Introduction

C-reactive protein (CRP) and fecal calprotectin (FeCal) are non-invasive inflammatory biomarkers used to assess disease activity in UC. The Phase 3 QUASAR induction study evaluated the efficacy and safety of guselkumab (GUS), an IL-23 p19 subunit antagonist, in patients (pts) with moderately to severely active UC. Here, we analyze the effect of GUS treatment on CRP and FeCal through Week (Wk) 12 in pts with elevated CRP and/or FeCal.

Aims & Methods

Pts with a modified Mayo score of 5-9 and a Mayo endoscopy subscore ≥2 at baseline (BL) were randomized 3:2 to receive either GUS 200mg IV or placebo (PBO) IV at Wks0, 4, and 8. CRP and FeCal were assessed at BL, Wk4, Wk8 (for CRP only), and Wk12.

Results

A total of 701 pts were evaluated and approximately 50% of randomized pts had a history of inadequate response/intolerance to advanced therapies (ADT) for UC; 47.4% of these pts had inadequate response/intolerance to ≥2 ADT classes. Median BL concentrations of CRP and FeCal were similar between the GUS-treated and PBO-treated pts (4.34 vs 3.83mg/L and 1651 vs 1606mg/kg, respectively). Among pts with elevated CRP and/or FeCal at BL, greater reductions in CRP and FeCal were observed at the earliest timepoint assessed (Wk4) with GUS and continued through Wk12 compared with PBO (Table).
At BL, 248 GUS-treated pts and 160 PBO-treated pts had elevated CRP (>3mg/L); the proportions were similar between treatment groups (58.9% vs 57.1%, respectively). Among these pts, median change from BL in CRP concentration (mg/L) at Wk12 for the GUS and PBO cohorts were -3.99 and -0.51mg/L, respectively (nominal p<0.001); the proportions of pts achieving 50% and 75% reduction in CRP levels (or ≤3mg/L) at Wk12 were higher for GUS-treated pts than those receiving PBO (59.7% vs 28.1% and 47.2% vs 19.4%, respectively; both nominal p<0.001). Similarly, a higher proportion of GUS-treated pts achieved CRP≤3mg/L at Wk12 than PBO-treated pts (40.3% vs 16.3%, nominal p<0.001).
At BL, 333 GUS-treated pts and 225 PBO-treated pts had elevated FeCal (>250mg/kg); the proportions were similar between treatment groups (79.1% vs 80.4%, respectively). Median change from BL in FeCal concentration (mg/kg) for pts with elevated FeCal at BL at Wk12 were -800 and -86mg/kg for the GUS and PBO cohorts, respectively (nominal p<0.001); the proportions of pts achieving 50% and 75% reduction in FeCal levels (or ≤250 mg/kg) at Wk12 were higher for GUS-treated pts than those receiving PBO (51.1% vs 33.8% and 41.4% vs 23.6%, respectively; both nominal p<0.001). A larger percentage of pts treated with GUS achieved FeCal≤250mg/kg at Wk12 than pts treated with PBO (29.4% vs 17.3%, nominal p<0.001).

Conclusion

In this phase 3 induction study, pts with moderately to severely active UC and elevated inflammatory markers treated with GUS 200mg IV induction showed greater improvement from BL in both CRP and FeCal levels compared with PBO. Differences were observed as early as the first assessments at Wk4 and continued through Wk12.

Disclosure

Tadakazu Hisamatsu received consulting fees from Janssen Research & Development, LLC.
Laurent Peyrin-Biroulet reports personal fees from Janssen.
Axel Dignass reports fees for participation in clinical trials, review activities such as data monitoring boards, statistical analysis and end point committees from Janssen; consultancy fees from Janssen; and payment from lectures including service on speakers bureaus from Janssen.
Kuan-Hsiang G. Huang, Matthew Germinaro, Nicole Houck,Ye Miao, and Hongyan Zhang are employees of Johnson & Johnson and own company stock/stock options.
Marjorie Argollo reports consulting fees from Janssen.
Ken Takeuchi has served as a speaker for Janssen.
Rafal Filip reports lecture fees and research/education support from Janssen.
Jessica R. Allegretti is a consultant and speaker for Janssen.
Brian G. Feagan received consulting fees from Janssen; a member of the speakers bureau for Janssen; support for attending meetings and/or travel from Janssen; and participation on a Data Safety Monitoring Board or Advisory Board from Janssen.
Bruce E. Sandsreports grants, consulting and speaking fees and other support from Janssen.

Introduction

Tofacitinib, filgotinib, and upadacitinib, are Janus kinase inhibitors (iJAKs) approved for inflammatory bowel disease (IBD) treatment. Although no direct comparative studies exist, potential differences in efficacy and safety are attributed to in vitro-demonstrated affinity of each molecule for different JAK isoforms. JAK1 plays a crucial role in modulating cytokine-mediated immune responses, such as IL-6 and interferon, which are involved in inflammation and skin homeostasis. Its inhibition can promote conditions that may trigger acne.
Acne may be increased in iJAK-treated patients, meaning a clinical challenge for gastroenterologists.

Aims & Methods

A retrospective study was conducted at ten referral centers in Spain, including all IBD patients who had received iJAK therapy and had at least 3 months of follow-up. Demographic data, disease-related variables, and acne characteristics when appropriate, were collected. Univariate and multivariate logistic regressions were used to identify risk factors for acne; model discrimination was assessed by AUC.

Results

A total of 549 patients included: 258 (47%) were women; 354 (64%) had ulcerative colitis, 191 (35%) had Crohn’s disease and 1% had indeterminate colitis. Mean age was 41 years (IQR 30-52). 219 patients (40%) were treated with tofacitinib, 281 (51%) with upadacitinib, and 49 (9%) with filgotinib.
Ninety patients (16%) developed acne during iJAK treatment: 69% were mild, with only 4 severe cases (4%). Acne occurred early (median onset 42 days, IQR 7-122), predominantly on the face (56%), trunk (13%) or both (31%). Acne morphology included comedones (60%), papules (59%), pustules (39%), nodular-cystic (12%), scarring (9%); 48% showed more than one morphology.
Thirty-six patients received specific acne treatment: 89% topical (antiseptics, benzoyl peroxide, retinoids), 69% systemic (antibiotics, retinoids, antiandrogens), and 44% combined treatment. 83% of those patients responded to acne specific treatment, and only 8 patients (9% of those with acne; 1.5% overall) had to discontinue iJAK treatment, with acne resolving in all cases.
Acne developed in 26%, 6% and 6% of upadacitinib, tofacitinib and filgotinib treated patients respectively (p=0.001). Multivariate analysis showed that acne development was associated with upadacitinib (OR 10.28;IC95%=4,7–22,6; p<0,001) and history of acne (OR 3.52; IC95%=1,5–8,3; p=0,004), while older age (>35 years, OR 0.31; IC95% 0,11–0,83; p=0,02) and Crohn’s disease (OR 0.47; IC95% 0,25–0,90; p=0,02) showed to be protective. This model was reliable in predicting acne development (AUC 0.79). Additionally, univariate analysis showed high dose of iJAK was also associated with acne development, which could not be confirmed in multivariate analysis.

Conclusion

Acne occurred in a relevant proportion of iJAK-treated patients, was generally mild and manageable with dermatological care, and rarely required treatment discontinuation. Risk factors for iJAK-associated acne included use of upadacitinib (probably reflecting a greater affinity for JAK1) and history of acne, while older age and Crohn’s disease were protective.
Gastroenterologists should be aware of both likelihood and management of this specific adverse event when considering iJAK therapy.

Disclosure

Y G-L, MC, GB, ER, IB, DC, M B-dA, LM, I M-J, DG, IV have provided scientific advisory / participated in educational activities / received unrestricted research grants / received payments for lecturing from Johnson & Johnson, ​Takeda, Pfizer, Amgen, AbbVie, Lilly, AlfaSigma, Ferring, Gilead.

Clinical Case Summary

Seronegative enteropathies pose a complex diagnostic challenge, as their histology mimics celiac disease (CeD) (1). We report a 51-year-old patient with hypertension and osteoporosis, referred for abdominal pain, weight loss, and constipation. Blood tests showed no anemia; anti-transglutaminase and anti-endomysium antibodies were negative, but HLA typing was compatible with CeD. Ileocolonoscopy excluded IBD and microscopic colitis, while OEGD revealed villous atrophy (MARSH 3c). Negative anti-enterocyte antibodies, and exclusion of drugs and infections, led to a diagnosis of seronegative CeD. A gluten-free diet was started, but after 1 year, symptoms improved only partially despite good adherence. OEGD showed persistent duodenal damage with increased intraepithelial lymphocytes (IELs), CD3+ and CD8+ T-cells with monoclonal TCR expression (fig. 1), consistent with RCeD type 1, despite no overt malabsorption. The patient began prednisone 50 mg/day, then switched to open-capsule budesonide, with some clinical benefit but persistent atrophy.
A year later, his daughter was diagnosed with CVID and a heterozygous STAT3 variant (c.1252T>C, p.Cys418Arg), somatically acquired in NK-cell leukemia. A luciferase assay confirmed its gain-of-function (GOF) effect (fig. 2). Family studies revealed the same germline variant in the patient. His diagnosis was revised to STAT3 GOF-associated enteropathy. Further investigations revealed hypogammaglobulinemia, splenomegaly, bronchiectasis, and emphysema. Treatment with Ruxolitinib (a JAK1/2 inhibitor) was started, resulting in clinical and histological remission (fig. 3).
STAT3 GOF enteropathy is a very rare condition (2,3) that should be considered in the differential diagnosis of seronegative villous atrophy. Anti-JAK therapy may be effective (4).

References

References of the images:
Figure 1: Histologic aspects at diagnosis
Figure 2: Luciferase assay of STAT3
Figure 3: Histologic aspects after 1 year of therapy

1. Schiepatti A, Sanders DS, Baiardi P, Caio G, Ciacci C, Kaukinen K, et al. Nomenclature and diagnosis of seronegative coeliac disease and chronic non-coeliac enteropathies in adults: the Paris consensus. Gut. 2022 Jun 8;71(11):2218–25.
2. Vogel TP, Leiding JW, Cooper MA, Forbes Satter LR. STAT3 gain-of-function syndrome. Vol. 10, Frontiers in Pediatrics. Frontiers Media SA; 2023.
3. Flanagan SE, Haapaniemi E, Russell MA, Caswell R, Allen HL, De Franco E, et al. Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease. Nat Genet. 2014;46(8):812–4.
4. Kaneko S, Sakura F, Tanita K, Shimbo A, Nambu R, Yoshida M, et al. Janus kinase inhibitors ameliorate clinical symptoms in patients with STAT3 gain-of-function. Immunotherapy Advances. 2023;3(1).