Effect of Interleukin‐6 Inhibitors on Rheumatoid Arthritis Pain: Overview of Evidence and Mechanistic Pathways

ABSTRACT

Rheumatoid arthritis (RA) is an autoimmune systemic disease in which pain remains a major and often refractory symptom even after clinical remission of the disease. Although historically attributed to joint inflammation, recent evidence reveals a multifactorial pathogenesis of RA pain, involving peripheral sensitization, central sensitization, and neuroimmune crosstalk. In these mechanisms, interleukin‐6 (IL‐6) plays a central role not only as one of the inflammatory mediators but also as a classic and trans‐signaling modulator for pain. This review synthesizes current mechanistic and clinical evidence on IL‐6 inhibitors, particularly sarilumab and tocilizumab, concerning their effect on pain in RA. Preclinical studies have already demonstrated that IL‐6 enhances the excitability of nociceptors through the upregulation of ion channels in dorsal root ganglia; it also promotes glial activation within the spinal cord; however, chronic pain sustains these processes. Blockade of IL‐6 receptor reverses these changes and alleviates mechanical hyperalgesia as well as allodynia in different models of diseases. Clinical trials of IL‐6 inhibitors have shown that these compounds provide major pain relief, sometimes better than tumor necrosis factor (TNF) inhibitors, most explicitly for patients with elevated baseline C‐reactive protein (CRP) or who do not respond to TNF inhibitors. Differences in their pharmacokinetics, receptor binding, and suppression of CRP may translate into differences in their analgesic profiles. However, it is analyzed that a subset of patients with persistently painful rheumatoid arthritis despite IL‐6 inhibition demonstrates the existence of non‐inflammatory drivers like nociplastic pain and the inadequacy of conventional indices of disease activity to capture the burden of pain.

This review synthesizes current mechanistic and clinical evidence on IL‐6 inhibitors, particularly sarilumab and tocilizumab, concerning their effect on pain in RA.

1. Introduction

Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disease of unknown etiology, characterized by typical inflammatory changes in the synovial membrane of small and larger joints, leading to articular and extra‐articular manifestations, functional disabilities, and a substantial socioeconomic and medical burden. RA is the most commonly diagnosed systemic inflammatory arthritis, marked by persistent synovial inflammation, progressive joint destruction, and chronic pain [1, 2]. Although disease‐modifying antirheumatic drugs (DMARDs) and biologic therapies have improved outcomes, pain remains one of the most burdensome symptoms for patients, often persisting despite achieving clinical remission [3, 4]. This pain is driven by both inflammatory and non‐inflammatory mechanisms, including peripheral sensitization because of ongoing synovitis and central sensitization caused by neuroinflammation and maladaptive plasticity within the central nervous system. Consequently, addressing RA pain requires a comprehensive, multimodal approach that recognizes its dual origins and the neuroimmune interplay underlying persistent pain in this disease [5, 6, 7].

Interleukin (IL)‐6 is a pro‐inflammatory cytokine that contributes to the pathogenesis of RA, exerting systemic effects via signaling through soluble forms of the IL‐6 receptor, known as “trans‐signaling”. Preclinical findings demonstrate that intra‐articular IL‐6 can produce long‐lasting peripheral sensitization to mechanical stimulation but also suggest an important role for IL‐6 in central pain sensitization, with local activity at neuron endings culminating in altered pain processing in the central nervous system because of persistent signaling from sensitized peripheral neurons (Figure 1) [8, 9]. Treatment with anti‐IL‐6 or anti‐IL‐6R agents seems to alleviate allodynia and hyperalgesia, so this approach may be a valid option when treating various conditions, including pathological pain as RA [9].

FIGURE 1.

IL‐6‐mediated mechanisms of pain in rheumatoid arthritis. Interleukin‐6 (IL‐6) contributes to pain in rheumatoid arthritis (RA) through multiple interrelated mechanisms. Peripherally, IL‐6 lowers the threshold of activation for nociceptors and increases excitability of sensory neurons via trans‐signaling through the IL‐6/sIL‐6R/gp130 complex. gp130 signaling initiates intracellular pathways—JAK/STAT3, MAPK/ERK, and PI3K/Akt, among others—that upregulate ion channels and sensitize them to include Nav1.7 and TRPV1, leading to hyperresponsiveness of nociceptors as well as hyperalgesia and allodynia. IL‐6 induces fibroblast‐like synoviocytes and macrophages to secrete algogenic mediators in the inflamed synovium. Such secretion includes prostaglandin E2 (PGE2), nerve growth factor (NGF), and leukotrienes (LTs). Most of these agents act through indirect pathways, increasing the excitability of nociceptors. Centrally, IL‐6 acts on the spinal cord dorsal horn both directly, by increasing the expression and activity of NMDA receptors, and indirectly, by activating microglia and astrocytes. NMDA receptor activation enhances calcium influx and synaptic efficiency, amplifying pain perception to identical afferent input. Simultaneously, IL‐6–stimulated glial cells release pro‐inflammatory mediators (e.g., IL‐1β, TNF‐α, and prostaglandins) that further lower nociceptive thresholds within the CNS, perpetuating central sensitization even in the absence of active peripheral inflammation. Together, these mechanisms explain both the inflammatory and non‐inflammatory components of RA‐associated pain and provide a strong rationale for IL‐6‐targeted therapies.

This review aims to provide a comprehensive and critical examination of the analgesic efficacy of IL‐6 inhibitors in RA, in both peripheral and central mechanisms of pain modulation. Figure 2 provides a graphical summary of the clinical impact, mechanistic pathways, and remaining challenges associated with IL‐6 inhibition in this context. We synthesize mechanistic and clinical evidence to highlight IL‐6's neuroimmune role in RA pain pathways, clarify the distinct role of IL‐6 inhibitors in current RA pain management, and identify key questions for future research.

FIGURE 2.

Schematic overview of the clinical impact, mechanistic pathways, and remaining challenges associated with interleukin‐6 inhibition in rheumatoid arthritis‐related pain.

2. Methods: Literature Search and Framing Approach

2.1. Narrative Review Methodology

This article is structured as a narrative review with scoping elements, designed to integrate preclinical, mechanistic, and clinical evidence on IL‐6‐mediated pain pathways and the analgesic effects of IL‐6 inhibitors in RA. Because the field spans molecular biology, neuroimmune mechanisms, and clinical trials, the aim was to synthesize concepts across disciplines rather than perform quantitative pooling or formal systematic evaluation. This approach is suited for generating a comprehensive, hypothesis‐driven overview of IL‐6 in RA‐related pain.

2.2. Databases and Timeframe

A targeted literature search was performed in PubMed and Scopus, supplemented by manual screening of reference lists from key articles to ensure adequate coverage. The search encompassed studies published between 2008 and May 2025, corresponding to the period during which major mechanistic discoveries and a relevant body of evidence on tocilizumab and sarilumab were conducted. Earlier foundational studies were included when required to contextualize IL‐6 biology or pain mechanisms.

2.3. Search Terms and Inclusion Criteria

Search terms combined general descriptors related to IL‐6 biology, IL‐6 receptor inhibitors, and pain in RA. Representative keywords included: “IL‐6”, “interleukin‐6”; “tocilizumab”, “sarilumab”, “IL‐6 inhibitors”; “rheumatoid arthritis”, and “pain”. Articles were considered eligible if they met one or more of the following criteria: (i) Reported mechanistic or preclinical findings relevant to IL‐6 or pain pathways; (ii) examined clinical outcomes of IL‐6 inhibitors in RA, including pain or patient‐reported outcomes (PROs); (iii) provided comparative evidence for IL‐6 inhibitors versus other RA treatments; (iv) offered conceptual, translational, or historical insights necessary to contextualize IL‐6 and pain in RA.

Exclusion criteria were limited to non‐English publications and studies unrelated to IL‐6, RA, or pain mechanisms.

The search strategy is shown in Table 1.

TABLE 1.

Summary of search strategy, timeframe, and inclusion/exclusion criteria.

Category	Details
Search Strategy	Targeted literature search in PubMed and Scopus, plus manual screening of reference lists.
Search Terms	Combined keywords related to IL‐6 biology, IL‐6 inhibitors, and RA pain: “IL‐6”, “interleukin‐6”; “tocilizumab”, “sarilumab”, “IL‐6 inhibitors”; “rheumatoid arthritis”, “pain”.
Timeframe	Studies published from 2008 to May 2025; earlier foundational studies included when necessary.
Inclusion Criteria	Articles reporting: –Mechanistic/preclinical findings on IL‐6 or pain pathways –Clinical outcomes of IL‐6 inhibitors in RA –Comparative evidence versus other RA treatments –Conceptual, translational, or historical insights on IL‐6 and pain in RA.
Exclusion Criteria	Non‐English publications and studies unrelated to IL‐6, RA, or pain mechanisms.

Abbreviations: IL‐6, interleukin‐6; RA, rheumatoid arthritis.

2.4. Evidence Synthesis Strategy and Limitations of the Narrative Approach

Evidence from preclinical, mechanistic, and clinical literature was organized thematically to integrate biological principles with clinical findings on pain outcomes. This narrative synthesis enabled the identification of recurring patterns, areas of convergence between experimental and clinical data, and implications for understanding IL‐6‐mediated nociception in RA.

As a narrative review, this work does not adhere to formal PRISMA methodology, nor does it include structured bias assessment. Although search steps were defined to enhance transparency and reduce selection bias, the heterogeneity of study designs and outcomes limits the feasibility of quantitative synthesis. Nevertheless, this approach remains appropriate for synthesizing mechanistic and clinical insights across a diverse and evolving body of literature, and it directly responds to reviewer recommendations for methodological clarity.

3. Pathophysiology of Pain in RA

3.1. Types of Pain in Rheumatoid Arthritis: Inflammatory, Nociceptive, Neuropathic, and Nociplastic Components

Pain perception in rheumatic disease involves several mechanisms, including inflammatory, nociceptive, neuropathic, and nociplastic components [10]. It is widely accepted that pain in RA is driven by the release of inflammatory mediators and activation of nociceptors. However, RA patients may also experience nociplastic and neuropathic pain components [10].

Nociceptive pain represents the ability to respond to noxious stimuli such as heat, cold, chemicals, or mechanical stress [10, 11]. This type of pain is considered protective [10]. Inflammatory pain, caused by inflammatory mediators, produces swelling, redness, heat, and pain [10, 12]. Key mediators include cytokines, leukotrienes, prostaglandins, and chemokines [10].

In contrast, neuropathic pain is considered maladaptive, as it increases the overall burden of pain symptoms [10]. Chronic activation of pain networks reflects abnormal functioning of the nervous system [10]. The mechanism of nociplastic pain is not fully understood [10]. It is characterized by increased CNS pain and sensory processing, together with altered pain modulation [10, 13]. Nociceptive pain is caused by damage to nonneural tissue; neuropathic pain results from a lesion or disease of the nervous system; and nociplastic pain arises from altered nociception, with central sensitisation as a major mechanism [14].

RA treatment has improved in the last few decades by implementing conventional synthetic and biologic DMARDs. These drugs are focused on suppressing activated cytokines and pro‐inflammatory pathways [10, 15]. Biologic DMARDs for RA include IL‐6 inhibitors, tumor necrosis factor‐alpha (TNF‐α) inhibitors, and Janus Kinase (JAK) inhibitors.

3.2. Central Sensitization: Mechanisms, Persistence, and Relevance in RA

Central sensitisation is closely reflected by nociplastic pain [14]. It is defined as an amplification of neural signaling within the CNS that produces pain hypersensitivity [14]. Woolf describes central sensitisation as a state characterized by hypersensitivity to pain, allodynia, hyperalgesia, after‐sensations, and enhanced temporal summation [16]. The literature also discusses whether neuroplasticity can be modified through behavioral changes [10, 17]. Behavioral interventions in patients with inflammatory conditions may influence neuroplastic processes [10, 17]. Central sensitisation has been documented in RA, and its presence predicts poorer treatment outcomes [14]. Therefore, individual assessment is critical. Clinical pain reflects the current excitability of central nociceptive circuits [16]. Dysregulation of CNS pain pathways contributes to hyperalgesia and allodynia [18]. It is important to recognize that both peripheral and central components of pain require treatment. In addition, non‐pharmacological interventions, such as physical therapy, can help reduce central sensitisation [14].

3.3. Interleukin‐6 in Pain Modulation: Systemic Effects, Blood–Brain Barrier Dynamics, and Glial Activation

The analgesic potential of neutralizing cytokines depends on which cytokine is mainly involved in the specific pain [19]. Central causes of pain arise from abnormalities in the CNS pain regulatory mechanisms [18]. RA pain arises from the interplay of deformity of joints and the processing of pain signals by peripheral, spinal, and supraspinal pain pathways [18]. The character, intensity, and distribution of pain depend on a combination of peripheral nociceptor activation and modulation of neurons [18]. Glial cells of the spinal cord could be activated in joint disease and produce and release cytokines [19, 20]. Several inflammatory cytokines, including TNF‐α, IL‐1β, IL‐6, and IL‐17, can directly alter the responses of nociceptive neurons [18, 19]. IL‐6 is a pleiotropic pro‐inflammatory cytokine [21]. Accordingly, IL‐6 is a key player in systemic inflammation and arthritis [19]. Specifically, IL‐6 has a significant role in arthritic joint pain, but IL‐6‐induced hyper‐excitability is difficult to reverse, contributing to the chronification of pain [19]. Moreover, IL‐6 binds to a membrane‐bound IL‐6 receptor (IL‐6R) or a soluble IL‐6R (sIL‐6R), permitting IL‐6 trans‐signaling onto cells that do not express the membrane receptor [19].

3.4. Brief Overview of JAK/STAT3 Relevance as Background for Later Mechanistic Focus

Pro‐inflammatory cytokines are major mediators in the pathogenesis of RA [19]. Pro‐inflammatory cytokines such as TNF‐α, IL‐1β, IL‐6, and IL‐17 act as pain mediators by directly acting on the nociceptive system [19]. Some DMARDs (e.g., JAK inhibitors) may work via multiple pathways to decrease pain [18]. The complex composed of IL‐6, IL‐6R, and glycoprotein 130 (IL‐6/IL‐6R/gp130) activates JAK, which activates different signaling mechanisms to execute various biochemical functions [21]. Moreover, the trans‐signaling mechanism activates various pathological routes, like JAK/STAT3, Ras/MAPK, PI3K–PKB/Akt, and regulation of CD4+ T cells and VEGF levels, which cause RA [21].

4. IL‐6 Inhibitors and Pain: Beyond Inflammation

4.1. Classic Versus Trans IL‐6 Signaling in Pain Modulation

IL‐6 signaling is undoubtedly one of the major points in the modulation of pain through two different mechanisms, classic signaling and trans‐signaling. Mechanisms and biological outcomes differ significantly, particularly when considering inflammation and pain [22]. Classic IL‐6 signaling means IL‐6 binds to a membrane‐bound IL‐6R, which is expressed only on a few cells; for example, hepatocytes or some leukocytes. The complex then associates with the signal‐transducing component glycoprotein 130 (gp130), leading to downstream signaling that is more commonly associated with regeneration and protection [23, 24].

Conversely, the IL‐6 trans‐signaling describes the binding of IL‐6 to a sIL‐6R. This complex can then bind to gp130 on virtually any cell because expression of gp130 is ubiquitous. It is primarily pro‐inflammatory and, in this mode, has been implicated in the pathogenesis of numerous inflammatory diseases, as well as modulating pain [23, 25]. The pro‐inflammatory aspects of trans‐signaling are thus very relevant to pain since they enhance the excitability of nociceptive neurons in sensitization [25, 26].

The various functions of these signaling pathways are crucial in understanding how they contribute to pain control. Central signaling is more limited and usually reduces inflammation. At the same time, trans‐signaling spreads more widely and increases inflammation, often exacerbating pain by mechanisms such as activating microglia and enhancing nerve cell response. This difference matters for treatment, as targeting IL‐6 trans‐signaling directly, rather than blocking all IL‐6, may provide a more effective way to manage inflammatory pain without compromising the beneficial effects of central signaling [27].

4.2. Dorsal Root Ganglia Sensitization and Astrocyte/Microglial Activation

Mechanistic evidence from the medical literature highlights IL‐6 as a key modulator of pain sensitisation through its actions on dorsal root ganglia (DRG) neurons and spinal dorsal horn pathways. IL‐6 signals via membrane‐bound IL‐6R in classic signaling and through sIL‐6R in trans‐signaling, which activates gp130, a critical mediator of neuroglial interactions. In DRG neurons, IL‐6 enhances T‐type calcium currents (particularly Cav3.2), increases action potential firing, and downregulates KV1.4 potassium channels. These changes promote neuronal hyperexcitability and mechanical allodynia, mediated through gp130 and MAP kinase‐interacting kinase (MNK)‐eIF4E signaling, and can be reversed by MNK inhibition [28, 29, 30, 31].

In the dorsal horn, IL‐6 is upregulated after injury or inflammation, where it contributes to central sensitization in synergy with TNF‐α, especially via microglial‐derived sIL‐6R [26]. In chronic pain states such as juvenile idiopathic arthritis and osteoarthritis, sustained IL‐6 elevation correlates with glial activation, increased glutamate receptor expression, and heightened neuronal activity. These changes are reversible with IL‐6 blockade [32, 33]. Mitchell et al. [34] confirmed in human TRPV1‐positive DRG neurons that IL‐6/sIL‐6R complexes activate protein synthesis through MNK1/2‐eIF4E, attenuated by the MNK inhibitor eFT508, supporting a conserved mechanism of IL‐6‐driven nociceptor plasticity.

Dubový et al. [35] reported increased IL‐6 and IL‐6R mRNA bilaterally in lumbar and cervical DRGs in a chronic constriction injury model, with stable gp130 expression, underscoring its central role in IL‐6 signaling.

Besides neuron sensitization, IL‐6 controls glial activation. This cytokine is produced by astrocytes and microglia when CNS inflammation is already evoked; thus, it further promotes neuroimmune reactions. IL‐6 inhibitors decrease such markers as c‐Fos, glial fibrillary acidic protein (GFAP), and Iba‐1 in the model of osteoarthritis, spinal cord injury, and neuropathy, resulting in pain behavior alleviation [36]. It has been demonstrated that IL‐6 from activated microglia can mediate astrocyte apoptosis and neurodegeneration. Those effects are rescued by knockdown of IL‐6 or receptor blockade [37]. In autoimmune encephalomyelitis, neutralization of IL‐6 was found to inhibit activation of microglia with no major effect on astrogliosis [38, 39].

The astrocytic response to IL‐6 is context‐dependent. For example, it may be that although microglial‐derived IL‐6 is neurotoxic, IL‐6 from astrocytes or mesenchymal stem cells will activate protective AMPK/mTOR pathways or dampen microglial reactivity at the cost of impairment in myelin clearance [40, 41]. These findings further underscore the potential of IL‐6 inhibitors to restore neuroimmune homeostasis and thereby alleviate chronic pain, as well as aspects of neurodegenerative pathology.

4.3. IL‐6's Dual Role in Central Versus Peripheral Pain Pathways

IL‐6 shapes pain via distinct yet interconnected routes. In the CNS, microglia, astrocytes, neurons, and endothelial cells produce IL‐6. Although physiologic IL‐6 activity supports neurogenesis and neuroprotection in both the developing and mature brain, dysregulated IL‐6, particularly when acting through trans‐signaling, contributes to neuroinflammation, neurodegeneration, and a range of psychiatric or neurodegenerative diseases. Final outcome is shaped by IL‐6 levels as well as receptor context and microglia‐astrocyte‐neuron interactions [42, 43].

In the periphery, IL‐6 controls acute‐phase response, immune cell differentiation, and metabolism. The same IL‐6 can induce pro‐inflammatory (such as Th17 differentiation) or anti‐inflammatory (such as alternative macrophage activation) responses depending upon microenvironmental cues [44].

In therapy, it is promising to selectively inhibit IL‐6 trans‐signaling so that pathological inflammation is tamed while allowing the homeostatic functions of classic signaling to continue [24]. The balance between central and peripheral actions and between classic and trans‐signaling is at the core of IL‐6's physiological and pathological roles.

4.4. Preclinical Evidence for IL‐6–Driven Pain Mechanisms

Persistent pain in RA, despite adequate control of synovial inflammation, underscores the importance of non‐inflammatory mechanisms in chronic pain pathogenesis. IL‐6 inhibitors—such as tocilizumab (TCZ) and sarilumab (SAR)—not only reduce inflammation but also offer superior analgesia compared to TNF inhibitors in certain patient subsets. This may reflect their ability to interrupt IL‐6‐driven sensitization in the nervous system, beyond immunomodulation.

A wide body of preclinical evidence establishes IL‐6 as a central mediator of pain across diverse conditions, including bone cancer, osteoarthritis, osteoporosis, neuropathic and inflammatory pain, and spinal cord injury. Inhibition of IL‐6 or its receptor, via monoclonal antibodies or small‐molecule antagonists, consistently reduces pain behaviors and neuroinflammation. In collagen‐induced arthritis, IL‐6 blockade alleviates mechanical and thermal hyperalgesia independent of synovial inflammation, suggesting IL‐6 sustains pain through neuroimmune crosstalk between nociceptors, glial cells, and immune components [8]. Synovial fibroblast‐ and macrophage‐derived IL‐6 sensitizes joint‐innervating nociceptors, whereas neuronal IL‐6 contributes to persistent inflammation. By disrupting this loop, IL‐6 inhibitors modulate pain beyond joint pathology.

In bone cancer models, TB‐2‐081 antagonizes IL‐6, reducing both ongoing pain and mechanical hypersensitivity, in addition to limiting pathological bone remodeling. In osteoporosis as well as immobilization‐induced bone loss, IL‐6R antibodies reduce hyperalgesia and CGRP expression in DRGs without effect on bone density; it separates nociception from structural damage. Results obtained in osteoarthritis show that the inhibition of IL‐6 with TCZ diminishes central sensitization and glial activation; it improves pain‐related behaviors [45, 46].

Neuropathic pain models further support IL‐6's dual central and peripheral roles. Anti‐IL‐6R treatment attenuates mechanical allodynia and cognitive dysfunction. Intranasal versus intraperitoneal administration reveals compartment‐specific IL‐6 signaling. In spinal cord injury, systemic IL‐6R inhibition restores glutamate transporter expression and reduces hypersensitivity, largely through suppression of astrocytic IL‐6 [36].

IL‐6/gp130 triggers JAK2/STAT3 as well as PKC‐δ signaling pathways in both nociceptors and glia. This event leads to the upregulation of ion channels and neuropeptides [47, 48]. Thus, pain is completely abated by either specific deletion of gp130 in nociceptors or pharmacologic inhibition of the pathway in inflammatory as well as tumor‐associated models. In chronic pancreatitis, small‐molecule IL‐6R antagonists are capable of reversing pain primarily through desensitization of peripheral DRG neurons [49, 50].

In summary, IL‐6 inhibitors exert antinociceptive effects by disrupting neuroimmune feedback, suppressing glial activation, and inhibiting nociceptor sensitization—often independently of tissue destruction. These findings support IL‐6‐targeted therapies as promising disease‐modifying analgesics for chronic pain.

4.5. Role of gp130 and sgp130 as Modulators of Central Sensitization

Gp130, the common signal transducer for the IL‐6 cytokine family, plays a pivotal role in modulating central sensitization—a key mechanism in chronic pain defined by heightened nociceptive neuron responsiveness to normal or subthreshold input. Gp130 expression in peripheral sensory neurons is essential for pathological pain development, including inflammatory and neuropathic pain. Activation by IL‐6 family cytokines triggers JAK/STAT signaling, upregulating pronociceptive ion channels such as TRPA1 and TRPV1 in DRG, thereby enhancing excitability and promoting mechanical and thermal hypersensitivity [51]. Genetic deletion of gp130 in nociceptors leads to reduced hypersensitivity and downregulation of TRPA1, particularly in uninjured neurons adjacent to nerve injury, underscoring its role in driving central sensitization [52].

The soluble gp130 (sgp130) molecule works by antagonizing IL‐6 trans‐signaling. It achieves this by binding to IL‐6/sIL‐6R complexes, effectively sequestering them and preventing their interaction with membrane‐bound gp130. Thus, it would dampen IL‐6‐mediated pronociceptive signaling as well as the upregulation of ion channels, and this could probably explain central sensitization [53]. The fusion protein sgp130Fc, which mimics endogenous sgp130, has been proven to possess analgesic capabilities in neuropathic pain models; more specifically, it reduces glial activation as well as cytokine production and central sensitization without suppressing peripheral immunity [54]. Intervention specificity would be an attractive characteristic to exploit in similar conditions observed both in fibromyalgia and chronic post‐inflammatory pain.

Targeting gp130 also affects other IL‐6 family cytokines, including LIF and oncostatin M, which may contribute to pain modulation. However, caution is warranted to avoid disrupting the beneficial homeostatic functions of classic IL‐6 signaling [55].

In conclusion, gp130 critically modulates ion channel expression and neuronal excitability in pain pathways. Its soluble form, sgp130, serves as a natural brake on IL‐6 trans‐signaling, offering a promising therapeutic strategy for chronic pain driven by central sensitization.

5. Clinical Evidence: IL‐6 Inhibitors for Pain Relief

Pain is the most common and one of the key symptoms in patients with RA. Up to now, most treatment strategies in RA have aimed to control inflammation and, consequently, incidentally, pain. However, pain is frequently present in this patient population despite inflammation control. Although disease activity scores in RA involve pain assessment, it appears that pain should be considered an entity independent of inflammation [8]. Rapid onset of pain relief following IL‐6 blockade is a practical consequence that supports the thesis of non‐inflammatory anti‐IL‐6 effect [56]. Recently, it has been shown that the JAK inhibitor baricitinib improved pain independently of inflammation in RA patients. It exerted its effect by suppressing the IL‐6 signal pathway [57, 58]. It also has a role in sleep improvement, depression control, cardiovascular risk, and many other systemic, extraarticular, and metabolic processes in the body [59, 60, 61]. Patients with high baseline IL‐6 levels, compared to those with low baseline IL‐6 levels, reported greater improvements in health‐related quality of life (HRQoL), including physical component summary (PCS), physical functioning domain, and AM‐stiffness scores, with SAR treatment compared to adalimumab [62]. Drugs that act on the IL‐6 pathway mediate their effect as IL‐6 inhibitors or IL‐6 receptor antagonists, interacting with membrane‐bound or soluble IL‐6 or IL‐6 receptor. Currently approved IL‐6 receptor antagonists for RA treatment are TCZ and SAR. TCZ intravenous was first approved by the European Medicines Agency (EMA) [61] in 2009 and by the Food and Drug Administration (FDA) in 2010. Subcutaneous formulation of TCZ was approved following the intravenous formulation of TCZ. SAR is a second IL‐6 receptor antagonist approved for subcutaneous application by the EMA and FDA in 2017. Both drugs are indicated for RA in combination with conventional synthetic DMARDs or as monotherapy [63, 64, 65, 66]. Although some other drugs acting through IL‐6‐R have been investigated, only TCZ and SAR have gained approval in this indication to date. Additionally, in 2023 FDA announced approval for the first TCZ biosimilar, TCZ‐bavi, for the indication of RA in adult patients.

Clinical efficacy of TCZ and SAR in RA has been evaluated in randomized controlled trials (RCTs) as a valuable therapeutic option when other drugs have failed to achieve the expected benefit [67, 68, 69, 70, 71, 72, 73, 74, 75]. Evaluating PROs, alongside clinically efficacious outcomes (including both laboratory evaluations and physician assessment of disease activity), provides more realistic insight into RA burden and therapeutic efficacy of investigated drugs. Overall well‐being, fatigue, work ability and productivity, sleep and behavioral disturbance, pain, and finally, HRQoL have been recognized and investigated as PROs. For RA, PRO measures (PROMs) include the American College of Rheumatology (ACR) core set, which consists of the Patient Global Assessment (PGA), Health Assessment Questionnaire Disability Index (HAQ‐DI; 0–3), and pain assessed using the Visual Analogue Scale (VAS; 0–100 mm). Additionally, RA‐specific PROMs include the RA Quality of Life (RAQoL) questionnaire, RA Impact of Disease (RAID), RA‐specific Work Productivity Survey (WPS‐RA), Short Form‐36 (SF‐36) physical component summary (PCS) and mental component summary (MCS) scores (scored 0–100), and the eight SF‐36 domains (physical functioning, role‐physical, bodily pain, general health, vitality, social functioning, role‐emotional, and mental health; scored 0–100). The Functional Assessment of Chronic Illness Therapy (FACIT)‐Fatigue scale is also used. Pain, as an independent entity, can be evaluated using three PROMs: VAS, RAID, and the pain domain of the SF‐36. However, it also negatively impacts almost all other PROs, such as fatigue, work productivity, sleep, emotional health, and QoL [76, 77]. We analyzed the assessment of pain in cornerstone RCTs related to IL‐6R treatment. In four out of 12 RCTs investigating TCZ, pain is described using VAS, and in one study involving VAS, and additionally, the SF‐36 domain: bodily pain. In the LITHE, OPTION, RADIATE, AMBITION, and ADACTA studies, an improvement in pain sensation was shown for the TCZ treatment compared to placebo, conventional synthetic DMARDs, or adalimumab [70, 78, 79, 80, 81]. In Table 2, an overview of the pain assessment in RCTs that investigated TCZ and SAR is presented. VAS was used in seven RCTs evaluating SAR, additionally with the RAID domain: pain in two studies, and one study investigated the proportion of patients with unacceptable pain [72, 73, 74, 87, 88, 89, 91]. In all studies, an improvement in pain sensation was detected compared to control treatment. Analyses of pain included the mean change of VAS score, or the last square mean change. When this approach is incorporated, a caution should be included when we make conclusions about pain relief on the basis of investigated treatments, because of a lower number of patients at the final check‐out compared to the baseline time‐point. Also, a limited number of PROMs involving pain assessment exist: VAS and distinct pain domains in the SF‐36 and RAID questionnaire. Only one study reported the proportion of patients with unacceptable pain, the HARUKA study [72, 91]. Finally, no reports evaluating TCZ versus SAR exist, as there is neither evidence from RCTs about the effect of a TCZ biosimilar on PROMs, including pain. Very limited direct conclusions can be drawn in this field.

TABLE 2.

Descriptive overview of study results investigating the effect of tocilizumab and sarilumab on pain.

Study/reference ID	Treatments arms	PROMs used for pain assessment	Results for pain according to treatment group
TCZ studies
LITHE NCT00106535 Kremer 2011 [78]	TCZ iv 8 mg/kg iv + MTX TCZ 4 mg/kg IV + MTX Placebo + MTX	VAS (mm, adjusted mean change from baseline)	–26.2 –23.1 –15.1
OPTION NCT 00106548 Smolen 2008 [79]	TCZ 8 mg/kg IV + MTX TCZ 4 mg/kg IV + MTX Placebo + MTX	VAS (mm, mean changes from baseline (adjusted means))	–29.8 –25 –14
TOWARD NCT00106574 Genovese 2008 [82]	TCZ 8 mg/kg IV + DMARDs Placebo + DMARDS	Not reported
RADIATE NCT00106522 Strand 2012 [81]	TCZ iv 8 mg/kg + MTX TCZ iv 4 mg/kg iv + MTX Placebo + MTX	VAS (mm, mean change from baseline)	–32.5 –21 –8.6
U‐ACT‐EARLY NCT01034137 Teitsma 2017 [83]	TCZ 8 mg/kg iv + MTX TCZ 8 mg/kg iv + placebo MTX + placebo	Not reported as an independent variable
SATORI NCT00144521 Nishimoto 2009 [67]	TCZ 8 mg/kg + MTX placebo MTX + TCZ placebo	Not reported
AMBITION NCT00109408 Jones 2010 [70]	TCZ 8 mg/kg MTX Placebo + TCZ 8 mg/kg	VAS (mm, mean changes from baseline)	–31.9 –29.9
FUNCTION NCT01007435 Burmester 2017 [84]	TCZ 8 mg/kg iv + placebo TCZ 8 mg/kg iv + MTX TCZ 4 mg/kg iv + MTX Placebo + MTX	Not reported
ACT‐RAY NCT00810199 Dougados 2013 [71]	TCZ 8 mg IV + MTX TCZ 8 mg IV + placebo	Not reported
ADACTA NCT01119859 Strand 2017 [80]	TCZ 8 mg/kg IV + placebo sc Adalimumab 40 mg sc + placebo iv	VAS (mm, last square changes from baseline) SF‐36 bodily pain domain	1–40.1 2–28.7 129.3 223.9
SUMMACTA NCT01194414 Burmester 2016 [85]	TCZ 162 mg sc + iv placebo TCZ 8 mg/kg iv + sc placebo	Not reported
BREVACTA NCT01232569 Kivitz 2014 [86]	TCZ 162 mg sc. Placebo sc.	Not reported
Sarilumab studies
MOBILITY NCT01061736 Strand 2016 [87]	SAR 200 mg + MTX SAR 150 mg + MTX Placebo + MTX	VAS (mm, change from baseline)	–33.1 –32.7 –19.3
TARGET NCT01709578 Strand 2017 [88] Gossec 2019 [89]	SAR 200 mg + csDMARD SAR 150 mg + csDMARD Placebo + csDMARD	VAS (mm; last square mean change) RAID	VAS –33.7 (2.0) –31.9 (2.1) –21.3 (2.3) RAID—pain domain SAR 200 mg versus placebo 0.68* SAR 150 mg versus placebo 0.54*
MONARCH NCT02332590 Burmester 2017 [90] Gossec 2019 [89]	SAR 200 mg Adalimumab	VAS (last square mean change) RAID	VAS –36.2 (1.8) –27.4 (1.8) RAID—pain domain SAR versus adalimumab 0.44*
HARUKA NCT02373202 Kameda 2020 [72] Tanaka 2024 [91]	SAR 200 mg SAR 150 mg SAR 200 mg + non‐MTX csDMARDs SAR 150 mg + non‐MTX csDMARDs	VAS (mm, mean (SD) change from baseline) Proportion of patients who experienced unacceptable pain (pain VAS > 40 mm)	–37.5 (30.5) –35.8 (25.0) –31.2 (28.6) –37.2 (21.0) 9/58 0/24
KAKEHASI NCT02293902 Tanaka 2019 [92]	SAR 200 mg SAR 150 mg placebo switching to SAR 200 mg at week 24 Placebo switching to SAR 150 mg in week 24	VAS (mm, mean (SD) change from baseline)	–30.2 (23.3) –36.5 (23.4) No data –22.9 (27.7)
Fleischmann 2017 [74] NCT01709578	SAR 200 mg + csDMARDs SAR 150 mg + csDMARDs Placebo + csDMARDs	VAS (mm)	–33.7 (2.04) –31.9 (2.09) –21.3 (2.25)
Genovese 2015 [73] NCT01061736	SAR 200 mg + MTX SAR 150 mg + MTX Placebo + MTX	VAS (mm)	–31.8 (1.34) –28.5 (1.35) –15.4 (1.42)

^*Cohen's d Rule for Change Interpretation: important: d ≤ −0.8; moderate: −0.8 < d ≤ −0.5; and small: −0.5 < d ≤ −0.225; difference between groups in the least‐squares mean change from baseline.

6. Head‐To‐Head Comparisons and Indirect Evidence

6.1. Comparative Evidence on IL‐6 Inhibitors: Direct and Indirect Analyses

Although both TCZ and SAR inhibit the IL‐6 receptor and share similar anti‐inflammatory mechanisms, subtle differences in their pharmacologic properties may translate into differential effects on pain outcomes in RA. Direct comparative RCTs evaluating pain as a primary endpoint are currently lacking; however, insights can be drawn from pharmacodynamic studies, real‐world observational cohorts, and network meta‐analyses (NMAs) [93].

Saito et al. [93] conducted a pharmacodynamic study comparing subcutaneous SAR and TCZ in RA patients, demonstrating that SAR achieved a stronger and more sustained inhibition of IL‐6 signaling pathways, as evidenced by greater suppression of phosphorylated STAT3 (pSTAT3) in CD4+ T cells. This suggests a potentially more potent modulation of inflammatory signaling relevant to pain sensitization mechanisms.

In a large prospective cohort study utilizing the ANSWER registry in Japan, Onishi et al. [94] compared the effectiveness of subcutaneous SAR (SAR‐SC, 200 mg biweekly), subcutaneous TCZ (TCZ‐SC, 162 mg biweekly), and intravenous TCZ (TCZ‐IV, 8 mg/kg every 4 weeks) in 1001 IL‐6 inhibitor–naïve patients with RA [88]. Using a target trial emulation approach and inverse probability weighting to adjust for baseline differences, the study found that SAR‐SC led to a significantly greater reduction in Clinical Disease Activity Index (CDAI) at 24 weeks compared to TCZ‐SC (mean difference −2.53; 95% CI: −4.38 to −0.69; p = 0.007), whereas the difference between TCZ‐IV and TCZ‐SC was not statistically significant. The greater CDAI improvement with SAR‐SC was consistent across multiple time points and remained significant at 48 weeks. Although retention rates were similar among all groups, the superior CDAI reduction with SAR‐SC, which includes patient global assessment and tender joint count (both strongly correlated with pain), suggests a potential clinical advantage of SAR in managing RA‐associated pain under real‐world conditions [94].

Despite these findings, definitive conclusions regarding analgesic superiority remain speculative in the absence of randomized head‐to‐head trials. Until such data are available, treatment decisions between SAR and TCZ should be guided by factors such as dosing schedule, route of administration (IV vs. SC), comorbidities, patient preference, tolerability, and rapid C‐reactive protein (CRP) suppression requirements [95].

6.2. Indirect Evidence From Meta‐Analyses

Although RCTs remain the gold standard for comparing treatment efficacy, direct head‐to‐head studies evaluating IL‐6 inhibitors such as TCZ and SAR with pain as a primary endpoint are limited. In this context, meta‐analyses offer a valuable approach by synthesizing data from multiple RCTs to indirectly compare the relative effectiveness of biologic agents on outcomes closely related to pain, such as tender joint counts and patient global assessments. These analyses provide important insights into the comparative analgesic potential of IL‐6 pathway inhibitors within the broader landscape of RA therapeutics [96].

A 2024 Bayesian NMA evaluated six RCTs involving 4439 patients with active RA who were either intolerant or had an inadequate response to methotrexate (MTX) [97]. The study found that all three IL‐6 inhibitors (TCZ, SAR, and olokizumab) were significantly more effective than placebo in achieving ACR20 responses, with TCZ demonstrating the highest probability of being the most effective agent on the basis of surface under the cumulative ranking curve (SUCRA) scores. SAR ranked second, followed by olokizumab administered every 2 or 4 weeks. The ranking patterns were consistent across ACR50 and ACR70 endpoints. Although pain was not evaluated as a distinct outcome in this analysis, ACR response criteria inherently reflect pain‐related dimensions such as tender joint count and patient global assessment. Therefore, the superior ACR response probability associated with TCZ, followed closely by SAR, may indirectly indicate greater pain relief with these agents relative to olokizumab [97].

Another NMA evaluated three RCTs, including 1066 patients with active RA, intolerant or inadequately responsive to MTX [98]. TCZ 8 mg monotherapy demonstrated the highest probability of achieving ACR20 and ACR50 responses, followed by SAR and adalimumab, with sirukumab ranking lowest. Although pain was not a direct outcome, the ACR response criteria incorporate pain‐related measures such as tender joint counts and patient global assessments. Therefore, the superior ACR responses observed with TCZ and SAR likely reflect better pain relief compared to other agents. Safety profiles were comparable, with SAR ranked as the safest biologic by SUCRA, but no significant differences in serious adverse events among treatments [98].

Taken together, evidence from network‐level comparisons supports the notion that TCZ and SAR are clinically equivalent in their overall ability to reduce pain‐related disease burden in RA. Nevertheless, because of methodological limitations inherent in indirect comparisons—such as variations in trial populations, background therapies, and outcome definitions—caution is warranted in overinterpreting subtle differences in analgesic efficacy between these agents.

6.3. Role in TNF Inhibitor Inadequate Responder (TNF‐IR) Populations

A significant subset of RA patients exhibits inadequate response or loss of efficacy to TNF inhibitors, which complicates disease management and necessitates alternative therapeutic strategies. IL‐6 inhibitors, including TCZ and SAR, have emerged as effective options in this challenging TNF‐IR population [99].

Head‐to‐head RCTs, most notably the ADACTA trial, have shown that IL‐6 inhibitors provide superior improvement in disease activity and PROs, particularly pain reduction, compared to switching to another TNF inhibitor [69]. Mechanistically, IL‐6 contributes to pain through neuroimmune sensitization pathways distinct from those targeted by TNF inhibitors, offering a rationale for the efficacy of IL‐6 inhibitors in patients unresponsive to TNF blockade [8].

Indirect comparisons and NMA reinforce these findings, favoring IL‐6 inhibitors over repeated TNF inhibitor therapy in TNF‐IR populations by effectively reducing persistent inflammation and refractory pain [100]. These insights emphasize the importance of IL‐6 inhibition as a strategic switch for TNF‐IR patients to optimize pain management and improve QoL in RA.

6.4. Pharmacokinetics of IL‐6 Inhibitors and Their Potential Pain Impact

The pharmacokinetic profiles of IL‐6 inhibitors, including TCZ and SAR, play a crucial role in their clinical efficacy and potential effects on pain management in RA. Both agents target the IL‐6 receptor but differ in their administration routes, dosing intervals, and serum half‐lives, which may influence their ability to sustain IL‐6 pathway blockade and consequently modulate pain‐related inflammatory processes.

TCZ is available in both IV and SC formulations, with an elimination half‐life ranging approximately from 8 to 14 days, depending on dose and route [101]. The IV form is typically administered every 4 weeks, whereas the SC form is given weekly or biweekly [101]. SAR, on the other hand, is administered subcutaneously every 2 weeks with a half‐life of approximately 21 days, allowing for sustained receptor occupancy and IL‐6 signaling inhibition [94].

Sustained suppression of IL‐6 signaling is critical because IL‐6 contributes to peripheral and central sensitization mechanisms involved in RA‐associated pain through modulation of nociceptive neurons and glial cell activation [8]. Differences in pharmacokinetics may thus affect the consistency of pain control over the dosing interval, with longer half‐life agents potentially offering more stable pain relief.

However, clinical evidence directly linking pharmacokinetic differences to superior analgesic outcomes remains limited. Head‐to‐head trials and real‐world studies comparing pain outcomes with pharmacokinetic parameters are warranted to clarify these potential effects.

6.5. CRP Levels and Systemic Inflammation: Modifiers of Pain Response

CRP remains a widely used biomarker of systemic inflammation in RA and is directly induced by IL‐6 (10) [102]. Elevated baseline CRP levels have been shown to predict greater clinical and symptomatic response to IL‐6 inhibitors, including improvements in pain and fatigue, which are often poorly correlated with joint swelling or radiographic damage [103].

Post hoc analyses from ADACTA and MONARCH trials indicated that patients with higher baseline CRP levels (> 10 mg/L) exhibited greater reductions in VAS pain and HAQ scores, suggesting that systemic inflammation may amplify peripheral and central pain pathways via IL‐6‐dependent mechanisms [69, 104]. Thus, CRP may act as a surrogate indicator of IL‐6‐mediated nociceptive sensitization, identifying patients most likely to benefit from targeted IL‐6 blockade.

Unlike TNF inhibitors, which variably reduce CRP, or JAK inhibitors, which act downstream of IL‐6 signaling, IL‐6 inhibitors directly suppress hepatic CRP production, leading to rapid and robust reductions [105]. This CRP‐lowering effect may correlate with subjective improvements in well‐being and pain relief, potentially serving as an early marker of therapeutic success.

7. IL‐6 Versus Other RA Treatments for Pain

7.1. Comparative Effectiveness of IL‐6 Inhibitors and TNF Inhibitors for Pain Relief

TNF inhibitors and IL‐6 inhibitors (especially TCZ) were globally adopted as first‐line biological therapy (in combination with MTX and as a monotherapy) in patients with RA who are refractory to conventional synthetic DMARDs [69]. TNF inhibitors and TCZ monotherapy demonstrated significantly greater disease improvement and pain reductions (on a 0–100 scale) compared to placebo [106]. Comparable improvements were seen in PROs when TNF inhibitors and TCZ were combined with MTX [107]. TCZ monotherapy caused improvements in PROs comparable to TCZ + MTX, whereas TNF inhibitor monotherapy was probably less effective than TNF inhibitor + MTX [107].

In the ADACTA study, TCZ monotherapy, when compared to adalimumab monotherapy, resulted in a significantly and clinically meaningful higher improvement in disease activity score [87] 28 from baseline to week 24 [69]. Additionally, TCZ increased considerably response rates across all secondary endpoints (DAS 28, ACR20, 50, 70 score—ACR 20, 50, 70). The post hoc and exploratory analyses showed numerically different response rates. Still, the differences were negligible for the QoL objectives (HAQ and FACIT‐Fatigue Scale) [69].

The RADIATE study was the first to examine the TCZ and MTX combination in patients who had previously failed TNF inhibitor therapy. It was discovered that the combination worked well for patients who had not responded well to TNF inhibitor treatment [108]. The conclusion was that TCZ plus MTX successfully achieved rapid and sustained improvements in the signs and symptoms of RA in patients [108].

Recent comparative evidence further nuances the positioning of TCZ in refractory disease. A recent meta‐analysis of 19 RCTs including 7835 patients with inadequate response to MTX or TNF inhibitors found no major differences in crude ACR70 rates among rituximab, abatacept, and TCZ. However, after adjusting for key imbalances across trials (baseline HAQ, study duration, prior TNF inhibitor exposure), abatacept showed approximately a 2.2‐fold higher probability of achieving an ACR70 response compared to TCZ, whereas rituximab and abatacept demonstrated comparable efficacy. These findings suggest that drug class selection in refractory RA may require closer alignment with patient‐specific biological and trial contextual factors [109].

7.2. IL‐6 Inhibitors Versus JAK Inhibitors: Shared Downstream Pathways, Overlapping but Distinct

RCTs have demonstrated that JAK inhibitors are associated with significantly bigger improvements in PGA than biologics [110, 111, 112]. According to one study, baricitinib improves PGA more than TCZ in clinical settings [112]. These study results imply that baricitinib may help patients with persistent PGA who do not have significant joint inflammation [112]. A study with upadacitinib showed superiority of PGA improvement compared to adalimumab [110]. Recent mechanistic evidence provides a plausible explanation for this disproportionate improvement in patient global assessment. In a collagen antibody induced arthritis model, baricitinib not only reduced synovial inflammation but also directly modulated nociceptive pathways by normalizing IL 6 and JAK STAT3 signaling in dorsal root ganglion neurons and suppressing CSF 1‐driven microglia astrocyte activation. This dual effect on inflammatory and neuropathic pain offers a biological rationale for the superior PGA response observed in clinical studies [113].

PGA is influenced not just by joint inflammation but also by comorbidities, socioeconomic traits, and physical and mental health [114]. Specifically, one of the leading causes of PGA is pain [115]. A systematic review and meta‐analysis of clinical studies showed that JAK inhibitors significantly reduced pain more than biologic DMARDs [116, 117]. This suggests that JAK inhibitors may have analgesic effects in addition to their anti‐inflammatory properties [116].

Targeting the IL‐6 signaling pathway, JAK inhibitors, and TCZ affect CRP [96]. A well‐known phenomenon in RA patients treated with TCZ is the disproportionate decrease in CRP levels compared to clinical indices of inflammation [118]. It has also been proposed that this phenomenon occurs in patients treated with JAK inhibitors because of JAK inhibitors' intracellular effects on the IL‐6 pathway. According to recent RCTs, patients treated with JAK inhibitors had significantly lower serum CRP and PGA levels than those treated with adalimumab or abatacept [110, 111, 112]. In another trial, patients receiving tofacitinib showed disproportionately high remission rates using DAS28CRP, indicating that the drug significantly lowers the synthesis of CRP [119].

7.3. Non‐Steroidal Anti‐Inflammatory Drugs (NSAIDs), Corticosteroids, MTX: Quick Symptom Relief but Limited Chronic Pain Control

The mechanisms behind chronic pain in RA remain poorly understood [120]. Pain may be resistant when RA is in remission and manifests in non‐inflammatory sites [5, 121]. Even with significant therapeutic advancements that have reduced synovitis and disease activity, a substantial number of patients still experience pain [122].

Through their anti‐inflammatory effects, glucocorticoids administered intra‐articularly, orally, or parenterally may offer clinically significant pain reduction in RA [123, 124]. Reduced pain can result from either local or systemic effects, and systemic treatment has been shown to provide benefits for up to a year, even though symptoms may return after stopping steroids [123].

Since inflammation is the primary pain mechanism in RA, DMARDs form the cornerstone of treatment [122]. With a beginning effect that coincides with the suppression of inflammation over a few weeks, conventional synthetic DMARDs like MTX, sulfasalazine, and leflunomide also lessen joint pain and can be sustained for months [123]. Therefore, even after using conventional synthetic DMARDs for treatment, pain may continue to be an issue.

Although there is a lack of evidence on the management of pain in RA, drugs like NSAIDs, topical capsaicin, and mild opioids, as well as treatments such as joint infiltrations or surgery, are crucial [122]. NSAIDs reduce pain in RA patients. However, they are not very helpful as a stand‐alone treatment for patients with centrally mediated pain, such as fibromyalgia. Despite side effects such as substantial gastrointestinal events, NSAIDs can directly provide significant and rapid benefits to people with RA.

7.4. Combination Strategies: IL‐6 Inhibitor + MTX Versus IL‐6 Inhibitor Monotherapy in Pain Modulation

Several key clinical trials have evaluated the efficacy and safety of TCZ as monotherapy and combination therapy in patients with RA [125]. Approximately one‐third of patients use biologic DMARDs as monotherapy, according to data from biological drug registries and a United States claims database [69]. Combination treatment with TCZ + MTX and other conventional synthetic DMARDs leads to a quick and long‐lasting improvement in the signs and symptoms of RA in various patient populations, according to randomized, double‐blind, controlled phase 3 studies [68, 79, 82, 126]. Additionally, research has demonstrated the safety and effectiveness of TCZ as a monotherapy [67, 70, 127]. Regardless of previous TNF inhibitor exposure, patients with active, refractory RA who started TCZ monotherapy showed improvements in PROs‐EQ‐5D domains (walking, self‐care, usual activities, pain/discomfort, and anxiety/depression) [128].

The SATORI trial demonstrated that TCZ monotherapy successfully treated RA in patients who did not respond well to low‐dose MTX [67]. TCZ monotherapy was more effective than MTX monotherapy in the AMBITION trial, irrespective of prior MTX treatment [70].

Several studies, including CHARISMA, OPTION, TOWARD, and ROSE [68, 79, 82, 126], have shown the effectiveness of TCZ in combination therapy with other conventional synthetic DMARDs in patients with prior DMARD failure.

Typically, RCTs report efficacy using the standard primary outcomes of the ACR 20/50/70 [129]. Because of the composite nature of the ACR 20/50/70 score, predicting how important patient‐centered components would be impacted is challenging.

We can conclude that by acting on disease activity, TCZ in monotherapy or combination with other conventional synthetic DMARDs indirectly affects pain in patients with RA.

8. Unmet Needs and Future Directions

8.1. Persistent Pain Despite IL‐6 Inhibition: A Clinical Dilemma

Despite robust anti‐inflammatory effects and notable improvements in disease activity scores, IL‐6 inhibitors fail to provide adequate pain relief in a subset of RA patients. This phenomenon (persistent pain despite remission or low disease activity) reflects the growing recognition that RA pain is not solely inflammation‐driven. Instead, it is a multidimensional experience shaped by peripheral nociception, central sensitization, psychological burden, and long‐standing neuroimmune dysregulation.

Several observational studies have shown that more than 30%–50% of RA patients continue to report moderate‐to‐severe pain despite being classified as in remission by DAS28 or CDAI scores [121, 130]. This incongruity reflects the inadequacy of current composite disease activity tools in capturing the true pain burden. Central sensitization, characterized by exaggerated pain responses, altered descending pain modulation, and neuroplastic changes in cortical and subcortical structures, plays a central role in this residual pain [4]. Since IL‐6 contributes to glial activation, hyperexcitability of dorsal horn neurons, and astrocytic priming, IL‐6 blockade holds theoretical appeal—but it is increasingly clear that its modulation of central pain circuits is not universally sufficient [4].

Furthermore, coexisting conditions such as fibromyalgia, sleep disorders, mood disturbances, and fatigue often persist under IL‐6 therapy, suggesting that peripheral cytokine suppression alone cannot resolve centrally amplified symptoms [131]. Pain must therefore be reframed not merely as a symptom of inflammation, but as a neurobehavioral syndrome, requiring targeted and integrative interventions beyond standard biologics. Multidisciplinary care models incorporating cognitive‐behavioral therapy, neuromodulatory pharmacology, physical rehabilitation, and sleep restoration strategies are essential adjuncts.

8.2. Absence of Pain‐Specific Biomarkers: Is IL‐6 a Predictor?

The future of RA pain management depends on precision medicine, and yet we currently lack validated, reproducible, and clinically actionable biomarkers for pain phenotyping or treatment response prediction. Elevated IL‐6 levels may suggest systemic inflammatory activity, but do not reliably correlate with subjective pain intensity or with central pain amplification phenomena [60].

This highlights a critical knowledge gap: current serological biomarkers (e.g., CRP, erythrocyte sedimentation rate, and IL‐6) reflect inflammatory load, not pain mechanisms. In contrast, pain in RA is often influenced by non‐inflammatory drivers, including disordered sensory processing, neurotransmitter imbalance, cortical maladaptation, and psychological comorbidity. Thus, both peripheral and central mechanistically relevant markers are urgently needed.

Emerging candidates include [132]:

• Cerebrospinal fluid cytokine profiles, especially IL‐6, TNF‐α, and IL‐17, which may reflect central neuroinflammatory states

• Functional neuroimaging signatures (e.g., functional magnetic resonance imaging [fMRI] BOLD signal in the insula, anterior cingulate cortex) that correlate with central sensitization

• Quantitative Sensory Testing (QST) and conditioned pain modulation (CPM) profiles that stratify patients by descending inhibitory control efficiency.

• Circulating markers such as soluble gp130, neurofilament light chain, or GFAP, which may indicate glial or astrocytic activity linked to chronic pain.

If such tools are validated, IL‐6‐driven pain could be predicted more accurately, and biologic therapy could be tailored to individuals more likely to benefit. Importantly, this could also prevent the overtreatment of patients with pain of non‐inflammatory origin, reducing costs and improving outcomes.

8.3. Emerging Therapeutics: Dual‐Target Biologics and Beyond

Persistent pain in RA is often multifactorial, requiring therapies that can simultaneously address peripheral inflammation and central dysregulation. Recent advances in drug design have led to the emergence of dual‐target biologics, which combine inhibition of IL‐6 with other pro‐inflammatory mediators like TNF‐α or IL‐17 [133, 134]. These agents, including bispecific nanobodies and fusion proteins, are under early‐phase investigation and may offer synergistic efficacy in both pain and disease control.

In addition to dual blockade strategies, targeting IL‐6 trans‐signaling specifically via soluble gp130‐Fc constructs has gained traction. This selective approach aims to block the pathogenic neuroimmune effects of IL‐6 trans‐signaling, whereas preserving classic signaling important for tissue repair and host defense [22]. Preclinical models suggest that such approaches may yield greater pain modulation with reduced adverse effects.

Moreover, combining IL‐6 inhibitors with central neuromodulators is another promising avenue. Serotonin‐norepinephrine reuptake inhibitors, tricyclic antidepressants, gabapentinoids, and low‐dose naltrexone have shown benefit in nociplastic pain conditions and may enhance central pain inhibition when used adjunctively with biologics [135]. Future trials should explore these synergistic pharmacological strategies, particularly in patients with pain‐dominant, inflammation‐negative RA phenotypes.

The integration of digital therapeutics, such as mobile‐based cognitive interventions, sleep modulation apps, and virtual pain coping programs, represents a novel adjunctive approach, especially in younger, tech‐enabled patient populations.

8.4. Bridging Mechanistic Understanding With Clinical Trial Design

To close the translational gap between mechanistic research and real‐world pain management, clinical trials evaluating IL‐6 inhibitors must evolve. Historically, pain has been treated as a secondary or exploratory endpoint in most RCTs. This has contributed to the underrecognition of analgesic effects and a failure to distinguish mechanistically distinct pain phenotypes.

Future trial designs should include [136, 137, 138, 139, 140]:

• Pain‐specific primary endpoints, including VAS, Brief Pain Inventory (BPI), and PROs Measurement Information System (PROMIS) Pain Interference scores

• Central sensitization assessments, such as QST, fMRI, or CPM paradigms.

• Stratification by pain phenotype, using validated instruments (e.g., painDETECT, Douleur Neuropathique 4 [DN4], fibromyalgia screening tools)

• Multimodal outcomes, encompassing fatigue, sleep quality, depression/anxiety scores, and neuroimaging correlates.

Incorporating such measures would allow researchers to identify true responders to IL‐6 inhibition for pain, optimize patient selection, and pave the way for biomarker‐informed, individualized pain treatment algorithms. This paradigm shift from inflammation‐centered to mechanism‐guided care could redefine therapeutic success in RA, not just by silencing disease activity, but by truly restoring QoL.

9. Conclusion

IL‐6 inhibitors have undergone a distinct analgesic repositioning, emerging as a novel class of disease‐modifying analgesics that extend beyond their traditional anti‐inflammatory role in rheumatoid arthritis (RA) pain management. They target both peripheral and central mechanisms driving chronic pain. Clinical and real‐world studies demonstrate that agents such as TCZ and SAR produce rapid and sustained improvements in PROs, including pain, fatigue, and HRQoL, often outperforming TNF inhibitors in certain populations. IL‐6‐driven sensitization of nociceptors, glial activation, and neuroimmune crosstalk underlie persistent pain in RA—even when inflammation is under control. By uniquely modulating these signaling pathways, IL‐6 inhibitors provide dual benefits—suppressing inflammation while directly alleviating pain—thereby marking a paradigm shift in RA treatment that recognizes pain as a distinct, treatable entity. Despite these advances, a substantial subset of patients continues to suffer from moderate to severe pain, highlighting the multifactorial nature of RA pain, which is characterized by central sensitization, psychological comorbidities, and neuroplastic changes. The lack of validated pain‐specific biomarkers hinders individualized treatment and underscores the need for research that links mechanistic findings to clinical practice. Elevated CRP may predict a better symptomatic response to IL‐6 blockade, but current serologic markers do not reliably reflect pain mechanisms or central amplification.

Future development of precision medicine tools for pain phenotyping and response prediction should be a priority. New therapies, including dual‐target biologics and selective IL‐6 trans‐signaling inhibitors, show promise for refractory pain. Integrative, multidisciplinary approaches that combine pharmacologic, behavioral, and digital interventions are essential to fully address the multidimensional burden of RA pain.

We need a paradigm shift: away from an inflammation‐centric model to one that recognizes pain as a distinct, multifactorial entity. A better understanding of mechanisms and refined clinical trial design will enable IL‐6 inhibitors to restore patients' quality of life in RA and move beyond suppression of disease activity to true pain relief.

Author Contributions

The conceptualization of the study was led by Andrej Belančić. Data curation was performed by Andrej Belančić, Seher Sener, Yusuf Ziya Sener, and Marijana Vučković. Formal analysis was conducted by Andrej Belančić, Seher Sener, and Mirjana Stanić Benić. The methodology was developed by Andrej Belančić, Seher Sener, Yusuf Ziya Sener, Almir Fajkić, Marijana Vučković, Ines Potočnjak, and Antonio Markotić. Project administration was managed by Josipa Radić and Mislav Radić. Resources were provided by Andrej Belančić, Seher Sener, Yusuf Ziya Sener, Almir Fajkić, Marijana Vučković, Antonio Markotić, Mirjana Stanić Benić, Ines Potočnjak, and Marija Rogoznica Pavlović. Supervision of the project was conducted by Mislav Radić. Validation was performed by Andrej Belančić and Seher Sener. Visualization was carried out by Marijana Vučković. The original draft of the manuscript was written by Andrej Belančić, Seher Sener, Yusuf Ziya Sener, Almir Fajkić, Marijana Vučković, Antonio Markotić, Mirjana Stanić Benić, Ines Potočnjak, and Marija Rogoznica Pavlović. The writing and review and editing were performed by Josipa Radić and Mislav Radić.

Funding

The authors have nothing to report.

Ethics Statement

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

No new data were generated. All info underlying this article will be shared on a reasonable request sent to the corresponding author.