Penicillamine Hydroxychloroquine

The mechanism of action of penicillamine, MTX, and hydroxychloroquine in the treatment of rheumatoid arthritis is unknown. 

In addition to relying on safety and efficacy data, the initial DMARD choice depends on disease severity, patient characteristics (i.e., comorbidities, likelihood of adherence), cost, and clinician experience with the medication.1,7 Methotrexate alone or in combination therapy is the initial treatment of choice for patients with aggressive disease. Patients with early, mild disease may receive monotherapy with sulfasalazine or hydroxychloroquine. Agents such as azathioprine, D-penicillamine, and gold salts are used rarely today because of concerns about toxicity and reduced efficacy.1,15... 

Outcome measurements used in the evaluation of the outcome of treatment of RA with sulfasalazine, parenteral gold salts, D-penicillamine, hydroxychloroquine, prednisolone, MTX, cyclophosphamide (CyC), and azathioprine in single drug therapy cannot be compared with endpoints used in SBC-5-lMNs and biological-DMARDs combined with MTX. 

With the combination of traditional DMARDs complete remissions are obtained in 30% of early RA over a period of 5 years. These remissions last on average less than 10 months. After 5 years only half of the patients continue with MTX and less than 25% stay on other DMARDs. After 5 years non-compliance is mostly due to adverse effects and lack of efficacy of NSAIDs, hydroxychloroquine, sulfasalazine, prednisone, d-penicillamine, azafhio-prine, and gold salts. Only MTX retains some efficacy. With these therapeutic modalities joint erosions progress to permanent joint destruction, deformities and disability. 

Sulfasalazine (Azulfidine) is approved for the treatment of rheumatoid arthritis and ulcerative colitis. It is also used to treat ankylosing spondylitis and Crohn s disease. Comparisons of sulfasalazine with other DMARDs suggest that it is more effective than hydroxychloroquine, azathioprine, and oral gold compounds. It is at least as effective as intramuscular gold and penicillamine. It has a greater degree of toxicity than hydroxychloroquine but less than gold compounds and penicillamine. After 5 years, approximately 75% of patients have discontinued sulfasalazine therapy, primarily because of a lack of efficacy as opposed to intolerable side effects. 

The disease modifying drugs (DMDs/ DMARDs) used are gold, d-penicillamine, hydroxychloroquine, sulfasalazine and immuno-suppressants like methotrexate, azathioprine, cyclosporin etc. 

Specific criteria for the diagnosis of rheumatoid arthritis in adults are listed in Table 16-1. In addition to the adult form of this disease, there is also a form of arthritis that occurs in children known commonly as juvenile rheumatoid arthritis, or by the more recent term juvenile idiopathic arthritis (JIA). Juvenile arthritis differs from the adult form of this disease—the age of onset (younger than 16 years) and other criteria help to differentiate these two types of rheumatoid joint disease.69,109 Drug treatment of adult and juvenile rheumatoid arthritis is fairly similar, however, with the exception that children may not respond as well to certain medications (e.g., hydroxychloroquine, gold compounds, penicillamine) compared to adults.79 80 Consequently, in this chapter most of the discussion of the management of rheumatoid arthritis is directed toward the adult form. 

Bunch TW, O Duffy JD, Tompkins RB, O Fallon WM Controlled trial of hydroxychloroquine and D-penicillamine singly and in combination in the treatment of rheumatoid arthritis. Arthritis Rheum 1984 27(3) 267-76. 

Jessop JD, O Sullivan MM, Lewis PA, Williams LA, Camilleri JP, Plant MJ, Coles EC. A long-term five-year randomized controlled trial of hydroxychloroquine, sodium aurothiomalate, auranofin and penicillamine in the treatment of patients with rheumatoid arthritis. Br J Rheumatol 1998 37(9) 992-1002. 

Clinically important, potentially hazardous interactions with acitretin, antacids, cholestyramine, dapsone, furazolidone, halofantrine, hydroxychloroquine, methotrexate, methoxsalen, mivacurium, nilotinib, penicillamine, sulfonamides... 

The consideration here will concern itself with chrysotherapy (gold), D-penicillamine, and the antimalarial drug hydroxychloroquine (Fig. 5-6). 

Quinoline antimalarials such as hydroxychloroquine (Fig. 5-6) and chloroquine have been found to have antiarthritic properties however, the onset of clinical improvement, as with penicillamine and gold, takes months. Irreversible retinopathy, including retinal opacity, can be encountered. Lesser toxicities include skin pigmentation and alopecia. Proposals to possible mechanisms of action are speculative at best. It should be emphasized that none of the slow-action antiarthritic agents discussed earlier should be considered as initial therapy in RA. The salicylates and other NSAIDs deserve this distinction. If results are unsatisfactory gold may be considered as the subsequent therapeutic step. Penicillamine would be a logical alternate, as would short-term steroids or cytotoxic agents. 

Second choice—disease-modifying agents Gold salts P-Penicillamine Hydroxychloroquine... 

D. Pharmacokinetics and Clinical Use Sulfasalazine, hydroxychloroquine, methotrexate, cyclosporine, penicillamine and leflunomide are given orally. Infliximab and etanercept are given by injection. Gold compounds are available for parenteral use (gold sodium thiomalate and au-rothioglucose) and for oral administration (auranofin). 

Slow-acting antirheumatic drugs Methotrexate Hydroxychloroquine, sulfasalazine Infliximab, etanercept, leflunomide, penicillamine, gold... 

Older disease-modifying antirheumatic drugs (DMARDs) used frequently in rheumatoid arthritis include hydroxychloroquine, methotrexate, steroids, and sulfasalazine. Gold salts and penicillamine may be effective but cause severe toxicity (see Chapter 36). 

The synthetic DMARDs include gold salts, hydroxychloroquine, and sulfasalazine. Less common synthetic DMARDs are penicillamine and minocycline. Synthetic immunosuppressants used for the treatment of inflammatory diseases include the antimetabolites methotrexate, leflunomide, and azathioprine. 

The manufacturers say that the concurrent use of leflunomide and other DMARDs (they list azathioprine, chloroquine, hydroxychloroquine, intramuscular or oral gold and penicillamine) has not yet been studied but they say that combined use is not advisable because of the increased risk of serious adverse reactions (haemo- or hepatotoxicity). As the active metabolite of leflunomide has a long half life of 1 to 4 weeks the manufacturers say that a washout of colestyramine or activated charcoal should be given if patients are to be started on other DMARDs. See also Methotrexate, below. 

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