Rheumatoid Arthritis

Pathogenesis and Pathophysiology. Rheumatoid arthritis (RA) is an immune complex disease. The most important autoantibody in RA is the rheumatoid factor, an antibody, usually of the IgM or IgG class, which reacts with immunoglobulins. The original triggering mechanism may be exposure to a microbial antigen. Autoantibodies to other cellular antigens such as histones, single-stranded DNA, filaments, collagen, and nuclear antigens have been described. Immune complexes composed of IgG combined with IgM or IgG anti-IgG antibodies cause inflammation of the synovium in the joints. Although the largest and most pathogenic immune complexes are found in the joints, others can be detected in the blood of patients with extra- articular manifestations such as vasculitis.

Epidemiology and Risk Factors. Rheumatoid arthritis is a chronic multisystem disease that affects 1 to 2 percent of the population. Disease onset is between 35 and 50 years of age in 80 percent of cases. Women account for 75 percent of cases. An increased risk in nulliparous women and a putative protective effect of oral contraception suggest a hormonal role in disease expression. Although there is a genetic predisposition to developing the disorder, genetic factors probably account for only about 30 percent of the risk of developing RA. y

Clinical Features and Associated Disorders. The onset of RA is typically insidious, with prodromal malaise, fatigue, and generalized weakness. Characteristic symmetrical polyarthritis develops within weeks to months. Articular signs and symptoms preferentially affect the cervical spine and the metacarpophalangeal, proximal interphalangeal, wrist, elbow, knee, ankle, forefoot, and subtalar joints. Progression of joint disease leads to bony erosion and joint deformity. Extra-articular manifestations including rheumatoid nodules in subcutaneous, cutaneous, connective, and pulmonary tissues, pleuritis, interstitial fibrosis, pneumonitis, and pericardial effusions tend to occur in patients with high levels of circulating rheumatoid factor. Felty's syndrome (rheumatoid arthritis, splenomegaly, neutropenia, anemia, and thrombocytopenia) is seen in some patients with long-standing disease.

A few patients develop systemic vasculitis heralded by the development of ischemic skin lesions, mononeuritis multiplex, or documented visceral vasculitis. Although this syndrome is usually seen in men who have had RA for more than 10 years, it may be seen in women at disease presentation. y

Neurological manifestations occur in patients with moderate to severe RA. They may be caused by direct effects of the disease process or secondary effects from bone or joint involvement. Rheumatoid nodules frequently form in the dura mater, where they tend to be asymptomatic except in cases of extensive involvement with pachymeningitis.^! The occurrence of symptomatic CNS vasculitis is rare, even in the setting of active systemic vasculitis. y , y Clinical signs of rheumatoid CNS vasculitis include seizures, dementia, hemiparesis, cranial nerve palsy, blindness, hemispheral dysfunction, cerebellar ataxia, and dysphasia. Pathologic examination reveals chronic perivasculitis, transmural chronic inflammatory cell infiltration, intimal collagen proliferation with luminal narrowing, and fibrinoid necrosis of the media of small arteries. y Changes in the articular architecture of the cervical spine may produce CNS dysfunction at the cervicomedullary junction or spinal cord level. Significant disease of the cervical spine is present in


up to 70 percent of patients with advanced disease. The major changes in the cervical spine include vertebral body erosion and collapse, y rheumatoid discitis, dural thickening and fibrosis with spinal cord compression, and most commonly atlantoaxial subluxation. Subluxation of C1 on C2 may be in the anterior, posterior, or vertical directions, or there may be multiple cervical subluxations resulting in a "staircase appearance" of the cervical spine. y Cervical subluxation is often asymptomatic. In patients who are symptomatic, the most striking features are myelopathic. However, other symptoms have been reported, including occipital headachey and obstructive hydrocephalus. y Brain stem syndromes result from pseudoaneurysm of the vertebral artery, y direct compression of the medulla by eroded, displaced odontoid fragments, and rheumatoid granulomata. Neurological manifestations more commonly result from intermittent or sustained anterior cord compression, sometimes complicated by compression-induced ischemia in the distribution of branches of the anterior spinal artery. Most patients with radiographic evidence of subluxation are asymptomatic. Common symptoms and signs include neck pain, weakness affecting arms before legs, flexor spasms, sphincter disturbances, paresthesias, hyperreflexia, and sensory changes. y

Peripheral nerve disease in RA results from nerve entrapment, segmental demyelination, or vasculitic involvement of the vasa nervorum. Entrapment or compression of peripheral nerves occurs in 45 percent of patients and affects the median, ulnar, posterior interosseous, tibial, common peroneal, or posterior tibial nerves. y Other patterns of neuropathy seen in RA are distal sensorimotor or sensory polyneuropathy and mononeuritits multiplex. Vasculitic changes underlie all types of noncompressive neuropathies in RA.y Myositis may be seen but is not usually a prominent feature of the disorder.

Differential Diagnosis and Evaluation. RA must be distinguished from degenerative osteoarthritis and from deforming inflammatory arthritis associated with other connective tissue disorders. The diagnosis of RA is based on a clinical picture of symmetrical polyarthritis, radiological confirmation of joint erosion, and the demonstration of antibodies including RF by immunologic tests. CNS signs should be explored using magnetic resonance imaging studies of the brain and spinal cord as clinically indicated. Electromyography is useful in the differentiation of various peripheral nerve syndromes.

Management. The treatment of RA is generally divided into first, second, and third line therapies. First line therapy for joint disease employs nonsteroidal anti-inflammatory drugs. Second line therapies include gold, D-penicillamine, sulfasalazine, and hydrochloroquine. Third line agents include corticosteroids and cytotoxic agents. Rheumatoid vasculitis with central or peripheral nervous system manifestations should be treated as any other systemic vasculitis using immunosuppression with corticosteroids and cytotoxic agents. The role of other immunotherapies such as plasmapheresis or intravenous immunoglobulin is not known.y The prognosis is similar to that of systemic necrotizing vasculitis. Cervical subluxation should be treated conservatively with analgesics, muscle relaxants, and neck immobilization. Protection from inadvertent and iatrogenic trauma is essential. Patients with severe vertebral displacement and marked or progressive myelopathy should be considered for surgical fixation. y

Prognosis and Future Perspectives. RA is a chronic disease, and the remission rate over 10 years is less than 10 percent. y RA is associated with excess mortality, with a three-fold increase in the risk of death. Causes of death attributable to the disease process include infection and renal disease whereas those likely related to treatment are gastrointestinal disorders. y Vasculitic peripheral neuropathy often improves, but the survival of patients with systemic rheumatoid vasculitis is poorer than others with RA.y Atlantoaxial subluxation is most often clinically static, and surgical fixation is not necessary in the majority of cases. y

Arthritis Joint Pain

Arthritis Joint Pain

Arthritis is a general term which is commonly associated with a number of painful conditions affecting the joints and bones. The term arthritis literally translates to joint inflammation.

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