## 4 Discussion  
HOA leads to a spectrum of impairments, including pain, diminished grip strength, limited range of motion, and joint stiffness, collectively resulting in compromised hand functionality and hindered daily activities. Regrettably, the therapeutic options for HOA remain limited [4; 10]. Nevertheless, BT--a traditional therapeutic and rehabilitative intervention--has emerged as a promising strategy for managing HOA. Indeed, preliminary evidence suggests its effectiveness in alleviating pain, enhancing function, and improving quality of life, particularly in patients with mild-to-moderate HOA. Long-term studies have indicated that the beneficial effects of BT can persist up to 3-6-12 months after treatment [17; 22]. Additionally, some studies have reported a reduction in the usage of symptomatic medications, such as acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs), among patients subjected to BT [22; 24]. Moreover, the various studies analyzed have also demonstrated the safety of BT treatment for patients with HOA, resulting in a limited number of adverse effects, and with any adverse effects that were present being of mild nature. The beneficial effects seem likely to be due to the combination of its thermal, mechanical, and chemical properties that have an impact on neuroendocrine and immunological responses [16]. Mineral-rich water appears superior to tap water in terms of its effects, and mud treatment followed by mineral-rich baths seem to provide additional benefits compared to baths alone [23; 24]. Indeed, several studies have shown that BT performs antioxidant and anti-inflammatory activities, reducing the release of reactive oxygen species (ROS), nitrogen, and inflammatory mediators, such as prostaglandin E2 (PGE2), leukotriene B4 (LTB4), adipokines, and pro-inflammatory cytokines in preclinical models able to reproduce OA conditions and in OA patients [27; 28]. Furthermore, spa therapy has been demonstrated to increase serum levels of cortisol in patients with primary knee OA [16; 29]. Although specific studies on the mechanisms underlying the effects of BT on HOA have never been conducted, current knowledge suggests that BT may modulate important factors involved in the onset and progression of this disease. For instance, different studies have demonstrated that BT reduces the production of IL-1\(\beta\), the serum levels of which were associated with loss of hand function and radiological erosions in HOA patients and an association between hand OA and SNPs in genes encoding IL-18 [16; 17; 30]. In addition, an interesting comparative study in patients with knee OA has revealed that mud-bath therapy can modify the expression levels of microRNAs, including miR-146a, which was found up-regulated in the plasma of hand OA patients, and is associated with clinical manifestations of hand OA, particularly with joint pain [31; 32]. To date, in this context, little research has attempted to identify the mechanisms of HOA, therefore further studies are needed in this field [5]. As shown by the studies analyzed in our review, the role of BT as a complementary intervention in the management of HOA seems to be particularly significant, especially in the initial stages of the disease when HOA is still in a mild or moderate form. During these phases, BT, which can target specific mechanisms involved in the onset and progression of the disease, could have a role not only in reducing painful symptoms but also in preventing the potential development of future functional limitations. Therefore, it is believed that in the early stages of the disease, this treatment could be recommended to patients. In a previous review that synthesized the available information at that time concerning the clinical outcomes and underlying mechanisms of BT as a therapeutic approach for managing HOA, only three RCTs were evaluated.