Therapy in RCDII: Rationale for Combination Strategies?

Abstract

Refractory coeliac disease type II (RCDII) is characterized by a continuous gluten-independent duodenal immune activation with an extremely high risk of malignant transformation. It is therefore considered as an indolent lymphoma. RCDII is characterized by the presence of villous atrophy (Marsh III A-C) in combination with an aberrant intra- epithelial lymphocyte (IEL) population consisting of >20% sCD3-CD7+iCD3+ IELs. The sCD3-CD7+iCD3+ IELs are a heterogeneous lineage-negative cell population, consisting of cells that do or do not express CD127/IL7Rα. Experiments using IEL from non-RCDII patients have indicated that while the CD127- cells are IL-15 responsive, the CD127+ cells are not. Together with the observation that some patients express an aberrant (monoclonal) TCRγδ phenotype, this confirms the heterogeneity of the aberrant IEL population in RCDII and suggests that the aberrant cells are heterogeneous with respect to their response to common γ-chain cytokines. Although cladribine with or without autologous stem cell transplantation is effective in the treatment of signs and symptoms of RCDII and improves survival as compared to symptomatic topical steroid therapy, cladribine failures still bear a high risk of malignant transformation, and the rate of enteropathy-associated T-cell lymphoma (EATL) development in this subgroup is extremely high. It might be hypothesized that the heterogenous nature of aberrant IEL and the high risk of malignant transformation require a treatment strategy which is effective despite this heterogeneity. RCDII should be seen more in the light of a low-grade/no mass lymphoma or pre-EATL. We would suggest an upfront combination therapy approach integrating inhibition of downstream Jak-STAT signalling pathways with conventional therapy (2-CDA) to hopefully effectively treat signs and symptoms of RCDII and accomplish a more effective EATL prevention.

Recognising and Managing Refractory Coeliac Disease: A Tertiary Centre Experience

“…The capsule endoscopy should be repeated after a year to exclude the development of EATL in view of the high risk. It has been proposed that RCD type 2 should be renamed pre-EATL [ 17 ]. Double balloon enteroscopy may be required depending on the findings on capsule endoscopy in order to make a better assessment of an abnormality and obtain samples if required.…”

A Refractory Celiac Patient Successfully Treated With Mesenchymal Stem Cell Infusions

“…1,2 The few cases in which recovery from malnutrition with improvement of mucosal architecture has been observed were those treated with hematopoietic stem cell transplant, 6,7 and all the other therapeutic options have proved unfruitful. 4 However, in view of the aggressiveness of bone marrow transplant, alternative and safer strategies are eagerly awaited. Thanks to their peculiar biological properties, MSCs represent an attractive and safe tool for cellular treatment in immunemediated conditions.…”

“…1 Interleukin (IL)-15 plays a pivotal role in promoting T-cell cytotoxicity, survival, and lymphomagenesis, 3 although the therapeutic use of its blocking agents is still awaited. Therefore, the current treatment is based on the use of nontargeted immunomodulating agents that do not substantially modify the patients' outcome, 4 and autologous hematopoietic stem cell transplant, although performing better, 5,6 cannot be applied in all cases because of the substantial risk of morbidity and mortality in this clinical setting.…”

Improving outcomes of refractory celiac disease – current and emerging treatment strategies

“…One such agent already in use for rheumatoid arthritis and ulcerative colitis is the JAK3 inhibitor tofacitinib 92 that inhibits downstream signaling from the common g-chain receptor component of IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21, and it may find value in the setting of RCD2 in combination with other agents. 93 …”