Abstract
Objectives
Patients with autonomic dysfunction, or dysautonomia, often report discolouration of their dependent extremities, which is thought to be from venous pooling or acrocyanosis. A subset of patients with SSc are affected by dysautonomia but may be challenging to identify. We sought to determine whether patients with SSc who report discolouration in their feet have a higher burden of autonomic symptoms, including orthostatic, gastrointestinal (GI), urinary, secretomotor and pupillomotor.
Methods
167 patients with SSc completed the Composite Autonomic Symptom Score (COMPASS)-31 survey, which queries whether the patient experiences discolouration of the feet or hands. We compared the COMPASS-31 subdomain scores between SSc patients with and without foot discolouration. Seventy-nine patients with postural orthostatic tachycardia syndrome (POTS) also completed the COMPASS-31 questionnaire for comparison.
Results
We found that extremity discolouration is common in POTS and more often affects the feet, whereas in SSc, the hands are more frequently involved; 62% of SSc patients report colour changes in their feet. These patients are more likely to have other autonomic symptoms, including orthostatic (11.7 ± 10.6 vs 8.6 ± 9.9, P = 0.06), GI (11.3 ± 4.3 vs 8.8 ± 4.3, P = 0.0003), urinary (1.4 ± 1.5 vs 0.8 ± 1.3, P = 0.002) and secretomotor (7.0 ± 3.8 vs 5.9 ± 3.8, P = 0.06) symptoms. These associations persist in a multivariable model after adjusting for potential confounders.
Conclusion
Dependent extremity discolouration is common in dysautonomia. Patients with SSc who report colour changes in their feet are more likely to report other symptoms of autonomic dysfunction.
Keywords: scleroderma, SSc, dysautonomia, acrocyanosis, Raynaud’s, COMPASS-31
Rheumatology key messages.
Discolouration of the extremities, particularly in the feet, is common in patients with autonomic dysfunction.
In SSc, the hands more frequently change colour than the feet.
The subset of SSc patients with foot colour changes have more autonomic symptoms.
Introduction
SSc is an autoimmune fibrotic disease that commonly presents with Raynaud’s phenomenon in addition to multi-system organ dysfunction. A subset of patients with SSc suffer from dysautonomia or dysfunction of the autonomic nervous system, which can manifest with a diverse array of symptoms [1, 2]. Cardiovascular dysautonomia causes orthostatic intolerance from impaired vasomotor response to changes in position and results in symptoms such as dizziness with standing, palpitations, brain fog and fatigue [3]. Other symptoms of dysautonomia include gastrointestinal (GI) dysmotility, sicca syndrome, vasomotor dysfunction resulting in colour changes in the extremities, and urinary and visual symptoms [4].
Many features of dysautonomia, including GI dysmotility and vasomotor dysfunction, overlap with those of SSc. This presents a clinical dilemma because it is difficult to identify the subset of patients who suffer from autonomic dysfunction and would benefit from further diagnostic testing and targeted autonomic treatments. Vasomotor dysfunction from dysautonomia is particularly challenging to identify in SSc. Although patients with dysautonomia can have Raynaud’s phenomenon, they also frequently have discoloured distal extremities due to venous pooling or acrocyanosis, which can be exacerbated by temperature changes and are commonly misattributed to Raynaud’s phenomenon [5, 6]. Patients may be started on a Raynaud’s treatment algorithm with calcium channel blockers or sildenafil, which could lead to vasodilation and may exacerbate their already dysfunctional haemodynamics. Especially with the current surge in dysautonomia due to the coronavirus disease 19 (COVID-19) pandemic, it is essential to identify tools to distinguish between Raynaud’s phenomenon secondary to SSc and vasomotor dysfunction from dysautonomia.
Raynaud’s phenomenon in SSc is more common in the hands [7], whereas acrocyanosis in dysautonomia is more often observed in the dependent extremities [8]. This led us to hypothesize that SSc patients with colour changes in the lower extremities have SSc-dysautonomia overlap and have a higher overall autonomic symptom burden.
Methods
SSc patients were recruited for this study during clinical evaluations at the Johns Hopkins Scleroderma Center. The Johns Hopkins IRB approved this study, and all patients signed informed consent. This cohort was part of a scleroderma–GI disease study and therefore was enriched for patients with more significant GI symptoms [9]. Demographic and clinical data for all SSc study participants were obtained from the Johns Hopkins Scleroderma Center Research Registry (see supplementary data S1, available at Rheumatology online). Patients from the Johns Hopkins POTS Clinic were used as a comparison group, and were included if they had diagnosed postural orthostatic tachycardia syndrome (POTS).
All patients completed the Composite Autonomic Symptom Score (COMPASS)-31, a self-administered survey that quantifies self-reported autonomic symptoms. This tool consists of 31 questions that fall into six domains of autonomic dysfunction: orthostatic intolerance, vasomotor dysfunction, secretomotor dysfunction, GI dysfunction, bladder dysfunction and pupillomotor dysfunction [10]. The questionnaire was scored as previously described to give a total score ranging from 0 to 100, where 100 represents the maximum severity of autonomic symptoms [10].
Statistical analysis
Questions 5 and 6 of the COMPASS-31 specifically ask whether the patient has experienced colour changes (red, white or purple) in the extremities in the past year and to specify whether this occurs in the hands or feet, or both. The mean score for each subdomain was used for data imputation. The Wilcoxon rank-sum test was used to compare the COMPASS-31 total and subdomain scores between patients with and without colour changes in their extremities. Multi-variable linear regression models adjusted for possible covariates, including age, sex and race. All statistical analyses were conducted using JMP Version 9 (SAS Institute Inc., Cary, NC). All statistical tests were two-sided, and significance was defined as P < 0.05.
Results
Patient cohort
One-hundred and sixty-seven patients with SSc and 79 patients with POTS completed the COMPASS-31 questionnaire. Twenty-three SSc patients had missing data that were imputed. There was no missing data for the POTS cohort. The mean age of the SSc cohort was 59 ± 13 years; 90% were female, 80% were white and 27% had diffuse cutaneous disease. All SSc patients had a history of Raynaud’s phenomenon. The mean age of the POTS cohort was 42 ± 14 years, 88% were female and 88% were white. The mean total COMPASS-31 score was 33.3 ± 15.7 in the SSc cohort and 50.7 ± 15.4 in the POTS cohort. Twenty-three percent (39/167) of the SSc cohort had data available on the presence or absence of peripheral artery disease (PAD); out of these 39 individuals, 1 patient (3%) had PAD.
Colour changes in the lower extremities are significantly more common in POTS than in SSc
Colour changes in the extremities, particularly in the feet, were common in POTS; 45/79 (57%) and 38/79 (48%) reported colour changes in their feet and hands, respectively, and 32/79 (41%) had colour changes in both their hands and feet. The prevalence of colour changes in the hands was significantly higher in SSc compared with POTS [137/167 (82%) vs 38/79 (48%), P < 0.001], whereas there was no difference in the prevalence of colour changes in the feet between the two cohorts [103/167 (62%) vs 45/79 (57%), P = 0.49]. Patients with POTS were significantly more likely to have isolated colour changes in the feet compared with SSc [13/79 (16%) vs 4/167 (2%), P < 0.0001]. Figure 1 shows representative images of colour changes in the feet in patients with POTS (Fig. 1C and D) and SSc (Fig. 1A and B).
Figure 1.
Representative images of colour changes in the dependent extremities in (A and B) SSc and (C and D) postural orthostatic tachycardia syndrome (POTS)
SSc patients with colour changes in the feet have more pronounced autonomic symptoms
Given our finding that patients with POTS have more colour changes in their lower extremities compared with their upper extremities, we examined autonomic symptom burden among the subset of SSc patients with colour changes in their feet; 103/167 SSc patients (62%) reported colour changes in the feet, all of whom also reported colour changes in their hands. In the SSc cohort, the presence of colour changes in the feet, compared with those without colour changes in the feet, was significantly associated with more vasomotor symptoms (3.6 ± 0.6 vs 1.6 ± 1.4, P < 0.0001), GI symptoms (11.3 ± 4.3 vs 8.8 ± 4.3, P = 0.0003), urinary symptoms (1.4 ± 1.5 vs 0.8 ± 1.3, P = 0.002) and a higher total COMPASS-31 score (37.0 ± 14.9 vs 27.4 ± 15.1, P < 0.0001). There also was a trend towards more orthostatic symptoms (11.7 ± 10.6 vs 8.6 ± 9.9, P = 0.06) and secretomotor symptoms (7.0 ± 3.8 vs 5.9 ± 3.8, P = 0.06), whereas there was no difference in pupillomotor symptoms (2.0 ± 1.2 vs 1.7 ± 1.2, P = 0.15) among SSc patients with colour changes in the feet (Fig. 2).
Figure 2.
Comparison of the COMPASS-31 total score and subdomain scores between SSc patients with and without colour changes in their feet. COMPASS-31, Composite Autonomic Symptom Score-31
Next, we excluded the 26 SSc patients with inactive Raynaud’s who had not reported colour changes in their hands or feet over the past year. We then directly compared autonomic symptoms among patients with colour changes in their feet (n = 103) and those with colour changes isolated to their hands (n = 38). We determined that patients with colour changes in their feet had significantly higher (worse) total COMPASS-31 scores (37.0 ± 14.9 vs 29.0 ± 16.4, P = 0.004), GI dysfunction scores (11.3 ± 4.3 vs 9.2 ± 4.4, P = 0.009), vasomotor scores (3.6 ± 0.6 vs 2.7 ± 0.7, P < 0.0001) and urinary dysfunction scores (1.4 ± 1.5 vs 0.6 ± 1.4, P = 0.0008) compared with patients with colour changes restricted to the hands. There also was a trend towards higher orthostatic symptoms (11.7 ± 10.6 vs 8.5 ± 10.7, P = 0.11) but no difference in pupillomotor or secretomotor scores (P > 0.05).
Multivariable model adjusting for covariates
We then constructed a multivariable linear regression model to determine whether the relationship between colour changes in the feet (independent variable) and the COMPASS-31 score and subdomain scores (dependent variables) remained after adjusting for potential confounders in the SSc cohort. After adjusting for sex, age and race in the model, colour changes in the feet were associated with a higher total COMPASS-31 score (β = 4.9, P = 0.0002), vasomotor score (β = 1.0, P < 0.0001), GI symptoms (β = 1.3, P = 0.0004), urinary dysfunction (β = 0.3, P = 0.02) and secretomotor symptoms (β = 0.7, P = 0.04). After adjusting for covariates, there was a trend towards an association with orthostatic intolerance (β = 1.5, P = 0.08). Colour changes in the feet were not associated with pupillomotor symptoms (β = 0.1, P = 0.31).
Distinct clinical features associate with SSc patients who have colour changes in the feet
Next, we examined the clinical features associated with colour changes in the feet in SSc (Supplementary Table S1, available at Rheumatology online). Patients with foot discolouration were more likely to be white (90.4% vs 64.1%, P < 0.0001). There was no difference in age, sex, scleroderma type (limited or diffuse) or disease duration. There also was no difference in organ disease severity measured by the Medsger disease severity scale for any organ except that patients with colour changes in their feet were more likely to have significant GI disease (84.3% vs 70.3%, P = 0.05). There was no difference in the Medsger severity score for Raynaud’s phenomenon between groups; both groups had a similar frequency of vasodilator use (calcium channel blockers and/or phosphodiesterase inhibitors).
Discussion
Autonomic dysfunction is a common complication of SSc that can be easily missed as it has many overlapping features with SSc. Identifying autonomic dysfunction in SSc is important as numerous available treatments can improve quality of life. Furthermore, given that several standard treatments for SSc, such as vasodilators, may exacerbate symptoms of dysautonomia, an appropriate diagnosis of dysautonomia is important to prevent unnecessary harm. Here, we show that colour changes in the feet are common in POTS and that patients with SSc who have colour changes in the feet have significantly more symptoms that suggest dysautonomia across multiple domains of the COMPASS-31 questionnaire than patients without such colour changes. Our findings suggest that colour changes in the feet may help identify SSc patients with a high dysautonomia symptom burden who may benefit from further evaluation. Black SSc patients were significantly less likely to report colour changes in their feet, possibly because colour changes are less visible on darker skin.
We found that SSc patients with colour changes in the feet have more GI symptoms, urinary symptoms, a trend towards more orthostatic symptoms, and more secretomotor dysfunction after adjusting for demographic covariates. As expected, they also had more vasomotor symptoms. Colour changes in the feet were not associated with severe Raynaud’s phenomenon or treatment with vasodilators, suggesting that these factors do not mediate our findings. Furthermore, colour changes in the feet were not associated with other organ manifestations of SSc, such as pulmonary or cardiac involvement, suggesting that this may represent a distinct phenotype of scleroderma with high autonomic symptom burden.
Our study did not address the underlying mechanism of colour changes in the extremities in POTS or SSc. Still, the association with autonomic symptoms in SSc suggests that they could have a common pathophysiology linked to dysautonomia. The high prevalence of colour changes in the distal extremities in POTS is consistent with numerous reports in the literature [6, 11–13]. Proposed mechanisms include venous pooling from vasomotor dysfunction or acrocyanosis from blood vessel vasospasm. It is still being determined if similar mechanisms underlie the colour changes in the feet observed in SSc, and more research is needed to better characterize this phenomenon. Future studies should ask whether the colour changes are triphasic or are associated with changes in temperature or position. Advanced imaging of blood vessels can also be utilized to further understand the pathophysiology of this phenomenon in both conditions.
Strengths of this study are that it includes a large, well-characterized patient cohort with SSc. Limitations are that autonomic symptoms were assessed by a validated patient-reported questionnaire, which was applied as a surrogate for dysautonomia. Objective testing did not confirm dysautonomia due to the high costs associated with these studies. Since this was a retrospective study, we did not collect more detailed information on the colour changes, such as associated triggers or persistence. This study was hypothesis-generating, and future studies should perform autonomic testing to determine whether patients with colour changes in the feet have objective evidence of dysautonomia.
In conclusion, this study demonstrates that colour changes in the distal extremities are common in the autonomic disorder POTS and in SSc, and that patients with SSc who report colour changes in their feet have a higher autonomic symptom burden across multiple organ systems. These findings suggest that the presence of colour changes in the feet may be a clinical sign of dysautonomia and that screening affected patients more thoroughly for other autonomic symptoms should be considered.
Supplementary Material
Contributor Information
Brittany L Adler, Division of Rheumatology, Johns Hopkins University, Baltimore, MD, USA.
Kamini Kuchinad, Division of Rheumatology, Johns Hopkins University, Baltimore, MD, USA.
Seeun Judy Jeong, Department of Physical Medicine and Rehabilitation, Johns Hopkins University, Baltimore, MD, USA.
Lauren E Stiles, Department of Neurology, Stony Brook University Renaissance School of Medicine, Stony Brook, NY, USA; Dysautonomia International, East Moriches, NY, USA.
Ami A Shah, Division of Rheumatology, Johns Hopkins University, Baltimore, MD, USA.
Tae Chung, Department of Physical Medicine and Rehabilitation, Johns Hopkins University, Baltimore, MD, USA.
Zsuzsanna H McMahan, Division of Rheumatology, Department of Internal Medicine, The University of Texas Health Science Center at Houston, Houston, TX, USA.
Supplementary material
Supplementary material is available at Rheumatology online.
Data availability
The data underlying this article will be shared on reasonable request to the corresponding author.
Funding
NIAMS (R01AR081382-01A1, P30 AR070254, K24 AR080217, T32 AR048522-19), the Chresanthe Staurulakis Memorial Discovery Fund, the Jerome L. Greene Award, the Donald B and Dorothy L Stabler Foundation, and the Johns Hopkins inHealth initiative.
Disclosure statement: Z.H.M. is a consultant for Boehringer Ingelheim. The remaining authors have declared no conflicts of interest.
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Associated Data
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Supplementary Materials
Data Availability Statement
The data underlying this article will be shared on reasonable request to the corresponding author.