Rheumatoid Arthritis: Treatment of Newly Diagnosed Disease

If left unchecked, rheumatoid arthritis (RA) causes progressive, irreversible damage to cartilage and bone. Pain, loss of function, work disability, and family hardships result, and death may ensue. In the era before early aggressive treatment with disease-modifying antirheumatic drugs (DMARDs), the work disability rate in patients who had had RA for 10 years was between 30% and 60%.^1-6 The rate of disability increases with increasing disease duration (Figure). In one large cohort, excess mortality associated with RA was 27% per person-year.⁷

Although a key goal of treatment is to reduce pain and improve quality of life, prevention of damage is also crucial because the pathological, destructive processes of RA can continue even when the patient feels well. DMARDs help prevent joint destruction in patients with RA. The evidence favoring early use of DMARDs is substantial, and any delay in the initiation of such therapy can lead to significantly worse outcomes.^8-11 The most recent American College of Rheumatology (ACR) guidelines state that DMARD therapy should not be delayed for more than 3 months after diagnosis.¹² In some cases, a delay of even 3 months may preclude an optimal long-term outcome.¹³

However, prompt consultation with a rheumatologist is not always available. These specialists are in critically short supply, and the average time new patients must wait for an appointment exceeds 5 weeks; moreover, this imbalance between supply and demand is expected to worsen in the near future.¹⁴ It is thus imperative that primary care practitioners be comfortable with prescribing DMARDs for patients with newly diagnosed RA.

Here we review the initial oral treatment options for RA, and we describe an initial approach that is ef-fective and well tolerated in most patients.

INITIAL EVALUATION

History and physical examination. Suspect RA in patients older than 18 years who have bilateral joint pain and swelling in the hands, wrists, or feet and who complain of at least 60 minutes of morning stiffness. The most commonly affected joints are the small joints of the hands, wrists, and feet.

Ask the patient about the distribution and severity of joint pain, duration of morning stiffness, effects on activities of daily living, and systemic symptoms such as fatigue. Examine the joints for pain, tenderness, palpable synovitis, and range of motion. A visual analog score of disease activity may be obtained by asking the patient to mark his or her perceived level of arthritis activity on a 100-mm line; record the result in millimeters.¹⁵

Diagnostic studies. Measure the level of rheumatoid factor, which has a sensitivity of 69% and specificity of 85%, and of anti-cyclic citrullinated peptide, which has a sensitivity of 67% and specificity of 95%.¹⁶ Seropositivity on both of these tests in a patient with characteristic symptoms accurately predicts persistent RA.¹⁷ The laboratory assessment should also include measurement of erythrocyte sedimentation rate and C-reactive protein level, in addition to such routine values as creatinine level, complete blood cell count, and hepatic enzyme levels, which may be necessary before therapy with DMARDs can be initiated. Baseline radiographs of the hands, wrists, and feet should be obtained.

Strongly discourage tobacco smoking; there is evidence that smoking is associated with more severe RA.¹⁸

OVERVIEW OF RA PHARMACOTHERAPY

The 3 principal types of agents used in oral RA pharmacotherapy are:

• NSAIDs.
• Corticosteroids.
• Orally administered DMARDs, which include methotrexate, sulfasalazine, hydroxychloroquine, and leflunomide (Table A, Table B).

Biologic DMARDs (infliximab, adalimumab, etanercept, rituximab, anakinra, and abatacept), which must be administered by injection or intravenous infusion, also have an important role in the treatment of RA^19,20 and are frequently prescribed by rheumatologists in combination with oral agents.²¹ However, in our opinion, it is generally advisable to start a patient with newly diagnosed RA on an NSAID and an oral DMARD, sometimes with the addition of an oral corticosteroid. In certain situations, initial use of a biologic DMARD may be called for, but this is an unresolved issue. Thus, such a regimen is probably best left to the rheumatologist, and consequently biologic DMARDs will not be discussed here.

NSAIDs

Nonselective NSAIDs and selective cyclooxygenase 2 (COX-2) inhibitors have fast-acting analgesic and anti-inflammatory properties. Because they do not affect disease progression, they should not be used as monotherapy for RA. Also, agents from both classes are contraindicated in patients with renal insufficiency.²²

Selective COX-2 inhibitors have a significantly lower risk of serious adverse GI effects than do nonselective NSAIDs²³; however, they are no more effective than the latter²⁴ and are more expensive. Gastroprotective agents, such as proton-pump inhibitors,²⁵ may be used as adjuncts to nonselective NSAID therapy. Both selective and nonselective NSAIDs may have cardiovascular effects.

CORTICOSTEROIDS

In addition to providing excellent short-term relief of RA symptoms, corticosteroids have a disease-modifying effect when used in combination with an oral DMARD.^19,26,27 However, the use of corticosteroids in RA is an art rather than a science.

Corticosteroids have drawbacks that militate against their use as a first-line therapy for RA. The well-known adverse effects associated with long-term use include osteoporosis, immunosuppression, weight gain, glucose intolerance, hypertension, hyperlipidemia, cataracts, skin atrophy, and acne.²⁸ An important drawback even to short-term use is corticosteroids' profound masking of inflammatory manifestations. This effect makes it very difficult for a rheumatologist to perform a baseline assessment in a newly referred patient with RA who has already been given corticosteroids. Keep this in mind when deciding whether to prescribe corticosteroids for a patient who will soon be referred to a rheumatologist.

For select patients, we believe it is appropriate to prescribe corticosteroids on diagnosis of RA. Patients in whom such therapy is recommended should have:

• A clear diagnosis of RA that is well documented by a complete physical examination.
• Relatively severe symptoms and significant functional impairment requiring prompt relief.

If a patient will be seeing a rheumatologist in a week or so, it may be advisable to delay the administration of corticosteroids to allow accurate assessment of disease activity and prognosis by the specialist.

Acceptable corticosteroid dosing regimens include low-dose regimens (eg, oral prednisone, 5 to 10 mg/d)^26,27 and high-dose tapers (eg, oral prednisone, 60 mg/d tapered over 7 weeks to between 5 and 10 mg/d).¹⁹ Because of the risk of osteoporosis, prescribe oral calcium (1 to 1.5 g/d) and vitamin D (800 IU/d) for all patients receiving corticosteroid therapy.²⁹ In addition, consider treatment with bisphosphonates, which are very effective at preventing corticosteroid-induced osteoporosis.²⁹ Measurement of bone mineral density is also recommended.

ORAL DMARDs

Here we will discuss methotrexate, sulfasalazine, hydroxychloroquine, and leflunomide. Less commonly used oral DMARDs include minocycline, azathioprine, cyclosporine, and penicillamine.

Methotrexate. This agent is a potent inhibitor of dihydrofolate reductase, an enzyme that is part of the tetrahydrofolate synthesis pathway necessary for DNA replication. Methotrexate was originally developed in 1948 for use in high doses as a chemotherapeutic agent, but it has also been used since 1972 in much lower doses to treat inflammatory diseases, such as RA and psoriasis.³⁰ The anti-inflammatory effects of methotrexate appear to be independent of its inhibition of dihydrofolate reductase; instead these effects are achieved via the accumulation of adenosine, which modulates T-lymphocyte activation and decreases the expression of cell surface adhesion molecules.³¹

The advantages of methotrexate include favorable efficacy and toxicity profiles,³² low cost, weekly dosing, and an established track record. In fact, in theACR guidelines, the efficacy of methotrexate is the standard by which all DMARDs are evaluated.¹² Disadvantages include the potential for hepatic, pulmonary, and hematological toxicity; the need to abstain from alcohol during treatment; and the anxiety associated with taking a "chemotherapy" drug.

The most common adverse events reported with methotrexate therapy-particularly during the first 1 or 2 years-are dose-dependent GI complaints, including GI discomfort, dyspepsia, nausea, anorexia, diarrhea, and stomatitis.³³ Supplemental folate (starting at a dosage of 1 mg/d and increasing as needed up to 3 mg/d) decreases the severity of these adverse events with only a small effect on efficacy, thereby improving continuation rates; folate is thus recommended for almost all patients.³⁴

Asymptomatic elevations in hepatic enzymes (aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase) are common with methotrexate treatment, but the risk of liver damage is low.³⁵ The ACR recommends hepatic enzyme testing every 4 to 8 weeks, with cessation of the drug and consideration of liver biopsy if levels rise to greater than 2 to 3 times the upper limit of normal.¹² In general, whenever elevated transaminase levels are detected, reduce the methotrexate dose sufficiently to restore normal transaminase and albumin levels.

Using the same interval employed for hepatic enzyme testing, obtain complete blood cell counts to monitor for myelosuppression and measure the creatinine level to monitor the kidneys' ability to excrete the drug (deterioration of renal function results in reduced clearance of methotrexate).¹² Pulmonary toxicity has been reported; consider it in any patient receiving methotrexate who shows telltale signs and symptoms.³⁶ Methotrexate is teratogenic and abortifacient and thus is contraindicated in pregnancy (class X).³⁷

Sulfasalazine. This sulfa drug, developed in the late 1930s, has potent anti-inflammatory effects in inflammatory bowel disease and RA. It delays the clinical and radiographic progression of RA,³⁸ and its long-term efficacy appears to be only slightly inferior to that of methotrexate.³⁹ Sulfasalazine has few serious adverse effects, and its primary disadvantage is its twice-daily dosing.

Nausea, vomiting, dyspepsia, anorexia, headache, and rash are the most commonly reported adverse effects of sulfasalazine⁴⁰; use of the enteric-coated form of the drug may decrease the GI effects.⁴¹ Hematological disturbances, such as leukopenia, occur in 2% to 3% of patients⁴⁰; thus, obtain a complete blood cell count every 2 to 4 weeks for the first 3 months and every 3 months thereafter.¹² Sulfasalazine appears to be generally safe in pregnancy (class B) but may cause kernicterus if used near term.⁴²

Hydroxychloroquine. Antimalarial drugs, such as hydroxychloroquine, have been used for decades in the treatment of RA. These agents may act via disruption of antigen processing.⁴³ Unlike methotrexate and sulfasalazine, hydroxychloroquine used alone has not been proved to delay radiographic progression of RA.⁴⁴ However, early treatment with hydroxychloroquine does significantly reduce signs and symptoms of disease.⁴³ In addition, it is extremely safe and well tolerated, and laboratory monitoring is not necessary.¹²

Rash, abdominal cramps, and diarrhea are infrequent adverse effects.¹² Severe adverse retinal effects have been reported but are extremely rare.⁴⁵ The ACR recommends a baseline ophthalmological examination and yearly examinations thereafter.¹² However, this recommendation has been the subject of controversy.^46-48 The American Academy of Ophthalmology suggests an examination within the first year of treatment for all patients, and then yearly examinations for high-risk patients only (those treated with hydroxychloroquine for more than 5 years, those receiving a dosage higher than the recommended one, patients with a high proportion of body fat, those with kidney or liver disease or preexisting retinal disease, and patients older than 60 years).⁴⁷

Leflunomide. This agent is a pyrimidine synthesis inhibitor that selectively affects the proliferation of T lymphocytes.⁴⁹ Leflunomide is a relatively new oral DMARD. Its efficacy is comparable to that of sulfasalazine and methotrexate,⁵⁰ and it significantly affects the radiographic progression of RA.⁵¹ Disadvantages include various possible adverse effects and the lack of long-term clinical experience.

Diarrhea, alopecia, and elevated hepatic enzymes are the most common adverse effects of leflunomide. Diarrhea is usually responsive to symptomatic treatment, and alopecia is usually transient.⁵² The recommended monitoring regimen is the same as that for methotrexate: regular complete blood cell counts and measurements of hepatic enzyme and creatinine levels.¹² Like methotrexate, leflunomide is an FDA class X drug with proven teratogenic effects. Unlike methotrexate, leflunomide and its active metabolites can be removed from the hepatobiliary circulation through administration of cholestyramine.

THERAPEUTIC RECOMMENDATIONS

Based on our clinical experience, we believe that a combination of methotrexate, folic acid, and an NSAID is an excellent initial regimen that is generally well tolerated. The other oral DMARDs discussed above may also be excellent options depending on patient and physician preference.

Methotrexate is usually started at 7.5 to 10 mg/wk orally.⁵³ If an improvement in signs and symptoms is not seen after 4 to 8 weeks, the dosage may be increased by 2.5 to 5 mg/wk each month, to a maximum of 20 to 25 mg/wk. An oral corticosteroid may be added to the initial regimen based on clinical judgment.

REFERRAL TO A RHEUMATOLOGIST

We recommend that all patients with newly diagnosed RA be evaluated by a rheumatologist as soon as possible. Because of the shortage of rheumatologists, we strongly encourage primary care practitioners to make direct contact with a local rheumatologist to arrange for an expedited evaluation.

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