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Rheumatoid arthritis: neurologic manifestations …
- Updated 06.19.2024
- Released 12.04.2001
- Expires For CME 06.19.2027
Rheumatoid arthritis: neurologic manifestations
Introduction
Overview
Rheumatoid arthritis is a systemic autoimmune disease that can potentially affect any organ. Neurologic complications are well recognized, causing distinct increases in morbidity and mortality. Multidisciplinary conservative therapies include disease activity control with disease-modifying antirheumatic drugs, glucocorticoids, and new biological agents, in addition to symptomatic treatments. Neurologic complications of newer biological therapies and immunosuppressive drugs represent an increasing clinical challenge. Physical and occupational therapies also have a role.
Key points
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• Degenerative disease of the cervical and lumbar spine is a common manifestation in rheumatoid arthritis. | |
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• Entrapment neuropathies are common in rheumatoid arthritis, and patients with rheumatoid arthritis are at increased risk of such neuropathies compared to the general population. | |
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• Neurologic complications of newer biological therapies and immunosuppressive drugs are an increasing concern. |
Historical note and terminology
Neurologic complications of rheumatoid arthritis have been known for many years. In the 19th century, Piters and Villard and later Bannatyne described infiltration of small round cells in the nerve sheath, in the perivascular region, and among nerve fibers, as well as thickening of intima of blood vessels with encroachment on the vascular luminal wall. In 1942 Freund and colleagues reviewed the earlier reports on the rheumatoid arthritis neuropathy and reported “perineuritic nodules” in autopsied specimens of patients with rheumatoid arthritis. These nodules consisted of chronic inflammatory cells in peripheral nerves. However, the significance of these observations was unknown until Ball described the presence of systemic arteritis that included peripheral neuropathy, which could complicate rheumatoid arthritis. Three years later, Hart and colleagues reported 10 rheumatoid arthritis patients with peripheral neuropathy and attributed it to diffuse arteritis (16). Neuropathy, therefore, was considered as an important complication of rheumatoid arthritis. Lastly, Ferguson and Slocumb indicated that development of peripheral neuropathy in rheumatoid arthritis has prognostic values (13). In their view, rheumatoid arthritis patients with peripheral neuropathy due to vasculitis had decreased survival compared to patients without neuropathy. With introduction of modern neurology in the last 25 years, other neurologic complications of rheumatoid arthritis such as cerebral vasculitis and cervical myelopathy have also been recognized.
Clinical manifestations
Presentation and course
Rheumatoid arthritis is a chronic inflammatory arthropathy, often occurring as part of a more systemic immunopathological syndrome, of unknown etiology. It is characterized by persistent inflammatory synovitis that usually involves peripheral joints in a symmetric distribution. The hallmark of rheumatoid arthritis is synovial inflammation that causes cartilage destruction, bone erosion, and subsequent alterations of joint structure. The course of rheumatoid arthritis can be variable. Some patients have only a mild oligoarticular disease of short duration with minimal joint damage, whereas a larger group of patients experience a destructive and progressive disease with remarkable functional impairment. Other patients manifest involvement of other organ systems including the nervous system. The 1987 revised criteria for the classification and diagnosis of rheumatoid arthritis are presented in Table 1.
Table 1. American College of Rheumatology Revised Criteria for Diagnosing Rheumatoid Arthritis
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Guidelines for classification: | ||
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• At least four of the seven criteria are required to classify a patient as having rheumatoid arthritis. | ||
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Criteria: | ||
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• Morning stiffness* | ||
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- Rheumatoid nodules | ||
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* Must be present for at least 6 weeks | ||
In two thirds of patients, rheumatoid arthritis manifests with systemic presentations such as fatigue, anorexia, generalized weakness, and vague musculoskeletal symptoms followed by synovitis. This prodrome may last for weeks or months before specific symptoms appear. The specific symptoms of rheumatoid arthritis gradually develop and involve several joints, especially those of the hands, wrists, knees, and feet in a symmetric fashion. In approximately 10% of patients, the onset of rheumatoid arthritis is more acute, with a rapid manifestation of polyarthritis, frequently accompanied by constitutional symptoms such as fatigue, lymphadenopathy, and splenic enlargement. In one third of individuals, symptoms may be limited to one or a few joints.
Synovitis causes swelling, tenderness, and restriction of movement of joints. Joint swelling is due to accumulation of synovial fluid associated with inflammation, synovial hypertrophy, and thickening of joint capsule. Pain predominantly originates from the joint capsule, which is richly supplied by pain fibers and is sensitive to distension. Rheumatoid arthritis most frequently affects specific joints such as the proximal interphalangeal and metacarpophalangeal joints. Synovitis of the wrist joint is almost a uniform feature of rheumatoid arthritis and leads to restriction of motion, deformity, and median nerve entrapment (carpal tunnel syndrome). Synovial inflammation of the elbow joint may appear early in the course of disease. The knee joint is often affected with synovial hypertrophy, effusion, and ligamentous laxity. Arthritis in the forefoot, ankles, and subtalar joints can cause severe pain during ambulation. Axial involvement is generally limited to the cervical spine. Using pulsed arterial spin labeling MRI technique joint pain seems to involve neural processing in the medial frontal cortex (26).
Persistent inflammation of the joints leads to a number of characteristic joint deformities. These can be attributed to a variety of pathologic events, including laxity of supporting soft tissue structures (weakening of ligaments, tendons, and the joint capsule) cartilage degradation, and muscle imbalance.
Extra-articular manifestations of rheumatoid arthritis. Rheumatoid arthritis is a systemic disease with a number of extra-articular manifestations. Generally, they occur in patients with high titers of autoantibodies to the Fc component of immunoglobulin G (rheumatoid factors). Extra-articular manifestations of rheumatoid arthritis are present in 10% to 20% of patients. These extra-articular sites include skin (livido reticularis, purpura, skin infarcts, and ulcerations), heart (pericarditis, myocarditis, endocarditis, and coronary vasculitis), lung (pulmonary nodules, pleuritis, and interstitial disease), eye (episcleritis and keratoconjunctivitis sicca), and the nervous system. In patients with advanced rheumatoid arthritis, almost all organs are affected. Of these various complications, we will only focus on nervous system involvement in rheumatoid arthritis. Neurologic complications of rheumatoid arthritis may occur in the central or peripheral nervous systems (see Table 2). Involvement of the peripheral nervous system is the most common clinically manifest neurologic complication of rheumatoid arthritis, but the frequency of cervical spine abnormalities is underestimated.
Table 2. Neurologic Complications of Rheumatoid Arthritis
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Central nervous system and psychiatric complications | ||
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• Aseptic meningitis | ||
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Spinal stenosis | ||
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Peripheral nervous system | ||
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• Compression/entrapment neuropathies | ||
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- Carpal tunnel syndrome | ||
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- Tarsal tunnel syndrome | ||
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• Demyelinating neuropathy | ||
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• Demyelinating neuropathy due to TNF-alpha inhibitors | ||
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• Sensory/sensorimotor polyneuropathy | ||
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• Vasculitic neuropathy (mononeuritis multiplex) | ||
Central nervous system manifestations. Central nervous system vasculitis and aseptic meningitis are rare manifestations of rheumatoid arthritis. They may each present in isolation or concurrently. They can present with mental status changes, focal neurologic deficits, headaches, or seizures (47). The average age of onset is 62 years, and it tends to occur later in the course of the disease. However, in 17% of patients it can be the presenting manifestation of rheumatoid arthritis. Active systemic disease is present in only one third of cases. MRI can show pachymeningeal or leptomeningeal involvement, as well as cerebral infarcts (12).
Conventional angiography is the most sensitive imaging modality in detecting vasculitis; magnetic resonance and CT angiography can also be helpful, less invasive alternatives in diagnostically challenging cases. Meningeal biopsy can show lymphocytic infiltration, findings of vasculitis, or rheumatoid nodules (12). Serological testing shows elevated erythrocyte sedimentation rate, C-reactive protein, rheumatoid factor, and cyclic citrullinated protein antibodies in the majority of cases, whereas cerebrospinal fluid testing typically shows lymphocytic pleocytosis (47).
Response to treatment with high-dose corticosteroids, methotrexate, azathioprine, or rituximab has been reported; maintenance treatment is often required. TNF-alpha inhibitors should be avoided in cases with rheumatoid arthritis and aseptic meningitis as there have been reported cases of TNF-alpha-induced aseptic meningitis (07).
Spinal stenosis. Cervical spine degenerative disease in the form of cervical spine instability, or spinal stenosis due to pannus formation or degenerative arthritis, is a common manifestation of rheumatoid arthritis, which can be seen early in the course of the disease (42). Although upper cervical spinal stenosis, such as atlantoaxial subluxation or stenosis, is considered a typical manifestation of rheumatoid arthritis, patients with rheumatoid arthritis are at higher risk of developing cervical spinal stenosis at subaxial levels as well. In fact, subaxial cervical spinal stenosis is more frequently encountered among patients with rheumatoid arthritis than atlantoaxial stenosis (32).
Longstanding disease and increased disease activity have been associated with an increased risk of developing more severe degenerative cervical spine disease (04; 27). Earlier initiation of treatment and the use of more effective disease-modifying treatments may reduce its frequency and severity (40).
Cervical spinal stenosis and spine instability in rheumatoid arthritis can be the result of erosive arthritis leading to accelerated degenerative joint disease, whereas upper cervical stenosis at the atlantoaxial level can be the result of pannus formation (42).
Presentation can vary from asymptomatic to nonspecific musculoskeletal complaints, such as neck pain or limited neck range of motion. Symptoms of cervical radiculopathy vary depending on the anatomical distribution of root involvement and can include arm pain; paresthesia, which are often positional; or arm weakness. Upper cervical radiculopathy, as a result of C2 to C4 root impingement, can present with posterior headaches, anterior or posterior neck paresthesia, or external auricular paresthesia. Symptoms of myelopathy include arm weakness or paresthesia, impaired hand dexterity, gait instability or frequent falls, bladder urgency, or incontinence. In cases of more severe myelopathy, proximal leg sensory symptoms and leg weakness can occur. Upper cervical spinal stenosis resulting in cervicomedullary junction involvement can present with lower facial paresthesia due to spinal trigeminal nucleus involvement or lower brainstem symptoms, such as Lhermitte sign, vertigo, or dysphagia. However, dysphagia can also occur as a result of larger anterior vertebral osteophytes compressing the esophagus.
Exam findings of cervical radiculopathy can include sensory loss or weakness following a dermatomal or myotomal distribution, respectively, as well as hypoactive or absent deep tendon reflexes in the arms. Presence of hyperreflexia, including Hoffman or Babinski sign; more diffuse weakness or sensory loss; Romberg sign; and a wide-based, unsteady gait can be features of myelopathy and suggest more severe spinal stenosis. However, these can be presenting manifestations of cervical spine involvement in cases of cervical spine degenerative disease without associated prominent pain or sensory symptoms.
Lumbar spine degenerative disease is also more frequently encountered in rheumatoid arthritis compared to the general population and seems to be associated with increased disease activity (44). Patients with rheumatoid arthritis may also have more progressive degenerative spine disease; rheumatoid arthritis has been identified as a risk factor for reoperation and lumbar fusion within 2 years after lumbar laminectomy (15). Symptoms can range from asymptomatic to back pain with associated radicular pain, leg weakness, paresthesia, and, in more severe cases, neurogenic claudication and sphincter involvement. Exam findings can include sensory loss or weakness following a radicular distribution and hypoactive or absent leg reflexes. In severe cases, gait instability can ensue due to deafferentation.
Peripheral neuropathy. Peripheral neuropathies are commonly encountered among patients with rheumatoid arthritis. These are often the result of peripheral nerve entrapment. Less commonly, patients with rheumatoid arthritis can present with axonal sensory or sensorimotor polyneuropathy (01). Vasculitic neuropathy in the form of mononeuritis multiplex can be seen in severe, untreated rheumatoid arthritis, although this is a rare manifestation with the more regular use of effective disease-modifying treatments. Demyelinating neuropathy (chronic inflammatory demyelinating polyneuropathy) is rarely seen in patients with rheumatoid arthritis (01) and usually represents a coexisting inflammatory neuropathy rather than a manifestation of rheumatoid arthritis; however, demyelinating neuropathy can be seen as a complication of TNF-alpha inhibitor use (36).
By far the most common peripheral neuropathy in rheumatoid arthritis is carpal tunnel syndrome. The association between carpal tunnel syndrome and rheumatoid arthritis has been well known and has been re-demonstrated in recent studies (38; 48). Its frequency is estimated to be up to 30% of patients with rheumatoid arthritis in one study (20), whereas another study reported a 3-fold risk of developing carpal tunnel syndrome in patients with rheumatoid arthritis compared to the general population (41). Similar to the general population, the second most common peripheral nerve entrapment is ulnar neuropathy at the elbow. Ulnar nerve entrapment at the wrist, at Guyon canal, can also be seen but rarely.
Carpal tunnel syndrome manifests as pain or paresthesia typically affecting the lateral palm and lateral three fingers; at times, symptoms may involve the hand more diffusely. These tend to be exacerbated with physical activities involving repetitive hand use. On exam, Tinel sign at the wrist is typically present, whereas thenar atrophy and weakness in the abductor pollicis brevis can be seen in more severe cases. Ulnar neuropathy at the elbow typically presents with medial hand paresthesia and hand weakness in more severe cases. Exam findings can include sensory loss in the fifth digit, with splitting of the fourth digit due to its dual sensory innervation by the median and ulnar nerve; Tinel sign at the elbow; and ulnar distribution hand weakness in more severe cases. Tarsal tunnel syndrome, presenting as exertional pain in the sole, is a less common entrapment neuropathy in the general population. This has also been reported in higher frequency in patients with rheumatoid arthritis (18). However, given the lack of standardized electrodiagnostic criteria for the diagnosis of tarsal tunnel syndrome as well as the multiple mimics that are also frequently present in rheumatoid arthritis, including lumbar radiculopathy, polyneuropathy, or musculoskeletal origin symptoms, this can be more difficult to definitively diagnose than other entrapment neuropathies.
Symptoms and signs of polyneuropathy include sensory symptoms and deficits, weakness, and hypoactive or absent deep tendon reflexes. These typically have distal onset with slow, proximal expansion over time and symmetric distribution. Wide-based, unsteady gait can be seen in more severe cases. Demyelinating neuropathy can present with progressive, diffuse, or multifocal weakness; sensory loss; and gait instability. Mononeuritis multiplex typically presents with acute/subacute onset, stepwise progressing, painful motor and sensory deficits following individual nerve distributions. This usually occurs in the context of active, untreated rheumatoid arthritis and is usually accompanied by constitutional symptoms and other manifestations of active systemic disease. However, over time, confluent neurologic deficits due to mononeuritis multiplex can mimic a distal symmetric polyneuropathy.
Prognosis and complications
Neurologic complications of treatment of rheumatoid arthritis. Infectious complications, including those that involve the nervous system, of classical immunosuppressive therapy with corticosteroids, and cytotoxic and cytotoxic agents, are well recognized and occur in patients with rheumatoid arthritis. These include infections with mycobacteria, fungi, and viruses. Included in these complications are lymphomas, some involving the CNS along with other organs, including those caused by viruses, particularly with Epstein-Barr virus (31). Although monoclonal antibodies are more focused in their effects on the immune system than corticosteroids and agents such as cyclophosphamide, azathioprine, methotrexate, and mycophenolate mofetil, they clearly have immunosuppressive effects and are associated with an increase in infections including progressive multifocal encephalopathy (PML).
PML has been reported with treatment with several of the monoclonal antibodies used in rheumatologic autoimmune disorders including rheumatoid arthritis (03). There is no proven effective therapy for PML, and discontinuation of the suppressive therapy is advisable. When plasma exchange has been used to reduce circulating levels of natalizumab in patients with multiple sclerosis who have or are suspected to have PML, some patients develop immune reconstitution inflammatory syndrome (IRIS) (39).
TNF-alpha inhibitors have been shown to increase risk of relapse and worsen neurologic outcomes in patients with multiple sclerosis. Their use has also been implicated in the development of demyelinating disease in the absence of a history of multiple sclerosis. These can present as optic neuritis, clinically isolated syndrome, or multiple sclerosis–like disease, more often after infliximab, etanercept, or adalimumab use (23). However, population-based studies suggest that the risk of central demyelination with TNF-alpha inhibitors may be less than previously estimated (28). A study conducted in Denmark showed no association of TNF-alpha inhibition with the development of neuroinflammatory complications (22). The majority of cases occur within the first year from treatment initiation (23; 28), and neurologic symptoms tend to improve or stabilize without requiring treatment in the majority of patients (23; 28). Demyelinating peripheral neuropathy has also been described in association with TNF-alpha inhibitors, usually in the form of chronic inflammatory demyelinating polyradiculoneuropathy (02). Contrary to central demyelinating syndromes, demyelinating neuropathies associated with TNF-alpha inhibitors progress even after withdrawal of the offending agent. Response to steroids is suboptimal, and long-term treatment with intravenous immunoglobulin is required (02).
Biological basis
Etiology and pathogenesis
The cause of rheumatoid arthritis is unknown. It has also been hypothesized that rheumatoid arthritis is a manifestation of the response to an infectious agent in a genetically susceptible individual. Because rheumatoid arthritis has a worldwide distribution, this agent must be ubiquitous. Alternatively, if the disease is triggered by an infection, different infectious agents could be involved. In Guillain Barre syndrome, more than one agent has been associated with this disorder. A number of possible causative agents have been suggested, including mycoplasma, Epstein-Barr virus, cytomegalovirus, parvovirus, and rubella virus, but solid evidence in favor of any of these candidates is lacking. The role of “superantigens” in pathogenesis of rheumatoid arthritis remains speculative.
Another controversial issue is the process by which an infectious agent might cause chronic inflammatory arthritis in susceptible hosts. It is possible that persistent infection of articular structures or retention of microbial products in the synovial tissues generates a state of chronic inflammatory response and immune activation. Another hypothesis is that the microorganism or response to the microorganism might induce an immune response to components of the joints by changing its integrity and revealing antigenic self-peptides that are usually buried. In this regard, reactivity to type II collagen and heat shock protein has been shown in rheumatoid arthritis. A third hypothesis suggests that an infecting microorganism may prime the host to cross-reactive determinants expressed within the joint as a result of “molecular mimicry.” Evidence of similarity between the human leukocyte antigen-DR4 molecule itself and products of certain gram-negative bacteria and Epstein-Barr virus has lent support to this possibility. The final hypothesis is that products of the infecting microorganism, such as hsp65 class of heat shock protein of E. coli, may induce rheumatoid arthritis. Though external events such as surgery or trauma, infections, or childbirth seem to trigger the onset of rheumatoid arthritis, a clear relationship has not been established.
Synovial inflammation is central to the pathophysiology of rheumatoid arthritis. Synovitis of rheumatoid arthritis is characterized by microvascular injury along with hyperplasia and hypertrophy of the synovial lining cells. This is followed by perivascular infiltration of mononuclear cells consisting of human leukocyte antigen-DR-positive antigen presenting cells in close contact with T cells, most of which express the helper/memory phenotype (CD4+CD45+) and belong to the T helper Th1 type (35). Other histopathologic features are vascular thrombosis, microvascular injury, neovascularization, and edema of the synovial membrane (25).
Genetic studies have demonstrated an association between rheumatoid arthritis and MHC class II antigens human leukocyte antigen-DRB1*0404 and DRB1-*0401. Human leukocyte antigen class II molecules on macrophages and dendritic cells present specific antigen peptides to CD4+ T cells. The antigen could be either an exogenous antigen, such as viral protein, or an endogenous protein. Possible endogenous antigens include citrullinated protein (keratin, profilaggrin, and filaggrin), human cartilage protein glycoprotein 39, and heavy-chain-binding protein (08).
Scattered throughout the inflamed tissue are both CD4+ and CD8+ T cells, which express the early activation antigen, CD69. Besides the T cells, a variable number of activated B cells and antibody-producing plasma cells are also present. The activation of B cells by CD4+ T cells occurs through cell-surface contact and through binding of alphaL-beta2 integrin, CD154 (CD40 ligand), and CD28. Both polyclonal immunoglobulin and the autoantibody rheumatoid factor are produced inside the synovium, which results in the local formation of immune complexes. Rheumatoid factors are autoantibodies reactive with the Fc portion of IgG and are found in the sera of approximately 80% of rheumatoid arthritis patients. Rheumatoid factor is a prominent constituent of immune complexes in the sera and synovial fluids, synovial tissue, and cartilage. Lastly, the activated synovial fibroblasts produce a variety of enzymes such as collagenase, cathepsins, and matrix metalloproteinases that can degrade the articular matrix.
Activated lymphocytes, macrophages, and fibroblasts produce cytokines and chemokines that appear to account for many of the histopathologic and clinical manifestations of rheumatoid arthritis synovitis. These effector molecules include T cell products such as interleukin-2, interferon-gamma, interleukin-6, interleukin-10, interleukin-13, interleukin-16, interleukin-17, granulocyte-macrophage colony stimulating factor, tumor necrosis factor-alpha, transforming growth factor-beta; activated myeloid cell products, such as interleukin-1, tumor necrosis factor-alpha, interleukin-6, interleukin-8, interleukin-10, interleukin-12, granulocyte-macrophage colony stimulating factor, macrophage CSF, platelet-derived growth factor, insulin-derived growth factor, and transforming growth factor-beta; and synovial endothelial cell and fibroblast products, such as interleukin-1, interleukin-6, interleukin-8, granulocyte-macrophage colony stimulating factor, interleukin-15, interleukin-16, interleukin-18, and macrophage-CSF.
In addition to the generation of proinflammatory cytokines that propagate the inflammation, anti-inflammatory pathways are also being activated during the course of rheumatoid inflammation by release of various cytokines and mediators such as interleukin-1 receptor antagonist, soluble tumor necrosis factor-alpha p75 and p55 receptors, soluble interleukin-1 receptor type I and receptor type II, interleukin-10, interleukin-11, interleukin-13, and interleukin-16. Clearly, the ongoing anti-inflammatory pathways are insufficient to down-regulate the inflammation in many patients.
Epidemiology
The prevalence of rheumatoid arthritis in the United States is 0.8% of the population. All races are affected, and women are three times more likely than men to be affected. In older patients, the prevalence increases but the sex difference decreases. The onset of rheumatoid arthritis is most often during the fourth or fifth decade of life. The extra-articular manifestations of rheumatoid arthritis can occur at any age after onset. Siblings of affected individuals are two to four times more likely to develop rheumatoid arthritis than are unrelated persons (30).
Genetic studies have demonstrated a genetic predisposition. Genes in the major histocompatibility complex have been linked with rheumatoid arthritis in addition to their potential genetic markers that may confer susceptibility to rheumatoid arthritis independently of the major histocompatibility complex (33). Monozygotic twins are four times more likely to be concordant for rheumatoid arthritis than dizygotic twins, who have a similar risk of developing rheumatoid arthritis as nontwin siblings. Only 15% to 20% of monozygotic twins are concordant for rheumatoid arthritis, a point that implies the role of other nongenetic factors in the pathogenesis of rheumatoid arthritis.
The highest risk of concordance for rheumatoid arthritis is observed in twins who have two human leukocyte antigen-DRB1 alleles known to be associated with rheumatoid arthritis. The class II major histocompatibility complex allele human leukocyte antigen-DR4 and related alleles are major genetic risk factors for rheumatoid arthritis. Earlier studies have demonstrated that as many as 70% of patients with classic rheumatoid arthritis carry human leukocyte antigen-DR4 compared to 28% of control individuals. Various populations such as North American and European whites, Japanese, and native populations of India, Mexico, South America, and Southern China have demonstrated the association between human leukocyte antigen-DR4 and rheumatoid arthritis. However, such an association has not been detected in other populations such as Israeli Jews and Asian Indians. There is an association between human leukocyte antigen-DR1 and rheumatoid arthritis in Israeli Jews.
From a molecular viewpoint, human leukocyte antigen-DR consists of two chains, alpha and beta. The alpha chain is nonpolymorphic, whereas the beta chain is highly polymorphic. Differences in the amino acids of the beta chain are responsible for allelic variations in the human leukocyte antigen-DR molecule. The major amino acids are located in the three hypervariable regions of the molecule. Each of the human leukocyte antigen-DR molecules associated with rheumatoid arthritis has a similar sequence of amino acids in the third hypervariable region of the beta chain of the molecule. The beta chains of the human leukocyte antigen-DR molecules clustered with rheumatoid arthritis, including human leukocyte antigen-Dw4 (DRB1*0401), human leukocyte antigen-DRw14 (DRB1*0404), human leukocyte antigen-Dw15 (DRB1*0405), human leukocyte antigen-DR1 (DRB1*0101), and human leukocyte antigen-Dw16 (DRB1*1402), contain the same amino acids at positions 67 through 74, with the exception of a single change of one basic amino acid for another (arginine--> lysine) in position 71 of human leukocyte antigen-Dw4 (37). All other human leukocyte antigen-DR beta chains have amino acid changes in this region that change either their charge or hydrophobicity. These findings indicate that a particular amino acid sequence in the third hypervariable region of the human leukocyte antigen-DR molecule is a major genetic component conveying susceptibility to rheumatoid arthritis, regardless of whether it happens in human leukocyte antigen-DR4, human leukocyte antigen-DR1, or human leukocyte antigen-Dw16.
The genes in the human leukocyte antigen-D complex that may protect an individual against rheumatoid arthritis include human leukocyte antigen-DR5 (DRB1*1101), human leukocyte antigen-DR2 (DRB1*1501), human leukocyte antigen-DR3 (DRB1*0301), and human leukocyte antigen-DR7 (DRB1*0701). These genes have been detected at a lower frequency in patients with rheumatoid arthritis compared to controls. Early aggressive disease and extra-articular manifestations are observed in those with DRB1*0401 or DRB1*0404.
Prevention
Rheumatoid cervical spine disorders are so common that cervical spine radiographs should be taken in every patient with rheumatoid arthritis during the disease course; they all carry a high risk for atlantoaxial subluxation (09). There are no specific measures for prevention of rheumatoid arthritis-related myelopathy, although immunosuppression of the underlying disease may be effective in delaying the progression of the underlying myelopathic process by slowing the changes in the spinal canal.
Differential diagnosis
Considerations in the differential diagnosis of rheumatoid arthritis are numerous and depend in part on the clinical presentation. Neurologic manifestations in patients with rheumatoid arthritis should be differentiated from overlapping, primary neurologic diseases versus a complication of rheumatoid arthritis or its treatment as treatment may differ in each case. A list of diseases that can mimic rheumatoid arthritis include acute rheumatic fever, acute viral arthritis (rubella, hepatitis B, parvovirus), amyloidosis, bacterial endocarditis, inflammatory bowel disease, osteoarthritis, systemic lupus erythematosus, polymyalgia rheumatica, reactive arthritis, sarcoidosis, serum sickness, primary Sjogren syndrome, vasculitis syndromes, and Whipple disease. Obtaining a detailed history, a laboratory work-up, and adherence to the diagnostic criteria of rheumatoid arthritis should allow the accurate diagnosis in the majority of patients.
Associated or underlying disorders
Patients with rheumatoid arthritis are at increased risk of cardiovascular disease, including stroke. Rheumatoid arthritis has been shown to be an independent risk factor for stroke, more so in women (24; 29; 19). Risk factors for stroke in rheumatoid arthritis seem to be comprised of a combination of traditional risk factors as well as risk factors inherent to the systemic disease. A common genetic background conferring a higher risk of stroke has been suggested (49). However, there is growing evidence that increased disease activity may further increase the risk of cardiovascular disease and stroke (17; 43). Rheumatoid arthritis patients treated with JAK inhibitors also seem to have a slightly higher risk of stroke (14). Diagnostic workup, prevention, and treatment of stroke in patients with rheumatoid arthritis is otherwise identical to strokes in patients without rheumatoid arthritis.
Diagnostic workup
MRI is the imaging method of choice to detect pannus formation, as well as to visualize root or spinal cord compression and evaluate for spinal cord signal changes (34). CT is preferred to visualize the bony structures and can be helpful in surgical planning, whereas flexion and extension spine x-rays are a simple test that can detect spine instability. Electrodiagnostic studies can be helpful in diagnostically challenging cases and to exclude other mimics, such as entrapment neuropathies, which are also often present in patients with rheumatoid arthritis. In particular, the presence of active denervation on needle EMG is helpful in further localizing and quantifying the degree of root dysfunction when assessing the severity of spinal stenosis in cases in which surgery is being considered.
Electrodiagnostic testing can reliably diagnose carpal tunnel syndrome; nerve ultrasound is also a painless and reliable alternative. Apart from median nerve enlargement, the diagnostic finding of carpal tunnel syndrome on nerve ultrasound, tenosynovial thickening, or cystic masses can be seen (21). Confirmation of clinical suspicion of carpal tunnel syndrome with electrodiagnostic testing and/or nerve ultrasound is recommended, as clinical symptoms alone can be of low specificity in patients with rheumatoid arthritis (21). These modalities are also helpful in diagnosing ulnar neuropathy at the elbow (46), although the sensitivity of electrodiagnostic testing for the latter is not as high. An advantage of electrodiagnostic testing is the ability to detect active denervation changes in the affected muscles, which implies higher risk of progression of motor symptoms. Among patients with polyneuropathy, electrodiagnostic testing is helpful in further characterizing the underlying physiology (axonal vs. demyelinating) and evaluating for other mimics, such as peripheral nerve entrapment or radiculopathy. Polyneuropathy associated with rheumatoid arthritis is typically of axonal physiology. The presence of demyelinating features should prompt further evaluation for coexisting inflammatory neuropathies, such as chronic inflammatory demyelinating polyradiculoneuropathy or TNF-alpha-induced peripheral neuropathy. In cases of suspected polyneuropathy, bloodwork for other treatable causes of neuropathy can be helpful, including hemoglobin A1c or glucose tolerance test, vitamin B12 and B6 levels, thyroid-stimulating hormone, and serum immunofixation electrophoresis (11). Screening for celiac disease can be considered as patients with systemic autoimmune diseases can be at higher risk of developing other inflammatory diseases. Spine imaging can also be considered in patients with other symptoms or signs suggestive of radiculopathy or spinal stenosis, keeping in mind that the latter are common manifestations of rheumatoid arthritis and may coexist with peripheral neuropathy in patients with rheumatoid arthritis. However, as spinal stenosis can often be asymptomatic or be present with minimal symptoms, careful correlation of imaging findings with the distribution of symptoms and exam findings is needed to assess causation of symptoms. Lumbar puncture is helpful in evaluating for demyelinating neuropathy as this is often associated with albuminocytologic dissociation.
Nerve biopsy can be helpful in diagnostically challenging cases of demyelinating or vasculitic neuropathy. If vasculitis is suspected, combined muscle and nerve biopsy can increase the diagnostic yield and is recommended (10). Vasculitic neuropathy is usually accompanied by features of active systemic disease (elevated C-reactive protein, hypocomplementemia, or elevated rheumatoid factor). In less advanced cases, electrodiagnostic testing reveals a multifocal pattern of axonal mononeuropathies, although pseudo-conduction block can be seen if nerve conduction studies are done over the site of nerve infarction earlier in the course of the neuropathy. Active denervation findings are typically present earlier in the course of the neuropathy. It is important to mention that as Wallerian degeneration typically occurs after 3 to 4 weeks of an acute insult, in this case nerve infarction, electrodiagnostic testing can be normal if done within that timeframe and may not be helpful in confirming the diagnosis in acute cases. As deficits are often irreversible if untreated, this neuropathy represents a medical emergency requiring prompt recognition and initiation of treatment to mitigate its effects, prior to awaiting any of the above studies’ results.
Management
Physical and occupational therapy are helpful in cases of spinal stenosis with milder symptoms or neurologic deficits. Oral medications for neuropathic pain can help control more severe sensory symptoms. Cases with myelopathic signs, severe cervical canal stenosis with corresponding cord signal changes, cervical or lumbar spine instability, or refractory pain warrant a spine surgery consultation (42). Whether to pursue surgery should balance the risks of spine disease progression if untreated versus the risk of surgical complications, which may be higher in patients with rheumatoid arthritis and cervicomedullary junction disease, compared to the general population (05).
Carpal tunnel syndrome can be treated with wrist splinting, occupational therapy, steroid injections, and, in refractory cases or cases with weakness present, carpal tunnel release. Ulnar neuropathy is less responsive to medical treatments; for more severe or refractory cases, a number of techniques for ulnar nerve decompression are available (46). Physical therapy is useful symptomatic treatment in cases of polyneuropathy with weakness or gait instability. Topical treatments, such as lidocaine or topical diclofenac can be used for neuropathic pain. Oral agents for neuropathic pain that can be used for painful paresthesia include gabapentin, pregabalin, tricyclic antidepressants, or duloxetine. Use of tricyclic antidepressants can be limited by their side effects of dry eyes and dry mouth in patients with coexisting Sjogren syndrome or sicca symptoms. Demyelinating neuropathies, including those related to TNF-alpha inhibitors, are responsive to steroids and intravenous immunoglobulin, similar to chronic inflammatory demyelinating polyradiculoneuropathy. There are no large-scale randomized controlled trials regarding the response to immunotherapy of axonal polyneuropathy related to rheumatoid arthritis.
Special considerations
Pregnancy
There is overwhelming evidence that pregnancy has a beneficial effect on rheumatoid arthritis. Approximately 75% of patients improve during pregnancy (06; 45). Improvement often begins in the first trimester, and, with few exceptions, is maintained throughout pregnancy. However, fluctuation in disease activity is common, even in those whose rheumatoid arthritis improves or goes into remission. Therapy based on the immunosuppressive factors in pregnancy is an obvious research path to cure rheumatoid arthritis. This approach is currently under investigation in multiple sclerosis where improvement in the third trimester is well established.
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Contributors
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Author
-
Pantelis P Pavlakis MD PhD
Dr. Pavlakis of Athens Medical Center has no relevant financial relationships to disclose.
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Editor
-
Francesc Graus MD PhD
Dr. Graus, Emeritus Professor, Laboratory Clinical and Experimental Neuroimmunology, Institut D’Investigacions Biomédiques August Pi I Sunyer, Hospital Clinic, Spain, has no relevant financial relationships to disclose.
See Profile
Former Authors
- Alireza Minagar MD
- Tarakad S Ramachandran MD
- Robert P Lisak MD
Patient Profile
- Age range of presentation
-
- 2 to 65+ years
- Sex preponderance
-
- female>male, >2:1
- Heredity
-
- heredity may be a factor
- Population groups selectively affected
-
- none selectively affected
- Occupation groups selectively affected
-
- none selectively affected
ICD & OMIM codes
- ICD-10
-
- Rheumatoid arthritis, unspecified: M06.9
- ICD-11
-
- Rheumatoid arthritis, serology unspecified: A20.Z
- OMIM
-
- Rheumatoid arthritis: #180300
- Rheumatoid arthritis, systemic juvenile: #604302
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