Rheumatoid arthritis and joint response metabolism

One of the immunological cornerstones that emerges strongly in rheumatoid arthritis is the imbalance of T cells, the cells that act as the conductors of the immune system. In particular, the delicate relationship between pro-inflammatory effector cells and regulatory cells appears profoundly altered. In patients with active rheumatoid arthritis, Th17 cells (Teff), known for their production of inflammatory cytokines such as IL-17, are increased, while regulatory T cells (Treg), tasked with curbing autoimmune responses and maintaining tolerance, appear reduced in both number and functionality. This imbalance, often quantified as the Th17/Treg ratio, is heavily skewed in favor of the former and is directly correlated with clinical severity and serological markers of the disease (Wang et al., 2012) [1]. It is as if the accelerator of autoimmunity were pressed to the floor, while the regulatory brake were weakened.

The abnormalities of Tregs are not limited to their scarcity, but also involve an intrinsic functional defect. Studies have shown that Tregs in patients with RA are unable to effectively suppress joint inflammation, contributing to the persistence of the autoimmune response. Similar defects, observed in other autoimmune diseases such as multiple sclerosis, confirm that regulatory dysfunction is a common thread in many immune pathologies (Buckner, 2010) [2]. Conversely, the expansion or restoration of Tregs appears to correlate with clinical improvements, so much so that it is now considered one of the most promising therapeutic strategies (Zhang et al., 2024) [3].

The role of Tregs manifests even in the early stages of the disease: patients with untreated rheumatoid arthritis show a significant reduction in these cells compared to healthy controls. It is interesting to note that treatment with methotrexate, one of the first-line drugs, not only reduces clinical disease activity but also increases the number and functionality of Tregs, suggesting that part of its therapeutic benefit derives precisely from this immunoregulatory modulation (Avdeeva et al., 2020) [4]. In other words, in addition to "turning off" inflammation, methotrexate also seems to "re-educate" the immune system to regain a balance between T eff and T reg cells.

A similar discussion applies to follicular regulatory T cells (Tfr), a specialized subset of Tregs that acts within germinal centers (specialized areas within lymphatic follicles), regulating the activity of follicular helper T cells (Tfh, a form of effector T cells). The latter are known to stimulate B cells (immune cells that contribute to the body's defense by producing antibodies) and promote the production of autoantibodies, a key feature of RA. In patients in stable remission, an increase in Tfr cells and a reduction in the Tfh/Tfr ratio are observed, associated with lower levels of autoantibodies such as rheumatoid factor (an autoantibody frequently associated with rheumatoid arthritis) and anti-CCP (autoantibodies used primarily to help diagnose rheumatoid arthritis). This suggests that the rebalancing between Tfr and Tfh represents a marker of remission and a potential therapeutic target (Liu et al., 2018) [5]; (Wang et al., 2019) [6]; (Cao et al., 2020) [7].

Ultimately, the picture that emerges is that of an immune system that has lost the harmony between its components. Effector cells, such as Th17 and Tfh, take over, fueling chronic inflammation that leads to joint damage and autoantibodies, while regulatory cells, Treg and Tfr, are weakened or dysfunctional, unable to restore tolerance. Traditional therapies like methotrexate, and more innovative ones based on the inhibition of mTOR or the expansion of Tregs, share the goal of restoring this lost balance, transforming an "out of control" immune system into a machine once again capable of making a clear distinction. It is precisely in this regained balance that the key to lasting remission and, perhaps, a future cure lies.

The link between rheumatoid arthritis and hormonal metabolism became clear when several studies documented the early and widespread presence of alterations in the insulin pathway in patients with RA. It is crucial to emphasize that the first step is not insulin resistance itself, but hyperinsulinemia: the liver, in response to glycemic oscillations not correctly managed by first-phase insulin production, reduces its insulin clearance, causing hyperinsulinemia, as we saw in chapter 2. This condition precedes insulin resistance and represents its triggering cause: it is therefore chronic hyperinsulinemia that paves the way for insulin resistance, and not the other way around, as we have already seen in previous chapters.

Therefore, this state of insulin resistance, characterized by a reduced ability of peripheral tissues, particularly muscles and adipose tissue, to respond to the action of insulin, represents a true metabolic anomaly. In patients with rheumatoid arthritis, insulin resistance has been observed even in the absence of classic risk factors such as obesity or diabetes, suggesting that it is not a simple consequence of lifestyle, but an integral part of the disease's pathophysiology.

A 2017 study showed that more than half of patients with early rheumatoid arthritis already had altered HOMA-IR index values, a marker of insulin resistance, compared to a quarter of healthy subjects. This alteration was associated with a reduction in appendicular lean mass, i.e., the muscular component of the limbs, and with more intense disease activity (Müller et al., 2017) [8]. Similarly, another study conducted in China in 2022 documented a direct correlation between insulin resistance and inflammatory markers such as CRP and ESR, confirming that the more active the disease, the greater the metabolic alteration (Ye et al., 2022) [9].

This is not a passing phenomenon: in 2019, other researchers observed that the hyperbolic balance between insulin sensitivity and pancreatic β-cell secretion is compromised in patients with RA. Under normal conditions, when insulin sensitivity drops, the pancreas responds by increasing secretion to compensate; in patients with rheumatoid arthritis, this response appears inefficient and unstable, a sign of systemic dysfunction (Tejera-Segura et al., 2019) [10]. Even in patients not treated with glucocorticoids, known for their diabetogenic effects, IR was confirmed, demonstrating that it is not the therapy that causes it, but the disease itself that determines it (Hoes et al., 2011) [11].

All this leads us to a key concept: rheumatoid arthritis is not only a disease of the immune system, but also a hormonal metabolic disease, rooted in an alteration of insulin metabolism and aggravated by insulin resistance.

Within this interplay between immunity and metabolism, the true silent and powerful protagonist that emerges in the context of rheumatoid arthritis is mTOR, our cellular kinase, a central protein stimulated by the insulin pathway, which acts as a metabolic and immunological control center. Under normal conditions, as we know, mTOR regulates cell growth and survival by responding to energy, hormonal, and inflammatory signals. However, when the body is chronically exposed to inflammation and altered metabolic stimuli, as occurs in rheumatoid arthritis, this pathway becomes hyperactivated, contributing directly to immune dysfunction (Perl, 2016) [12]. It is within the insulin pathway, therefore, that the root cause is unleashed, and it becomes evident that the involvement of mTOR in the progression of RA is far from marginal; its action is that of a control room orchestrating T-cell differentiation, favoring the expansion of effector Th1, Th2, and Th17 lymphocytes (active cells of the immune system) responsible for the production of inflammatory cytokines, while simultaneously hindering the development of regulatory T cells (Treg), which are fundamental for maintaining immunological tolerance. This imbalance between Teff and Treg is one of the central nodes of the autoimmune response in RA (Zhang et al., 2023) [13].

In practice, it is as if mTOR functions as an amplifier of immune reactions, transforming every metabolic signal into a pro-inflammatory impulse. When this pathway is hyperactive, even a small stimulus can trigger a disproportionate reaction, fueling chronic synovitis (persistent inflammation of the synovial membrane, the thin tissue that lines the joints), macrophage activation (which plays an essential role in defense against infections, wound healing, and the maintenance of tissue homeostasis), bone destruction, and the production of autoantibodies (antibodies produced by the immune system that, instead of attacking viruses or bacteria, mistakenly recognize and attack components of one's own body). It is not surprising, therefore, that mTOR is now considered the emerging therapeutic target in rheumatoid arthritis (Perl, 2016) [12]; (Zhang et al., 2023) [13].

However, the key is not just to inhibit the proliferation of T lymphocytes, but to reprogram the immunological balance: several studies have in fact demonstrated that the selective inhibition of mTOR, for example via sirolimus (rapamycin, an mTOR inhibitor drug), not only reduces the activity of effector cells but also promotes the expansion of regulatory T cells, restoring a healthier ratio between Th17 and Treg. This rebalancing has been shown to improve the probability of remission and reduce clinical flare-ups, even in patients already treated with conventional drugs (Niu et al., 2020) [14].

It is interesting to note that, even in vitro, rapamycin allows for the effective expansion of Treg cells while maintaining their suppressive capacity intact, thus offering a concrete biological basis for a potential use in personalized cell therapies for RA (Battaglia et al., 2012) [15]. This finding is reinforced by experimental evidence according to which, in the absence of mTOR, naive T cells (virgin precursor cells) tend to spontaneously differentiate into Treg cells rather than into inflammatory effector cells, demonstrating the decisive role that mTOR plays in deciding “what type of soldier” the immune system should recruit (Delgoffe et al., 2009) [16].

In addition to immune regulation, the mTOR pathway also participates in the tissue progression of the disease, promoting synovial proliferation (an abnormal increase in the number of cells lining the synovial membrane, the tissue that covers the joints) and angiogenesis (the biological process through which new blood vessels are formed from existing ones). In this sense, it has been observed that blocking the PI3K/AKT/mTOR pathway is capable of reducing joint inflammation, the formation of new vessels, and structural damage, even in animal models. It is as if one were able to remove fuel from the local inflammatory engine, returning the joint environment to a quieter and more controlled condition (Ba et al., 2021) [17].

In light of this evidence, mTOR is not just a supporting actor but the main protagonist of inflammation in rheumatoid arthritis: it is a central hub, a transducer that translates metabolic, immune, and environmental signals into concrete cellular actions. Inhibiting it with precision does not mean suppressing the immune system, but re-educating it to distinguish between danger and normality. This is precisely the most advanced frontier of immunometabolic medicine: intervening not only on the symptoms but on the internal logic of the insulin pathway that generates them.

In recent years, interest in the mTOR therapeutic target has taken a leap forward in practical terms as well, moving beyond the limits of molecular theory to enter early clinical scenarios. Rapamycin, also known as sirolimus, is the progenitor of this new class of immunometabolic drugs: a selective inhibitor of mTORC1 capable of reducing the proliferation of effector T cells, supporting the expansion of Tregs, and, consequently, rebalancing the entire immune microenvironment.

More recent clinical confirmation of the effect of rapamycin in rheumatoid arthritis was obtained in 2019 in a randomized study conducted on patients with active disease. The addition of low-dose sirolimus—the pharmacological name for rapamycin—to conventional therapy for 24 weeks was associated with a significant reduction in disease activity, documented by a decrease in the DAS28 (a score indicating how active rheumatoid arthritis is), the ESR (a test that can indicate the presence of an inflammatory state in the body), and the number of tender and swollen joints. In parallel, an increase in regulatory T cells was observed in patients treated with sirolimus compared to those on conventional therapy alone: these results therefore provide clinical evidence that pharmacological inhibition of mTOR can contribute to the modulation of the immune response in rheumatoid arthritis, favoring the recovery of Tregs and accompanying an improvement in the main indicators of disease activity (Wen et al., 2019) [18].

Further clinical confirmation was provided in 2020 in patients with rheumatoid arthritis characterized by low disease activity or remission according to the DAS28. The study involved 55 patients previously treated with conventional antirheumatic drugs, 35 of whom received sirolimus while 20 continued conventional therapy. Before treatment, patients had significantly lower quantities and proportions of CD4⁺CD25⁺FOXP3⁺ regulatory T cells compared to healthy controls. After the administration of sirolimus, an increase in circulating Tregs was observed, accompanied by a significant reduction in the Th17/Treg ratio, indicating a rebalancing between pro-inflammatory and regulatory lymphocyte populations. Furthermore, after 12 weeks, a higher percentage of patients treated with sirolimus had reached remission according to the DAS28: these results therefore reinforce the hypothesis that pharmacological inhibition of mTOR via rapamycin can promote the expansion of FOXP3⁺ Treg cells and contribute to the restoration of immunological balance in rheumatoid arthritis (Niu et al., 2020) [14].

Beyond systemic administration, new targeted delivery technologies are changing the paradigm. Through nanoparticles, smart hydrogels, and catalytic nanomotors, it is now possible to concentrate rapamycin directly at the site of inflammation, increasing its efficacy and reducing side effects. The results are impressive: from nano-hydrogels that provide prolonged release of autoantigenic peptides (antigens that come from the body itself and, under normal conditions, should not activate the immune system) and rapamycin, inducing active immune tolerance (Cao et al., 2025) [19], to smart nanomotors loaded with rapamycin, capable of autonomously heading toward M1 inflammatory macrophages and promoting their reconversion into the M2 anti-inflammatory phenotype, synergistically counteracting inflammation, oxidative stress, and cartilage destruction (Ma et al., 2025) [20].

In animal models, these strategies have been shown to reduce joint inflammation, protect cartilage, and promote the regeneration of damaged tissues. This result was achieved not only by suppressing the inflammatory response but by re-educating the immune system to recognize its own joint tissue as “not an enemy,” through an action that is no longer purely suppressive, but flexible.

Strategically designed nanoparticle formulations have also shown promising results: in addition to improving the bioavailability of rapamycin, these platforms allow for controlled release and a reduction in systemic toxicity, optimizing the effect on the immune system. It has been demonstrated, for example, that rapamycin delivered in this way reduces the activation of dendritic cells (immune system cells specialized in “capturing” antigens and presenting them to T lymphocytes), lowers the levels of cytokines such as IL-6, TNF, and IL-1β (three potent pro-inflammatory cytokines, produced primarily by macrophages, that coordinate and amplify the immune response), and improves clinical parameters of RA in animal models (Shao et al., 2017) [21].

In parallel, other molecules that interfere with immune metabolism are also emerging. Iguratimod (a drug), for example, reduces the function of follicular helper T (Tfh) cells through the suppression of the mTOR–HIF1α axis, limiting the glycolysis necessary for their activation. The result is a lowering of the antibody response and a reduction in autoimmunity (Bai et al., 2022) [22].

These new frontiers mark a paradigm shift: it is no longer just about turning off inflammation, but about reordering the immune response at its root, acting on cellular metabolism through the remodulation of the insulin pathway. The strategy shifts from attacking the enemy to educating the defense system, in an attempt to restore that dynamic balance we call immune tolerance.

In rheumatoid arthritis, the persistent activation of mTOR is particularly significant because it can support the expression of HIF-1α, transforming the metabolism of the cells involved in the immune response. As we have seen previously, HIF-1α promotes a shift toward a predominantly glycolytic metabolism, providing activated cells with a metabolic program compatible with an intense inflammatory response. The most recent evidence indicates that, in rheumatoid arthritis, this relationship can involve different cell populations, from macrophages to Th17 lymphocytes, and even myeloid cells present in the synovial microenvironment.

A first, particularly significant demonstration was obtained by studying the effect of berberine (a natural substance present in some plants) in a mouse model (the use of laboratory mice to study a disease or biological mechanism) of collagen-induced arthritis. The authors showed that the activation of AMPK (the cell's energy sensor) leads to the inhibition of mTORC1 and the subsequent reduction of HIF-1α, limiting the glycolysis of M1 macrophages and favoring the rebalancing of M1/M2 polarization. The use of leucine (an essential amino acid that contributes to protein synthesis and the regulation of mTOR) also allowed for experimental interference with these effects, supporting the functional role of the AMPK–mTORC1–HIF-1α axis in the metabolic reprogramming of macrophages during arthritis (Cheng et al., 2023) [23].

A second important contribution came from the study of synovial fibroblasts (cells that line the joints), cells that acquire strongly altered metabolic and functional characteristics in rheumatoid arthritis. In 2025, it was shown that the PI3K–AKT–mTOR pathway contributes to the activation of HIF-1α and the subsequent induction of glycolysis (the process by which the cell uses glucose to produce energy). Experimental modulation of this cascade using “Er Miao San” (a traditional Chinese medicine formula) resulted in a reduction of HIF-1α and important components of glycolytic metabolism, including GLUT1 (a transporter that allows glucose to enter cells), accompanied by a decrease in the activation, migration, and invasiveness of synovial fibroblasts (Zhang et al., 2025) [24].

The functional relevance of HIF-1α also emerges directly in human macrophages exposed to the rheumatoid arthritis microenvironment: in 2025, macrophages derived from human monocytes treated with serum from patients with rheumatoid arthritis showed an increase in glycolysis, HIF-1α expression, and the production of the pro-inflammatory cytokine IL-1β. Inhibition of glycolysis reduced HIF-1α, while inhibition of HIF-1α decreased the production of IL-1β. This delineated a glycolysis–HIF-1α–IL-1β circuit capable of self-sustaining the inflammatory activation of macrophages (Jia et al., 2025) [25].

Even more direct evidence of the link between mTOR and HIF-1α was obtained in 2026 by studying Th17 lymphocytes, a central population in the pathogenesis of rheumatoid arthritis. The accumulation of lactate increased mTORC1 activity, documented through the phosphorylation of S6K and 4EBP1 (two important targets of mTORC1), and simultaneously increased HIF-1α, favoring Th17 differentiation. Conversely, the inhibition of LDHA (the enzyme that transforms pyruvate into lactate) or the MCT1 transporter (a transporter that facilitates the passage of lactate through the cell membrane) reduced the activation of the mTORC1–HIF-1α axis and Th17 differentiation (Zhang et al., 2026) [26].

Finally, further confirmation arrived in 2026 through the study of myeloid-derived suppressor cells (MDSC, cells that suppress the immune system's response) from patients with rheumatoid arthritis. RA synovial fibroblasts increased the expression of the TREM1 receptor (an immune cell receptor that helps amplify inflammation) in MDSCs through cell contact, triggering a well-defined molecular sequence: TREM1 → PI3K → AKT → mTOR → HIF-1α. This cascade increased glycolytic flux and favored the acquisition of pro-inflammatory characteristics. Pharmacological blockade of the pathway, on the other hand, attenuated metabolic reprogramming and contributed to the recovery of the immunoregulatory function of MDSCs (Deng et al., 2026) [27].

Taken together, this evidence allows us to outline a coherent model. In rheumatoid arthritis, mTOR does not just represent a regulator of cell growth, but can act upstream of HIF-1α and contribute to the metabolic reprogramming of the cells involved in the disease. When mTORC1 remains active, HIF-1α favors the maintenance of a glycolytic metabolism compatible with the activity of pro-inflammatory cells, involving macrophages, Th17 lymphocytes, and other myeloid populations (families of blood cells, many of which are involved in immune defense). Conversely, the inhibition of mTORC1 is associated with a reduction in HIF-1α and glycolysis, with a consequent attenuation of various inflammatory programs. This creates a sequence that is particularly significant in the pathogenesis of rheumatoid arthritis: mTOR activation → increase in HIF-1α → increase in glycolysis → support of the pro-inflammatory immune phenotype.

As we have seen in the previous chapters, vitamin D, in its active form, plays a fundamental coordinating role, guiding the activity of the immune system like a true conductor. Vitamin D acquires specific functions that go well beyond bone metabolism: it acts as an immune modulator, regulating the activity of both the innate immune system (the body's first line of defense, present from birth) and the adaptive immune system (the defense system acquired by the body after exposure to a foreign agent). Numerous studies have shown that patients with RA have significantly lower average serum levels of vitamin D compared to healthy controls, with an inverse correlation between vitamin D concentration and disease activity: the lower the levels, the more severe the clinical picture (Sukharani et al., 2021) [28]; (Lee and Bae, 2016) [29]; (Lin et al., 2016) [30].

Vitamin D deficiency is not a sporadic phenomenon, but an extremely frequent condition: in India, for example, a meta-analysis estimated a prevalence of 56% in patients with RA, with an additional 20% in a state of insufficiency. Here too, serum levels showed a negative correlation with disease activity, suggesting that vitamin D may represent a key regulator of joint inflammation (Bose et al., 2023) [31]. Similarly, other cross-sectional investigations have confirmed that patients with more involved joints or more severe clinical forms have lower vitamin D concentrations (Tv et al., 2023) [32].

From a mechanistic point of view, vitamin D appears to exert a protective effect by re-educating the immune balance: it has been demonstrated that its active form, 1,25-dihydroxyvitamin D3, inhibits the differentiation of Th17 cells and promotes the expansion of regulatory T cells (Tregs), also acting through the suppression of IL-6 signaling (a signaling protein produced by immune system cells to amplify the immune response). In animal models, this translates into a reduction in the incidence and severity of arthritis, with protection of the joints from bone destruction (Zhou et al., 2019) [33]. In simple terms, vitamin D helps to curb the action of cells that "drive" inflammation, while boosting those that "contain" it.

These data are also reflected in clinical practice: in a randomized study conducted on 150 patients with RA, it was shown that vitamin D supplementation with 60,000 IU/month leads to a significant improvement in DAS28 scores and serum vitamin D levels after 12 weeks of treatment (Chandrashekara and Patted, 2017) [34]. Another study highlighted that vitamin D supplementation, associated with standard therapy with DMARDs (disease-modifying antirheumatic drugs), not only improves clinical activity but also increases the number of circulating Treg cells, suggesting a real immunomodulatory effect capable of rebalancing the immune response (El-Banna and Gado, 2020) [35].

Finally, it should not be forgotten that vitamin D also exerts an impact on muscle health: in inflammatory rheumatic diseases, including rheumatoid arthritis, vitamin D deficiency is associated with reduced strength, fatigue, and sarcopenia (a condition characterized by a progressive loss of muscle mass), indirectly worsening the patients' quality of life. This means that correcting the deficiency has an effect not only on inflammation but also on muscle function, with broader benefits for the overall management of the disease (Hysa et al., 2024) [36].

Taken together, this evidence tells us that vitamin D represents a critical modulator in the context of rheumatoid arthritis, as it helps to contain the excessive activation of pro-inflammatory pathways; in fact, as we saw in chapter 6 dedicated to the immune system, through the modulation of mTOR, it reduces the production of inflammatory mediators and limits the abnormal proliferation of effector T lymphocytes and stimulates the production of regulatory T lymphocytes, processes that are central to the pathogenesis of the disease. This regulatory effect promotes better control of the immune response, preventing autoimmune aggression against joint tissues.

Furthermore, the ability of vitamin D to support cellular energy balance and reduce oxidative stress contributes to preserving the integrity of the joints, slowing down the degenerative processes typical of rheumatoid arthritis. In deficient patients, by contrast, mTOR hyperactivity is associated with greater clinical severity, increased joint stiffness and pain, and more rapid disease progression.

In this framework, vitamin D is configured as an essential element not only for bone metabolism but also as an immunometabolic ally, capable of improving the quality of life of patients with rheumatoid arthritis through the containment of inflammation and the protection of joint functionality.