Neurologic manifestations of rheumatoid arthritis

INTRODUCTION — 

Rheumatoid arthritis (RA) is associated with nonarticular manifestations, including neurologic abnormalities. RA is commonly associated with stroke, peripheral polyneuropathy, compression neuropathies, dysautonomia, and sarcopenia; neurologic side effects from the drugs used to treat RA may also occur. Other neurologic manifestations associated with RA, such as central nervous system (CNS) vasculitis and rheumatoid meningitis, are comparatively rare [1].

Neurologic and muscular disorders associated with RA will be reviewed here. Other nonarticular and non-neurologic problems associated with RA are presented separately, including detailed discussions of the clinical manifestations, diagnosis, and treatment of rheumatoid vasculitis:

●(See "Overview of the systemic and nonarticular manifestations of rheumatoid arthritis".)

●(See "Clinical manifestations and diagnosis of rheumatoid vasculitis".)

●(See "Treatment of rheumatoid vasculitis".)

PATHOGENESIS — 

Rheumatoid arthritis (RA) causes neurologic and muscular complications through several mechanisms.

●Rheumatoid synovitis and pannus may compress or invade adjacent structures (including the spinal cord and peripheral nerves), resulting in myelopathy, radiculopathy, and entrapment neuropathies.

●Other neurologic manifestations may be mediated by the chronic inflammation associated with active RA, including autoimmune mechanisms that have not been well elucidated.

●Drugs used to treat RA may be associated with neurologic complications.

The introduction of biologic disease-modifying antirheumatic drugs (DMARDs), along with more aggressive and effective strategies for the treatment of RA, may have led to a reduction in the frequency of many of the neurologic manifestations of RA [2-4].

DRUG-ASSOCIATED EFFECTS — 

Medications utilized to treat rheumatoid arthritis (RA) can lead to various neurologic complications.

As an example, may are associated with opportunistic infections that can potentially affect the central nervous system (CNS) [5]. (See 'Opportunistic infections affecting the central nervous system' below.).

A number of immunomodulatory drugs (eg, methotrexate, rituximab) (table 1) used in the treatment of RA are also associated with posterior reversible encephalopathy syndrome [6,7]. (See "Reversible posterior leukoencephalopathy syndrome", section on 'Immunosuppressive therapy'.)

Other adverse effects associated with specific drugs include the following:

●Nonsteroidal antiinflammatory drugs (NSAIDs) – NSAIDs may result in headaches, drowsiness, and aseptic meningitis. (See "Nonselective NSAIDs: Overview of adverse effects".)

●Glucocorticoids – Glucocorticoids can cause a glucocorticoid-induced myopathy, depression, psychosis, and benign intracranial hypertension. (See "Major adverse effects of systemic glucocorticoids" and "Glucocorticoid-induced myopathy".)

●Antimalarials – Antimalarials, such as hydroxychloroquine, can cause dizziness, headache, tinnitus, seizures, and neuromyopathy. (See "Antimalarial drugs in the treatment of rheumatic disease" and "Drug-induced myopathies".)

●Methotrexate – Methotrexate can cause headaches and impair the ability to concentrate. (See "Major adverse effects of low-dose methotrexate".)

●Sulfasalazine – Sulfasalazine can cause headaches. (See "Sulfasalazine: Pharmacology, administration, and adverse effects in the treatment of rheumatoid arthritis".)

●Leflunomide – Leflunomide is associated with headaches and, less commonly, peripheral neuropathy. (See "Pharmacology, dosing, and adverse effects of leflunomide in the treatment of rheumatoid arthritis".)

●Tumor necrosis factor alpha (TNF-alpha) inhibitors – TNF-alpha inhibitors may increase the risk of demyelinating disorders of the CNS, albeit a very rare complication. Even more rarely, progressive multifocal leukoencephalopathy (PML) and peripheral neuropathy have been reported in patients treated with anti-TNF therapies (as it has with rituximab). (See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects", section on 'Demyelinating disease' and 'Progressive multifocal leukoencephalopathy' below.)

CENTRAL NERVOUS SYSTEM MANIFESTATIONS — 

Disorders of the central nervous system (CNS) as a direct consequence of rheumatoid arthritis (RA) are uncommon, in part due to the widespread use of biologic disease-modifying antirheumatic drugs (DMARDs) [8].

Stroke

●Epidemiology – RA is associated with both an increased risk of stroke and subsequent death from stroke.

A 2021 meta-analysis of 29 cohort studies of patients with RA demonstrated an increased risk of stroke after adjusting for age and sex (relative risk 1.38, 95% CI 1.29-1.48) [9]. Both ischemic and hemorrhagic stroke appear to be increased. A 2008 meta-analysis reported an increase in the risk of death from stroke in patients with RA compared with the general population (weighted-pooled summary estimate of standardized mortality ratios of 1.52, 95% CI 1.40-1.67) [10]. However, both meta-analyses reported significant heterogeneity among the studies analyzed, limiting the ability to draw firm conclusions.

●Stroke mechanism – The mechanism of increased stroke risk in RA is uncertain and likely multifactorial [11]. Both traditional cardiovascular risk factors and markers of RA severity contribute to an increased cardiovascular risk in patients with RA, including for stroke and transient ischemic attack [12-15].

Analogous to coronary artery disease, chronic inflammation has been implicated in accelerated development of cerebrovascular atherosclerosis; inflammation may also worsen insulin resistance and contribute to diabetes-related complications including cerebral small vessel disease and lacunar infarction. RA has also been associated with an increased risk of atrial fibrillation which can lead to embolic stroke. Glucocorticoid and nonsteroidal antiinflammatory drugs (NSAIDS) may also contribute to thrombotic risk [11]. Additionally, patients with RA have an increased risk of herpes zoster infection, which is associated with stroke [16]. CNS vasculitis is rare. These associations are discussed in more detail separately. (See "Coronary artery disease in rheumatoid arthritis: Pathogenesis, risk factors, clinical manifestations, and diagnostic implications", section on 'Pathogenesis' and "Overview of heart disease in rheumatoid arthritis".)

●Primary prevention and management – Improved management of RA is believed to have reduced the overall risk of cardiovascular complications.

Otherwise, stroke prevention and management strategies are similar to that in the general population:

•(See "Overview of primary prevention of cardiovascular disease in adults".)

•(See "Overview of secondary prevention of ischemic stroke".)

•(See "Initial assessment and management of acute stroke".)

Cervical subluxation and myeloradiculopathy — Cervical myeloradiculopathy resulting from atlantoaxial subluxation, atlantoaxial impaction, and/or subaxial subluxation is a potentially serious complication of RA and is discussed separately. (See "Cervical subluxation in rheumatoid arthritis".)

Central nervous system vasculitis — Isolated CNS vasculitis is rare in patients with RA; the literature consists only of case reports of intracranial arteritis associated with RA [17-25].

●Clinical presentation – Headache and mental status changes were the most common reported symptoms among patients with RA presenting with CNS vasculitis [17-27]. Seizures, cranial nerve palsies, blindness, paralysis, dementia, aphasia, gait disorders, and intracranial hemorrhage have also been reported. Fever is not typically present, and blood pressure is usually normal.

Most forms of systemic vasculitis (eg, Anti-neutrophil cytoplasmic antibody [ANCA]-associated vasculitis) are not associated with CNS vasculitis. However, patients with rheumatoid vasculitis, which is typically associated with peripheral ischemia, may rarely develop CNS vasculitis as well.

Isolated spinal vasculitis has also been reported in a patient with longstanding seropositive RA [28].

In most reports, patients with CNS vasculitis had a long duration of erosive, seropositive RA with rheumatoid nodules [17,19-21,23,29,30]. However, not all patients had active synovitis at the time of vasculitis diagnosis.

●Laboratory findings – The erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are typically elevated in patients with RA-associated vasculitis, whereas these tests are typically normal for patients with primary angiitis of the CNS [29]. Systemic rheumatoid vasculitis may cause decreased levels of serum complement C3.

Cerebrospinal fluid (CSF) with high protein, pleocytosis, and low glucose are consistent with CNS vasculitis, but these findings are not specific for this condition, and not all patients exhibit these findings [31].

●Evaluation and treatment – The evaluation and treatment of RA-associated CNS vasculitis are similar to the approach used for treatment of rheumatoid vasculitis. (See "Treatment of rheumatoid vasculitis".)

Rheumatoid nodules — Rheumatoid nodules are most commonly subcutaneous in location; they rarely occur in the CNS.

●Clinical presentation – Rheumatoid nodules are rarely found in the cerebral leptomeninges and within the choroid plexus [22,31-40]. Often an incidental finding, they may rarely present as a mass lesion with focal neurologic findings.

Extradural nodules in the spinal canal may cause nerve root compression, spinal cord compression, and spinal stenosis [41,42].

Most patients with CNS nodules have severe seropositive erosive joint disease, peripheral subcutaneous rheumatoid nodules, high-titer rheumatoid factors, and, less commonly, additional extraarticular features, including pulmonary or ocular involvement [33,35,41].

●Diagnosis and management – These nodules are typically detected by magnetic resonance imaging (MRI), which demonstrates isointense to hypointense T1 signal relative to skeletal muscle with or without contrast enhancement [37,43]. Some nodules may have surrounding edema.

A definitive diagnosis of a rheumatoid nodule requires biopsy, which we would consider only if the patient is symptomatic and/or if surgical decompression is required or there is concern for another treatable disease.

The approach to the diagnosis and management of rheumatoid nodules is discussed elsewhere. (See "Rheumatoid nodules".)

Rheumatoid meningitis — Rheumatoid meningitis, or aseptic meningitis in a patient with RA, is a rare condition characterized by an inflammatory infiltrate of the meninges without distinct rheumatoid nodules [31,44-52]. Most patients have seropositive RA, though the duration of systemic RA can be variable [51,53]. Rheumatoid meningitis has also been associated with tumor necrosis factor (TNF) inhibitor therapy, although these agents are not clearly causal [54-56].

●Clinical, laboratory, and radiologic findings – Symptoms are variable between patients and may include altered mental status, fever, headaches, seizures, cranial nerve dysfunction, and hemiparesis or paraparesis [57]. Fever is more commonly reported than in RA patients with CNS rheumatoid nodules or CNS vasculitis.

Rheumatoid meningitis is detected by MRI, which demonstrates meningeal thickening and/or enhancement [51]. Both the pachymeninges (dura) and the leptomeninges (arachnoid and pia mater) may be involved [53].

Examination of the CSF is performed to exclude infectious and carcinomatous meningitis. Elevated CSF protein is the most common abnormality, but pleocytosis and depressed glucose have also been described. Rheumatoid factor and anti-citrullinated peptide antibodies have been detected in the CSF in a small number of cases, but these tests are not routinely obtained [52,58].

●Diagnosis – Diagnosis is generally made by the combination of systemic RA, a compatible neurologic syndrome and imaging features, and exclusion of other causes such as infections.

Meningeal biopsy can show plasma cells and rheumatoid nodules, but the histopathologic findings may also be nonspecific and range from inflammatory cellular infiltrates to granulomatous disease to vasculitis [58,59].

●Treatment – The optimal therapy for rheumatoid meningitis is unknown but commonly includes high doses of glucocorticoids.

In several case reports, treatment with pulse glucocorticoids (methylprednisolone 250 to 1000 mg intravenously [IV] daily for three days) followed by an oral prednisone taper improved neurologic symptoms [46,47,51,57,60,61]. In another case, a patient with rheumatoid meningitis had resolution of severe seizures and MRI abnormalities after treatment with two doses of rituximab (two infusions of 1 g each, with a two-week interval between infusions) plus methylprednisolone 250 mg IV daily for three consecutive days followed by an oral prednisone taper [49].

Hyperviscosity syndrome — Hyperviscosity syndrome has been reported in a very small number of patients with seropositive RA [62-65]. Affected patients typically have longstanding, active RA, and high titers of rheumatoid factor.

Its neurologic manifestations are similar to those of hyperviscosity occurring in Waldenström macroglobulinemia and include headache, visual changes, vertigo, tinnitus, hearing loss, and cognitive dysfunction [62,63]. Systemic manifestations include bleeding (eg, gastrointestinal, gingival, epistaxis).

This syndrome and its acute management are discussed in greater detail separately. Immunosuppression after acute management reduces the risk of recurrence [62]. (See "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of Waldenström macroglobulinemia", section on 'Hyperviscosity syndrome' and "Treatment and prognosis of Waldenström macroglobulinemia", section on 'Emergency management of hyperviscosity'.)

Opportunistic infections affecting the central nervous system

Progressive multifocal leukoencephalopathy — Progressive multifocal leukoencephalopathy (PML), which is associated with the polyoma John Cunningham (JC) virus, has been reported in rare patients with RA taking immunosuppressive agents, most frequently rituximab. The absolute risk of developing PML in RA is very small.

In an observational study from the United States using a nationwide inpatient sample database, the rate of PML in hospitalized patients with RA was estimated at 0.4 per 100,000 discharges, which is twice the rate in the background population [66]. PML was reported in only two patients with RA prior to their use of biologic DMARDs [67].

In patients with RA, rituximab is the most frequently implicated treatment in the development of PML; however, the estimated absolute risk of PML is only one case per 25,000 patients with RA treated with rituximab [68,69]. There has been at least one case reported in association with use of adalimumab in RA [70], one with infliximab [71], and another in a patient treated with tocilizumab [72]. There have been at least two cases of leukoencephalopathy in an RA patient treated with methotrexate [73,74].

The clinical manifestations and diagnosis of PML and its management are the same in patients with and without RA. (See "Progressive multifocal leukoencephalopathy (PML): Epidemiology, clinical manifestations, and diagnosis" and "Progressive multifocal leukoencephalopathy (PML): Treatment and prognosis".)

Other opportunistic infections — When evaluating a patient with rheumatoid arthritis for a CNS finding, we consider the possibility of other opportunistic infections, including pyogenic and intracellular bacteria (eg, Staphylococcus, Listeria, Nocardia, Salmonella), mycobacteria (tuberculosis), fungi (eg, Cryptococcus, Candida), viruses (eg, herpes virus), and parasites (eg, Toxoplasma, Strongyloides) [75].

Because of concomitant immunosuppression, especially prednisone use, patients with RA may not develop all of the cardinal features of infection (eg, fever).

Opportunistic infections associated with DMARD therapy for RA are discussed in detail elsewhere. (See "Overview of infections associated with immunomodulatory (biologic) agents".)

PERIPHERAL NERVOUS SYSTEM MANIFESTATIONS

Compression or entrapment neuropathy — Entrapment neuropathies are common among patients with rheumatoid arthritis (RA) [76].

Carpal tunnel syndrome — Carpal tunnel syndrome (CTS) is due to compression of the median nerve as it travels through the carpal tunnel of the wrist. In patients with RA, this compression may be due to increased intracarpal pressure in the wrist caused by synovial pannus, joint erosions, or ligamentous laxity.

●Epidemiologic features – A study of 12,312 patients with CTS demonstrated that RA is associated with an increased risk of CTS (odds ratio adjusted for body mass 2.43) [77]. CTS is detected in 6 to 14 percent of patients with RA undergoing electrophysiologic studies [78-81]. There is no correlation between CTS and sex, duration of RA, functional class, the presence of other extraarticular disease, seropositivity, or the level of acute phase reactants [82,83].

●Clinical manifestations, diagnosis, management – Symptoms include paresthesia and pain in a median nerve distribution (figure 1). Findings of atrophy and weakness of the thenar muscles occur with more advanced disease. By contrast, some patients may have electrophysiological findings of median nerve compression at the wrist with minimal clinical symptoms. (See "Carpal tunnel syndrome: Clinical manifestations and diagnosis", section on 'Clinical features'.)

Patients with RA may have symptoms caused by concurrent cervical radiculopathy (also common in RA) with asymptomatic median nerve compression. Also, advancing arthritis in small joints of the hands may simulate weakness in thumb abductor muscles. Hence, the patient's symptoms, the presence of any joint damage or neurologic deficit, and electrophysiological findings must be interpreted in concert for appropriate diagnosis and management.

The clinical manifestations, diagnosis, and treatment of CTS are described in detail elsewhere. (See "Carpal tunnel syndrome: Clinical manifestations and diagnosis" and "Carpal tunnel syndrome: Treatment and prognosis".)

Tarsal tunnel syndrome — Estimates of the prevalence of tarsal tunnel syndrome in patients with RA have ranged from 5 to 33 percent [18-21,84]. However, most of these studies predated the use of biologic disease-modifying antirheumatic drugs (DMARDs); it is unclear if modern therapeutics have made tarsal tunnel syndrome less common.

Symptoms include paresthesia and pain in the sole of the foot and the first through third toes. Findings of atrophy and weakness of the intrinsic foot muscles occur with more advanced disease.

Tarsal tunnel syndrome is due to compression of the tibial nerve as it passes near the medial malleolus [85]. It may result from tenosynovitis, inflammation of the flexor retinaculum, or valgus deformities. (See "Overview of lower extremity peripheral nerve syndromes", section on 'Tarsal tunnel syndrome'.)

The clinical manifestations, diagnosis, and treatment of tarsal tunnel syndrome in patients with RA are described in detail elsewhere. (See "Overview of lower extremity peripheral nerve syndromes", section on 'Tarsal tunnel syndrome'.)

Less common compressive neuropathies — Although unusual, compressive neuropathies other than CTS and tarsal tunnel syndrome have been reported in patients with RA.

Examples of compressive neuropathy in the upper extremities include:

●Median nerve entrapment at the elbow, which causes pronator teres syndrome (ie, discomfort in the forearm and numbness/weakness of the thumb and index fingers). (See "Overview of upper extremity peripheral nerve syndromes", section on 'Pronator teres syndrome'.)

●Ulnar nerve entrapment at the elbow, which causes cubital tunnel syndrome (ie, pain/numbness along the medial aspect of the forearm along with weakness in the intrinsic muscles of the hand). (See "Overview of upper extremity peripheral nerve syndromes", section on 'Ulnar neuropathy at the elbow and wrist'.)

●Ulnar nerve entrapment at the wrist, which causes Guyon canal syndrome (ie, numbness and/or weakness of the fourth and fifth digits) [86]. (See "Overview of upper extremity peripheral nerve syndromes", section on 'Ulnar neuropathy at the elbow and wrist'.)

●Additionally, the anterior and posterior interosseous nerves can be impacted [87-93]. (See "Overview of upper extremity peripheral nerve syndromes", section on 'Anterior interosseous neuropathy' and "Overview of upper extremity peripheral nerve syndromes", section on 'Posterior interosseous neuropathy'.)

Nerves in the lower extremity affected by a compressive neuropathy produce leg weakness and impaired gait (table 2). Those more commonly affected in patients with RA include:

●Femoral nerve palsy complicates distended synovitis of the hip and may lead to sensory and motor defects [94]. (See "Overview of lower extremity peripheral nerve syndromes", section on 'Femoral nerve'.)

●The common peroneal and tibial nerves may be compressed by a popliteal cyst, which may form in response to RA. (See "Popliteal (Baker's) cyst" and "Overview of lower extremity peripheral nerve syndromes", section on 'Fibular (peroneal) nerve'.)

Compressive neuropathies may also develop coincident with other neurologic issues, which may make their diagnosis more challenging [87].

The evaluation of compressive neuropathies, as well as other neuropathies affecting the extremities, are described in detail elsewhere. (See "Overview of upper extremity peripheral nerve syndromes", section on 'Overview of diagnostic testing' and "Overview of lower extremity peripheral nerve syndromes", section on 'Diagnostic testing'.)

Distal polyneuropathy — The prevalence of peripheral polyneuropathy among patients with RA since the introduction of biologic DMARDs is unclear.

●Clinical presentation – Distal sensory neuropathy typically presents in a slowly progressive fashion and may adopt one of the following patterns:

•Symmetric paresthesias and burning sensations, which tend to be worse in the feet than in the hands [89,95,96]

•Discomfort that may be difficult to distinguish from myalgia and arthralgia but is neuropathic in origin [89,95]

•Decreased vibratory, pinprick, and light touch sensation

•Decreased or absent deep tendon reflexes and abnormalities of both sensory and motor nerve conduction [95,97]

In one study of 25 patients, neuropathy usually developed after the arthritis, and there was no relation between duration of RA and neuropathy [95]. It is not associated with rheumatoid vasculitis.

●Evaluation – Electrodiagnostic studies are useful to characterize the neuropathy. In these patients, neuropathic abnormalities detected by nerve conduction and electromyography (EMG) studies are most often axonal, although demyelinating features are sometimes present [79,98].

The yield of sural nerve biopsy is low, given the mild pathologic changes and patchy distribution of lesions. However, sural nerve biopsy may demonstrate a mild proliferative endarteritis or normal vasculature with segmental demyelination and remyelination and areas of axonal degeneration [97,99]. There may also be a mild loss of predominantly large myelinated fibers [88,95].

Pathologic findings range from normal histopathology to perineural thickening to vasculopathy, and rarely, vasculitis or amyloidosis, suggesting these neuropathies have varied pathogenesis [79,89,92,95,97,99,100].

Other causes of polyneuropathy should be considered and excluded. The evaluation of polyneuropathy is described in detail elsewhere. (See "Overview of polyneuropathy", section on 'Diagnostic evaluation'.)

●Management – Most patients with RA and polyneuropathy are treated symptomatically for neuropathic pain with medications and nonpharmacologic approaches. (See "Overview of pharmacologic management of chronic pain in adults", section on 'Pharmacologic therapy for neuropathic or nociplastic pain' and "Management of diabetic neuropathy", section on 'Topical therapies or neuromodulation'.)

In patients with clearly progressive neuropathy, use of immunomodulation by both biologic and nonbiologic agents may be appropriate based upon evidence of efficacy in autonomic neuropathy [101]. Intravenous immunoglobulin may also be used as an adjunct to existing RA therapy extrapolating from treatment of other inflammatory neuropathies.

Other forms of polyneuropathy — Severe pain, significant weakness, and multiple mononeuropathies are typical manifestations of rheumatoid vasculitis-associated neuropathy. Aside from multiple mononeuropathy presentation, vasculitic neuropathy also often affects distal nerves and can cause a painful, progressive, seemingly confluent neuropathy. Electrodiagnostic studies are required to characterize the neuropathy and generally show asymmetry. (See "Overview of polyneuropathy", section on 'Diagnostic evaluation' and "Clinical manifestations and diagnosis of vasculitic neuropathies".)

The diagnosis and management of rheumatoid vasculitis is discussed elsewhere. (See "Clinical manifestations and diagnosis of rheumatoid vasculitis" and "Treatment of rheumatoid vasculitis".)

Dysautonomia — Autonomic nervous system dysfunction has been detected by a variety of tests in many patients with RA [102-105]. The clinical significance of these observations is uncertain; many patients are asymptomatic. Furthermore, dysautonomic symptoms may not correlate with abnormalities on autonomic testing.

Dysautonomia is associated with several clinical manifestations, including orthostatic hypotension, postural tachycardia syndrome, urinary dysfunction, erectile dysfunction, anhydrosis, and constipation. In one systematic review, the authors noted a distinct clinical profile of impaired cardiovascular reflexes and low heart rate variability, suggesting reduced cardiac parasympathetic activity [105].

The mechanism of autonomic dysfunction in RA is uncertain. Some studies suggested a role for autoimmunity, inflammation, and/or vasculitis; markers of RA disease activity appear to correlate with the presence and severity of dysautonomia [103-106]. Medications and comorbidities may also play a role.

Specific syndromes are evaluated and treated symptomatically, for example:

●(See "Mechanisms, causes, and evaluation of orthostatic hypotension".)

●(See "Postural tachycardia syndrome", section on 'Autonomic testing'.)

●(See "Evaluation of male sexual dysfunction" and "Treatment of male sexual dysfunction".)

In one case series including 42 patients with RA, initiation of DMARDs was associated with improvement on autonomic testing [101].

MUSCLE MANIFESTATIONS

Sarcopenia — Sarcopenia, or loss of skeletal muscle mass, is reported in approximately 15 to 30 percent of patients with rheumatoid arthritis (RA) [107,108].

Sarcopenia may be caused by disuse atrophy due to pain, joint damage, active joint inflammation associated with RA, and corticosteroid associated myopathy. Chronic inflammation due to RA may directly impair muscle function via effects on muscle metabolism and adipose tissue [109]. However, muscle biopsy reveals type II fiber atrophy; there is no muscle inflammation, necrosis, regeneration, or vasculitis [99,110-112].

●Risk factors – Risk factors for sarcopenia include the presence of rheumatoid factor, joint deformities, elevated C-reactive protein (CRP), self-reported disability, longer disease duration, osteoporosis, older age, and increased body mass index [113-115].

●Clinical manifestations – Symptoms include a decrease in skeletal muscle strength or physical performance as well as loss of muscle mass [116]. Typical complaints are slowness of motion, generalized weakness, gait imbalance, difficulty climbing stairs, and/or difficulty lifting moderate weights [117]. Longstanding glucocorticoid use may cause similar symptoms but also causes ectopic fat deposition, which is not a feature of RA-related sarcopenia.

●Treatment – Effective treatment requires medical therapy for RA to control joint inflammation and reduce pain to enable implementation of an appropriate strengthening exercise program as well as a healthy diet. The use of strength training is described in detail elsewhere. (See "Nonpharmacologic therapies for patients with rheumatoid arthritis", section on 'Physical activity and exercise'.)

Myositis overlap syndrome — Very infrequently, inflammatory myositis can occur as part of an overlap syndrome with RA [118,119]. Such patients present with symmetric, progressive proximal muscle weakness and elevated creatine kinase. (See "Overview of and approach to the idiopathic inflammatory myopathies", section on 'Overlap syndromes'.)

In patients with RA, histopathology shows variable levels of myofiber necrosis and regeneration, with focal or diffuse infiltration of lymphocytes, plasma cells, and mononuclear cells into the endomysium, perimysium, and perivascular areas [99,110,111,120]. Laboratory testing may not demonstrate myositis-specific antibodies.

The muscle disease of patients with RA-myositis overlap is diagnosed and managed using the same strategies developed for the idiopathic inflammatory myopathies, which are discussed in detail elsewhere. (See "Initial treatment of dermatomyositis and polymyositis in adults".)

SUMMARY AND RECOMMENDATIONS

●Central nervous system (CNS) manifestations

•Stroke – The risk of ischemic and hemorrhagic stroke is somewhat increased in patients with RA; stroke mechanisms, acute management, and primary and secondary prevention strategies are similar to patients without RA.

•Uncommon CNS manifestations – Other disorders of the CNS that are associated with RA include cervical myelopathy from atlantoaxial subluxation, atlantoaxial impaction, and/or subaxial subluxation; CNS vasculitis; rheumatoid nodules; rheumatoid meningitis; and the hyperviscosity syndrome. These are more likely in patients with poorly controlled or undertreated disease. (See 'Central nervous system manifestations' above.)

When evaluating a patient with CNS manifestations, it is important to remember that opportunistic infections may present with atypical clinical manifestations in patients receiving chronic immunosuppression. These infections include bacteria, mycobacteria, fungi, viruses, parasites, and progressive multifocal leukoencephalopathy (PML). (See 'Opportunistic infections affecting the central nervous system' above.)

In addition, adverse effects of drugs (eg, encephalopathy, reversible posterior leukoencephalopathy) may be responsible for some CNS manifestations. (See 'Drug-associated effects' above.)

●Peripheral nervous system manifestations – Patients with RA are at higher risk for certain compression neuropathies, particularly carpal tunnel and tarsal tunnel syndrome.

A distal polyneuropathy may also occur in some patients with RA.

Pain, rapidly progressive neuropathy, or multifocal mononeuropathy may occur in a patient presenting with rheumatoid vasculitis. (See 'Peripheral nervous system manifestations' above.)

●Muscle disease – Sarcopenia or loss of skeletal muscle mass is common in patients with RA and may be associated with weakness. It is likely multifactorial in its pathogenesis; glucocorticoid myopathy is an alternative diagnosis in patients receiving chronic glucocorticoid therapy. (See 'Sarcopenia' above.)

Very infrequently, inflammatory myositis can occur as part of an overlap syndrome with RA. (See 'Myositis overlap syndrome' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Peter H Schur, MD, who contributed to earlier versions of this topic review.