Treatment of patients with symptomatic SSc and esophageal involvement is still an area of unmet need, as there is no available treatment with established efficacy. Administration of PPIs and prokinetic drugs do not appear to provide substantial symptomatic relief in patients with SSc and esophageal symptoms [5]. Pathophysiology of gastrointestinal dysmotility in SSc is multifactorial and different neurotransmitters could be involved in this process [15, 16]. Serotonin (5-HT) is considered a key neurotransmitter and acute studies, both in healthy subjects and patients with SSc, have shown that agonists of specific class of its receptors, such as 5-HT1A, could be a putative therapeutic option [6, 8, 9]. Buspirone had been initially developed for clinical use in the treatment of depression and anxiety disorders. Its mechanisms of action are thought to include agonistic actions, mainly on 5-HT1A receptors, but also on dopamine D2 receptors. Buspirone is absorbed rapidly and almost completely with a tmax = 0.89 ± 0.15 h [17].
To the best of our knowledge no previous study has prospectively investigated whether a pharmaceutical agent may help patients with SSc and esophageal involvement. The results of our open-label, prospective 4-week trial suggest that the 5-HT1A receptor agonist, buspirone, given orally for 4 weeks, significantly increases the LES resting pressure by 41 % to 220 % over the baseline values in almost 70 % of patients with SSc. Furthermore, patients with a less dilated esophagus as detected on chest CT had a better response to buspirone administration. This is an important aspect of our study, as patients with SSc undergo routine chest CT as a screening test for lung fibrosis. Many studies have suggested that measurement of esophageal coronal diameter on chest CT is a marker of the functional status of the esophagus in SSc and a dilated esophagus represents more severe visceral involvement [18, 19].
Herein, the 4-week administration of buspirone also alleviated heartburn and regurgitation in the majority of patients. Buspirone seems more effective for GERD-related symptoms, whereas symptoms related to esophageal hypomotility, such as dysphagia and chest pain are not affected. Thus, we could suggest that buspirone administration may be most helpful for the subgroup of SSc patients with reflux symptoms. An objective assessment of reflux response with pH-impedance measurement could certainly enhance our results.
As all patients were on PPIs before and during the study period, the strategy with add-on buspirone could be a worthwhile therapeutic option. Keeping in mind the anecdotal evidence that persistent reflux contributes significantly to the development of interstitial lung disease and/or progress, which is the leading cause of death in SSc, the potential beneficial effect of buspirone becomes more important. Buspirone-associated improvement in the severity of reflux symptoms can be explained by a strong stimulatory effect on LES resting pressure. However, other mechanisms cannot be excluded. Comorbid psychiatric diseases in patients with a chronic disorder, such as SSc, and especially anxiety, are common [20, 21]. Buspirone is used as anxiolytic drug in clinical practice. Therefore, a potential alteration in the sensitivity by decreasing the anxiety level may play a role in symptom improvement. As we did not include measurement of anxiety scores, this is a limitation of the present study. However, in the event that the main mechanism underlying symptom improvement with buspirone was the anxiolytic effect of the drug, other non-reflux symptoms should have been improved.
A limitation of the present study, due to restrictive regulatory rules that we were unable to overcome, is that it is not a randomized, placebo-controlled investigation and there is a lack of a control arm. Another limitation is the relatively small number of patients studied; however, we have to keep in mind that patients with SSc due to the chronic nature of their disease have several medical disabilities, making recruitment very challenging. The use of a validated questionnaire, such as the UCLA STCC SSc-GI [22] rather than a self-reported one could strengthen our results, however, this questionnaire, which covers a broad spectrum of gastrointestinal symptoms in patients with SSc, is not validated in Greek. Moreover, the majority of available questionnaires are focused on reflux symptoms rather than on dysmotility-associated symptoms characterizing SSc.
Buspirone was well-tolerated in the present study. Treatment interruption due to adverse effects (dizziness and nausea) was observed in only 4 out of 30 patients. Patients who completed the study reported sporadic and self-limited adverse effects that did not affect their daily activities.