Introduction

RCD is defined by persistent or recurrent malabsorptive symptoms and villous atrophy despite adherence to a gluten free diet (GFD) for at least 6-12 months. RCD can be classified as type I (normal intraepithelial lymphocyte phenotype) or type II (abnormal or aberrant IEL phenotype, i.e. IELs that have lost surface expression of CD3and CD8but retained cytoplasmic CD3expression. RCD II can be diagnosed by immunohistochemistry (reduced CD8 staining), molecular analysis (TCR gene rearrangement studies) or flow cytometry. Flow cytometry provides a rapid, quantitative assessment of the degree of aberrancy (% of abnormal IELs/total number IELs) in patients with non-healing CD and may help predict the risk of future development of EATL.

Aims & Methods

The aim of this study was to evaluate the utility of flow-cytometry for the prediction of EATL and mortality in patients with RCDII in a tertiary referral centre.
The results of all flow cytometry assays performed on duodenal biopsies since commencement of the service were reviewed in addition to patient outcomes. RCD II was defined as a % aberrancy of IELs of >20%.

Results

55 assays were performed on 38 patients. RCD II was identified in 10 patients (6 females), all of whom had evidence of clonality on TCR gene rearrangement studies. 3/10 had normal staining for CD³/CD⁸ and would have been misdiagnosed on immunohistochemistry alone. Median age of RCD II diagnosis was 63 years, and median time to RCD II development from CD diagnosis was 9 years. Mean and median follow up was 6 years. The mean and median % aberrancy of IELs were 73% and 79%. The mean and median % aberrancy of those who died (n=5, 4EATL, 1 neuro-coeliac) were 75% and 80% respectively, and of those who survived were 68% and 66%, respectively. All patients were treated with budesonide which improved clinical and histological findings but serial flow studies where available failed to demonstrate a reduction in the degree of aberrancy. 5 patients received ASCT for RCD II alone. On follow up, 1 patient had complete loss of clonality in spite of persistent aberrancy (43%) 11 yrs post ASCT. A further patient demonstrated a drop in aberrancy from 52% to 21% within 4 months of ASCT but experienced a steady rise again to 47%, 55%, and 72% at 1, 2 and 8 years post ASCT with the eventual development of EATL at 9 years post ASCT.

Conclusion

Flow cytometry is an efficient and reliable method to asses for RCDII. Mortality risk appears to correlate with the degree of aberrancy. Serial measurements demonstrating a steady rise in the percentage of aberrant IELs may signal impending EATL.

Introduction

The presence of an aberrant clonal IEL population is the hallmark of RCDII. We have observed patients who have clinical features of RCDII but do not fit the classical immunophenotypic or molecular features of same.

Aims & Methods

Our aim was to describe the profile of RCDII patients who present with classical aberrancy in the absence of clonality or atypical aberrancy +/- clonality.
We conducted a retrospective review of flow cytometry and TCR-GR analysis of RCDII patients in University Hospital Galway over a 14 year period.

Results

We included 13 RCDII patients, 5 males and 7 females, with a median age of 62 years at RCDII diagnosis. 6 patients had classical RCDII, median 80% aberrant IELs (cytoCD3+/sCD3-/sCD8-) and had a clonal TCR-GR. Of the remaining 7 patients, 4 had classical aberrancy (median 52%) without clonality, including 1 who lost the TCR-GR clone 1 year post autologous stem cell transplant but whose aberrancy persisted (43%) 10 years later, and 1 who subsequently developed a clonal TCR-GR on follow up. 2 patients had an atypical aberrant IEL population without clonal TCR-GRs; one of whom developed lymphoma 3 years post RCDII diagnosis and the other remains under surveillance (16% classical aberrancy, 41%NK cells). The remaining patient has a mixed aberrant IEL population (71% cytoCD3+/sCD3-/sCD8+, 19% cytoCD3+/sCD3-/sCD8-) but has a clonal TCR-GR. Mortality rate for the classical RCD II was 66% compared to 14% in variant RCD II.

Conclusion

​The heterogeneity of RCDII poses many diagnostic challenges. Newer sequencing technologies will likely aid the expansion of the diagnostic criteria to include variant RCDII. While follow up is ongoing, variant RCDII maybe associated with a lower mortality.

Clinical Case Summary

Coeliac disease is an autoimmune disorder triggered by gluten exposure. It often overlaps with microscopic colitis, particularly in refractory cases, posing treatment challenges. Upadacitinib, a Janus Kinase (JAK) 1 inhibitor, targets key inflammatory pathways by blocking JAK enzyme activity. We describe the efficacy of Upadacitinib in treating refractory coeliac disease with concomitant microscopic colitis, resulting in clinical and histological remission.
A 46-year-old woman diagnosed with coeliac disease in 2014, initially presenting with chronic diarrhea. Coeliac serology revealed markedly elevated anti-Gliadin IgG levels and Tissue Transglutaminase IgA. Duodenal biopsies demonstrated mild villous blunting, crypt hyperplasia, and increased number of intraepithelial lymphocytes (IELs). Following diagnosis, her symptoms resolved with strict adherence to gluten-free diet.
Despite continued dietary adherence, she experienced recurrent symptoms over subsequent years. In March 2021, repeat endoscopy appeared normal macroscopically, though histology revealed increased IELs and mild villous blunting. Concurrent colonoscopy identified features consistent with microscopic colitis.Two Budesonide courses yielded minimal improvement; coeliac serology remained elevated.
During this period, she was also initiated on Upadacitinib for psoriatic arthritis. Her symptoms subsequently resolved over several months of treatment. At approximately 12 months, serology showed normalization of coeliac antibodies, remaining negative since October 2022. Recent endoscopy in March 2025 revealed no evidence of active coeliac disease, and duodenal biopsies showed restoration of normal villous architecture and no significant increase in IELs.
This case supports the potential of JAK inhibitors in treating refractory coeliac disease with microscopic colitis, especially when standard therapies fail. Recognizing the frequent overlap of these conditions is crucial for effective management.

References

Figure 1 - Index endoscopy in March 2021. Endoscopic findings of normal duodenum examined under WLE, NBI or TXI
Figure 2 - Endoscopy findings part way through Upadacitinib therapy, demonstrating decreased folds found in duodenum with patchy, subtle changes best visualised under TXI
Figure 3 - Latest endoscopy findings in March 2025 whilst on Upadacitinib for 3 years, demonstrating normal duodenum without endoscopic evidence of coeliac disease