Systemic sclerosis (SSc) is a chronic autoimmune disease of unknown aetiology. Pathogenetically, it is characterised by immune dysregulation, vasculopathy and excess collagen deposition, which determines cutaneous fibrosis and multi-organ involvement.1 Microvascular structural damage is responsible for vascular manifestations such as Raynaud's phenomenon (RP), telangiectasias, myocardial involvement, antral vascular ectasia, pulmonary arterial hypertension, digital ulcers (DU) and scleroderma renal crisis.2 Vasculopathy is secondary to the immunoinflammatory process, which determines endothelial dysfunction and damage.2,3 This is expressed by the decrease in the synthesis and release of prostacyclin and nitric oxide (NO), causing vasospasm, in situ thrombosis and intimal proliferation, which contributes to fibrosis and vascular wall stiffness with stenosis. In addition to the loss and obliteration of capillaries, there is an absence of new vessel formation. In SSc, angiogenesis is severely compromised.2–5 Abnormalities in microcirculation can be detected early by periungual capillaroscopy.

SSc impairs patients’ quality of life and determines socio-economic personal and health repercussions. There is currently no curative treatment. The latter is usually symptomatic, and in some cases it achieves patient stabilisation for a variable period of time. Some drugs can have important side effects, which does not favour adherence to treatment and can impact on the patients’ quality of life. Furthermore, some pharmacological treatments are expensive or are unavailable in Uruguay (e.g., intravenous prostacyclin analogues).

Exposure to artificial gravity (AG) through human centrifugation is the basis of the treatment called gravity therapy (GT) and has been used in Uruguay for more than 40 years. It has been applied for the treatment of vascular pathologies and RP, but also in lymphoedema, complex regional pain syndrome, and for physical rehabilitation of other medical conditions, with successful results.6–18

Isasi M.E. and Isasi E.S. showed that the frictional vector of the haemodynamic forces generated by GT, through human centrifugation, constitutes a vascular mechanical stimulus that induces the synthesis and release of vasodilatory substances such as prostacyclin and possibly NO.6,9,15,18 In addition to sustained vasodilation, it increases vascular endothelial turnover and collateral circulation.7–10 Since the vascular endothelium is sensitive to mechanical stress/stimulation during hypergravity, it has been speculated that endothelial cells would play a central role in the observed therapeutic effects.6,13,19,20 Also the randomised controlled study by Mitropoulos et al.21 suggests that mechanical/biophysical stimulation has the potential to improve microvascular endothelial dysfunction in SSc patients. In this regard, it is possible that the haemodynamic forces generated by GT induce the synthesis and release of other biologically active substances, growth factors and cytokines and modulate endothelial gene expression, in analogy to the effects of shear stress on the endothelium.6

GT has been used in Uruguay since 1990 for the treatment of SSc and has been shown to improve RP, microcirculation, DUs and cutaneous sclerosis.11,12,22,23 In the studies carried out, patients showed an increase in pulse wave amplitude, a reduction in ischaemic pain, and in the frequency and severity of RP attacks, together with an increase in DU healing which, in severe cases, prevented digital amputation, the use of opioid analgesics and hospitalisation.11,12,22,23 It also improved skin colour, temperature, sensitivity and mobility (due to reduced oedema in the hands).11,12 GT has been shown to improve cutaneous sclerosis also in patients with morphea,24 and post-GT improvement of digestive symptoms, such as mouth opening, mild oesophagitis and oesophageal hypomotility, described in patients with SSc.25

It is a safe and well-tolerated treatment in patients of a wide age range, with no significant side effects under the conditions applied. The hypergravity protocol is adjusted (number of sessions, maximum g level reached) according to the patient's tolerance, age and clinical characteristics.6 Transient dizziness or nausea may occur when the patient is not yet accustomed to the procedure, or occasionally vomiting/dizziness related to head movement during centrifugation (Coriolis effects),6 Patient training is important for better tolerance and continuity of treatment.

Given the extensive experience in Uruguay with GT and its efficacy in SSc, with an excellent safety profile, availability and low cost, added to the fact that it is a therapeutic option that is not widely known in the scientific community, this research we are conducting could provide future scientific, health and economic benefits.

To assess the efficacy of GT in skin and vascular conditions, in quality of life and functional capacity, and its safety profile in patients with SSc.

A total of 50 patients were included. Women predominated (96%), Caucasian (98%), and the mean age of the cohort was 62 ± 12 years. Table 1 contains the demographic characteristics, the SSc status at the start of GT and at the time of inclusion in the study, the cutaneous extension and the immunological profile of the patients.

Analysis of cutaneous efficacy

For this analysis, 3 patients without scleroderma and 22 without pre- and/or post-GT data were excluded. A total of 25 patients were analysed. Post-GT, a significant improvement in mRSS was observed (pre-GT 19.2 ± 8.7 vs. post-GT 5.4 ± 5.0 points, t-test, p < .05), average mRSS reduction post vs. pre-GT: 13.8 ± 5.7 points (Table 2, Fig. 2). 75% of patients improved mRSS by 11 points or more. The mean time to complete 20 GT sessions was 137.2 ± 99.3 days. The mean reduction in mRSS in patients who received 10 sessions was 8.8 points vs. 13.1 in those who received 20 sessions. The reduction in mRSS post-GT was greater in patients with higher initial mRSS (R = .84, p < .05) (Fig. 3). The value of the variation in mRSS pre/post-GT was not significantly related to the time of evolution of SSc at the beginning of GT (<1 year, 1−4 years, >4 years), with the immunological profile of the patients or with the cutaneous extension of SSc. In the RRP, 36/38 (95%) of the patients who completed the questionnaire reported improvement at the cutaneous level, 87% responded that it improved quite a bit or a lot and 8% that it improved little. On the other hand, a significant improvement was observed in the number of patients with puffy fingers (pre-GT 25/50 [50%] vs. post-GT 10/50 [20%], McNemar test, p < .05), but not in the frequency of patients with telangiectasias, pitting scars or sclerodactyly (Table 3).

Table 2.

Modified Rodnan score (mRSS) pre and post gravity therapy and its variation.

	n	Q25	mean	Q75	SD	min	max
Pre-GT	25	15	19.2	24	8.7	2	37
Post-GT	25	2	5.4	8	5.0	0	19
Variation	25	11	13.8	17	5.7	0	23

A significant decrease in mRSS is observed, pre-GT 19.2 ± 8.7 and post-GT 5.4 ± 5.0 (t-test, p < .05). The average reduction in mRSS post- vs. pre- GT was 13.8 ± 5.7 points.

Figure 2.

Modified Rodnan Score (mRSS) values ​​pre- and post-gravity therapy. Twenty-four patients (96%) improved mRSS post-GT (points are below the x = y line), except for one patient (4%), who did not show any changes. In addition, 75% of patients improved mRSS by 11 points or more.

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Figure 3.

Comparison between the pre-treatment modified Rodnan score (mRSS) and its change. A significant correlation is observed between the magnitude of the reduction in mRSS (post-GT - pre-GT) and the initial pre-GT value (R = .84, p < .05). The reduction in mRSS was greater in patients with higher initial mRSS.

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Table 3.

Effects of gravity therapy on puffy fingers, sclerodactyly, pitting scars and telangiectasias.

Clinical symptom	Time of registration	Number of patients (%)
Puffy fingers	BGT	25 (50)
	AGT	10 (20)
Sclerodactyly	BGT	36 (72)
	AGT	33 (66)
Pitting scars	BGT	5 (10)
	AGT	2 (4)
Telangiectasias	BGT	15 (30)
	AGT	10 (24)

A significant improvement was observed in the number of patients with puffy fingers (pre-GT 50% vs. post-GT 20%, McNemar test, p < .05), but not in telangiectasias, pitting scars or sclerodactyly.

BGT: before gravity therapy; AGT: after gravity therapy; n = 50 patients.

Analysis of vascular efficacy

A significant decrease in the severity of RP was observed in most patients, the majority with severe RP at baseline: pre-GT grade 3–4 RP, 43/48 (89.6%) patients vs. post-GT, grade ≤2, 42/47 (89.4%) patients. In total, 38/48 (81%) of the patients improved the grade of RP, while 9 did not register changes. Therefore, the probability of having severe RP grade 3–4 decreases post-GT (McNemar test, p < .05) (Table 4). From the patient's perspective, 32/35 (91%) of the patients reported improvement in RP, 74% responded that it improved quite a bit or a lot and 17% that it improved little. On the other hand, a notable improvement was observed in vascular pain quantified by VAS (pre-GT, 7.6 ± 2.2, post-GT, 1.4 ± 1.2, p < .05). The RRPs report significant improvement in vascular pain and also in joint/muscle pain (Table 5). Regarding the DUs, pre-GT, 7 patients had 15 fingers with critical ischemia, post-GT, 5 achieved complete healing of fingers and 2 patients partial healing (1 amputation each). In total, there was improvement of DU in 11 fingers (Table 4, Fig. 4).

Table 4.

Effect of gravitational therapy in the Reynaud phenomenon, digital ulcers and vascular pain.

		Number of patients (%)
Severity of RP	BGT	G 0: 1 (2)G 1: 1 (2)G 2: 3 (6.2)G 3: 35 (72.9)G 4: 8 (16.7)
	AGT	G 0: 13 (27.7)G 1: 21 (44.7)G 2: 8 (17)G 3: 0G 4: 1 (2.1)
Digital ulcers	BGT	7 (14.5)
	AGT	0
		Mean ± SD
Vascular pain by VAS	BGT	7.6 ± 2.2
	AGT	1.4 ± 1.2

Quantitative variables are expressed as mean ± standard deviation, and qualitative variables as number (percentage).

BGT: before gravity therapy; AGT: after gravity therapy; VAS: visual analogue scale. 2 patients without BGT data and 7 patients without AGT data; RP: Raynaud's phenomenon.

A significant decrease in the severity of RF was observed in the majority of patients (most with severe RF at baseline): pre-GT grade 3–4, 43 (89.6%) of patients vs. post-GT, 46 (89.4%) grade ≤2, McNemar test, p < .05), as well as vascular pain measured by VAS: pre-GT, 7.6 ± 2.2, post-GT, 1.4 ± 1.2, p < .05).

Table 5.

Results reported by the patients in a gravitational therapy questionnaire.

Variable	Improvement (% of patients)
Quality of life	97
Reynaud’s phenomenon	89.5
Skin	95
Capacity for ADL	89.5
Mood	65
Sleep disorders	37

Other variables	% patients
Vascular pain (VAS > 4), pre-GT	65
Vascular pain (VAS ≤ 4), post-GT	84a
Muscular/joint pain (VAS > 4), pre-GT	60
Muscular/joint pain (VAS ≤ 4), post-GT	74a
Tolerance to “good” GT	100%
100% adherence to sessions	87%

ADL: activities of daily living.

The results correspond to questionnaires completed by 38 patients.

a

Wilcoxon test, p < .05.

Figure 4.

Effect of gravity therapy on digital vascular lesions in patients with systemic sclerosis. (A) Images of the effect of gravity on a digital ulcer of a left lower limb at baseline and its evolution with gravity in a patient with SSc. (B) Evolution of digital necrosis in a patient with mixed connective tissue disease at baseline (left) and post-GT (right). These images do not correspond to patients in this study. Adapted from: Isasi et al., 2022, doi: 10.3389/fphys.2022.952723. Photos courtesy of the Gravitational Therapy Centre.

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GT significantly improved skin involvement in patients with SSc, as previously demonstrated in previous studies by Isasi et al.11,12,23 The more sessions performed the greater the benefit, which is evident from the comparison of the decrease in mRSS depending on whether 10 or 20 sessions are performed. However, as previously published,11,12 when improvement appears, it is early, and is already observed in the first 10 sessions. The time in which the results were achieved (20 sessions) was relatively short (just over 4 months). Although long-term follow-up of patients was not an objective of this study, the maintenance over time of the improvement in mRSS post-GT is variable, as evidenced by the review of clinical records and according to the opinion of CGT experts. The indication for annual maintenance GT should therefore be individualised. Patients with the highest initial mRSS were those who showed the greatest reduction in mRSS post-GT, probably due to their greater capacity for improvement due to more extensive skin involvement, and at the expense of improving skin areas with less fibrotic involvement. The initial mRSS and its post-GT variation were not related to the time of evolution of SSc at the beginning of GT, nor to the immunological profile of the patients or the cutaneous extension of the disease. This should be interpreted with caution, since the number of patients with mRSS presented in this study is small, there are no previous complete investigations of SSc patients treated with GT that allow comparing the results of this study with other cohorts, and a control group of patients (without GT) was not included in this analysis.

A significant improvement was recorded in the number of patients with puffy fingers, with the decrease in hand oedema being a fact previously reported by Isasi et al.12 However, GT did not influence the frequency of patients with sclerodactyly, pitting scars or telangiectasias.

At the vascular level, the severity of RP decreased significantly after GT in most patients. Moreover, there was a cure of DU, which prevented hospitalisation and eventual digital amputation, and the use of vasodilators such as intravenous prostacyclins, not available in Uruguay, was not necessary. Patients significantly improved ischaemic pain, which decreased the use of opioid analgesics. These results are similar to those previously reported.11,12 Functional capacity measured by CHFS and MHISS improved, although the number of patients with these data was small.

In the RRP, most patients reported improvement in skin, RP, ischaemic pain and joint/muscle pain (statistically significant improvement), and other data emerge, such as improvement in mood and sleep disorders, reported by a smaller number of patients. All these benefits necessarily impact on quality of life and functional capacity, and this was stated by the majority of patients in the GT questionnaire. In this study, no significant adverse effects were recorded, similar to that observed in the GTC, even with patient follow-ups for more than 20 years. This is also reflected in the GT questionnaire, in which all patients expressed good tolerance to the treatment and high adherence to it.

Although this study has limitations given its descriptive and retrospective design and the absence of a control group of patients with SSc, not treated with GT, the results are highly promising. The effect of drug treatment on the results was not analysed, which could be a starting point for future research.

This research study contributes to the dissemination of GT and its results, which coincide with the benefits observed in daily clinical practice and with those reported by patients. Controlled and randomised clinical trials are needed, to compare the effects of GT vs. conventional drug treatment. In addition, more basic research is needed to unravel the biological mechanisms and the cellular and molecular bases of clinical improvement, as well as for its international validation and widespread use.

GT improved cutaneous and vascular involvement, quality of life and functional capacity in patients with SSc with an excellent safety profile. Randomised controlled clinical trials are needed to corroborate these observational results.

L.F.S., E.I., M.E.I.: conception and design of the work, data collection, analysis and interpretation of data and results, statistical analysis, writing of the manuscript, critical revision of the manuscript. AP, S.P.: data collection.

This research did not receive any specific support from public sector agencies, commercial sector or non-profit entities.