Abstract
Objective
To gain a better understanding of preferred treatment modalities and referrals to better treat and manage pain symptoms, we conducted a retrospective longitudinal cohort study of patients with hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD).
Patients and Methods
A retrospective analysis of self-reported data in 290 patients diagnosed with hEDS or HSD according to the 2017 Criteria from November 1, 2019, to June 12, 2023, who completed intake and outtake questionnaires. Patients were asked questions on the severity of hypermobile, joint and muscle pain, and whether clinical referral and/or medications/treatments improved their pain.
Results
Less than 30% of patients with hEDS and HSD reported improvement of hypermobility, joint or muscle pain from any of 17 treatment modalities listed in the outtake questionnaire. Patients self-reported that physical activity/exercise significantly or borderline significantly improved pain symptoms (hypermobility pain hEDS, n=36 (46.8%) vs 10 (76.9%), P=.07; HSD, n=77 (47.8%) vs 16 (88.9%), P=.001; joint pain hEDS, n=29 (45.3%) vs 17 (73.9%), P=.03; HSD, n=59 (42.8%) vs 32 (86.5%), P<.0001; muscle pain hEDS, n=25 (44.6%) vs 12 (75.0%), P=.05; HSD, n= 59 (45.4%) vs 25 (89.3%), P<.0001), whereas patients with HSD reported that physical therapy also improved pain (hypermobility pain HSD, n=78 (48.5%) vs 15 (83.3%), P=.006; joint pain HSD, n=62 (44.9%) vs 28 (75.7%), P=.001; muscle pain HSD, n=60 (46.2%) vs 20 (71.4%), P=.02). In contrast, patients with hEDS reported that topical medications made their muscle pain worse (n=27 (48.2%) vs 3 (18.8%), P=.05) and patients with HSD that injections made their joint pain worse (n=39 (28.3%) vs 4 (10.8%), P=.03). Most patients reported that referrals improved their pain. However, 40% or more reported that referrals to allergy and immunology and rheumatology departments worsened their pain.
Conclusion
This study identified patient perceptions on treatments and referrals that improved or made their pain worse. These findings provide a starting point for future treatment guidelines, decision aids, and research on patient-reported outcomes.
Ehlers-Danlos syndromes (EDS) are a group of connective tissue disorders that involve key features such as widespread distribution of fragile connective tissue in the skin, joints, ligaments, and internal organs.1 The most common subtype of EDS is hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobility spectrum disorders (HSD).2 Primary symptoms of hEDS/HSD include chronic muscle and joint pain, subluxations/dislocations, headache, brain fog, and fatigue.1,3, 4, 5 Approximately 70% of patients with hEDS/HSD self-report having or are diagnosed with fibromyalgia, a condition associated with widespread muscle and joint pain.4,6,7 A number of symptoms increase the pain burden in patients with hEDS/HSD including recurrent subluxations/dislocations (ie, hypermobility pain), joint pain, muscle pain, headaches/migraine, gastrointestinal symptoms, pelvic pain, back and neck pain known to be related to spinal instability, and others.
Pain, fatigue, and hypermobility/instability of joints may lead to a sedentary lifestyle for patients with hEDS/HSD,8,9 where muscle weakness may further aggravate symptoms. Current treatment options for pain for hEDS/HSD focus on physical therapy (PT), exercise, occupational therapy (OT), psychological therapies, and nutritional changes.8,10, 11, 12 To date, there have only been a few research reports describing care strategies that reduce pain for people with hEDS/HSD. Some previous studies report mixed results and high dropout rates, suggesting patient dissatisfaction.11 In 2016, Arthur et al13 sent a questionnaire to 1179 patients diagnosed with EDS, prior to the 2017 criteria, to determine treatment modalities that patients perceived as most helpful for pain control.13 They reported that opioids, surgical interventions, splints and braces, avoidance of potentially dangerous activities, and heat therapy were most beneficial. Using the 2017 diagnostic criteria, Song et al10 examined 76 patients with hEDS for patient-perceived improvements after referral/treatment and found that OT (70%), including splints and bracing, surgery (59%), and steroids (52%) were most beneficial. Patients with hEDS from the study by Song et al10 reported that the modalities that made their symptoms worse included neuropathic modulators (47%), opiates (22%), and PT (18%). These findings were similar to Arthur et al,13 with both studies reporting that patients found splints/braces, surgery, and steroids were beneficial. A study by Guedry et al14 in 2023 received surveys from 353 patients diagnosed with hEDS or HSD using the 2017 criteria and reported that patients used PT (82%), massage (68%), yoga (58%), chiropractic therapy (48%), and meditation (43%) to relieve pain symptoms but did not report the percentage of patients that perceived benefit from these therapies and so cannot be compared with the previous 2 studies.14 Thus, rehabilitation and reduction of pain in patients with hEDS/HSD is not well understood and is complicated by the highly heterogenous presentation of the condition. The goal of this study was to gain insight on which treatment modalities and referrals patients perceived as improving or worsening their pain at our EDS clinic and whether they differed by diagnosis of hEDS or HSD. This preliminary study provides important guidance for future research.
Patients and Methods
Diagnosis Criteria
Patients were diagnosed with hEDS or HSD by clinical evaluation with physicians who are experts in this condition according to the 2017 diagnostic guidelines set forth by the International Consortium on EDS and Related Disorders.2
Study Design
Adult patients (≥18 years old) that were diagnosed with hEDS or HSD at the Mayo Clinic Florida EDS Clinic were sent an outtake questionnaire 1 year later (range, 2 months to 3 years) on average; 290 patients who completed the intake and outtake questionnaire from November 1, 2019, to June 12, 2023, were included in the study. At the time of the initial clinic visit, treatment interventions were discussed with patients and referrals recommended. Referrals for treatment depended on the patient’s needs identified by the intake questionnaire, which was used to assess the patients’ systemic symptoms/comorbidities and always included a referral to OT, PT, and cognitive behavioral therapy (CBT). Intake questionnaires were filled out by patients prior to their initial visit and outtake questionnaires were sent to patients 1 year after their initial appointment when initial referrals should have been completed. However, for this study, we did not determine whether patients attended the referral appointments or completed the recommended treatments.
Referrals
Patients diagnosed with hEDS and HSD at the Mayo Clinic Florida EDS Clinic are routinely referred by the diagnosing physician to PT, OT, CBT, and other departments/programs based on the needs of the patient. We divided referrals based on whether the primary purpose of the referral to the department or program was to reduce pain (acupuncture, health coaching, fibromyalgia treatment program, mind-body therapy, OT, the pain rehabilitation center, pelvic floor therapy, physical medicine and rehabilitation, PT, and the psychology department) or a referral to another department (allergy and immunology, cardiology, gastroenterology, genetics, neurology, optometry, orthopedics. rheumatology, and women’s health).
Patients reported in the outtake questionnaire what referrals they attended and whether they benefited from the referral (strongly disagree, disagree, neutral, agree, and strongly agree). In tables, we reported data for this category combining strongly disagree, disagree, and neutral into a category named unchanged or worse and combining agree and strongly agree into another category named improved. In Figure 1, we combined strongly disagree and disagree into a category named worse, we kept neutral and combined agree and strongly agree into a category named improved to best illustrate the findings.
Figure 1.
Therapies that improved or made pain worse in patients with hypermobile Ehlers-Danlos syndrome (hEDS) or hypermobility spectrum disorders (HSD). Data show odds ratios with 95% CIs for (A) hypermobile pain, (B) joint pain, and (C) muscle pain in patients diagnosed with hEDS or HSD according to the 2017 diagnostic criteria. Odds ratios to the left of the red line indicate therapies that made pain worse, while those to the right of the red line indicate therapies that improved pain. P values indicating whether the therapy improved vs made their symptoms worse/neutral are shown on the right (Table 3, Table 4, Table 5).
Pain Assessment and Treatment Methods
Intake and outtake questionnaires included questions related to the patients’ joint pain using a score of 1 to 10 so that we were able to compare pain levels before and after treatment. We also have information on which patients were diagnosed with fibromyalgia as a measure of the percent widespread pain in patients. The outtake questionnaire asked patients to report all treatment modalities that improved their symptoms or reduced their pain. These included referrals to acupuncture, chiropractor, CBT, exercise, heat therapy, injections, massage, medical marijuana, medications, meditation, OT, physical activity, PT, rest, surgery, topical medications, transcutaneous electrical nerve stimulation unit, and other. We asked next what pain medication improved their symptoms or reduced their pain. These included acetaminophen (ie, Tylenol and Excedrin), cannabidiol (CBD; cannabis) derivatives, nonsteroid anti-inflammatory drugs (ie, ibuprofen, Aleve, and Motrin), muscle relaxers, opioids, and other.
Statistical Analyses
Statistical distributions for continuous variables were summarized in the form of mean, total number (n), and categorical variables with frequency and percentage. Patients were categorized into 2 groups based on a diagnosis of hEDS or HSD. Mann-Whitney U test was used for continuous data and Fisher's exact contingency test was used for categorical data. P values of ≤.05 were considered significant. All analyses were performed using Prism (version 10.3.1; GraphPad). The specific statistical test used to obtain results are listed in the legend of each table and figure.
Results
Patient Demographic Characteristics and Self-reported Pain Symptoms
Demographic characteristics for patients diagnosed with hEDS or HSD who responded to the outtake questionnaire (n=269) are shown in Table 1. Most patients with hEDS and HSD in this study were women, White, non-Hispanic, and approximately 35 years of age (Table 1), as reported previously.4,5 In this study, we examined 3 self-reported categories of pain including hypermobility pain, joint pain, and muscle pain, which were defined for the patients in the outtake questionnaire. All patients in this study reported experiencing hypermobility pain (hEDS n=90, 100%; HSD n=179, 100%) (Table 1). Most patients in this study self-reported experiencing joint and/or muscle pain (joint pain hEDS n=78, 86.7%; HSD n=164, 91.9%; muscle pain hEDS n=64, 71.1%; and HSD n=148, 82.7%) (Table 1). Patients with HSD self-reported muscle pain more often than patients with hEDS (P=.04) (Table 1).
Table 1.
Demographic Characteristics and Self-reported Pain Symptoms of Patients Seen at the EDS Clinic Who Took the Outtake Questionnaire (n=269)
| Condition | hEDS (n=90), n (%) | HSD (n=179), n (%) | Pa |
|---|---|---|---|
| Sex | |||
| Female | 84 (93.3) | 170 (95.0) | .58 |
| Male | 5 (5.6) | 7 (3.9) | .54 |
| Other | 1 (1.1) | 2 (1.1) | >.99 |
| Age (y) | n=81 | n=168 | .98 |
| Mean | 35.5 | 35.6 | |
| Range (SD) | 18.5-62.2 | 17.7-65.9 | |
| Female age (y) | n=75 | n=161 | |
| <25 | 13 (17.3) | 39 (24.2) | .31 |
| 25-50 | 49 (65.3) | 98 (60.9) | .57 |
| >50 | 13 (17.3) | 24 (14.9) | .70 |
| Male age (y) | n=5 | n=5 | |
| <25 | 1 (20.0) | 2 (40.0) | >.99 |
| 25-50 | 4 (80.0) | 3 (60.0) | >.99 |
| >50 | 0 (0.0) | 0 (0.0) | NA |
| Raceb | n=81 | n=168 | |
| American Indian/Alaskan Native | 0 (0.0) | 2 (1.2) | >.99 |
| Asian | 1 (1.2) | 1 (0.6) | .55 |
| African American/Black | 0 (0.0) | 2 (1.2) | >.99 |
| Native Hawaii/Pacific Islander | 0 (0.0) | 0 (0.0) | NA |
| White | 75 (92.6) | 152 (90.5) | .64 |
| Multiple races | 2 (2.5) | 5 (3.0) | >.99 |
| Other | 2 (2.5) | 4 (2.4) | >.99 |
| Unknown | 1 (1.2) | 2 (1.2) | >.99 |
| Ethnicity | n=81 | n=168 | |
| Hispanic/Latino | 7 (8.6) | 8 (4.8) | .26 |
| Not Hispanic Latino | 74 (91.4) | 155 (92.3) | .81 |
| Unknown | 0 (0.0) | 5 (3.0) | .18 |
| Pain symptoms | |||
| Hypermobility pain | 90 (100) | 179 (100) | >.99 |
| Joint pain | 78 (86.7) | 164 (91.9) | .21 |
| Muscle painc | 64 (71.1) | 148 (82.7) | .04 |
EDS, Ehlers-Danlos syndrome; hEDS, hypermobile Ehlers-Danlos syndrome; HSD, hypermobility spectrum disorders.
P values result from Fisher's exact test for categorical data and Mann-Whitney rank test for numeric data.
All men in the data set were White.
Pain symptoms that were significantly different by diagnosis.
As an indication of widespread pain prior to treatment, 24.8% (n=22) of patients diagnosed with hEDS were also diagnosed with fibromyalgia. In contrast, 75.2% (n=135) of patients in this study that were diagnosed with HSD were also diagnosed with fibromyalgia. Thus, based on this assessment, pain was more widespread in patients with HSD prior to treatments/referrals.
We also obtained information on joint pain from the intake and outtake questionnaires. We asked patients to rate their pain from 1 to 10 with 10 being worse. At intake, patients with hEDS reported that their worst joint pain was 8.3±1.6 and on outtake that their worst joint pain was 8.3±1.5, thus, unchanged. At intake, patients with HSD reported that their worst joint pain was 8.5±1.5 and at outtake their worst joint pain was 7.9 ±1.7, thus, somewhat improved. Overall, these data indicate that both patients with hEDS and HSD in this study rank their worst joint pain as severe.
Self-reported Pain Medication Use
The most frequently used pain medications reported by patients in this study were nonsteroid anti-inflammatory drugs (hEDS n=41, 45.6%; HSD n=95, 53.1%), acetaminophen (hEDS n=32, 35.6%; HSD n=78, 43.6%), muscle relaxers (hEDS n=14, 15.6%; HSD n=51, 28.5%), CBD derivatives (hEDS n=17, 18.9%; HSD n=33, 18.4%), other medications (hEDS n=4, 4.4%; HSD n=26, 14.5%) and opioids (hEDS n=9, 10.0%; HSD n=15, 8.4%) (Table 2). More patients with HSD self-reported taking muscle relaxers (P=.02) and other medications (P=.01) than patients with hEDS (Table 2).
Table 2.
Self-reported Medications Used by Patients From the EDS Clinic Outtake Questionnaire (n=269)
| Medicationsa | hEDS (n=90), n (%) | HSD (n=179), n (%) | Pb |
|---|---|---|---|
| NSAIDs | 41 (45.6) | 95 (53.1) | .25 |
| Acetaminophen | 32 (35.6) | 78 (43.6) | .24 |
| Muscle relaxersc | 14 (15.6)c | 51 (28.5)c | .02c |
| CBD derivatives | 17 (18.9) | 33 (18.4) | >.99 |
| Otherc | 4 (4.4)c | 26 (14.5)c | .01c |
| Opioids | 9 (10.0) | 15 (8.4) | .66 |
CBD, cannabidiol; EDS, Ehlers-Danlos syndrome; hEDS, hypermobile Ehlers-Danlos syndrome; HSD, hypermobility spectrum disorders; NSAID, nonsteroidal anti-inflammatory drug.
Medications are listed according to the highest percentage in HSD.
P values obtained from Fisher's exact test.
Medications that were significantly different by diagnosis.
Self-reported Treatment Modalities Used to Reduce Pain
The 17 treatment modalities listed in the outtake questionnaire included acupuncture, chiropractor, CBT, exercise, heat therapy, injections (ie, Botox), massage, medical marijuana, oral medication, meditation, OT, physical activity, PT, rest, surgery, topical medications, transcutaneous electrical nerve stimulation unit, and other (Supplemental Table 1, available online at http://www.mcpiqojournal.org). The top 5 treatments self-reported by patients with hEDS and HSD were rest, heat therapy, massage, oral medication, and exercise (Supplemental Table 1). There were no significant differences in the percentage of patients with hEDS and that of the patients with HSD self-reporting using any of the 17 treatment modalities (Supplemental Table 1).
Treatment Modalities That Reduced Pain
Less than 15% of patients reported that the 17 treatment modalities improved their hypermobility pain (hEDS n=13/90, 14.4%; HSD n=18/179, 10.1%). Less than 30% of patients reported that the treatment modalities reduced their joint pain (hEDS n=23/87, 26.4%; HSD n=37/175, 21.1%). Similarly, less than 25% of patients reported that the treatment modalities improved their muscle pain (hEDS n=16/72, 22.2%; HSD n=28/158, 17.7%).
Patients with hEDS did not report that any of the 17 treatment modalities improved their hypermobility pain, although exercise was borderline significant (n=36 [46.8%] vs 10 [76.9%], P=.07) (Table 3, Figure 1A). In contrast, patients with HSD reported that exercise (n=77 [47.8%] vs 16 [88.9%], P=.001) and PT (n=78 [48.5%] vs 15 [83.3%], P=.006) significantly reduced their hypermobility pain (Table 3, Figure 1A). Treatment modalities that were self-reported to improve joint pain were exercise (29 [45.3%] vs 17 [73.9%], P=.03) for patients with hEDS and exercise (59 [42.8%] vs 32 [86.5%], P<.001) and PT (62 [44.9%] vs 28 [75.7%], P=.001) for patients with HSD (Table 4, Figure 1B). However, patients with HSD reported that injections made their joint pain worse (n=39 [28.3%] vs 4 [10.8%], P=.03) (Table 4, Figure 1B). The only treatment modality for patients with hEDS that was self-reported to improve muscle pain was exercise (n=25 [44.6%] vs 12 [75.0%], P=.05) (Table 5, Figure 1C). In contrast, topical (n=27 [48.2%] vs 3 [18.8%], P=.05) and oral (borderline significant; n=40 [71.4%] vs 7 [43.8%], P=.07) medications were reported to make muscle pain worse in patients with hEDS (Table 5, Figure 1C). For patients with HSD, exercise (n=59 [45.4%] vs 25 [89.3%], P<.001) and PT (n=60 [46.2%] vs 20 [71.4], P=.02) were beneficial for muscle pain (Table 5, Figure 1C).
Table 3.
Treatments Self-reported to Improve Hypermobile Pain in Patients with hEDS (n=90) and HSD (n=179)
| Treatmentsa | hEDS unchanged or worse (n=77), n (%) | hEDS improved (n=13), n (%) | hEDS Pb | HSD unchanged or worse (n=161), n (%) | HSD improved (n=18), n (%) | HSD Pb |
|---|---|---|---|---|---|---|
| Rest | 62 (80.5) | 12 (92.3) | .45 | 137 (85.1) | 17 (94.4) | .48 |
| Heat therapy | 52 (67.5) | 11 (84.6) | .33 | 111 (68.9) | 12 (66.7) | .80 |
| Exercisec | 36 (46.8)c | 10 (76.9)c | .07c | 77 (47.8)c | 16 (88.9)c | .001c |
| Massage | 43 (55.8) | 7 (53.9) | >.99 | 100 (62.1) | 10 (55.6) | .62 |
| Oral medication | 55 (71.4) | 7 (53.9) | .21 | 97 (60.3) | 8 (44.4) | .22 |
| Physical therapyc | 37 (48.1) | 6 (46.2) | >.99 | 78 (48.5)c | 15 (83.3)c | .006c |
| Topical medication | 32 (41.6) | 5 (38.5) | >.99 | 67 (41.6) | 7 (38.9) | >.99 |
| Marijuana | 22 (28.6) | 4 (30.8) | >.99 | 44 (27.3) | 8 (44.4) | .17 |
| Acupuncture | 11 (14.3) | 3 (23.1) | .42 | 14 (8.7) | 4 (22.2) | .09 |
| Injections | 29 (37.7) | 3 (23.1) | .37 | 40 (24.8) | 4 (22.2) | >.99 |
| CBT | 12 (15.6) | 2 (15.4) | >.99 | 15 (9.3) | 3 (16.7) | .40 |
| Meditation | 19 (24.7) | 2 (15.4) | .73 | 34 (21.1) | 4 (22.2) | >.99 |
| TENS unit | 19 (24.7) | 2 (15.4) | .73 | 37 (23.0) | 2 (11.1) | .37 |
| Chiropractor | 16 (20.8) | 1 (7.7) | .45 | 35 (21.7) | 4 (22.2) | >.99 |
| Other | 9 (11.7) | 1 (7.7) | >.99 | 22 (13.7) | 4 (22.2) | .30 |
| Surgery | 11 (14.3) | 0 (0.0) | .36 | 20 (12.4) | 2 (11.1) | >.99 |
| Nothing | 0 (0.0) | 0 (0.0) | >.99 | 4 (2.5) | 0 (0.0) | >.99 |
CBT, cognitive behavioral therapy; hEDS, hypermobile Ehlers-Danlos syndrome; HSD, hypermobility spectrum disorders; TENS, transcutaneous electrical nerve stimulation.
Treatments are listed in order of the highest percentage in those who improved with hEDS.
P values obtained from Fisher's exact test.
Treatments that led to borderline or significant improvement.
Table 4.
Treatments Self-reported to Improve Joint Pain in Patients with hEDS (n=87) or HSD (n=175)
| Treatmentsa | hEDS unchanged or worse (n=64), n (%) | hEDS improved (n=23), n (%) | hEDS Pb | HSD unchanged or worse (n=138), n (%) | HSD improved (n=37), n (%) | HSD P |
|---|---|---|---|---|---|---|
| Rest | 53 (82.8) | 18 (78.3) | .76 | 119 (86.2) | 32 (86.5) | >.99 |
| Exercisec | 29 (45.3)c | 17 (73.9)c | .03c | 59 (42.8)c | 32 (86.5)c | <.001c |
| Heat therapy | 43 (67.2) | 17 (73.9) | .61 | 94 (68.1) | 25 (67.6) | >.99 |
| Massage | 36 (56.3) | 13 (56.5) | >.99 | 83 (60.1) | 25 (67.6) | .45 |
| Oral medication | 47 (73.4) | 13 (56.5) | .19 | 84 (60.9) | 18 (48.7) | .19 |
| Physical therapyc | 29 (45.3) | 13 (56.5) | .47 | 62 (44.9)c | 28 (75.7)c | .001c |
| Marijuana | 17 (26.6) | 9 (39.1) | .29 | 44 (31.9) | 8 (21.6) | .31 |
| Meditation | 13 (20.3) | 8 (34.8) | .26 | 27 (19.6) | 10 (27.0) | .37 |
| Topical medication | 29 (45.3) | 8 (34.8) | .47 | 61 (44.2) | 12 (32.4) | .26 |
| Injectionsc | 26 (40.6) | 6 (26.1) | .31 | 39 (28.3) | 4 (10.8) | .03 |
| Acupuncture | 9 (14.1) | 5 (21.7) | .51 | 12 (8.7) | 6 (16.2) | .22 |
| Chiropractor | 11 (17.2) | 5 (21.7) | .76 | 33 (23.9) | 5 (13.5) | .26 |
| TENS unit | 17 (26.6) | 4 (17.4) | .57 | 32 (23.2) | 6 (16.2) | .50 |
| CBT | 10 (15.6) | 3 (13.0) | >.99 | 12 (8.7) | 6 (16.2) | .22 |
| Other | 7 (10.9) | 3 (13.0) | .72 | 18 (13.0) | 8 (21.6) | .20 |
| Surgery | 10 (15.6) | 1 (4.4) | .28 | 18 (13.0) | 4 (10.8) | >.99 |
| Nothing | 0 (0.0) | 0 (0.0) | - | 4 (2.9) | 0 (0.0) | .58 |
CBT, cognitive behavioral therapy; hEDS, hypermobile Ehlers-Danlos syndrome; HSD, hypermobility spectrum disorders; TENS, transcutaneous electrical nerve stimulation.
Treatments are listed in order of the highest percentage in those who improved in hEDS.
P obtained from Fisher's exact test.
Treatments that led to significant improvement.
Table 5.
Treatments Self-reported to Improve or Worsen Muscle Pain in Patients With hEDS (n=72) or HSD (n=158)
| Treatmentsa | hEDS unchanged or worse (n=56), n (%) | hEDS improved (n=16), n (%) | hEDS Pb | HSD unchanged or worse (n=130), n (%) | HSD improved (n=28), n (%) | HSD P |
|---|---|---|---|---|---|---|
| Exercisec | 25 (44.6)c | 12 (75.0)c | .05c | 59 (45.4)c | 25 (89.3)c | <.001c |
| Rest | 47 (83.9) | 12 (75.0) | .47 | 112 (86.2) | 26 (92.9) | .53 |
| Physical therapyc | 26 (46.4) | 11 (68.8) | .16 | 60 (46.2)c | 20 (71.4)c | .02c |
| Heat therapy | 41 (73.2) | 10 (62.5) | .53 | 90 (69.2) | 21 (75.0) | .65 |
| Massage | 34 (60.7) | 9 (56.5) | .78 | 80 (61.5) | 21 (75.0) | .20 |
| Oral medication | 40 (71.4)c | 7 (43.8)c | .07c | 81 (62.3) | 15 (53.6) | .40 |
| Acupuncture | 8 (14.3) | 5 (31.3) | .15 | 13 (10.0) | 4 (14.3) | .51 |
| Chiropractor | 10 (17.9) | 5 (31.3) | .30 | 32 (24.6) | 5 (17.9) | .62 |
| Injectionsc | 22 (39.3) | 5 (31.3) | .77 | 38 (29.2)c | 3 (10.7)c | .06c |
| Marijuana | 17 (30.4) | 5 (31.3) | >.99 | 43 (33.1) | 6 (21.4) | .27 |
| Meditation | 14 (25.0) | 4 (25.0) | >.99 | 27 (20.7) | 9 (32.1) | .22 |
| TENS unit | 14 (25.0) | 3 (18.8) | .75 | 29 (22.3) | 7 (25.0) | .81 |
| Topical medicationc | 27 (48.2)c | 3 (18.8)c | .05c | 57 (43.9) | 10 (35.7) | .53 |
| Other | 5 (8.9) | 2 (12.5) | .65 | 19 (14.6) | 5 (17.9) | .77 |
| CBT | 10 (17.9) | 1 (6.25) | .44 | 12 (9.2) | 4 (14.3) | .49 |
| Surgery | 7 (12.5) | 1 (6.25) | .68 | 18 (13.9) | 3 (10.7) | >.99 |
| Nothing | 0 (0.0) | 0 (0.0) | NA | 3 (2.3) | 0 (0.0) | >.99 |
CBT, cognitive behavioral therapy; hEDS, hypermobile Ehlers-Danlos syndrome; HSD, hypermobility spectrum disorders; TENS, transcutaneous electrical nerve stimulation.
Treatments are listed in order of the highest percentage in those who improved in hEDS.
P values obtained from Fisher's exact test.
Treatments that led to significant or borderline significant improvement or made symptoms worse.
Self-reported Improvement in Pain After Referrals
To determine which referrals patients thought were most beneficial to reduce pain, we obtained information on whether their symptoms were worse, neutral, or improved after their referral treatment based on our outtake questionnaire. We divided assessments based on whether the primary purpose of the referral to the department or program was to reduce pain (acupuncture, health coaching, fibromyalgia treatment program, mind-body therapy, OT, the pain rehabilitation center, pelvic floor therapy, physical medicine and rehabilitation, PT, and the psychology department) or a referral to another department (allergy and immunology, cardiology, gastroenterology, genetics, neurology, optometry, orthopedics, rheumatology, and women’s health) (Figure 2).
Figure 2.
Outcomes data for referrals. Outcomes data for patients diagnosed with (A) hypermobile Ehlers-Danlos syndrome (hEDS) or (B) hypermobility spectrum disorders (HSD) are shown for pain referrals (left) and other departmental referrals (right).
Most patients reported that referrals benefited their symptoms (Figure 2). Approximately 75% of patients with hEDS and HSD reported that referrals to acupuncture, optometry, or genetics were beneficial (Figure 2). Similarly, approximately 60% of patients with hEDS and HSD reported that the mind-body therapy program improved their pain. Over 65% of patients with hEDS viewed a referral to psychology as beneficial, whereas only approximately 40% of patients with HSD considered this referral beneficial, with approximately 35% reporting that it made their symptoms worse. Approximately 65% of patients with HSD reported that referral to the pain rehabilitation program was beneficial, whereas only approximately 25% of patients with hEDS considered it beneficial. The most negatively reported referral for both patients with hEDS and HSD was to allergy and immunology followed by rheumatology.
Comparing patients with hEDS with those with HSD for their perceived outcomes from individual referrals, we found that there were no significant differences for any of the comparisons (Supplemental Figure 1, available online at http://www.mcpiqojournal.org). The referral that varied the most between patients with hEDS and those with HSD was a referral to psychology (Supplemental Figure 1A, available online at http://www.mcpiqojournal.org).
Discussion
In this study, we examined 3 commonly reported pain symptoms in patients diagnosed with hEDS or HSD—hypermobility, joint, and muscle pain. We found that significantly more patients with HSD reported that they experienced muscle pain compared with patients with hEDS (Table 1) and used more muscle relaxers (Table 2). Less than 10% of patients at our clinic reported using opioids (Table 2). The top 5 treatments used by patients with hEDS and those with HSD were rest (hEDS, 82%; HSD, 86%), heat therapy (hEDS, 70%; HSD, 69%), massage (hEDS, 56%; HSD, 62%), oral medication (hEDS, 69%; HSD, 59%), and exercise (hEDS, 51%; HSD, 52%) (Supplemental Table 1, available online at http://www.mcpiqojournal.org). A study by Guedry et al14 in 2023 examined 353 patients diagnosed with hEDS or HSD using the 2017 criteria and reported that patients used PT (82%), massage (68%), yoga (58%), chiropractic therapy (48%), and meditation (43%) to relieve pain symptoms.14 However, this study did not report patient outcomes from treatment.
In this study, the modality that patients with hEDS or patients with HSD reported to be the most beneficial at reducing hypermobility, joint, and muscle pain was physical activity/exercise (Figure 1). In contrast, PT was reported to improve pain only in patients with HSD but not in patients with hEDS. Patients with hEDS/HSD have also been reported to use alternative therapies to reduce pain, such as Chinese therapies, herbal medications, and cannabis/CBD derivatives.15 Demes et al15 reported in 500 patients diagnosed with hEDS or HSD, patients perceived opioids, PT, and marijuana as the most beneficial therapies for pain.15 This contrasts with our findings that found that exercise, rest, heat therapy, and massage were the most beneficial therapies for pain. Arthur et al13 reported that opioids, surgical interventions, splints and braces, avoidance of potentially dangerous activities, and heat therapy were most beneficial.13 Patients in our study similarly found that opioids and heat therapy were effective. Patients with hEDS in the study by Song et al10 reported that OT, surgery, and steroids were the most beneficial in reducing pain. Patients with hEDS from the study by Song et al10 reported that the modalities that made their symptoms worse were neuropathic modulators, opiates, and PT.10 Similarly, patients with hEDS from our study reported that topical medications made their muscle pain worse, whereas patients with HSD reported that injections made their joint pain worse. However, our patients reported that PT was beneficial.
Treating pain in patients with hEDS/HSD is complex due to the many different origins of pain (ie, subluxations/dislocations, migraine, and irritable bowel syndrome) and the heterogeneous presentation of the symptoms. Patients with hEDS/HSD may limit their involvement in physical activities due to kinesiophobia (fear of movement and injury).9 For example, Stanitski et al16 found that 83% of patients with hEDS reported joint dislocation. Ainsworth and Aulicino17 described dislocation of the shoulder (63%) and knee joints (57%) in patients with hEDS.8 Despite high rates of dislocations/subluxations in patients with hEDS/HSD in our study, approximately 50% of patients reported that they exercise to reduce pain and that exercise improved their pain. General conditioning-based exercise to improve musculoskeletal strength is considered an important self-management strategy for symptom management for patients with hEDS/HSD.8,18,19 Previous studies have shown that exercise therapy can improve joint stability and reduce symptom-related hypermobility and pain in patients with hypermobility.20, 21, 22 Gentle impact exercises where there is a lower risk for injury such as walking and swimming may be ideal.23 However, more research is needed regarding specific joint-related exercises vs systemic exercise approaches and whether differences exist in patients with hEDS vs HSD.
In this study, patients with HSD reported that PT improved their pain symptoms. At Mayo Clinic, we refer patients with hEDS/HSD to physical therapists specializing in joint hypermobility. This may be one reason that patients with HSD in this study reported a benefit from PT. Several studies have found that pain and proprioception improve with PT in patients with hEDS/HSD compared with usual care.11 Common PT exercises for hypermobility include elastic band row, hip abduction and adductions, sideways elastic band walking, hip bridges, and others. Proprioception exercises include mini squats, forward lunges, and single-leg balance.11 Our findings suggest that PT-related exercise may reduce pain, which should improve quality of life. Still, more research is needed to understand better if PT and other forms of exercise reduce pain, subluxations/dislocations, and/or improve fatigue in these patients.
Interestingly, injections and topical medications were significantly reported by patients to make their pain/symptoms worse (Figure 1). Although we obtained information about classes of medications that patients were taking (Table 2), we did not obtain specific information in our questionnaires about the type of injections or topical medications that were used. Patients with hEDS/HSD are known to have issues with local anesthetic/lidocaine resistance.24 As many as 88% of patients with EDS report local anesthetic resistance as being complete, partial, or rapidly waning in effect.25 The reason for local anesthetic resistance is not currently known. Additionally, patients with hEDS/HSD are reported to have elevated mast cell activity,26 which may increase the likelihood of adverse reactions to topical medications such as creams, ointments, gels, balms, and salves. Another possibility is that hypermobile patients may have collagen/extracellular matrix defects that affect dermal or enteric drug absorption.
Overall, most patients with hEDS and HSD reported that referrals improved their pain (Figure 2). This contrasted to findings with treatments/therapies, which overall patients reported did not improve their pain. There are several possible reasons for these differences including that many of the treatments are patient administered rather than physician-prescribed therapies, the diversity of treatments examined in the study, and the lack of information on dose or method of treatment. hEDS and HSD are lifelong conditions, and so self-management of symptoms is central to effective treatment.27 In this way, patients can serve as active partners in the management of their health and wellbeing. Self-management interventions have been found to improve pain in chronic pain conditions such as osteoarthritis.28,29 Future research is needed to better understand the most effective strategies to reduce pain in hEDS/HSD patients. A surprising finding was that approximately 65% of hEDS and 40% of patients with HSD reported that a referral to allergy and immunology made their symptoms worse (Figure 2). Similarly, approximately 40% of patients with hEDS and HSD reported that a rheumatology referral made their symptoms worse. It is unclear what aspect of the referrals led to this negative impression, and more research is needed to understand the issues better. Owing to the complex nature of pain in patients with hEDS/HSD, a multidisciplinary approach is needed to improve patient outcomes of reduced pain and improved quality of life.
Limitations and Future Directions
This study has several strengths. First, it is a large study examining treatment outcomes in patients diagnosed with hEDS or HSD using the 2017 criteria. To our knowledge, this is the first study that compares treatment outcomes between hEDS and HSD. An important limitation of the study is that the frequency and duration of treatment modalities and referrals were not measured. If we asked the patients to self-report if they were compliant or adhered to the program, the data would likely be inaccurate due to recall bias and/or subjectivity. These are weaknesses, in general, of self-reported data. Additionally, many of the modalities such as rest, heat, and topical medication are administered by the patients and so could not be assessed for compliance. In future studies, we plan to examine specific treatments (ie, PT) with the provider monitoring compliance and then ask for self-reported outcomes. The current study was designed to be hypothesis generating for future research. Additionally, in future studies, it will be important to assess quality of life using validated questionnaires to gain a better understanding of pain levels and/or disability prior to and after interventions. Finally, similar to most other studies of hEDS/HSD, males were only a small percentage of the total sample. Another important point is that we do not know why patients in this study considered referrals to the pain rehabilitation center and allergy/immunology, for example, so negatively. We know that many patients with hEDS/HSD have long histories of being dismissed by physicians and/or being told that their symptoms including pain are psychological leading to medically related stress. In the future, we would like to determine the reasons for the negative impressions of specific programs and departments.
Conclusions
In this study, we found that patients with hEDS or HSD reported that exercise reduced their hypermobility, joint, and muscle pain, whereas PT only reduced these forms of pain in patients with HSD. In contrast, oral and topical medications made their pain worse. A relatively high percentage of patients reported that most referrals improved their pain. These findings provide a starting point for future treatment guidelines, decision aids, and patient-reported outcomes research.
Potential Competing Interests
Dr Bruno reports honoraria from University of Kansas and University of Oklahoma and leadership roles in the Myocarditis Foundation and Medical Advisory Board. Dr Fairweather reports travel support from Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC) Conference in Spain and CHROUS SEOUL 2023 meeting in Seoul, South Korea and is a member of the Board of the Atwal Clinic and Scientific Advisory Board of the Myocarditis Foundation. The other authors report no competing interests.
Ethics Statement
This retrospective study was approved by the Mayo Clinic Institutional Review Board (IRB# 19-011260) and informed consent was waived by the IRB for all patients. The research adhered to the principles outlined in the Declaration of Helsinki.
Acknowledgments
Drs Wilson, Bruno and Fairweather contributed equally to this work as first authors. Drs Bruno, Fairweather and Knight contributed equally to this work as senior authors.
Footnotes
Grant support: This study was supported by funding from the Ehlers-Danlos Society MicroGrant (to D.F. and D.R.T.K.); Mayo Clinic RACER Award (to D.R.T.K.); Mayo Clinic STARDOM Award (to D.F. and D.R.T.K.); Mayo Clinic’s Division of General Internal Medicine (to K.A.B., D.F., and D.R.T.K.); the Ralph E. Pounds and Kathy Olesker Pounds Fund in Research Related to Chronic Pain (to D.F.); National Institutes of Health R01 HL164520 (to D.F.); National Institutes of Health R21 AR084101 (to D.F., K.A.B., and D.R.T.K.); and National Institutes of Health R21 AI163302, R21 AI180863, American Heart Association 23SCEFIA1153414, and Department of Defense CDMRP PR210385 (to K.A.B.). None of the funding associated with this manuscript was involved in the study design, collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the article for publication. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies or Mayo Clinic.
Supplemental material can be found online at http://www.mcpiqojournal.org. Supplemental material attached to journal articles has not been edited, and the authors take responsibility for the accuracy of all data.
Supplemental Online Material
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