2
LETTERS 69 1 painful, aphthous ulcers and repeated episodes of a “pseu- doseptic” right knee effusion. He had a 2-year history of chronic, low-grade anterior uveitis of the right eye, treated with topical corticosteroids. More recently, he had devel- oped multiple painful scrotal and penile ulcers. In August 1982, the patient complained of excruciating substernal “burning” pain when swallowing liquids or solids. Simulta- neous with the sudden onset of this symptom, he noted the reappearance of a painful right knee effusion and a tempera- ture to 102°F. On admission, he was ambulatory and ap- peared dehydrated. His temperature was 101°F. There were multiple 0.5-cm diameter ulcerations on the buccal mucosa, and 2 similar-appearing ulcerations on the scrotum. The right knee was warm and had a tense effusion. A papule appeared in the right antecubital fossa at a venipuncture site. The patient was treated with intravenous fluids. The right knee was aspirated, yielding 90 cc of sterile, turbid fluid with a white cell count of 40,000/mm~. No corticosteroid was injected. After this procedure, his temperature remained normal. Barium studies of the esophagus showed normal results. On endoscopy, several discrete ulcers similar in appearance to his oral aphthae were noted in the mid- esophagus, 30 cm from the incisors. One ulcer was larger than the others, measuring 1 cm in diameter, but all had white eschar bases and heaped-up, inflamed margihs. The remainder of the esophagus appeared normal. Biopsies of the lesions demonstrated suppurative esophagitis with focal ulceration. Cytologic examination revealed only reactive squamous cells. Colonoscopy and an upper gastrointestinal series with small bowel follow-through disclosed no other ulcerations nor any evidence of inflammatory bowel disease. Although we had planned to initiate therapy with systemic corticosteroids, the patient reported spontaneous improvement in his odynophagia, beginning approximately 1 week after onset of symptoms. Rapid resolution of symp- toms subsequently occurred, such that after 2 weeks he was asymptomatic on an unrestricted diet. Repeat endoscopy was not performed. As Lockhart et a1 have commented (3), esophageal ulceration should be suspected in patients with BehCet’s syndrome who develop odynophagia, and endoscopy may be necessary to establish the diagnosis. In our patient, esopha- geal ulceration was a self-limited symptomatic process. The time course from onset of pain to resolution was similar to that which the patiedt experienced with each crop of oral aphthae. Although our experience indicates spontaneous remission can occur, the course is not always so benign (1,4). Therefore, we do not suggest that treatment be rou- tinely withheld, but only that claims of drug efficacy be questioned. Lee S. Shapiro, MD William M. Notis, MD Norman R. Romanoff, MD Albany, NY 1. Parkin JV, Wight DGD: Behcet’s disease and the alimentary tract. Postgrad Med J 51:260-264, 1975 2. Lebwohl 0, Forde KA, Berdon WE, Momson S, Challop R: Ulcerative esophagitis and colitis in a pediatric patient with Behcet’s syndrome. Am J Gastroenterol68:550-555, 1977 3. Lockhart JM, McIntyre W, Caperton EM: Esophageal ulceration in Behcet’s syndrome. Ann Intern Med 84572-573, 1976 4. Brodie TE, Ochsner JL: Behcet’s syndrome with hlcerative oesophagitis: report of the first case. Thorax 28:637-640, 1973 Gynecomastia associated with low dose methotrexate therapy To the Editor: Low dose methotrexate has recently been recog- nized as an effective treatment in rheumatoid arthritis refrac- tory to usual remission-inducing agents (1,2j. We present a patient with methotrexate-associated gynecomastia, a previ- ously unreported complication of this therapy. A 19-year-old white man developed symmetric poly- arthritis, daily fevers to over 102”F, lymphadenophthy, and splenomegaly. A diagnosis of adult Still’s disease was made. Nonsteroidal antiinflammatory medication controlled his fevers, but active synovitis persisted. Rapid progression of joint erosions prompted initiation of gold therapy but this was stopped after a 490-mg cumulative dose, because of leukopenia. Penicillamine was given for 16 months, to a maximal dose of 1,OOO mg daily, without response. Penicillamine was then discontinued and oral weekly methotrexate (3 2.5-mg doses spaced 12 hours apart) was begun. Other medications, unchanged for the previous year, were prednisone 8.0 mg daily and Naprosyn 750 mg daily. With this regimen the patient noted prompt improvement in stiffness and joint pain. Two weeks after beginning metho- trexate therapy he complained of bilateral breast swelling and tenderness. Libido, sexual function, and hair patterns were normal. He denied marijuana use. While he was receiving methotrexate, serum testosterone was 3.7 mg/ml (normal 4.0-12.0 mg/ml) and luteinizing hormone (LH) was 7.1 mIUlml (normal 3-12 mIU/ml). Methotrexate was stopped. Further endocrinologic evaluation within 2 weeks of discontinuing methotrexate revealed: T4 6.7 mg/ml (normal 4.5-11.5 mg/ml), T3 uptake 31.1% (normal 25-35%), T7 2.1 (normal 1.4-3.4 units), 17 ketosteroids 7 mg/24 hours (nor- mal 10-20 mg/24 hours), ketogenic steroids 15.2 mg/24 hours (normal 5-23 mg/24 hours), estradiol33 pg/ml (normal 8-38). Beta human chorionic gonadotropin was undetectable. Liver function study results were normal. Results of roentgeno- grams of the chest and sella turcica were normal. Breast tenderness abated within 1 week of stopping methotrexate and breast size gradually decreased. Because gynecomastia was unacceptable to the patient, the drug was not reinstituted. A flare of fever and arthritis occurred 3 months later. Pulse methylprednisolone controlled the fever but active synovitis persisted. Methotrexate was reinstituted

Gynecomastia Associated with Low Dose Methotrexate Therapy

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Page 1: Gynecomastia Associated with Low Dose Methotrexate Therapy

LETTERS 69 1

painful, aphthous ulcers and repeated episodes of a “pseu- doseptic” right knee effusion. He had a 2-year history of chronic, low-grade anterior uveitis of the right eye, treated with topical corticosteroids. More recently, he had devel- oped multiple painful scrotal and penile ulcers. In August 1982, the patient complained of excruciating substernal “burning” pain when swallowing liquids or solids. Simulta- neous with the sudden onset of this symptom, he noted the reappearance of a painful right knee effusion and a tempera- ture to 102°F. On admission, he was ambulatory and ap- peared dehydrated. His temperature was 101°F. There were multiple 0.5-cm diameter ulcerations on the buccal mucosa, and 2 similar-appearing ulcerations on the scrotum. The right knee was warm and had a tense effusion. A papule appeared in the right antecubital fossa at a venipuncture site.

The patient was treated with intravenous fluids. The right knee was aspirated, yielding 90 cc of sterile, turbid fluid with a white cell count of 40,000/mm~. No corticosteroid was injected. After this procedure, his temperature remained normal. Barium studies of the esophagus showed normal results. On endoscopy, several discrete ulcers similar in appearance to his oral aphthae were noted in the mid- esophagus, 30 cm from the incisors. One ulcer was larger than the others, measuring 1 cm in diameter, but all had white eschar bases and heaped-up, inflamed margihs. The remainder of the esophagus appeared normal. Biopsies of the lesions demonstrated suppurative esophagitis with focal ulceration. Cytologic examination revealed only reactive squamous cells. Colonoscopy and an upper gastrointestinal series with small bowel follow-through disclosed no other ulcerations nor any evidence of inflammatory bowel disease.

Although we had planned to initiate therapy with systemic corticosteroids, the patient reported spontaneous improvement in his odynophagia, beginning approximately 1 week after onset of symptoms. Rapid resolution of symp- toms subsequently occurred, such that after 2 weeks he was asymptomatic on an unrestricted diet. Repeat endoscopy was not performed.

As Lockhart et a1 have commented (3), esophageal ulceration should be suspected in patients with BehCet’s syndrome who develop odynophagia, and endoscopy may be necessary to establish the diagnosis. In our patient, esopha- geal ulceration was a self-limited symptomatic process. The time course from onset of pain to resolution was similar to that which the patiedt experienced with each crop of oral aphthae. Although our experience indicates spontaneous remission can occur, the course is not always so benign (1,4). Therefore, we do not suggest that treatment be rou- tinely withheld, but only that claims of drug efficacy be questioned.

Lee S. Shapiro, MD William M. Notis, MD Norman R. Romanoff, MD Albany, NY

1. Parkin JV, Wight DGD: Behcet’s disease and the alimentary tract. Postgrad Med J 51:260-264, 1975

2. Lebwohl 0, Forde KA, Berdon WE, Momson S , Challop R: Ulcerative esophagitis and colitis in a pediatric patient with Behcet’s syndrome. Am J Gastroenterol68:550-555, 1977

3. Lockhart JM, McIntyre W, Caperton EM: Esophageal ulceration in Behcet’s syndrome. Ann Intern Med 84572-573, 1976

4. Brodie TE, Ochsner JL: Behcet’s syndrome with hlcerative oesophagitis: report of the first case. Thorax 28:637-640, 1973

Gynecomastia associated with low dose methotrexate therapy

To the Editor: Low dose methotrexate has recently been recog-

nized as an effective treatment in rheumatoid arthritis refrac- tory to usual remission-inducing agents (1,2j. We present a patient with methotrexate-associated gynecomastia, a previ- ously unreported complication of this therapy.

A 19-year-old white man developed symmetric poly- arthritis, daily fevers to over 102”F, lymphadenophthy, and splenomegaly. A diagnosis of adult Still’s disease was made. Nonsteroidal antiinflammatory medication controlled his fevers, but active synovitis persisted. Rapid progression of joint erosions prompted initiation of gold therapy but this was stopped after a 490-mg cumulative dose, because of leukopenia. Penicillamine was given for 16 months, to a maximal dose of 1,OOO mg daily, without response.

Penicillamine was then discontinued and oral weekly methotrexate (3 2.5-mg doses spaced 12 hours apart) was begun. Other medications, unchanged for the previous year, were prednisone 8.0 mg daily and Naprosyn 750 mg daily. With this regimen the patient noted prompt improvement in stiffness and joint pain. Two weeks after beginning metho- trexate therapy he complained of bilateral breast swelling and tenderness. Libido, sexual function, and hair patterns were normal. He denied marijuana use. While he was receiving methotrexate, serum testosterone was 3.7 mg/ml (normal 4.0-12.0 mg/ml) and luteinizing hormone (LH) was 7.1 mIUlml (normal 3-12 mIU/ml). Methotrexate was stopped.

Further endocrinologic evaluation within 2 weeks of discontinuing methotrexate revealed: T4 6.7 mg/ml (normal 4.5-11.5 mg/ml), T3 uptake 31.1% (normal 25-35%), T7 2.1 (normal 1.4-3.4 units), 17 ketosteroids 7 mg/24 hours (nor- mal 10-20 mg/24 hours), ketogenic steroids 15.2 mg/24 hours (normal 5-23 mg/24 hours), estradiol33 pg/ml (normal 8-38). Beta human chorionic gonadotropin was undetectable. Liver function study results were normal. Results of roentgeno- grams of the chest and sella turcica were normal.

Breast tenderness abated within 1 week of stopping methotrexate and breast size gradually decreased. Because gynecomastia was unacceptable to the patient, the drug was not reinstituted. A flare of fever and arthritis occurred 3 months later. Pulse methylprednisolone controlled the fever but active synovitis persisted. Methotrexate was reinstituted

Page 2: Gynecomastia Associated with Low Dose Methotrexate Therapy

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with rapid improvement in arthritis. However, gynecomastia recurred, arid methotrexate was stopped.

We believe this patient's gynecomastia was second- ary to methotrexate because of the close temporal associa- tion with initiation of therapy, its resolution when metho- trexate was discontinued, add recurrence with reinstitution of therapy. No other etiology was identifiable. The mecha- nism of methotrexate-related gynecomastia in our patient is not clear. A number of cytotoxic drugs, in antineoplastic doses, may cause gynecomastia (3-6). Leydig cell injury has been commonly implicated in that setting although multiple factors may be involved (3-5). Since his Libido, secondary sex characteristics, and LH level were all normal, the marginally low serum testosterone level in our patient is of uncertain significance. Methotrexate, in the dose range being used for antiarthritic therapy, may cause oligospennia (7). Reduced libido has also been rarely observed (8). We know of no other reports of gynecomastia associated with methotrexate therapy.

Although gynecomastia is primarily a cosmetic prob- lem, it was psychologically disabling to our patient and prevented further methotrexate therapy. Although such an Occurrence is uncommon, it should be kept in mind by the increasing number of physicians using this treatment in refractory arthritis. Awareness of this possible iatrogenic side e5ect will do much to limit the psychologic stress associated with the occurrence of gynecomastia and will assist in limiting an extensive search for another underlying cause.

Dennis W. Del Paine, MD James C. Leek, MD Christopher Jakle. MD Dick L. Robbins, MD

1.

2.

3.

4.

5.

6.

7.

8.

University of California, Davis, Medical Center

Sacramento. CA Michaels RM, Nashel DJ, Leonard A, Sliwitlski AJ, Derbes SJ: Weekly intravenous methotrexate in the treatment of rheumatoid arthritis: Arthritis Rheum 25:3j9-341, 1982 Willkens RF, Watson MA: Methotrexate: a perspective of its use in the treatment of rheumatic diseases. J Lab Clin Med 100:314- 321, 1982 Sherins RJ, Olweny CLM, Ziegler JL: Gynecomastia and gonad- al dysfunction in adolescent boys treated with combination chemotherapy for Hodgkin's disease. N Engl J Med m:12-16, I978 Glass AR. Berenberg J: Gynecomastia after chemotherapy for lymphoma. Arch Intern Med 139: lO48-lO49, 1979 Turner AR, Morrish DW, Berry J, MacDonald RN: Gynecomas- tia after cytotoxic therapy for metastatic testicular cancer. Arch Intern Med 142:896-897, 1982 Schorer AE, Oken MM, Johnson GJ: Gynecomastia with nitro- sourea therapy. Cancer Treat Rep 62574-576. 1978 Sussman A, Leonard JM: Psoriasis, methotrexate, and oligosper- mia. Arch Dermatol 116:215-217, 1980 Nyfors A: Benefits and adverse drug experiences during long- term methotrexate treatment of 248 psoriatics. Dan Med Bull 25:208-21 I , 1978

Lupus screening questionnaire

To the Editor: A survey for identifying individuals with systemic

lupus erythematosus (SLE) was tested in two field trials, with the goal of identifying previously undiagnosed cases. The survey involved the administration of the questionnaire designed by Liang et al (Liang ME, Meenan RF, Cathcart ES, Schur PH: A screening strategy for population studies in systemic lupus erythematosus. Arthritis Rheum 23: 153-157, 1980). slightly modified, and antinuclear antibody (ANA) testing of positive respondents. These surveys were super- vised by trained Lupus Foundation volunteers as part of an annual Health Fair at two shopping centers in the St. Louis area.

Study design. The slightly modified questionnaire is shown in Table 1. In the Liang study a screening model consisting of administration of the questionnaire followed by ANA testing for those individuals answering positively to 3 or more questions had a higher predictability than other models tested. We used the same approach, and in addition obtained several demographic items. The questionnaire was self-administered at a lupus booth; trained Lupus Founda- tion volunteers were available to answer ,questions, identify positive respondents and recommend ANA testing (which was provided free), and discourage participation by individ- uals with known rheumatic diseases. The experiment was conducted at two shopping centers over a 2-day period. At one center respondents were actively recruited from the shopping population by the booth volunteers. At the other center, shoppers were not recruited; participants could avail themselves of a battery of blood tests for a small fee and were given the option of having extra blood drawn for an

Table 1. Lupus screening questionnaire

Sex Ethnic group Year of birth

F- Black - 19 M- White ~

Other (specify)

Circle Yes or N o for each question below

1. Do your fingers become pale, numb or uncomfortable in the cold? Yes N o

2. Does your skin break out after you have been out in the sun? (not sunburn) Yes No

3. Rapid loss of hair? Yes No 4. Arthritis or rheumatism for more than 3 months? Yes No 5 . A prominent rash on your cheeks for more than a

month? Yes N o 6. Sores in your mouth for more than 2 weeks? Yes N o 7. For more than a few days, pain when you breathe

deeply (pleurisy)? Yes N o 8. A seizure, convulsion or fit? Yes No 9. Protein (albumin) in your urine? Yes No

10. Low blood counts (anemia, low white cell count or low platelet count)? Yes N o

Have you ever had . . .