Functional gastrointestinal disorders are increased in joint hypermobility‐related disorders with concomitant postural orthostatic tachycardia syndrome

Individuals with hypermobility spectrum disorders/hypermobile Ehlers‐Danlos syndrome (HSD/hEDS) frequently fulfill criteria for Rome IV functional gastrointestinal disorders (FGIDs). Postural orthostatic tachycardia syndrome (POTS) is also commonly reported in HSD/hEDS and may impact on co‐morbidity with and severity of FGIDs, although this remains to be studied. We determined the impact of concomitant POTS and HSD/hEDS on their association with Rome IV FGIDs.


| INTRODUC TI ON
The majority of subjects with HSD/hEDS are young-to-middle aged women, 1,2 in whom co-morbidity commonly stems from gastrointestinal complaints, which are most often attributable to functional gastrointestinal disorders (FGIDs). 4 Between 60% to over 90% of individuals with HSD/hEDS fulfill criteria for a Rome IV FGID, 4,5 with widespread somatic symptom reporting and opiate use being important mediating factors for gut symptoms. 4 Postural orthostatic tachycardia syndrome (POTS) is a poorly understood condition that also predominantly affects young-to middle-aged women, between the ages of 15-45 years, and has a population prevalence of 0.2%-1%. 6,7 POTS is characterized by an excessive rise in heart rate of more than 30 beats per minute, without associated hypotension, that occurs within 10 minutes of standing and settles with recumbency. 6,7 Symptoms associated with orthostatic intolerance include pre-syncope, blurred vision, breathlessness, palpitations, chest pain, and paresthesia. 6,7 Moreover, a wide array of upper and lower gastrointestinal symptoms-such as dysphagia, reflux, nausea, abdominal pain, bloating, and altered bowel habit-are reported by up to 80% of subjects with POTS. 8,9 The etiology of gastrointestinal symptoms in POTS is not entirely clear. 9,10 The role of abnormal splanchnic blood flow has been questioned due to limited and conflicting results. 10 A prevailing hypothesis is autonomic dysfunction of the GI tract, 11 a concept supported by case-control studies demonstrating abnormal gastric myoelectrical activity in POTS compared with controls, 12,13 and gastrointestinal symptoms being more prevalent in POTS patients with autonomic neuropathy than in those without autonomic neuropathy. 14 However, there are also data showing that between one-third and two-thirds of POTS patients with gastrointestinal symptoms have gastric emptying rates within the normal range, 9 which casts doubt on autonomic dysautonomia being solely responsible. 9,10 Moreover, a substantial proportion of subjects with POTS have GI symptoms irrespective of posture. 8,10 Hence, other pathophysiological factors may be of relevance, including psychological distress, central sensitisation, and behavioral amplification which-independently associated with FGIDs-are frequently observed in POTS. 8,10 In summary, GI symptoms seem to be common in POTS, with the etiology being unclear but potentially multi-factorial. 9,10 Of late, there has been growing interest in outlining a relationship between HSD/hEDS and POTS, although a biologically plausible mechanism to directly interlink these conditions remains elusive. 15 Between 60 and 80 percent of patients with HSD/ hEDS have a disorder of orthostatic intolerance, such as POTS. 9 Conversely, up to a fifth of patients with POTS have HSD/hEDS. 16 A few studies have noted increased symptom burden in individuals with comorbid HSD/hEDS and POTS, as opposed to either one alone. 17,18 However, these studies are small and those pertinent to gastroenterology limited to evaluating esophageal symptoms of dysphagia and reflux only. 17 There have been no studies examining how POTS in HSD/hEDS affects the whole repertoire of Rome IV FGIDs, in terms of their individual presence, but also symptom severity. We aimed to study this in depth by using a large sample of individuals with HSD/hEDS.

| Ethics
The study was deemed IRB-exempt by the University of Sheffield (UK) as all study participants were anonymous to the investigators.

| Study design and participants
In October 2018, an online health questionnaire from our research group was sent out by the charity organization Ehlers-Danlos Support UK to its 3874 contactable members. Following an e-mail reminder at 2 weeks, the survey was closed at 1 month. In total, 777 subjects with a medical diagnosis of EDS completed the survey, giving a response rate of 20%. Of these, 665 had a diagnosis of hEDS, which was subsequently re-classified as HSD/hEDS given that the society allows its members to use the terms hEDS and HSD interchangeably. Following exclusion of 49 HSD/hEDS subjects known to also have organic GI disease (28 celiac disease, 22 inflammatory bowel disease, 2 gastrointestinal cancers) this left 616 subjects with HSD/hEDS eligible for analysis.

| Questionnaire
The comprehensive questionnaire collected information on the following:

Key Points
• In this large cohort of subjects with HSD/hEDS, over a third reported a doctor diagnosis of POTS.
• The high functional gastrointestinal disorder burden in HSD/hEDS is further amplified in those with concomitant POTS.
• How POTS arises in HSD/hEDS, and is associated with increased GI symptoms, requires elucidation in future research.
1. Medical history-this included basic demographic data in addition to asking HSD/hEDS subjects if they had been given a doctor diagnosis of POTS, chronic fatigue syndrome, and fibromyalgia.

| Statistical analysis
Statistical analysis was carried out using SPSS version 25.0 software, with significance set at a P-value of < 0.05. There were no missing data because the online questionnaire required participants to complete each applicable question before being allowed to move onto the next step. Categorical variables were summarized by descriptive statistics, including total numbers and percentages, with comparisons between groups performed using the chi-square test.
Continuous variables were summarized by mean and standard deviation, with difference between two independent groups assessed using the two-group Student's t test.
We then performed binary logistic regression to establish the strength of associations for FGIDS in HSD/hEDS subjects with POTS compared to those without POTS. This was initially performed unadjusted and then adjusted for general health factors that were significant on univariate analysis.

| General characteristics of HSD/hEDS subjects
The 616 included subjects with HSD/hEDS were predominantly female (93%) and of white race (94%) and had a mean age of 39 years. Nearly, all individuals with HSD/hEDS (98%) had an FGID according to Rome IV diagnostic criteria, with the most commonly afflicted organ domains being the bowel (90%), gastroduodenal (70%), esophageal (56%), and anorectal (53%) regions. The vast majority (84%) had more than one affected GI organ region, and this has been described in more detail in a recent publication using the same population cohort. 4 The mean PHQ-9 and GAD-7 score among individuals with HSD/hEDS were 14.1 and 9.6, suggestive of moderate levels of depression and generalized anxiety, respectively.
The overall prevalence of any FGID did not differ in HSD/hEDS subjects with and without concomitant POTS (99% vs 97%, P = 0.13).
The majority of subjects in both groups reported FGIDs from more than one organ region, although this was noted to be more com-

| Odds ratio for FGIDs in HSD/hEDS subjects with POTS vs without POTS
The increased odds ratio for FGIDs in those HSD/hEDS subjects with POTS, compared to those without POTS, is shown in Table 2.
Following adjustments for factors significant on univariate analysis (ie, age, chronic fatigue, fibromyalgia, and depression scores) the increased odds ratio for FGIDs among POTS-positive subjects remained essentially unaltered. Similarly, the unadjusted and adjusted odds ratio for experiencing gastrointestinal symptoms "at least one day per week" also remained increased in those with concomitant POTS (Table 3). The high prevalence of Rome IV FGIDs in HSD/hEDS has been described in a recent publication 4 and is in line with previous reports using historic criteria, 5 with relevant factors mediating this association being high somatic symptom reporting behavior and the use of opiates. 4 Our current analyses suggest that the co-presence of POTS is also associated with amplified gastrointestinal illness burden.

| D ISCUSS I ON
However, the literature is shrouded in uncertainty and controversy as to how POTS arises in HSD/hEDS and contributes toward the GI symptoms. 15 There is currently no biologically plausible pathophysiological mechanism to directly link HSD/hEDS with POTS. 15 Suggestions of laxity of blood vessels in hEDS/HSD as a cause of POTS speculative and devoid of evidence; notably, what argues further against such a mechanism is that POTS is rarely linked with vascular EDS. 23 Rather, the presence of POTS in HSD/hEDS has been hypothesized to arise as a secondary epiphenomenon, or as a common final pathway, due to the combination of commonly observed confounding factors seen in this cohort such as somatic hypervigilance, psychological distress, central sensitisation with behavioral amplification, physical de-conditioning, poor oral intake, and the use of drugs that can affect neuronal function and possess vasoactive properties (eg, opiates). 8,15 In fact, the management of POTS-while being outside the scope of this paper-does entail addressing the aforementioned factors. 6 With regard to how POTS contributes toward GI symptoms, this may, in part, be due to autonomic dysfunction for which there is some, albeit limited, evidence. [8][9][10][11][12][13][14] However, the literature questions this as a sole mechanism given that dysautonomia would not readily explain: (a) why a proportion of individuals with POTS have such debilitating non-orthostatic GI symptoms, (b) why GI symptoms can persist despite the POTS being controlled, and (c) why "pain-related symptoms" are so pronounced throughout the GI tract. 10 An alternate hypothesis is that, in such instances, POTS is merely a bystander and that some of the proposed factors relevant to its genesis within HSD/hEDS are integral toward further exacerbating the dysfunctional brain-gut axis. 8,15 Further research is needed to disentangle this complex matrix and provide some clarity. In conclusion, the high functional gastrointestinal disease burden in HSD/hEDS is further amplified in those with concomitant POTS.
How POTS arises in HSD/hEDS, and is associated with increased GI symptoms, requires elucidation in future research.

ACK N OWLED G M ENT
The study was performed in accordance with the STROBE statement.