Our main findings from this systematic review with meta-analysis indicate that interventions with RE improved muscle strength, physical disability, and the physical component of QOL in SSc patients compared to the control group. When performing sensitivity analysis, RT showed better efficacy than RE to improve functional disability and QOL. There were no differences in the mental component of QOL. Regarding body composition and physical performance, since the number of studies that could be included in a meta-analysis was limited. Although a previous systematic review [18] had a similar objective to ours by summarizing the effects of physical therapy in patients with SSc, this is the first systematic review specifically aimed at summarizing the effects of interventions with RE compared to other exercise modalities and controls on specific outcomes, including adherence, in patients with SSc.

Although it is established that interventions with RE enhance strength in diverse populations, there is a paucity of data on SSc. Given the gravity of this disease, which encompasses involvement of the locomotor system, it is imperative to ascertain the effects of this intervention on muscle strength. Previous literature already shows that patients diagnosed with SSc, frequently exhibit diminished muscle strength, limited physical activity and low exercise engagement [3, 18]. This reduction in muscle strength appears to significantly impact their physical disability and QOL in SSc patients [41]. Additionally, it is important to observe that previous literature already demonstrated that handgrip strength is associated with lower risk of mortality in chronic diseases [41], which may be a reason to recommend RE for SSc patients. In our systematic review, considering included studies, it was possible to note that only four of them [29, 30, 37, 38] controlled training structure with objective measures, which we considered as RT. However, only two of those studies were included in meta-analyses, since the study from Yakut et al. (2021) [30], compared two different RT protocols (supervised vs home-based) and showed significant difference between groups for handgrip strength after intervention period (p < 0.001). On the other hand, the study from Piga et al. (2014) [33], which compared two interventions without supervision and with similar exercise protocols, did not show significant difference between groups for any of the muscle strength assessments. In addition, when performing sensitivity analyses, both RE and RT showed significant differences compared to the control group, suggesting that interventions with RE may be a useful non-pharmacological strategy to improve strength in SSc patients whether or not they had a well-structured training program. These findings are in line with previous literature that demonstrated signigicant improvement of muscle strength in rheumatic diseases patients who underwent RT [42] and RE [43], considering our definition of these two kinds of intervention.

Regarding the meta-analysis evaluating physical disability, patients who underwent interventions with RE exhibited significant improvements compared to those in the CON group. We performed subgroup analyses to elucidate the effects of RE on physical disability, separating the studies based on the use of different questionnaires: HAQ-DI [29, 32, 37], SHAQ [34], and HAQ total [31]. Interestingly, when separated by the HAQ version, both SHAQ and HAQ total did not show significant differences between groups. To clarify these findings, we performed sensitivity analysis excluding either RT or RE from the metanalysis and only when considering studies with rigorous, structured and progressive RT protocol [29, 30, 37, 38], the difference between groups was significant, suggesting that the periodization of training program may be the key point to improve functional disability. Additionally, the study from Yakut et al. (2021) [30] have demonstrated that RT leads to a significant improvement in HAQ compared to other protocols, with higher intensities being necessary for greater efficacy. Furthermore, a previous systematic review emphasized the use of non-pharmacological therapies to improve hand function and activities of daily living in patients with SSc [12] RE Our findings demonstrated that interventions with RE may be effective to improve QOL, considering the physical domain. We performed sensitivity analyses, considering only RE or RT to verify if any of those would be better to improve the physical domain of QOL, and the studies that performed a structured RT [29, 30, 37, 38] presented significant differences between groups for this outcome. On the other hand, studies that performed RE [31,32,33,34,35,36] did not show significant differences between groups. Two studies [36, 38] assessed QOL through different tools - the NHP and the EQ-5D-5 L - and the intervention groups from both studies showed significant differences for the QOL improvement compared to the CON. Despite the fact that we did not consider the study from Sari et al., 2023 [36] for the RT group, it is important to note that the intervention group of this study underwent “clinical Pilates”, which may be considered as RT but, as the protocol was not clear, we considered it as RE. These findings corroborate a previous systematic review [44] that analyzed the effects of resistance training (RT) on general health-related QOL in patients with rheumatic diseases, which included 32 studies in qualitative synthesis and 29 for the quantitative synthesis and found significant difference in favor of RT when compared to control group. Additionally, when compared to other exercise interventions, there were no significant differences, even with low intensity RT, which demonstrates that, even with low intensity, interventions with RE could improve the general QOL in patients with rheumatic diseases. Lastly, they did not find significant differences between groups for the individual components of SF-36 (mental and physical components), which is partly in line with our findings, since we found significant differences between groups for the physical component of QOL.

Only one study [29] assessed body composition by fat-free mass evaluation and did not show significant difference between RE vs CON groups. Regarding physical performance, although a statistical comparison between RE and CON was not feasible, the results suggest that RE has a clinically meaningful impact on physical performance. Mitropoulos et al. (2020) stated in the methods section that they would assess physical performance using the 6MWT. However, these data were not provided in the paper or elsewhere. We contacted the corresponding author to obtain these data, but he was unable to provide them. Our findings are consistent with the findings of a previous systematic review [44], which demonstrated a significant improvement in the 6 Minute Walk Test (6MWT) with RE in patients with chronic obstructive pulmonary disease. Thus, we speculate that RE may be a valuable addition for health professionals prescribing therapy or training for SSc patients.

Seven studies in this review provided adherence data [29,30,31, 33, 34, 36, 38]. Among these studies, only three studies [29, 30, 38] reported adherence consistent with the expected sample size, while most studies in this review had higher dropout rates. This underscores the challenge of maintaining patients in the prescribed exercise program, a difficulty also noted in a prior systematic review with SSc patients [45]. Studies with SSc patients should prioritize adherence monitoring, considering that assessing patient adherence is vital for improving exercise prescriptions, especially for populations like the elderly [46]. Additionally, the negative impacts of the RE regimens remain unclear due to the lack of standardized evaluation methods. Ensuring good adherence to these exercises is crucial for improving the quality of life (QOL), cardiovascular function, metabolic and glandular health, muscle structure and function, lung mechanics, mobility, and reducing systemic inflammation in patients with systemic sclerosis (SSc). These exercises have beneficial effects on both the physiological and psychological components of the condition [46].

Despite finding a significant effect of interventions with RE on muscle strength, physical disability, and physical component of QOL, caution is warranted when applying these interventions to SSc patients, due to the moderate to high risk of bias assessed in most included studies and the very low quality of evidence for the main outcomes. The absence of standardization presents a significant challenge when attempting to perform statistical analysis across multiple studies. The integration of both quantitative and qualitative analyses can become complex when studies employ disparate evaluation methodologies. The heterogeneity of the intervention protocols in the included studies presents challenges for health professionals in offering interventions with RE as a strategy for SSc patients. Additionally, the reproducibility of the RCTs is hindered by the lack of clarity surrounding the exercise variables in most of the studies. The findings of this study suggest the potential efficacy of interventions incorporating RE in enhancing muscle strength, irrespective of the presence of a structured exercise program. On the other hand, when considering functional disability and quality of life, our results suggest that only structured RT was able to improve these outcomes. However, it is important to note that there were no trials with RT or RE that were not combined with other interventions, which may be a confounding factor, especially when considering functional disability and QOL, which may be influenced by interventions such as aerobic training, breathing and/or stretching exercises. Yet, differences between RT and RE may be related to physiological mechanisms. As mentioned above, muscle strength is dependent on exercise intensity, with recruitment of type IIa and IIx muscle fibres and larger motor units activated by a resistance stimulus [47]. In addition, these effects appear to be greater in the initial phase of the intervention [47] which is consistent with our findings in studies within 12 weeks of duration. Conversely, interventions with RE were only able to improve functional disability and QOL when the exercise protocol was well structured. These findings are in line with previous literature showing that structured resistance exercises combined with aerobic training can improve symptoms, functional disability and QOL in many populations [48,49,50]. Nevertheless, the physiological pathways remain not well described, but we speculate that it may be related to the systemic effects of a structured protocol, which may not be present in a protocol that only involves fingers, hands, fists and mouth exercises, as we may see in three included studies [31, 33, 34]. Previous literature has demonstrated that a structured RT produces a systemic metabolic stress, that may be useful for maintaining or even regaining health, with the anti-inflammatory effects (IL-6 and irisin), binding of myostatin by the follistatin and decorin and the production of BDNF by a variety of tissues, such as muscle, liver, adipose tissue and brain [47]. It has been suggested in the literature that, depending on the therapeutic target, the mTOR or AMPK pathways can be activated for myokine production [47]. Although there is a discussion about the role of myokines in rheumatic diseases, previous study suggests that muscle production of these cytokines may have an anti-inflammatory effect [51] which we understand could be an explanation for our findings, but as we said, it is not yet determined. Further research is required utilizing well-described interventions and assessment methods, with a comparison of two or more non-pharmacological interventions, and with one or more groups performing exclusively RT. This will facilitate a more comprehensive understanding of the effects of interventions with RE on muscle strength, body composition, physical performance, physical disability, and QOL in SSc patients. In addition, our findings support the EULAR recommendations for the use of RE as a treatment for SSc [40]. It is important to note that we standardized the duration of the interventions across the included studies to 12 weeks for the meta-analyses to ensure consistency in the statistical analysis.

The research has some limitations. Few RCTs compared interventions with RE to other non-pharmacological modalities, as seen in other populations (e.g. older individuals or RA) [52, 53]. Most of the studies included [31, 34, 35, 37] did not utilize machines or free weights, which are commonly used and studied in other populations, such as older individuals and those with other rheumatic conditions [54, 55] In the majority of studies, the interventions with RE were combined with other exercise interventions. This methodological choice limits the possibility of analyzing the REs effect alone or describing the physiological explanation for its effects on outcomes. However, we hypothesized that RT may be a better strategy to improve muscle strength, functional disability and QOL in SSc patients, according to our findings. Finally, it was not possible to perform meta-analyses considering the body composition and physical performance in SSc patients, due to the low number of studies that assessed these outcomes.

Our findings suggest that interventions with RE may be a safe and effective non-pharmacological strategy, demonstrating significant improvements in physical capacities such as muscle strength, physical function, and the physical component of quality of life in patients with SSc. Given the impairing nature of SSc and the concomitant concerns regarding its severity and the practice of high-intensity resistance training [56, 57], it was deemed worthwhile to broaden our evaluation to encompass interventions with RE, as well as its safety. Furthermore, our review suggests that RT may be the most effective non-pharmacological intervention, demonstrating the importance of controlling training variables such as intensity, volume, density, frequency and duration of exercise programmes. We believe that SSc patients would benefit of a well-structured RT, considering our findings and previous literature. These results provide health professionals with multiple intervention options, allowing them to consider factors such as aerobic limitations, nutritional and inflammatory status, functional capacity, and disease severity, rather than adopting a one-size-fits-all approach for patients with SSc.

Our results suggest that interventions with RE may be a useful addition to the treatment of patients with systemic sclerosis, in improving muscle strength, physical disability and the physical component of quality of life. The best intervention with RE protocol for patients with SSc remains undefined. Different protocols should prioritize individual aspects such as aerobic limitations, nutritional and inflammatory status, functional capacity, and disease severity, rather than adopting a one-size-fits-all approach for patients with systemic sclerosis.