Other conventional disease-modifying anti-rheumatic drugs

Other conventional disease-modifying anti-rheumatic drugs (DMARDs) that are less widely used than methotrexate, leflunomide, sulfasalazine, and hydroxychloroquine, and for which there is less efficacy and safety data, include the tetracycline (a type of antibiotic) minocycline (Minocin), the chelator D-penicillamine (Cuprimine, Depen), gold salts including auranofin (Ridaura) and sodium aurothiomalate (Myochrysine), and the immunosuppressive drugs azathioprine (Imuran) and cyclosporine (Neoral).1



Minocycline (Minocin) is a tetracycline antibiotic. It is manufactured by several different companies and available in tablets for oral administration at doses of 50, 75, and 100 mg. Another tetracycline, doxycycline, is also used as a DMARD in RA. Minocycline has typically been given at a dose of 100 mg twice daily in clinical trials.1,2

It is not known exactly how tetracyclines work to improve symptoms in RA, but potential mechanisms include their action in decreasing the production of chemicals that regulate the immune response and chemicals that play a role in joint destruction. Evidence of the effectiveness of minocycline comes from several randomized, controlled trials. The greatest benefit appears to be when it is used early in the course of RA. A review of several studies of minocycline in RA conducted in over 500 patients found that minocycline or another tetracycline resulted in significant improvements in joint pain, tenderness and swelling, physical functioning, and inflammatory markers compared with placebo. In a study comparing minocyline to hydroxychloroquine, at 2 years minocycline resulted in a significantly higher rate of ACR50 response (60% versus 33%; P=0.04).1

The most common side effects associated with minocycline include rash, headaches, dizziness, gastrointestinal (GI) side effects (nausea, vomiting, and diarrhea).1,2



D-penicillamine (Cuprimine, Depen) is a chelator (a medicine that removes heavy metal from the blood by means of a chemical reaction). Because of potential toxicities, D-penicillamine is started at a low dose and gradually increased to a target dose. D-penicillamine is typically started at 250 mg per day (given on an empty stomach), with the daily dose increased by 125-250 mg over the course of 1 to 3 months until reaching a maximum dose of 1000 mg per day. Most patients with RA require 500-750 mg/day for a minimum of 3 months before symptom improvement occurs.1

The mechanism of action for D-penicillamine in RA is not known. It is not immunosuppressive nor anti-inflammatory. Evidence of the effectiveness of the drug in RA comes from six randomized, controlled clinical trials conducted in over 600 patients. In these studies, D-penicillamine resulted in significant benefit in terms of RA symptom improvement compared with placebo. While D-penicillamine has been shown to result in efficacy comparable to azathiorpine and gold salts, it is associated with more frequent side effects. In fact, toxicity (risk for side effects) is a major limiting factor in the use of D-penicillamine. The most common side effects include rash, stomatitis, and pruritus, and fever, nausea, loss of taste, and anorexia may occur early in treatment. Due to its side effect profile and potential for toxicity, patients who receive D-penicillamine must be monitored closely during treatment. Patients who experience rashes or oral ulcers (mouth sores) should discontinue the drug at once.1


Auranofin and sodium aurothiomalate

Auranofin (Ridaura) and sodium aurothiomalate are gold salts. Auranofin is formulated for oral administration. Sodium aurothiomalate is available in different formulations for parenteral administration, typically for intramuscular injection. Up until 1990, intramuscular gold was a cornerstone treatment for RA. The mechanism of action of gold salts is not known. It is thought that gold may act on macrophages and cytokines in the joint space to interfere with the immune response.1

Auranofin has limited efficacy and is not often used. Intramuscular sodium aurothiomalate is typically started at a week 1 test dose of 10 mg. The next dose at week 2 is given at 25 mg, then, in the absence of side effects, subsequent weekly doses are given at 50 mg. Clinical response should occur after 20 weeks and a cumulative dose of approximately 1000 mg.1,3

Results from several randomized, controlled studies show that parenteral gold results in a significant slowing of radiographic progression versus placebo, at least as great as methotrexate. Clinical evidence suggests that about one-third of patients with RA respond to treatment, one-third will fail to respond, and one-third will experience toxicities within the first year of treatment. The potential for toxicity (side effects) is a major limitation with gold salts. Adverse effects occur in 30% to 40% of patients and include pruritis (itching), stomatitis, and dermatitis. Because of the potential for side effects and toxicity, close monitoring is important during treatment with gold salts.1



Azathioprine (Imuran) is an immunosuppressant. It works on the level of cell DNA to inhibit proliferation of cells or cause cell death. Azathiorpine is taken orally and typically started at a dose of 50 mg per day. Thereafter, the daily dose is increased every 1 to 2 weeks by 25-50 mg until a maximum target dose of 2.5 mg/kg/day is reached. Azathioprine may take up to several months to achieve full clinical efficacy.1,4

Evidence for the effectiveness of azathioprine comes from a limited number of short-term, controlled trials, in which it provided significant benefits versus placebo. These benefits continued in long-term extensions of these studies. Results from radiographic studies of azathioprine have been inconsistent in terms of ability to slow disease progression (damage to joints). Results from comparative studies suggest that azathioprine is equal in potency in controlling disease activity to gold salts (parenteral) and less potent than methotrexate. However, it is less effective than both in slowing or stopping joint erosion.1

Adverse effects cause discontinuation in up to 30% of patients who receive azathioprine. The most common side effects include GI effects (nausea, vomiting, and diarrhea). Myelosuppression (suppression of the ability of bone marrow to produce blood cells and platelets) occurs commonly with azathioprine. Regular monitoring, including weekly complete blood counts and monthly liver function testing is necessary until a stable dose has been established, after which monitoring can occur less frequently.1,4



Cyclosporine (Neoral) is a medication derived from fungus. It is an immunosuppressant that inhibits production of T-cells. It is started at a dose of 2.5 mg/kg per day, given in divided doses. The dose is increased by 0.5 mg/kg per day every 4 to 8 weeks until a maximum target dose of 4.0 mg/kg per day is achieved. There is wide variation in how the drug is absorbed (how the body metabolizes the drug) by different patients. Note that grapefruit juice can in increase absorption and decrease metabolism and should not be consumed while taking cyclosporine.1,5

Results from a limited number of trials have shown that cyclosporine is significantly more effective than placebo in providing RA disease control. One 2-year study found that cyclosporine provided efficacy comparable to methotrexate both in terms of disease control and radiographic progression in patients with early RA. Other studies have confirmed the benefits of cyclosporine in terms of slowing radiographic progression. It is typically used in combination with methotrexate. Results from three studies have shown that this combination results in more rapid disease control than methotrexate or sulfasalazine alone.1

Common side effects with cyclosporine include nausea, hair growth on the body, tremor, paresthesias (abnormal sensations), and overgrowth of the gum tissue. Some patients are affected by significant bone pain requiring dose reduction or discontinuation. Serious side effects that can occur early in treatment include hypertension and decreased kidney function.1,4

Written by: Jonathan Simmons | Last reviewed: September 2013.
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