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Celiac.com 08/14/2024 - Refractory celiac disease type II, commonly referred to as RCDII, is a rare and severe form of celiac disease. Unlike typical celiac disease, RCDII does not respond to a gluten-free diet. This condition is marked by the clonal expansion of abnormal intraepithelial lymphocytes, which can lead to high mortality rates due to the lack of effective treatment options. One promising treatment involves the use of tofacitinib, a small-molecule inhibitor targeting specific enzymes known as JAK1 and JAK3. This study explores the potential of tofacitinib to induce clinical remission in patients with RCDII. Study Overview and Methodology This open-label clinical study involved six patients diagnosed with RCDII, who had not responded to previous treatments, including the drug cladribine. Four patients were treated according to the study protocol in the Netherlands, while two patients in Germany received similar treatment outside the protocol. The patients were given 10 mg of tofacitinib twice daily for 12 weeks. The study aimed to assess both the clinical and immunologic responses to the treatment. Baseline Characteristics of Patients At the beginning of the study, all patients exhibited significant symptoms of malabsorption, such as weight loss, diarrhea, abdominal pain, and low levels of albumin in the blood. Small intestine biopsies showed a high percentage of abnormal intraepithelial lymphocytes, ranging from 70% to 90%. Two patients also had ulcerative jejunitis, a severe condition causing ulcers in the small intestine. Histological examinations revealed varying degrees of villous atrophy, a condition where the finger-like projections in the small intestine are damaged, affecting nutrient absorption. Clinical Response to Tofacitinib Treatment All patients completed the 12-week treatment course with tofacitinib. Within a span of two to fourteen days, patients experienced a noticeable resolution of diarrhea and abdominal pain. Additionally, they showed significant weight gain, with a median increase of over 12% by the end of the 12 weeks. One patient with severe ulcerative jejunitis was even able to discontinue total parenteral nutrition by week nine. However, upon discontinuation of tofacitinib, all patients quickly relapsed, experiencing weight loss and a return of symptoms. When tofacitinib treatment was resumed, patients again showed rapid and complete clinical improvement. Immunologic and Histologic Findings The primary immunologic endpoint was to achieve a reduction of at least 20% in the number of abnormal intraepithelial lymphocytes. This goal was not met by any patient. The median percentage of abnormal cells remained relatively unchanged from baseline to the end of the 12-week treatment period. Despite this, four out of six patients showed significant improvement in the histology of their small intestine, indicating mucosal healing. This improvement was particularly evident in patients with ulcerative jejunitis. Adverse Events and Safety Throughout the study, all patients experienced adverse events. The most common was lymphopenia, a condition characterized by low levels of lymphocytes in the blood. One patient suffered a serious adverse event, developing a pulmonary embolism associated with a line sepsis caused by a bacterial infection. This patient continued to receive tofacitinib at a reduced dose of 5 mg twice daily, with continued clinical improvement. No other serious infections were reported, and there was no progression to enteropathy-associated T-cell lymphoma in any patient. Extended Follow-Up and Long-Term Outcomes During an extended follow-up period of up to two years, the patients continued to show persistent clinical remission while on a reduced dose of tofacitinib. The median weight gain further increased, and duodenal biopsies indicated ongoing histologic improvement. Capsule endoscopy revealed complete or near-complete resolution of intestinal ulcerations in patients with ulcerative jejunitis. These findings suggest that tofacitinib not only provides short-term relief but also contributes to long-term clinical remission in patients with RCDII. Implications for Future Treatment of Celiac Disease This study is significant for several reasons. First, it demonstrates that tofacitinib can induce rapid and sustained clinical remission in patients with refractory celiac disease type II, a condition that has been notoriously difficult to treat. Second, the study's findings suggest that while tofacitinib may not reduce the number of abnormal intraepithelial lymphocytes, it effectively mitigates their harmful activity. This functional impact is crucial for improving patient outcomes. For those with celiac disease, particularly the rare and severe RCDII, this study offers hope for a viable treatment option where none previously existed. It also underscores the importance of continued research and clinical trials to explore and refine new therapies. The potential for tofacitinib to change the treatment landscape for RCDII patients is substantial, offering a path to better management and improved quality of life. Read more at: cghjournal.org