Rheumatoid Arthritis--Update on New Tberapies.

RHEUMATOID ARTHRITIS (RA) is a systemic, synovial-based arthritis. Studies have shown that disability occurs quickly, radiographic progression with erosions and bone loss can be rapid and continues to progress over decades, and mortality rates in severe end-stage disease are comparable to three-vessel coronary artery disease or stage IV Hodgkin's lymphoma.

Traditional therapy based on a therapeutic pyramid of increasingly efficacious and toxic medications, starting with NSAIDs, has been supplanted by earlier, more aggressive treatment. Methotrexate became the drug of choice in the 1990s, but synovial proliferation continues and bone loss progresses in spite of methotrexate treatment. Combination therapy has become widely used and studies indicate a better response in RA using multiple agents. One combination, methotrexate, hydroxychloroquine, and sulfasalazine, has been shown to produce a 50% improvement at 24 months in 77% of patients, compared with a 50% response rate in 33% receiving methotrexate alone.

In the past several years, three new agents have been approved by the FDA for the treatment of rheumatoid arthritis, and others are on the way. These new agents are leflunomide (Arava), etanercept (Enbrel), and infliximab (Remicade).

Leflunomide is a pyrimidine synthesis inhibitor with a long half-life that blocks T cell clonal expansion. Studies of leflunomide in RA have shown an ACR 20 response rate at 1 year of about 45%, compared with a response of 35% to 57% for methotrexate. Recently, the combination of leflunomide and methotrexate has been used, and the combination was found to be superior to methotrexate alone. Adverse effects of the combination included an increased amount of diarrhea, nausea, dizziness, and elevation in results of liver function tests.

Etanercept is a tumor necrosis factor soluble receptor which binds TNF and makes it biologically inactive. Etanercept produced an ACR 20 of 72% and ACR 50 of 49% at 2 years, compared with a lower response with methotrexate (ACR 20, 59%; ACR 50, 42%). Sixty-three percent of patients receiving etanercept had no change in their Sharp scores at 2 years, and 70% had no erosions. In a study using etanercept plus methotrexate, 71% of patients taking the combination had an ACR 20, versus 27% with an ACR 20 receiving methotrexate and placebo.

Infliximab is a mouse fusion monoclonal antibody targeted on TNF. It is given by intravenous infusion and is always given in combination with methotrexate. In the ATTRACT trial at 54 weeks, the combination of infliximab 3 mg/kg every 8 weeks (the FDA approved dose) and methotrexate produced an ACR 20 response in 42%. Results for higher and more frequent doses were better (59% with ACR 20 at 10 mg/kg every 8 weeks). Results at 102 weeks were similar for the 3 mg/kg every 8 weeks and methotrexate group but slightly lower from the peak at 54 weeks for the higher dose groups (48% for 10 mg/kg every 8 weeks). Sharp x-ray scores were significantly better in the infliximab/ methotrexate groups than in the placebo group (P[less than].001).

As with any new drug, toxicities with these new biologic agents are being discovered as they are put into wide use outside of controlled research trials. Etanercept has been associated with rare cases of pancytopenia including aplastic anemia, although most patients were on concomitant immunosuppressive drugs (eg, methotrexate) and no causal relationship has been established. There have also been rare reports of demyelinating illnesses (multiple sclerosis, myelitis, and optic neuritis) with etanercept, although no causal relationship has been established. Both etanercept and infliximab have been associated with infections and should be used with caution in patients predisposed to infections (eg, diabetes) or with recurrent infections, (eg, pneumonia and cellulitis). There have been recent reports of activation of tuberculosis in patients receiving infliximab.

A number of questions remain in the present treatment regimens for rheumatoid arthritis. Should single agents or combination agents be used early? Should biological agents be used early? Studies are under way to answer these questions. It is clear that the treatment of RA in the 21st century will be early, aggressive, and targeted, and the outcomes will be better.

From the Department of Rheumatology, Brookwood Medical Center, Birmingham, Ala.

Rheumatoid Arthritis

* Systemic, Synovial-based Arthritis

* Usual Onset in Middle Aged during Most Productive Years

* Progressive, Disabling, Destructive

* Leads to Deformity, Disability, Premature Death

* Systemic Disease: Fatigue, Anemia, Interstitial Lung Disease, Osteoporosis, Vasculitis, Neuropathy, Valvular Heart Disease, Ophthalmopathy

Risk Factors for Poor Outcomes in RA

High-titer rheumatoid factor

Nodules

Early erosions

Shared epitope HLA DRB1

Education level

Functional status

RA Treatment --Standard DMARD's

* Hydroxychloroquine (Plaquenil)

* Sulfasalazine (Azulfidine EN)

* Minocycline (Minocin, Dynacin)

* Methotrexate (Rheumatrex)

* IM Gold Salts (Solganol, Aurolate)

* Oral Gold Salts (Ridaura)

* Cyclosporine (Neoral)

* Azathioprine (Imuran)

* D-Penicillamine (Depen, cuprimine)

Methotrexate

* Became "Gold Standard" for RA treatment

* Weekly treatment (7.5 mg/wk with increasing doses up to 25 mg/wk po or SQ)

* Efficacious but does not eliminate the disease--Bone Loss Progresses, Synovial Proliferation Continues

* Toxicity--Liver, Lung, non-Hodgkin B Cell Lymphoma

* Cannot be used in Patients with pre-existing Liver, Kidney, or Lung Disease or Patients who drink Alcohol

New DMARD's

* Leflunomide (Arava)-Monotherapy or in combination with Methotrexate

* Etanercept (Enbrel)-Monotherapy or in combination with Methotrexate

* Infliximab (Remicade)--Must be given in combination with Methotrexate to avoid an immune response

* IL-1ra--Monotherapy or in combination with Methotrexate

MTX-Sulfasalazine-Hydroxychloroquine

* Inexpensive combination (All Generic)

* No Increased Toxicity over MTX Alone

* Confusing Recent report that MTX-Sulfasalazine and MTX-Hydroxychloroquine is as effective

* Present status: being used but not considered most effective

* No radiologic data

Leflunomide (Arava) Summary

* Pyrimidine synthesis inhibitor

* Long half-life

* Efficacy comparable to methotrexate (7.5-15 mg/wk) or sulfasalazine

* Toxicity similar to methotrexate

* In combination with methotrexate, improves signs and symptoms in methotrexate-failing RA

Etanercept (Enbrel)

* Binds TNF making it biologically inactive

* Currently approved for:

* RA

* Alone or in combination with methotrexate

* Improvement in signs and symptoms

* Preventing structural damage

* JRA 

* Inadequate response to DMARD therapy

Infliximab (Remicade) ATTRACT Trail: Summary of Efficacy

* In patients with an inadequate response to methotrexate, infliximab is more effective than placebo in controlling signs and symptoms of rheumatoid arthritis

* Data presented suggests reduced clinical efficacy at one year at recommended dose; reduced clinical efficacy at two years at all doses

* Significant reduction in radiographic progression compared to placebo/MTX

Interleukin-1 (IL-1)

* Pro-inflammatory cytokine

* Important mediator of joint damage

* Activates collagenase and stromelysin

* Inhibits synthesis of collagen and proteoglycan 

* Stimulates bone resorption by activating osteoclasts through an intermediary cytokine, osteoprotegerin ligand

IL-1ra

* A naturally-occurring protein that inhibits IL-1[beta] activity through competitive binding to IL-1R

* Due to the up-regulation of IL-1[beta] in RA, the supply of naturally-occurring IL-1ra becomes inadequate to regulate the immune response

* Since binding time of IL-1ra is brief, a molar excess of IL-1ra is required to ensure that cellular activation Is inhibited

Summary

* Etanercept, infliximab, and leflunomide are effective DMARDs

* Optimal methotrexate efficacy requires higher doses

* Radiographic progression of patients on leflunomide was comparable to patients on methotrexate (7.5-15 mg/wk) or sulfasalazine

* Leflunomide plus methotrexate is more effective than placebo plus methotrexate

My Approach to PA Rx

* "Benign" appearance -no significant synovitis--start with Hydroxychloroquine, add Sulfasalazine proceed to Methotrexate

* "Malignant" appearance--start with Methotrexate, add prednisone early, try and qualify patient for biological agents