Treatment of rheumatoid arthritis 

How is the diagnosis made? Are rheumatoid nodules always present? When should joints be tapped? Are other tissues involved besides the joints? How should management be approached? How is the prognosis determined? Which medications are used for treatment? What additional agents can be considered? Are antimalarials or sulfasalazine effective? When is surgery appropriate?

Awareness of prognostic factors in rheumatoid arthritis drives decision making in medical management of the disease in its several manifestations.

Mild disease is generally treated with nonsteroidal anti-inflammatory agents plus hydroxychloroquine. Moderate disease may require additional agents, but all have side effects. Surgery offers improved function and quality of life in patients who are able to carry out the necessary rehabilitation programs.

How is the rheumatoid arthritis diagnosis made?

Because we know little about what causes rheumatoid arthritis, the diagnosis is based upon a set of clinical criteria. Morning stiffness of at least one hour's duration; symmetrical polyarthritis (including joints of the hands); rheumatoid nodules; characteristic radiographic changes, such as erosions; and serum rheumatoid factors establish the clinical diagnosis. These symptoms may not all be present early in the course of the illness, or they may exist in a subtle form, emphasizing that diagnosis remains the province of the experienced clinician. Other forms of inflammatory arthritis must also be excluded, including gout, the spondyloarthropathies with peripheral joint involvement, and other connective tissue disorders with symptoms that may mimic or overlap those of rheumatoid arthritis.

Diagnostic acumen is essential because the choice of rheumatoid arthritis therapy and approach to management are based upon accuracy of diagnosis, as well as on the assessment of prognostic factors.

Are rheumatoid nodules always present?

On histopathologic examination, a rheumatoid nodule appears as a ring of granulation tissue made up of lymphocytes and plasma cells surrounding connective tissue cells palisaded around a central core of fibrinoid necrosis. Rheumatoid nodules are among the most characteristic findings in patients with rheumatoid arthritis, but they occur in slightly less than half of Caucasians with the disease and are rarer in Asians and Africans. Superficial nodules vary in size from several millimeters in diameter to masses that are many times as large. They are usually painless and most often appear under the skin at the ulnar border of the elbow and forearm. Also commonly involved are the areas over the sacrum, heels, posterior occiput, and spine, as well as the tendon sheaths of the hand and around the feet. Nodules may break down, ulcerate, and become infected; sacral pressure sores may develop over them. Inflammatory aggregates pathologically identical to nodules may be found in the sclera of the eye, pleura, pericardium, and lung. The latter presentation enlarges the differential diagnosis of the pulmonary coin lesion in patients with rheumatoid arthritis. Nodules are almost always associated with high titers of IgM rheumatoid factor in the serum and usually indicate serious and chronic disease.

When should joints be tapped?

There are two basic reasons for doing arthrocentesis in any patient, and these criteria apply to those with rheumatoid arthritis. The first is diagnostic: Synovial fluid in rheumatoid arthritis is inflammatory in character. It may appear turbid, have reduced viscosity, and contain an increased number of leukocytes. There are no crystals. Routine analysis, therefore, does not add a great deal to clinical assessment, but the absence of crystals can be helpful in the elderly patient when the possibility of polyarticular chondrocalcinosis is being considered. Also important is the absence of microorganisms. In the patient with an established diagnosis of rheumatoid arthritis, the sudden appearance of marked inflammation in a joint can indicate infection, and microbiologic culture of synovial fluid is often an important step.

The second reason for performing arthrocentesis is for local injection therapy. Although local steroid injection provides only transient relief in most cases, its benefit can be considerable in the temporary suppression of inflammation and pain and in the gain or return of comfortable function.

Are other tissues involved besides the joints?

Fortunately, organ and visceral complications are unusual, but when they occur, they can be severe. Rheumatoid vasculitis may lead to devastating complications of peripheral gangrene, deeply burrowing skin ulcers, and mononeuritis multiplex. Inflammation of the sclera may not only produce chronic episcleritis but may damage the sclera to the point of causing uveal penetration or exposure. Corneal involvement may lead to "melting" of this structure. Both ocular conditions threaten the integrity of the eye. In the heart, pericarditis and aortic valve involvement may lead to regurgitation. Alveolitis, chronic pleurisy, and rheumatoid nodules have also been found in the lungs. These features and other rare manifestations have led to the concept that rheumatoid arthritis or, more properly, rheumatoid disease can on occasion be a widespread inflammatory and life-threatening disorder. Treatment of patients in this category should be carried out with the assistance of physicians experienced in rheumatology.

How should rheumatoid arthritis management be approached?

There are many therapeutic agents, all with side effects, and none is a definitive rheumatoid arthritis cure. A basic philosophic split exists among rheumatologists about how to approach patients with rheumatoid arthritis. One view holds that mild clinical disease should be treated with mild agents and that the risk of side effects should be kept to a minimum in patients in this category. This approach could be called the optimistic view. It recognizes the possibility that spontaneous remissions can occur in rheumatoid arthritis, particularly in the first year, and tries to expose the patient to the least toxic medications capable of controlling disease manifestations. The other view recognizes rheumatoid arthritis as a serious, disabling, deforming, and progressive disease that requires early treatment with agents most likely to induce remissions or modify the disease course. In this view, the risks of medication toxicity or side effects are outweighed by the risks of chronic rheumatoid arthritis. Given these options, some guidance may be beneficial in helping to predict the clinical course.

How is the rheumatoid arthritis prognosis determined?

Unfortunately, we do not have the ability to make precise predictions, but there are general signs that point to a poor prognosis. These include sustained active disease, especially of more than one year's duration; bony erosions; radiographic evidence of joint destruction; cartilage loss; chronically swollen joints; high levels of IgM rheumatoid factor; and extra-articular manifestations, including nodules, vasculitis, neuropathy, skin ulcers, and ocular scleritis. Hereditary factors, such as HLA type DR 4, are also important prognostic indicators. Socioeconomic status and support also play an important role: Most demographic studies have found that patients with poor socioeconomic status tend to do worse than those of better socioeconomic status. Though it is still impossible to predict accurately the clinical course of any individual patient, assessment of these factors provides clues about the likelihood of chronic sustained or disabling disease. These are the patients for whom more aggressive therapy is felt to be warranted. However, modification of therapy, based on these factors along with others, including compliance, the presence of other medical conditions or limitations, allergies, and the ability to carry out the therapeutic program, must be weighed before the course of therapy is chosen.

Which rheumatoid arthritis medications are used for treatment?

Those who favor the stepwise approach generally begin with a nonsteroidal anti-inflammatory agent plus hydroxychloroquine for mild disease. Moderate rheumatoid arthritis may require the addition of gold, sulfasalazine, or methotrexate. These agents, plus corticosteroids, azathioprine, or penicillamine, can be used for severe manifestations. For unusual situations, such as vasculitis, cyclophosphamide, chlorambucil, and high-dose corticosteroids have been used. Another approach utilizes steroids and the more potent agents earlier, with the hope of preventing irreversible joint damage. All of these agents have been used singly and in combination; consultation with a rheumatologist is advisable in selecting and monitoring therapy.

Prednisone is probably the most often prescribed glucocorticoid. Usually given in the morning, with low oral doses of 5-7.5 mg per day, it can be used as maintenance therapy or as an adjunct to other agents. Prednisone has been given at higher doses to control severe disease manifestations and to provide early therapy for patients who are given slower-acting agents; doses can then be tapered with time. High-dose intravenous bolus therapy (e.g., 0.5-1.0 g methylprednisolone for three days) has been used for the same purpose as the higher-dose oral agents. Injections of depot methylprednisolone are also employed.

The side effects of glucocorticoids are well-known to practitioners and include psychological changes, fluid retention, worsening of hyperglycemia in diabetes mellitus, hypertension, cosmetic changes, hair loss, weight gain, acne, osteoporosis, muscle weakness, skin fragility, and avascular necrosis of bone. There may also be impaired wound healing and diminished resistance to infection. Many of these effects are dose-and time-related. Rarely, atrophy of fat and connective tissue occurs at local injection sites. Ocular hypertension may result after weeks to months of rheumatoid arthritis treatment.

What additional agents can be considered?

Gold salts for rheumatoid arthritis may be given orally or by injection and are associated with rheumatoid arthritis remission in more than half of treated patients. Skin rash, thrombocytopenia, proteinuria, and very rarely leukopenia, may occur. Oral gold therapy may induce diarrhea. There have been very rare reports of lung disease and polyneuropathy in patients receiving gold therapy.

Methotrexate is usually given orally on a once-weekly schedule. It also may be administered intravenously, intramuscularly, or by subcutaneous injection. Although there are many areas of potential toxicity with this agent, regular monitoring generally allows its safe administration. There may be rash, hair loss, stomatitis, nausea at the time of administration, and bone marrow suppression. Significant hepatic toxicity is extremely unusual in patients with rheumatoid arthritis. Liver function test monitoring is performed at intervals; the practice of obtaining liver biopsies is diminishing. Pneumonitis can be a serious problem, and methotrexate is generally not given when there is significant underlying pulmonary disease. Because of the risk of teratogenicity, methotrexate is contraindicated in pregnant patients. Concomitant use of oral folic acid may alleviate some side effects.

Penicillamine is given orally and has a profile of side effects similar to those of gold. There may be rash, bone marrow suppression, and proteinuria; in addition, a number of autoantibodies have been found in patients after penicillamine treatment. During treatment, a few patients have developed disorders that may have autoimmune bases, including myasthenia gravis, Goodpasture's syndrome, polymyositis, pemphigus, and galactorrhea.

Azathioprine has also been associated with induction of remission in rheumatoid arthritis. Toxic reactions are rare and have included bone marrow suppression, gastrointestinal disorders, pancreatitis, and rash. The question of induction of malignancies with azathioprine has not been completely resolved. Most evidence thus far supports the view that the risk in rheumatoid arthritis patients is extremely small.

Are antimalarials or sulfasalazine effective?

Antimalarial medications and sulfasalazine have proven very effective, either alone or in combination with the previously mentioned agents. Among the antimalarials, hydroxychloroquine is the most widely used. Side effects are very rare but include rash, gastrointestinal intolerance, and very infrequently, vertigo. Retinopathy, although a side effect with an extremely small risk, generates the most concern. Regular eye examinations are generally scheduled for patients on long-term therapy. Ultraviolet-blocking eyeglasses to prevent retinal exposure to UV radiation have been suggested for patients receiving hydroxychloroquine.

Use of sulfasalazine has been associated with rash, malaise, gastrointestinal intolerance, and very rarely, hemolytic anemia and methemoglobinemia. Idiosyncratic reactions of aplastic anemia, thrombocytopenia, and agranulocytosis have also been reported.

Dosages or treatment protocols for all the medications available for rheumatoid arthritis are not given here for two reasons: First, because there are so many varying dosages, routes of administration, and combinations of agents used, even a partial list would be very extensive. Second, because of this and the need to monitor for toxicity and effectiveness, patients for whom this therapy is indicated should be referred early to a rheumatologist, who can help develop a therapeutic approach, modify it as needed, and assist in follow-up.

When is rheumatoid arthritis surgery appropriate?

Over the past decades, there have been revolutionary advances in surgery of the bones and joints. The major indications, pain and loss of function, remain the same, although techniques and results are improving constantly. There are many potential problems of comorbidity in the patient with chronic rheumatoid arthritis. Intercurrent bouts and progression of illness, changes in the tissues from chronic steroid use or illness, and potential susceptibility to infection in patients with altered immune responsiveness may all interfere with a successful outcome. Nonetheless, orthopaedic surgical procedures applied to selected individuals have without question improved function and quality of life for many patients. Replacement surgery of the hip and knee has allowed ambulation and mobility in patients whose ability to continue independent living was threatened. Foot and ankle surgery have made possible wearing shoes and walking. In the upper extremities, shoulder and elbow surgery have enabled patients to continue to eat, dress, and groom themselves independently. Hand surgery has contributed to increased function by allowing patients to perform many tasks needed in daily living, such as handling keys, money, utensils, and papers.

Stabilization of the cervical spine in rare instances of instability and subluxation has been valuable in pain relief and in protection of the spinal cord and nerve roots. In all these cases, success depends on active cooperation between surgeons and medical doctors. Success is also related to the patient's ability to carry out the needed rehabilitation programs in terms of motivation, as well as general health status and function of the other joints. In a chronically ill and disabled patient, this can be a difficult undertaking. With careful patient selection and patient education, however, the rewards can be great.

Finally, rheumatoid nodules can present difficulties at times. Infection, tissue breakdown, and drainage occur rarely, and surgical removal may be needed.