Introduction

Microscopic colitis (MC) is an inflammatory condition of the large intestine encompassing the subtypes lymphocytic colitis and collagenous colitis. MC has been linked to various autoimmune conditions, but reports on autoimmune thyroid disorders (AITD) have mostly been cross-sectional and none has included stratified results or corroborated the association with sensitivity analyses.

Aims & Methods

To examine the association of MC and its subtypes with prior diagnosis of AITD, a matched case-control study was performed using the nationwide ESPRESSO cohort in Sweden. Diagnosis of AITD was ascertained from either ICD-based records of Graves' disease or Hashimoto-specific prescribed drugs. All biopsy-confirmed MC patients diagnosed 2006-2017 were compared separately with regards to prevalent AITD to two groups: i) biopsy-free general population matched on birth year, sex and county of residence at index year; and ii) biopsy-free full siblings to account for unmeasured confounders from common genetic risk and early environmental factors. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated via conditional logistic models stratifying on the matching variables or family groups and adjusting for education attainment, birth country, and history of celiac disease, inflammatory bowel disease, asthma, rheumatoid arthritis, psoriasis and type 1 diabetes. Sex difference in the association was tested via an "exposure × sex" interaction term. Separate analyses on MC subtypes and a sensitivity analysis of MC cases with at least 1-year follow-up before the index date (to minimize surveillance bias) were also carried out.

Results

A total of 10,448 MC cases and 49,935 controls were identified 2006-2017, among whom 1205 (11.5%) and 3791 (7.6%) were exposed to AITD, respectively. Compared to controls, MC patients were more frequently affected by at least one of the six other autoimmune comorbidities (8.3% vs 3.3%). As shown in Table 1, MC associated significantly with prevalent AITD at an OR of 1.60 (95% CI: 1.49-1.72) after adjusting for all covariates. This association appeared non-differential between collagenous colitis and lymphocytic colitis, and between males and females (P_interaction=0.4 for MC). When full siblings were compared to, the OR for MC association with AITD attenuated but remained statistically significant (OR: 1.22; 95% CI: 1.08-1.39). Sensitivity analyses also supported our main results.
Table 1. Odds ratios for the AITD-MC association.

Conclusion

Our findings corroborate the known association between MC and AITD and also support the notion that MC patients to a larger extent exhibit a predisposition towards autoimmune conditions. Our findings underscore the importance of investigating the underlying mechanisms of this association and emphasize the need for clinicians to consider MC in AITD patients presenting with diarrhoea.

Disclosure

Dr Ludvigsson has coordinated a study for the Swedish IBD quality register (SWIBREG). That study received funding from the Janssen Corporation. Dr Ludvigsson has also received financial support from MSD to develop a paper reviewing national healthcare registers in China, and has an ongoing study on celiac disease funded by Takeda. Dr Ebrahimi has served as an advisory board member for Boehringer Ingelheim.
This work was supported by the Karolinska Institutet (Ludvigsson), Stockholm County Council (Ludvigsson).
XK was supported by the Swedish Research Council (2022-00164).
JS was supported by the European Crohn's and Colitis Organization, the Stiftelsen Professor Nanna Svartz fond, and the Swedish Society for Medical Research.
FE was supported by the Swiss National Science Foundation (P500PM_210866).
None of the funding organisations has had any role in the design and conduct of the study, in the collection, management, and analysis of the data, or in the preparation, review, and approval of the manuscript.

Introduction

The lack of reliable intestinal fibrosis imaging modalities hampers anti-fibrotic therapy development. Gallium-68 Fibroblast Activation Protein inhibitor (⁶⁸GaFAPi) PET/CT offers promising in vivo fibrosis visualization via Fibroblast Activation Protein (FAP) targeting. Despite reported overexpression of FAP in chronic inflammatory and fibrotic diseases, data in inflammatory bowel disease (IBD) and the potential use of ⁶⁸Ga-FAPi PET/CT as a non-invasive fibrosis biomarker remains sparse. We performed the first in-human study to investigate ⁶⁸Ga-FAPi PET/CT to detect and quantify fibrosis in IBD patients using pharmacokinetic modelling.

Aims & Methods

Symptomatic patients with active Crohn’s disease (CD) or ulcerative colitis (UC) waiting for surgical resection were invited to the study and consented. Patients underwent a 60-minute dynamic ⁶⁸Ga-FAPi PET/CT scan, followed by 12 minutes of static imaging within 12 weeks before surgery. Arterial and peripheral blood samples were obtained during the first 10 scans to validate image- versus plasma-derived input function. Two blinded readers independently assessed the PET/CT images, wherein bowel segments showing increased uptake against local background were delineated and validated by a non-blinded third reader. Bowel segment uptake, time-activity-curves (TAC) and input functions were analyzed using irreversible (2T3k), reversible two-tissue compartment models (2T4k), reference tissue models, and standardized uptake values acquired on static images 50-60 minutes post-injection (SUV_50-60). Surgical resection specimens were selected based on ⁶⁸Ga-FAPi PET/CT with focus on segments with high FAPi uptake. In the tissue samples, gene expression and protein levels of FAP were determined using quantitative polymerase chain reaction (qPCR) and immunohistochemistry. To allocate samples to a fibrotic, inflamed or combined phenotype, hematoxylin and eosin and Masson’s trichrome staining were performed for inflammatory activity and fibrosis scoring by a blinded pathologist (GH) using previously described histological inflammation and fibrosis scores.¹

Results

In total, 15 CD and 4 UC patients (mean age 39 years, median disease duration 12 years) underwent FAPi PET/CT prior to surgery. On these 19 scans, 50 bowel regions of interest were identified and 52 transmural surgical samples were acquired. FAPi tracer uptake was markedly increased in inflamed and fibrotic regions of all participants compared to reference, non-pathologic bowel segments (SUV_50-60 ranging 1.0 to 11 versus 0.3 to 1.1). Although a higher tracer activity was seen in all patients, the inflammatory bowel segments showed the highest peak in tracer activity, followed by a decline in uptake, indicating increased blood flow, vascular permeability and reversible, potentially non-specific or low-binding affinity, uptake. Contrarily, the TAC of patients with a more fibrotic phenotype, showed a low peak uptake followed by a relatively stable plateau, suggesting a more irreversible or higher binding affinity uptake component.

Conclusion

⁶⁸Ga-FAPi PET/CT shows significant promise for IBD assessment as uptake aligns with histological fibrosis scoring, enhanced FAP gene and protein expression in resected inflammatory and stenotic specimens in CD and UC patients. Pharmacokinetic analyses suggests more frequent irreversible uptake kinetics, indicating higher FAP binding affinity, in predominantly fibrotic segments compared to inflamed regions, thus underscoring its potential to differentiate fibrosis from inflammation.

References

1. Ke BJ, Abdurahiman S, Biscu F, Zanella G, et al. Intercellular interaction between FAP+ fibroblasts and CD150+ inflammatory monocytes mediates fibrostenosis in Crohn's disease. J Clin Invest. 2024 Jul 23;134(16):e173835. doi: 10.1172/JCI173835. PMID: 39042469; PMCID: PMC11324301.

Disclosure

M.L.: Consultancy/lecture fees from Abbvie, Bristol Myers Squibb, Eli Lilly, Galapagos, Janssen-Cilag, Johnson & Johnson, Medtronic, Pfizer, Takeda, Tillotts. Central reader for Alimentiv. Grants received from ZonMW, Galapagos, NFU transformation deal, and TKI (unrelated)
G.R.A.M.D.: research grants from Abbvie, Alimentiv, BMS, J&J, Pfizer, Takeda; consulting fees from Abbvie, Agomab, Alimentiv, AstraZeneca, AMT, Bristol Meiers Squibb, Boehringer Ingelheim, Celltrion, Eli Lilly, Exeliom Biosciences, Galapagos, Index Pharmaceuticals, Glaxo Smith Kline, Pfizer, Johnson and Johnson, Polpharma, Procise Diagnostics, Prometheus laboratories, Prometheus Biosciences, Protagonist, and Ventyx; speaker’s fees from Abbvie, Celltrion, Galapagos, Pfizer, and Takeda; data monitoring board: Galapagos, AstraZeneca, Seres Health (unrelated)