Use of vonoprazan, a novel potassium-competitive acid blocker, for the treatment of proton pump inhibitor-refractory reflux esophagitis in patients with systemic sclerosis

Abstract

Objective:

Proton pump inhibitor-refractory reflux esophagitis is one of the intractable conditions of systemic sclerosis for which new treatments are required. Vonoprazan is a novel potassium-competitive acid blocker and has been shown to have several advantages over conventional proton pump inhibitors, including a long duration of gastric acid suppression.

Methods:

To investigate the efficacy of vonoprazan for treating proton pump inhibitor-refractory reflux esophagitis in patients with systemic sclerosis, 10 patients with proton pump inhibitor-refractory reflux esophagitis who were switched to vonoprazan were selected from our systemic sclerosis database. Reflux esophagitis was evaluated by endoscopy, and gastroesophageal reflux disease–related symptoms were assessed by the frequency scale for the symptoms of gastroesophageal reflux disease questionnaire before and after switching from proton pump inhibitor to vonoprazan at an average interval of 3.5 [2–5.5] months.

Results:

After switching patients to vonoprazan, the endoscopic findings of reflux esophagitis were significantly improved (p = .033), and six patients (60%) achieved mucosal healing. The total frequency scale for the symptoms of gastroesophageal reflux disease score was also significantly decreased (p = .043), mainly by improving the acid reflux score. Vonoprazan was well tolerated and was continued for 15.5 [11.25–23.75] months in all patients.

Conclusion:

Vonoprazan is a potential treatment option for treating proton pump inhibitor-refractory reflux esophagitis in systemic sclerosis patients.

Introduction

Systemic sclerosis (SSc) is a connective tissue disease characterized by microvasculopathy, immune activation, and excessive fibrosis in the skin and various internal organs. ¹ The gastrointestinal tract is the most frequently affected internal organ system and is involved in approximately 90% of patients with SSc. ² In addition, the gastrointestinal tract involvement is known as one of the leading causes of SSc-related death. ³ Gastroesophageal reflux disease (GERD) is associated with weight loss, depression, and impaired quality of life, and reflux esophagitis increases the risk of esophageal stricture and dysplasia, including Barrett’s esophagus and esophageal adenocarcinoma.^2,3 According to the updated European League Against Rheumatism (EULAR) recommendations for the treatment of SSc, proton pump inhibitors (PPIs) and prokinetic drugs are recommended as treatments for SSc-related GERD. ⁴ However, some patients experience reflux esophagitis refractory to the maximum dose of conventional PPIs. In this case, the combination of PPIs with antacids, H₂ blockers or a gamma-aminobutyric acid receptor type B agonist or surgical intervention are potential options, but there is no evidence to support anecdotal treatments in SSc patients. ⁵ The treatment refractoriness of SSc-related GERD could be attributable to the long acid exposure time in the esophagus and decreased esophageal motility. ⁶ In clinical practice, PPI-refractory GERD is one of the intractable conditions of SSc for which new treatments are required. ²

Vonoprazan is a novel potassium-competitive acid blocker and has been shown to have several advantages over conventional PPIs, including a long duration of gastric acid suppression. ⁷ Recent studies have demonstrated the superiority of vonoprazan over conventional PPIs in terms of healing mucosal breaks and their maintenance in patients with reflux esophagitis. ⁷ The high mucosal healing rates were also reported in patients with PPI-refractory reflux esophagitis treated with vonoprazan.^8–10 Here, we examined the efficacy of vonoprazan for treating PPI-refractory reflux esophagitis in SSc patients using a single-center cohort database.

Methods

Study population

This report describes a single-center, retrospective study enrolling SSc patients with PPI-refractory reflux esophagitis. Patients were selected from the SSc database at Nippon Medical School Hospital since August 2014 based on (1) the fulfillment of the 2013 American College of Rheumatology (ACR)/EULAR classification criteria for SSc; ¹¹ (2) reflux esophagitis confirmed by endoscopy; (3) switch from PPI to vonoprazan due to PPI-refractory reflux esophagitis, which was defined as having esophageal mucosal breaks despite continuous treatment by an 8-week or longer administration of standard-dose PPI (30 mg daily for lansoprazole, 20 mg daily for rabeprazole, and 20 mg daily for esomeprazole; these dosages were the maximum approved by health insurance system in Japan); ⁸ and (4) availability of a follow-up endoscopy conducted within 10 months. Vonoprazan was started on the same day of the baseline endoscopy at 20 mg once daily, and the dosage was adjusted if necessary. This study was approved by the Ethics Committee at Nippon Medical School Hospital (27-07-462), and written informed consent was obtained from all patients.

Clinical assessment

According to our prospectively collected SSc database, a complete medical history, physical examination, and laboratory evaluations were performed for each patient at the time of enrollment, and limited evaluations were conducted at each follow-up visit. ¹² Information on organ involvement and treatment, including medications, such as PPIs, H₂ blockers, antacids, and vonoprazan, was recorded on a regular basis.

The efficacy of vonoprazan was assessed by serial changes in the endoscopic findings and the frequency scale for the symptoms of gastroesophageal reflux disease (FSSG) questionnaire before and after switching from PPI to vonoprazan. The Los Angeles (LA) classification was used for the endoscopic grading of reflux esophagitis. ¹³ An endoscopic response was defined as mucosal healing. The FSSG score, including the components of acid reflux and dysmotility, was developed for objective evaluation of GERD symptoms. ¹⁴ Esophageal function was examined by high-resolution manometry (HRM; Starlet, Star Medical, Inc., Tokyo, Japan) to measure lower esophageal sphincter basal pressure and the distal contractile integral (DCI). ¹⁵ Esophageal motility was classified according to the Chicago Classification v3.0 criteria. ¹⁶ The normal cutoff value of each parameter with the Starlet system was determined by referring to examination values from healthy subjects.

Statistical analysis

All continuous variables are shown as the median and interquartile range (IQR). Paired continuous variables were compared with nonparametric Wilcoxon’s test. Statistical analysis was performed using SPSS 25.0 statistical software (SPSS; Chicago, IL, USA).

Results

Of the 260 patients registered in our SSc database, 15 patients had PPI-refractory reflux esophagitis, requiring a switch from PPI to vonoprazan, but 5 patients did not receive a timely follow-up endoscopic evaluation or were lost during follow-up. As a result, 10 patients who underwent follow-up endoscopy and completed the FSSG questionnaire at an interval of 3.5 [2–5.5] months were eligible for this study. The patients’ demographic and clinical characteristics at baseline are shown in Table 1. The mean disease duration from non-Raynaud’s symptoms was 11.3 ± 7.5 years, and half of the patients were classified as having diffuse cutaneous SSc. All the patients took a maximum dose of PPIs for 8 weeks or longer with concomitant use of antacids (n = 8) and/or H₂ blocker (n = 1), and four patients experienced a switch from other PPIs. The circumferential extent of reflux esophagitis was variable among the patients, ranging from LA-A to D. HRM demonstrated that the DCI was remarkably decreased, and all but one patient showed absent contractility. Despite the use of PPIs, these patients had severe acid reflux and dysmotility symptoms, as shown by the FSSG score.

Table 1.

Baseline characteristics of the SSc patients examined.

Demographic and clinical characteristics	n = 10
Female	90%
Age (years)	58.5 [49.5–66.25]
Disease duration (years)	10 [5.25–13]
Diffuse cutaneous SSc	50%
SSc-related autoantibodies
Anti-topoisomerase I	30%
Anticentromere	40%
Anti-U1RNP	20%
Organ involvement
Digital ulcer	60%
Upper GI involvement	100%
Lower GI involvement	30%
ILD	70%
Heart involvement	20%
Pulmonary arterial hypertension	10%
Renal crisis	0
PPI
Lansoprazole	40%
Rabeprazole	50%
Esomeprazole	10%
Endoscopic reflux esophagitis classification
LA-A	20%
LA-B	30%
LA-C	30%
LA-D	20%
HRM parameters
Lower esophageal sphincter pressure (mm Hg)	18.05 [9.725–21.275]
DCI (mm Hg/cm/s)	6.25 [1.825–24.45]
Esophageal motility by HRM
Normal	10%
Absent contractility	90%
FSSG score
Total score (maximum 48)	21 [15.25–28]
Acid reflux score (maximum 28)	14.5 [11.25–16]
Dysmotility score (maximum 20)	7.5 [4–10.75]

SSc: systemic sclerosis; U1 RNP: U1 ribonucleoprotein; GI: gastrointestinal; ILD: interstitial lung disease; PPI: proton pump inhibitor; LA: Los Angeles; HRM: high-resolution manometry; DCI: distal contractile integral; FSSG: frequency scale for the symptoms of gastroesophageal reflux disease; IQR: interquartile range.

Continuous variables are shown as the median [IQR].

After switching from PPI to vonoprazan, the endoscopic findings of reflux esophagitis were significantly improved (p = .033), and six patients (60%) achieved mucosal healing and thus were classified as endoscopic responders (Figure 1). The total FSSG score was also significantly decreased (p = .043), mainly by improving the acid reflux score (14.5 [11.25–16] to 7 [0–16.75], p = .051) rather than the dysmotility score (7.5 [4–10.75] to 2 [0–11], p = .12). Interestingly, the endoscopic response and changes in the FSSG score were not always concordant; the FSSG scores were improved even in two endoscopic nonresponders, which resulted in an improvement of either the endoscopic findings or GERD-related symptoms in 80% of SSc patients with PPI-refractory reflux esophagitis. In contrast, in the remaining two nonresponders, reflux esophagitis worsened with a sustained high FSSG score. When the baseline characteristics were compared between six endoscopic responders and four nonresponders, the nonresponders tended to have a higher frequency of lower gastrointestinal involvement, such as a history of pseudoileus and/or massive weight loss (75% vs 0%).

Figure 1.

Serial changes in the Los Angeles (LA) classification for endoscopic grading of reflux esophagitis and the frequency scale for the symptoms of gastroesophageal reflux disease (FSSG) score before and after vonoprazan treatment. The hashtag indicates endoscopic responders, while the asterisk denotes nonresponders. Statistical comparisons were made using Wilcoxon’s test.

Vonoprazan was well tolerated and was continued for 15.5 [11.25–23.75] months in all patients, including the nonresponders, who were treated with a double dose of vonoprazan in combination with antacids.

Discussion

This analysis using cohort database demonstrated that mucosal healing was achieved in 60% of SSc patients with PPI-refractory reflux esophagitis by treatment with vonoprazan, a novel potassium-competitive acid blocker. In addition, vonoprazan improved GERD-related symptoms as assessed by the FSSG score, and an improvement of either the endoscopic findings or GERD-related symptoms was observed in 80% of the patients. Taken together with no short-term safety concerns, these findings suggest the potential utility of vonoprazan for the treatment of PPI-refractory reflux esophagitis in SSc patients.

Vonoprazan is a new class of drug that competitively blocks the potassium-binding site of H+, K+-adenosine triphosphatase and has an alkaline pKa of 9.06, which enables it to reach a high level of accumulation in acidic environments, such as the intracellular canaliculi of parietal cells. ⁷ As a result, acid suppression with vonoprazan is much quicker and more profound than that of conventional PPIs. ⁷ In addition, vonoprazan is superior to conventional PPIs in terms of the 24-h pH > 4 holding time, ¹⁷ thereby achieving good control of nocturnal acid breakthrough in the majority of patients with GERD. Since a longer acid exposure time in the esophagus in SSc patients versus non-SSc controls has been shown to be one of the major contributing factors for PPI resistance, ⁶ vonoprazan may be an ideal treatment option to overcome this underlying mechanism.

The high mucosal healing rate of ~90% was also reported in patients with PPI-refractory reflux esophagitis treated with vonoprazan.^8–10 On the contrary, the mucosal healing rate in this study was 60%, potentially reflecting the refractoriness of SSc-related reflux esophagitis. The endoscopic nonresponders tended to have concomitant lower gastrointestinal involvement, while the baseline parameters of endoscopic severity, the FSSG score, and esophageal motility evaluated by HRM were not different between the responders and nonresponders. This finding suggests that refractoriness to vonoprazan might be associated with impaired peristalsis of the entire digestive tract and the resultant prolonged gastric retention time, rather than insufficient suppression of nocturnal acid breakthrough.

These results suggest that vonoprazan is a potential treatment option for PPI-refractory reflux esophagitis in SSc patients. Our study had a major limitation, which was a preliminary, database-based study of a small number of patients lacking a control group, but future randomized controlled trials are warranted.