
==== Front
Curr Ther Res Clin Exp
Curr Ther Res Clin Exp
Current Therapeutic Research, Clinical and Experimental
0011-393X
1879-0313
Elsevier

S0011-393X(24)00026-2
10.1016/j.curtheres.2024.100756
100756
Case Report
Rapid Remission With Upadacitinib in a Child With Refractory Crohn's Disease and ATM Mutation: A Case Report
Liu Yan MD
Song XiaoMei MD
Xiang LingYa MD
Tan Wei MD
Zou Min MD
Guo Hong MD hguo_cgh2021@163.com
⁎
Department of Gastroenterology, Chongqing General Hospital, Chongqing University, Chongqing, China
⁎ Address correspondence to: Hong Guo, MD, Chongqing General Hospital, 118, Xingguang Avenue, Liangjiang New Area, Chongqing, 401147, China. hguo_cgh2021@163.com
30 7 2024
2024
30 7 2024
101 10075614 3 2024
20 7 2024
© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Managing pediatric Crohn's disease (PCD) presents challenges due to severe complications and higher biologic therapy needs. Transitioning from anti–tumor necrosis factor agents to off-label therapies adds complexity. Although upadacitinib has demonstrated efficacy and tolerability in adult inflammatory bowel disease and pediatric atopic dermatitis, there are limited data for its application in PCD. This case report delineates successful remission with upadacitinib in a child with CD refractory to infliximab, ustekinumab, adalimumab, thalidomide, and prednisone. Notably, the patient carried an ataxia telangiectasia mutated (ATM) gene mutation. These findings provide valuable evidence for PCD management and highlight the potential benefits of upadacitinib in this population.

Key words

ataxia telangiectasia mutated
case report
child
refractory Crohn's disease
upadacitinib
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pmcIntroduction

Inflammatory bowel disease (IBD) is a chronic relapsing disease that afflicts millions of patients with bowel damage and extraintestinal manifestations, including ulcerative colitis (UC) and Crohn's disease (CD). Pediatric CD (PCD), referring to the onset of the disease in individuals aged <18 years, is characterized by a higher disease burden compared with that in adult-onset patients, encompassing escalated rates of disease progression, the occurrence of penetration and/or stenosis, perianal complications, and the need for biologic therapy. Moreover, children and adolescents with PCD encounter hindrances in growth, delayed onset of puberty, and the psychological repercussions associated with chronic illness.

The main therapeutic modalities for IBD have involved 5-aminosalicylate, corticosteroids, immunomodulators, biologics, and small-molecule agents. Presently, within the spectrum of biologics and small molecules, only anti–tumor necrosis factor (TNF) agents (including infliximab [IFX] and adalimumab) have been approved by the Food and Drug Administration for PCD. However, the immunogenic nature of anti-TNF agents can lead to potential risks such as allergic reactions, adverse events, and the primary or secondary loss of response.1 Transitioning to alternative therapeutic agents in patients with PCD, especially those with a genetic mutation and refractory to TNF inhibitors, poses significant challenges for clinicians, involving factors such as the need for off-label treatment, insurance claim denials, uncertainty in dosage and tolerability, and the risks of treatment delays.

Upadacitinib (UPA) is a selective Janus kinase (JAK)-1 inhibitor known for its rapid onset and strong efficacy. It has been proven to be effective and tolerable in treating pediatric atopic dermatitis (AD), adult CD, and UC2; however, it has not been approved for PCD, and there are very few prior reports of such patients. Here, we present a case of a child with CD refractory to multiple therapies, carrying an ataxia telangiectasia mutated(ATM) gene mutation, who achieved remission with UPA. Our aim was to provide valuable evidence for treating refractory PCD, particularly in patients with this gene mutation, to promote the progress of medical insurance coverage.

Case Description

At the age of 11 years, a male child presented with intense abdominal pain, diarrhea, perianal discomfort, and weight loss. Diagnostic modalities, including laboratory analyses, computed tomography enterography, perianal magnetic resonance imaging, gastrointestinal endoscopy, and capsule endoscopy, converged to confirm the diagnosis of CD (Montreal classification A1L3B2pG1) and thalassemias. At diagnosis, his PCD Activity Index (PCDAI) score was 50, indicating severe disease activity. We conducted immune-related laboratory examinations, including profiles for antinuclear antibodies, vasculitis antibodies, immunoglobulins, and lymphocyte subsets, all of which were within normal ranges. The interleukin (IL)-6 and TNF-α levels were 19.1 pg/mL (reference range, 0–5.3 pg/mL) and 24.7 pg/mL (reference range, 0–4.6 pg/mL), respectively.

Despite a 2-year regimen of IFX, the patient encountered the challenge of secondary nonresponse without remission, even with an optimized IFX dosage (5 mg/kg every 4 weeks) and enteral nutrition therapy. Then, the patient underwent surgical treatment for active perianal lesions. Subsequent therapeutic interventions, including 1 year-long ustekinumab therapy in combination with thalidomide followed by a 4-month adalimumab regimen, failed to alleviate symptoms or improve clinical indices. All drug concentrations remained within the optimal therapeutic range as assessed through therapeutic drug monitoring. Significantly, a subsequent alternative 1-month oral prednisone therapy was prematurely self-terminated due to the onset of severe depressive symptoms. In the following 6 months, the patient refrained from seeking hospital-based treatment, opting instead for self-management of partial enteral nutrition and intermittent oral administration of traditional Chinese medicine decoctions.

During this period, to explore the underlying causes of the patient's treatment refractoriness and alternative therapeutic mechanisms, whole exome sequencing was conducted. However, no mutations with clinically relevant and compelling evidence of pathogenicity were revealed, except for a mutation in the ATM gene (Table 1), a critical regulator in the repair of DNA damage. Previous studies have shown that ATM gene mutations can lead to ataxia telangiectasia, a genetic disorder presenting symptoms such as ataxia, telangiectasia, growth retardation, immunologic abnormalities, and an increased cancer risk.3 In this patient's case, growth retardation and suspected immune dysfunction were observed, with no other manifestations. Through literature review, it was found that ATM gene mutations may exhibit a minor association with the onset of IBD.4 Furthermore, there is a possible relationship between the ATM and JAK-STAT pathways, suggesting that JAK inhibitors might be considered a potential therapy for this patient.5Table 1 Ataxia telangiectasia mutated gene mutation.

Table 1Gene name	Mutation site	Chromosomal location (hg19)	Mutation type	Zygotic state	
ATM	8.5NM_000051: exon44:
c.6451dupA:
p.R2151Kfs*10	chr11:10
8190783	Frameshift insertion mutation	Heterozygote	
ATM = ataxia telangiectasia mutated.

Upon rehospitalization at the age of 15 years, the patient presented with alarming symptoms of emaciation, abdominal pain, 6 to 8 daily episodes of diarrhea with blood presence, and growth retardation. In addition, his PCDAI score had risen to 62, with a diminished body mass index (BMI) of 12.5 kg/m2. Laboratory results are detailed in Table 1, and the Simple Endoscopic Score for CD reached 27 (Figure). After the improvement of hemoglobin and albumin levels through nutritional support and blood transfusion, a daily dose of 45 mg of UPA was commenced by reviewing the literature and obtaining informed consent from the parents of the child. Remarkably, within 2 weeks, a discernible improvement in symptoms and clinical indicators was observed. By the eighth week, biomarker remission was achieved, synchronizing with a substantially reduced PCDAI score of 5 and a BMI elevation to 16.0 kg/m2. A follow-up colonoscopy at 12 weeks further substantiated the therapeutic efficacy, revealing a Simple Endoscopic Score for CD of 12 (Figure). Then, the dosage was initially reduced to 30 mg daily. After 4 weeks, fecal calprotectin returned to normal, and the dosage was further reduced to 15 mg daily for maintenance therapy. By the 26th week, the patient exhibited a positive mental state and favorable indicators (Table 2), with a BMI elevation of 18.6 kg/m2. Throughout the treatment period, we implemented a standardized procedure for potential adverse event management and screening. Apart from mild leukopenia at week 26, no other adverse events, including infections, thrombosis, lipid abnormalities, cardiovascular events, or malignancies, were observed.Figure Colonoscopy images before and after the treatment with upadacitinib. (A, a) Ascending colon, (B, b) descending colon, (C, c) sigmoid colon, and (D, d) rectum.

Figure

Table 2 Laboratory values relative to upadacitinib initiation.

Table 2Laboratory Index	Week 0	Week 2	Week 8	Week 12	Week 26	Reference range	
White blood cell (109/L)	10.8	8.5	7.2	6.2	3.8	4.1–11	
Hemoglobin (g/L)	81	92	115	115	125	129–172	
ESR (mm/h)	30	17	16	16	7	0–15	
CRP (mg/L)	37	6.39	5.53	2.9	3.83	≤10	
Albumin (g/L)	28.6	37	46	40.9	44.2	42–56	
Abbreviations: ESR = erythrocyte sedimentation rate; CRP = C-reactive protein.

Discussion

The incidence of PCD is escalating, frequently leading to an augmented disease burden and an elevated demand for biologic therapy compared with adult-onset CD. Effective management of PCD necessitates consideration of growth, development, and psychological aspects alongside disease-specific treatment. In this case, the patient presented severe depression during prednisone therapy, highlighting the potential neuropsychiatric adverse reactions associated with corticosteroids,6 which underscores the imperative need for heightened awareness regarding the psychological and mental health of individuals undergoing corticosteroid therapy, with special consideration for pediatric patients.

The primary treatment modalities for PCD encompass approved corticosteroids, immunomodulators, enteral nutrition, anti-TNF agents, off-label vedolizumab, ustekinumab, and JAK inhibitors.7 In this case, the patient encountered a secondary nonresponse to IFX and a primary nonresponse to adalimumab. IFX, a human–mouse chimeric monoclonal anti-TNF agent, emerges as the preferred biologic for patients with PCD, which can induce and maintain remission for moderate-to-severe CD in children. A previous study revealed that adalimumab could induce remissions more frequently than placebo in patients with CD who experienced intolerance or secondary nonresponse to IFX.8 Nevertheless, in instances where patients exhibit refractoriness to anti-TNF agents, the utilization of off-label biologics with other mechanisms becomes a necessary recourse. Among these alternatives, ustekinumab, an IL-12/23 inhibitor, has demonstrated both efficacy and tolerability in pediatric patients with moderate-to-severe CD, as supported by prior studies. However, this patient did not achieve remission from ustekinumab. Exclusive enteral nutrition plays a pivotal role in the therapeutic approach to PCD. However, the induction and maintenance of remission in individuals with severe CD cannot be accomplished solely through exclusive enteral nutrition.

When the patient experienced refractoriness to multiple therapies, his therapeutic approach became intricate and challenging. Through whole exome sequencing, a mutation in the ATM gene was identified. One study suggested that in the intestinal epithelium of mice with telomere dysfunction, the activation of ATM induced by DNA damage led to the subsequent ATM-mediated phosphorylation and activation of the YAP1 transcriptional coactivator, which upregulates pro–IL-18, a pivotal immune regulator implicated in the pathogenesis of IBD.4 It is possible that the ATM/YAP1/pro–IL-18 pathway might be a potential contributor to IBD. Regarding the association between JAK inhibitors and ATM gene mutations in this patient, recent research reported that the ATM–JAK–PD-L1 signaling pathway has been implicated in fostering cancer cell proliferation and metastasis. Additionally, one study reported in a rat model of ischemia-reperfusion injury with DNA damage that the JAK-STAT and ATM/Chk2 pathways were simultaneously activated and concurrently inhibited by JAK inhibitors, indicating potential crosstalk between these 2 pathways.5 Previous research elucidated the interaction between the DNA damage-regulated kinase ATM/ATR and the cell signaling regulatory protein SOCS1,9 which is now definitively identified as a negative regulator of the JAK1-STAT pathway.10 We hypothesized that mutations in the ATM gene, blocking DNA damage repair, might activate the JAK-STAT pathway, leading to inflammatory responses and immune dysfunction, which were potentially modulated by JAK inhibitors. Nevertheless, further studies are required to clarify the relationship between the ATM gene and IBD, as well as to understand the interaction between the ATM gene and the JAK-STAT pathway in inflammatory and immune-related disorders.

Consequently, an alternate approach was pursued utilizing an oral small-molecule JAK inhibitor, UPA. Then, the patient exhibited rapid remission of clinical symptoms, laboratory results, and endoscopic observations. The dysregulation of immune responses in patients with IBD involves a crucial role played by the JAK-STAT pathway, including suppression of regulatory T cells, upregulation of proinflammatory cytokines, and proangiogenic factors.11 Intracellular enzymes known as JAKs (JAK1, JAK2, JAK3, and TYK2) are responsible for transmitting signals related to cytokines and growth factors, participating in diverse cellular processes such as inflammatory responses, hematopoiesis, and immune surveillance.12

UPA serves as a selective and reversible inhibitor of JAK1, acting precisely within cells and effectively targeting the downstream inflammatory pathway with an enhanced safety profile. UPA has demonstrated efficacy and tolerability in pediatric AD, adult CD, and UC in clinical trials and real-world experience,2 which have received the corresponding Food and Drug Administration approval. The recommended dosage, which varies across different diseases, is 15 mg daily for pediatric AD.13 During the induction phase of adult IBD treatment, the recommended dosage is 45 mg daily, and for the maintenance phase, a dosage of 15 mg daily is advised. In cases where patients face refractory or severe conditions, a maintenance dosage of 30 mg once daily is considered. At the time of writing this paper, data in PCD are limited to a single-center small-sample experience and 1 case report. In this recent study, 75% of 20 adolescents with IBD, including 9 with CD, achieved steroid-free remission after 6-month course of UPA, with minimal adverse effects noted.14 Seventy-five percent of the patients were administered an induction dose of 45 mg daily, followed by a maintenance dose of 30 mg daily. In another case, a 12-year-old patient with refractory CD attained clinical remission after an 8-week regimen of UPA at 45 mg daily.15 Consequently, we commenced an induction regimen of 45 mg daily for this patient, followed by a gradual dose reduction for maintenance.

Regarding tolerability, previous research reported increased risk of infections, anemia, neutropenia, lipid abnormalities, creatine kinase elevation, and thrombosis after the UPA therapy.2,13 Concerning our case, no adverse events were observed during the follow-up period, indicating the tolerability of high-dose UPA induction therapy in PCD patients.

Limitations

This case report has certain limitations. The interaction between the patient's ATM gene and the JAK-STAT pathway is based on postliterature speculation, with no direct experimental evidence for validation. Future studies involving analyses of the patient's intestinal tissue samples could potentially verify this connection.

Conclusion

Presently, when pediatric patients with CD exhibit intolerance or refractoriness to anti-TNF agents, especially those with a genetic mutation, the transition to alternative off-label therapies poses a challenge. The existing data on PCD treated with UPA remain limited. Herein, we report a case of a PCD patient refractory to multiple biologics, carrying an ATM gene mutation, effectively treated with UPA, with the aim of contributing valuable evidence for the management of PCD and advancing high-quality clinical trials and insurance coverage for this vulnerable population.

Declaration of competing interest

None.

Appendix Supplementary materials

Image, application 1

Acknowledgments

Fully informed written consent was obtained from the parents of the patient included in this study.

Authors Contributors

Y. Liu reviewed the literature and drafted the manuscript. M. Zou reviewed the literature and critically reviewed the paper. X. Song, L. Xiang, and H. Guo participated in the clinical assessment and treatment of the patient and critically reviewed the paper. All authors read and approved the final manuscript.

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.curtheres.2024.100756.
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