922
BRIEF REPORTS
MANAGEMENT OF RHEUMATOID ARTHRITIS WITH ORAL GOLD MICHAEL H. WEISMAN and DENISE M. HANNIFIN
The initial 3 months’ uncontrolled clinical trials outside the United States (1,2) of a new absorbable, orally administered, gold-containing compound for rheumatoid arthritis (RA) have suggested that the drug Auranofin is well tolerated, safe, and effective. A potential concern, however, was the observation that the administered dosages of 6 and 9 mg per day were associated with a progressive rise in blood gold levels, suggesting a net “positive” gold balance and continuous gold accumulation within the body. This study was designed to extend observations of efficacy and toxicity of Auranofin for one year in a larger group of patients with a lower potentially safer dosage schedule. Our results, although preliminary and uncontrolled, indicate that Auranofin, at 4 mg per day, is associated with regression of disease activity in twothirds of patients taking the drug, and there was no evidence of significant toxicity or progressive accumulation of gold within the body. Patients and methods. Sixteen RA patients were enrolled in the study, 11 females and 5 males, with ages ranging from 24 to 65 years and a mean of 52 years. No patient had prior chrysotherapy, penicillamine, or cytotoxic drugs, and there was no concurrent corticosteroid therapy (with the exception of one patient taking 3 mg of prednisone and this was continued). All patients were ambulatory and able to care for themselves (14 functional class 2, 2 functional class 3). Two-thirds of the patients had their disease longer than 5 years (mean 11 years), and all patients were positive for serum rheumatoid factor. The initial trial lasted 6 months and these patients have been followed up for an additional 6 From the University of California School of Medicine, San Diego, California. Supported in part by NIH training grant AM-07062, Arthritis Foundation Clinical Center Grant, and UCSD General Clinical Research Center, PHS/DHEW NIH grant RR827. Address reprint requests to Dr. Michael H. Weisman, University of California, University Hospital, 225 West Dickinson Street, San Diego, California 92103. Submitted for publication October 26, 1979; accepted in revised form February 22, 1979. Arthritis and Rheumatism, Vol. 22, No.8 (August 1979)
months. Auranofin was administered to all patients in the identical daily dosage schedule of 4 mg for one month and 2 mg for the next 2 months, followed by 4 mg for the remaining 3 months and the rest of the year. The initial study design was to evaluate the efficacy of an “induction” course of 4 mg for one month followed by a low (2 mg) maintenance dose which would avoid gold accumulation in the body. When a dose of 2 mg did not seem adequate therapeutically, the maintenance dose was raised to 4 mg in each patient at the 3 months’ point in the trial. Clinical assessments were made monthly by a single observer throughout, and the total number of tender and swollen joints were recorded as a raw score out of a possible 66 affected joints. Grip strength, 50 foot walking times, and morning stiffness were assessed at each visit, and an ESR (by the Westergren method) was obtained. An overall assessment of the patient’s condition was made at each visit by both the patient and the observer. Standard laboratory assessments of toxicity were made monthly, and at the conclusion of the trial, stored sera from each visit were tested simultaneously for rheumatoid factor activity (by the Bentonite flocculation test) and IgG and IgM levels (using commercial radial immunodifhsion plates). Gold concentrations were determined by atomic absorption using a graphite furnace on heparinized whole blood samples at the Smith, Kline and French Laboratories, Philadelphia, Pennsylvania. Statistical significancewas determined by the Student’s t test. Results. Therapeutic observations (Tables 1 and 2). Sixteen patients started and 15 completed the 6 month trial; 1 patient (see below) was dropped for presumed toxicity. The mean values for joint tenderness and swelling improved for the entire group (Pc 0.01). Morning stiffness also improved dramatically with complete disappearance of this symptom in 7 of 15 patients. There were no statistically significant changes in 50 foot walking times or grip strength. Based on these observationsas well as a “global” assessment of improvement noted by the patients and
BRIEF REPORTS
923
Table 1. Comparison of the number of active joints and morning stiffness for the whole group of 15 patients from the beginning to the end of the trial Week 0 Number of tender joints (mean f SEM) Number of swollen joints (mean f SEM) Morning stiffness/ minutes (mean 2SEM)
41.6 f 4.0 42.4 f 1.8 141 f 37
Week 26 32.9 f 5.1 28.8 f 2.7 39 f 18
P* < 0.01 < 0.01 < 0.01
Statistical evaluation done with Student’s t test.
the observer, 10 of the 15 patients were considered to have actually responded to the medication and these 10 were selected to continue on maintenance therapy at the end of 6 months. We then asked if there were other additional objective criteria of improvement for these 10 patients when compared to the remaining 5. Changes in rheumatoid factor (BFT titers) and ESR were compared between the two groups, and the patients judged to have responded had a statistically significant improvement in these two measurements as contrasted to the nonresponders who showed no change (Table 2). The initial values of both groups were not statistically different. Serum IgG, IgM, or albumin levels did not change during the study period. A profound diminution in constitutional symptoms (weakness, easy fatigability, progressive weight loss) was prominent in 6 of the 10 responders. Timing of improvement was gradual for 7 of the 10, occurring in the second 3 months of the trial; in 3 patients, however, a clearcut improvement began after 4 weeks of drug therapy. Toxicity. No patient displayed any sign of dermal, hematologic, or renal toxicity. Five patients had loose stools only during the first week; 2 other patients noted their stools to be less formed throughout the period of drug administration, but there was no increase in amount or frequency of the stools. One patient was dropped from the study at week 12 because of the development of low grade liver enzyme abnormalities in the fourth week. A liver biopsy, however, revealed chronic changes (fibrosis) and the enzyme abnormalities have
persisted for 1 year after discontinuation of the gold, a result consistent with a form of chronic liver disease independent of Auranofin administration. Gold levels. Whole blood gold levels are plotted in Figure 1; the 10 responders are compared with the 5 nonresponders, and those responding had lower mean gold levels with the differences reaching statistical significance at 20 and 26 weeks. The mean gold level for the entire group of 15 patients (not shown) reached a plateau and did not continue to rise when the dose was held constant at 4 mg per day during the second 3 months of the trial. Followup observations. At the conclusion of the 6 months’ trial all 10 responders elected to stay on the drug, and this group has been followed for an additional 6 months. Two patients voluntarily discontinued the medication at month 7-both subsequently regressed to disease activity of pretreatment levels and have been restarted on the drug. The remaining 8, with 1 exception, have maintained their satisfactory therapeutic response. One patient experienced exacerbation of his disease to pretreatment levels at month 9. Without exception, no patient has experienced any dermal, renal, or hematopoietic toxicity for the 1 year of drug administration (grand total of 150 patient/months). Discussion. The total number of patients treated with oral chrysotherapy from this series and from those abroad (1,2) has reached 32 (Table 3); the patients reported herein have been followed for the longest period (1 year), and there has been no serious toxicity attributable to the drug in any patient. This is reflected in the
Table 2. Comparison of the changes in rheumatoid factor and ESR* between the 10 patients considered to have responded and the 5 patients considered not to have responded Responders
BFTt (log, mean titer f SEM) ESR (mm/hr mean f SEM)
* ESR
=
$ NS
=
Week 0
Week 26
Statistical significance
Week 0
Week 26
Statistical significance
9.7 f 0.1 43.7 f 2.1
6.8 f 0.9 25.7 4.1
P = < 0.01 P= 5 years
CCC
Henry Ford
Auranofin 32 2 53
99 24 49 79
36 14 48 (median) 81
17 4 45 84
66 34
33 30 37
50 50
Total number of patients who have received Auranofin-this ences 1, 2. t Empire Rheumatism Council Trial, reference 5. $ Cooperating Clinics Committee Trial, reference 4. $ Henry Ford Hospital Trial, reference 8.
1M) 38 9 53
study combined with those in refer-
BRIEF REPORTS
Acknowledgments. The authors gratefully acknowledge the advice and help of Donald T. Walz, PhD, Lee Greene, PhD, Thomas G. Lawrence, Jr., MD, John Scavulli, MD, Harry G. Bluestein, MD, and Nathan J. Zvaifler, MD, and the expert secretarial assistance of Deborah Ann Frank. REFERENCES Finkelstein AE, Walz DT, Batista V, Mizraji M, Roisman F, Misher A Auranofin. New oral gold compound for treatment of rheumatoid arthritis. AM Rheum Dis 35:25 I257, 1976 Berglof F, Berglof K, Walz DT: Auranofin: an oral chrysotherapy agent for the treatment of rheumatoid arthritis. J Rheumatol5:68-74, 1978 Freyberg RH, ZiE M, Baum J: Gold therapy for rheumatoid arthritis, Arthritis and Allied Conditions. Eighth edi-
925
4.
5.
6.
7. 8.
tion. Edited by JL Hollander, DJ McCarty. Philadelphia, Lea BE Febiger, 1972, pp 455482 The Cooperative Clinics Committee of the ARA: A controlled trial of gold salt therapy in rheumatoid arthritis. Arthritis Rheum 16353-358, 1973 Empire Rheumatism Council: Gold therapy in rheumatoid arthritis. Final report of a multicenter controlled trial. Ann Rheum Dis 20315-333, 1961 Gottlieb NL, Kiem IM, Penneys NS, Schultz DR: The influence of chrysotherapy on serum protein and immunoglobulin levels, rheumatoid factor, and antiepithelial antibody titers. J Lab Clin Med 86:962-972, 1975 Gottlieb N L Chrysotherapy. Bull Rheum Dis 27:912-917, 1977 Sigler JW, Bluhm GB, Duncan H, Sharp JT, Ensign DC, McCrum WR: Gold salts in the treatment of rheumatoid arthritis: a double-blind study. Ann Intern Med 8021-26, 1974
APPARENT VASCULITIS ASSOCIATED WITH PROPYLTHIOURACIL USE BRIAN D. HOUSTON, MICHAEL E. CROUCH, JAMES E. BRICK, and ANTHONY G. DiBARTOLOMEO
Propylthiouracil is among the drugs which have been implicated as causing vasculitis (1); however, the incidence and clinical findings have not been well described. We describe a young woman with Graves' disease who developed a reaction to propylthiouracil resembling a vasculitis. Case report. A 26-year-old white female was admitted to West Virginia University Hospital in May 1977 with multiple necrotic ulcerations on the lower extremities. The lesions had developed one month prior to admission and were accompanied by nasal congestion, malaise, and a temperature of 101'F. The patient had From the West Virginia University School of Medicine, Department of Medicine, Morgantown, West Virginia. Brian D. Houston, MD; Michael E. Crouch, MD, James E. Brick, MD,Anthony G. DiBartolomeo, MD. Address reprint requests to Brian D. Houston, MD, Department of Medicine, West Virginia University School of Medicine, Morgantown, West Virginia Submitted December 26, 1978; accepted in revised form March 9, 1979.
taken propylthiouracil sporadically for the previous 13 years; her general indication for therapy was the sensation that her neck was more swollen than usual. Two months before the onset of the rash, she began taking 50 mg of propylthiouracil per day. She denied any previous skin rash, sinus drainage, arthralgias, or renal disease. The patient had a pulse of 150 per minute, blood pressure of 120/80, and a temperature of 37.5OC. She had a smooth symmetrically enlarged thyroid gland approximately five times normal size. Exophthalmos was present. Examination of the nasal septum showed normal results. She had numerous necrotic ulcerations and purpuric lesions over her lower extremities. There were two 4 X 5 cm ulcerations over the left foot and ankle (Figure l), extending into the subcutaneous tissue and down to the extensor tendons. Laboratory Sndings included a WBC of 6,900 with 64 polymorphonuclear leukocytes and 1 eosinophil. Hemoglobin was 11.4 gm%. The serum creatinine
BRIEF REPORTS
MANAGEMENT OF RHEUMATOID ARTHRITIS WITH ORAL GOLD MICHAEL H. WEISMAN and DENISE M. HANNIFIN
The initial 3 months’ uncontrolled clinical trials outside the United States (1,2) of a new absorbable, orally administered, gold-containing compound for rheumatoid arthritis (RA) have suggested that the drug Auranofin is well tolerated, safe, and effective. A potential concern, however, was the observation that the administered dosages of 6 and 9 mg per day were associated with a progressive rise in blood gold levels, suggesting a net “positive” gold balance and continuous gold accumulation within the body. This study was designed to extend observations of efficacy and toxicity of Auranofin for one year in a larger group of patients with a lower potentially safer dosage schedule. Our results, although preliminary and uncontrolled, indicate that Auranofin, at 4 mg per day, is associated with regression of disease activity in twothirds of patients taking the drug, and there was no evidence of significant toxicity or progressive accumulation of gold within the body. Patients and methods. Sixteen RA patients were enrolled in the study, 11 females and 5 males, with ages ranging from 24 to 65 years and a mean of 52 years. No patient had prior chrysotherapy, penicillamine, or cytotoxic drugs, and there was no concurrent corticosteroid therapy (with the exception of one patient taking 3 mg of prednisone and this was continued). All patients were ambulatory and able to care for themselves (14 functional class 2, 2 functional class 3). Two-thirds of the patients had their disease longer than 5 years (mean 11 years), and all patients were positive for serum rheumatoid factor. The initial trial lasted 6 months and these patients have been followed up for an additional 6 From the University of California School of Medicine, San Diego, California. Supported in part by NIH training grant AM-07062, Arthritis Foundation Clinical Center Grant, and UCSD General Clinical Research Center, PHS/DHEW NIH grant RR827. Address reprint requests to Dr. Michael H. Weisman, University of California, University Hospital, 225 West Dickinson Street, San Diego, California 92103. Submitted for publication October 26, 1979; accepted in revised form February 22, 1979. Arthritis and Rheumatism, Vol. 22, No.8 (August 1979)
months. Auranofin was administered to all patients in the identical daily dosage schedule of 4 mg for one month and 2 mg for the next 2 months, followed by 4 mg for the remaining 3 months and the rest of the year. The initial study design was to evaluate the efficacy of an “induction” course of 4 mg for one month followed by a low (2 mg) maintenance dose which would avoid gold accumulation in the body. When a dose of 2 mg did not seem adequate therapeutically, the maintenance dose was raised to 4 mg in each patient at the 3 months’ point in the trial. Clinical assessments were made monthly by a single observer throughout, and the total number of tender and swollen joints were recorded as a raw score out of a possible 66 affected joints. Grip strength, 50 foot walking times, and morning stiffness were assessed at each visit, and an ESR (by the Westergren method) was obtained. An overall assessment of the patient’s condition was made at each visit by both the patient and the observer. Standard laboratory assessments of toxicity were made monthly, and at the conclusion of the trial, stored sera from each visit were tested simultaneously for rheumatoid factor activity (by the Bentonite flocculation test) and IgG and IgM levels (using commercial radial immunodifhsion plates). Gold concentrations were determined by atomic absorption using a graphite furnace on heparinized whole blood samples at the Smith, Kline and French Laboratories, Philadelphia, Pennsylvania. Statistical significancewas determined by the Student’s t test. Results. Therapeutic observations (Tables 1 and 2). Sixteen patients started and 15 completed the 6 month trial; 1 patient (see below) was dropped for presumed toxicity. The mean values for joint tenderness and swelling improved for the entire group (Pc 0.01). Morning stiffness also improved dramatically with complete disappearance of this symptom in 7 of 15 patients. There were no statistically significant changes in 50 foot walking times or grip strength. Based on these observationsas well as a “global” assessment of improvement noted by the patients and
BRIEF REPORTS
923
Table 1. Comparison of the number of active joints and morning stiffness for the whole group of 15 patients from the beginning to the end of the trial Week 0 Number of tender joints (mean f SEM) Number of swollen joints (mean f SEM) Morning stiffness/ minutes (mean 2SEM)
41.6 f 4.0 42.4 f 1.8 141 f 37
Week 26 32.9 f 5.1 28.8 f 2.7 39 f 18
P* < 0.01 < 0.01 < 0.01
Statistical evaluation done with Student’s t test.
the observer, 10 of the 15 patients were considered to have actually responded to the medication and these 10 were selected to continue on maintenance therapy at the end of 6 months. We then asked if there were other additional objective criteria of improvement for these 10 patients when compared to the remaining 5. Changes in rheumatoid factor (BFT titers) and ESR were compared between the two groups, and the patients judged to have responded had a statistically significant improvement in these two measurements as contrasted to the nonresponders who showed no change (Table 2). The initial values of both groups were not statistically different. Serum IgG, IgM, or albumin levels did not change during the study period. A profound diminution in constitutional symptoms (weakness, easy fatigability, progressive weight loss) was prominent in 6 of the 10 responders. Timing of improvement was gradual for 7 of the 10, occurring in the second 3 months of the trial; in 3 patients, however, a clearcut improvement began after 4 weeks of drug therapy. Toxicity. No patient displayed any sign of dermal, hematologic, or renal toxicity. Five patients had loose stools only during the first week; 2 other patients noted their stools to be less formed throughout the period of drug administration, but there was no increase in amount or frequency of the stools. One patient was dropped from the study at week 12 because of the development of low grade liver enzyme abnormalities in the fourth week. A liver biopsy, however, revealed chronic changes (fibrosis) and the enzyme abnormalities have
persisted for 1 year after discontinuation of the gold, a result consistent with a form of chronic liver disease independent of Auranofin administration. Gold levels. Whole blood gold levels are plotted in Figure 1; the 10 responders are compared with the 5 nonresponders, and those responding had lower mean gold levels with the differences reaching statistical significance at 20 and 26 weeks. The mean gold level for the entire group of 15 patients (not shown) reached a plateau and did not continue to rise when the dose was held constant at 4 mg per day during the second 3 months of the trial. Followup observations. At the conclusion of the 6 months’ trial all 10 responders elected to stay on the drug, and this group has been followed for an additional 6 months. Two patients voluntarily discontinued the medication at month 7-both subsequently regressed to disease activity of pretreatment levels and have been restarted on the drug. The remaining 8, with 1 exception, have maintained their satisfactory therapeutic response. One patient experienced exacerbation of his disease to pretreatment levels at month 9. Without exception, no patient has experienced any dermal, renal, or hematopoietic toxicity for the 1 year of drug administration (grand total of 150 patient/months). Discussion. The total number of patients treated with oral chrysotherapy from this series and from those abroad (1,2) has reached 32 (Table 3); the patients reported herein have been followed for the longest period (1 year), and there has been no serious toxicity attributable to the drug in any patient. This is reflected in the
Table 2. Comparison of the changes in rheumatoid factor and ESR* between the 10 patients considered to have responded and the 5 patients considered not to have responded Responders
BFTt (log, mean titer f SEM) ESR (mm/hr mean f SEM)
* ESR
=
$ NS
=
Week 0
Week 26
Statistical significance
Week 0
Week 26
Statistical significance
9.7 f 0.1 43.7 f 2.1
6.8 f 0.9 25.7 4.1
P = < 0.01 P= 5 years
CCC
Henry Ford
Auranofin 32 2 53
99 24 49 79
36 14 48 (median) 81
17 4 45 84
66 34
33 30 37
50 50
Total number of patients who have received Auranofin-this ences 1, 2. t Empire Rheumatism Council Trial, reference 5. $ Cooperating Clinics Committee Trial, reference 4. $ Henry Ford Hospital Trial, reference 8.
1M) 38 9 53
study combined with those in refer-
BRIEF REPORTS
Acknowledgments. The authors gratefully acknowledge the advice and help of Donald T. Walz, PhD, Lee Greene, PhD, Thomas G. Lawrence, Jr., MD, John Scavulli, MD, Harry G. Bluestein, MD, and Nathan J. Zvaifler, MD, and the expert secretarial assistance of Deborah Ann Frank. REFERENCES Finkelstein AE, Walz DT, Batista V, Mizraji M, Roisman F, Misher A Auranofin. New oral gold compound for treatment of rheumatoid arthritis. AM Rheum Dis 35:25 I257, 1976 Berglof F, Berglof K, Walz DT: Auranofin: an oral chrysotherapy agent for the treatment of rheumatoid arthritis. J Rheumatol5:68-74, 1978 Freyberg RH, ZiE M, Baum J: Gold therapy for rheumatoid arthritis, Arthritis and Allied Conditions. Eighth edi-
925
4.
5.
6.
7. 8.
tion. Edited by JL Hollander, DJ McCarty. Philadelphia, Lea BE Febiger, 1972, pp 455482 The Cooperative Clinics Committee of the ARA: A controlled trial of gold salt therapy in rheumatoid arthritis. Arthritis Rheum 16353-358, 1973 Empire Rheumatism Council: Gold therapy in rheumatoid arthritis. Final report of a multicenter controlled trial. Ann Rheum Dis 20315-333, 1961 Gottlieb NL, Kiem IM, Penneys NS, Schultz DR: The influence of chrysotherapy on serum protein and immunoglobulin levels, rheumatoid factor, and antiepithelial antibody titers. J Lab Clin Med 86:962-972, 1975 Gottlieb N L Chrysotherapy. Bull Rheum Dis 27:912-917, 1977 Sigler JW, Bluhm GB, Duncan H, Sharp JT, Ensign DC, McCrum WR: Gold salts in the treatment of rheumatoid arthritis: a double-blind study. Ann Intern Med 8021-26, 1974
APPARENT VASCULITIS ASSOCIATED WITH PROPYLTHIOURACIL USE BRIAN D. HOUSTON, MICHAEL E. CROUCH, JAMES E. BRICK, and ANTHONY G. DiBARTOLOMEO
Propylthiouracil is among the drugs which have been implicated as causing vasculitis (1); however, the incidence and clinical findings have not been well described. We describe a young woman with Graves' disease who developed a reaction to propylthiouracil resembling a vasculitis. Case report. A 26-year-old white female was admitted to West Virginia University Hospital in May 1977 with multiple necrotic ulcerations on the lower extremities. The lesions had developed one month prior to admission and were accompanied by nasal congestion, malaise, and a temperature of 101'F. The patient had From the West Virginia University School of Medicine, Department of Medicine, Morgantown, West Virginia. Brian D. Houston, MD; Michael E. Crouch, MD, James E. Brick, MD,Anthony G. DiBartolomeo, MD. Address reprint requests to Brian D. Houston, MD, Department of Medicine, West Virginia University School of Medicine, Morgantown, West Virginia Submitted December 26, 1978; accepted in revised form March 9, 1979.
taken propylthiouracil sporadically for the previous 13 years; her general indication for therapy was the sensation that her neck was more swollen than usual. Two months before the onset of the rash, she began taking 50 mg of propylthiouracil per day. She denied any previous skin rash, sinus drainage, arthralgias, or renal disease. The patient had a pulse of 150 per minute, blood pressure of 120/80, and a temperature of 37.5OC. She had a smooth symmetrically enlarged thyroid gland approximately five times normal size. Exophthalmos was present. Examination of the nasal septum showed normal results. She had numerous necrotic ulcerations and purpuric lesions over her lower extremities. There were two 4 X 5 cm ulcerations over the left foot and ankle (Figure l), extending into the subcutaneous tissue and down to the extensor tendons. Laboratory Sndings included a WBC of 6,900 with 64 polymorphonuclear leukocytes and 1 eosinophil. Hemoglobin was 11.4 gm%. The serum creatinine
