We employed the QSART to assess sweating ability. A low ARSV and/or prolonged sweat latency in the QSART can be used to diagnose abnormalities of the postganglionic sympathetic fibres or eccrine sweat glands associated with poor acetylcholine-induced sudomotor responses16,17. The sweating responses of individuals living in Japan are more pronounced in summer than in winter18. The changes in sweating activity measured by the QSART confirmed the involvement of the peripheral nervous system in altering sudomotor activity during seasonal acclimation19.
In the present study, we assessed both sweating ability and its association with the clinical severity of Raynaud’s symptoms in patients with SCTDs. We found that none of the disease groups showed an apparent decrease in sweat volume compared to healthy participants (Supplementary Table S1 online). However, it was a novel finding that approximately one in three patients (34%) showed less sweating in summer than in winter (Fig. 1). This phenomenon was more common in patients with SSc than in healthy participants.
Because of the unique seasonal changes in sweating ability shown in the present study, we anticipated that patients with SCTDs have a dysregulated sweating ability due to abnormal peripheral nerve responses. While problems associated with heat adaptation are major factors for heat stroke20, there are no specific data available on the risk of heat stroke in patients with SCTDs. Li et al21 noted that left uncontrolled, recent trends in global warming will lead to an increased risk of heat stroke in 1.2 billion people by the year 2100. According to this assumption, we should pay attention to the relationship between global warming and seasonal perspiration in patients with SCTDs.
We focused on RNAP-positive SSc patients because they may have characteristic sweating abnormalities that are not present in other patient groups. Patients with RNAP-positive SSc had prolonged sweat latencies (Fig. 4), with 44% of them showing a poor response to acetylcholine (Table 2). Furthermore, RNAP-positive patients showed both less sweating and smaller seasonal differences than ACA-positive or Topo1-positive patients (see Supplementary Fig. S4a, Fig. S4b online). Patients with a high degree of skin stiffness showed less sweating than patients with a low degree of skin stiffness or no skin stiffness (Fig. 2); 57% of patients with an MRSS > 10 were RNAP positive.
Autoantibodies reactive with RNA polymerase (RNAP) III are confirmed to be strongly associated with diffuse or extensive cutaneous involvement and renal crisis22,23. Severe and rapidly progressive cutaneous fibrosis may attenuate the response to acetylcholine by disrupting and reducing the number of eccrine sweat glands and nerve fibres. In some patients with SS, eccrine sweat gland dysfunction is associated with autoimmune mechanisms mediated by CD8 T cells24 or M3 receptor-specific autoantibodies25. As we did not perform pathological assessment of eccrine glands, we cannot exclude the possibility that RNAP is directly associated with eccrine gland dysfunction. Further research on sweat gland impairment and the autonomic nervous system in RNAP-positive SSc patients may lead to a better understanding of peripheral circulation in patients with SCTDs.
Our results also indicated that patients with a higher degree of the pain in the RCS evaluation had a higher sweat volume (Fig. 3 and Supplementary Table S3). Regarding this phenomenon, we anticipated that the neuronal transmitters that convey pain signals might be involved in sweating ability. It has been reported that patients with Raynaud’s symptoms exhibit abnormal responses to pain-associated neurotransmitters, including substance P, glutamate, and calcitonin gene-related peptides26, which may contribute to Raynaud-related pain. On the other hand, substance P and calcitonin gene-related peptide are expressed in normal sweat gland secretory cells or around the sweat glands27,28 and contribute to gland secretion in response to harmful stimuli. Taken together, these findings suggest that the response to neurotransmitters might link the pain in Raynaud’s phenomenon and increased sweating in winter.
Increased winter sweating with severe pain in Raynaud's phenomenon might explain the phenomenon of increased winter sweating in some SCTD patients shown in Fig. 1. Tabata et al. studied sweating in SSc patients by using capillaroscopy and reported that 7 out of 21 patients developed increased sweating, although they did not perform a seasonal analysis29. The mechanism by which the overactivity of the sympathetic nerves that causes Raynaud’s phenomenon affects sweating remains to be explored in additional studies involving a larger patient cohort, autonomic function tests, and pathological examination.
In conclusion, most patients did not show decreased sweating compared to healthy participants, but RNAP-positive patients with SSc had impaired sweating. One in three patients with an SCTD showed more sweating activity in winter than in summer, which is the opposite of the regular change. Although sweat volume was not associated with the total RCS, the pain of Raynaud's phenomenon increased the volume of sweating.
A limitation of this study was the small sample size for each disease. Our study did not consider the effects of regularly used drugs, including external agents such as moisturizers, the obscurity of patients' answers about Raynaud's symptoms, the practice of sports, the living environment, and patients' physical constitutions. In SSc patients, the reduced permeability of acetylcholine due to the hardness of the skin should be considered. Further study in combination with other autonomic nervous system assessments and more detailed patient backgrounds can provide a better understanding of the signs and biomarkers associated with peripheral nerve disorders and contribute to the development of treatment strategies for patients with autonomic peripheral circulatory disorders.