LETTERS 119

joints. There was a modest reduction in the sedimentation rate in the 2 patients with rheumatoid arthritis, but no change in their rheumatoid factor titers.

Despite the unpredictable spontaneous variations in rheumatoid and psoriatic arthritis, the observed clinical improvement in these 3 patients while on phenytoin therapy merits further study.

Arthur M. Bobrove, MD Palo Alto Medical Foundation Polo Alto, CA

Toxicity from methotrexate may be dose related

To the Editor: We were interested to read the report by Michaels

and associates ( I ) suggesting that once-weekly intravenous methotrexate doses ranging from 10 to 50 mg suppressed the activity of unresponsive rheumatoid arthritis. The authors raise some important questions concerning short term ad- verse effects and potential long term hepatic toxicity. We offer commentary on these issues.

The apparent increased risk of neoplasia after the use of chlorambucil, cyclophosphamide, and azathioprine (2.3) tends to deter their use as therapy for other than serious illness. Michaels et al(1) note that the carcinogenic potential of methotrexate is minimal (2-4). This difference supports the choice of methotrexate when an immunosuppressant, cytotoxic drug is indicated. However, the mild, acute toxici- ty experienced by 12 of 14 patients in Michaels’ report indicates that methotrexate is not necessarily clearly prefer- able to these other agents (5,6). The authors speculate that a smaller weekly dose might reduce methotrexate toxicity.

Willkens and coworkers (7) reported some improve- ment in disease parameters in 26 of 32 patients treated with weekly oral doses of methotrexate ranging from 7.5 to 15 mg. Therapy was discontinued in 4 patients because of side effects which could not be controlled by dosage manipula- tion. The incidence of mild effects was not detailed.

We have also performed retrospective studies on our patients treated with methotrexate (8). Of patients treated at the Cleveland Clinic for a mean length of therapy of 34 months at a mean weekly oral dose of 7.53 mg, only 8 of 45 were found to have signs and symptoms that might represent methotrexate toxicity. Modest reduction of dosage and/or modification of alcohol consumption were the only measures necessary to deal with these mild adverse effects.

A second population consisting of 28 patients was treated and studied at the Dartmouth-Hitchcock Center. These patients were followed for a mean of 12 months and received a mean weekly oral dose of 8.36 mg methotrexate. Thirteen of the 28 patients showed some adverse signs or symptoms which might have been the result of methotrexate therapy. These effects were also easily controlled by dosage modification in all but 1 patient, who experienced sufficient

nausea that the drug was discontinued. Response to treat- ment in both groups was similar to the response seen in Willkens’ patient population (8). These preliminary findings suggest that the incidence of acute toxicity is lowered when weekly doses of methotrexate are lowered, while efficacy is retained.

The second issue which Michaels et al (1) raise involves hepatotoxicity and the need for liver biopsy. It has been estimated that psoriasis patients treated with doses of methotrexate ranging from 7.5 mg to 35 mg per week showed 3-5% incidence of cirrhosis and a 6% incidence of fibrosis (9). Mackenzie has reported liver biopsy findings in 2 groups of patients (10). The treatment group was composed of 60 patients with rheumatoid arthritis receiving prolonged meth- otrexate therapy (mean 4 years). They had received a mean weekly dose of 8.67 mg and a mean total dose of 1,837 mg. A matched group of 25 patients with rheumatoid arthritis who were not taking the medication was also studied. Liver biopsies were obtained from each patient in both groups. The biopsy results showed changes of chronic inflammation consistent with a diagnosis of severe rheumatoid arthritis in each group but revealed little real difference between the groups.

In some cases liver biopsy appears to be the only accurate measure of hepatotoxicity (1 I ) . The incidence of serious hepatic side effects with low doses of methotrexate may be sufficiently small, however, that less invasive sero- logic and clinical followup could often be preferable to liver biopsy. At the present time we favor the conservative approach recently outlined for the treatment of psoriasis (12).

We agree with Michaels et al that methotrexate appears useful in the treatment of rheumatoid arthritis, and we suggest that toxicity may be dose related. Furthermore, the low incidence of toxicity may favor methotrexate as the cytotoxic drug of choice in the treatment of rheumatoid arthritis. Controlled prospective studies are indicated and needed.

William S. Wilke, MD Allen H. Mackenzie, MD Arthur L. Scherbel, MD Clevelrrnd Clinic Cleveland, Ohio Gerald D. Groff, MD Thomas H. Taylor, MD Dartmorcth-Hitchcock Center White River Junction, Vermont

1. Michaels RM, Nashel DJ, Leonard A. Sliwinski AJ. Derbes SJ: Weekly intravenous methotrexate in the treatment of rheuma- toid arthritis. Arthritis Rheum 25:339-341, 1982

2. Grunwald HW, Rosner F: Acute leukemia and immunosuppres- sive therapy for non-neoplastic diseases. Arch Intern Med 139:

3. Casciato DA, Scott JL: Acute leukemia following prolonged

4. Bailin PL, Tindall JP, Roenigk HH Jr, Hogan MD: Is metho-

461-466, 1979

agent therapy. Medicine W32-47, 1979

1 20 LETTERS

trexate therapy for psoriasis carcinogenic? A modified retro- spective-perspective-prospective analysis. JAMA 232:359-362, 1975

5 . Williams HJ, Reading JC, Ward JR, O’Brien WM: Comparison of high and low dose cyclophosphamide therapy in rheumatoid arthritis. Arthritis Rheum 23521-527, 1980

6. DeSilva M, Hazleman BL: Long-term azathioprine in rheuma- toid arthritis: a double-blind study. Ann Rheum Dis 40:560-563, 1981

7. Willkens RF, Watson MA, Paxson CS: Low dose pulse metho- trexate therapy in rheumatoid arthritis. J Rheumatol7:501-505, 1980

8. Groff GD, Shenberger KN, Taylor TH, Wilke WS, Harris ED: The potential value of low dose methotrexate in rheumatoid arthritis. Submitted for publication

9. Hanno R, Gruber GG. Owen LG, Callen JP: Methotrexate in psoriasis: a brief review of indications, usage and complications of methotrexate therapy. Am Acad Dermatol 2:171-174, 1980

10. Mackenzie AH: Liver biopsy findings after methotrexate thera- py for rheumatoid arthritis (abstract). J Rheumatol (suppl) 1:73, I974

11. Podurgiel AJ, McGill DB, Ludwig J, Taylor WF, Muller SA: Liver injury associated with methotrexate therapy for psoriasis. Mayo Clin Proc 48:747-791, 1973

12. Roenigk HH, Auerbach R, Maibach HI, Weinstein GD: Metho- trexate guidelines-revised. Am Acad Dermatol 6: 145-155, 1982

Pac-Man phalanx

To the Editor: Leisure activities have long been recognized as re-

sponsible for certain types of musculoskeletal and soft tissue injuries. Often, these injuries result from repetitive motion to the affected area, as in tenhis elbow, or from abnormal stress to the affected area, as in genu amoris (Pinals RS: Genu amoris. Arthritis Rheum 19637-638, 1976). In the last decade, home video computer game units have been de- signed to provide the simulation of some of these more strenuous activities within the comfort of one’s personal living quarters. This shift, however, is not without signifi- cant concern t o the physician.

A 32-year-old male rheumatologist recently pur- chased the “Pac-Man” cartridge for his Atari Home Video Unit. After several games which required sustained hyperex- tension and flexion of the right thumb, the patient noted intense pain and stiffness in the interphalangeal region. There was no previous history of musculoskeletal discom- fort, and there was no recent trauma to the hand. Physical findings were unremarkable, and there was full range of motion of the affected joint, though with discomfort. X-rays were not performed and histocompatibility phenotyping done several years earlier was not diagnostic. Examination of the contralateral hand was unremarkable. The condition

rapidly subsided following cessation of play, and no medica- tion was required.

With the increasing emergence of this form of leisure activity, it is likely that “Pac-Man Phalanx,” as well as other conditions of this type, will become more widely recognized.

Allan Gibofsky, MD, FACP The Hospital f o r Special Surgery N e w York HospitnCCornell University Medical Center New York. N Y

The association of amyloid deposits and osteoarthritis

To the Editor: In the February 1982 issue Egan et a1 (1) refer to our

recent study on microdeposition of amyloid in the joihts (2) and support our view that the location of amyloid in the central areas of fibrillation of fibrocartilaginous discs may be related to chronic mechanical stress..

The authors refer also to a recent report by Falk et al, describing amyloid in severely calcified and malformed aortic valves (3), and suggest that this form of amyloid deposition might be the result of a similar mechanical pathogenesis. In an earlier study on localized amyloidosis of sclerocalcific mitral and aortic valves, 1 have seen amyloid deposits in sclerotic, noncalcified areas (4). Further study (to be published) shows that amyloid is generally found in fusing commissures, particularly around old thrombotic material. Moreover, 2 cases revealed clear histochemical evidence of amyloid deposits originating in the deep layers of a throm- bus. These findings suggest that localized amyloidosis of sclerocalcific heart valves is associated with age-related modifications of thrombus and not with chronic mechanical stress, as originally thought.

Yves A. Goffin Universite Libre de Britxelles Brussels, Belgium

1. Egan MS, Goldenberg DL, Cohen AS, Segal D: The association of amyloid deposits and osteoarthritis. Arthritis Rheum 25:204- 208, 1982

2. Goffin YA, Thoua Y, Potvliege PR: Microdeposition of amyloid in the joints. Ann Rheum Dis 40:27-33, 1981

3. Falk E, Ladefogad C, Christensen- HE: Amyloid deposits on calcified aortic valves. Acta Pathol Microbiol Scand (A) 89:23- 26, 1981

4. Goffin YA: Microscopic amyloid deposits in the heart valves: a common local complication of chronic damage and scarring. J Clin Pathol 33:262-268, 1980