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APPENDIX B. 11 PANEL ON DRUGS USED IN RHEUMATIC DISEASES a. Statement on the Use of Combination Drugs ⢠The Panel on Drugs Used in Rheumatic Diseases records its opposition to combinations of drugs. In the list of drugs the Panel has reviewed, in no instance was it shown conclusively that drugs which were combined into one preparation worked synergistically, i.e., that one drug when added to another improved the action of the original drug ⢠. In all situ- ations where more than one drug is needed, the fixed dosage imposed by the use of the combination prevents adequate titration and individualiza- tion according to the needs of the patient. Colbenemid is an example of a combination drug that illustrates these shortcomings. Numerous in- stances were reviewed in which a drug was added for insufficient scien- tific reason (e.g., ascorbic acid added to gluocorticoid, or vitamin B12 to corticotrophin). The Panel feels strongly that the convenience to the patient in the use of a combination is heavily outweighed by the cited disadvantages, and it would favor disapproval of all the combinations that the Panel has reviewed. 223
b. Statement on the Use of Corticosteroids and Corticotrophins Systemic glucocorticoids and corticotrophin are effective in the acute control of the symptoms and signs of rheumatoid arthritis, systemic lupus erythematosus, and rheumatic fever. These preparations will also control the acute arthritic symptoms of scleroderma and some of the acute symptoms of necrotizing arteritis and polymyositis. No other class of drugs approaches the anti-inflammatory potency of the adrenocortical steroids. Of the several forms available (preinisone, dexamethasone, triamcinolone, etc.), none is clearly "better" than the others with regard to anti-inflammatory potency. Parenteral glucocorti- coids should be used for systemic effect only when the patient is unable to tolerate oral medication. 1 In the long-term maintenance of rheumatoid arthritis, the hazards of continued treatment with glucocorticoids or corticotrophin often out- weigh the advantages of disease suppression. When used, these drugs should be adjuncts and not the sole therapy. In the treatment of sclero- derma (progressive systemic sclerosis), the lack of effect on visceral manifestations and the probable hazard of accelerated renal involvement is so great that the long-term use of these agents should be avoided. In systemic lupus erythematosus, the benefits of the treatment outweigh the hazards, and maintenance therapy with these agents may be the pro- cedure of choice. It should be stressed that some patients with SLE do not need steroids and that, in some situations, patients survive for years with SLE. In necrotizing arteritis, the evidence is inconclusive, and no statement can be made regarding the benefits as contrasted with the ~azards. In polymyositis, the reduction in the serum enzymes that can be achieved with steroids is believed to be due to the suppression of the myositis process and its attendant destruction of muscle. Chronic administration is justified in active disease. In acute rheumatic fever with carditis, treatment beyond 3 months is seldom required, and in that period the benefits may outweigh the hazards. In psoriatic arthritis, as in rheumatoid arthritis, the hazards of continued treatment often out- weigh the advantages of disease suppression. In addition, the risk of a flareup of the psoriasis after steroid withdrawal is great.2 In un- complicated ankylosing spondylitis, glucocorticoids and corticotrophin should not be used in long-term management.3 A general rule for all long-term treatment with these agents is that the smallest possible dose be used to control a given symptom or sign. A second general rule is that, when the agent is reduced, it must be reduced gradually. At this time, the only exception to these state- ments is found in chronic high-dose steroid therapy for the nephritis of systemic lupus. Some believe this treatment has advantages outweigh- ing the hazards, although there is not complete agreement on this. 224
--- ·-·--- - In all patients receiving long-term therapy with systemic gluco- corticoids or corticotrophin, one must anticipate and expect the develop- ment of the following untoward events which are generally dependent on the dose used and which are characteristic of the Cushingoid state: 1. Osteoporosis and spontaneous fractures. This has not been modified by high protein or calcium intake, by physical ex- ercise, or by the administration of anabolic steroids. 2. The development of a peptic ulcer. This is more commonly seen when salicylates are administered concomitantly, but it is also seen when salicylate& are not administered. A peptic ulcer may develop silently and present itself as catastrophic bleeding or perforation. 3. Decreased resistance to infection and decreased ability to counteract and localize infection. These effects result in altered patterns of response to infection, and this makes the effects difficult to recognize and diagnose. 4. Impaired wound healing and thin, fragile, skin. 5. In rheumatoid arthritis, an increased frequency of gener- alized necrotizing arteritis may be found. 6. Decreased carbohydrate tolerance, making latent diabetes overt. 1. Rises in blood pressure and fluid retention, particularly with corticotrophin, cortisone, and hydrocortisone. 8. An increasing tendency to development of aseptic necrosis of bone, especially of the femoral head. 9. The development of posterior subcapsular cataracts is not uncommon. Also, long-term use of systemic steroids may · give rise to increased intraocular pressure. 10. The development in varying degree of steroid myopathy, and loss of muscle mass, this is possibly seen more frequently with the 9-alpha-fluoroglucocorticoids. 11. In children, suppression of growth with chronic administra- tion of glucocorticoids and corticotrophin may be seen even at low doses. This effect is in addition to the other un- toward events outlined in this section. 12. One may anticipate adrenal unresponsiveness after sustained administration of glucocorticoids. During periods of stress, increased amounts of glucocorticoids may be required. Admin- istration of corticotrophin will increase adrenal size and 225
will lead to an adrenal which will respond to exogenous corticotrophin. It will also lead to suppression of the pituitary and thus, during stress, the adrenal glands may be unresponsive. Both adrenal and pituitary suppres- sion are almost invariably temporary, and function will ultimately return within varying periods after withdrawal. Many of these effects are the more threatening because, for the following two reasons, the agents cannot be ab- ruptly withdrawn: First, the temporary suppression of pituitary-adrenal responsiveness, and second, the near certainty of sharply increased activity of the underly- ing connective-tissue disease. DO~ATION: 1. West, H.F. Long-term intramuscular prednisone therapy. Ann. Rheum. Dis. 21:191-193, 1962. 2. Reed, W.B., s.w. Becker, R. Rohde, and C.L. Heiskell. Psoriasis and arthritis. Arch. Derm. 83:541-548, 1961. 3. Polley, H. Common rheumatic disorders: III. Rheumatoid spondylitis. Amer. Practit. 12:403-408, 1961. BIBLIOGRAPHY: 1. Osteoporosis and spontaneous fractures. (a) Clinical state: Rosenberg, E.F. Rheumatoid arthritis, osteoporosis and frac- tures related to steroid therapy. Acta Med. Scand. 162 (Sup- plement 341):211-224, 1958. (b) Ineffectiveness of preventive treatment: Kendall, P.H. Side effects of corticosteroids. Ann. Phys. Med. 7:253-257, 1964. Thorn, G.W. Clinical considerations in the use of corticoste- roids. New Eng. J. Med. 274:755-781, 1966. 2. Peptic ulcer, perforation and hemorrhage. Bowen, R., J.G. Mayne, J.C. Cain, and L.G. Bartholomew. Peptic ulcer in rheumatoid arthritis and r~lationship to steroid treat- ment. Proc. Mayo Clin. 35:537-544, 1960. Couris, G.D., M.A. Block, and C.E. Rupe. Gastrointestinal complications of collagen diseases. Arch. Surg. (Chicago) 89: 695-700, 1964. 226
Kammerer, W.H., R.H. Freiberger and A.L. Rivelis. Peptic ulcer in rheumatoid patients on corticosteroid therapy; a clinical experimental and radiologic study. Arthritis Rheum. 1:122-141, 1958. 3. Decreased resistance to infection and ability to counteract and localize infection. Bywaters, E.G. Present status of steroid treatment in rheum- atoid arthritis. Proc. Roy. Soc. Med. 58:649-652, 1965. Kellgren, J.E., J. Ball, R.W. Fairbrother, and K.L. Barnes: Suppurative arthritis complicating rheumatoid arthritis. Brit. Med. J. 1:1193-1200, 1958. Rimoin, D.L., and J.E. Wennberg. Acute septic arthritis com- plicating rheumatoid arthritis. J.A.M.A. 196:617-621, 1966. Thompson, M. Suppurative arthritis complicating rheumatoid arthritis. Brit. Med. J. 2:451, 1958. 4. Impaired wound healing, thin fragile skin, and ecchymoses. Nashelsky, G.M., and C.J. Smyth. Subcutaneous hemorrhages in rheumatoid patients treated with prednisone. Ann. Rheum. Dis. 17:76-81, 1958. 5. Increased frequency of generalized necrotizing arteritis. johnson, R.L., C.J. Smyth, G.W. Holt, A. Lubchenco, and E. Valentine. Steroid therapy and vascular lesions in rheumatoid arthritis. Arthritis Rheum. 2:224-229, 1959. Kemper, J.W., A.H. Baggenstoss, and C.H. Solcumb. The rela- tionship of therapy with cortisone to the incidence of vascu- lar lesions in rheumatoid arthritis. Ann. Intern. Med. 40: 831-851, 1957. Sokoloff, L., and J.J. Bunim,Jr. Vascular lesions in rheuma- toid arthritis. J. Chronic Dis. 5:668-687, 1957. 6. Altered carbohydrate tolerance. Bishop, M.P., and J.H. Glynn. Diabetes caused by ACTH treat- ment of rheumatoid arthritis. Proc. Roy. Soc. Med. 45: 168- 170, 1952. Bollett, A.J., R.L. Black, and J.J. Bunim. Major undesirable side-effects resulting from prednisolone and prednisone. J.A.M.A. 158:459-463, 1955. 227
Kalant, N. Effect of cortisone on development of diabetic aci- dosis. Lancet 1:925-927, 1958. 7. Fluid retention. Thorn, G.W. Clinical considerations in the use of corticoste- roids. New Eng. J. Med. 274:755-781, 1966. 8. Aseptic necrosis. (a) Osteoarthritis: Chandler, G.N., D.T. Jones, V. Wright, and S.J. Hartfall. Charcot's arthropathy following intra-articular hydrocortisone. Brit. Med. J. 1:952-953, 1959. (b) Rheumatoid arthritis and lupus erythematosus: Dubois, E.L., and L. Cozen. Avascular (aseptic) bone necrosis associated with systemic lupus erythematosus. J.A.M.A. 174: 966-971, 1960. Ruderman, M., and D.J. McCarty,Jr. Aseptic necrosis in sys- temic lupus erythematosus: report of a case involving 6 joints. Arthritis Rheum. 7:709-717, 1964. Sweetman, D.R., R.M. Mason, and R.O. Murray. Steroid arthrop- athy of the hip. Brit. Med. J. 1:1392-1394, 1960. Velayos, E.E., J.D. Leidholt, C.J. Smyth, and R. Priest. Arthropathy associated with steroid therap~ Ann. Intern. Med. 64:759-771, 1966. ~. Subcapsular cataracts. Crews, S.J. Posterior subcapsular lens opacities in patients on long-term corticosteroid therapy. Brit. Med. J. 1:1644- 1647, 1963. Gordon, D.M., W.H. Kammerer, and R.H. Freyberg. Examination for posterior subcapsular cataracts. A preliminary report of results in forty-five rheumatoid patients treated with corti- costeroids. J.A.M.A. 175:127-129, 1961. Nowicki, N.J. The ocular manifestations of collagen diseases and of agents used in their treatment. Med. Clin. N. Amer. 49(1):131-139, 1965. 10. Steroid myopathy. Coomes, E.N. The rate of recovery of reversible myopathies and 228
the effects of anabolic agents in steroid myopathy. Neurology 15:523-530, 1965. Golding, D.N., S.M. Murray, G.W. Pearce, and M. Thompson. Cor- ticosteroid myopathy. Ann. Phys. Med. 4:171-177, 1961. Syme, J.R. Muscle wasting complicating treatment with dexa- methasone. Med. J. Aust. 2:420-421, 1960. 11. Growth retardation. Ward, D.J., M. Hartog, and B.M. Ansell. Corticosteroid-induced dwarfism in Still's disease treated with human growth hormone. Clinical and metabolic effects including hydroxyproline excre- tion in two cases. Ann. Rheum. Dis. 25:416-421, 1966. 12. Adrenal unresponsiveness. Graber, A.L., R.L. Ney, W.E. Nicholson, D.P. Island, and G.W. Liddle. Natural history of pituitary-adrenal recovery follow- ing long-term suppression with corticosteroids. Trans. Assoc. Amer. Phys. 77:296-306, 1962. Harter, J.G., W.J. Reddy, and G.W. Thorn. Studies on an inter- mittant corticosteroid dosage regimen. New Eng. J. Med. 269: 591-596, 1963. Nelson, J.K., J.S. Mackay, B. Sheridan, and J.A. Weaver. Inter- mittent therapy with corticotropin. Lancet 2:78-83, 1966. Paris, J. Pituitary-adrenal suppression after protracted admin- istration of adrenal cortical hormones. Proc. Mayo Clin. 36: 305-317, 1961. 13. Increased renal involvement in scleroderma. Cohen, S.M. Fatal malignant hypertension following prednisone therapy of diffuse systemic sclerosis. Circulation 16: 868, 1957. Rodnan, G.P., G.E. Schreiner, and R.L. Black. Renal involve- ment in progressive systemic sclerosis (generalized sclero- derma). Amer. J. Med. 23:445-462, 1957. 14. Neuropathy. Good, A.E., R.P. Christopher, G.R. Koepke, L.F. Bender, and M.E. Tarter. Peripheral neuropathy associated with rheumatoid arthritis. A clinical and electrodiagnostic study of 70 con- secutive rheumatoid arthritis patients. Ann. Intern. Med. 63: 87-99, 1965. 229
Pallia, C.A., and J.T. Scott. Peripheral neuropathy in rheum- atoid arthritis. Brit. Med. J. 1:1141-1147, 1965. 15. Hypercortisonism. Rotstein, J., and R.A. Good. Steroid pseudorheumatism. Arch. Intern. Med. 99:545-555, 1957. Slocumb, C.H. Symposium on certain problems arising from clin- ical use of cortisone; rheumatic complaints during chronic hypercortisonism and syndromes during withdrawal of cortisone in rheumatic patients. Proc. Mayo Clin. 28:655-657, 1953. 16. Psychiatric problems. Bollett, A.J., R.L. Black, and J.J. Bunim. Major undesirable side-effects resulting from prednisolone and prednisone. J.A.M.A. 158:459-463, 1955. Glaser, G.H. Psychotic reactions induced by corticotropin (ACTH) and cortisone. Psychosom. Med. 15:280-291, 1953. 17. Congenital abnormalities. Harris, J.W., and I.P. Ross. 'Cortisone therapy in early preg- nancy: relation to cleft palate. Lancet 1:1045-1047, 1956. 23('
c. Statement on the Use of Cortisol and Cortisone In general, cortisol and cortisone, like the other orally administered corticosteroid drugs, have anti-inflammatory effectiveness in the treat- ment of certain rheumatic diseases; however, in addition to the customary toxic manifestations of corticosteroid therapy, cortisol and cortisone induce increased sodium retention and potassium excretion, and may cause hypokalemic alkalosis.2 From Goodman and Gilman2 , one can extrapolate the following electro- lyte-regulating potencies of equal anti-inflammatory doses of the various orally administered adrenocortical hormones: Cortisol 1 Cortisone 1 Prednisone 0.23 Prednisolone 0.2 6-Methylprednisolone 0 Triamcinolone 0 Dexamethasone 0 In other words, in equal anti-inflammatory doses, cortisol and corti- sone have 5 times the salt-retaining and potassium-losing effects of prednisone and prednisolone. The summary statement in Arthritis and Allied Conditional seems appro- priate: "The synthetic steroids discussed in this chapter are therapeu- tically superior to the naturally occurring steroids. Many troublesome effects that often complicated cortisone or cortisol therapy occur infre- quently, or notal all, when the newer compounds are used." Specific toxic manifestations are sodium retention, potassium loss, hypertension, edema, and congestive heart failure. There seems no real role for corti- sol and cortisone in the treatment of the rheumatic diseases in view of these factors. DOCUMENTATION: 1. Black, R.L. The use of synthetic corticosteroids in rheumatoid arthritis, p. 379. In J.L. Hollander, Ed. Arthritis and Allied Conditions. (7th ed.) Philadelphia: Lea & Febiger, 1966. 2. Travis, R.H., and G. Sayers. Adrenocorticotropic hormone (ACTH, corticotropin), pp. 1608-1648. In L.S. Goodman and A. Gilman, Eds. The Pharmacological Basis of Therapeutics (3rd ed.) New York: The Macmillan Co., 1965. 231
d. Statement Concerning the Package Inserts in Drugs Used in Rheumatic Diseases The Panel on Drugs Used in Rheumatic Diseases recommends that the following ill-defined and vague claims be modified or deleted from the package inserts for drugs in this category: A. Fibrositis, myositis, arthritis, spondylitis, torticollis B. Lumbago, "stiff neck", whiplash injury, rheumatism, rheumatic, and arthritides The claims in the first category are of such different etiologies that it would be better to specify the diseases, e.g., osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis, or to modify the claims in order to specify the etiology. The claims of the second category are vague and ill-defined, and the objective criteria necessary to evaluation of the efficacy of the drugs to which they apply are thus greatly compromised. Finally, the claims are so imprecise and unscientific as to be objectionable to the Panel, and they ought to be deleted entirely from the package inserts. 232
