Journal of the Royal Society of Medicine Volume 84 September 1991
513
Editorials
The gold standard in rheumatoid arthritis
The introduction of gold salts into the rheumatological pharmacopoeia was the result of. some assumptions of questionable validity. Robert Koch, who had discovered the tubercle bacillus in 1882, tested a number of substances for their effect upon pure cultures of the organism: especially noteworthy in their capacity to inhibit growth were gold cyanide compounds. Several types of gold salts were subsequently used in the treatment of tuberculosis and other infections, apparently with beneficial results'. In France, Jacques Forestier started to use gold for rheumatoid arthritis in 1928. He wrote 'If gold salts are active in a chronic disease like human tuberculosis, why should they not be active in another chronic disease in which an important infectious factor seems to be present?' 2. Forestier had no controlled observations but reported great benefit in more than 60% of patients with 25% of 'ill-effects due to over-dosage', such as stomatitis and erythema. He noted that the only active salts were those which contained a high proportion of gold (40-60%) combined with a sulphur radical and the debate has continued as to what extent the thiol moiety may be responsible for therapeutic benefit. After 10-20 years of experience with chrysotherapy, during which it was generally felt that the drug was useful but toxic, controlled trials were considered to be mandatory, especially with the realization that the more recently-introduced treatment with corticosteroids had only a limited part to play. The best known of these was the multicentre study conducted by the Empire Rheumatism Council3, a double-blind trial in which a total dose of 1.0 g of sodium aurothiomalate was given in 20 weekly intramuscular injections, a control group of patients receiving only minute doses of 0.01 mg. Significant clinical improvement by all criteria (except radiographic appearance) was found in the treated patients at the conclusion of treatment, the improvement tending to disappear 18 and 30 months later. A number of other trials showed similar resuts. The mode of action of gold salts remains unknown. It is possible that they suppress rheumatoid inflammation by interfering with the activity of mononuclear phagocytes in the inflamed synovial membrane and other types of cellular damage can occur. A particularly instructive case, never published, was a patient seen personally 30 years ago with florid rheumatoid disease, showing swollen tender joints and numerous rheumatoid nodules, both subcutaneous and pulmonary. She received a course of gold injections in a higher dosage than would now be considered desirable, and after a few weeks she went into a dramatic remission. It was as if she had never had the disease. Swollen joints, nodules all disappeared. Unfortunately, so did her bone marrow, -
and she developed a devastating aplastic anaemia. Anxious weeks followed with blood transfusion, steroids and antibiotics. Then, slowly, the marrow started to regenerate. Back came the red cells, granulocytes and platelets. And back came the swollen, painful joints and nodules . . . Gold is still widely prescribed. We have learnt how to monitor its use, and with careful supervision it is reasonably safe. There are various treatment schedules and it has not been possible to assess them all in a comparative manner. The modern tendency is to use the drug fairly early in the disease and to continue low-dose treatment (in patients who have responded) for a long period. To quote Forestier again, 'No very strict rules can be given on the particular point. It is a matter of clinical and laboratory experience which can only be determined for the individual by the physician. This is the part of gold treatment which really belongs to the art of medicine.' Within the experience of every rheumatologist is the patient who improves on gold for a period of months or years and who then relapses even while the drug is continued. Oral gold (auranofin) has also been shown to be clinically efficacious4. Gold salts were the first of a number of compounds which have been found to possess a slow action in suppressing the activity of rheumatoid arthritis. They have been termed second-line or diseasemoifying anti-rheumatic drugs (DMARDs) in contrast to the first-line non-steroidal anti-inflammatory drugs (NSAIDs), which more rapidly inhibit inflammatory symptoms but which have minimal effect on the pattern of disease; and in contrast again to systemic immunosuppressive agents such as cyclophosphamide, azathioprine, chlorambucil and methotrexate, the last drug now enjoying a wave of popularity. However, nomenclature and clification are difficult and unsatisfactory: methods of action are poorly understood and there is a good deal of overlap between anti-infl mmatory, immunosuppressive and cytotoxic properties. Such slow-acting compounds are antimalarials, penicillamine and sulphasalazine. Observation of improvement in patients with discoid and systemic lupus erythematosus following the use of antimalarial drugs5 led to their use in rheumatoid arthritis; controlled trials indicated that chloroquine6 and hydroxychloroquine7 are safe and moderately effective. They have been said to stabilize lysozomal membranes, interfere with sulphydryl interchange reactions, inhibit phospholipase A2 activity, and trap free radicals8. Concern was formerly felt about ocular complications, especially irreversible retinopathy, but it now appears that this was a rare feature following
prolonged overdosage9. Penicillamine, a low molecular weight sulphydryl amino acid, was used therapeutically in rheumatoid O141-76891/ arthritis following the discovery of its ability to 090513-02/$02.00/O
dissociate IgM rheumatoid factor and a number of clinical trials demonstrated its efficacy10. The drug has various biochemical effects - chelation of heavy metals, participatio n thiol-disulphide exchange
© 1991 The Royal Society of Medicine
514
Journal of the Royal Society of Medicine Volume 84 September 1991
reactions and interference with collagen crosslinking - but its action in rheumatoid arthritis may be related more to direct inhibition of T lymphocyte function, helper cells being particularly sensitive11. Although the mode of action thus appears to be different from that of gold, the two drugs are comparable in terms ofboth therapeutic efficacy and toxicity. Skin rashes, marrow suppression and renal lesions are common to both, although penicillamine has some rare special side-effects such as a myasthenic syndrome. Sulphasalazine, an azo compound of sulphapyridine and 5-aminosalicylic acid, was first used in 1941 for the treatment of rheumatoid arthritis and ulcerative colitis. It fell out of favour for the treatment of arthritis but was later reintroduced, several trials indicating that it exerts a disease-modifying effect. The sulphapyridine moiety is thought to be the more important, but the mode of action is not understood. In a recent comparative trial it was found that the risk of treatment termination due to lack of efficacy was less for gold than for penicillamine or sulphasalazine, but serious adverse effects were more common with gold and penicillamine than with sulphasalazine; to this extent sulphasalazine could be considered the agent of first choice12. Others, however, have found that the proportion of patients stopping therapy because of adverse reactions or lack of effect was similar with regard to penicillamine and sulphasalazine13. As with gold and penicillamine, regression of nodules as well as of synovitis has been noted with sulphasalazine14. In terms of joint damage present after 48 weeks, sulphasalazine has been found to be superior to hydroxychloroquine'5. Although there is convincing evidence as to the efficacy of second-line drugs in rheumatoid arthritis, it should be appreciated that few patients improve in all criteria of assessnent and complete remission is seldom achieved. Over 50% of patients will have discontinued a particular drug within 2 years, because of either loss of efficacy or toxicity. The use of numerous cytotoxic drugs concurrently is common practice in oncology, but here the stakes are high. Combinations of, say, azathioprine, hydroxychloroquine and gold have come to be used in rheumatoid arthritis, but controlled data of efficacy and toxicity are hard to come by. Gold and the other drugs discussed probably act at relatively distal sites of inflammatory and destructive pathways initiated by activated T cells. Removal of lymphocytes by whole-body irradiation or thoracic duct drainage produces a rapid amelioration in the symptoms of rheumatoid arthritis, but this is transient; these are not practical methods of treatment. Modern molecular biology aims at a more radical approach such as developing monoclonal antibodies directed towards potential targets on activated T cells such as CD7 and IL2, also those directed against the CD4 molecules (present on all T-helper cells) and the ODS marker (found on the small subset of B cells producing rheumatoid factor and ther autoant ibodies). There are sufficient leads here to stimulate the further numerous lines of therapeutic research which are now taking place int this country and ovetrseas16.
But a buoyant air of optimism - dating for nearly half a century from the annus mirabilis of 1948 which saw the publication of the Rose-Waaler test, the LE cell phenomenon and the introduction of cortisone - cannot belie the fact that we are dealing with a complex system of unknown antigens and almost certainly multiple collateral inflammatory processes. Apart from a stroke of serendipity, rheumatoid arthritis will probably remain on the gold standard, if not for another 60 years, at any rate for a little while to come.
J T Scott Consultant Physician Charing Cross Hospital Fulham Palace Road London W6 8RF
References 1 Rodnan GP, Benedek TG. The early history of antirheumatic drugs. Arthritis Rheum 1970;13: 145-65 2 Forestier J. Rheumatoid arthritis and its treatment by gold salts. J Lab Clin Med 1935;20:827-40 3 Empire Rheumatism Council. Gold therapy in rheumatoid arthritis, final report of a multicentre controlled trial. Ann Rheum Dis 1961;20:315-34 4 Bombardier C, Ware J, Russell IJ, et al. Auranofin therapy and quality of life in patients with rheumatoid arthritis. Am J Med 1986;81:565-78 5 Page F. Treatment of lupus erythematosus with mepacrine. Lancet 1951;ii:755-758 6 Freedman A, Steinberg VI. Chloroquine in rheumatoid arthritis. A double-blindfold trial of treatment for one year. Ann Rheum Dis 1960;19:243-50 7 Hamilton EBD, Scott JT. Hydroxychloroquine sulfate ("Plaquenil") in treatment of rheumatoid arthritis. Arthritis Rheum 1962;5:502-12 8 Zvaifler NJ. Antimalarial treatment of rheumatoid arthritis. Med Clin North Am 1968;52:759-64 9 Marsman. CDG, Livesey SJ, Jessop JD, Mills PV, Richards I. Screening for hydroxychloroquine retinal toxicity: Is it necessary? Eye 1990;4:572-6 10 Multicentre trial group. Controlled trial of D(-)penicillamine in severe rheumatoid arthritis. Lancet 1973; i:275-80 11 Lipsky PE. Mechanism of action of slow-acting drugs in rheumatoid arthritis. Clin Exp Rheumatol 1989;
7:177-80 12 Situyanake RD, Grindulis KA, McConkey B. Long-term treatment of rheumatoid arthritis with sulphasalazine, gold, or penicillamine: a comparison,using life-table
methods. Ann Rheum Dis 1987;46:177-80 13 Capell HA, Marabani M, Madhok R, Torley H, Hunter JA. Degree and extent of response to sulphasalazine or penicillamine therapy for rheumatoid arthritis:'tesults from a routine clinical environment over a two-year period. Q J Med 1990;75:335-44 14 Englert HJ, Hughes GRV, Walport MJ. Sulphasalazine and regression of rheumatoid nodules. Ann Rheum Dis
1987;46:244-5 15 Van der Heijde DM, van Riel PL, Nuver-Zwart HH, Gribnau FW, van de Putte LB. Effects of hydroxychloroquine and sulphasalazine on progression of joint damage in rheumatoid arthritis. Lancet 1989;i:
10)36-8 16 Maimi RN. Heberden Oration 1988.8Exploring immune pathways in rheumatoid arthritis. Br J Rheumatol 1989;28:466-79
513
Editorials
The gold standard in rheumatoid arthritis
The introduction of gold salts into the rheumatological pharmacopoeia was the result of. some assumptions of questionable validity. Robert Koch, who had discovered the tubercle bacillus in 1882, tested a number of substances for their effect upon pure cultures of the organism: especially noteworthy in their capacity to inhibit growth were gold cyanide compounds. Several types of gold salts were subsequently used in the treatment of tuberculosis and other infections, apparently with beneficial results'. In France, Jacques Forestier started to use gold for rheumatoid arthritis in 1928. He wrote 'If gold salts are active in a chronic disease like human tuberculosis, why should they not be active in another chronic disease in which an important infectious factor seems to be present?' 2. Forestier had no controlled observations but reported great benefit in more than 60% of patients with 25% of 'ill-effects due to over-dosage', such as stomatitis and erythema. He noted that the only active salts were those which contained a high proportion of gold (40-60%) combined with a sulphur radical and the debate has continued as to what extent the thiol moiety may be responsible for therapeutic benefit. After 10-20 years of experience with chrysotherapy, during which it was generally felt that the drug was useful but toxic, controlled trials were considered to be mandatory, especially with the realization that the more recently-introduced treatment with corticosteroids had only a limited part to play. The best known of these was the multicentre study conducted by the Empire Rheumatism Council3, a double-blind trial in which a total dose of 1.0 g of sodium aurothiomalate was given in 20 weekly intramuscular injections, a control group of patients receiving only minute doses of 0.01 mg. Significant clinical improvement by all criteria (except radiographic appearance) was found in the treated patients at the conclusion of treatment, the improvement tending to disappear 18 and 30 months later. A number of other trials showed similar resuts. The mode of action of gold salts remains unknown. It is possible that they suppress rheumatoid inflammation by interfering with the activity of mononuclear phagocytes in the inflamed synovial membrane and other types of cellular damage can occur. A particularly instructive case, never published, was a patient seen personally 30 years ago with florid rheumatoid disease, showing swollen tender joints and numerous rheumatoid nodules, both subcutaneous and pulmonary. She received a course of gold injections in a higher dosage than would now be considered desirable, and after a few weeks she went into a dramatic remission. It was as if she had never had the disease. Swollen joints, nodules all disappeared. Unfortunately, so did her bone marrow, -
and she developed a devastating aplastic anaemia. Anxious weeks followed with blood transfusion, steroids and antibiotics. Then, slowly, the marrow started to regenerate. Back came the red cells, granulocytes and platelets. And back came the swollen, painful joints and nodules . . . Gold is still widely prescribed. We have learnt how to monitor its use, and with careful supervision it is reasonably safe. There are various treatment schedules and it has not been possible to assess them all in a comparative manner. The modern tendency is to use the drug fairly early in the disease and to continue low-dose treatment (in patients who have responded) for a long period. To quote Forestier again, 'No very strict rules can be given on the particular point. It is a matter of clinical and laboratory experience which can only be determined for the individual by the physician. This is the part of gold treatment which really belongs to the art of medicine.' Within the experience of every rheumatologist is the patient who improves on gold for a period of months or years and who then relapses even while the drug is continued. Oral gold (auranofin) has also been shown to be clinically efficacious4. Gold salts were the first of a number of compounds which have been found to possess a slow action in suppressing the activity of rheumatoid arthritis. They have been termed second-line or diseasemoifying anti-rheumatic drugs (DMARDs) in contrast to the first-line non-steroidal anti-inflammatory drugs (NSAIDs), which more rapidly inhibit inflammatory symptoms but which have minimal effect on the pattern of disease; and in contrast again to systemic immunosuppressive agents such as cyclophosphamide, azathioprine, chlorambucil and methotrexate, the last drug now enjoying a wave of popularity. However, nomenclature and clification are difficult and unsatisfactory: methods of action are poorly understood and there is a good deal of overlap between anti-infl mmatory, immunosuppressive and cytotoxic properties. Such slow-acting compounds are antimalarials, penicillamine and sulphasalazine. Observation of improvement in patients with discoid and systemic lupus erythematosus following the use of antimalarial drugs5 led to their use in rheumatoid arthritis; controlled trials indicated that chloroquine6 and hydroxychloroquine7 are safe and moderately effective. They have been said to stabilize lysozomal membranes, interfere with sulphydryl interchange reactions, inhibit phospholipase A2 activity, and trap free radicals8. Concern was formerly felt about ocular complications, especially irreversible retinopathy, but it now appears that this was a rare feature following
prolonged overdosage9. Penicillamine, a low molecular weight sulphydryl amino acid, was used therapeutically in rheumatoid O141-76891/ arthritis following the discovery of its ability to 090513-02/$02.00/O
dissociate IgM rheumatoid factor and a number of clinical trials demonstrated its efficacy10. The drug has various biochemical effects - chelation of heavy metals, participatio n thiol-disulphide exchange
© 1991 The Royal Society of Medicine
514
Journal of the Royal Society of Medicine Volume 84 September 1991
reactions and interference with collagen crosslinking - but its action in rheumatoid arthritis may be related more to direct inhibition of T lymphocyte function, helper cells being particularly sensitive11. Although the mode of action thus appears to be different from that of gold, the two drugs are comparable in terms ofboth therapeutic efficacy and toxicity. Skin rashes, marrow suppression and renal lesions are common to both, although penicillamine has some rare special side-effects such as a myasthenic syndrome. Sulphasalazine, an azo compound of sulphapyridine and 5-aminosalicylic acid, was first used in 1941 for the treatment of rheumatoid arthritis and ulcerative colitis. It fell out of favour for the treatment of arthritis but was later reintroduced, several trials indicating that it exerts a disease-modifying effect. The sulphapyridine moiety is thought to be the more important, but the mode of action is not understood. In a recent comparative trial it was found that the risk of treatment termination due to lack of efficacy was less for gold than for penicillamine or sulphasalazine, but serious adverse effects were more common with gold and penicillamine than with sulphasalazine; to this extent sulphasalazine could be considered the agent of first choice12. Others, however, have found that the proportion of patients stopping therapy because of adverse reactions or lack of effect was similar with regard to penicillamine and sulphasalazine13. As with gold and penicillamine, regression of nodules as well as of synovitis has been noted with sulphasalazine14. In terms of joint damage present after 48 weeks, sulphasalazine has been found to be superior to hydroxychloroquine'5. Although there is convincing evidence as to the efficacy of second-line drugs in rheumatoid arthritis, it should be appreciated that few patients improve in all criteria of assessnent and complete remission is seldom achieved. Over 50% of patients will have discontinued a particular drug within 2 years, because of either loss of efficacy or toxicity. The use of numerous cytotoxic drugs concurrently is common practice in oncology, but here the stakes are high. Combinations of, say, azathioprine, hydroxychloroquine and gold have come to be used in rheumatoid arthritis, but controlled data of efficacy and toxicity are hard to come by. Gold and the other drugs discussed probably act at relatively distal sites of inflammatory and destructive pathways initiated by activated T cells. Removal of lymphocytes by whole-body irradiation or thoracic duct drainage produces a rapid amelioration in the symptoms of rheumatoid arthritis, but this is transient; these are not practical methods of treatment. Modern molecular biology aims at a more radical approach such as developing monoclonal antibodies directed towards potential targets on activated T cells such as CD7 and IL2, also those directed against the CD4 molecules (present on all T-helper cells) and the ODS marker (found on the small subset of B cells producing rheumatoid factor and ther autoant ibodies). There are sufficient leads here to stimulate the further numerous lines of therapeutic research which are now taking place int this country and ovetrseas16.
But a buoyant air of optimism - dating for nearly half a century from the annus mirabilis of 1948 which saw the publication of the Rose-Waaler test, the LE cell phenomenon and the introduction of cortisone - cannot belie the fact that we are dealing with a complex system of unknown antigens and almost certainly multiple collateral inflammatory processes. Apart from a stroke of serendipity, rheumatoid arthritis will probably remain on the gold standard, if not for another 60 years, at any rate for a little while to come.
J T Scott Consultant Physician Charing Cross Hospital Fulham Palace Road London W6 8RF
References 1 Rodnan GP, Benedek TG. The early history of antirheumatic drugs. Arthritis Rheum 1970;13: 145-65 2 Forestier J. Rheumatoid arthritis and its treatment by gold salts. J Lab Clin Med 1935;20:827-40 3 Empire Rheumatism Council. Gold therapy in rheumatoid arthritis, final report of a multicentre controlled trial. Ann Rheum Dis 1961;20:315-34 4 Bombardier C, Ware J, Russell IJ, et al. Auranofin therapy and quality of life in patients with rheumatoid arthritis. Am J Med 1986;81:565-78 5 Page F. Treatment of lupus erythematosus with mepacrine. Lancet 1951;ii:755-758 6 Freedman A, Steinberg VI. Chloroquine in rheumatoid arthritis. A double-blindfold trial of treatment for one year. Ann Rheum Dis 1960;19:243-50 7 Hamilton EBD, Scott JT. Hydroxychloroquine sulfate ("Plaquenil") in treatment of rheumatoid arthritis. Arthritis Rheum 1962;5:502-12 8 Zvaifler NJ. Antimalarial treatment of rheumatoid arthritis. Med Clin North Am 1968;52:759-64 9 Marsman. CDG, Livesey SJ, Jessop JD, Mills PV, Richards I. Screening for hydroxychloroquine retinal toxicity: Is it necessary? Eye 1990;4:572-6 10 Multicentre trial group. Controlled trial of D(-)penicillamine in severe rheumatoid arthritis. Lancet 1973; i:275-80 11 Lipsky PE. Mechanism of action of slow-acting drugs in rheumatoid arthritis. Clin Exp Rheumatol 1989;
7:177-80 12 Situyanake RD, Grindulis KA, McConkey B. Long-term treatment of rheumatoid arthritis with sulphasalazine, gold, or penicillamine: a comparison,using life-table
methods. Ann Rheum Dis 1987;46:177-80 13 Capell HA, Marabani M, Madhok R, Torley H, Hunter JA. Degree and extent of response to sulphasalazine or penicillamine therapy for rheumatoid arthritis:'tesults from a routine clinical environment over a two-year period. Q J Med 1990;75:335-44 14 Englert HJ, Hughes GRV, Walport MJ. Sulphasalazine and regression of rheumatoid nodules. Ann Rheum Dis
1987;46:244-5 15 Van der Heijde DM, van Riel PL, Nuver-Zwart HH, Gribnau FW, van de Putte LB. Effects of hydroxychloroquine and sulphasalazine on progression of joint damage in rheumatoid arthritis. Lancet 1989;i:
10)36-8 16 Maimi RN. Heberden Oration 1988.8Exploring immune pathways in rheumatoid arthritis. Br J Rheumatol 1989;28:466-79
