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Treat RA early, aggressively for best outcomes

From the June ACP Observer, copyright © 2007 by the American College of Physicians.

By Ryan DuBosar

SAN DIEGO—Rheumatoid arthritis treatments given within 15 days of the initial presentation compared with four months after diagnosis showed remarkable improvement in outcomes.

A critical window of opportunity exists early in the disease onset, when primary care providers are likely to pick up the condition, said John J. Cush, MD, a rheumatologist at the University of Texas Southwest Medical School, who cited the research showing the dramatic improvement in patients who receive early treatment (Lard, LR, Am J Med. 2001 Oct 15;111(6):446-51.). Dr. Cush led a session on "What the internist should know about co-managing patients receiving newer immunosuppressive therapies."

Progressive radiographic damage occurs early, said Dr. Cush, and 70% of patients have radiographic damage within the first three years. Patients with end-stage disease also develop severe functional declines and work disability, often followed by premature death.

Aggressive treatment following the initial visit of a patient with RA not only improves patient outcomes but can reduce the billions of dollars spent on hospitalization, which represents more than half of the overall costs of RA, said Dr. Cush. "I'm asking you to assume a greater degree of responsibility," he told internists in the audience. "The vast majority of people in primary care have not done so for a variety of reasons."

Window of opportunity

In 1995, the goal was to improve pain, avoid damage and preserve function. Today, Dr. Cush said, the goal of therapy is prevention and remission. Four goals include:

  • completely suppress immune-driven inflammation,
  • induce immunologic tolerance,
  • prevent damage, promote healing of tissues, and
  • minimize untoward effects of treating agents.

A 1999 study showed that 51.7% of all rheumatoid arthritis costs were related to hospital admissions, and 26.7% were related to drugs (before biologic disease-modifying antirheumatic drugs (DMARDs) became available). The rest were related to associated health provider visits (1.4%), physician visits (8.6%), testing (4.7%) and other expenses (7.5%).

"When they go into the hospital, costs will skyrocket," he said. "If we do better with the drugs we have, to drive down the costs overall."

Comanagement tactics

Internists should diagnose and treat patients aggressively, and then refer patients for diagnostic confirmation, assessment of disease severity and consideration of alternative DMARDs and biologic regimens, Dr. Cush said. Internists must aggressively manage risk factors such as weight reduction, immunizations and osteoporosis, he said, while rheumatologists must work with the internist to optimally and aggressively manage RA patients with DMARDs or biologic agents.

"You get them first, I get them later," Dr. Cush told internists. "It's easier for me to make the diagnosis later when they have fully manifest disease. When they see you early in the process, the diagnosis may be more challenging."

The primary care doctor screens for the onset of RA, initiates a prescription of NSAIDs, prednisone or DMARDs and possibly refers the patient. The internist should be proactive in initiating DMARD therapy and therefore must be knowledgeable on comfortable in using drugs like methotrexate, hydroxychloroquine and sulfasalazine. The rheumatologist can help refine the therapeutic plan and ensure proper safety monitoring for the agent and disease.

The need for referral is dependent upon the internists comfort in RA management. Many rheumatologists recommend that internists refer when the new-onset arthritis patient has three or more swollen joints; positive metatarsal and metacarpal pressure squeeze tests; joint symptoms more than six weeks; morning stiffness that lasts more than 45 minutes; and any abnormal labs (erythrocyte sedimentation rate, C-reactive protein, rheumatoid factor and anti-cyclic citrullinated peptide antibodies).

Enhanced communication between Internists and rheumatologists can help to establish locally appropriate referral criteria, Dr. Cush suggested. This will help facilitate early diagnosis and avoids unnecessary treatment delays.

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Deciding on drugs

Prednisone, a powerful anti-inflammatory, is effective at low doses (2.5-10 mg/d). 10+ mg/d may protect against bone erosion. But high doses equal higher mortality and infections, and result in weight gain, acne, striae, bruises, weakness, osteoporosis, infection, cataracts, adrenal insufficiency and peptic ulcers. Steroids are rapidly effective—but, are chronically dangerous.

Injectable and oral gold is no longer the gold standard, Dr.Cush said. Of his 600 RA patients, only one still uses it. Its clinical response varies between 30%-50%. Fewer than 40% of patients continue to use it after two years. Common side effects include rash, itch, oral ulcers, proteinuria and diarrhea. Rare complications include thrombocytopenia, leukopenia, pneumonitis and colitis.

Hydroxychloroquine is the safest but weakest DMARD, with a clinical response of between 30%-40%. Side effects include rash, itching, nausea and diarrhea. The risk of retinopathy requires monitoring visual fields by a slit lamp exam annually.

Sulfasalazine's clinical response is about 50%, with potential side effects of diarrhea, abdominal pain, rash, LFTs, oligospermia, Stevens-Johnson syndrome, anemia, leukopenia, and thrombocytopenia. A higher dose is associated with increased effect, but also with GI toxicity.

Leflunomide has a clinical response of about 50%, with durability less than methotrexate. Common side effects include diarrhea, nausea, alopecia and hypertension. It is not advised in patients with hepatitis B and C, persistent hepatic dysfunction, with hepatotoxic agents or in patients with a history of alcohol abuse. However, toxicity can be effectively managed by administering cholestyramine 8 grams three times a day for 5-11 days. Like methotrexate, leflunomide is contraindicated in those patients planning to become pregnant, Dr. Cush said.

Methotrexate is the standard of care and the anchor of all DMARD combination therapies, Dr. Cush said. Its early aggressive use leads to better outcomes and a combination prescription should be encouraged. Clinical response rates vary between 46% and 63%, and it's durable, with more than 65% of patients able to continue the drug for two years.

Side effects include mucositis, painful oral ulcers, nausea, vomiting, and diarrhea. Uncommon side effects include "the blahs," which can be treated, as well as rash, alopecia and photosensitivity. Rare side effects include leukopenia, hypersensitivity pneumonitis, hepatitis and hepatic cirrhosis. Physicians should monitor complete blood counts, and order liver function tests monthly for three months, then every six weeks.

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12 Commandments of RA therapy

  • Make an early diagnosis;
  • Assess risk factors for disease severity;
  • Make a goal of remission (elimination of synovitis and disease activity);
  • Avoid undertreatment;
  • Analgesics, NSAIDs and corticosteroids are palliative only;
  • Early DMARD therapy is necessary and effective in all;
  • Use the most effective DMARD (at optimal doses) first;
  • All patients should be on methotrexate, DMARDs or biologic agents;
  • Risk factors/comorbidities influence prescribed DMARDs;
  • Use aggressive therapy when aggressive disease is evident;
  • Measure disease activity and burden of disease; and
  • Treat to a goal (i.e., Health Assessment Questionnaire=0, Disease Activity Score<1.6, number of swollen joints=0).

Source: adapted from Wolfe et al J Rheum 2002:

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