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The timing of menarche in juvenile rheumatoid arthritis
JOURNAL OF ADOLESCENT HEALTHCARE 1988;9:483-487
The Timing of Menarche in Juvenile Rheumatoid Arthritis PATRICIA A. FRASER, M.D., M.P.H., SUSAN HOCH, M.D., DIANE ERLANDSON, R.N., M.S., RAYMOND PARTRIDGE, M.D., AND JEAN M. JACKSON, M.D .
A study of the age of menarche in juvenile rheumatoid arthritis (JRA) patients was undertaken to determine what factors affect the timing of menarche. There was a significant difference between the mean age of menarche for the 68 JRA patients and 46 controls (p :::: 0.015). No clear etiology for this difference Was elucidated. Polyarticular-onset JRA patients had the oldest age of menarche, but this finding was of marginal statistical significance (p<0.OS,Pco,...<0.25). The multivariate model that included onset type, steroid use, and duration of disease weakly predicted age of menarche in the JRA group. This model suggests that, exclusive of height and weight parameters, duration of disease was the most important predictor of menarche in JRA.
KEY WORDS:
Juvenile rheumatoid arthritis Menarche Sexual maturation Growth in juvenile rheumatoid arthritis
Juvenile rheumatoid arthritis ORA) is primarily a chronic, systemic, rheumatic disease of childhood and adolescence . Diagnostic criteria set forth by the American Rheumatisim Association (ARA) provide an algorithm for diagnosis and classification (1). Once the identified diagnostic exclusions have been considered (1), the diagnosis of JRA can be enter-
From Brigham andWomen's Hospital, Boston, Massachusetts. Address reprint requests to: Patricia A. Fraser, M.D., M.P.H., Department of Rheumatology-Immunology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115. Manuscript accepted October 20, 1987.
tained in patients less than age 16 years who have ar thritis of at least 6 weeks ' duration . The initial pattern of symptoms in the first 6 months provides the classification system for JRA by onset subtype (1). Arthritis in association with high fever (2:103°F) characterizes the systemic-onset subtype of JRA. In the absence of systemic symptoms, JRA is also classified by the number of joints affected. The pauciarticular subtype requires patients to have arthritic involvement of less than five joints . Patients with involvement of five or more joints comprise the polyarticular subtype. Deviation from normal growth is a well-documented potential consequence of JRA and may occur with any subtype (1-5). Corticosteriod therapy, which retards growth, is sometimes necessary for the control of JRA symptoms (5,6). Delayed sexual maturation has been reported in JRA patients who were severely affected by the disease (2). To assess the magnitude of the effect of JRA on female sexual development, this study compared the mean age of menarche in a group of IRA patients with controls. The possible effects of subtype, age of on set, duration of the disease, and steroid use on the age of menarche were also investigated.
Methods Data were collected as part of a larger computerized longitudinal database on JRA patients (7) who were followed at the Robert B. Brigham Hospital and later at the Robert Brigham Arthritis Center of the Brigham and Women's Hospital, Boston. From 1964 to 1981, data was recorded annually on 94 female JRA patients. The 64 patients from this computerized database who had complete data on subtype,
© Society for Adolescent Medicine, 1988 Publ ished by Elsevier Science Publish ing Co., Inc., 655 Avenue of the Americas, New York, NY 10010
483
0197-0070/88/$3 .50
484
FRASER ET AL.
age of menarche, and steroid use were entered. The remaining four patients in this study were not part of this database but were followed by the investigators (P.F., S.H., R.P) during the same period. All 68 study patients fulfilled ARA criteria for JRA (2). Age of disease onset of IRA diagnosis and the duration of JRA prior to menarche were calculated in years. Although the presence or absence of oral corticosteroid use was recorded, the exact dose was not available. The nine patients who experienced menarche before the onset of JRA (six polyarticular and three pauciarticular) were excluded from the analysis. Menarchal information was available on 46 sisters. The sisters who comprised the control group were not on corticosteroids and did not have JRA. A detailed medical history on sisters was not part of this investigation, so it is not known whether any of the sisters suffered from any other chronic disease. One monozygotic twin pair was included in the study. All subjects were white. The STATVIEW program (Brainpower, Inc., Calabasas, CA) on the Macintosh Plus computer and the FEXACT program on the Tops-20 system at the Dana-Farber Cancer Institute were used for data analysis. Student's unpaired t test, analysis of variance (ANOVA), simple and multiple linear regression, l, and Fisher's exact tests were the statistical techniques employed. For the multivariate model the strength of association between the outcome variable and the multiple independent variables was measured by the multiple correlation coefficient R2 (8). When multiple statistical comparisons were made, the p value was multiplied by the number of comparisons made (9) and was denoted Peorr' All reported p values were two sided.
Results The patient group was composed of 15 patients with systemic-onset disease (22%), 18 patients with polyarticular disease (26.5%), and 35 patients with pauciarticular disease (51.5%) at onset. One of the monozygotic twin pair under study had systemiconset JRA requiring steroid therapy. The age of menarche for the diseased twin was 18 years, while the unaffected twin's menarche occurred at age 15. The mean age of menarche for the controls (12.5 years) and the entire JRA group (13.2 years) were significantly different (p = 0.015). Additional analyses were performed to determine which factors were responsible for this observed difference in menarchal age between JRA patients and their sisters. Comparison by onset type revealed a difference
JOURNAL OF ADOLESCENT HEALTH CARE Vol. 9, No.6
Table 1. Summary of Study Groups By Subtype of Onset of JRA
Group" Polyarticular Systemic
Il
Pauciarticular
18 15 35
Sisters (controls)
46
Mean age of menarche (SD) 13.4 (1.5) 13.1 (1.7) 13.0 (1.5) 12.5 (1.5)
Mean duration of .fRA"
6.6 6.3 7.0
Steroid use (%) 27.8 53.3 20.0 0
"Menarche prediction model (subtype) p=O.4l. "Menarche prediction model (duration) p=O.09. 'Menarche prediction model (steroid) p = 0.91 Best model (subtype + duration + steroid) p = 0.04.
(p < 0.05) between the average age of menarche for
the polyarticular JRA patients (13.3 years) and the controls. When this P value was corrected for the number of possible comparisons, this difference was not significant (Peorr < 0.25). The mean ages of the systemic and pauciarticular JRA patients (13.1 and 13.0 years, respectively) did not differ from controls (12.5 years) (Table 1). Twenty patients (five polyarticular, seven pauciarticular, and eight systemic) received oral corticosteroids at some time during the course of their disease. Data on the dose and the duration of steroid use was not available. The steroid-treated JRA patients represented 29.4% of all JRA patients. Within the polyarticular, pauciarticular, and systemic-onset types, the steroid-treated patients represented 27.8%, 20%, and 53.3% of these groups, respectively. Steroid use was significantly more frequent among JRA subtypes than controls (p = 0.0183). When the 2 x 4 table was partitioned to examine this contrast more closely, systemic-onset JRA and polyarticular-onset patients accounted for this increase. The systemic-onset JRA group had significantly different steroid use than the pauciarticular (p
November 1988
of 6.3 and 6 years, respectively. The pauciarticularonset patients had the earliest mean age of onset (5.9 years). The mean ages of onset for the systemic and polyarticular patients were similar (6.8 years). There were four patients who developed their disease at the maximum age of disease onset of 13 years (two polyarticular, one systemic, and 1 pauciarticular). Based on a study of juvenile diabetes mellitus that showed that disease onset near puberty may cause menarehal delay (10), we constructed age-ofdisease-onset categories « 11, ?ell years). There were 55 JRA patients (12 systemic, 14 polyarticular, and 29 pauciarticular) within the category age of disease onset at less than 11 years and 13 (three systemic, four polyarticular, and six pauciarticular) with age of disease onset of 11 years or older. Age of disease onset was not an important predictor of the age of menarche whether the exact age or the age categories «11 years, ~11 years) were considered (p = 0.9 and 0.37, respectively) . There was also no association between IRA subtype and age category (p = 0.87). Further analysis within the JRA patient group revealed that patients with age of onset less than 11 years were more likely to be steroid treated (p = 0.007). In spite of the association between steroid treatment and young age , steroid use was not helpful as the sale predictor of menarche (p = 0.91) or in combination with the age category variable (p=0.88). The duration of JRA prior to menarche ranged from 0 to 15 years. The mean duration of JRA was 6.7 years (6.3, 6.6 and 7.0 years for the systemic, polyarticular, and pauciarticular subtypes, respectively). The prediction model that was limited to the single variable duration of JRA was of borderline significance as a predictor.of age of menarche (p = 0.09). The multivariate model of steroid use , subtype, and duration of JRA provided the best prediction model for the age of menarche in JRA (p = 0.04). This model explained only 12% (R2 = 0.12) of the variability of the age of menarche among the study subjects and was considered a weak predictive model overall (Table 1).
Discussion Our retrospective study shows that JRA patients experience an older age of menarche than their unaffected sisters. Delayed menarche has been observed in several chronic diseases such as cystic fibrosis (CF), diabetes mellitus (OM), and homozygous sickle cell disease (10-17). Moshang and Holsclaw studied the timing of menarche in CF and observed an older age of menarche in their 63 CF patients com-
MENARCHE IN ]RA
485
pared to controls (11). Menarche may also be delayed in DM (13-16). Tattersall and Pyke showed that monozygotic twins who were discordant for Type 1 OM at puberty were also discordant for age of menarche (13). Similarly, the diseased, steroidtreated twin in our study of JRA experienced menarche 3 years after her healthy twin. Although several variables were evaluated and their interrelationships explored, it was not possible to determine why the age of menarche in JRA may differ from controls. Duration of disease was the single best predictor of age of menarche in JRA, but considered singly it did not reach statistical significance. The possible importance of the duration of disease to the age of menarche in JRA contrasts with Type 10M. The research of Pezzini et a1. showed that delayed menarche in their Type 1 OM patients was not influenced by the duration of disease (14). The effect of steroid use was also examined . We used corticosteroid use as a marker of the severity of the disease. This variable differentiated among JRAsubtypes and also obviously distinguished JRA patients from controls . Our finding predicated on severity of disease contrasts with those in CF (12) but is similar to the results from studies in Type 1 DM (13,15,16). Age of disease onset was similar among the JRA subtypes and was not an important determinant of menarche in JRA. The effect of age of disease onset in Type 1 OM remains controversial. In a study of 987 OM patients with an onset of their disease long after the onset of puberty, lonescu-Tirgoviste et aI. demonstrated that menarche was Significantly delayed (15). Because their subjects developed DM long after the onset of puberty, it suggests that the age of disease onset of OM may not affect menarche. In contrast, Schriock et al. found that menarche occurred significantly earlier in their group of patients who had the onset of DM before the age of 11 years when compared to the age of menarche among patients with an onset at 11 years of age or later (10). The authors concluded that the onset of OM during puberty results in a delay in menarche. The best available multivariable model of steroid use, subtype, and duration of JRA had low predictive power. The reasons for the poor predictive ability of this model may be found in other investigations of growth and development. Studies in normal children have shown that the timing of menarche may be dependent on body composition (18). Menarche is also correlated with skeletal maturation, height, and weight (19). Studies of menarche in CF, OM, and sickle cell disease (55) support the important effect of body composition on men-
486
FRASER ET A L.
arche in chronic diseases. Mitchell-Heggs and colleagues found that 65%.of thei r CF patients were below the third percentile for weight and were between the 25th and 50th percentile for height (12). By multiple univariate analyses they showed that body composition, in conjunction with disease activity, was an important determinant of menarche in CP. Tattersall and Pyke's monozygotic twin study showed that OM-affected twins were shorter than their healthy twins (13). Graham and colleagues' multivariate analysis of 55 children revealed height and weight to have some predictive ability, but showed the fetal hemoglobin level to be the most important predictor of menarchal age (17). A recent study of growth in JRA showed significant growth retardation in systemic-onset patients (5). Height and weight measurements at menarche were not available on the patients Of the controls in our study so our study cannot answer the important question of whether height and weight are the major determinants of the timing of menarche in JJ
JOURNAL OF ADOLESCENT HEALTH CARE Vol. 9, No.6
steroids are first used, the duration of steroid use, the dosage used, or the relationship of steroid use to the onset of puberty are factors in the timing of menarche in JRA patients. The possible value of monitoring hormonal levels (luteinizing hormone, follicle-stimulating hormone, and estradiol) should also be considered. For the practitioner who confronts the diagnostic dilemma of an adolescent JRA patient who has not experienced menarche, the results of this study would favor the deferral of an extensive work-up until after the patient's 18th birthday. Th is s tudy was supported by a grant from the New England Peabody Home for Crippled Children.
References 1. IRA Criteria Subcommittee of the Diagnostic and Therapeutic Criteria Committee of the American Rheum atism Asso ciation Section uf the Arthri tis Foundation . Current proposed revision of IRA criteria . Arthritis Rheum 1977;20:195-9 . 2. Kuhns JG, Swaim LT. Disturbanc es of growth in chronic arthritis in children. Am J Dis Child 1933;43:1118-33. 3. Coss [A, Boots RH. Juvenile rheumatoid arthritis. J Ped iatr 1946;29:143-56 . 4. Ansell BM, Bywaters EGL. Growth in Still's disease. Ann
Rheum Dis 1956;15:295-319. 5. Bernstein BH, Stobie 0, Singsen BB, et al. Growth retardation in juvenile rheumatoid arthritis (JRA). Arthritis Rheum 1977;20:212-6. 6. Ward OJ, Hartog M, Ansell BM. Corticosteroid-induced dwarfism in Still's disease treated with human growth hormone. Ann Rheum Dis 1966;26:416-21. 7. Stillman IS, Barry PE. Juvenil e rheumatoid arthritis: Series 2. Arthritis Rheum 1977;20:171-5 . 8. Kleinbaum DG, Kupper I.L. Multiple regression analysis . In : Kleinbaum DG, Kupper LL, eds . Appl ied regression analysis and other multivariable methods. North Scituate: Duxbury Press , 1978;131-57. 9. Godfrey K. Comparing the means of several groups. N Engl I Med 1985;313:1450- 6 10. Schriock EA, Winter RJ. Tra isman HS. Diabetes meIlitus and its effects on menarche. J Adolesc Health Care 1934;5:101-4. 11. Mosh ang 1', Holsclaw DS. Menarch al determinants in cystic fibrosis . Am J Dis Child . 1980134;1139-42. 12. Mitchell-Heggs P, Mearns M, Batten [C . Cystic fibrosis in adolescents and adults. Q uart JMed 1976; new series 45:479504. 13. Tattersall RB, Pyke DA. Growth in diabetic children . Lancet. 1973;2:1105-9 . 14. Pezzini MB, Bisatta E, Cont erno P, e t al. Studia della svilluppo puberal e e del ciclo rnes tru ale. Minerv Ginecol 1983;35:16173. 15. lonescu-Tirgoviste C, Popa E, Chela D. Delayed menarche as an indicator of a prediabetic state. Diabetologia 1980;20:510-1. 16. Pickup J, Williams G, Johns P, et al. Clinical features of brittle
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diabetic patients unresponsive to optimized subcutaneous insulin therapy (continuous subcutaneous insulin infusion). Diabetes Care 1983;6:279-84. 17. Graham C, Maude GH, Serjeant GR. Delayed menarche in homozygous sickle cell disease. West Indian Med J 1986;35:18-22. 18. Frisch RF, Revelle R, Cook S. Components of weight at menarche and the initiation of the adolescent growth spurt in girls: Estimated total water, lean body weight and fat. Human Bioi 1973;45:469-83.
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19. Eisenberg E. Menarche: The transition from childhood to womanhood. Adv Pediatr 1984;31:359-69. 20. Jacobs J. Juvenile rheumatoid arthritis. In: Pediatric rheumatology for the practitioner, 1st ed. New York: SpringerVerlag; 1982: 179-273. 21. Brewer EJ, Giannini EH, Person DA, eds. Manifestations of disease. In: Juvenile rheumatoid arthritis, 2nd ed. Philadelphia: W.B. Saunders, 1982:1-53. 22. Baum J. The many faces of pediatric arthritis. J Musculoskeletal Med 1986; 35:35-41.
The Timing of Menarche in Juvenile Rheumatoid Arthritis PATRICIA A. FRASER, M.D., M.P.H., SUSAN HOCH, M.D., DIANE ERLANDSON, R.N., M.S., RAYMOND PARTRIDGE, M.D., AND JEAN M. JACKSON, M.D .
A study of the age of menarche in juvenile rheumatoid arthritis (JRA) patients was undertaken to determine what factors affect the timing of menarche. There was a significant difference between the mean age of menarche for the 68 JRA patients and 46 controls (p :::: 0.015). No clear etiology for this difference Was elucidated. Polyarticular-onset JRA patients had the oldest age of menarche, but this finding was of marginal statistical significance (p<0.OS,Pco,...<0.25). The multivariate model that included onset type, steroid use, and duration of disease weakly predicted age of menarche in the JRA group. This model suggests that, exclusive of height and weight parameters, duration of disease was the most important predictor of menarche in JRA.
KEY WORDS:
Juvenile rheumatoid arthritis Menarche Sexual maturation Growth in juvenile rheumatoid arthritis
Juvenile rheumatoid arthritis ORA) is primarily a chronic, systemic, rheumatic disease of childhood and adolescence . Diagnostic criteria set forth by the American Rheumatisim Association (ARA) provide an algorithm for diagnosis and classification (1). Once the identified diagnostic exclusions have been considered (1), the diagnosis of JRA can be enter-
From Brigham andWomen's Hospital, Boston, Massachusetts. Address reprint requests to: Patricia A. Fraser, M.D., M.P.H., Department of Rheumatology-Immunology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115. Manuscript accepted October 20, 1987.
tained in patients less than age 16 years who have ar thritis of at least 6 weeks ' duration . The initial pattern of symptoms in the first 6 months provides the classification system for JRA by onset subtype (1). Arthritis in association with high fever (2:103°F) characterizes the systemic-onset subtype of JRA. In the absence of systemic symptoms, JRA is also classified by the number of joints affected. The pauciarticular subtype requires patients to have arthritic involvement of less than five joints . Patients with involvement of five or more joints comprise the polyarticular subtype. Deviation from normal growth is a well-documented potential consequence of JRA and may occur with any subtype (1-5). Corticosteriod therapy, which retards growth, is sometimes necessary for the control of JRA symptoms (5,6). Delayed sexual maturation has been reported in JRA patients who were severely affected by the disease (2). To assess the magnitude of the effect of JRA on female sexual development, this study compared the mean age of menarche in a group of IRA patients with controls. The possible effects of subtype, age of on set, duration of the disease, and steroid use on the age of menarche were also investigated.
Methods Data were collected as part of a larger computerized longitudinal database on JRA patients (7) who were followed at the Robert B. Brigham Hospital and later at the Robert Brigham Arthritis Center of the Brigham and Women's Hospital, Boston. From 1964 to 1981, data was recorded annually on 94 female JRA patients. The 64 patients from this computerized database who had complete data on subtype,
© Society for Adolescent Medicine, 1988 Publ ished by Elsevier Science Publish ing Co., Inc., 655 Avenue of the Americas, New York, NY 10010
483
0197-0070/88/$3 .50
484
FRASER ET AL.
age of menarche, and steroid use were entered. The remaining four patients in this study were not part of this database but were followed by the investigators (P.F., S.H., R.P) during the same period. All 68 study patients fulfilled ARA criteria for JRA (2). Age of disease onset of IRA diagnosis and the duration of JRA prior to menarche were calculated in years. Although the presence or absence of oral corticosteroid use was recorded, the exact dose was not available. The nine patients who experienced menarche before the onset of JRA (six polyarticular and three pauciarticular) were excluded from the analysis. Menarchal information was available on 46 sisters. The sisters who comprised the control group were not on corticosteroids and did not have JRA. A detailed medical history on sisters was not part of this investigation, so it is not known whether any of the sisters suffered from any other chronic disease. One monozygotic twin pair was included in the study. All subjects were white. The STATVIEW program (Brainpower, Inc., Calabasas, CA) on the Macintosh Plus computer and the FEXACT program on the Tops-20 system at the Dana-Farber Cancer Institute were used for data analysis. Student's unpaired t test, analysis of variance (ANOVA), simple and multiple linear regression, l, and Fisher's exact tests were the statistical techniques employed. For the multivariate model the strength of association between the outcome variable and the multiple independent variables was measured by the multiple correlation coefficient R2 (8). When multiple statistical comparisons were made, the p value was multiplied by the number of comparisons made (9) and was denoted Peorr' All reported p values were two sided.
Results The patient group was composed of 15 patients with systemic-onset disease (22%), 18 patients with polyarticular disease (26.5%), and 35 patients with pauciarticular disease (51.5%) at onset. One of the monozygotic twin pair under study had systemiconset JRA requiring steroid therapy. The age of menarche for the diseased twin was 18 years, while the unaffected twin's menarche occurred at age 15. The mean age of menarche for the controls (12.5 years) and the entire JRA group (13.2 years) were significantly different (p = 0.015). Additional analyses were performed to determine which factors were responsible for this observed difference in menarchal age between JRA patients and their sisters. Comparison by onset type revealed a difference
JOURNAL OF ADOLESCENT HEALTH CARE Vol. 9, No.6
Table 1. Summary of Study Groups By Subtype of Onset of JRA
Group" Polyarticular Systemic
Il
Pauciarticular
18 15 35
Sisters (controls)
46
Mean age of menarche (SD) 13.4 (1.5) 13.1 (1.7) 13.0 (1.5) 12.5 (1.5)
Mean duration of .fRA"
6.6 6.3 7.0
Steroid use (%) 27.8 53.3 20.0 0
"Menarche prediction model (subtype) p=O.4l. "Menarche prediction model (duration) p=O.09. 'Menarche prediction model (steroid) p = 0.91 Best model (subtype + duration + steroid) p = 0.04.
(p < 0.05) between the average age of menarche for
the polyarticular JRA patients (13.3 years) and the controls. When this P value was corrected for the number of possible comparisons, this difference was not significant (Peorr < 0.25). The mean ages of the systemic and pauciarticular JRA patients (13.1 and 13.0 years, respectively) did not differ from controls (12.5 years) (Table 1). Twenty patients (five polyarticular, seven pauciarticular, and eight systemic) received oral corticosteroids at some time during the course of their disease. Data on the dose and the duration of steroid use was not available. The steroid-treated JRA patients represented 29.4% of all JRA patients. Within the polyarticular, pauciarticular, and systemic-onset types, the steroid-treated patients represented 27.8%, 20%, and 53.3% of these groups, respectively. Steroid use was significantly more frequent among JRA subtypes than controls (p = 0.0183). When the 2 x 4 table was partitioned to examine this contrast more closely, systemic-onset JRA and polyarticular-onset patients accounted for this increase. The systemic-onset JRA group had significantly different steroid use than the pauciarticular (p
November 1988
of 6.3 and 6 years, respectively. The pauciarticularonset patients had the earliest mean age of onset (5.9 years). The mean ages of onset for the systemic and polyarticular patients were similar (6.8 years). There were four patients who developed their disease at the maximum age of disease onset of 13 years (two polyarticular, one systemic, and 1 pauciarticular). Based on a study of juvenile diabetes mellitus that showed that disease onset near puberty may cause menarehal delay (10), we constructed age-ofdisease-onset categories « 11, ?ell years). There were 55 JRA patients (12 systemic, 14 polyarticular, and 29 pauciarticular) within the category age of disease onset at less than 11 years and 13 (three systemic, four polyarticular, and six pauciarticular) with age of disease onset of 11 years or older. Age of disease onset was not an important predictor of the age of menarche whether the exact age or the age categories «11 years, ~11 years) were considered (p = 0.9 and 0.37, respectively) . There was also no association between IRA subtype and age category (p = 0.87). Further analysis within the JRA patient group revealed that patients with age of onset less than 11 years were more likely to be steroid treated (p = 0.007). In spite of the association between steroid treatment and young age , steroid use was not helpful as the sale predictor of menarche (p = 0.91) or in combination with the age category variable (p=0.88). The duration of JRA prior to menarche ranged from 0 to 15 years. The mean duration of JRA was 6.7 years (6.3, 6.6 and 7.0 years for the systemic, polyarticular, and pauciarticular subtypes, respectively). The prediction model that was limited to the single variable duration of JRA was of borderline significance as a predictor.of age of menarche (p = 0.09). The multivariate model of steroid use , subtype, and duration of JRA provided the best prediction model for the age of menarche in JRA (p = 0.04). This model explained only 12% (R2 = 0.12) of the variability of the age of menarche among the study subjects and was considered a weak predictive model overall (Table 1).
Discussion Our retrospective study shows that JRA patients experience an older age of menarche than their unaffected sisters. Delayed menarche has been observed in several chronic diseases such as cystic fibrosis (CF), diabetes mellitus (OM), and homozygous sickle cell disease (10-17). Moshang and Holsclaw studied the timing of menarche in CF and observed an older age of menarche in their 63 CF patients com-
MENARCHE IN ]RA
485
pared to controls (11). Menarche may also be delayed in DM (13-16). Tattersall and Pyke showed that monozygotic twins who were discordant for Type 1 OM at puberty were also discordant for age of menarche (13). Similarly, the diseased, steroidtreated twin in our study of JRA experienced menarche 3 years after her healthy twin. Although several variables were evaluated and their interrelationships explored, it was not possible to determine why the age of menarche in JRA may differ from controls. Duration of disease was the single best predictor of age of menarche in JRA, but considered singly it did not reach statistical significance. The possible importance of the duration of disease to the age of menarche in JRA contrasts with Type 10M. The research of Pezzini et a1. showed that delayed menarche in their Type 1 OM patients was not influenced by the duration of disease (14). The effect of steroid use was also examined . We used corticosteroid use as a marker of the severity of the disease. This variable differentiated among JRAsubtypes and also obviously distinguished JRA patients from controls . Our finding predicated on severity of disease contrasts with those in CF (12) but is similar to the results from studies in Type 1 DM (13,15,16). Age of disease onset was similar among the JRA subtypes and was not an important determinant of menarche in JRA. The effect of age of disease onset in Type 1 OM remains controversial. In a study of 987 OM patients with an onset of their disease long after the onset of puberty, lonescu-Tirgoviste et aI. demonstrated that menarche was Significantly delayed (15). Because their subjects developed DM long after the onset of puberty, it suggests that the age of disease onset of OM may not affect menarche. In contrast, Schriock et al. found that menarche occurred significantly earlier in their group of patients who had the onset of DM before the age of 11 years when compared to the age of menarche among patients with an onset at 11 years of age or later (10). The authors concluded that the onset of OM during puberty results in a delay in menarche. The best available multivariable model of steroid use, subtype, and duration of JRA had low predictive power. The reasons for the poor predictive ability of this model may be found in other investigations of growth and development. Studies in normal children have shown that the timing of menarche may be dependent on body composition (18). Menarche is also correlated with skeletal maturation, height, and weight (19). Studies of menarche in CF, OM, and sickle cell disease (55) support the important effect of body composition on men-
486
FRASER ET A L.
arche in chronic diseases. Mitchell-Heggs and colleagues found that 65%.of thei r CF patients were below the third percentile for weight and were between the 25th and 50th percentile for height (12). By multiple univariate analyses they showed that body composition, in conjunction with disease activity, was an important determinant of menarche in CP. Tattersall and Pyke's monozygotic twin study showed that OM-affected twins were shorter than their healthy twins (13). Graham and colleagues' multivariate analysis of 55 children revealed height and weight to have some predictive ability, but showed the fetal hemoglobin level to be the most important predictor of menarchal age (17). A recent study of growth in JRA showed significant growth retardation in systemic-onset patients (5). Height and weight measurements at menarche were not available on the patients Of the controls in our study so our study cannot answer the important question of whether height and weight are the major determinants of the timing of menarche in JJ
JOURNAL OF ADOLESCENT HEALTH CARE Vol. 9, No.6
steroids are first used, the duration of steroid use, the dosage used, or the relationship of steroid use to the onset of puberty are factors in the timing of menarche in JRA patients. The possible value of monitoring hormonal levels (luteinizing hormone, follicle-stimulating hormone, and estradiol) should also be considered. For the practitioner who confronts the diagnostic dilemma of an adolescent JRA patient who has not experienced menarche, the results of this study would favor the deferral of an extensive work-up until after the patient's 18th birthday. Th is s tudy was supported by a grant from the New England Peabody Home for Crippled Children.
References 1. IRA Criteria Subcommittee of the Diagnostic and Therapeutic Criteria Committee of the American Rheum atism Asso ciation Section uf the Arthri tis Foundation . Current proposed revision of IRA criteria . Arthritis Rheum 1977;20:195-9 . 2. Kuhns JG, Swaim LT. Disturbanc es of growth in chronic arthritis in children. Am J Dis Child 1933;43:1118-33. 3. Coss [A, Boots RH. Juvenile rheumatoid arthritis. J Ped iatr 1946;29:143-56 . 4. Ansell BM, Bywaters EGL. Growth in Still's disease. Ann
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