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Drug Therapy in Rheumatic Diseases
Symposium on Rheumatic Disease
Drug Therapy in Rheumatic Diseases Robert L. Roe, M.D. *
The rheumatic diseases appear to be of diverse etiology. Immunologic mechanisms are often at work and hereditary, environmental, and infectious factors have been implicated in one or more of the disorders. Although the exact pathogenesis of the rheumatic diseases is unclear, the inflammatory process is one shared in common by most, if not all, of the acute rheumatologic processes. For this reason, the majority of the drugs used in the treatment of arthritis and the allied rheumatic conditions are anti-inflammatory a,gents. These agents, either singly or in appropriate combination, are the mainstay of pharmacologic therapy for both acute and chronic arthritis, although in chronic conditions, physical medicine, and surgery often play equally important roles. Drugs with anti-inflammatory activity range from salicylate, one of the oldest and most widely used medicinals, to corticosteroids. They include the non salicylate nonsteroidal anti-inflammatory agents, colchicine, antimalarials, gold, and experimental agents such as penicillamine and levamisole. It is important to remember that anti-inflammatory agents in general do not alter the underlying disease but rather alter one or more systemic manifestations of that disease by relatively nonspecific means. As a consequence, one must set an attainable therapeutic end point (generally relief of evidence of inflammation) and achieve it using the smallest possible doses of the least toxic agent or agents. Therapy with a more toxic agent should be considered only when a maximum tolerated dose of the initial agent is ineffective. Inflammation is an elaborate scheme of interacting events involving multiple chemical mediators. 28 • 34 Furthermore, it is undoubtedly a normal protective mechanism. As a consequence, total inhibition of the inflammatory response is undoubtedly inimical to the host. Nevertheless, because inflammation is responsible for much of the morbidity of the rheumatic diseases it must be inhibited. Inhibition can be accomplished using a variety of nonsteroidal drugs as well as steroids, and it is these drugs that will be discussed herein. One must keep in mind that the animal models developed to assess the effectiveness of new anti-inflammatory drugs are generally poor imitations of human disease and on oc'Chief of Rheumatology Unit, San Francisco General Hospital; Assistant Clinical Professor of Medicine, University of California, San Francisco
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casion are poorly reproducible. Too little is known about the entry of drugs into the sites of inflammation or how drugs actually inhibit or reverse the inflammatory response. The animal models used not only may provide contradictory results on occasion but they may also yield results that cannot be readily extrapolated to human patients. In addition, they certainly result in the development of agents with almost identical therapeutic or toxic effects. NON-STEROIDAL ANTI-INFLAMMATORY AGENTS
Aspirin The salicylates are the first-line drug in the treatment of the majority of non-life threatening rheumatic disorders. Potions rich in salicylic acid are as old as herbal therapy and are ubiquitous in the modern pharmacopoeia; currently, more than 200 prescription and nonprescription products contain aspirin. 24 Aspirin39 is the standard of therapy for the rheumatic disorders, and all other agents must be measured against it. Salicylates have been used since antiquity, and in the second century A.D. Galen related most of the pharmacologic effects of salicylates that we now recognize. There is evidence that salicylates both inhibit the production of mediators of inflammation and interfere with the peripheral effects of such mediators. It is essential when using aspirin for anti-inflammatory action, however, to keep in mind its multiplicity of pharmacologic effects, both beneficial and toxic. 29 For the majority of patients, the usual therapeutic range of serum concentrations of salicylate is 15 to 30 mg per 100 m!. However, such high levels are not required to produce the analgesic effect of salicylates. Aspirin has a half-life that increases as its concentration in serum increases. 25 But determinations of drug level cannot substitute for careful medical observation and judgment. Dosing must always be interpreted in a context of all clinical data. The therapeutic indication for aspirin or salicylate must always be kept in mind as well. Effects on platelets, for instance, can occur with doses as small as 10 mg per kg of body weight, whereas manifest evidence of the uncoupling of oxydative phosphorylation requires approximately 60 mg per kg body weight. The anti-inflammatory activity of salicylates is perhaps the most important rationale for clinical use of these drugs. It is probable that they both inhibit the production of mediators of inflammation and interfere with the peripheral effects of such mediators, probably by blocking a route leading to or from the speCific receptors for the vasoactive peptide agonists. Aspirin can inhibit the release of histamine, inhibit the effect of exogenously administered bradykinen, inhibit prostaglandin synthetase, render neutrophils nonresponsive to chemotactic stimuli, interfere with granulocyte adherence, and at high concentrations interfere with the formation of antigen-antibody complex. Aspirin also may stabilize lysosomal membrane and suppress lymphocyte function (i.e., transformation and antibody synthesis). The mechanism of all of these effects is unclear but may be related in part to the uncoupling of energy production and to interference with normal cyclic AMP metabolism.
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Additional pharmacologic effects of aspirin include analgesia, antipyresis, normalization of carbohydrate intolerance in diabetic patients, depression of concentrations of free fatty acids and cholesterol, inhibition of platelet aggregation, and the well recognized diaphasic effect on urate clearance. Toxic effects include frequent gastrointestinal irritation with minor blood loss, occasional massive gastrointestinal blood loss, pylorospasm and centrally mediated vomiting, hepatic injury in normal persons as well as in patients with rheumatic disease, sodium and water retention, tinnitus, allergy, nephropathy, and, with massive doses, hypoprothrombinemia. In man, unlike some experimental animals, it appears that aspirin rarely, if ever, causes nephropathy when used alone 26 although it may increase the amount of urinary sediment. Nevertheless, recent literatureS suggests an average decrease in creatinine clearance of 25 per cent in normal persons who just started salicylate therapy. This, however, does not appear to result from impairment of glomerular function. Although the half-life of aspirin may approach 18 hours with large doses, patients with active rheumatologic disorders generally require a dose every 4 to 6 hours to achieve optimal clinical control. The appropriate dose of aspirin varies widely from patient to patient, although a salicylate level in excess of 20 mg per 100 ml is usually required for maximal efficacy. In patients without preexisting hearing loss, the onset of tinnitus can be used to assess salicylate level. In a recent study,30 of 52 patients who experienced tinnitus, the serum salicylate level was invariably greater than 19.6 mg per 100 ml and averaged 30.4 mg per 100 ml, but the aspirin dose varied from 12 to 36 tablets per day.
Acetaminophen Acetaminophen, called paracetamol in the United Kingdom, is a derivative of paraamino phenol,17 It is a non salicylate analgesic and antipyretic agent that has no anti-inflammatory effect. Therefore, even though it does not cause the gastric erosion and bleeding associated with aspirin, its application in patients with active rheumatoid arthritis or other rheumatic disorders is limited. The toxicity of acetaminophen is limited to rare hypersensitivity and even rarer hepatotoxicity. Fatal hepatic necrosis has occurred in patients poisoned with acetaminophen. Acetaminophen has also been implicated in causing renal injury when used in large doses as part of a combination of analgesics over a prolonged period of time. Its application in rheumatic diseases should be limited to analgesia in patients intolerant to aspirin.
Indomethacin Indomethacin is an indole derivative and a potent anti-inflammatory agent. 9 • 12 In addition, it is a more potent antipyretic drug than aspirin and is particularly effective in treating fever in patients with lymphoma or other malignant processes. It is a poor analgesic except when pain is caused by inflammation. Although the mechanism of its anti-inflammatory action is unclear, indomethacin inhibits prostaglandin synthetase, may decrease chemotaxis and the mobility of polymorphonucleocytes,
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and may affect the function of both T and B lymphocytes. In addition, indomethacin uncouples oxidative phosphorylation as does aspirin. Indomethacin is of therapeutic value and is one of the drugs of choice for acute gouty arthritis, pseudo gout, and ankylosing spondylitis. It is of value in the treatment of moderate to severe rheumatoid arthritis in adults and of severe osteoarthritis of the hip, which is intriguing because the latter is generally not an inflammatory process. Indomethacin also is effective in the treatment of Reiter's disease, psoriatic arthritis, bursitis, tendinitis, traumatic synovitis, and the pain of both pleuritis and pericarditis. The use of indomethacin is contraindicated in children and in pregnant or lactating women. It is also contraindicated in patients with severe sensitivity to aspirin. In the treatment of acute gouty arthritis or acute pseudogout, 200 mg of indomethacin should be administered the first day followed by 150 mg per day for 3 days. For other indications, the usual dose is 25 mg two or three times a day with an increase by 25 to 50 mg per day at weekly intervals until a satisfactory response is achieved. The maximum total daily dose should be between 150 and 200 mg. A therapeutic trial with indomethacin as with the majority of the other nonsteroidal anti-inflammatory agents should probably not exceed 2 weeks if there is no response. Toxic manifestations of indomethacin include headache, dizziness, vertigo, and rarely somnolence, confusion, hallucination, sodium and water retention, gastric upset, anorexia, nausea, diarrhea, rash,3 and very rarely pancreatitis. Major toxic manifestations include gastrointestinal bleeding, ulceration or perforation, hepatotoxicity, and rarely aplastic anemia. Adverse reactions tend to be dose related although they may emerge any time during therapy. The drug must always be discontinued for any of the major toxic reactions.
Phenylbutazone Phenylbutazone, a congener of aminopyrine, is a potent anti-inflammatory drug. 6 • 32 However, it is a poor analgesic and a weak antipyretic agent and is too toxic to be used for these purposes. 6 • 32 The drug is also uricosuric and causes uncoupling of oxidative phosphorylation. It, like indomethacin, should be used as the drug of choice in only a few conditions, specifically acute gout, acute pseudogout, and ankylosing spondylitis. It may be useful, however, for short term treatment of seronegative arthritis, psoriatic arthritis, and the inflammatory nonarticular syndromes including tendinitis, capsulitis, and tenosynovitis. Phenylbutazone should not be used in doses greater than 600 mg per day, and then only for a brief duration. The only condition for which long-term use is justified is ankylosing spondylitis, and the dose should be the smallest that will control symptoms, preferably 200 mg per day. The majority of the toxic manifestations of phenylbutazone are related to both dose and duration of treatment and are more common in the elderly. 13,44 The manifestations include nausea, vomiting, diarrhea, vertigo, insomnia, and sodium retention. Severe manifestations include stomatitis, gastritis, colitis, hepatitis, renal failure,2 myocardiopathy, and
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suppression of bone marrow production. Marrow suppression can occur suddenly after only a few doses, or more gradually after long-term therapy. Complete blood counts should be obtained weekly or semi-weekly to monitor for gradual marrow failure. It is impossible to monitor for acute failure, which appears to occur in less than 0.002 per cent of treated patients. Phenylbutazone avidly binds to protein and competes with coumarins and oral hypoglycemic agents for such binding, thereby potentiating their effects. It also stimulates the enzyme system responsible for its own metabolism and the metabolism of such agents as phenobarbital, diphenylhydantoin, and digitoxin. Discontinuance of phenylbutazone therapy in patients simultaneously treated with these drugs will therefore require alteration of their dosage as well.
NEWER NONSTEROIDAL ANTI-INFLAMMATORY AGENTS
Three of the newer nonsteroidal anti-inflammatory agents are ph enylalkinoic acids; the anti-inflammatory property of this series was first established in 1968.! The parent compound, ibufenac, was roughly equal to aspirin22 in efficacy but was a potent hepatotoxin causing hepatocellular necrosis and death. The compounds of this series were thus initially suspected of being hepatotoxins, although they have shown little if any such toxicity. All are analgesic and antipyretic, and at least at higher doses, have anti-inflammatory activity. They all decrease platelet aggregation and cause sodium and water retention. In general, they have the same signs of toxicity including gastrointestinal symptoms such as epigastric distress, nausea, vomiting, constipation, and anorexia, neurologic effects such as headache, inability to concentrate, depression, nervousness, and tinnitus, and cutaneous effects such as rash and pruritus. All have an efficacy similar to that of high doses of aspirin but with potentially less frequent toxicity. The mechanisms by which the newer nonsteroidal anti-inflammatory agents combat inflammation are no more clearly defined than are the mechanisms of the older agents. 7 All of them inhibit prostaglandin synthetase, but because prostaglandins appear only in the later phases of inflammation, the agents may interact with other mediators as well. Additional evidence suggests that most may also stabilize lysosomal membranes. 4o Considerable research must be done before exact mechanisms can be determined. Because each of the new agents has had relatively limited clinical exposure, they will be briefly reviewed in sequence.
Fenoprofen Calcium Fenoprofen calcium is a phenylalkinoic acid that is rapidly absorbed, reaching peak plasma levels in 2 hours. However, its half-life is only 3 hours and therefore dosing is required 4 times per day. The efficacy of fenoprofen is approximately equal to that of aspirin, with perhaps less toxicity than high doses of salicylate. 2 ! Adverse reactions to this agent include gastrointestinal, neurologic, and cutaneous manifes-
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tations. Fenoprofen calcium has also been associated with renal lesions in some experimental animals and elevated levels of blood urea nitrogen in a few patients. Disturbances in liver function have been reported occasionally. The agent may interact with oral hypoglycemic and anticoagulant drugs because of its avid protein binding. The usual dose is 2400 to 3200 mg per day orally in four divided doses.
Ibuprofen Ibuprofen, which differs from the parent compound ibufenac by a single methyl group, has been marketed in the United States for a longer period of time than the other agents of this series. It is equal to or more effective than indomethacin or aspirin, and peak plasma levels are achieved within 90 minutes of administration. 5 • 14 Its half-life is approximately 2 hours and thus the recommended dosage regimen is four times a day. Ibuprofen avidly binds to protein. About 60 per cent of the dose is excreted in the urine and the remainder is excreted in the intestinal tract. Adverse reactions include gastrointestinal, neurologic, and cutaneous manifestations as well as edema, increased bleeding time, and occasional elevation of liver function tests. Other manifestations of hepatotoxicity have not been reported. The agent may interact with other protein-bound drugs such as anticoagulant and hypoglycemic drugs. The usual dose is 2400 mg per day orally in three or four divided doses. Naproxen Naproxen is also a phenylalkinoic acid. It may inhibit lysosomal release in addition to inhibiting prostaglandin synthetase. It has a halflife of approximately 13 hours, and therefore a more constant blood level of drug can be maintained with less frequent dosing. 35 The agent is 99 per cent protein bound. Naproxen is equal to or more effective than indomethacin or aspirin and probably has less gastrointestinal toxicity than aspirin. 15 Adverse reactions include gastrointestinal, neurologic, and cutaneous manifestations, and rarely edema and increased bleeding time. The drug's avid protein-binding makes its potential for interaction with oral coagulants and hypoglycemic drugs significant. The usual dose is 250 mg orally twice a day. Tolmetin Tolmetin,4 although a pyrole and not an indole, is related to indomethacin. It is, in fact, the indomethacin molecule with the methoxybenzene ring amputated. It is rapidly absorbed and has a short plasma half-life of approximately 45 minutes. The short half-life results in a lack of accumulation even after multiple doses. 36 Tolmetin has an efficacy approximating that of aspirin but with somewhat less gastrointestinal toxicity. A large number of additional nonsteroidal anti-inflammatory agents are under development, are undergoing animal or human trials, or have been marketed outside the United States. A conservative estimate of the
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number of agents is 80 to 100. It is unlikely that any will offer significant advantages over those available at present. OTHER ANTI-INFLAMMATORY DRUGS
Colchicine Colchicine, like the salicylates, has been used since antiquity. It has clinically significant anti-inflammatory effectiveness only in cases of acute gouty arthritis, although it occasionally has efficacy in acute pseudogout and perhaps in the arthritis of both sarcoidosis and familial mediterranean fever. Although the mechanism of action of colchicine is unclear, it has been postulated that it interferes with the activation of the complement cascade, inhibits leukocyte migration, or inhibits the endocytosis of urate crystals in joints. In therapeutic oral doses, colchicine almost invariably causes gastrointestinal toxicity by the time it controls the symptoms of acute gouty arthritis. For this reason, its use in treating active arthritis is less popular than in the past, and other antiinflammatory agents such as indomethacin and phenylbutazone are being used more regularly. Colchicine continues to have a place in the prophylaxis of gout, and prophylactic doses of colchicine, 0.6 to 1.8 mg per day, may be required for months after the institution of uricosuric or xanthine oxidase inhibitor therapy to prevent the induction of acute arthritis. When tophi are present, colchicine therapy should be continued until they have resolved. If indicated for acute arthritis, 1 mg of colchicine may be administered intravenously and repeated once after 4 hours; larger intravenous doses have been associated with sudden death. Five to 15 per cent of patients have an incomplete or minimal response to colchicine, even when therapy is instituted, including intravenously, early in the course of acute disease.
Antimalarial Agents The 4-aminoquinoline antimalarials have been used to treat rheumatoid arthritis for over 30 years. Both chloroquine and hydroxychloroquine are effective in the treatment of rheumatoid arthritis.46 They are also effective in the treatment of the subcutaneous manifestations and sometimes the inflammatory nondermatologic manifestations of systemic lupus erythematosus. The therapeutic effect noted is often one of "steroid sparing." At present, hydroxychloroquine is still approved but chloroquine is no longer approved by the Food and Drug Administration for use in treatment of the rheumatic disorders. Hydroxychloroquine is rapidly and almost completely absorbed from the gastrointestinal tract and is deposited in the eyes, liver, and spleen in concentrations hundreds of times that found in plasma. Fifty per cent of the drug is protein bound in plasma. It or its metabolites are cleared by the kidneys, and the urine may contain small amounts of hydroxychloroquine and its metabolites long after discontinuance of therapy. Urinary clearance is enhanced by acidification and decreased by alkalinization. Hydroxychloroquine is concentrated in the nuclear and lysosomal constituents of cells and interacts with nucleoprotein and native deoxyribonucleic acid (DNA). It stabilizes the DNA molecule, blocks deoxy-
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ribonuclease, and inhibits DNA polymerase. These effects are probably important in the antimalarial and antibacterial actions of the agents. They have also been implicated in the efficacy of the drug in patients with systemic lupus erythematosus. In addition, hydroxychloroquine may be an anti-inflammatory agent because of its ability to stabilize lysosomal membranes, suppress lymphocyte responsiveness, and impair leukocyte chemotaxis. In addition to mild to moderate rheumatoid arthritis and discoid and systemic lupus erythematosus, hydroxychloroquine has also been recommended for use in patients with Sjogren's syndrome. It is contraindicated in psoriasis because it may cause exfoliative dermatitis. The usual initiating dose of hydroxy chloroquine is 200 mg orally two or three times daily. Clinical response may require 4 to 12 weeks before it is detectable and may not be maximal for 6 months. Once clinical improvement is seen, the maintenance dose is decreased to 200 to 400 mg per day. During therapy, retinal toxicity must be carefully searched for. The antimalarial agents selectively accumulate in pigmented tissues of the eye,lO, 43 probably because of binding to melanin pigment. Retinal toxicity is the most serious complication of hydroxychloroquine and may be progressive even after the drug is discontinued. Edema of the retina occurs early, followed later by optic atrophy, diffuse depigmentation of the peripheral retina, and narrowing of the retinal vessels. The retinal damage may result from photic injury induced by the drug when bound to the retina. Cutaneous pigmentary changes often accompany retinal toxicity. Because of the potential severity of retinal toxicity, patients receiving long-term antimalarial therapy should have detailed ophthalmologic examinations two or three times a year. This will enable discontinuance of therapy at the first retinal sign of toxicity and may lead to arrest or reversal of retinal damage. Other adverse toxic manifestations of the antimalarial drugs are headache, dizziness, vertigo, tinnitus, skin eruptions, and gastrointestinal complaints including diarrhea, nausea, and abdominal cramping. Long-term use can cause a reversible neuromyopathy, dyplopia, loss of accommodation, corneal opacification, and hyperpigmentation of the skin and mucous membranes. The corneal deposits and the majority of the other nonretinal toxic manifestations resolve with discontinuance of the drug.
Gold Gold has been used as a medicinal for approximately 4000 years. The Sumerians and the Egyptians used it topically, often mixed with honey, or as foil. During the early part of the twentieth century, it was used in the treatment of such widely varied diseases as tuberculosis and other infectious processes and decubitus ulcers. It was probably used initially in patients with rheumatoid arthritis because this disease was suspected to be infectious in etiology. Although two reports on the parenteral use of gold in the treatment of rheumatoid arthritis appeared in the German literature in 1927, Forestier published the first careful study of that application in patients with chronic rheumatoid arthritis in 1929. 20
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The early parenteral use of gold in patients with rheumatoid arthritis was plagued with reports of great toxicity, probably related to the high doses used. More recently, however, the Empire Rheumatism Council:J3 and the Cooperating Clinics Committee of the American Rheumatism Association l l have both demonstrated good effectiveness with acceptable toxicity in the majority of patients treated. In fact, a double-blind study published in 1974 37 demonstrated not only clinical improvement but also significant slowing of the mean progression rate of bone and articular destruction, determined roentgenographically, in the groups treated with gold. At present, gold is administered as water-soluble compounds; colloidal preparations are no longer used. Absorption of gold is most consistent after intramuscular administration. Two agents in common use are aurothioglucose (Solganal) and gold sodium thiomalate (Myochrysine), both of which are approximately 50 per cent gold by weight. After intramuscular administration, either gold compound is rapidly absorbed and reaches a peak plasma level within a few hours. The serum half-life of the gold is 5.2 days, enabling the attainment of an almost constant serum concentration of gold when it is administered weekly. Approximately 30 per cent of an administered dose is excreted in the urine and 10 per cent in the stool over a 7 day period. In plasma, gold binds principally to albumin and fibrinogen; however, more than 50 per cent of each dose binds to protein in the liver, kidneys, spleen, adrenal glands, synovium, lymph nodes, and bone marrow in descending order of concentration. Most investigators have found no correlation between serum gold concentrations and either therapeutic effect or toxicity; nor have they found high dose maintenance therapy more efficacious than standard maintenance therapy. The mechanism of action of this nonsteroidal anti-inflammatory agent in patients with rheumatoid arthritis has not been elucidated; however, potential modes of action include inhibition of lysosomal enzymes, stabilization of lysosomal membranes, decreased phagocytic activity of macrophages and polymorphonuclear leukocytes in synovial fluid, decreased migratory activity of inflammatory cells, prevention of increased capillary permeability in inflamed states, and stabilization of collagen. Although it has been well demonstrated that gold salts inhibit a number of enzymes in vivo, it is unclear which, if any, of the listed effects is important in patients with rheumatoid arthritis. The only generally accepted indication for chrysotherapy is active rheumatoid arthritis, seronegative or seropositive, adult or juvenile. Contraindications to its use include pregnancy, renal disease, previous lack of response to gold, or previous toxic reactions to it. A variety of regimens of administration have been advocated. 19 All begin with an initial intramuscular dose of 10 mg followed in 1 week by a second dose of 25 mg. Thereafter, weekly doses of 25 to 50 mg are employed to achieve a total dose of 1000 mg; if significant improvement has not occurred with this cumulative dose, therapy is discontinued. If improvement has occurred, the dose is continued with decreased frequency to a total dose of 1800 to 2000 mg. Therapy is generally discontinued once a patient has been in remission for 1 year.
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Adverse reactions occur in approximately one third of the patients receiving gold salt therapy.18 The principal toxic manifestations are stomatitis, dermatitis, nephritis, and blood dyscrasias. Stomatitis may be minimally symptomatic but can be associated with a sore mouth or throat and is often preceded by a metallic taste. Skin reactions range from simple pruritus to exfoliative dermatitis and occur in about 20 per cent of the patients. Nephrotoxicity:J8 has been reported in from 3 to 17 per cent of patients and usually manifests as proteinuria and rarely progresses to nephrotic syndrome or acute tubular necrosis. In as many as 70 per cent of patients with proteinuria during gold therapy, electron microscopy reveals changes typical of membranous glomerular nephritis. Enterocolitis and hepatitis may occur but are rare. The most severe reaction, which is potentially lethal, is suppression of bone marrow production that can progress to aplastic anemia. Because of the risk of toxicity, each patient must be evaluated carefully before each dose of gold. A careful history should be elicited with respect to the presence of rash, metallic taste, stomatitis, and other symptoms, and a complete blood count, including a platelet count, and urinalysis should be carried out. If toxicity of any sort becomes manifest, therapy must be discontinued immediately and the patient followed closely. Two additional routes of administration of gold compounds have been used in patients with rheumatoid arthritis. One is intra-articular administration of radioactive gold colloid in the treatment of chronic synovitis, which is becoming increasingly popular in Europe. The other is oral administration of a series of gold compounds in which the gold is complexed with trialkylphosphines. These compounds exhibit antiarthritis activity after oral administration in both animals with adjuvant arthritis and in patients with rheumatoid arthritis in short term trials. The future of both of these therapeutic modalities awaits further evaluation. CORTICOSTEROIDS 31
The discovery by Hench and others in 1948 of the therapeutic potential of corticosteroids required that those compounds be considered not only hormones but also drugs. Shortly after their discovery, it was noted that corticosteroids have a marked anti-inflammatory effect in patients with rheumatoid arthritis; this is now well documented and corticosteroids are currently the most potent anti-inflammatory agents available. The mechanism by which the corticosteroids achieve their antiinflammatory effect has not been elucidated. However, the remarkable stabilizing effects of steroids on the lysosomal membrane must represent the important keystone of their anti-inflammatory action. In addition, corticosteroids interfere with the formation of kinins and impair the migration of polymorphonuclear leukocytes (apparently without causing significant reduction of phagocytic or bactericidal actions), cause a decrease in the number and activity of mast cells, and potentially lyse lymphocytes, and interfere with the expression of cellmediated immunity. Corticosteroids are used regularly in the management of systemic lupus erythematosus, polymyositis, polymyalgia rheumatica, temporal or
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giant cell arteritis, mixed connective tissue disease syndrome,45 and severe rheumatoid arthritis unresponsive to other therapy. Large doses (the equivalent of 1 to 2 mg of prednisone per kg of body weight per day) of corticosteroids are reserved for patients with polymyositis, temporal or giant cell arteritis, and lupus erythematosus complicated by nephritis, central nervous system involvement, and possibly hemolytic anemia and thrombocytopenia, although the last two will usually respond to lower dose steroid therapy. Other manifestations of lupus erythematosus including arthritis, pleuritis, and pericarditis may respond to nonsteroidal anti-inflammatory agents. If not, smaller doses of corticosteroids are generally adequate for lupus serositis and dermatitis, as well as polymyalgia rheumatica, mixed connective tissue disease, and rheumatoid arthritis. The mixed connective tissue disease syndrome must be distinguished from other forms of progressive systemic sclerosis because of the salutory response to corticosteroids in the majority of patients. Although rheumatoid arthritis was the first disease to be treated by corticosteroids, considerable controversy remains about their use in this condition. Much of the controversy was engendered by the extent and severity of side effects experienced by the initial patients who were treated with steroids and who received excessive doses for prolonged periods of time. Nevertheless, there are patients with rheumatoid arthritis who will require corticosteroids to ensure adequate therapeutic efficacy. In these patients, every effort must be made to minimize the toxicity of the drug. Toxic effects include suppression of the hypothalamic-pituitary-adrenal axis, diabetes, myopathy, osteoporosis, aseptic necrosis, disorder of mood, posterior subcapsular cataract formation, increased intraocular pressure, salt and water retention, spontaneous bruising, acne, hirsutism, retardation of growth in children, and increased susceptibility to infection. It appears that suppression of the hypothalamic-pituitary-adrenal axis is a side effect of corticosteroid therapy that correlates well with the anticipated development of other side effects,27 which may in fact require longer duration of therapy to become clinically overt. If this is true, then those therapeutic regimens that are known to minimize suppression of the hypothalamic-pituitaryadrenal axis (i.e., alternate day administration of corticosteroid or daily administration of corticosteroids as a single morning dose of < 7.5 mg of prednisone) should minimize toxic manifestations. EXPERIMENTAL AGENTS
Penicillamine Penicillamine is a sulfur-containing amino acid that is useful as a chelator and has been used in the treatment of Wilson's disease and heavy metal poisoning. It cleaves disulfide bridges and inhibits collagen cross linking, but its mechanism of action in patients with rheumatoid arthritis is unclear. Its ability to reduce the titer of rheumatoid factor, however, is well established. Several multicenter trials in Britain have demonstrated its efficacy in the treatment of rheumatoid disease, and a
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recent study16 demonstrated that doses of both 600 and 1200 mg daily added to a standard treatment regimen produced statistically significant improvement in relief of pain, grip strength, erythrocyte sedimentation rate, and hemoglobin concentration. Improvement usually began 4 to 8 weeks after starting treatment but was not complete until at least 12 weeks. There was no evidence to suggest that it effected the healing of erosive bone lesions. The use of penicillamine has been associated with significant adverse reactions although using the lower dose regimen (600 mg per day) seems to decrease the incidence of adverse effects significantly. Adverse reactions in decreasing frequency include development of a positive antinuclear antibody determination, loss of the sense of taste or the development of a metallic taste, rash, pruritus, gastrointestinal symptoms, occasionally neutropenia, pancytopenia, or immune complex nephropathy, and rarely myasthenia. Penicillamine is more convenient than gold to administer. It appears to have approximately equal efficacy and to be a practical treatment for active rheumatoid arthritis. At present, the use of this agent must be considered experimental. Any physician prescribing it for rheumatoid arthritis should be included under an investigational new drug application filed with the Food and Drug Administration. Patients who receive penicillamine should have close clinical laboratory follow-up. Levamisole Levamisole is an antihelminthic drug with properties of immunostimulation. Studies of adjuvant arthritis in the raf'12 suggest that levamisole is effective not only in restoring an impaired cellular immune response but also in enhancing an already activated system. The timing of administration appears to be crucial, however, and continuous therapy may result in loss of efficacy. In clinical trials,23,41 the onset of enhancement of in vitro measurements of cell-mediated immunity seems to correlate with clinical improvement of rheumatoid arthritis. It must be cautioned that the clinical trials of this agent are inconclusive. Some have shown it to be as effective as penicillamine in patients with rheumatoId arthritis and others have shown it to be ineffective. Its usefulness in the treatment of rheumatoid arthritis must therefore await substantial further study.
CONCLUSION The objective of nonspecific anti-inflammatory therapy is to relieve symptoms. In selected patients such therapy may also slow, prevent, or reverse the destructive effects of the inflammatory process. None of the wide variety of anti-inflammatory agents reviewed herein is without some inherent toxicity, although some are much more toxic than others. The physician prescribing any of these agents must keep in mind both the potential benefits and the risks attendant to their use, and balance the potential benefit against the potential risk.
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REFERENCES 1. Adams, S. S., Hebborn, P., and Nicholson, J. S.: Some aspects of the pharmacology of ibufenac, a non-steroidal anti-inflammatory agent. J. Pharm. Pharmacol., 20:305-312, 1968. 2. Amold, L., Collins, C., and Starmes, G. A.: Further studies of the acute effects of phenylbutazone, oryphenbutazone and indomethacin on the rat kidney. Pathology, 8:135-141, 1976. 3. Boardman, P. L., and Hart, F. D.: Side-effects of indomethacin. Ann. Rheumat. Dis., 26: 127-132, 1967. 4. Brooke, P. M., Watkins, C. F., StuITock, R. D., et al.: Clinical evaluation of tolmetin. CUIT. Med. Res. Opinion, 2:323-328, 1974. 5. Brooks, C. D., Schmid, F. R., Biundo, J, et al.: Ibuprofen and aspirin in the treatment of rheumatoid arthritis. A cooperative double-blind study. Rheumatol. Phys. Med., 10 (Suppl.):48-63, 1970. 6. Bruck, E., Fearnley, M. E., Meanock, 1., et al.: Phenylbutazone therapy; relation between toxic and therapeutic effects and the blood level. Lancet, 1 :225-228, 1954. 7. Brune, K., Graf, P., and Glatt, M.: Inhibition of prostaglandin synthesis in vivo by nonsteroid anti-inflammatory drugs: evidence for the importance of pharmacokinetics. Agents Actions, 6:159-164,1976. 8. Burry, H. C., and Dieppe, P. A.: Apparent reduction of endogenous creatinine clearance by salicylate treatment. Brit. Med. J., 2:16-17,1976. 9. Calabro, J. J.: Long-term reappraisal of indomethacin. Drug Ther., 5:47-60, 1975. 10. CaIT, R. E., Henkind, P., Rothfield, N., et al.: Ocular toxicity of antimalarial drugs. Longterm follow-up. Amer. J. Ophthal., 66:738-744,1968. 11. The Cooperating Clinics Committee of the American Rheumatism Association: A controlled trial of cyclophosphamide in rheumatoid arthritis. New Eng. J. Med., 283:883889,1970. 12. The Cooperating Clinics Committee of the American Rheumatism Association: A threemonth trial of indomethacin in rheumatoid arthritis, with special reference to analysis and inference. Clin. Pharmacol. Ther., 8:11-37, 1967. 13. Cuthbert, M. F.: Adverse reactions to non-steroidal antirheumatic drugs. Curr. Med. Res. Opinion, 2:600-610, 1974. 14. Davies, E. F., and Avery, G. S.: Ibuprofen: a review of its pharmacological properties and therapeutic efficacy in rheumatic disorders. Drugs, 2:416-446, 1971. 15. Diamond, H., Alexander, S., Kuzell, W., et al.: A multi-center double-blind crossover comparison study of naproxen and aspirin in patients with rheumatoid arthritis. Scand. J. Rheumatol. (Suppl.) 2:171-175,1973. 16. Dixon, A. St. J., Davies, J., Dormandy, T. L., et al.: Synthetic D(-)penicillamine in rheumatoid arthritis. Double-blind controlled study of a high and low dosage regimen. Ann. Rheumat. Dis., 34:416-421, 1975. 17. Editorial: Acetaminophen. Med. Lett. Drugs Ther., 18:73-74, 1976. 18. Editorial: Gold for rheumatoid arthritis. Brit. Med. J., 1 :471-472,1971. 19. Editorial: Gold therapy in rheumatoid arthritis. Med. Lett. Drugs Ther., 7: 109-111, 1965. 20. Forestier, J.: L'aurotherapie dans les rhumatismes chroniques. Bull. memo Soc. med. d'Hop. Paris, 53:323-327,1929. 21. Fries, J. F., and Britton, M. C.: Fenoprofen calcium in rheumatoid arthritis. A controlled double-blind crossover evaluation. Arthr. Rheum., 16:629-634, 1973. 22. Hart, F. D., and Boardman, P. L.: Ibufenac (4-isobutylphenyl acetic acid). Ann. Rheum. Dis., 24:61-65, 1965. 23. Huskisson, E. C., Dieppe, P. A., Scott, J., et al.: Immunostimulant therapy with levamisole for rheumatoid arthritis. Lancet, 1 :393-395, 1976. 24. Leist, E. R., and Banwell, J. G.: Products containing aspirin. New Eng. J. Med., 291 :710712, 1974. 25. Levy, G., and Tsuchiya, T.: Salicylate accumulation kinetics in man. New Eng. J. Med., 287:430-432, 1972. 26. Macklon, A. F., Craft, A. W., Thompson, M., et al.: Aspirin and analgesic nephropathy. Brit. Med. J., 1 :597-600, 1974. 27. McAllen, M.: Long-term side effects of corticosteroids. Respiration, 27 (Suppl.):250-259, 1970. 28. McQueen, E. G.: Anti-inflammatory drug mechanisms. Drugs, 6:104-117,1973. 29. Mills, J. A.: Drug therapy: nonsteroidal anti-inflammatory drugs. New Eng. J. Med., 290:781-784,1002-1005,1974. 30. Mongan, E., Kelly, P., Nies, K., et al.: Tinnitus as an indication of therapeutic serum salicylate levels. J.A.M.A., 226:142-145, 1973. 31. Myles, A. B., and Daly, J. R.: Corticosteroid and ACTH Treatment. Principles and Problems. London, Edward Arnold Ltd., 1974.
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32. Paulus, H. E., and Whitehouse, M. W.: Nonsteroid anti-inflammatory agents. Ann. Rev. PharmacoL, 13:107-125, 1973. 33. The Research Sub-committee of the Empire Rheumatism Council: Gold therapy in rheumatoid arthritis. Report of a multi-centre controlled triaL Ann. Rheum. Dis., 19:95-119,1960. 34. Rooney, P. J., Lee, P., Brookes, P., et al.: Reflections on possible mechanisms of action of anti-inflammatory drugs. Curr. Med. Res. Opinion, 1 :501-516, 1973. 35. Runkel, R., Forchielli, E., Boost, G., et al.: Naproxen-metabolism, excretion and comparative pharmacokinetics. Scand. J. RheumatoL 2 (SuppL):24-36, 1973. 36. Selley, M. L., Glass, J., Triggs, E. J., et aL: Pharmacokinetic studies of tolmetin in man. Clin. PharmacoL Ther., 1 7: 599-605, 1975. 37. Sigler, J. W., Bluhm, G. B., Duncan, H., et al.: Gold salts in the treatment of rheumatoid arthritis. A double-blind study. Ann. Intern. Med., 80:21-26, 1974. 38. Silverberg, D. S., Kidd, E. G., Shnitka, T. K., et al.: Gold nephropathy. A clinical and pathologic study. Arthritis Rheum., 13:812-825, 1970. 39. Smith, M. J. H., and Smith, P. K.: The Salicylates. New York, Interscience Publishers, 1966, p. 313. 40. Smith, R. J., Sabin, C., Gilchrest, J., et al.: Effect of anti-inflammatory drugs on lysosomes and lysosomal enzymes from rat liver. Biochem. PharmacoL, 25:2171-2177, 1976. 41. Szpilman, H., Luft, S., Glinska-Urban, D., et al.: Levamisole and cell-mediated immunity and serum-immunoglobulins in rheumatoid arthritis. Lancet, 2:208-209, 1976. 42. Trabert, U., Rosenthal, M., and Muller, W.: The effect of levamisole on adjuvant arthritis in the rat. J. RheumatoL, 3:166-174,1976. 43. Ullberg, S., Lingquist, N. G., and Sjiistrand, S. E.: Accumulation of chorio-retinotoxic drugs in the foetal eye. Nature, 227: 1257-1258, 1970. 44. Von Rechenberg, H. R.: Phenylbutazone. London, Edward Arnold Ltd., 1962. 45. Yount, W. J., Utsinger, P. D., Puritz, E. M., et aL: Corticosteroid therapy of the collagen vascular disorders. MED. CLIN. N. AMER., 57:1343-1355,1973. 46. Zvaifler, N. J.: Antimalarials in the treatment of rheumatoid arthritis. Mod. Treat., 8 :769-777, 1971. San Francisco General Hospital Medical Center Building 40, Room 4101 1001 Potrero Avenue San Francisco, California 9411 0
Drug Therapy in Rheumatic Diseases Robert L. Roe, M.D. *
The rheumatic diseases appear to be of diverse etiology. Immunologic mechanisms are often at work and hereditary, environmental, and infectious factors have been implicated in one or more of the disorders. Although the exact pathogenesis of the rheumatic diseases is unclear, the inflammatory process is one shared in common by most, if not all, of the acute rheumatologic processes. For this reason, the majority of the drugs used in the treatment of arthritis and the allied rheumatic conditions are anti-inflammatory a,gents. These agents, either singly or in appropriate combination, are the mainstay of pharmacologic therapy for both acute and chronic arthritis, although in chronic conditions, physical medicine, and surgery often play equally important roles. Drugs with anti-inflammatory activity range from salicylate, one of the oldest and most widely used medicinals, to corticosteroids. They include the non salicylate nonsteroidal anti-inflammatory agents, colchicine, antimalarials, gold, and experimental agents such as penicillamine and levamisole. It is important to remember that anti-inflammatory agents in general do not alter the underlying disease but rather alter one or more systemic manifestations of that disease by relatively nonspecific means. As a consequence, one must set an attainable therapeutic end point (generally relief of evidence of inflammation) and achieve it using the smallest possible doses of the least toxic agent or agents. Therapy with a more toxic agent should be considered only when a maximum tolerated dose of the initial agent is ineffective. Inflammation is an elaborate scheme of interacting events involving multiple chemical mediators. 28 • 34 Furthermore, it is undoubtedly a normal protective mechanism. As a consequence, total inhibition of the inflammatory response is undoubtedly inimical to the host. Nevertheless, because inflammation is responsible for much of the morbidity of the rheumatic diseases it must be inhibited. Inhibition can be accomplished using a variety of nonsteroidal drugs as well as steroids, and it is these drugs that will be discussed herein. One must keep in mind that the animal models developed to assess the effectiveness of new anti-inflammatory drugs are generally poor imitations of human disease and on oc'Chief of Rheumatology Unit, San Francisco General Hospital; Assistant Clinical Professor of Medicine, University of California, San Francisco
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casion are poorly reproducible. Too little is known about the entry of drugs into the sites of inflammation or how drugs actually inhibit or reverse the inflammatory response. The animal models used not only may provide contradictory results on occasion but they may also yield results that cannot be readily extrapolated to human patients. In addition, they certainly result in the development of agents with almost identical therapeutic or toxic effects. NON-STEROIDAL ANTI-INFLAMMATORY AGENTS
Aspirin The salicylates are the first-line drug in the treatment of the majority of non-life threatening rheumatic disorders. Potions rich in salicylic acid are as old as herbal therapy and are ubiquitous in the modern pharmacopoeia; currently, more than 200 prescription and nonprescription products contain aspirin. 24 Aspirin39 is the standard of therapy for the rheumatic disorders, and all other agents must be measured against it. Salicylates have been used since antiquity, and in the second century A.D. Galen related most of the pharmacologic effects of salicylates that we now recognize. There is evidence that salicylates both inhibit the production of mediators of inflammation and interfere with the peripheral effects of such mediators. It is essential when using aspirin for anti-inflammatory action, however, to keep in mind its multiplicity of pharmacologic effects, both beneficial and toxic. 29 For the majority of patients, the usual therapeutic range of serum concentrations of salicylate is 15 to 30 mg per 100 m!. However, such high levels are not required to produce the analgesic effect of salicylates. Aspirin has a half-life that increases as its concentration in serum increases. 25 But determinations of drug level cannot substitute for careful medical observation and judgment. Dosing must always be interpreted in a context of all clinical data. The therapeutic indication for aspirin or salicylate must always be kept in mind as well. Effects on platelets, for instance, can occur with doses as small as 10 mg per kg of body weight, whereas manifest evidence of the uncoupling of oxydative phosphorylation requires approximately 60 mg per kg body weight. The anti-inflammatory activity of salicylates is perhaps the most important rationale for clinical use of these drugs. It is probable that they both inhibit the production of mediators of inflammation and interfere with the peripheral effects of such mediators, probably by blocking a route leading to or from the speCific receptors for the vasoactive peptide agonists. Aspirin can inhibit the release of histamine, inhibit the effect of exogenously administered bradykinen, inhibit prostaglandin synthetase, render neutrophils nonresponsive to chemotactic stimuli, interfere with granulocyte adherence, and at high concentrations interfere with the formation of antigen-antibody complex. Aspirin also may stabilize lysosomal membrane and suppress lymphocyte function (i.e., transformation and antibody synthesis). The mechanism of all of these effects is unclear but may be related in part to the uncoupling of energy production and to interference with normal cyclic AMP metabolism.
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Additional pharmacologic effects of aspirin include analgesia, antipyresis, normalization of carbohydrate intolerance in diabetic patients, depression of concentrations of free fatty acids and cholesterol, inhibition of platelet aggregation, and the well recognized diaphasic effect on urate clearance. Toxic effects include frequent gastrointestinal irritation with minor blood loss, occasional massive gastrointestinal blood loss, pylorospasm and centrally mediated vomiting, hepatic injury in normal persons as well as in patients with rheumatic disease, sodium and water retention, tinnitus, allergy, nephropathy, and, with massive doses, hypoprothrombinemia. In man, unlike some experimental animals, it appears that aspirin rarely, if ever, causes nephropathy when used alone 26 although it may increase the amount of urinary sediment. Nevertheless, recent literatureS suggests an average decrease in creatinine clearance of 25 per cent in normal persons who just started salicylate therapy. This, however, does not appear to result from impairment of glomerular function. Although the half-life of aspirin may approach 18 hours with large doses, patients with active rheumatologic disorders generally require a dose every 4 to 6 hours to achieve optimal clinical control. The appropriate dose of aspirin varies widely from patient to patient, although a salicylate level in excess of 20 mg per 100 ml is usually required for maximal efficacy. In patients without preexisting hearing loss, the onset of tinnitus can be used to assess salicylate level. In a recent study,30 of 52 patients who experienced tinnitus, the serum salicylate level was invariably greater than 19.6 mg per 100 ml and averaged 30.4 mg per 100 ml, but the aspirin dose varied from 12 to 36 tablets per day.
Acetaminophen Acetaminophen, called paracetamol in the United Kingdom, is a derivative of paraamino phenol,17 It is a non salicylate analgesic and antipyretic agent that has no anti-inflammatory effect. Therefore, even though it does not cause the gastric erosion and bleeding associated with aspirin, its application in patients with active rheumatoid arthritis or other rheumatic disorders is limited. The toxicity of acetaminophen is limited to rare hypersensitivity and even rarer hepatotoxicity. Fatal hepatic necrosis has occurred in patients poisoned with acetaminophen. Acetaminophen has also been implicated in causing renal injury when used in large doses as part of a combination of analgesics over a prolonged period of time. Its application in rheumatic diseases should be limited to analgesia in patients intolerant to aspirin.
Indomethacin Indomethacin is an indole derivative and a potent anti-inflammatory agent. 9 • 12 In addition, it is a more potent antipyretic drug than aspirin and is particularly effective in treating fever in patients with lymphoma or other malignant processes. It is a poor analgesic except when pain is caused by inflammation. Although the mechanism of its anti-inflammatory action is unclear, indomethacin inhibits prostaglandin synthetase, may decrease chemotaxis and the mobility of polymorphonucleocytes,
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and may affect the function of both T and B lymphocytes. In addition, indomethacin uncouples oxidative phosphorylation as does aspirin. Indomethacin is of therapeutic value and is one of the drugs of choice for acute gouty arthritis, pseudo gout, and ankylosing spondylitis. It is of value in the treatment of moderate to severe rheumatoid arthritis in adults and of severe osteoarthritis of the hip, which is intriguing because the latter is generally not an inflammatory process. Indomethacin also is effective in the treatment of Reiter's disease, psoriatic arthritis, bursitis, tendinitis, traumatic synovitis, and the pain of both pleuritis and pericarditis. The use of indomethacin is contraindicated in children and in pregnant or lactating women. It is also contraindicated in patients with severe sensitivity to aspirin. In the treatment of acute gouty arthritis or acute pseudogout, 200 mg of indomethacin should be administered the first day followed by 150 mg per day for 3 days. For other indications, the usual dose is 25 mg two or three times a day with an increase by 25 to 50 mg per day at weekly intervals until a satisfactory response is achieved. The maximum total daily dose should be between 150 and 200 mg. A therapeutic trial with indomethacin as with the majority of the other nonsteroidal anti-inflammatory agents should probably not exceed 2 weeks if there is no response. Toxic manifestations of indomethacin include headache, dizziness, vertigo, and rarely somnolence, confusion, hallucination, sodium and water retention, gastric upset, anorexia, nausea, diarrhea, rash,3 and very rarely pancreatitis. Major toxic manifestations include gastrointestinal bleeding, ulceration or perforation, hepatotoxicity, and rarely aplastic anemia. Adverse reactions tend to be dose related although they may emerge any time during therapy. The drug must always be discontinued for any of the major toxic reactions.
Phenylbutazone Phenylbutazone, a congener of aminopyrine, is a potent anti-inflammatory drug. 6 • 32 However, it is a poor analgesic and a weak antipyretic agent and is too toxic to be used for these purposes. 6 • 32 The drug is also uricosuric and causes uncoupling of oxidative phosphorylation. It, like indomethacin, should be used as the drug of choice in only a few conditions, specifically acute gout, acute pseudogout, and ankylosing spondylitis. It may be useful, however, for short term treatment of seronegative arthritis, psoriatic arthritis, and the inflammatory nonarticular syndromes including tendinitis, capsulitis, and tenosynovitis. Phenylbutazone should not be used in doses greater than 600 mg per day, and then only for a brief duration. The only condition for which long-term use is justified is ankylosing spondylitis, and the dose should be the smallest that will control symptoms, preferably 200 mg per day. The majority of the toxic manifestations of phenylbutazone are related to both dose and duration of treatment and are more common in the elderly. 13,44 The manifestations include nausea, vomiting, diarrhea, vertigo, insomnia, and sodium retention. Severe manifestations include stomatitis, gastritis, colitis, hepatitis, renal failure,2 myocardiopathy, and
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suppression of bone marrow production. Marrow suppression can occur suddenly after only a few doses, or more gradually after long-term therapy. Complete blood counts should be obtained weekly or semi-weekly to monitor for gradual marrow failure. It is impossible to monitor for acute failure, which appears to occur in less than 0.002 per cent of treated patients. Phenylbutazone avidly binds to protein and competes with coumarins and oral hypoglycemic agents for such binding, thereby potentiating their effects. It also stimulates the enzyme system responsible for its own metabolism and the metabolism of such agents as phenobarbital, diphenylhydantoin, and digitoxin. Discontinuance of phenylbutazone therapy in patients simultaneously treated with these drugs will therefore require alteration of their dosage as well.
NEWER NONSTEROIDAL ANTI-INFLAMMATORY AGENTS
Three of the newer nonsteroidal anti-inflammatory agents are ph enylalkinoic acids; the anti-inflammatory property of this series was first established in 1968.! The parent compound, ibufenac, was roughly equal to aspirin22 in efficacy but was a potent hepatotoxin causing hepatocellular necrosis and death. The compounds of this series were thus initially suspected of being hepatotoxins, although they have shown little if any such toxicity. All are analgesic and antipyretic, and at least at higher doses, have anti-inflammatory activity. They all decrease platelet aggregation and cause sodium and water retention. In general, they have the same signs of toxicity including gastrointestinal symptoms such as epigastric distress, nausea, vomiting, constipation, and anorexia, neurologic effects such as headache, inability to concentrate, depression, nervousness, and tinnitus, and cutaneous effects such as rash and pruritus. All have an efficacy similar to that of high doses of aspirin but with potentially less frequent toxicity. The mechanisms by which the newer nonsteroidal anti-inflammatory agents combat inflammation are no more clearly defined than are the mechanisms of the older agents. 7 All of them inhibit prostaglandin synthetase, but because prostaglandins appear only in the later phases of inflammation, the agents may interact with other mediators as well. Additional evidence suggests that most may also stabilize lysosomal membranes. 4o Considerable research must be done before exact mechanisms can be determined. Because each of the new agents has had relatively limited clinical exposure, they will be briefly reviewed in sequence.
Fenoprofen Calcium Fenoprofen calcium is a phenylalkinoic acid that is rapidly absorbed, reaching peak plasma levels in 2 hours. However, its half-life is only 3 hours and therefore dosing is required 4 times per day. The efficacy of fenoprofen is approximately equal to that of aspirin, with perhaps less toxicity than high doses of salicylate. 2 ! Adverse reactions to this agent include gastrointestinal, neurologic, and cutaneous manifes-
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tations. Fenoprofen calcium has also been associated with renal lesions in some experimental animals and elevated levels of blood urea nitrogen in a few patients. Disturbances in liver function have been reported occasionally. The agent may interact with oral hypoglycemic and anticoagulant drugs because of its avid protein binding. The usual dose is 2400 to 3200 mg per day orally in four divided doses.
Ibuprofen Ibuprofen, which differs from the parent compound ibufenac by a single methyl group, has been marketed in the United States for a longer period of time than the other agents of this series. It is equal to or more effective than indomethacin or aspirin, and peak plasma levels are achieved within 90 minutes of administration. 5 • 14 Its half-life is approximately 2 hours and thus the recommended dosage regimen is four times a day. Ibuprofen avidly binds to protein. About 60 per cent of the dose is excreted in the urine and the remainder is excreted in the intestinal tract. Adverse reactions include gastrointestinal, neurologic, and cutaneous manifestations as well as edema, increased bleeding time, and occasional elevation of liver function tests. Other manifestations of hepatotoxicity have not been reported. The agent may interact with other protein-bound drugs such as anticoagulant and hypoglycemic drugs. The usual dose is 2400 mg per day orally in three or four divided doses. Naproxen Naproxen is also a phenylalkinoic acid. It may inhibit lysosomal release in addition to inhibiting prostaglandin synthetase. It has a halflife of approximately 13 hours, and therefore a more constant blood level of drug can be maintained with less frequent dosing. 35 The agent is 99 per cent protein bound. Naproxen is equal to or more effective than indomethacin or aspirin and probably has less gastrointestinal toxicity than aspirin. 15 Adverse reactions include gastrointestinal, neurologic, and cutaneous manifestations, and rarely edema and increased bleeding time. The drug's avid protein-binding makes its potential for interaction with oral coagulants and hypoglycemic drugs significant. The usual dose is 250 mg orally twice a day. Tolmetin Tolmetin,4 although a pyrole and not an indole, is related to indomethacin. It is, in fact, the indomethacin molecule with the methoxybenzene ring amputated. It is rapidly absorbed and has a short plasma half-life of approximately 45 minutes. The short half-life results in a lack of accumulation even after multiple doses. 36 Tolmetin has an efficacy approximating that of aspirin but with somewhat less gastrointestinal toxicity. A large number of additional nonsteroidal anti-inflammatory agents are under development, are undergoing animal or human trials, or have been marketed outside the United States. A conservative estimate of the
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number of agents is 80 to 100. It is unlikely that any will offer significant advantages over those available at present. OTHER ANTI-INFLAMMATORY DRUGS
Colchicine Colchicine, like the salicylates, has been used since antiquity. It has clinically significant anti-inflammatory effectiveness only in cases of acute gouty arthritis, although it occasionally has efficacy in acute pseudogout and perhaps in the arthritis of both sarcoidosis and familial mediterranean fever. Although the mechanism of action of colchicine is unclear, it has been postulated that it interferes with the activation of the complement cascade, inhibits leukocyte migration, or inhibits the endocytosis of urate crystals in joints. In therapeutic oral doses, colchicine almost invariably causes gastrointestinal toxicity by the time it controls the symptoms of acute gouty arthritis. For this reason, its use in treating active arthritis is less popular than in the past, and other antiinflammatory agents such as indomethacin and phenylbutazone are being used more regularly. Colchicine continues to have a place in the prophylaxis of gout, and prophylactic doses of colchicine, 0.6 to 1.8 mg per day, may be required for months after the institution of uricosuric or xanthine oxidase inhibitor therapy to prevent the induction of acute arthritis. When tophi are present, colchicine therapy should be continued until they have resolved. If indicated for acute arthritis, 1 mg of colchicine may be administered intravenously and repeated once after 4 hours; larger intravenous doses have been associated with sudden death. Five to 15 per cent of patients have an incomplete or minimal response to colchicine, even when therapy is instituted, including intravenously, early in the course of acute disease.
Antimalarial Agents The 4-aminoquinoline antimalarials have been used to treat rheumatoid arthritis for over 30 years. Both chloroquine and hydroxychloroquine are effective in the treatment of rheumatoid arthritis.46 They are also effective in the treatment of the subcutaneous manifestations and sometimes the inflammatory nondermatologic manifestations of systemic lupus erythematosus. The therapeutic effect noted is often one of "steroid sparing." At present, hydroxychloroquine is still approved but chloroquine is no longer approved by the Food and Drug Administration for use in treatment of the rheumatic disorders. Hydroxychloroquine is rapidly and almost completely absorbed from the gastrointestinal tract and is deposited in the eyes, liver, and spleen in concentrations hundreds of times that found in plasma. Fifty per cent of the drug is protein bound in plasma. It or its metabolites are cleared by the kidneys, and the urine may contain small amounts of hydroxychloroquine and its metabolites long after discontinuance of therapy. Urinary clearance is enhanced by acidification and decreased by alkalinization. Hydroxychloroquine is concentrated in the nuclear and lysosomal constituents of cells and interacts with nucleoprotein and native deoxyribonucleic acid (DNA). It stabilizes the DNA molecule, blocks deoxy-
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ribonuclease, and inhibits DNA polymerase. These effects are probably important in the antimalarial and antibacterial actions of the agents. They have also been implicated in the efficacy of the drug in patients with systemic lupus erythematosus. In addition, hydroxychloroquine may be an anti-inflammatory agent because of its ability to stabilize lysosomal membranes, suppress lymphocyte responsiveness, and impair leukocyte chemotaxis. In addition to mild to moderate rheumatoid arthritis and discoid and systemic lupus erythematosus, hydroxychloroquine has also been recommended for use in patients with Sjogren's syndrome. It is contraindicated in psoriasis because it may cause exfoliative dermatitis. The usual initiating dose of hydroxy chloroquine is 200 mg orally two or three times daily. Clinical response may require 4 to 12 weeks before it is detectable and may not be maximal for 6 months. Once clinical improvement is seen, the maintenance dose is decreased to 200 to 400 mg per day. During therapy, retinal toxicity must be carefully searched for. The antimalarial agents selectively accumulate in pigmented tissues of the eye,lO, 43 probably because of binding to melanin pigment. Retinal toxicity is the most serious complication of hydroxychloroquine and may be progressive even after the drug is discontinued. Edema of the retina occurs early, followed later by optic atrophy, diffuse depigmentation of the peripheral retina, and narrowing of the retinal vessels. The retinal damage may result from photic injury induced by the drug when bound to the retina. Cutaneous pigmentary changes often accompany retinal toxicity. Because of the potential severity of retinal toxicity, patients receiving long-term antimalarial therapy should have detailed ophthalmologic examinations two or three times a year. This will enable discontinuance of therapy at the first retinal sign of toxicity and may lead to arrest or reversal of retinal damage. Other adverse toxic manifestations of the antimalarial drugs are headache, dizziness, vertigo, tinnitus, skin eruptions, and gastrointestinal complaints including diarrhea, nausea, and abdominal cramping. Long-term use can cause a reversible neuromyopathy, dyplopia, loss of accommodation, corneal opacification, and hyperpigmentation of the skin and mucous membranes. The corneal deposits and the majority of the other nonretinal toxic manifestations resolve with discontinuance of the drug.
Gold Gold has been used as a medicinal for approximately 4000 years. The Sumerians and the Egyptians used it topically, often mixed with honey, or as foil. During the early part of the twentieth century, it was used in the treatment of such widely varied diseases as tuberculosis and other infectious processes and decubitus ulcers. It was probably used initially in patients with rheumatoid arthritis because this disease was suspected to be infectious in etiology. Although two reports on the parenteral use of gold in the treatment of rheumatoid arthritis appeared in the German literature in 1927, Forestier published the first careful study of that application in patients with chronic rheumatoid arthritis in 1929. 20
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The early parenteral use of gold in patients with rheumatoid arthritis was plagued with reports of great toxicity, probably related to the high doses used. More recently, however, the Empire Rheumatism Council:J3 and the Cooperating Clinics Committee of the American Rheumatism Association l l have both demonstrated good effectiveness with acceptable toxicity in the majority of patients treated. In fact, a double-blind study published in 1974 37 demonstrated not only clinical improvement but also significant slowing of the mean progression rate of bone and articular destruction, determined roentgenographically, in the groups treated with gold. At present, gold is administered as water-soluble compounds; colloidal preparations are no longer used. Absorption of gold is most consistent after intramuscular administration. Two agents in common use are aurothioglucose (Solganal) and gold sodium thiomalate (Myochrysine), both of which are approximately 50 per cent gold by weight. After intramuscular administration, either gold compound is rapidly absorbed and reaches a peak plasma level within a few hours. The serum half-life of the gold is 5.2 days, enabling the attainment of an almost constant serum concentration of gold when it is administered weekly. Approximately 30 per cent of an administered dose is excreted in the urine and 10 per cent in the stool over a 7 day period. In plasma, gold binds principally to albumin and fibrinogen; however, more than 50 per cent of each dose binds to protein in the liver, kidneys, spleen, adrenal glands, synovium, lymph nodes, and bone marrow in descending order of concentration. Most investigators have found no correlation between serum gold concentrations and either therapeutic effect or toxicity; nor have they found high dose maintenance therapy more efficacious than standard maintenance therapy. The mechanism of action of this nonsteroidal anti-inflammatory agent in patients with rheumatoid arthritis has not been elucidated; however, potential modes of action include inhibition of lysosomal enzymes, stabilization of lysosomal membranes, decreased phagocytic activity of macrophages and polymorphonuclear leukocytes in synovial fluid, decreased migratory activity of inflammatory cells, prevention of increased capillary permeability in inflamed states, and stabilization of collagen. Although it has been well demonstrated that gold salts inhibit a number of enzymes in vivo, it is unclear which, if any, of the listed effects is important in patients with rheumatoid arthritis. The only generally accepted indication for chrysotherapy is active rheumatoid arthritis, seronegative or seropositive, adult or juvenile. Contraindications to its use include pregnancy, renal disease, previous lack of response to gold, or previous toxic reactions to it. A variety of regimens of administration have been advocated. 19 All begin with an initial intramuscular dose of 10 mg followed in 1 week by a second dose of 25 mg. Thereafter, weekly doses of 25 to 50 mg are employed to achieve a total dose of 1000 mg; if significant improvement has not occurred with this cumulative dose, therapy is discontinued. If improvement has occurred, the dose is continued with decreased frequency to a total dose of 1800 to 2000 mg. Therapy is generally discontinued once a patient has been in remission for 1 year.
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Adverse reactions occur in approximately one third of the patients receiving gold salt therapy.18 The principal toxic manifestations are stomatitis, dermatitis, nephritis, and blood dyscrasias. Stomatitis may be minimally symptomatic but can be associated with a sore mouth or throat and is often preceded by a metallic taste. Skin reactions range from simple pruritus to exfoliative dermatitis and occur in about 20 per cent of the patients. Nephrotoxicity:J8 has been reported in from 3 to 17 per cent of patients and usually manifests as proteinuria and rarely progresses to nephrotic syndrome or acute tubular necrosis. In as many as 70 per cent of patients with proteinuria during gold therapy, electron microscopy reveals changes typical of membranous glomerular nephritis. Enterocolitis and hepatitis may occur but are rare. The most severe reaction, which is potentially lethal, is suppression of bone marrow production that can progress to aplastic anemia. Because of the risk of toxicity, each patient must be evaluated carefully before each dose of gold. A careful history should be elicited with respect to the presence of rash, metallic taste, stomatitis, and other symptoms, and a complete blood count, including a platelet count, and urinalysis should be carried out. If toxicity of any sort becomes manifest, therapy must be discontinued immediately and the patient followed closely. Two additional routes of administration of gold compounds have been used in patients with rheumatoid arthritis. One is intra-articular administration of radioactive gold colloid in the treatment of chronic synovitis, which is becoming increasingly popular in Europe. The other is oral administration of a series of gold compounds in which the gold is complexed with trialkylphosphines. These compounds exhibit antiarthritis activity after oral administration in both animals with adjuvant arthritis and in patients with rheumatoid arthritis in short term trials. The future of both of these therapeutic modalities awaits further evaluation. CORTICOSTEROIDS 31
The discovery by Hench and others in 1948 of the therapeutic potential of corticosteroids required that those compounds be considered not only hormones but also drugs. Shortly after their discovery, it was noted that corticosteroids have a marked anti-inflammatory effect in patients with rheumatoid arthritis; this is now well documented and corticosteroids are currently the most potent anti-inflammatory agents available. The mechanism by which the corticosteroids achieve their antiinflammatory effect has not been elucidated. However, the remarkable stabilizing effects of steroids on the lysosomal membrane must represent the important keystone of their anti-inflammatory action. In addition, corticosteroids interfere with the formation of kinins and impair the migration of polymorphonuclear leukocytes (apparently without causing significant reduction of phagocytic or bactericidal actions), cause a decrease in the number and activity of mast cells, and potentially lyse lymphocytes, and interfere with the expression of cellmediated immunity. Corticosteroids are used regularly in the management of systemic lupus erythematosus, polymyositis, polymyalgia rheumatica, temporal or
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giant cell arteritis, mixed connective tissue disease syndrome,45 and severe rheumatoid arthritis unresponsive to other therapy. Large doses (the equivalent of 1 to 2 mg of prednisone per kg of body weight per day) of corticosteroids are reserved for patients with polymyositis, temporal or giant cell arteritis, and lupus erythematosus complicated by nephritis, central nervous system involvement, and possibly hemolytic anemia and thrombocytopenia, although the last two will usually respond to lower dose steroid therapy. Other manifestations of lupus erythematosus including arthritis, pleuritis, and pericarditis may respond to nonsteroidal anti-inflammatory agents. If not, smaller doses of corticosteroids are generally adequate for lupus serositis and dermatitis, as well as polymyalgia rheumatica, mixed connective tissue disease, and rheumatoid arthritis. The mixed connective tissue disease syndrome must be distinguished from other forms of progressive systemic sclerosis because of the salutory response to corticosteroids in the majority of patients. Although rheumatoid arthritis was the first disease to be treated by corticosteroids, considerable controversy remains about their use in this condition. Much of the controversy was engendered by the extent and severity of side effects experienced by the initial patients who were treated with steroids and who received excessive doses for prolonged periods of time. Nevertheless, there are patients with rheumatoid arthritis who will require corticosteroids to ensure adequate therapeutic efficacy. In these patients, every effort must be made to minimize the toxicity of the drug. Toxic effects include suppression of the hypothalamic-pituitary-adrenal axis, diabetes, myopathy, osteoporosis, aseptic necrosis, disorder of mood, posterior subcapsular cataract formation, increased intraocular pressure, salt and water retention, spontaneous bruising, acne, hirsutism, retardation of growth in children, and increased susceptibility to infection. It appears that suppression of the hypothalamic-pituitary-adrenal axis is a side effect of corticosteroid therapy that correlates well with the anticipated development of other side effects,27 which may in fact require longer duration of therapy to become clinically overt. If this is true, then those therapeutic regimens that are known to minimize suppression of the hypothalamic-pituitaryadrenal axis (i.e., alternate day administration of corticosteroid or daily administration of corticosteroids as a single morning dose of < 7.5 mg of prednisone) should minimize toxic manifestations. EXPERIMENTAL AGENTS
Penicillamine Penicillamine is a sulfur-containing amino acid that is useful as a chelator and has been used in the treatment of Wilson's disease and heavy metal poisoning. It cleaves disulfide bridges and inhibits collagen cross linking, but its mechanism of action in patients with rheumatoid arthritis is unclear. Its ability to reduce the titer of rheumatoid factor, however, is well established. Several multicenter trials in Britain have demonstrated its efficacy in the treatment of rheumatoid disease, and a
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recent study16 demonstrated that doses of both 600 and 1200 mg daily added to a standard treatment regimen produced statistically significant improvement in relief of pain, grip strength, erythrocyte sedimentation rate, and hemoglobin concentration. Improvement usually began 4 to 8 weeks after starting treatment but was not complete until at least 12 weeks. There was no evidence to suggest that it effected the healing of erosive bone lesions. The use of penicillamine has been associated with significant adverse reactions although using the lower dose regimen (600 mg per day) seems to decrease the incidence of adverse effects significantly. Adverse reactions in decreasing frequency include development of a positive antinuclear antibody determination, loss of the sense of taste or the development of a metallic taste, rash, pruritus, gastrointestinal symptoms, occasionally neutropenia, pancytopenia, or immune complex nephropathy, and rarely myasthenia. Penicillamine is more convenient than gold to administer. It appears to have approximately equal efficacy and to be a practical treatment for active rheumatoid arthritis. At present, the use of this agent must be considered experimental. Any physician prescribing it for rheumatoid arthritis should be included under an investigational new drug application filed with the Food and Drug Administration. Patients who receive penicillamine should have close clinical laboratory follow-up. Levamisole Levamisole is an antihelminthic drug with properties of immunostimulation. Studies of adjuvant arthritis in the raf'12 suggest that levamisole is effective not only in restoring an impaired cellular immune response but also in enhancing an already activated system. The timing of administration appears to be crucial, however, and continuous therapy may result in loss of efficacy. In clinical trials,23,41 the onset of enhancement of in vitro measurements of cell-mediated immunity seems to correlate with clinical improvement of rheumatoid arthritis. It must be cautioned that the clinical trials of this agent are inconclusive. Some have shown it to be as effective as penicillamine in patients with rheumatoId arthritis and others have shown it to be ineffective. Its usefulness in the treatment of rheumatoid arthritis must therefore await substantial further study.
CONCLUSION The objective of nonspecific anti-inflammatory therapy is to relieve symptoms. In selected patients such therapy may also slow, prevent, or reverse the destructive effects of the inflammatory process. None of the wide variety of anti-inflammatory agents reviewed herein is without some inherent toxicity, although some are much more toxic than others. The physician prescribing any of these agents must keep in mind both the potential benefits and the risks attendant to their use, and balance the potential benefit against the potential risk.
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