While rheumatoid arthritis primarily affects joints, problems involving other organs of the body are known to occur. Extra-articular ("outside the joints") manifestations other than anemia (which is very common) are clinically evident in about 15–25% of individuals with rheumatoid arthritis. It can be difficult to determine whether disease manifestations are directly caused by the rheumatoid process itself, or from side effects of the medications commonly used to treat it – for example, lung fibrosis from methotrexate or osteoporosis from corticosteroids.
The arthritis of joints known as synovitis is inflammation of the synovial membrane that lines joints and tendon sheaths. Joints become swollen, tender and warm, and stiffness limits their movement. With time RA nearly always affects multiple joints (it is a polyarthritis), most commonly small joints of the hands, feet and cervical spine, but larger joints like the shoulder and knee can also be involved. Synovitis can lead to tethering of tissue with loss of movement and erosion of the joint surface causing deformity and loss of function.
Rheumatoid arthritis typically manifests with signs of inflammation, with the affected joints being swollen, warm, painful and stiff, particularly early in the morning on waking or following prolonged inactivity. Increased stiffness early in the morning is often a prominent feature of the disease and typically lasts for more than an hour. Gentle movements may relieve symptoms in early stages of the disease. These signs help distinguish rheumatoid from non-inflammatory problems of the joints, often referred to as osteoarthritis or "wear-and-tear" arthritis. In arthritis of non-inflammatory causes, signs of inflammation and early morning stiffness are less prominent with stiffness typically less than 1 hour, and movements induce pain caused by mechanical arthritis. In RA, the joints are often affected in a fairly symmetrical fashion, although this is not specific, and the initial presentation may be asymmetrical.
As the pathology progresses the inflammatory activity leads to tendon tethering and erosion and destruction of the joint surface, which impairs range of movement and leads to deformity. The fingers may suffer from almost any deformity depending on which joints are most involved. Medical students are taught to learn names for specific deformities, such as ulnar deviation, boutonniere deformity, swan neck deformity and "Z-thumb," but these are of no more significance to diagnosis or disability than other variants, since they occur in osteoarthritis as well. "Z-thumb" or "Z-deformity" consists of hyperextension of the interphalangeal joint, fixed flexion and subluxation of the metacarpophalangeal joint and gives a "Z" appearance to the thumb.
The rheumatoid nodule, which is sometimes cutaneous, is the feature most characteristic of rheumatoid arthritis. It is a type of inflammatory reaction known to pathologists as a "necrotizing granuloma". The initial pathologic process in nodule formation is unknown but may be essentially the same as the synovitis, since similar structural features occur in both. The nodule has a central area of fibrinoid necrosis that may be fissured and which corresponds to the fibrin-rich necrotic material found in and around an affected synovial space. Surrounding the necrosis is a layer of palisading macrophages and fibroblasts, corresponding to the intimal layer in synovium and a cuff of connective tissue containing clusters of lymphocytes and plasma cells, corresponding to the subintimal zone in synovitis. The typical rheumatoid nodule may be a few millimetres to a few centimetres in diameter and is usually found over bony prominences, such as the olecranon, the calcaneal tuberosity, the metacarpophalangeal joint, or other areas that sustain repeated mechanical stress. Nodules are associated with a positive RF (rheumatoid factor) titer and severe erosive arthritis. Rarely, these can occur in internal organs or at diverse sites on the body.
Several forms of vasculitis occur in rheumatoid arthritis. A benign form occurs as microinfarcts around the nailfolds. More severe forms include livedo reticularis, which is a network (reticulum) of erythematous to purplish discoloration of the skin caused by the presence of an obliterative cutaneous capillaropathy.
Fibrosis of the lungs is a recognized response to rheumatoid disease. It is also a rare but well recognized consequence of therapy (for example with methotrexate and leflunomide). Caplan's syndrome describes lung nodules in individuals with rheumatoid arthritis and additional exposure to coal dust. Pleural effusions are also associated with rheumatoid arthritis. Another complication of RA is Rheumatoid Lung Disease. It is estimated that about one quarter of Americans with RA develop Rheumatoid Lung Disease. Kidneys Renal amyloidosis can occur as a consequence of chronic inflammation. Rheumatoid arthritis may affect the kidney glomerulus directly through a vasculopathy or a mesangial infiltrate but this is less well documented (though this is not surprising, considering immune complex-mediated hypersensitivities are known for pathogenic deposition of immune complexes in organs where blood is filtered at high pressure to form other fluids, such as urine and synovial fluid). Treatment with Penicillamine and gold salts are recognized causes of membranous nephropathy. Heart and blood vessels People with rheumatoid arthritis are more prone to atherosclerosis, and risk of myocardial infarction (heart attack) and stroke is markedly increased. Other possible complications that may arise include: pericarditis, endocarditis, left ventricular failure, valvulitis and fibrosis. Many people with rheumatoid arthritis do not experience the same chest pain that others feel when they have angina or myocardial infarction. To reduce cardiovascular risk, it is crucial to maintain optimal control of the inflammation caused by rheumatoid arthritis (which may be involved in causing the cardiovascular risk), and to use exercise and medications appropriately to reduce other cardiovascular risk factors such as blood lipids and blood pressure. Doctors who treat rheumatoid arthritis patients should be sensitive to cardiovascular risk when prescribing anti-inflammatory medications, and may want to consider prescribing routine use of low doses of aspirin if the gastrointestinal effects are tolerable.
The eye is directly affected in the form of episcleritis which when severe can very rarely progress to perforating scleromalacia. Rather more common is the indirect effect of keratoconjunctivitis sicca, which is a dryness of eyes and mouth caused by lymphocyte infiltration of lacrimal and salivary glands. When severe, dryness of the cornea can lead to keratitis and loss of vision. Preventive treatment of severe dryness with measures such as nasolacrimal duct occlusion is important.
Cytokine production in joints and/or hepatic Kupffer cells leads to increased activity of hepatocytes with increased production of acute-phase proteins, such as C-reactive protein, and increased release of enzymes such as alkaline phosphatase into the blood. In Felty's syndrome, Kupffer cell activation is so marked that the resulting increase in hepatocyte activity is associated with nodular hyperplasia of the liver, which may be palpably enlarged. Although Kupffer cells are within the hepatic parenchyma, they are separate from hepatocytes. As a result there is little or no microscopic evidence of hepatitis (immune-mediated destruction of hepatocytes). Hepatic involvement in RA is essentially asymptomatic.
Anemia is by far the most common abnormality of the blood cells. Rheumatoid arthritis may cause a warm autoimmune hemolytic anemia. The red cells are of normal size and colour (normocytic and normochromic). A low white blood cell count (neutropenia) usually only occurs in patients with Felty's syndrome with an enlarged liver and spleen. The mechanism of neutropenia is complex. An increased platelet count (thrombocytosis) occurs when inflammation is uncontrolled, as does the anemia.
Peripheral neuropathy and mononeuritis multiplex may occur. The most common problem is carpal tunnel syndrome caused by compression of the median nerve by swelling around the wrist. Atlanto-axial subluxation can occur, owing to erosion of the odontoid process and or/transverse ligaments in the cervical spine's connection to the skull. Such an erosion (>3mm) can give rise to vertebrae slipping over one another and compressing the spinal cord. Clumsiness is initially experienced, but without due care this can progress to quadriplegia.
Constitutional symptoms including fatigue, low grade fever, malaise, morning stiffness, loss of appetite and loss of weight are common systemic manifestations seen in patients with active rheumatoid arthritis.
Local osteoporosis occurs in RA around inflamed joints. It is postulated to be partially caused by inflammatory cytokines. More general osteoporosis is probably contributed to by immobility, systemic cytokine effects, local cytokine release in bone marrow and corticosteroid therapy.
The incidence of lymphoma is increased in RA, although it is still uncommon.