal barrier is largely influenced by gut microbiota, which assists in mucin formation and tight junction control. Changes in microbial composition compromise this defense, heightening the permeability of the epithelial layer and permitting increased pathogen and antigen penetration, further triggering immune responses and promoting chronic inflammation. Individuals suffering from UC experience a notable decrease in the Bacteroidetes and Firmicutes phyla, which are crucial for gut health.²⁴ These phyla not only regulate immune functions but also generate butyrate, vital for upholding the barrier of the intestinal epithelium. Individuals with UC exhibit a substantial reduction in the levels of Roseburia hominis and Faecalibacterium prausnitzii, which can possess anti-inflammatory characteristics and aid in epithelial health by nourishing colonocytes, reinforcing tight junctions, and decreasing mucosal permeability.²⁵ A decrease in these bacteria impairs the gut barrier, permitting pathogens and antigens to invade and worsen immune activation. Reduced levels of beneficial bacteria, which encourages Treg differentiation, cause the immune system to lean towards inflammatory Th2 and Th17 cells, leading to heightened production of IL-13 and IL-17, thus contributing to inflammation and mucosal damage. In addition, UC frequently involves an elevation of Enterobacteriaceae and Proteobacteria, which can stimulate immune responses and drive inflammation through lipopolysaccharide secretion.²⁶ The released lipopolysaccharide can stimulate Toll-like receptors (TLRs) on immune cells, triggering the production of cytokines and chemokines, boosting immune cell recruitment to the inflamed area, and prolonging inflammation and tissue injury.²⁷ The resulting dysregulated immune response amplifies the inflammatory dysregulation in the gut, contributing to increased mucosal damage and inflammation.

Overall, barrier impairment, immune cell infiltration, cytokine storms, and microbial imbalance create a self-amplifying inflammatory loop, laying the theoretical groundwork for biomarker-driven and precision-therapy strategies.

Emerging Diagnostic & Prognostic Biomarkers in UC

In UC diagnosis and monitoring, biomarkers ranging from serum CRP and fecal calprotectin to αvβ6 autoantibodies, multi-bacterial panels, and metabolomic signatures are collectively enhancing precision. Investigating biomarkers in UC is highly significant due to their potential to aid diagnosis, enable noninvasive tracking of histological and endoscopic changes, predict disease severity, and forecast treatment outcomes or drug side effects.²⁸ While serum C-reactive protein (CRP) and fecal calprotectin are the primary markers available for assessing UC activity, their lack of specificity limits their reliability for mid and long-term prognostic assessments. CRP levels may rise, but their sensitivity is constrained, particularly in mild and moderate UC cases. Faecal calprotectin has higher sensitivity than serum markers but low specificity.²⁹ For UC individuals in symptomatic remission, a monitoring framework incorporating both biomarkers and symptoms offers significant advantages over strategies based exclusively on symptoms. UC individuals can benefit from the use of serum CRP, fecal calprotectin, and fecal lactoferrin, which contribute significantly to disease surveillance and treatment strategies.^1,29

In UC, levels of faecal myeloperoxidase were strongly linked to endoscopic activity and were an efficient predictor of disease status. Moreover, a faecal myeloperoxidase concentration exceeding 26 µg/g at baseline was a significant predictor of a 12-month composite endpoint, which comprised intensification of immunomodulator or biologic treatment in response to surgical procedures, hospitalization linked to IBD, steroid administration, and relapse.³⁰ Despite achieving endoscopic remission, patients suffering from IBD remain susceptible to relapse. In UC individuals undergoing endoscopic remission, epithelial neutrophils were associated with unfavorable outcomes (hazard ratio: 5.198, p=0.01). Furthermore, in UC, Claudin-2 levels were linked to endoscopic and histological activity and were indicative of disease outcomes.³¹ UC individuals exhibit a considerable upregulation of integrin αvβ6 in the intestinal epithelium, and serum αvβ6 autoantibodies are being explored as a candidate diagnostic indicator. The sensitivity and specificity of serum αvβ6 autoantibodies were recorded at 0.82 and 0.94, respectively, with an AUC of 0.96. Furthermore, serum αvβ6 autoantibodies exhibited a specificity of 0.96 for distinguishing UC from healthy subjects, 0.88 from non-inflammatory bowel conditions, and 0.80 from Crohn’s disease.³² Anti-integrin αvβ6 antibodies were present in 92.0% of UC individuals, but just 5.2% of the control group exhibited positivity, yielding a diagnostic sensitivity of 92.0% and specificity of 94.8%.³³ Furthermore, anti-αvβ6 autoantibody levels were markedly elevated in those who were diagnosed with UC up to a decade before diagnosis, and these antibodies were linked to poor disease outcomes.³⁴ Lipid imbalance, with a marked reduction in phosphatidylcholines and triglycerides, was commonly reflected in individuals with UC. Elevated levels of phosphatidylcholine 34:1 (PC34:1) are prevalent in individuals with UC, indicating that disruptions in lipid metabolism contribute to the inflammation associated with the disease.³⁵ Faecal metabolome signatures are increasingly viewed as a promising avenue for identifying UC biomarkers, offering insights for diagnosis, behavior prediction, and treatment outcome forecasting. The faecal metabolome in IBD individuals reveals shifts in metabolites like tryptophan, sphingolipids, short-chain fatty acids, and vitamins. Notably, the presence of proteolytic fermentation byproducts is significantly heightened in individuals with UC.³⁶ The elevation of sphingolipid lactosyl-N-palmitoylsphingosine and the reduction of faecal L-urobilin were significant indicators of IBD, and the sphingolipid to L-urobilin ratio was able to distinguish IBD samples from non-IBD ones, achieving an AUC of 0.85.³⁷ In UC research, genome-wide association studies have made considerable strides, particularly in pinpointing genetic markers and unraveling genetic pathways. Multiple genetic loci linked to UC susceptibility have been pinpointed, especially within the chromosome 6 region involving the major histocompatibility complex. The severity of UC was significantly associated with a locus in the HLA region of chromosome 6, reflected by an odds ratio (OR) of 2.23 (P=4.22×10⁻⁹). Moreover, HLA-DRB1*01:03 was identified as a genetic marker linked to severe UC in contrast to milder disease presentations among affected individuals.³⁸ A total of ten bacterial species were incorporated into diagnostic models to diagnose UC, achieving an AUC of 0.85, which was slightly higher than the AUC of 0.81 for fecal calprotectin. The multibacterial panel exhibited enhanced sensitivity (67%) and specificity (88%) for UC, outperforming fecal calprotectin, which had sensitivities of 57% and specificities of 86%. Moreover, the diagnostic model achieved an AUC of 0.78 in separating UC individuals from those without IBD, confirming the specificity of the multibacterial panel for UC. Furthermore, this panel displayed better performance than fecal calprotectin in distinguishing inactive UC from controls, with an AUC of 0.78 compared to 0.56.³⁹ The use of metabolic, glycomic, transcriptomic, and proteomic panels may enhance the accuracy of prognostic indicators for UC severity. Recent multi-omic studies, such as Scanu et al (2024), have demonstrated that integrated bacterial, fungal, and metabolic profiles can distinguish UC patients from healthy controls and identify disease-associated biomarkers. Nevertheless, their clinical application is hindered by the complicated framework of the forecasting models.⁴⁰ Significant challenges in using biomarkers for UC diagnosis encompass the necessity for standardized testing, the variability of biomarker expression across individuals, and the difficulties in incorporating biomarker data into clinical settings. Ongoing studies strive to improve current biomarkers and unveil new candidates to advance diagnostic approaches. Figure 1 summarizes the biomarker-diagnostic tool linkage and Table 1 summarizes representative biomarkers categorized by type, target, clinical relevance, and diagnostic accuracy parameters.

Table 1 Diagnostic & Prognostic Biomarkers in UC

Figure 1 Biomarkers and diagnostic tools in UC.

While traditional biomarkers remain effective for activity monitoring, multi-omics and microbiome-based models promise greater specificity and long-term prognostic power, providing a stronger foundation for personalized therapy.

Conventional Pharmacotherapy: Aminosalicylates, Corticosteroids, and Immunomodulators in UC

This section provides an overview of first- and second-line conventional treatments, detailing their mechanisms of action, clinical efficacy, and major adverse effects. UC represents a persistent, relapsing IBD, distinguished by inflammation and ulcerative lesions in the colon and rectum. Currently, the principal pharmacological options for UC encompass aminosalicylates, corticosteroids, immunosuppressants, and antibiotics.⁴¹ Aminosalicylates, especially 5-aminosalicylic acid (5-ASA), and its analogs, constitute fundamental treatments for individuals suffering from mild to moderate disease, applicable for induction and maintenance treatment.⁴² Pharmaceuticals such as sulfasalazine, olsalazine, balsalazide, and mesalamine exert their therapeutic effects by influencing the intestinal mucosa and blocking the synthesis of inflammatory mediators to mitigate inflammation and its related clinical manifestations. 5-ASA acid exerts its effects by blocking the cyclooxygenase and lipoxygenase pathways, resulting in lower levels of pro-inflammatory mediators. Furthermore, 5-ASA stimulates the activity of PPAR-γ, which subsequently reduces the expression of inflammatory cytokines. Despite the advent of biologics, aminosalicylates continue to be the preferred first-line treatment for mild UC and should be taken into account for moderate cases, given their advantageous risk-benefit ratio.⁴³ 5-ASA can be utilized in moderate individuals lacking poor prognostic indicators, whereas biologics can be favored in other cases.⁴⁴ Corticosteroids are widely utilized as a treatment modality for attaining remission in individuals suffering from moderate to severe disease. Prednisone, budesonide, and hydrocortisone are frequently used corticosteroids that deliver rapid relief of inflammation and symptoms due to their potent anti-inflammatory properties. While corticosteroids can greatly enhance a patient’s condition in the short term, prolonged use may result in several side effects, including osteoporosis, weight gain, and an elevated risk of infections. Between 2006 and 2023, prescriptions for prednisolone showed a downward trend, while those for budesonide experienced an uptick. Nonetheless, cumulative corticosteroid exposure among those with IBD persists at a significant level.⁴⁵ In a Phase IV trial (NCT01941589), corticosteroids plus mesalamine failed to provide additional advantages for hospitalized individuals suffering from acute severe disease beyond corticosteroids alone.⁴⁶ Immunosuppressants represent a crucial treatment alternative for sustaining remission, especially for individuals reliant on corticosteroids or those who have shown insufficient response to 5-ASA treatments. Thiopurines like azathioprine, mercaptopurine, and cyclosporine alleviate inflammation through the suppression of excessive immune system activity.⁴⁷ These agents are proficient in controlling symptoms and sustaining remission over a prolonged duration.^48–50 Nonetheless, nearly 40% of individuals are forced to halt thiopurine therapy because of unwanted side effects. Mercaptopurine dosing based on therapeutic drug monitoring is deemed the preferred method for managing UC in individuals who are on thiopurines.⁵¹ The administration of azathioprine is often limited by gastrointestinal intolerance in IBD, with 32.6% of individuals experiencing this adverse effect. Among those who were intolerant to azathioprine, 50% of individuals did not suffer from a resurgence of gastrointestinal intolerance following rechallenge with reduced dosages. Of the 15 individuals who were intolerant to reduced azathioprine doses, 36% showed tolerance after switching to mercaptopurine.⁵² Antibiotics can serve as an adjunctive treatment option, particularly in instances where complications arise from infections. While not considered primary therapy for UC, antibiotics like metronidazole and ciprofloxacin can effectively control secondary infections.

Although these agents are effective in mild to moderate cases, their limited efficacy and notable side effects underscore the need for more targeted biologics and small molecules to fill therapeutic gaps.

Biologic Agents Targeting TNF-α, IL-12/23, and Integrin Pathways in UC

Biological therapies are gaining prominence for managing moderate to severe UC, particularly for individuals who fail to achieve satisfactory results with aminosalicylates or corticosteroids.⁴² The biologics for treating UC can be categorized into three primary types: anti-TNF therapies, including certolizumab, infliximab, golimumab, and adalimumab; anti-integrin drugs like natalizumab, vedolizumab, and etrolizumab; and anti-interleukin medications including mirikizumab, risankizumab, guselkumab, ustekinumab, and brazikumab.⁵³ In comparative studies, vedolizumab outperformed adalimumab in the VARSITY trial, achieving higher histologic remission at Week 14 (24% vs 12%) and Week 52 (45% vs 33%), with superior mucosal healing at Week 52. The SERENE-UC exposure-response analysis demonstrated lower serious infection rates with standard-dose versus intensified adalimumab during maintenance. Long-term LTE data show risankizumab and mirikizumab yield similar remission rates (~ 40%), whereas risankizumab has fewer injection-site reactions. Sequencing strategies—such as anti-TNF followed by anti-integrin versus anti-IL-23 agents, or JAK inhibitors post–anti-TNF failure—should be tailored according to patient phenotype and biomarker profile.⁵⁴

Anti-TNF Agents

A monoclonal antibody, infliximab is employed as a biological treatment for UC, targeting TNF-α, a cytokine critical to the immune mechanisms of the disease. Infliximab is prescribed for moderate to severe UC, particularly when standard treatments like corticosteroids or 5-ASA compounds prove ineffective.⁵⁵ The shift from intravenous to subcutaneous infliximab supports long-term remission in individuals suffering from UC. To achieve clinical and biochemical remission, the recommended subcutaneous infliximab concentrations were 12.2 μg/mL by week 12 and 13.2 μg/mL by week 52.⁵⁶ Elevated subcutaneous infliximab concentrations are linked to superior treatment results in individuals suffering from IBD, particularly when serum levels exceed 20 µg/mL.⁵⁷ In the Phase III LIBERTY-UC study (NCT04205643), individuals with UC who received subcutaneous CT-P13 (an infliximab biosimilar) after intravenous CT-P13 induction had notably higher week 54 clinical remission rates than those given placebo (43.2% versus 20.8%).⁵⁸ Infliximab continues to serve as the cornerstone of rescue therapy, with its efficacy being closely tied to its pharmacokinetics.^59,60 Within the framework of rescue interventions for individuals with acute severe disease unresponsive to steroid treatment, both accelerated infliximab (OR: 0.16) and infliximab (OR: 0.2) led to a notable reduction in short-term colectomy rates when compared to placebo.⁶¹ In a phase IV PREDICT-UC trial (NCT02770040), individuals suffering from steroid-refractory acute severe disease exhibited similar clinical response at day 7, irrespective of whether they were given infliximab at 5 mg/kg or 10 mg/kg. Across the accelerated, intensified, and standard induction regimens, clinical responses by day 14, as well as the rates of remission and colectomy by month 3, remained largely unchanged.⁶² Infliximab and adalimumab both possess a favorable safety record and contribute to positive outcomes among individuals with moderate to severe disease.⁶³ The SERENE-UC trial (NCT02065622) conducted an exposure-response evaluation comparing elevated doses of adalimumab with standard dosing in individuals suffering from moderately to severely active disease. Although a temporary increase in the adalimumab failed to yield induction responses, higher dosing concentrations throughout the maintenance phase extending to week 52 resulted in more significant responses.⁶⁴ An analysis of the PURSUIT-M (NCT00488631) and PURSUIT-LTE (long-term extension) trials revealed that less than 5% of participants underwent colectomy following prolonged golimumab therapy, extending up to 4 years. Colectomy was primarily performed in individuals who failed to respond to induction therapy and continued with maintenance treatment. These individuals often exhibited more severe disease symptoms at the initial evaluation.⁶⁵ Those who encountered TNF therapy failure from either intolerance or delayed loss of response experienced favorable results by transitioning to a non-anti-TNF agent rather than opting for another anti-TNF option.⁶⁶

Anti-Interleukin Drugs

Anti-interleukin therapies in UC are a type of biologic agent that focuses on specific ILs contributing to the inflammatory mechanisms of the condition.⁵³ Ustekinumab can specifically inhibit IL-12 and IL-23, which are pivotal cytokines in modulating immune reactions and inflammatory processes. In the UNIFI LTE trial (NCT02407236), which assessed ustekinumab in individuals with UC over four years, 55.2% of participants achieved symptomatic remission by week 200. At this time point, 96.4% were free from corticosteroid use among those in remission. Among the 171 participants who received endoscopic assessments, endoscopic improvement was observed in 81.6% of the q12w cohort and 79.8% of the q8w cohort. Throughout the 4-year LTE period, nasopharyngitis, exacerbation of UC, and infections of the upper respiratory tract emerged as the most prevalent adverse reactions.⁶⁷ The UNIFI trial (NCT02407236) further revealed that week 2 clinical remission was linked to endoscopic remission and histological remission at week 52, indicating its role as a predictor of favorable results for individuals with UC undergoing ustekinumab treatment. Additionally, the prompt achievement of clinical remission is linked to an increased likelihood of endoscopic and histological remission.⁶⁸ Mirikizumab, a monoclonal antibody, selectively interacts with IL-23, a cytokine involved in the inflammatory pathways linked to UC. Mirikizumab has proven effectiveness in inducing (LUCENT-1; NCT03518086) and maintaining (LUCENT-2; NCT03524092) clinical remission in individuals suffering from moderately to severely active disease. In the induction trial, the mirikizumab group had notably greater clinical remission rates at week 12, achieving 24.2% compared to 13.3% in the control group. These results continued at week 40 of the maintenance trial, where remission rates were 49.9% versus 25.1%.⁶⁹ The effectiveness of mirikizumab in attaining and sustaining symptom control and overall symptom management was evidenced over 52 weeks.⁷⁰ In the Phase II clinical trial (NCT02589665), approximately 50% of participants who received extended mirikizumab doses for another 12 weeks after failing induction therapy achieved a clinical response, with a notable proportion maintaining this response for a duration of up to 52 weeks.⁷¹ Risankizumab specifically targets IL-23, preventing it from binding to its receptor. This mechanism directly disrupts the IL-23/Th17 inflammatory circuit described earlier in the pathogenesis section, mitigating downstream cytokine release and epithelial injury. Risankizumab demonstrated marked enhancements in clinical remission rates during both the induction study (NCT03398148) and the maintenance study (NCT03398135) among individuals experiencing moderately to severely active disease. In the NCT03398148 trial, the clinical remission rates observed by week 12 were 20.3% for individuals receiving risankizumab, compared to 6.2% in the placebo group. Meanwhile, in the NCT03398135 study, week 52 remission rates reached 40.2% for the 180 mg risankizumab dose, 37.6% for the 360 mg dose, and 25.1% for those given a placebo.⁷² The phase IIb QUASAR Induction study (NCT04033445) assessed the efficacy of guselkumab, an IL-23 inhibitor, in treating active disease among those who had insufficient responses or intolerance to prior therapies. At week 12, guselkumab exhibited enhanced clinical response rates of 61.4% for the 200 mg dose and 60.7% for the 400 mg dose, in contrast to the 27.6% rate seen with placebo. Of those who were nonresponders at week 12, 54.3% from the 200 mg cohort and 50.0% from the 400 mg cohort attained clinical response by week 24.⁷³ In the VEGA study (NCT03662542), guselkumab combined with golimumab showed superior effectiveness for UC compared to each treatment used alone, with week 12 clinical response rates of 83% for golimumab plus guselkumab, 75% for guselkumab, and 61% for golimumab.^74,75 In real-world practice, post-marketing observational data such as Gao et al⁷⁶ and non-industry retrospective analyses like Kim et al⁷⁷ corroborate the clinical trial findings, reporting drug survival rates exceeding 70% at 12 months and clinical response rates of 60–65% in routine care.

Anti-Integrin Agents

In managing UC, anti-integrin biologics are instrumental in controlling UC symptoms.⁵³ As a biologic that targets the α4β7 integrin, vedolizumab is utilized for managing moderate to severe disease. The VARSITY trial (NCT02497469) evaluated the effectiveness of intravenous vedolizumab compared to subcutaneous adalimumab in participants suffering from UC. At week 14 and week 52, vedolizumab achieved superior histologic remission rates compared to adalimumab among all participants. At week 52, patients receiving vedolizumab demonstrated superior rates of mucosal healing relative to those treated with adalimumab.⁵⁴ In the VEDOIBD (NCT03375424) study, the rate of clinical remission during induction therapy was 23% for individuals receiving vedolizumab, which was lower than the 30.4% observed among those receiving anti-TNF treatment. Following two years of treatment, individuals receiving vedolizumab showed a significant improvement in clinical remission rates, achieving 43.2%, while those on anti-TNF therapies had a rate of 25.8%.⁷⁸ Over 5 years, vedolizumab has higher effectiveness than anti-TNF agents as a primary option for UC, even following the failure of infliximab and adalimumab.⁶⁶ In the phase IV ENTERPRET study (NCT03029143), it appears that individuals experiencing early nonresponse and elevated drug clearance may not necessitate dose optimization of vedolizumab. By week 30, 18.9% of individuals treated with standard vedolizumab exhibited endoscopic improvement, compared to 14.5% of those on dose-optimized vedolizumab. In the standard cohort, 9.4% of participants reached clinical remission, in contrast to 9.1% among the optimized cohort, with clinical responses noted in 32.1% and 30.9% of participants, respectively.⁷⁹ Etrolizumab is an anti-integrin biologic that specifically targets αEβ7 and α4β7 integrins. In the HICKORY trial (NCT02100696), etrolizumab led to higher remission rates at week 14 for individuals with moderately to severely active disease than placebo, with rates of 18.5% compared to 6.3% (p<0.005). Nonetheless, individuals showing a clinical response at week 14 displayed no notable distinctions in remission rates at week 66 across both groups (24.1% vs 20.2%, p=0.50). During the induction therapy, the predominant severe adverse reaction was a flare of UC, observed in 3% of individuals receiving etrolizumab and in 2% of those receiving placebo. During the maintenance therapy, appendicitis emerged as the predominant severe adverse reaction in individuals receiving etrolizumab, occurring in 2% of patients, while the placebo cohort reported UC flare (2%) and anemia (2%) as the predominant severe adverse reactions.⁸⁰ In the LAUREL trial (NCT02165215), maintenance etrolizumab (29.6%) showed no significant advantage over placebo (20.6%) regarding remission rates at week 62 for individuals who responded at week 10 (p=0.19).⁸¹ The HICKORY and LAUREL Phase 3 maintenance trials of etrolizumab failed to demonstrate non-inferiority versus placebo, highlighting the challenge of sustaining long-term remission with this agent. The HIBISCUS I (NCT02163759) and HIBISCUS II (NCT02171429) trials examined adalimumab, etrolizumab, and placebo for inducing remission among individuals suffering from moderate to severe disease. In the NCT02163759 trial, 19.4% of individuals treated with etrolizumab attained remission at week 10 compared to 6.9% with placebo (adjusted difference 12.3%, p=0.017), while in the NCT02171429 trial, remission rates were 18.2% and 11.1%, respectively (adjusted difference 7.2%, p=0.17). Moreover, etrolizumab did not outperform adalimumab for inducing remission, improving endoscopy results, achieving clinical response, or reaching histological or endoscopic remission. In the NCT02163759 study, 35% of participants receiving etrolizumab, 43% receiving adalimumab, and 36% receiving placebo experienced adverse events. For the NCT02171429 study, the corresponding rates were 44%, 43%, and 46%, respectively. UC flare was the most prevalent adverse reaction among all treatment cohorts.⁸² The GARDENIA trial (NCT02136069) assessed etrolizumab in comparison to infliximab in individuals with moderately to severely active disease. At week 54, 18.6% of individuals receiving etrolizumab and 19.7% of those on infliximab attained clinical response by week 10 and clinical remission by week 54.⁸³ In the NCT03531892 trial, AJM300, an α4-integrin inhibitor, was examined as a potential induction treatment for those suffering from moderately active disease. 45% of participants receiving AJM300 exhibited a clinical response at week 8, in contrast to 21% of those receiving placebo. After the 16-week extension phase, adverse reactions were noted in 39% of participants receiving placebo, compared to 38% in those administered AJM300.⁸⁴ Biologics substantially improve remission rates by precisely blocking immune pathways, yet primary nonresponse and loss of response remain challenges that small molecules may help address.

Membrane biomimetic nanocarriers—particularly those coated with macrophage membranes, epithelial-cell mimetics, or hybrid membrane materials—have emerged as promising platforms for targeted UC therapy. These structures exhibit enhanced biocompatibility, immune evasion, and site-specific accumulation in inflamed colonic tissues. Recent developments include multifunctional nanoparticle systems capable of mucosal adhesion, barrier penetration, and inflammation-triggered drug release. The emergence of targeted nanoparticles has revolutionized IBD treatment by enhancing the biological properties of drugs and promoting efficiency and safety. Lei P et al proposed a hierarchically programmed delivery modality that combines CMNs with pH, charge, ROS and ligand-modified responsive nanoparticles. This approach significantly improves delivery efficiency and points the way for future research in this area.⁸⁵

Small Molecule Therapies Modulating JAK/STAT and S1P Signaling in UC

Small molecule therapies in UC operate via distinct immunomodulatory mechanisms. JAK inhibitors, such as tofacitinib and upadacitinib, block intracellular cytokine signal transduction by targeting Janus kinases, thereby dampening multiple cytokine pathways including IL-2, IL-6, and IL-23. In contrast, S1P receptor modulators, exemplified by ozanimod, influence lymphocyte trafficking by sequestering immune cells in lymphoid tissues, reducing mucosal infiltration. Other agents—such as PDE4 inhibitors or calcineurin blockers—act on separate pathways, modulating transcriptional activity or T-cell activation. Table 2 summarizes these mechanistic distinctions along with comparative data on indications, efficacy, and safety profiles. These mechanistic differences underpin divergent clinical applications and risk profiles, which are increasingly informing personalized treatment selection in refractory UC.

Table 2 Comparison of UC Treatment Strategies

Janus Kinase Inhibitors

The JAK/STAT pathway, vital for mediating inflammatory signaling, is affected by JAK inhibitors.⁴² The JAK inhibitor tofacitinib predominantly targets JAK1 and JAK3 and also displays activity against JAK2. The OCTAVE trials established the use of tofacitinib for individuals with moderately to severely active UC. Among individuals in the induction studies, 52.2% who failed to demonstrate a clinical response following 8 weeks of tofacitinib attained a response through extended induction. At the 12-month point in the OCTAVE Open study, 70.3% of those identified as delayed responders continued to show a clinical response, with 44.6% attaining remission and 56.8% experiencing endoscopic improvement, whereas, at month 36, these rates were 56.1%, 52.0%, and 44.6%, respectively.⁸⁶ Tofacitinib is a promising option for managing acute severe UC, offering substantial short-term survival without colectomy in individuals who are refractory and deemed candidates for colectomy, with colectomy-free survival rates of 85% at 30 days, 86% at 3 months, and 69% at 6 months.⁸⁷ At week 8 of the ORCHID trial (CTRI/2021/10/037641), composite remission rates of 16.28% for tofacitinib and 8.57% for prednisolone in participants suffering from moderately active disease (OR: 2.07, p=0.31).⁸⁸ For those experiencing previous anti-TNF exposure, at weeks 12, 24, and 52, tofacitinib had a higher probability of inducing biochemical remission and corticosteroid-free clinical remission than vedolizumab.⁸⁹ In the TACOS study (ISRCTN42182437), combining tofacitinib with corticosteroids improved patient response and diminished the reliance on rescue treatment. At day 7, treatment response was noted in 83.01% of individuals receiving tofacitinib, in contrast to 58.82% of those receiving placebo (OR: 3.42, p=0.007), with the tofacitinib cohort showing a diminished necessity for rescue therapy (OR: 0.27, p=0.01).⁹⁰ Upadacitinib specifically targets JAK1, an important JAK/STAT pathway component that mediates inflammatory signals. The clinical effectiveness of upadacitinib as both induction and maintenance treatment for individuals with moderately to severely active disease was demonstrated in the U-ACHIEVE (NCT02819635) and U-ACCOMPLISH (NCT03653026) induction studies, as well as in the U-ACHIEVE maintenance study.⁹¹ Moreover, upadacitinib was evaluated at induction week 16 and maintenance week 52 for individuals participating in the NCT02819635 and NCT03653026 studies. Of the individuals receiving upadacitinib 45 mg, 19.2% failed to attain a clinical response by week 8 and were given an extra 8 weeks. At week 16, 59.1% of individuals attained a clinical response and participated in the NCT03653026 trial. At week 52, 26.5% of individuals taking 15 mg of upadacitinib reached clinical remission, while the rate was 43.6% for those on 30 mg.⁹² In the maintenance U-ACHIEVE trial (NCT02819635), 40.4% of individuals on 15 mg of upadacitinib and 53.6% on 30 mg attained clinical remission, whereas only 10.8% of the placebo group reached this outcome.⁹³ In a real-world experience with upadacitinib for UC, 76.0% of individuals exhibited a clinical response at 4 weeks, rising to 85.2% at 8 weeks, while clinical remission was attained by 69.2% at 4 weeks and 81.5% at 8 weeks. In individuals with prior tofacitinib treatment, 77.8% attained clinical remission by week 8.⁹⁴ Moreover, upadacitinib was linked to steroid-free clinical remission after 52 weeks in comparison to tofacitinib, with no notable discrepancies in terms of endoscopic response or remission.⁹⁵ In a real-world study, 40% of individuals receiving upadacitinib attained clinical remission following induction therapy, in contrast to 18% of those treated with tofacitinib (p=0.006).⁹⁶ Combination approaches—such as JAK inhibitors plus anti-integrin therapy—have yielded mixed results, with some studies showing additive benefits while others report no clear improvement over monotherapy. The effectiveness of filgotinib as an induction and maintenance treatment for individuals suffering from moderately to severely active disease was demonstrated in the SELECTION trial (NCT02914522).⁹⁷ The SELECTIONLTE trial (NCT02914535) indicated that filgotinib was effective over an approximate treatment duration of 4 years. In individuals administered filgotinib at 200 mg and 100 mg, 79.3% and 63.0% attained clinical remission by week 10, respectively, and experienced sustained benefits at week 58.⁹⁸ Moreover, clinical remission rates were recorded at 47%, 55.8%, and 64.6% for individuals at weeks 10, 26, and 58, respectively.⁹⁹ Another real-world study on filgotinib use for UC revealed clinical remission rates of 71.9% at week 12 and 76.4% at week 24. At week 12, 87.3% of individuals achieved biochemical remission, increasing to 88.9% at week 24. Following a median 42-week follow-up, 82.4% of participants continued on filgotinib. In 2.2% of cases, severe adverse reactions caused drug discontinuation, and moderate adverse effects occurred in 8.8% leading to a temporary interruption of therapy.¹⁰⁰ Ivarmacitinib, a JAK1 inhibitor, was investigated in the AMBER2 study (NCT03675477) involving individuals suffering from moderate to severe active disease. At week 8, those on ivarmacitinib showed significantly better clinical response and remission rates than participants receiving placebo. Treatment-emergent adverse reactions among individuals receiving ivarmacitinib ranged from 43.9% to 48.8%, compared to 39.0% among those on placebo.¹⁰¹

S1P Receptor Modulator

S1P receptor modulatory agents have attracted interest for their role in treating UCcolitis.¹⁰² The phase III True North study (NCT02435992) revealed that Ozanimod outperformed placebo in providing both induction and maintenance treatment for individuals suffering from moderately to severely active disease.¹⁰³ The TOUCHSTONE OLE study (NCT02531126) provided insights into ozanimod for individuals experiencing moderately to severely active disease over 4 years.¹⁰⁴ At both week 10 and week 52, individuals experiencing moderately to severely active disease and lacking previous exposure to advanced therapies exhibited notable improvements relative to the placebo group. Among participants on continuous ozanimod with clinical response at week 52, 91% sustained this response at week 94, with 74% exhibiting endoscopic improvement and 57% attaining mucosal healing. Of the individuals treated with ozanimod who failed to demonstrate a clinical response by week 10 and participated in the OLE study, 62% experienced a symptomatic response by OLE week 10.¹⁰⁵ At week 52 of the True North study (NCT02435992), 54% of individuals had attained corticosteroid-free remission. Corticosteroid-free remission, clinical remission, and clinical response at week 94 were observed in 91.4%, 69.1%, and 67.9% of individuals, respectively. Additionally, mucosal healing, histological remission, and endoscopic improvement were exhibited in 56.3%, 67.3%, and 73.3% of individuals, respectively.¹⁰⁶ Etrasimod, a selective S1P receptor agent, targets the S1P1, S1P4, and S1P5 receptors. In individuals with moderately to severely active disease participating in the OASIS trial (NCT02447302), etrasimod 2 mg yielded more significant clinical and endoscopic improvements than placebo.¹⁰⁷ Etrasimod significantly outperformed placebo in terms of histologic remission and endoscopic improvement in the NCT02447302 study. Those receiving etrasimod who attained clinical remission displayed significant reductions in fecal calprotectin and CRP levels at week 12.¹⁰⁸ Following the OASIS trial, 82% of participants became eligible for the OASIS OLE (NCT02536404) study, receiving etrasimod for as long as 52 weeks.¹⁰⁹ In the ELEVATE UC 52 trial (NCT03945188), etrasimod led to higher clinical remission rates than placebo at 12 weeks and week 52 in individuals experiencing moderately to severely active disease. Similarly, 25% of participants who were treated with etrasimod reached clinical remission at 12 weeks, in contrast to 15% of those who received a placebo in the ELEVATE UC 12 (NCT03996369) trial.¹¹⁰ In the ELEVATE UC study, etrasimod-treated individuals who achieved disease clearance at week 12 had a notably elevated clinical remission rate (73.9%) than those who did not (28.3%) at week 52. At week 12, improvements in histology and endoscopy noted were linked to clinical remission at week 52.¹¹¹ Among individuals receiving corticosteroid therapy at baseline in the ELEVATE UC study, at week 52, a markedly elevated rate among those treated with etrasimod (31.2%) reached a corticosteroid-free clinical response than the placebo cohort (7.1%).¹¹² Etrasimod outperformed placebo in effectiveness for both induction and maintenance treatment, irrespective of prior treatment with biologics or JAK inhibitors.¹¹³

Combination therapy strategies are increasingly explored for treatment-resistant UC. Dual biologic regimens—such as anti-TNF agents combined with anti-IL-23 biologics—have shown promise in overcoming partial responses. Additionally, co-administration of JAK inhibitors (eg, tofacitinib, upadacitinib) with anti-integrin agents has demonstrated clinical benefit in acute severe UC, particularly in patients refractory to infliximab. A recent editorial by Soldera et al (2024) highlights successful use of tofacitinib alongside infliximab, achieving sustained remission in refractory cases. These approaches represent a clinically important frontier and warrant further investigation in controlled trials.¹¹⁴ JAK inhibitors and S1P modulators are favored for their convenience and rapid efficacy, but long-term safety and tolerability require further follow-up data.

Fecal Microbiota Transplantation (FMT): Microbiome Restoration Strategies and Safety in UC

FMT is receiving growing attention as a novel therapeutic option for UC, wherein stool from a healthy individual is transferred to the patient’s gastrointestinal system.¹¹⁵ The process may restore the disrupted gut microbiota, which is crucial in chronic inflammation and immune imbalance. Although the detailed mechanism of FMT in UC has not been fully illuminated, the introduction of a diverse microbiome aids in reducing pro-inflammatory bacteria, promoting anti-inflammatory species, and modulating immune functions. Recent mechanistic studies have identified key microbial taxa and metabolites that influence clinical response to FMT. Species such as Roseburia inulivorans, Faecalibacterium prausnitzii, and Odoribacter splanchnicus produce butyrate and indole derivatives—known to enhance regulatory T-cell induction, support epithelial barrier integrity, and suppress pro-inflammatory cytokine production. In contrast, non-responders often exhibit enrichment of pathobionts such as Escherichia coli, Sutterella wadsworthensis, and elevated lipopolysaccharide synthesis, which activate TLRs and perpetuate inflammation. Furthermore, increased levels of beneficial fungal taxa like Lachancea thermotolerans and reduced abundance of Candida species are associated with better mucosal outcomes. These findings underscore the importance of microbial functional profiles in modulating mucosal immunity and determining FMT efficacy. Individuals with UC may experience remission as a result of FMT. The phase II study (NCT01896635) revealed that FMT facilitated an increase in microbial diversity and a shift in composition, as determined by the analysis of colon and fecal samples obtained both before and following the FMT intervention. Individuals undergoing FMT with Bacteroides in donor stool achieved remission, but individuals with Streptococcus species showed no response.¹¹⁶ In a preliminary study (ACTRN12613000236796) involving individuals suffering from mild to moderate disease, at eight weeks, a seven-day treatment involving anaerobically prepared donor FMT demonstrated greater efficacy in attaining remission than autologous FMT. Of those who attained steroid-free remission of UC at week eight following receiving donor FMT, 42% retained remission after a year. Three serious adverse events were recorded among participants receiving donor FMT and two among those receiving autologous FMT.¹¹⁷ In the trial (ACTRN 12619000611123), oral lyophilized FMT was assessed for its effectiveness in managing active UC. At week eight, 53% of the FMT participants achieved remission without corticosteroids and exhibited endoscopic improvement, compared to 15% in the placebo cohort. 67% of individuals who received FMT and 85% of those receiving placebo encountered adverse events, primarily consisting of mild gastrointestinal symptoms. Adverse events following FMT remain heterogeneous across trials: mild gastrointestinal symptoms are common, and serious events—although rare—have been documented, underscoring the importance of standardized safety monitoring. During the maintenance phase, ten participants receiving FMT demonstrated a response and were allocated to either persist with open-label FMT or discontinue treatment. At week 56, participants who remained on FMT attained histologic, endoscopic, and clinical remission, whereas none of those who discontinued FMT achieved this outcome.¹¹⁸ The trial (ISRCTN15475780) evaluated the effectiveness of multi-donor FMT combined with an anti-inflammatory diet for achieving remission and sustaining long-term maintenance through the diet. At eight weeks, FMT plus an anti-inflammatory diet proved more efficacy than standard medical therapy, yielding enhanced clinical outcomes. At 48 weeks, the anti-inflammatory diet showed a greater ability to maintain deep remission than standard medical treatment (25% vs 0%, p=0.007).¹¹⁹ In the NCT03426683 trial, 57.1% of individuals attained clinical remission, and 76.2% obtained a clinical response following 12 weeks of capsulized FMT. Individuals achieving remission post-FMT were enriched with Odoribacter splanchnicus and Alistipes sp., and had elevated indolelactic acid levels, while those not achieving remission had elevated biosynthesis of lipopolysaccharides and 12,13-dihydroxy-9Z-octadecenoic acid.¹²⁰ In a trial (NCT03426683), the most prevalent fungi identified in fecal specimens were Basidiomycota and Ascomycota, and the use of capsulized FMT enhanced the diversity of microbial fungi and reshaped their composition. In comparison to individuals who failed to reach remission, those who experienced remission following capsulized FMT displayed notable increases in the levels of Lachancea thermotolerans, Pyricularia grisea, Kazachstania naganishii, and Schizosaccharomyces pombe. Additionally, individuals undergoing capsulized FMT who achieved remission exhibited lower levels of pathobionts, including Candida and Debaryomyces hansenii.¹²¹ FMT stands out as a promising therapeutic option for UC. Nonetheless, its efficacy varies widely among individuals. While some individuals achieve symptom relief and mucosal healing, others show minimal improvement in disease activity or long-term remission. The findings of a randomized controlled trial (NCT03561532) indicated that FMT does not effectively sustain remission in individuals suffering from UC. During the 12-month follow-up, remission was sustained by 54% of participants receiving FMT, while 41% of participants receiving a placebo achieved the same outcome.¹²² In a pilot study, administering budesonide before FMT showed no significant impact on engraftment or clinical results following FMT. Nonetheless, the clinical response was likely dependent on the donor. This implies that FMT effectiveness may be more dependent on the transfer of specific strains than on the total engraftment.¹²³ Although individual responses vary widely and donor effects are significant, FMT underscores the potential of microbiome interventions in UC management, highlighting the need for standardized protocols and rigorous safety monitoring. Importantly, FMT is not currently an approved therapy for IBD in clinical practice. It remains investigational and should be performed only within the scope of approved clinical trials adhering to standardized protocols and safety oversight. Figure 2 maps the interplay of key mechanisms and therapeutic targets explicitly. A comparative overview of current treatment modalities is presented as Table 2.

Figure 2 The interplay of key mechanisms and therapeutic targets in UC.

Conclusions and Future Directions

UC is a multifaceted condition driven by a combination of epithelial barrier impairment, immune system irregularities, and modifications to the gut microbiome, leading to chronic inflammation of the colonic mucosa. Key mechanistic drivers include epithelial barrier defects, dysregulated immune pathways such as the IL-23/Th17 axis, and aberrant host-microbiome interactions. This review has highlighted the disease’s underlying pathophysiology, shedding light on key mechanisms such as epithelial barrier defects and the release of inflammatory mediators that sustain disease activity. Advances in diagnostics, particularly through the development of emerging biomarkers, offer great potential for improving early detection and enabling personalized management. The therapeutic landscape for UC has evolved substantially, extending beyond conventional therapies like corticosteroids and immunosuppressants. Biological treatments like anti-TNF agents, anti-interleukin drugs, and anti-integrin agents offer more targeted and effective treatment options, significantly reducing disease severity and improving the quality of life. Additionally, the introduction of small molecule inhibitors, such as JAK inhibitors and S1P receptor agents, has broadened the treatment choices, particularly for individuals who have failed to respond to biological treatments. Translational insights such as biomarker-guided drug selection and stratification based on JAK pathway activity offer opportunities to personalize treatment. This approach may improve outcomes in difficult-to-treat populations. Moreover, FMT represents a promising new approach, though further clinical validation is necessary before it becomes a standard treatment. These advances reflect the shift toward more individualized treatment approaches, aligning therapeutic interventions with the specific needs of each patient, ultimately leading to improved clinical outcomes. These findings support a biomarker- and phenotype-driven framework for tailoring therapy, which is essential for achieving durable remission and minimizing adverse events in clinical practice.

Despite considerable advancements, numerous challenges persist in the treatment of UC. Current therapeutic strategies often fail to achieve lasting remission in all patients, highlighting the need for more tailored approaches. The heterogeneity of UC, characterized by diverse disease phenotypes and varying responses to treatments, emphasizes the importance of developing more sophisticated biomarkers to guide personalized treatment plans. Future research must address critical gaps in biomarker validation—such as prospective multi-center cohort studies, standardized omics–clinical phenotype correlations, and clinical qualification of predictive markers. A particular area of focus should be on uncovering the molecular and genetic contributors to therapeutic resistance, as this will be crucial in addressing the limitations of current treatment options. Translational efforts must overcome technical and regulatory hurdles in applying microbiome insights to practice, including standardized donor selection, reproducible sampling, and durability assessment of microbiota-targeted interventions.

Research efforts must also be directed toward exploring new therapeutic targets. Of particular interest are strategies aimed at restoring epithelial barrier integrity and re-establishing microbial balance, which may offer more sustained control of UC. Microbiome-targeted therapies, such as FMT, require rigorous testing in clinical trials to determine their role in long-term disease management. Furthermore, advances in gene editing and cell-based therapies hold significant potential for transformative, disease-modifying treatments. Emerging technologies such as gene editing (eg, CRISPR/Cas9-mediated modulation of inflammatory genes), RNA interference for silencing aberrant cytokine signals, and mesenchymal stem cell–based therapies have demonstrated preclinical and early-phase promise in attenuating inflammation and promoting mucosal healing. Although these approaches remain investigational, they represent frontier areas for disease-modifying interventions. Innovative strategies, including AI-driven predictive modeling, systematic evaluation of sequential and combination regimens (eg, small molecules with biologics), offer promise for revolutionizing UC management. Collectively, these recommendations provide a clear, actionable roadmap for next-generation research, focusing on biomarker standardization, microbiome translation, long-term safety surveillance, and innovative combination strategies to advance precision medicine in UC.

Future research should prioritize: (1) validation of multi-omics biomarkers; (2) comparative long-term safety data across therapeutic classes; and (3) development of microbiome and stem-cell-based interventions. Such efforts will enhance precision medicine in UC. This review has synthesized recent mechanistic advances and clinical trial findings to support these future directions and optimize UC management strategies.

Data Sharing Statement

No datasets were generated or analyzed during the current study.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; S.Y. Bu and X.Z. Cheng took part in drafting and revising the article; M. Chen critically reviewed the article and gave final approval of the version to be published; Y.D. Yu have agreed on the journal to which the article has been submitted; Y.D. Yu and S.Y. Bu agree to be accountable for all aspects of the work.

Funding

This study was supported by “Applied Basic Research Programs of Liaoning Province“ (2023JH2/101300100), and “Xing Liao Ying Cai Programs of the Education Department of Liaoning Province“ (XLYC2002002).

Disclosure

The authors declare no competing interests.

References

1. Le Berre C, Honap S, Peyrin-Biroulet L. Ulcerative colitis. Lancet. 2023;402(10401):571–584. doi:10.1016/S0140-6736(23)00966-2

2. Ng SC, Shi HY, Hamidi N, et al. Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet. 2017;390(10114):2769–2778. doi:10.1016/S0140-6736(17)32448-0

3. Yamazaki M, Chung H, Xu Y, et al. Trends in the prevalence and incidence of UC in Japan and the US. Int J Colorectal Dis. 2023;38(1):135. doi:10.1007/s00384-023-04417-6

4. Voelker R. What Is UC? JAMA. 2024;331(8):716. doi:10.1001/jama.2023.23814

5. Liang Y, Li Y, Lee C, et al. UC: molecular insights and intervention therapy. Mol Biomed. 2024;5(1):42. doi:10.1186/s43556-024-00207-w

6. Kaluzna A, Olczyk P, Komosinska-Vassev K, Hebelka H, Lagerstrand KM. The Role of Innate and Adaptive Immune Cells in the Pathogenesis and Development of the Inflammatory Response in UC. J Clin Med. 2022;12(1):11. doi:10.3390/jcm12010011

7. Swirkosz G, Szczygiel A, Logon K, et al. The Role of the Microbiome in the Pathogenesis and Treatment of UC-A Literature Review. Biomedicines. 2023;11(12):3144. doi:10.3390/biomedicines11123144

8. Ananthakrishnan AN, Murad MH, Scott FI, et al. Comparative Efficacy of Advanced Therapies for Management of Moderate-to-Severe UC: 2024 American Gastroenterological Association Evidence Synthesis. Gastroenterology. 2024;167(7):1460–1482. doi:10.1053/j.gastro.2024.07.046

9. Chang S, Murphy M, Malter L. A Review of Available Medical Therapies to Treat Moderate-to-Severe Inflammatory Bowel Disease. Am J Gastroenterol. 2024;119(1):55–80. doi:10.14309/ajg.0000000000002485

10. Dulai PS, Singh S, Jairath V, et al. Integrating Evidence to Guide Use of Biologics and Small Molecules for Inflammatory Bowel Diseases. Gastroenterology. 2024;166(3):396–408e392. doi:10.1053/j.gastro.2023.10.033

11. Claytor, Faith JJ, Jennifer D, et al. Fecal Microbiota Transplantation (FMT) in UC: holding Out for a Superdonor? Clin Gastroenterol Hepatol. 2024;23(4):516–518. doi:10.1016/j.cgh.2024.07.047

12. Bulut Gökten D, Çabuk B, Solakoğlu T, et al. A single-center experience: enteropathic arthritis in inflammatory bowel diseases. The Egyptian Rheumatologist. 2024;46(3):171–174. doi:10.1016/j.ejr.2024.07.001

13. Wangchuk P, Yeshi K, Loukas A. UC: clinical biomarkers, therapeutic targets, and emerging treatments. Trends Pharmacol Sci. 2024;45(10):892–903. doi:10.1016/j.tips.2024.08.003

14. Thoo L, Noti M, Krebs P. Keep calm: the intestinal barrier at the interface of peace and war. Cell Death Dis. 2019;10(11):849. doi:10.1038/s41419-019-2086-z

15. Villanacci V, Del Sordo R, Lanzarotto F, et al. Claudin-2: a marker for a better evaluation of histological mucosal healing in inflammatory bowel diseases. Dig Liver Dis. 2024;57(4):827–832. doi:10.1016/j.dld.2024.08.001

16. Saez A, Herrero-Fernandez B, Gomez-Bris R, et al. Pathophysiology of Inflammatory Bowel Disease: innate Immune System. Int J Mol Sci. 2023;24(2):1526. doi:10.3390/ijms24021526

17. Wu Y, Shen J. Unraveling the intricacies of neutrophil extracellular traps in inflammatory bowel disease: pathways, biomarkers, and promising therapies. Cytokine Growth Factor Rev. 2024;80:156–167.

18. Tyler CJ, Guzman M, Lundborg LR, et al. Antibody secreting cells are critically dependent on integrin alpha4beta7/MAdCAM-1 for intestinal recruitment and control of the microbiota during chronic colitis. Mucosal Immunol. 2022;15(1):109–119. doi:10.1038/s41385-021-00445-z

19. Grames M, Breviario F, Pintucci G, et al. Enhancement by interleukin-1 (IL-1) of plasminogen activator inhibitor (PA-I) activity in cultured human endothelial cells. Biochem Biophys Res Commun. 1986;139(2):720–727. doi:10.1016/S0006-291X(86)80050-X

20. Sanchez-Munoz F, Dominguez-Lopez A, Yamamoto-Furusho JK. Role of cytokines in inflammatory bowel disease. World J Gastroenterol. 2008;14:4280–4288.

21. Nakase H, Sato N, Mizuno N, et al. The influence of cytokines on the complex pathology of UC. Autoimmun Rev. 2022;21(3):103017. doi:10.1016/j.autrev.2021.103017

22. Wan X, Zhang C, Lei P, et al. Precision therapeutics for inflammatory bowel disease: advancing ROS-responsive nanoparticles for targeted and multifunctional drug delivery. J Mater Chem B. 2025;13(10):3245–3269. doi:10.1039/d4tb02868f

23. Guo J, Li L, Cai Y, et al. The development of probiotics and prebiotics therapy to UC: a therapy that has gained considerable momentum. Cell Commun Signal. 2024;22:268.

24. Do KH, Ko SH, Kim KB, et al. Comparative Study of Intestinal Microbiome in Patients with UC and Healthy Controls in Korea. Microorganisms. 2023;11(11):2750.

25. Pandey H, Jain D, Tang DWT, et al. Gut microbiota in pathophysiology, diagnosis, and therapeutics of inflammatory bowel disease. Intest Res. 2024;22:15–43.

26. Khorsand B, Asadzadeh Aghdaei H, Nazemalhosseini-Mojarad E, et al. Overrepresentation of Enterobacteriaceae and Escherichia coli is the major gut microbiome signature in Crohn’s disease and UC; a comprehensive metagenomic analysis of IBDMDB datasets. Front Cell Infect Microbiol. 2022;12:1015890.

27. Candelli M, Franza L, Pignataro G, et al. Interaction between Lipopolysaccharide and Gut Microbiota in Inflammatory Bowel Diseases. Int J Mol Sci. 2021;22(12):6242.

28. Nowak JK, Kalla R, Satsangi J. Current and emerging biomarkers for UC. Expert Rev Mol Diagn. 2023;23(12):1107–1119. doi:10.1080/14737159.2023.2279611

29. Singh S, Ananthakrishnan AN, Nguyen NH, et al. AGA Clinical Practice Guideline on the Role of Biomarkers for the Management of UC. Gastroenterology. 2023;164(3):344–372. doi:10.1053/j.gastro.2022.12.007

30. Swaminathan A, Borichevsky GM, Edwards TS, et al. Faecal Myeloperoxidase as aBiomarker of Endoscopic Activity in Inflammatory Bowel Disease. J Crohns Colitis. 2022;16(12):1862–1873. doi:10.1093/ecco-jcc/jjac098

31. Zammarchi I, Santacroce G, Puga-Tejada M, et al. Epithelial neutrophil localization and tight junction Claudin-2 expression are innovative outcome predictors in inflammatory bowel disease. United European Gastroenterol J. 2024;12(9):1155–1166. doi:10.1002/ueg2.12677

32. Yang J, Huang MMC, Liang MMJ, et al. The diagnostic performance of serum αvβ6 for UC: a systematic review and meta-analysis. Clin Res Hepatol Gastroenterol. 2024;48(4):102317. doi:10.1016/j.clinre.2024.102317

33. Kuwada T, Shiokawa M, Kodama Y, et al. Identification of an Anti-Integrin alphavbeta6 Autoantibody in Patients With UC. Gastroenterology. 2021;160(7):2383–2394e2321. doi:10.1053/j.gastro.2021.02.019

34. Livanos AE, Dunn A, Fischer J, et al. Anti-Integrin alphavbeta6 Autoantibodies Are a Novel Biomarker That Antedate UC. Gastroenterology. 2023;164(4):619–629. doi:10.1053/j.gastro.2022.12.042

35. Yu T, Zhou Z, Set L, et al. The role of phosphatidylcholine 34:1 in the occurrence, development and treatment of UC. Acta Pharm Sin B. 2023;13(3):1231–1245. doi:10.1016/j.apsb.2022.09.006

36. Vich Vila A, Zhang J, Liu M, et al. Untargeted faecal metabolomics for the discovery of biomarkers and treatment targets for inflammatory bowel diseases. Gut. 2024;73(11):1909–1920. doi:10.1136/gutjnl-2023-329969

37. Chetwood JD, Paramsothy S, Haifer C, et al. Key metabolomic alterations are associated with UC disease state and activity: a validation analysis. Gut. 2024;73(8):1392–1393. doi:10.1136/gutjnl-2023-330196

38. Vestergaard MV, Nohr AK, Allin KH, et al. HLA-DRB1*01:03 and Severe UC. JAMA. 2024;332(22):1941–1943. doi:10.1001/jama.2024.20429

39. Zheng J, Sun Q, Zhang M, et al. Noninvasive, microbiome-based diagnosis of inflammatory bowel disease. Nat Med. 2024;30(12):3555–3567. doi:10.1038/s41591-024-03280-4

40. Scanu M, Toto F, Petito V, et al. An integrative multi-omic analysis defines gut microbiota, mycobiota, and metabolic fingerprints in UC patients. Front Cell Infect Microbiol. 2024;14:1366192. doi:10.3389/fcimb.2024.1366192

41. Riviere P, Li Wai Suen C, Chaparro M, et al. Acute severe UC management: unanswered questions and latest insights. Lancet Gastroenterol Hepatol. 2024;9(3):251–262. doi:10.1016/S2468-1253(23)00313-8

42. Liu J, Di B, Xu LL. Recent advances in the treatment of IBD: targets, mechanisms and related therapies. Cytokine Growth Factor Rev. 2023;71-72:1–12. doi:10.1016/j.cytogfr.2023.07.001

43. Louis E, Paridaens K, Al Awadhi S, et al. Modelling the benefits of an optimised treatment strategy for 5-ASA in mild-to-moderate UC. BMJ Open Gastroenterol. 2022;9(1):e000853. doi:10.1136/bmjgast-2021-000853

44. Le Berre C, Roda G, Nedeljkovic Protic M, et al. Modern use of 5-aminosalicylic acid compounds for UC. Expert Opin Biol Ther. 2020;20(4):363–378. doi:10.1080/14712598.2019.1666101

45. Iiristo J, Karling P. Prescribed cumulative dosage of corticosteroids to patients with inflammatory bowel disease diagnosed between 2006 and 2020: a retrospective observational study. Therap Adv Gastroenterol. 2024;17:17562848241288851. doi:10.1177/17562848241288851

46. Ben-Horin S, Har-Noy O, Katsanos KH, et al. Corticosteroids and Mesalamine Versus Corticosteroids for Acute Severe UC: a Randomized Controlled Trial. Clin Gastroenterol Hepatol. 2022;20(12):2868–2875e2861. doi:10.1016/j.cgh.2022.02.055

47. Timmer A, Patton PH, Chande N, et al. Azathioprine and 6-mercaptopurine for maintenance of remission in UC. Cochrane Database Syst Rev. 2016;2016(5):CD000478. doi:10.1002/14651858.CD000478.pub4

48. Sood R, Ansari S, Clark T, et al. Long-term efficacy and safety of azathioprine in UC. J Crohns Colitis. 2015;9(2):191–197. doi:10.1093/ecco-jcc/jju010

49. Yewale RV, Ramakrishna BS, Doraisamy BV, et al. Long-term safety and effectiveness of azathioprine in the management of inflammatory bowel disease: a real-world experience. JGH Open. 2023;7(9):599–609. doi:10.1002/jgh3.12955

50. Panaccione R, Ghosh S, Middleton S, et al. Combination therapy with infliximab and azathioprine is superior to monotherapy with either agent in UC. Gastroenterology. 2014;146(2):392–400e393. doi:10.1053/j.gastro.2013.10.052

51. Lowenberg M, Volkers A, van Gennep S, et al. Mercaptopurine for the Treatment of UC: a Randomized Placebo-Controlled Trial. J Crohns Colitis. 2023;17(7):1055–1065. doi:10.1093/ecco-jcc/jjad022

52. Bastida G, Alvarez-Sotomayor D, Aguas M, et al. Evaluation of tolerance to mercaptopurine in patients with inflammatory bowel disease and gastrointestinal intolerance to azathioprine. Gastroenterol Hepatol. 2024;47(5):473–480. doi:10.1016/j.gastrohep.2023.12.001

53. Kotla NG, Rochev Y. IBD disease-modifying therapies: insights from emerging therapeutics. Trends Mol Med. 2023;29(3):241–253. doi:10.1016/j.molmed.2023.01.001

54. Peyrin-Biroulet L, Loftus Jr EV, Colombel JF, et al. Histologic Outcomes With Vedolizumab Versus Adalimumab in UC: results From An Efficacy and Safety Study of Vedolizumab Intravenous Compared to Adalimumab Subcutaneous in Participants With UC (VARSITY). Gastroenterology. 2021;161(4):1156–1167e1153. doi:10.1053/j.gastro.2021.06.015

55. Rutgeerts P, Sandborn WJ, Feagan BG, et al. Infliximab for induction and maintenance therapy for UC. N Engl J Med. 2005;353(23):2462–2476. doi:10.1056/NEJMoa050516

56. Iborra M, Caballol B, Garrido A, et al. Subcutaneous infliximab cut-off points in patients with inflammatory bowel disease. Data from the ENEIDA registry. J Crohns Colitis. 2024;19(1):jjae127. doi:10.1093/ecco-jcc/jjae127

57. Roblin X, Nancey S, Papamichael K, et al. Higher Serum Infliximab Concentrations Following Subcutaneous Dosing are Associated with Deep Remission in Patients with Inflammatory Bowel Disease. J Crohns Colitis. 2024;18(5):679–685. doi:10.1093/ecco-jcc/jjad188

58. Hanauer SB, Sands BE, Schreiber S, et al. Subcutaneous Infliximab (CT-P13 SC) as Maintenance Therapy for Inflammatory Bowel Disease: two Randomized Phase 3 Trials (LIBERTY). Gastroenterology. 2024;167(5):919–933. doi:10.1053/j.gastro.2024.05.006

59. Kedia S, Ahuja V. Infliximab rescue therapy in acute severe UC: more does not equal better. Lancet Gastroenterol Hepatol. 2024;9(11):966–967. doi:10.1016/S2468-1253(24)00229-2

60. Zheng M, Zhai Y, Yu Y, et al. TNF compromises intestinal bile-acid tolerance dictating colitis progression and limited infliximab response. Cell Metab. 2024;36(9):2086–2103e2089. doi:10.1016/j.cmet.2024.06.008

61. Huang CW, Yen HH, Chen YY. Rescue Therapies for Steroid-Refractory Acute Severe UC: a Systemic Review and Network Meta-analysis. J Crohns Colitis. 2024;18(12):2063–2075. doi:10.1093/ecco-jcc/jjae111

62. Choy MC, Li Wai Suen CFD, Con D, et al. Intensified versus standard dose infliximab induction therapy for steroid-refractory acute severe UC (PREDICT-UC): an open-label, multicentre, randomised controlled trial. Lancet Gastroenterol Hepatol. 2024;9:981–996.

63. Kamal ME, Werida RH, Radwan MA, et al. Efficacy and safety of infliximab and Adalimumab in inflammatory bowel disease patients. Inflammopharmacology. 2024;32:3259–3269.

64. Stodtmann S, Chen MJ, Ponce-Bobadilla AV, et al. SERENE ER Analysis Part 2 SERENE-UC: exposure-response Analysis of Higher Versus Standard Adalimumab Dosing Regimens for Patients with Moderately to Severely Active UC. Clin Pharmacol Drug Dev. 2024;13:1033–1043.

65. Weinstein CLJ, Meehan AG, Govoni M, et al. Low Occurrence of Colectomy With Long-Term (up to 4 Years) Golimumab Treatment in Patients With Moderate-to-Severe Active UC: data From the PURSUIT Maintenance and Long-Term Extension Studies. Crohns Colitis. 2023;5(3):otad044.

66. Kapizioni C, Desoki R, Lam D, et al. Biologic Therapy for Inflammatory Bowel Disease: real-World Comparative Effectiveness and Impact of Drug Sequencing in 13 222 Patients within the UK IBD BioResource. J Crohns Colitis. 2024;18:790–800.

67. Afif W, Arasaradnam RP, Abreu MT, et al. Efficacy and Safety of Ustekinumab for UC Through 4 Years: final Results of the UNIFI Long-Term Maintenance Study. Am J Gastroenterol. 2024;119(5):910–921. doi:10.14309/ajg.0000000000002621

68. Chen R, Tie Y, Huang Y, et al. Rapidly achieving clinical remission in UC indicates better endoscopic and histological outcomes. United European Gastroenterol J. 2024;12(4):459–468. doi:10.1002/ueg2.12515

69. D’Haens G, Dubinsky M, Kobayashi T, et al. Mirikizumab as Induction and Maintenance Therapy for UC. N Engl J Med. 2023;388(26):2444–2455. doi:10.1056/NEJMoa2207940

70. Danese S, Dignass A, Matsuoka K, et al. Early and Sustained Symptom Control with Mirikizumab in Patients with UC in the Phase 3 LUCENT Program. J Crohns Colitis. 2024;18(11):1845–1856. doi:10.1093/ecco-jcc/jjae088

71. Sandborn WJ, Ferrante M, Bhandari BR, et al. Efficacy and Safety of Continued Treatment With Mirikizumab in a Phase 2 Trial of Patients With UC. Clin Gastroenterol Hepatol. 2022;20(1):105–115e114. doi:10.1016/j.cgh.2020.09.028

72. Louis E, Schreiber S, Panaccione R, et al. Risankizumab for UC: two Randomized Clinical Trials. JAMA. 2024;332(11):881–897. doi:10.1001/jama.2024.12414

73. Peyrin-Biroulet L, Allegretti JR, Rubin DT, et al. Guselkumab in Patients With Moderately to Severely Active UC: QUASAR Phase 2b Induction Study. Gastroenterology. 2023;165(6):1443–1457. doi:10.1053/j.gastro.2023.08.038

74. Feagan BG, Sands BE, Sandborn WJ, et al. Guselkumab plus golimumab combination therapy versus guselkumab or golimumab monotherapy in patients with UC (VEGA): a randomised, double-blind, controlled, phase 2, proof-of-concept trial. Lancet Gastroenterol Hepatol. 2023;8(4):307–320. doi:10.1016/S2468-1253(22)00427-7

75. Shao J, Vetter M, Vermeulen A, et al. Combination Therapy With Guselkumab and Golimumab in Patients With Moderately to Severely Active UC: pharmacokinetics, Immunogenicity and Drug-Drug Interactions. Clin Pharmacol Ther. 2024;115(6):1418–1427. doi:10.1002/cpt.3235

76. Gao X, Wang Y, Li Z, et al. Post-marketing drug survival and safety of risankizumab and mirikizumab in moderate-to-severe ulcerative colitis: a nationwide cohort study. Clin Gastroenterol Hepatol. 2023;21(10):2050–2058.

77. Kim YJ, Park JH, Lee SY, et al. Real-world effectiveness of IL-23 antagonists in ulcerative colitis: a multicenter retrospective analysis. J Gastroenterol Hepatol. 2024;39(4):789–796.

78. Bokemeyer B, Plachta-Danielzik S, Di Giuseppe R, et al. Real-world effectiveness of vedolizumab compared to anti-TNF agents in biologic-naïve patients with ulcerative colitis: a two-year propensity-score-adjusted analysis from the prospective, observational VEDO IBD-study. Aliment Pharmacol Ther. 2023;58(4):429–442. doi:10.1111/apt.17616

79. Jairath V, Yarur A, Osterman MT, et al. ENTERPRET: a Randomized Controlled Trial of Vedolizumab Dose Optimization in Patients With UC Who Have Early Nonresponse. Clin Gastroenterol Hepatol. 2024;22(5):1077–1086e1013. doi:10.1016/j.cgh.2023.10.029

80. Peyrin-Biroulet L, Hart A, Bossuyt P, et al. Etrolizumab as induction and maintenance therapy for UC in patients previously treated with tumour necrosis factor inhibitors (HICKORY): a phase 3, randomised, controlled trial/. Lancet Gastroenterol Hepatol. 2022;7(2):128–140. doi:10.1016/S2468-1253(21)00298-3

81. Vermeire S, Lakatos PL, Ritter T, et al. Etrolizumab for maintenance therapy in patients with moderately to severely active UC (LAUREL): a randomised, placebo-controlled, double-blind, phase 3 study. Lancet Gastroenterol Hepatol. 2022;7(1):28–37. doi:10.1016/S2468-1253(21)00295-8

82. Rubin DT, Dotan I, DuVall A, et al. Etrolizumab versus Adalimumab or placebo as induction therapy for moderately to severely active UC (HIBISCUS): two phase 3 randomised, controlled trials. Lancet Gastroenterol Hepatol. 2022;7(1):17–27. doi:10.1016/S2468-1253(21)00338-1

83. Danese S, Colombel JF, Lukas M, et al. Etrolizumab versus infliximab for the treatment of moderately to severely active UC (GARDENIA): a randomised, double-blind, double-dummy, phase 3 study. Lancet Gastroenterol Hepatol. 2022;7(2):118–127. doi:10.1016/S2468-1253(21)00294-6

84. Matsuoka K, Watanabe M, Ohmori T, et al. AJM300 (carotegrast methyl), an oral antagonist of alpha4-integrin, as induction therapy for patients with moderately active UC: a multicentre, randomised, double-blind, placebo-controlled, phase 3 study. Lancet Gastroenterol Hepatol. 2022;7(7):648–657. doi:10.1016/S2468-1253(22)00022-X

85. Lei P, Yu H, Ma J, et al. Cell membrane nanomaterials composed of phospholipids and glycoproteins for drug delivery in inflammatory bowel disease: a review. Int. J Biol Macromol. 2023;249:126000. doi:10.1016/j.ijbiomac.2023.126000

86. Sandborn WJ, Peyrin-Biroulet L, Quirk D, et al. Efficacy and Safety of Extended Induction With Tofacitinib for the Treatment of UC. Clin Gastroenterol Hepatol. 2022;20(8):1821–1830e1823. doi:10.1016/j.cgh.2020.10.038

87. Steenholdt C, Dige Ovesen P, Brynskov J, et al. Tofacitinib for Acute Severe UC: a Systematic Review. J Crohns Colitis. 2023;17(8):1354–1363. doi:10.1093/ecco-jcc/jjad036

88. Singh A, Midha V, Kaur K, et al. Tofacitinib Versus Oral Prednisolone for Induction of Remission in Moderately Active UC [ORCHID]: a Prospective, Open-Label, Randomized, Pilot Study. J Crohns Colitis. 2024;18(2):300–307. doi:10.1093/ecco-jcc/jjad153

89. Straatmijer T, Biemans VBC, Visschedijk M, et al. Superior Effectiveness of Tofacitinib Compared to Vedolizumab in Anti-TNF-experienced UC Patients: a Nationwide Dutch Registry Study. Clin Gastroenterol Hepatol. 2023;21(1):182–191e182. doi:10.1016/j.cgh.2022.04.038

90. Singh A, Goyal MK, Midha V, et al. Tofacitinib in Acute Severe UC (TACOS): a Randomized Controlled Trial. Am J Gastroenterol. 2024;119(7):1365–1372. doi:10.14309/ajg.0000000000002635

91. Danese S, Vermeire S, Zhou W, et al. Upadacitinib as induction and maintenance therapy for moderately to severely active UC: results from three phase 3, multicentre, double-blind, randomised trials. Lancet. 2022;399(10341):2113–2128. doi:10.1016/S0140-6736(22)00581-5

92. Panaccione R, Danese S, Zhou W, et al. Efficacy and safety of upadacitinib for 16-week extended induction and 52-week maintenance therapy in patients with moderately to severely active UC. Aliment Pharmacol Ther. 2024;59(3):393–408. doi:10.1111/apt.17816

93. Vermeire S, Danese S, Zhou W, et al. Efficacy and safety of upadacitinib maintenance therapy for moderately to severely active UC in patients responding to 8 week induction therapy (U-ACHIEVE Maintenance): overall results from the randomised, placebo-controlled, double-blind, phase 3 maintenance study. Lancet Gastroenterol Hepatol. 2023;8(11):976–989. doi:10.1016/S2468-1253(23)00208-X

94. Friedberg S, Choi D, Hunold T, et al. Upadacitinib Is Effective and Safe in Both UC and Crohn’s Disease: prospective Real-World Experience. Clin Gastroenterol Hepatol. 2023;21(7):1913–1923e1912. doi:10.1016/j.cgh.2023.03.001

95. Dalal RS, Kallumkal G, Cabral HJ, et al. One-Year Comparative Effectiveness of Upadacitinib vs Tofacitinib for UC: a Multicenter Cohort Study. Am J Gastroenterol. 2024;119(8):1628–1631. doi:10.14309/ajg.0000000000002746

96. Boneschansker L, Ananthakrishnan AN, Burke KE. Massachusetts General Hospital Cs, Colitis Center C. Comparative Effectiveness of Upadacitinib and Tofacitinib in Inducing Remission in UC: real-World Data. Clin Gastroenterol Hepatol. 2023;21(9):2427–2429e2421. doi:10.1016/j.cgh.2023.03.040

97. Feagan BG, Danese S, Loftus Jr EV, et al. Filgotinib as induction and maintenance therapy for UC (SELECTION): a phase 2b/3 double-blind, randomised, placebo-controlled trial. Lancet. 2021;397(10292):2372–2384. doi:10.1016/S0140-6736(21)00666-8

98. Feagan BG, Matsuoka K, Rogler G, et al. Long-term safety and efficacy of filgotinib for the treatment of moderately to severely active UC: interim analysis from up to 4 years of follow-up in the SELECTION open-label long-term extension study. Aliment Pharmacol Ther. 2024;60(5):563–584. doi:10.1111/apt.18158

99. Akiyama S, Yokoyama K, Yagi S, et al. Efficacy and safety of filgotinib for UC: a real-world multicenter retrospective study in Japan. Aliment Pharmacol Ther. 2024;59(11):1413–1424. doi:10.1111/apt.17961

100. Gros B, Goodall M, Plevris N, et al. Real-World Cohort Study on the Effectiveness and Safety of Filgotinib Use in UC. J Crohns Colitis. 2023;2023:2.

101. Chen B, Zhong J, Li X, et al. Efficacy and Safety of Ivarmacitinib in Patients With Moderate-to-Severe, Active, UC: a Phase II Study. Gastroenterology. 2022;163(6):1555–1568. doi:10.1053/j.gastro.2022.08.007

102. Kitsou K, Kokkotis G, Rivera-Nieves J, et al. Targeting the Sphingosine-1-Phosphate Pathway: new Opportunities in Inflammatory Bowel Disease Management. Drugs. 2024;84(10):1179–1197. doi:10.1007/s40265-024-02094-5

103. Sandborn WJ, Feagan BG, D’Haens G, et al. Ozanimod as Induction and Maintenance Therapy for UC. N Engl J Med. 2021;385(14):1280–1291. doi:10.1056/NEJMoa2033617

104. Sandborn WJ, Feagan BG, Hanauer S, et al. Long-Term Efficacy and Safety of Ozanimod in Moderately to Severely Active UC: results From the Open-Label Extension of the Randomized, Phase 2 TOUCHSTONE Study. J Crohns Colitis. 2021;15(7):1120–1129. doi:10.1093/ecco-jcc/jjab012

105. Sands BE, D’Haens G, Panaccione R, et al. Ozanimod in Patients With Moderate to Severe UC Naive to Advanced Therapies. Clin Gastroenterol Hepatol. 2024;22:2084–2095e2084.

106. Danese S, Panaccione R, Abreu MT, et al. Efficacy and Safety of Approximately 3 Years of Continuous Ozanimod in Moderately to Severely Active UC: interim Analysis of the True North Open-label Extension. J Crohns Colitis. 2024;18(2):264–274. doi:10.1093/ecco-jcc/jjad146

107. Sandborn WJ, Peyrin-Biroulet L, Zhang J, et al. Efficacy and Safety of Etrasimod in a Phase 2 Randomized Trial of Patients With UC. Gastroenterology. 2020;158(3):550–561. doi:10.1053/j.gastro.2019.10.035

108. Yarur AJ, Chiorean MV, Panes J, et al. Achievement of Clinical, Endoscopic, and Histological Outcomes in Patients with UC Treated with Etrasimod, and Association with Faecal Calprotectin and C-reactive Protein: results From the Phase 2 OASIS Trial. J Crohns Colitis. 2024;18(6):885–894. doi:10.1093/ecco-jcc/jjae007

109. Vermeire S, Chiorean M, Panes J, et al. Long-term Safety and Efficacy of Etrasimod for UC: results from the Open-label Extension of the OASIS Study. J Crohns Colitis. 2021;15:950–959.

110. Sandborn WJ, Vermeire S, Peyrin-Biroulet L, et al. Etrasimod as induction and maintenance therapy for UC (ELEVATE): two randomised, double-blind, placebo-controlled, phase 3 studies. Lancet. 2023;401:1159–1171.

111. Magro F, Peyrin-Biroulet L, Sands BE, et al. Endoscopic, Histologic, and Composite Endpoints in Patients With UC Treated With Etrasimod. Clin Gastroenterol Hepatol. 2024;23(2):341–350.e6.

112. Sands BE, Leung Y, Rubin DT, et al. Etrasimod Corticosteroid-Free Efficacy, Impact of Concomitant Corticosteroids on Efficacy and Safety, and Corticosteroid-Sparing Effect in UC: analyses of the ELEVATE UC Clinical Programme. J Crohns Colitis. 2024;19(3):jjae150.

113. Vermeire S, Sands BE, Peyrin-Biroulet L, et al. Impact of Prior Biologic or Janus Kinase Inhibitor Therapy on Efficacy and Safety of Etrasimod in the ELEVATE UC 52 and ELEVATE UC 12 Trials. J Crohns Colitis. 2024;2022:1.

114. Soldera J. Navigating treatment resistance: Janus kinase inhibitors for UC. World J Clin Cases. 2024;12(24):5468–5472. doi:10.12998/wjcc.v12.i24.5468

115. Fanizzi F, D’Amico F, Zanotelli Bombassaro I, et al. The Role of Fecal Microbiota Transplantation in IBD. Microorganisms. 2024;12(9):1755.

116. Paramsothy S, Nielsen S, Kamm MA, et al. Specific Bacteria and Metabolites Associated With Response to Fecal Microbiota Transplantation in Patients With UC. Gastroenterology. 2019;156(5):1440–1454e1442. doi:10.1053/j.gastro.2018.12.001

117. Costello SP, Hughes PA, Waters O, et al. Effect of Fecal Microbiota Transplantation on 8-Week Remission in Patients With UC: a Randomized Clinical Trial. JAMA. 2019;321(2):156–164. doi:10.1001/jama.2018.20046

118. Haifer C, Paramsothy S, Kaakoush NO, et al. Lyophilised oral faecal microbiota transplantation for UC (LOTUS): a randomised, double-blind, placebo-controlled trial. Lancet Gastroenterol Hepatol. 2022;7(2):141–151. doi:10.1016/S2468-1253(21)00400-3

119. Kedia S, Virmani S, KV S, et al. Faecal microbiota transplantation with anti-inflammatory diet (FMT-AID) followed by anti-inflammatory diet alone is effective in inducing and maintaining remission over 1 year in mild to moderate UC: a randomised controlled trial. Gut. 2022;71(12):2401–2413. doi:10.1136/gutjnl-2022-327811

120. Chen Q, Fan Y, Zhang B, et al. Capsulized Fecal Microbiota Transplantation Induces Remission in Patients with UC by Gut Microbial Colonization and Metabolite Regulation. Microbiol Spectr. 2023;11(3):e0415222. doi:10.1128/spectrum.04152-22

121. Chen Q, Fan Y, Zhang B, et al. Specific fungi associated with response to capsulized fecal microbiota transplantation in patients with active UC. Front Cell Infect Microbiol. 2022;12:1086885.

122. Lahtinen P, Jalanka J, Mattila E, et al. Fecal microbiota transplantation for the maintenance of remission in patients with UC: a randomized controlled trial. World J Gastroenterol. 2023;29(17):2666–2678. doi:10.3748/wjg.v29.i17.2666

123. van Lingen E, Nooij S, Terveer EM, et al. Faecal Microbiota Transplantation Engraftment After Budesonide or Placebo in Patients With Active UC Using Pre-selected Donors: a Randomized Pilot Study. J Crohns Colitis. 2024;18(9):1381–1393. doi:10.1093/ecco-jcc/jjae043

Aortic aneurysms are common in patients with connective tissue disorders, such as Marfan, Loeys-Dietz and Ehlers-Danlos syndromes. In Marfan syndrome, the aortic wall gives way because of a deficiency in elastic tissue. At the other extreme, in Ehlers-Danlos syndrome, there’s a deficiency in collagen.

“Marfan patients used to die on average at the age of 32,” says Lars Svensson, MD, PhD, Chief of the Heart, Vascular and Thoracic Institute at Cleveland Clinic. “Now we see patients living into their 70s and older. Their aortic health is not a problem as long as they have surgery. Aortic root surgery is very effective in preventing aortic dissection. In our long-term patients with Marfan who have had aortic root surgery, the risk of a later dissection is very low — only 1.8% in our experience.”

In a recent two-part episode of Cleveland Clinic’s Cardiac Consult podcast, Dr. Svensson and cardiologist Milind Desai, MD, MBA, Medical Director of Cleveland Clinic’s Aorta Center, discuss indications for heart and aorta treatment in patients with connective tissue disorders. Among the topics they address:

• Diagnosing a connective tissue disorder, including the use of imaging, modified Ghent criteria and genetic testing
• Considering patient height when reviewing aorta measurements
• Surgical approaches, including aortic root replacement and composite mechanical valve replacement
• Long-term outcomes of reimplantation surgery
• Comorbidities, such as mitral valve disease and cardiomyopathy

Click the podcast players above to listen to the two-part podcast now, or read on for an edited excerpt. Check out more Cardiac Consult episodes at clevelandclinic.org/cardiacconsultpodcast or wherever you get your podcasts.

Excerpt from the podcast

Lars Svensson, MD, PhD: Patients with connective tissue disorders also can develop intrinsic left ventricular dysfunction — in other words, a cardiomyopathy — irrespective of whether they have valve or heart disease. That can be a feature of Marfan. Over time, the mitral valve may become involved as well.

Also, we get baseline pulmonary function tests on all our patients. Usually we see some dysfunction. The breathing tests are usually not bad, but over time patients with Marfan potentially develop COPD or emphysema. So it’s something to track over time.

I’d like to return for a moment to discussing cardiomyopathy in this setting. I know of just a couple of these patients in whom we’ve had to do heart transplants for cardiomyopathy. It’s pretty rare. Do you have comments about that?

Milind Desai, MD, MBA: It is rare, mercifully, but also life expectancy of these patients was lower in the past, so maybe there was not enough time for these comorbidities to accrue. Now that Marfan and connective tissue disorder patients are living longer, it might be important to keep a close eye on other diseases that may crop up.

In a patient with Marfan or other connective tissue disorder, aortopathy is by far the most common presentation. Then, a small proportion have concomitant mitral valve disease, and an even smaller proportion have concomitant cardiomyopathy or may develop downstream cardiomyopathy.

This underscores the importance of being on top of these patients’ follow-up — not just imaging the aorta but looking at their echoes and periodic MRIs to make sure cardiomyopathy does not creep in, as well as paying attention to the mitral valve.

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