Until recently, most patients with early rheumatoid arthritis (RA) were initially treated with NSAIDs (nonsteroidal anti-inflammatory agents) or low doses of corticosteroids. Only those patients who had continued inflammation of the joint lining (synovitis) or who had other non-joint complications of their rheumatoid disease were treated with one of several disease modifying agents (DMARDS).

The DMARDS are powerful drugs — some are cancer chemotherapy agents. Because they have significant side effects (see Table 1 below) and are very expensive, they were usually used alone. However, in the last few years, there has been increasing enthusiasm for the early institution of DMARD therapy and, even more recently, for the use of early combination DMARD therapy.

Table 1.
Frequently encountered clinically significant toxicities associated with DMARD therapy for rheumatoid arthritis.

Drug Adverse Reactions Fetotoxicity
Methotrexate Hepatoxicity
Sulfasalazine Dyspesia
Headache and vertigo
Abnormal liver function
Agranulocytosis (rare)
Azathioprine Nausea and dyspepsia
Bone marrow suppression
Hydroxychloroquine and chloroquine Rash
Retinal toxicity
Cyclosporine Nephrotoxicity
Parenteral gold salts Rash
Neutropenia and thrombocytopenia
Nephrotic syndrome
Penicillamine Rash
Hypogeusia (taste)
Nephrotic syndrome
Pemphigus (rare)
Goodpasture's syndrome (rare)

Why Do Combination Therapy?
Recent studies of the natural history of rheumatoid arthritis, using a single DMARD, have emphasized that, for some RA patients (those with a genetic predisposition or early functional disabilities), their condition will worsen rapidly.

In the early stages of RA, patients are generally healthier, with less irreversible joint damage, and, therefore, better able to withstand the potential adverse effects of these drugs. DMARDS don't all act at the same site and this, too, suggests that a combination DMARD therapy might have extra beneficial effects. Finally, the ineffectiveness and toxicity in clinical trials of another experimental therapy, monoclonal antibodies to T helper lymphocytes, has prompted increased interest in combination DMARDs.

Combined DMARDs vs. Single DMARD
Most of the clinical trials using more than one DMARD were confined to patients whose RA had already failed to respond to one or more of these drugs used as single agents. As might be expected, in this group of difficult patients with well established disease, the results of these studies were not very promising.

More recently, however, combination DMARD therapy was compared with single DMARD therapy in healthier patients. Some of these studies indicated that early combination therapy may be more effective than single agents. In all of these trials, the toxicity from the combination therapy was low and comparable to the single agents alone. No toxicity resulting from interaction between the different DMARDs has been reported and no significant drug interaction has been observed.

Three combinations that appear to be promising are sulfasalazine (SSZ) plus methotrexate (MTX), cyclosporine A plus MTX, and SSZ plus MTX plus hydoxychloroquine (HCQ).

One of the goals of early combination DMARD therapy has been to make remission of the RA happen, so that all anti-rheumatic therapy could be gradually withdrawn (step-down therapy), but this goal has clearly not been achieved in the trials reported to date.

While early combination DMARD therapy is NOT a major breakthrough in the treatment of RA, I believe that it is worth trying in some RA patients. These combinations appear to be quite safe and, therefore, patients should be encouraged to try this approach.