A 48-year-old female presented to our Rheumatology department with a 21-year history of polyarticular pain and swelling, and a 1-year history of recurrent bilateral lower limb numbness and weakness. The patient’s primary concerns at the most recent admission were worsening neuropathic symptoms and active articular disease, signifying a flare of her underlying condition. The complex chronology of her disease evolution, key interventions, and outcomes is summarized in Figure 1.

The patient’s autoimmune journey began in 2004 (age 27) with the insidious onset of symmetrical polyarthritis involving the proximal interphalangeal joints, metacarpophalangeal joints, wrists, shoulders, knees, and feet, accompanied by morning stiffness lasting over one hour. A diagnosis of RA was established at a local hospital. Initial treatment with methotrexate (MTX) was effective but was self-discontinued due to side effect concerns. Subsequently, disease control was suboptimal, involving periods of traditional Chinese medicine (3 years, ineffective), etanercept (approximately 2 years, discontinued due to cost), and tofacitinib (1 year, ineffective).

In 2020, a more structured regimen was initiated, consisting of subcutaneous etanercept (50 mg weekly) combined with oral MTX (12.5 mg weekly). This provided a period of relative stability until February 2024, when she experienced a flare with swelling and pain in her metacarpophalangeal joints. Etanercept was stopped, and her regimen was adjusted to MTX (increased to 15 mg weekly), iguratimod (25 mg twice daily), and hydroxychloroquine (200 mg daily).

A pivotal clinical turning point occurred in July 2024. The patient developed herpes zoster in the right thoracic region. During this acute infection, she self-discontinued all DMARDs. Shortly after the resolution of the shingles rash, she rapidly developed new neurological symptoms: numbness and hypoesthesia localized to the right knee and lower leg, followed by left foot numbness. Notably, she experienced significant right foot dorsiflexion weakness. This prompted her first hospitalization in August 2024.

The patient’s history is significant for multiple RA flares and the development of irreversible joint damage. Crucially, she had no documented history of diabetes, hypothyroidism, or other conditions commonly associated with PN. There was no relevant family history of hereditary neuropathies, diabetes mellitus, or autoimmune diseases.

Hospitalization 1 (August 2024): Admitted for acute-onset PN. Key findings included elevated inflammatory markers (erythrocyte sedimentation rate (ESR) 40 mm/h, high-sensitivity C-reactive protein (hs-CRP) 26.1 mg/L) and high titers of RA-associated antibodies (RF 187.7 IU/mL, ACPA 58.5 U/mL) (Table 1). CSF analysis showed mildly elevated protein (36.7 mg/dL) with normal cell count. The nerve conduction studies (NCS) and electromyography (EMG) conducted on August 5, 2024, have confirmed a moderate-to-severe lesion of the right common peroneal nerve (Table 2). A diagnosis of RA-associated PN was made. She received intravenous methylprednisolone therapy (80 mg daily for 5 days), leading to mild symptomatic improvement. Follow-up NCS/EMG on August 16 showed persistent but improved multifocal peripheral nerve involvement in the lower limbs (Table 2). She was discharged on a regimen of iguratimod, hydroxychloroquine, and neuropathic pain agents (pregabalin, oxcarbazepine).

Hospitalization 2 (December 2024): Represented with a severe systemic and worsening neurological symptoms. In the absence of any intercurrent infection, she reported intensified bilateral lower limb numbness and pain, cervical pain, and active polyarthritis with morning stiffness. Inflammatory markers were markedly elevated (ESR 56.1 mm/h, hs-CRP 45.8 mg/L, RF 496.5 IU/mL) (Table 1). Repeat NCS/EMG on December 4, 2024, demonstrated significant worsening and extension of the polyneuropathy, revealing severe right common peroneal nerve, moderate-to-severe left tibial nerve, and mild-to-moderate right tibial nerve involvement, affecting both motor and sensory fibers (Table 2). This objective evidence of progressive nerve injury despite previous therapy defined her condition as refractory.

Musculoskeletal System: Swan-neck deformities of the fingers and foot deformities consistent with long-standing RA. Active synovitis with swelling and tenderness was noted in the metacarpophalangeal joints.

Neurological System: Muscle tone was normal globally. Muscle strength was graded as 5/5 in all limbs, indicating substantial recovery from the severe right foot drop (0/5) documented in August. A distinct sensory disturbance was present: pinprick hypersensitivity was observed bilaterally below the mid-tibial level. Vibration sense (tested with a 128-Hz tuning fork) was diminished at both medial malleoli. Light touch sensation was decreased in a stocking distribution up to the mid-shins. Proprioception at the great toes was intact. Temperature sensation was normal. Deep tendon reflexes were symmetrically diminished in all four limbs. Plantar responses were flexor. No meningeal signs were present.

A comprehensive workup was performed to exclude alternative causes of neuropathy and assess disease activity.

Diagnosis: Based on the chronic, deforming polyarthritis, seropositivity, and the exclusion of other causes, the primary diagnosis was refractory seropositive RA. The secondary diagnosis of RA-associated PN was due to an acute-onset, stepwise progressive nerve injury that was confirmed by NCS/EMG. This injury was temporally linked to RA flares and responded positively to immunosuppression, suggesting that it was likely mediated by autoimmune vasculitis.

The diagnosis of RA-associated vasculitic neuropathy was favored based on: (1) temporal correlation with RA disease activity, (2) seropositivity and high inflammatory markers, (3) an asymmetric, multifocal, axonal sensorimotor pattern on serial NCS/EMG, and (4) response to immunosuppression. We actively excluded alternatives: Chronic inflammatory demyelinating polyneuropathy (CIDP)/Lewis-Sumner syndrome (MADSAM) was unlikely due to the absence of demyelinating features (e.g., conduction blocks, severe conduction velocity slowing) across all five studies and the acute, stepwise progression. Post-herpetic radiculopathy was considered, but the neuropathy rapidly evolved beyond the affected dermatome into a multifocal pattern. Guillain-Barré syndrome variants were excluded due to the chronic, relapsing course over months. Drug-induced neuropathy was excluded as no known neurotoxic agents were used at onset. Metabolic causes (diabetes, B12 deficiency, hypothyroidism) were ruled out by laboratory testing.

Given the refractory nature of both arthritis and neuropathy to previous DMARDs and TNF-inhibition, therapy was escalated during the second hospitalization.

The patient expressed profound relief at the stabilization of her condition following years of debilitating and progressive symptoms. She reported a significant improvement in quality of life and the ability to perform daily activities without pain. Informed consent was obtained for the publication of this case report.

Peripheral neuropathy (PN) is a common yet underdiagnosed extra-articular feature of RA, with reported prevalence ranging widely from 10% to over 75%, a variance attributable to differences in diagnostic methods and study populations (4, 5). A significant proportion of cases are subclinical, detectable only through electrophysiological studies (6). The clinical presentations are heterogeneous, encompassing distal symmetric sensory or sensorimotor polyneuropathy (the most common form), mononeuritis multiplex, and entrapment neuropathies like carpal tunnel syndrome (6, 19). Key risk factors for developing PN include longer disease duration, high disease activity (elevated ESR, CRP, DAS-28), seropositivity for RF and ACPA, and the presence of other systemic features such as rheumatoid nodules or vasculitis (6, 8). Our patient’s profile—with a 21-year history of active, seropositive RA, high inflammatory markers, and functional disability—placed her in a high-risk category for severe neuropathic complications.

The pathogenesis of PN in RA is multifactorial. Chronic systemic inflammation being a central driver (10), and pro-inflammatory cytokines directly contributing to neural dysfunction and hyperalgesia (20). A primary and severe mechanism is necrotizing vasculitis of the vasa nervorum (8), leading to ischemic nerve injury, which typically manifests as acute-onset mononeuritis multiplex (8, 9, 21) or asymmetric polyneuropathy with predominant axonal loss on electrophysiology, as seen in our patient. The presence of albuminocytologic dissociation in the CSF of our patient further supports an inflammatory, immune-mediated radiculoneuropathy. Beyond active vasculitis, chronic synovitis can cause compressive neuropathies (6), while longstanding disease and metabolic factors may lead to a distal symmetric axonal neuropathy (6, 7). Importantly, certain DMARDs have also been implicated in inducing or exacerbating PN (14, 22, 23), adding a layer of diagnostic and therapeutic complexity.

High-dose GCs remain a first-line intervention for severe, life- or organ-threatening extra-articular manifestations of RA, including active vasculitis and rapidly progressive PN (11). Their rapid, potent anti-inflammatory and immunosuppressive effects can halt acute immune-mediated nerve damage. In our case, intravenous methylprednisolone therapy was initiated to urgently suppress the presumed vasculitic process driving the stepwise neurological decline.

However, the profound and dose-dependent adverse effects of GCs render their long-term use highly problematic, a concern extensively documented in the provided literature (13, 24). The toxicity profile is broad, encompassing cardiovascular events (hypertension, accelerated atherosclerosis) (13, 24), metabolic disturbances (diabetes mellitus, dyslipidemia) (13, 24), osteoporosis with increased fracture risk (13, 24), osteonecrosis, cataracts, and a significantly elevated risk of serious infections (13, 24). The risk of infections, including opportunistic and reactivation of latent tuberculosis or herpes zoster, is of particular concern in RA patients already on other immunosuppressants (13). Our patient’s history of recent herpes zoster infection prior to presentation highlights this vulnerability.

Expert guidelines strongly advocate for using the lowest effective GCs dose for the shortest possible duration, employing them primarily as a “bridge” to control acute inflammation until a steroid-sparing immunosuppressive agent takes full effect (12, 13, 24). Prolonged use, especially at doses greater than 7.5–10 mg/day of prednisone equivalent, is associated with accrual of irreversible organ damage and increased mortality (12, 13, 24). Therefore, while our initial use of GCs was justified, a definitive, GCs-sparing strategy was imperative. The failure of the patient’s neuropathy to improve significantly on moderate-dose oral prednisone alone underscored the need for a more targeted and potent immunosuppressive agent.

The selection of tocilizumab as the foundational therapy for this case was underpinned by a strong pathophysiological and clinical rationale, informed by the understanding of IL-6’s central role in RA and its systemic complications.

Pathophysiological basis: IL-6 is a pleiotropic cytokine critically involved in the pathogenesis of RA (25, 26). It drives acute-phase responses (e.g., production of CRP and ESR elevation) (25, 27–29), B-cell differentiation into autoantibody-producing plasma cells (25, 26), T-cell activation (25, 26), and osteoclastogenesis, contributing to both joint destruction and systemic inflammation (25, 26). Crucially, IL-6 is a key mediator of endothelial activation and vascular inflammation (26, 30–32), directly implicating it in the development of vasculitic processes that can damage peripheral nerves. In our patient, the presence of severe systemic inflammation, as evidenced by markedly elevated acute-phase reactants (ESR and CRP) in the context of active polyarthritis and progressive neuropathy, is pathophysiologically linked to the overproduction of pro-inflammatory cytokines, notably IL-6 (7, 9, 33). Furthermore, IL-6 is a pivotal mediator of endothelial activation and vascular inflammation (32). It promotes the expression of adhesion molecules, facilitates leukocyte recruitment (30), and contributes to the breakdown of the blood-nerve barrier. In the context of RA, this endothelial dysfunction can culminate in necrotizing vasculitis of the vasa nervorum, leading to ischemic axonal injury (9) – the electrophysiological hallmark of the severe, asymmetric neuropathy observed in our patient. The rapid normalization of acute-phase reactants (ESR, CRP) following tocilizumab initiation not only reflects control of systemic inflammation but also suggests suppression of this IL-6-driven vascular inflammatory process (32), thereby creating a permissive environment for nerve recovery.

In this clinical context, our therapeutic sequence was deliberate. The initial use of intravenous methylprednisolone at 80 mg daily (approximately 1 mg/kg/day, rather than a standard high-dose pulse) served as a critical “bridge” therapy. This intermediate dose aimed to rapidly dampen the severe vasculitic inflammation while minimizing the risk of infection in a patient with recent herpes zoster, providing a window for the definitive steroid-sparing agent to take effect. The subsequent introduction of tocilizumab was therefore strategic, targeting the IL-6 pathway identified as central to her disease pathology. Given the well-established central role of IL-6 in driving synovitis, acute-phase responses, and vascular inflammation in RA, the blockade of the IL-6 receptor with tocilizumab represented a rational and targeted strategy to address the underlying inflammatory drive of both her articular and neuropathic disease (33).

Clinical efficacy in refractory RA and systemic manifestations: Tocilizumab has demonstrated superior efficacy in controlling articular inflammation in RA, including in patients with inadequate response to anti-TNF agents (17, 25, 34). Beyond joints, emerging evidence and case reports suggest its potential benefit in managing various extra-articular manifestations, including vasculitis and systemic inflammation (18, 20). While large randomized trials specifically for PN are lacking, the drug’s ability to comprehensively suppress the inflammatory milieu that fuels vasculitis and neural damage provides a strong therapeutic premise (18, 20, 25). Documented cases describe improvement in RA-related neuropathies and vasculitic skin ulcers following tocilizumab treatment (18, 20).

Advantages over alternative biologics: The patient had previously failed an anti-TNF agent (etanercept). Anti-TNF agents, while effective for arthritis, have a recognized paradoxical effect of potentially inducing or exacerbating demyelinating neuropathies and other autoimmune phenomena in a subset of patients (16). Switching to a biologic with a different mechanism of action was therefore indicated (34). Rituximab (a B-cell depletor) is another effective option for vasculitis (35), but tocilizumab was chosen for its rapid onset of action, its excellent effect on systemic inflammation (as reflected by acute-phase reactants), and its favorable GCs-sparing effect, which aligned with the urgent need to control the disease and taper prednisone quickly (17, 25).

The successful outcome in this case was achieved not by a single drug but through an integrated, sequential treatment strategy (11). The initial high-dose GCs provided immediate immunosuppression to arrest the active vasculitic nerve injury (9–11). Tocilizumab was introduced concurrently as the cornerstone maintenance therapy to provide deep and sustained IL-6 pathway inhibition (11, 17, 25, 34). The subsequent rapid and consistent normalization of ESR and CRP served as an objective biomarker confirming effective control of the systemic inflammatory drive (11, 17, 25, 34).

The clinical correlation was striking: the resolution of arthralgia and the dramatic improvement in neuropathic symptoms (numbness, weakness, and pain) paralleled the biochemical response. The 12-month follow-up nerve conduction study, showing significant improvement, provided objective electrophysiological evidence of nerve repair and functional recovery once the inflammatory insult was removed. This allowed for the successful and safe taper of prednisone to a minimal dose, thereby mitigating the long-term risks associated with GCs therapy. The continued remission on monthly tocilizumab monotherapy underscores the importance of maintaining targeted immunosuppression to prevent relapse of both articular and extra-articular disease.

An important consideration is whether the improvement in neuropathy was a direct effect of tocilizumab on nerve vasculature or secondary to the control of the systemic RA flare. Given the shared pathophysiological driver—IL-6-mediated systemic inflammation and endothelial injury—it is most plausible that tocilizumab simultaneously addressed both phenomena. The striking temporal correlation between IL-6 receptor blockade, normalization of inflammatory markers, and the objective electrophysiological recovery supports the conclusion that suppressing this central cytokine pathway resolved the common inflammatory substrate responsible for both the articular and neuropathic manifestations.