Herpes Zoster in Patients with Rheumatoid rthritis Treated with Weekly, Low-Dose Methotrexate MARY ANN S. ANTONELLI, M.D.,
Birmingham, Alabama, JAMES E.
Morgantown, WestVirginia, LARRY W. MORELAND, Morgantown, WestVirginia
M.D.,
BRICK, M.D.,
PURPOSE: Herpes zoster occurred in nine patients with methotrexate-treated rheumatoid arthritis. We compared these patients to a large group of methotrexate-treated rheumatoid arthritis patients in order to uncover potential factors explaining the occurrence of herpes zoster. PATIENTS AND METHODS: Data from 187 patients t~idng methotrexate were reviewed a n d compared with data from another nine patients w h o developed herpes zoster while t~blng t h e drug for rheumatoid arthritis, all from the ~qme university-based arthritis clinic. Literature pertinent to infection in rheumatoid arthritis patients treated with methotrexate is reviewed. RESULTS: Herpes zoster occurred in 14.5 cases per 1,000 patient-years in our methotrexatetreated rheumatoid arthritis patients, as compared with the general population incidence of 1.3 to 4.8 cases per 1,000 patient-years. The infection was imrelAted to duration of methotrexate usage, predni~one treatment, or the co-existence of diabetes mellitus, but appeared to occur in patients with high titers of rheumatoid factor a n d a n overall longer duration of rheumatoid arthritis. There were no cases of systemic dissemination or r e c u r r e n c e of herpes zoster despite 27.4 years cumulative follow-up on continued methotrexate therapy. CONCLUSIONS: Herpes zoster m a y o c c u r more frequently in patients with rheumatoid arthritis treated with low-dose methotrexate than in t h e general population. Herpes zoster in rheumatoid arthritis patients treated with methotrexate appears to be self-limited, benign, and statistically related to methotrexate use in the presence of longer-term rheumatoid disease.
From the Section of Rheumatology(MASA,JEB), WestVirginiaUniversity School of Medicine, Morgantown, West Virginia, and the Division of Clinical Immunologyand Rheumatology(LWM), Universityof Alabamaat Birmingham, Birmingham, Alabama. Requests for reprints should be addressedto Mary Ann S. Antonelli, M.D., WestVirginiaUniversitySchoolof Medicine,Sectionof Rheumatology, Morgantown,West Virginia 26506. Manuscript submitted June 28, 1990, and accepted in revised form November 19, 1990.
eekly, low-dose oral methotrexate is a widely
W prescribed treatment for rheumatoid arthritis [1-3]. The occurrence of herpes zoster in patients
taking methotrexate has been briefly commented upon in several methotrexate trials [4-6], but the frequency of this complication is unknown. We report nine cases of herpes zoster in our institutional experience with methotrexate in rheumatoid arthritis and suggest that weekly, low-dose methotrexate treatment in patients with rheumatoid arthritis may increase the risk of developing benign, symptomatic herpes zoster, usually in the setting of long-standing severe arthritis.
PATIENTS AND METHODS Data on patients developing herpes zoster were compared with the data extracted from charts on 187 retrospectively reviewed methotrexate-treated patients, designated registry patients and not developing herpes zoster, at West Virginia University Health Sciences Center during the period of 1979 through 1989. Methotrexate doses varied between 2.5 and 25 rag/week and averaged 15 rag/week. Rheumatoid factor tests were performed by a latex slide method in the laboratory of the West Virginia University Hospital. The registry group is comprised of rheumatoid arthritis patients who began therapy with methotrexate prior to 1987, with complete demographic and clinical data tabulated in preparation for other studies, including 96 patients previously reported by Brick et al [7]. Data analysis was performed using the MacSS statistical package from StatSoft, Tulsa, Oklahoma.
RESULTS All patients fulfilled the 1958 American Rheumatism Association criteria for defmite or classic rheumatoid arthritis [8]. Mean age of the registry patients was 56.7 years and included 13 patients with diabetes mellitis (7%). Fifty-one percent of the registry patients had been receiving low-dose prednisone (10 mg or less per day). Prednisone doses varied in each case; without a specific time marker, it was not meaningful to calculate an average daily dose. Ninety-one percent had positive results for rheumatoid factor (in 26%, the titer for rheumatoid factor was 1:1,280 or greater). Treatment with March 1991 The American Journal of Medicine Volume 90
295
HERPES ZOSTER IN METHOTREXATE-TREATED RHEUMATOID ARTHRITIS / ANTONELLI ET AL TABLE I Characteristics of Patients with Herpes Zoster (HZ)
Patient 1
Location of HZ Right arm
Sex F
Age at Onset of HZ
Rheumatoid Factor
62
1:1,280
Disease Duration Prior to MTX (years) 16
Medication at Onset of HZ Verapamil, lisinopril,
theophylline
2
C7-T2
F
57
1:1,280
5
3
Right neck, trunk
M
67
1:1,280
35
4
Face
M
58
1:320
5
Face
F
76
1:320
6
Left thorax
M
52
1:1,280
7
Disseminated
F
56
8
Right foot/ ankle
F
9
Left first division trigeminal
F
Dose/Week/ Duration of MTX Treatment 12.5 mg/
4 years
Other Medical Conditions Chronic lung
disease, hypertension, peptic ulcer disease
ASA, chlorpropamide, propranolol. amitriptyline, propoxyphene
7.5 rag/ 11 months
Diabetes, hepatitisB
Prednisone=. ASA
12.5 mg/ 2.7 y e a r s
Felty's, splenectomy
5
Prednisone
10 rag/ 1.3 y e a r s
Post-herpetic neuralgia
35
Prednisone
7.5 mg/ 1.8 years
None
6
Prednisone (up to 60 mg in prior 6 months), ASA 3.2 g/day
20 mg/ 8 months
Hemolytic anemia
1:320
22
Phenobarbital, ,5'-blocker, ibuprofen
10 mg/ 3 years
Rheumatoid vasculitis
67
1:640
25
Naproxen, sucralfate
12.5 rag/ 5 years
Mastectomy, 1972
58
]:320
Indomethacin, prednisone
lOmg/ 1 year
None
1.5
MTX = methotrexate: ASA = aspirin. • Prednisonedosage5 to 10 mg daily (of the five patients receiving prednisone, mean dose 7.45 [:t: 1.36] mg/day).
methotrexate averaged 3.23 years; the average disease duration was 10.9 (± 8) years at the time of analysis (Table I). Data from the nine patients in w h o m herpes zoster was found are presented in Table I. Infection was diagnosed on clinicalgrounds in these patients; none clinically had "zosteriform herpes simplex" (maxillary or sacral nerve involvement or previous vesicular eruptions in the same distribution [9]).All cases of herpes zoster resolved; three cases (Patients 4, 5, and 10) were treated with acyclovir;only Patient 4 developed post-herpetic neuralgia and Patient 7 had limited cutaneous dissemination. Patient 2 was treated with bipivucaine stellateganglion block during the acute herpes zoster as part of another study. All patients who developed herpes zoster had positive rheumatoid factor,the lowest titerof which was 1:320; in four (44%) patients with herpes zoster, the titerfor rheumatoid factor was 1:1,280 or greater (Table I). All patients developing herpes zoster had rheumatoid arthritis for at least 1.5 years 296
March 1991 The American Journal of Medicine Volume 90
(mean: 17 [± 12] years) before the development of herpes zoster (longer than registry patients, p
Birmingham, Alabama, JAMES E.
Morgantown, WestVirginia, LARRY W. MORELAND, Morgantown, WestVirginia
M.D.,
BRICK, M.D.,
PURPOSE: Herpes zoster occurred in nine patients with methotrexate-treated rheumatoid arthritis. We compared these patients to a large group of methotrexate-treated rheumatoid arthritis patients in order to uncover potential factors explaining the occurrence of herpes zoster. PATIENTS AND METHODS: Data from 187 patients t~idng methotrexate were reviewed a n d compared with data from another nine patients w h o developed herpes zoster while t~blng t h e drug for rheumatoid arthritis, all from the ~qme university-based arthritis clinic. Literature pertinent to infection in rheumatoid arthritis patients treated with methotrexate is reviewed. RESULTS: Herpes zoster occurred in 14.5 cases per 1,000 patient-years in our methotrexatetreated rheumatoid arthritis patients, as compared with the general population incidence of 1.3 to 4.8 cases per 1,000 patient-years. The infection was imrelAted to duration of methotrexate usage, predni~one treatment, or the co-existence of diabetes mellitus, but appeared to occur in patients with high titers of rheumatoid factor a n d a n overall longer duration of rheumatoid arthritis. There were no cases of systemic dissemination or r e c u r r e n c e of herpes zoster despite 27.4 years cumulative follow-up on continued methotrexate therapy. CONCLUSIONS: Herpes zoster m a y o c c u r more frequently in patients with rheumatoid arthritis treated with low-dose methotrexate than in t h e general population. Herpes zoster in rheumatoid arthritis patients treated with methotrexate appears to be self-limited, benign, and statistically related to methotrexate use in the presence of longer-term rheumatoid disease.
From the Section of Rheumatology(MASA,JEB), WestVirginiaUniversity School of Medicine, Morgantown, West Virginia, and the Division of Clinical Immunologyand Rheumatology(LWM), Universityof Alabamaat Birmingham, Birmingham, Alabama. Requests for reprints should be addressedto Mary Ann S. Antonelli, M.D., WestVirginiaUniversitySchoolof Medicine,Sectionof Rheumatology, Morgantown,West Virginia 26506. Manuscript submitted June 28, 1990, and accepted in revised form November 19, 1990.
eekly, low-dose oral methotrexate is a widely
W prescribed treatment for rheumatoid arthritis [1-3]. The occurrence of herpes zoster in patients
taking methotrexate has been briefly commented upon in several methotrexate trials [4-6], but the frequency of this complication is unknown. We report nine cases of herpes zoster in our institutional experience with methotrexate in rheumatoid arthritis and suggest that weekly, low-dose methotrexate treatment in patients with rheumatoid arthritis may increase the risk of developing benign, symptomatic herpes zoster, usually in the setting of long-standing severe arthritis.
PATIENTS AND METHODS Data on patients developing herpes zoster were compared with the data extracted from charts on 187 retrospectively reviewed methotrexate-treated patients, designated registry patients and not developing herpes zoster, at West Virginia University Health Sciences Center during the period of 1979 through 1989. Methotrexate doses varied between 2.5 and 25 rag/week and averaged 15 rag/week. Rheumatoid factor tests were performed by a latex slide method in the laboratory of the West Virginia University Hospital. The registry group is comprised of rheumatoid arthritis patients who began therapy with methotrexate prior to 1987, with complete demographic and clinical data tabulated in preparation for other studies, including 96 patients previously reported by Brick et al [7]. Data analysis was performed using the MacSS statistical package from StatSoft, Tulsa, Oklahoma.
RESULTS All patients fulfilled the 1958 American Rheumatism Association criteria for defmite or classic rheumatoid arthritis [8]. Mean age of the registry patients was 56.7 years and included 13 patients with diabetes mellitis (7%). Fifty-one percent of the registry patients had been receiving low-dose prednisone (10 mg or less per day). Prednisone doses varied in each case; without a specific time marker, it was not meaningful to calculate an average daily dose. Ninety-one percent had positive results for rheumatoid factor (in 26%, the titer for rheumatoid factor was 1:1,280 or greater). Treatment with March 1991 The American Journal of Medicine Volume 90
295
HERPES ZOSTER IN METHOTREXATE-TREATED RHEUMATOID ARTHRITIS / ANTONELLI ET AL TABLE I Characteristics of Patients with Herpes Zoster (HZ)
Patient 1
Location of HZ Right arm
Sex F
Age at Onset of HZ
Rheumatoid Factor
62
1:1,280
Disease Duration Prior to MTX (years) 16
Medication at Onset of HZ Verapamil, lisinopril,
theophylline
2
C7-T2
F
57
1:1,280
5
3
Right neck, trunk
M
67
1:1,280
35
4
Face
M
58
1:320
5
Face
F
76
1:320
6
Left thorax
M
52
1:1,280
7
Disseminated
F
56
8
Right foot/ ankle
F
9
Left first division trigeminal
F
Dose/Week/ Duration of MTX Treatment 12.5 mg/
4 years
Other Medical Conditions Chronic lung
disease, hypertension, peptic ulcer disease
ASA, chlorpropamide, propranolol. amitriptyline, propoxyphene
7.5 rag/ 11 months
Diabetes, hepatitisB
Prednisone=. ASA
12.5 mg/ 2.7 y e a r s
Felty's, splenectomy
5
Prednisone
10 rag/ 1.3 y e a r s
Post-herpetic neuralgia
35
Prednisone
7.5 mg/ 1.8 years
None
6
Prednisone (up to 60 mg in prior 6 months), ASA 3.2 g/day
20 mg/ 8 months
Hemolytic anemia
1:320
22
Phenobarbital, ,5'-blocker, ibuprofen
10 mg/ 3 years
Rheumatoid vasculitis
67
1:640
25
Naproxen, sucralfate
12.5 rag/ 5 years
Mastectomy, 1972
58
]:320
Indomethacin, prednisone
lOmg/ 1 year
None
1.5
MTX = methotrexate: ASA = aspirin. • Prednisonedosage5 to 10 mg daily (of the five patients receiving prednisone, mean dose 7.45 [:t: 1.36] mg/day).
methotrexate averaged 3.23 years; the average disease duration was 10.9 (± 8) years at the time of analysis (Table I). Data from the nine patients in w h o m herpes zoster was found are presented in Table I. Infection was diagnosed on clinicalgrounds in these patients; none clinically had "zosteriform herpes simplex" (maxillary or sacral nerve involvement or previous vesicular eruptions in the same distribution [9]).All cases of herpes zoster resolved; three cases (Patients 4, 5, and 10) were treated with acyclovir;only Patient 4 developed post-herpetic neuralgia and Patient 7 had limited cutaneous dissemination. Patient 2 was treated with bipivucaine stellateganglion block during the acute herpes zoster as part of another study. All patients who developed herpes zoster had positive rheumatoid factor,the lowest titerof which was 1:320; in four (44%) patients with herpes zoster, the titerfor rheumatoid factor was 1:1,280 or greater (Table I). All patients developing herpes zoster had rheumatoid arthritis for at least 1.5 years 296
March 1991 The American Journal of Medicine Volume 90
(mean: 17 [± 12] years) before the development of herpes zoster (longer than registry patients, p
