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Penicillamine: An anti-rheumatoid drug
Penicillamine: An Anti-Rheumatoid Drug
ISRAELI A. JAFFE, M.D., F.A.C.P. New York, New York
Penicillamine is now established as a useful disease remittive drug in the treatment of rheumatoid arthritis. Improvement during a successful course of treatment may be found in a decrease In the degree of synovitis, which is associated with a reduction in the level of rheumatoid factor and immune complexes in serum and synovial fluid. Vasculitic lesions also resolve. There is roentgenographic evidence of healing of the erosive lesions after two to three years of treatment. The multiplicity of adverse effects caused by the drug limits its usefulness, although with increasing experience more patients are being treated successfully. The induction of autoimmune side effects in a small number of patients treated with penlcillamine has elicited particular interest since this may represent a clue to its mechanism of action on the immune system. The over-all approach to the use of the drug, including currently accepted methods of dosing and safety monitoring, is reviewed. As of this writing, all of the slow-acting, disease-modifying drugs used in the treatment of rheumatoid arthritis have been “borrowed” from other disciplines in internal medicine. Injectable salts of gold were initially developed for the therapy of pulmonary tuberculosis. Chloroquine and hydroxychloroquine are primarily indicated for treatment and prophylaxis of malaria. The cytotoxic immunosuppressants, cyclophosphamide, azathioprine, and methotrexate, are used for the chemotherapy of malignancy and suppression of homograft rejection, Levamisole, which is believed to have a place in the experimental treatment of rheumatoid arthritis, is a canine vermifuge. Penicillamine, which has been shown to be effective as a disease suppressive agent in rheumatoid arthritis [ 11, was first introduced into clinical medicine because of its chelating properties, particularly the mobilization and excretion of excess tissue copper in patients with Wilson’s disease [2]. This is a brief review of the favorable clinical and laboratory changes observed during the treatment of a patient with penicillamine-responsive rheumatoid arthritis. It is suggested that this might serve as a model for the efficacy parameters that are to be expected from a drug classified as a disease-modifying or remittive agent in this disease. CLINICAL AND LABORATORY CHANGES DURING PENICILLAMINE THERAPY
From the College of Physicians and Surgeons, Columbia University, New York, New York. Requests for reprints should be addressed to Dr. Israeli A. Jaffe, College of Physicians and Surgeons, Columbia University, 161 Fort Washington Avenue, New York, New York 10032. _
Penicillamine is indicated in the treatment of rheumatoid arthritis when there is evidence of progressive disease despite attempts at control with simpler measures such as analgesics and nonsteroidal anti-inflammatory drugs. It is increasingly accepted that the application of penicillamine or injectable gold should be made prior to the intro-
December 30, 1983
The American Journal of Medicine
63
ORAL GOLD SYMPOSIUM-JAFFE
duction Of systemic corticosteroids whenever possible. The fumtional capaci@ of the patient, as influenced by the level of disease activity, is the pivotal assessment in the decision-making process. Whether penicillamine is chosen before or after a trial of injectable gold is of little consequence since the agent chosen initially is usually the one with which the treating physician has had the greatest experience. It is far more significant that a prior failure of response or the development of an untoward reaction to either one of these drugs does not preclude a favorable outcome with the other [3-51. These same observations also obtain with respect to penicillamine and the other therapeutically active compounds of the same chemical class, which are not available in the United States [6]. Patients giving a history of penicillin allergy are at no greater risk of having an untoward reaction to penicillamine than those without such a history [7]. Risk factors that have been associated with the development of major toxicity to penicillamine in some patients with rheumatoid arthritis are the HLA marker DRw3 [a], and a previous, serious adverse reaction to chrysotherapy [9]. Neither of these, however, precludes a trial with the drug, although extra care is warranted. By definition, penicillamine is a slow-acting drug in rheumatoid arthritis, with eight to 12 weeks often required before the earliest signs of a clinical response become manifest. In a penicillamine-responsive patient there is diminution in the degree of synovitis [lo], vasculitis [ 111, titer of rheumatoid factor, level of circulating immune complexes [ 121, and the erosive process in bone as evaluated by serial roentgenograms
[131. During the course of penicillamine treatSynovitis. ment there is a gradual reduction in the signs and symptoms of synovial inflammation. The earliest manifestation of this is usually a decrease in the intensity and duration of morning stiffness. Later in treatment, there will be a lessening of pain and tenderness. The use of analgesic and anti-inflammatory drugs is maintained as required for symptomatic control. Only after many months, however, may a gradual withdrawal in symptomatic therapies, particularly corticosteroids, be attempted. Synovial thickening may persist even though signs of active inflammation in a particular joint have abated, and the cellular exudate has been reduced (Figure 1). As the laboratory markers of inflammation, the erythrocyte sedimentation rate and C-reactive protein decline, patients often volunteer an increased sense of well-being and a diminution in easy fatiguability, which may precede the expected increase in hemoglobin. The remittive pattern is not linear, and exacerbations are to be expected throughout the course of treatment. Further increments in the maintenance dosage, up to 1.Oto 1.5 g a day, may be needed in some
64
December
30, 1983
The American
Journal
of Medicine
instances, particularly after the second year of treatment. Rheumatoid vasculitis is perhaps the most Vasculitis. serious of the extra-articular manifestations of rheumatoid disease, and it often results in death. Corticosteroids are of little if any benefit; however, impressive results have been attributed to both penicillamine and cyclophosphamide in reports which, of necessity, were anecdotal and uncontrolled [ 14-161. Since vasculitis is believed to be a fundamental feature of the pathologic process in articular as well as extra-articular rheumatoid arthritis [ 171, a disease-modifying agent should be effective in the management of this syndrome. Immune Complexes. Complexes of rheumatoid factor(s) and the patient’s own immunoglobulins may contribute to the inflammatory process in both the vascular compartment and within the joint [ 181. The level of immune complexes in both of these sites has been shown to decrease during a successful course of penicillamine therapy [ 12,191. Whether these complexes represent a component of the phlogistic process or are merely an epiphenomenon reflecting a more fundamental immunologic defect, their reduction during treatment is a valid marker of a basic or disease-modifying drug effect. Erosions. The healing of bony erosions, or a convincing demonstration of a reduction in the rate of the erosive process, is perhaps the single most important goal of remittive therapy. Treatment with injectable gold salts [20], cyclophosphamide [21], and penicillamine [ 131 has been found efficacious in this regard (Figure 2). TREATMENT REGIMEN The currently accepted treatment regimen for penicillamine is to commence therapy with a single daily dose of 125 to 250 mg. This is best absorbed when taken with water, and apart from food, vitamin and mineral supplements, and other drugs [22]. Increments are generally made at a-week intervals by 250 mg a day as tolerated. The drug may usually be administered in a single daily dose except when it is given in excess of 1.O g a day, when divided doses are better tolerated. As already indicated, eight to 12 weeks may be required for the onset of drug effect, and a similar time period is usually needed to evaluate the effect of further increments (and decrements) in the maintenance dose. The daily dose is flexible and may vary with the duration of treatment. The often temporary exacerbations or “escapes” alluded to previously are common and do not indicate that the treatment should be abandoned. An increase in symptomatic therapy, as well as in penicillamine, will usually suffice, although months may elapse before control is regained. Safety monitoring includes a complete blood count,
ORAL GOLD SYMPOSIUM-JAFFE
Flgure 1. The serial changes in rheumatoid synovial membrane before and six months after the institution of penicillamine therapy. (Top), the pretreatment sample of synovium was obtained from the &sum of the let? wrist during synovectomy and tendon repair. (Bottom), a biopsy specimen obtained from the right wrist during a similar surgical procedure after six months of treatment. Note the marked reduction in the cellular exudate in the post-treatment specimen, a/though the synovial thickening persists. Reproduced through the courtesy of Dr. E. Munthe.
with a direct platelet count, and a urinalysis; it is performed at two-week intervals for the first six months, and monthly thereafter. Equally important, however, is the education of the patient to the concept that any unusual event or symptom that develops while taking the drug, that is, fever, malaise, skin bleeding, and the like, should be cause for temporary cessation of treatment until the physician can adequately assess the problem. Since the effect of penicillamine is cumulative, a brief interruption will not compromise the final result and provides an added measure of safety. Although most adverse effects develop during the first 18 months of therapy, persistent vigilance is mandatory throughout the entire period of treatment.
COMPLICATIONS The precipitate development of neutropenia or marrow aplasia represents the most serious, potentially lifethreatening complication. The pure thrombocytopenias are more likely to be dose-related than idiosyncratic, and often the level of platelets can be titrated against dosage. A similar dose-toxicity relationship has been found with respect to proteinuria (without nephrotic syndrome), in which a modest reduction in the daily maintenance dose may permit continuation of therapy at a lower level of urinary protein excretion. The appearance of moderate and stable hematuria, determined microscopically or by dip-stick, is no longer considered
December 30, 1983
The American Journal of Medlcine
85
ORAL GOLD SYMPOSIUM--JAFFE
Figure 2. Roentgenographic changes in the hip joints of a 3 l-year-old female patient with rheumatoid arthritis. (Left), the pretreatment x-ray film shows considerable osteoporosis and bone destruction, with protrusion of both femoral heads into the acetabulum. (Right), after three years of penicillamine treatment that resulted in a marked amelioration in disease activity, the osseous lesions appear to have healed with considerable remineralization of the involved bone. Note the healing of the protrusio acetabulae bilaterally.
rare or an indication for drug withdrawal. The mechanism for this microhematuria is unknown. If the amount of hematuria shows a progressive increase, treatment must be interrupted while the problem is assessed and other causes for hematuria ruled out. The induction of autoimmune syndromes by penicillamine is unique in clinical medicine, since no other drug has been shown to produce such a wide spectrum of immunologically mediated adverse effects [23]. Myasthenia gravis [24], pemphigus [25], and SLE [26] all may be induced by the drug, along with the appropriate autoantibody as found in the spontaneously occurring disease [23]. The membranous glomerulopathy and hematologic toxicities-neutropenia, thrombocytopenia, aplastia anemia, pure red cell anemia, and thrombotic thrombocytopenic purpura-are undoubtedly mediated by immunologic mechanisms as well. All of these syndromes have been found in patients with Wilson’s disease treated with penicillamine; hence, they are a feature of the drug itself rather than the result of the abnormal immunologic responsiveness believed present in patients with rheumatoid arthritis. An understanding of the pathogenesis of penicillamine-induced autoimmunity might provide insight into the mode of action of the drug in rheumatoid arthritis, since penicillamine is neither cytotoxic nor immunosuppressive in experimental systems. One explanation
66
December 30. 1963
The American Journal of Medlclne
is that the drug, probably via its free SH group, is capable of avidly binding to cell surface antigens, thereby rendering them structurally altered and antigenic. This would be consistent with a haptene-like process. The alternative possibility is that it acts by exerting an immunoregulatory function, perhaps by a central action on the thymus [23]. This might explain its beneficial effects on the clinical and immunologic manifestations of rheumatoid arthritis, which are suppressed by the drug, and the seemingly paradoxical enhancement of the immune response against self antigens, resulting in development of the autoimmune syndromes. There is little experimental evidence to support either of these hypotheses. The most consistent laboratory studies have been those of Lipsky et al [27] who have shown that penicillamine, when accompanied by small amounts of supplemental copper in vitro, profoundly inhibits peripheral blood lymphocyte responsiveness. This phenomenon was subsequently shown to apply only to helper T cells, not to suppressor-cytotoxic T cells nor to B cells [28]. Sulfhydryl compounds other than penicillamine, also in the presence of small amounts of added copper, showed similar properties in this in vitro system [27,28]. Some of these compounds, which have a “penicillamine-like” action in rheumatoid arthritis, also have been found to induce autoimmunity in patients [29,30]. It is not yet possible
ORAL GOLD SYMPOSIUM-JAFFE
to synthesize all of these clinical and laboratory observations into a unified hypothesis that can satisfactorily explain the mode of action of penicillamine in rheumatoid arthritis. However, this is a subject of ongoing investigation in many centers, and further observations are awaited with interest. Data on the results of the long-term treatment of rheumatoid arthritis with penicillamine are incomplete, since it was approved for the treatment of rheumatoid arthritis in the United States only in 1978. Based upon the longer European experience, as well as my own series of patients, the following approximation after five years of follow-up can be made. About 20 percent of patients continue to receive treatment, for their disease relapses whenever an attempt is made to withdraw the drug. Of those no longer receiving penicillamine after five years, three groups of equal numbers of patients can be identified. In one group the patients have experienced a remission of disease, and further basic drug therapy is no longer required. In a second group treatment has been terminated because of the development of adverse effects that mandated discontinuance of the drug. In the third group therapy was withdrawn following loss of response after a period of time (secondary failure). In this latter group resumption of penicillamine therapy after one year or more without the drug was
often associated with a restoration of responsiveness equal to that which had been experienced initially. Because of the many variables that are present throughout a course of treatment, penicillamine administration to patients with rheumatoid arthritis must be individualized and cannot follow a rigid or fixed dosage protocol. Greatest success is achieved by those physicians who have painstakingly amassed their own clinical experience with the drug. This is especially noteworthy in the management of adverse effects, when the withdrawal rate falls as familiarity with the drug increases. This is also evident in the achievement of long-term efficacy. Here, the mastery of the subtle nuances required for the proper adjustment of the daily maintenance dose is reflected by the larger number of patients who derive benefit from the drug for a longer period of time. Despite the lack of a clear understanding of its action, as well as the high incidence of adverse reactions that may attend its use, penicillamine is increasingly accepted as a highly effective remittive agent for this disease. It is anticipated that it will serve as a prototype for disease-modifying drugs of this chemical class, which will afford comparable or even greater efficacy, with a more favorable benefit-to-risk ratio.
REFERENCES 1. 2. 3.
4.
5.
6.
7.
8.
9.
10. 11.
Multi-centre Trial Group:Controlledtrial of d-penicillamine in severe rheumatoid arthritis. Lancet 1973; I: 275-280. Walshe JM: Wilson’s disease: new oral therapy. Lancet 1956; I: 25-26. Webley M, Coomes E: An assessment of penicillamine therapy in rheumatoid arthritis and the influence of previous gold therapy. J Rheumatol 1979; 6: 20-24. Steven MM, Hunter JA, Murdoch RM, Capell HA: Does the order of second-line treatment in rheumatoid arthritis matter? Br Med J 1982; 1: 79-81. Kean WF, Colin JL Lock, Howard-Lock HE, Buchanan WW: Prior gold therapy does not influence the adverse effects of d-penicillamine in rheumatoid arthritis. Arthritis Rheum 1982; 25: 917-922. Jaffe IA: Thiol compounds with penicillamine-like activity and possible mode of action in rheumatoid arthritis. Clin Pharm and Ther Series, Praege Scientific 1983; 3: 555-568. Bell CL, Graziano FM: The safety of administration of penicillamine to penicillin sensitive individuals. Arthritis Rheum 1983; 26: 801-803. Panayi GS, Wooley P, Batchelor JR: Genetic basis of rheumatoid disease: HLA antigens, disease manifestations, and toxic reactions to drugs. Br Med J 1978; 2: 1326-1328. Halla JT, Cassidy J, Hardin JG: Sequential gold and penicillamine therapy in rheumatoid arthritis. Am J Med 1982; 72: 423-426. Hill HFH: The treatment of rheumatoid arthritis with penicillamine. Semin Arthritis Rheum 1977; 6: 361-388. Jaffe IA: The treatment of rheumatoid arthritis and necrotizing vasculitis with penicillamine. Arthritis Rheum 1970; 13: 436-443.
12.
13.
14.
15.
16.
17. 18.
19.
20.
21.
Jaffe IA: Penicillamine treatment of rheumatoid arthritis: effect on immune complexes. Ann NY Acad Sci 1975; 256: 330-337. Gibson T, Huskisson EC, Wojtulewski JA, et al: Evidence that d-penicillamine alters the course of rheumatoid arthritis. Rheum Rehab 1976; 15: 211-215. Jaffe IA: Rheumatoid vasculitis-report of a second case treated with penicillamine. Arthritis Rheum 1968; 11: 585-589. Fauci AS, Katz P, Haynes BF, Wolff SM: Cyclophosphamide therapy of severe systemic necrotizing vasculitis. N Engl J Med 1979; 301: 235-238. Abel T, Andrews B, Polley H, et al: Rheumatoid vasculitis: effect of cyclophosphamide on the clinical course and levels of circulating immune complexes. Ann Intern Med 1980; 93: 407-413. Bywaters EGL. Scott JT: The natural history of vascular lesions in rheumatoid arthritis. J Chron Dis 1963; 16: 905-914. Halla JT. Volanakis JE, Schrohenloher RE: Immune complexes in rheumatoid arthritis sera and synovial fluids. Arthritis Rheum 1979; 22: 440-448. Wollheim F: Effects of d-penicillamine on circulating protein complexes in rheumatoid arthritis and primary biliary cirrhosis. J Rheum 1981; 8 (suppl 7): 74-79. Sigler JW, Bluhm GB, Duncan H. Sharp JT, Ensign DC, McCrum WR: Gold salts in the treatment of rheumatoid arthritis: a double-blind study. Ann Intern Med 1974; 80: 21-26. Cooperating Clinics Committee of the American Rheumatism Association: A controlled trial of cyclophosphamide in rheumatoid arthritis. N Engl J Med 1970; 283: 883-889.
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22. 23.
24.
25.
26.
68
McLaughlin GE, Utsinger PD, Hicks JT: D-penicillamine: before, during, or after? Arthritis Rheum 1981; 24: 1453. Jaffe IA: Induction of autoimmune syndromes by penicillamine therapy in rheumatoid arthritis and other diseases. Springer Semin lmmunopathol 1981; 4: 193-207. Bucknall RC, Dixon A St J, Glick EN, Woodland J, Zutshi DW: Myasthenia gravis associated with penlcillamine treatment for rheumatoid arthritis. Br Med J 1975; 1: 600-602. Marsden RA, Ryan TJ, Vanhegan RI, Walshe M, Hill H, Mowat AG: Pemphigus foliaceus induced by penicillamine. Br Med J 1976; 2: 1423-1424. Crouzet J, Camus JP, Leca AP, Guillien P, Lievre JA: Lupus induced by penicillamine during the treatment of rheumatoid arthritis. Ann Med Intern 1974; 125: 71-79.
December 30, 1993
The American Journal of Medlcine
27.
28.
29.
30.
Lipsky PE, Ziff M: The effect of d-penicillamine on mitogeninduced human lymphocyte proliferation: synergistic inhibition by d-penicillamine and copper salts. J lmmunol 1978; 120: 1006-1013. Lipsky PE, Ziff M: Inhibition of human helper T cell function in vitro by’d-penicillamine and CuSO.,. J Clin Invest 1980; 65: 1069-1076. Amor B, Mery C, de Gery A: La tiopronine, nouvel antirheumatismal a action lente dans la polyarthrite rheumatoide. Rev Rhumat 1980; 47: 157-162. Amor B, Cherot A, Delbarre F: Syndrome nephrotique lie a I’emploi de la pyrithioxine dans le traitment de la polyarthrite rheumatoide. La Nouv Presse Med 1979; 8: 2023-2024.
ISRAELI A. JAFFE, M.D., F.A.C.P. New York, New York
Penicillamine is now established as a useful disease remittive drug in the treatment of rheumatoid arthritis. Improvement during a successful course of treatment may be found in a decrease In the degree of synovitis, which is associated with a reduction in the level of rheumatoid factor and immune complexes in serum and synovial fluid. Vasculitic lesions also resolve. There is roentgenographic evidence of healing of the erosive lesions after two to three years of treatment. The multiplicity of adverse effects caused by the drug limits its usefulness, although with increasing experience more patients are being treated successfully. The induction of autoimmune side effects in a small number of patients treated with penlcillamine has elicited particular interest since this may represent a clue to its mechanism of action on the immune system. The over-all approach to the use of the drug, including currently accepted methods of dosing and safety monitoring, is reviewed. As of this writing, all of the slow-acting, disease-modifying drugs used in the treatment of rheumatoid arthritis have been “borrowed” from other disciplines in internal medicine. Injectable salts of gold were initially developed for the therapy of pulmonary tuberculosis. Chloroquine and hydroxychloroquine are primarily indicated for treatment and prophylaxis of malaria. The cytotoxic immunosuppressants, cyclophosphamide, azathioprine, and methotrexate, are used for the chemotherapy of malignancy and suppression of homograft rejection, Levamisole, which is believed to have a place in the experimental treatment of rheumatoid arthritis, is a canine vermifuge. Penicillamine, which has been shown to be effective as a disease suppressive agent in rheumatoid arthritis [ 11, was first introduced into clinical medicine because of its chelating properties, particularly the mobilization and excretion of excess tissue copper in patients with Wilson’s disease [2]. This is a brief review of the favorable clinical and laboratory changes observed during the treatment of a patient with penicillamine-responsive rheumatoid arthritis. It is suggested that this might serve as a model for the efficacy parameters that are to be expected from a drug classified as a disease-modifying or remittive agent in this disease. CLINICAL AND LABORATORY CHANGES DURING PENICILLAMINE THERAPY
From the College of Physicians and Surgeons, Columbia University, New York, New York. Requests for reprints should be addressed to Dr. Israeli A. Jaffe, College of Physicians and Surgeons, Columbia University, 161 Fort Washington Avenue, New York, New York 10032. _
Penicillamine is indicated in the treatment of rheumatoid arthritis when there is evidence of progressive disease despite attempts at control with simpler measures such as analgesics and nonsteroidal anti-inflammatory drugs. It is increasingly accepted that the application of penicillamine or injectable gold should be made prior to the intro-
December 30, 1983
The American Journal of Medicine
63
ORAL GOLD SYMPOSIUM-JAFFE
duction Of systemic corticosteroids whenever possible. The fumtional capaci@ of the patient, as influenced by the level of disease activity, is the pivotal assessment in the decision-making process. Whether penicillamine is chosen before or after a trial of injectable gold is of little consequence since the agent chosen initially is usually the one with which the treating physician has had the greatest experience. It is far more significant that a prior failure of response or the development of an untoward reaction to either one of these drugs does not preclude a favorable outcome with the other [3-51. These same observations also obtain with respect to penicillamine and the other therapeutically active compounds of the same chemical class, which are not available in the United States [6]. Patients giving a history of penicillin allergy are at no greater risk of having an untoward reaction to penicillamine than those without such a history [7]. Risk factors that have been associated with the development of major toxicity to penicillamine in some patients with rheumatoid arthritis are the HLA marker DRw3 [a], and a previous, serious adverse reaction to chrysotherapy [9]. Neither of these, however, precludes a trial with the drug, although extra care is warranted. By definition, penicillamine is a slow-acting drug in rheumatoid arthritis, with eight to 12 weeks often required before the earliest signs of a clinical response become manifest. In a penicillamine-responsive patient there is diminution in the degree of synovitis [lo], vasculitis [ 111, titer of rheumatoid factor, level of circulating immune complexes [ 121, and the erosive process in bone as evaluated by serial roentgenograms
[131. During the course of penicillamine treatSynovitis. ment there is a gradual reduction in the signs and symptoms of synovial inflammation. The earliest manifestation of this is usually a decrease in the intensity and duration of morning stiffness. Later in treatment, there will be a lessening of pain and tenderness. The use of analgesic and anti-inflammatory drugs is maintained as required for symptomatic control. Only after many months, however, may a gradual withdrawal in symptomatic therapies, particularly corticosteroids, be attempted. Synovial thickening may persist even though signs of active inflammation in a particular joint have abated, and the cellular exudate has been reduced (Figure 1). As the laboratory markers of inflammation, the erythrocyte sedimentation rate and C-reactive protein decline, patients often volunteer an increased sense of well-being and a diminution in easy fatiguability, which may precede the expected increase in hemoglobin. The remittive pattern is not linear, and exacerbations are to be expected throughout the course of treatment. Further increments in the maintenance dosage, up to 1.Oto 1.5 g a day, may be needed in some
64
December
30, 1983
The American
Journal
of Medicine
instances, particularly after the second year of treatment. Rheumatoid vasculitis is perhaps the most Vasculitis. serious of the extra-articular manifestations of rheumatoid disease, and it often results in death. Corticosteroids are of little if any benefit; however, impressive results have been attributed to both penicillamine and cyclophosphamide in reports which, of necessity, were anecdotal and uncontrolled [ 14-161. Since vasculitis is believed to be a fundamental feature of the pathologic process in articular as well as extra-articular rheumatoid arthritis [ 171, a disease-modifying agent should be effective in the management of this syndrome. Immune Complexes. Complexes of rheumatoid factor(s) and the patient’s own immunoglobulins may contribute to the inflammatory process in both the vascular compartment and within the joint [ 181. The level of immune complexes in both of these sites has been shown to decrease during a successful course of penicillamine therapy [ 12,191. Whether these complexes represent a component of the phlogistic process or are merely an epiphenomenon reflecting a more fundamental immunologic defect, their reduction during treatment is a valid marker of a basic or disease-modifying drug effect. Erosions. The healing of bony erosions, or a convincing demonstration of a reduction in the rate of the erosive process, is perhaps the single most important goal of remittive therapy. Treatment with injectable gold salts [20], cyclophosphamide [21], and penicillamine [ 131 has been found efficacious in this regard (Figure 2). TREATMENT REGIMEN The currently accepted treatment regimen for penicillamine is to commence therapy with a single daily dose of 125 to 250 mg. This is best absorbed when taken with water, and apart from food, vitamin and mineral supplements, and other drugs [22]. Increments are generally made at a-week intervals by 250 mg a day as tolerated. The drug may usually be administered in a single daily dose except when it is given in excess of 1.O g a day, when divided doses are better tolerated. As already indicated, eight to 12 weeks may be required for the onset of drug effect, and a similar time period is usually needed to evaluate the effect of further increments (and decrements) in the maintenance dose. The daily dose is flexible and may vary with the duration of treatment. The often temporary exacerbations or “escapes” alluded to previously are common and do not indicate that the treatment should be abandoned. An increase in symptomatic therapy, as well as in penicillamine, will usually suffice, although months may elapse before control is regained. Safety monitoring includes a complete blood count,
ORAL GOLD SYMPOSIUM-JAFFE
Flgure 1. The serial changes in rheumatoid synovial membrane before and six months after the institution of penicillamine therapy. (Top), the pretreatment sample of synovium was obtained from the &sum of the let? wrist during synovectomy and tendon repair. (Bottom), a biopsy specimen obtained from the right wrist during a similar surgical procedure after six months of treatment. Note the marked reduction in the cellular exudate in the post-treatment specimen, a/though the synovial thickening persists. Reproduced through the courtesy of Dr. E. Munthe.
with a direct platelet count, and a urinalysis; it is performed at two-week intervals for the first six months, and monthly thereafter. Equally important, however, is the education of the patient to the concept that any unusual event or symptom that develops while taking the drug, that is, fever, malaise, skin bleeding, and the like, should be cause for temporary cessation of treatment until the physician can adequately assess the problem. Since the effect of penicillamine is cumulative, a brief interruption will not compromise the final result and provides an added measure of safety. Although most adverse effects develop during the first 18 months of therapy, persistent vigilance is mandatory throughout the entire period of treatment.
COMPLICATIONS The precipitate development of neutropenia or marrow aplasia represents the most serious, potentially lifethreatening complication. The pure thrombocytopenias are more likely to be dose-related than idiosyncratic, and often the level of platelets can be titrated against dosage. A similar dose-toxicity relationship has been found with respect to proteinuria (without nephrotic syndrome), in which a modest reduction in the daily maintenance dose may permit continuation of therapy at a lower level of urinary protein excretion. The appearance of moderate and stable hematuria, determined microscopically or by dip-stick, is no longer considered
December 30, 1983
The American Journal of Medlcine
85
ORAL GOLD SYMPOSIUM--JAFFE
Figure 2. Roentgenographic changes in the hip joints of a 3 l-year-old female patient with rheumatoid arthritis. (Left), the pretreatment x-ray film shows considerable osteoporosis and bone destruction, with protrusion of both femoral heads into the acetabulum. (Right), after three years of penicillamine treatment that resulted in a marked amelioration in disease activity, the osseous lesions appear to have healed with considerable remineralization of the involved bone. Note the healing of the protrusio acetabulae bilaterally.
rare or an indication for drug withdrawal. The mechanism for this microhematuria is unknown. If the amount of hematuria shows a progressive increase, treatment must be interrupted while the problem is assessed and other causes for hematuria ruled out. The induction of autoimmune syndromes by penicillamine is unique in clinical medicine, since no other drug has been shown to produce such a wide spectrum of immunologically mediated adverse effects [23]. Myasthenia gravis [24], pemphigus [25], and SLE [26] all may be induced by the drug, along with the appropriate autoantibody as found in the spontaneously occurring disease [23]. The membranous glomerulopathy and hematologic toxicities-neutropenia, thrombocytopenia, aplastia anemia, pure red cell anemia, and thrombotic thrombocytopenic purpura-are undoubtedly mediated by immunologic mechanisms as well. All of these syndromes have been found in patients with Wilson’s disease treated with penicillamine; hence, they are a feature of the drug itself rather than the result of the abnormal immunologic responsiveness believed present in patients with rheumatoid arthritis. An understanding of the pathogenesis of penicillamine-induced autoimmunity might provide insight into the mode of action of the drug in rheumatoid arthritis, since penicillamine is neither cytotoxic nor immunosuppressive in experimental systems. One explanation
66
December 30. 1963
The American Journal of Medlclne
is that the drug, probably via its free SH group, is capable of avidly binding to cell surface antigens, thereby rendering them structurally altered and antigenic. This would be consistent with a haptene-like process. The alternative possibility is that it acts by exerting an immunoregulatory function, perhaps by a central action on the thymus [23]. This might explain its beneficial effects on the clinical and immunologic manifestations of rheumatoid arthritis, which are suppressed by the drug, and the seemingly paradoxical enhancement of the immune response against self antigens, resulting in development of the autoimmune syndromes. There is little experimental evidence to support either of these hypotheses. The most consistent laboratory studies have been those of Lipsky et al [27] who have shown that penicillamine, when accompanied by small amounts of supplemental copper in vitro, profoundly inhibits peripheral blood lymphocyte responsiveness. This phenomenon was subsequently shown to apply only to helper T cells, not to suppressor-cytotoxic T cells nor to B cells [28]. Sulfhydryl compounds other than penicillamine, also in the presence of small amounts of added copper, showed similar properties in this in vitro system [27,28]. Some of these compounds, which have a “penicillamine-like” action in rheumatoid arthritis, also have been found to induce autoimmunity in patients [29,30]. It is not yet possible
ORAL GOLD SYMPOSIUM-JAFFE
to synthesize all of these clinical and laboratory observations into a unified hypothesis that can satisfactorily explain the mode of action of penicillamine in rheumatoid arthritis. However, this is a subject of ongoing investigation in many centers, and further observations are awaited with interest. Data on the results of the long-term treatment of rheumatoid arthritis with penicillamine are incomplete, since it was approved for the treatment of rheumatoid arthritis in the United States only in 1978. Based upon the longer European experience, as well as my own series of patients, the following approximation after five years of follow-up can be made. About 20 percent of patients continue to receive treatment, for their disease relapses whenever an attempt is made to withdraw the drug. Of those no longer receiving penicillamine after five years, three groups of equal numbers of patients can be identified. In one group the patients have experienced a remission of disease, and further basic drug therapy is no longer required. In a second group treatment has been terminated because of the development of adverse effects that mandated discontinuance of the drug. In the third group therapy was withdrawn following loss of response after a period of time (secondary failure). In this latter group resumption of penicillamine therapy after one year or more without the drug was
often associated with a restoration of responsiveness equal to that which had been experienced initially. Because of the many variables that are present throughout a course of treatment, penicillamine administration to patients with rheumatoid arthritis must be individualized and cannot follow a rigid or fixed dosage protocol. Greatest success is achieved by those physicians who have painstakingly amassed their own clinical experience with the drug. This is especially noteworthy in the management of adverse effects, when the withdrawal rate falls as familiarity with the drug increases. This is also evident in the achievement of long-term efficacy. Here, the mastery of the subtle nuances required for the proper adjustment of the daily maintenance dose is reflected by the larger number of patients who derive benefit from the drug for a longer period of time. Despite the lack of a clear understanding of its action, as well as the high incidence of adverse reactions that may attend its use, penicillamine is increasingly accepted as a highly effective remittive agent for this disease. It is anticipated that it will serve as a prototype for disease-modifying drugs of this chemical class, which will afford comparable or even greater efficacy, with a more favorable benefit-to-risk ratio.
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