THE purpose of this paper is to present observations suggesting that ascorbic acid possesses antirheumatic activity when administered in large doses. Because of the small number of patients treated so far, the relatively short period of follow-up study and the well known variability of rheumatic fever even when it is uninfluenced by therapy, the present communication must be considered preliminary in the strictest sense of the word. Nevertheless, the apparent responses of a group of 7 patients treated within the past three months have been sufficiently impressive to warrant this report.
Since January 2, 1950, ascorbic acid | has been given by mouth in doses of 1 gm. four times daily (total of 4 gm. per day) for periods varying from eight to twenty-six days to a total of 7 patients with rheumatic fever. There has been a follow-up period of twelve days to two months in 3 patients in whom therapy has been discontinued; at the time of this writing, March 20, 1950, 4 patients are still receiving treatment.
The results of treatment with ascorbic acid can best be presented by a brief description of the clinical course of each of the 7 patients:
CASE 1. P. L. is a 13-year-old boy whose pertinent findings prior to treatment included migratory polyarthritis, a temperature of 101° to 102° F. by rectum and elevation of the sedimentation rate. His heart seemed normal except for a slight systolic murmur. Ascorbic acid was given for a total of 8 days (January 2 through January 9, 1950). Within 24 hours of the beginning of treatment the joint manifestations had disappeared, and the fever had lessened. The temperature remained normal after the 2nd day of therapy, but the sedimentation rate continued to be elevated.
CASE 2. R. M. is a 14-year-old boy who has suffered for many months from persistent rheumatic fever, severe cardiac involvement and chronic hepatic congestion. Ascorbic acid therapy was begun on February 4, 1950, during a period of increasing rheumatic activity (possibly just a rheumatic fever cycle), manifested by temperature elevation to 102° F. by rectum, rise in the sedimentation rate and increased congestion of the liver. The fever began to lessen on February 5, and the temperature has remained normal since February 6. The size of the liver has not changed appreciably, and sedimentation rate is still elevated. Ascorbic acid was given for a total of only 8 days.
CASE 3. E. T. is a 15-year-old boy who for 6 weeks prior to therapy had been ill with migratory objective polyarthritis, fever, sinus tachycardia and a rapid sedimentation rate. Except for a slight systolic murmur, his heart seemed normal. With ascorbic acid therapy, which was given for a total 15 days (February 21 to March 7, 1950), there was prompt improvement in symptoms and reduction in fever. Since the 2nd day of treatment the temperature has been entirely normal, and there have been no symptoms or signs referable to the joints. By March 20 the sedimentation rate had fallen to within normal limits.
CASE 4. W. D. is a 14-year-old boy with rheumatic heart disease whose symptoms of rheumatic fever had been controlled by acetyl salicylic acid. However, after the omission of this drug and prior to treatment with ascorbic acid he had elevation of the temperature to 102° F. by rectum, several nosebleeds and a swollen painful knee. Ascorbic acid therapy was begun on February 22, 1950, and continued to the present time. Improvement was definite but gradual over a 4-day period. He has been symptom-free and afebrile since February 26. The sedimentation rate has fallen from an initial level of 1.4 to the slightly elevated level of 0.55 mm. per minute.
CASE 5. R. F. is an 11-year-old girl who, on admission to the hospital on March 6, 1950, was obviously acutely ill with active rheumatic fever, pancarditis and congestive heart failure. Pertinent findings included a temperature of 104° F by rectum, tender, swollen finger joints, a respiratory rate of 60 to 75, cardiac enlargement, murmurs of mitral regurgitation and aortic regurgitation, nodal rhythm, a ventricular rate of 160, a pericardial friction rub, marked enlargement and tenderness of the liver, and edema of the legs and lower back. Treatment with ascorbic acid was begun on the evening of March 6. The fever and joint symptoms gradually lessened and have been completely absent since March 13. The friction rub has not been audible since March 10. The cardiac rhythm reverted to normal within 24 hours of therapy, and the heart rate is now about 120. Hepatic congestion and peripheral edema have entirely disappeared. The patient now feels well and appears obviously much improved. The sedimentation rate is still elevated.
CASE 6. A. F. is an 18-year-old boy without cardiac involvement whose rheumatic-fever manifestations just prior to ascorbic acid therapy (given from March 7, 1950, to the present) consisted of elevation of the temperature to 101° F. by rectum, objective polyarthritis and elevation of the sedimentation rate. Treatment was followed by somewhat slow but steady improvement. The temperature has been normal since March 10, and the joint manifestations have remained completely subsided since March 11. The sedimentation rate is still elevated.
CASE 7. P. B. is a 5-year-old boy with known rheumatic heart disease who had a recrudescence of rheumatic fever on March 9, 1950. Manifestations included elevation of the temperature to 104° F. by rectum, sinus tachycardia, pallor and pain and tenderness of the right knee and both ankles. The joint symptoms subsided spontaneously prior to treatment, but the high fever continued. Ascorbic acid therapy was begun on March 14. Since that time there has been a steady decline in temperature, and fever has been entirely absent since March 17. The heart rate has slowed, and the patient’s appearance has greatly improved.
In 1933 Rinehart 1 proposed the concept that in C deficiency may play a role in the etiology of rheumatic fever, and since that time he and many other investigators have studied the metabolism of ascorbic acid in rheumatic fever and arthritis and have attempted to use it in the treatment of these diseases. However as far as we are aware, a beneficial effect of ascorbic acid on the course of active rheumatic fever has hitherto not been demonstrated. These previous therapeutic failures may perhaps be attributed to the fact that practically all investigators were thinking in terms of vitamin C deficiency and, hence, used doses of ascorbic acid considerably smaller than those used by us.
Although ascorbic acid is generally considered innocuous, and although no untoward reactions have been encountered in the course of our limited observations, there is obviously a need for careful toxicity studies. It is possible that individual doses of more than 1 gm. or total daily doses of more than 4 gm., if found harmless, may prove to be therapeutically even more effective.
The mechanism by which ascorbic acid may influence the rheumatic process is not known, but the large amounts required to produce the apparent effect suggest that it is not a simple matter of replacement therapy. The relation of ascorbic acid to the activity of the adrenal cortex 2 and the recently demonstrated value of adrenocortical activity in the treatment of rheumatic diseases 3, 4, 5 raise many interesting questions concerning the problem of mechanism that cannot be discussed in this short report.
Finally, it should be emphasized that, although our observations suggest that ascorbic acid when administered in sufficient amounts possesses anti-rheumatic activity, no final assessments can yet be made regarding the possible therapeutic value of this substance. Data are as yet insufficient to allow for a comparison of ascorbic acid with salicylates, cortisone, ACTH and other antirheumatic agents. Nevertheless, this preliminary report is offered, to stimulate further investigations of the therapeutic potentialities of ascorbic acid, of its relation to the antirheumatic action of adrenal hormones and of its possible local role in the tissue reactions that we call rheumatic fever. It also indicates the need for caution in interpreting apparent antirheumatic effects obtained from combinations of various hormones and ascorbic acid. 6
Observations suggesting that ascorbic acid in doses of 4 gm. daily possesses antirheumatic activity are presented.
The possible significance of these observations is briefly discussed, and the need for extending them is emphasized.
* From the Department of Pediatrics, Harvard Medical School, the House of the Good Samaritan (Children’s Medical Center) and thc Rheumatic Fever Division of the North Reading State Sanatorium.
This study was supported by grants from the Helen Hay Whitney Foundation and the National Heart Institute of the United States Public Health Service.
† Clinical associate in pediatrics, Harvard Medical School; associate
research director. House of the Good Samaritan; chief, Rheumatic Fever
Division. Children’s Hospital. Children’s Medical Center.
‡ Assistant in medicine. Harvard Medical School; research fellow, American Heart Association; assistant visiting physician, House of the Good Samaritan.
§ Assistant in pediatrics. Harvard Medical School; assistant physician, Children’s Hospital.
¶ Chief, Rheumatic Fever Division. sod assistant superintendent, North Reading State Sanatorium.
| The ascorbic acid for this study was supplied by Hoffman-LaRoche, Incorporated, Nutley, New Jersey.
We are indebted to Drs. George Sturgis, Joseph Knobloch, Royal Schaaf and Susan Butler for their help in the clinical supervision of the patients.
From The New England Journal of Medicine, Volume 242, April 20, 1950, Number 16, pp. 614-615
20 November, 2013.
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