C.A. Silva

Gonadal function in adolescents and young women with juvenile systemic lupus erythematosus

The authors analysed the gonadal function and age of menarche of 23 female adolescentsand young women with SLE, and correlated these with clinical, SLEDAI and therapeutic parameters. The presence of one or more clinical and laboratory parameters defined normal gonadal function: normal menstrual cycles with or without dysmenorrhea; elevated cervical mucus length; normal levels of plasma FSH, LH, estradiol, progesterone, prolactin and testosterone; normal urinary hormonal cytology; serial pelvic ultrasound compatible with ovulatory pattern; and present or previous pregnancy. The mean age of menarche (13.5§ 1.4 years) was greater than that found among 2578 healthy Brazilian adolescents (12.5§ 1.3 years; P = 0.0002). The delay in menarche correlated with an increase in the duration of the disease (P = 0.0085) and the cumulative dose of prednisone (P = 0.0013) used until the appearance of the menarche. The mean phase length in SLE was 31.5§ 10.3. Sixteen female (70%) patients showed normal and seven (30%) abnormal gonadal function. Gonadal function was not correlated with parameters of SLE. These results suggest that the patients of this study reach adulthood with a high chance of fertility.

Autoimmune primary ovarian insufficiency

Primary ovarian insufficiency (POI) is defined as sustained amenorrhea, increased follicle-stimulating hormone and low estrogen levels, whereas diminished ovarian reserve (DOR) is characterized as regular menses and alterations of ovarian reserve tests. POI of autoimmune origin may be associated with adrenal autoimmunity, non-adrenal autoimmunity or isolated. This autoimmune disease is characterized by serum ovarian, adrenocortical or steroidogenic cell autoantibodies. POI of adrenal autoimmune origin is the most frequent type observed in 60-80% of patients. Clinically, amenorrhea is the hallmark of POI, however before menstruation stops completely, irregular cycles occur. Infertility, hot flushes, vaginal atrophy, and dyspareunia are also common. Autoimmune oophoritis is characterized by mononuclear inflammatory cell infiltrate in the theca cells of growing follicles, with early stage follicles without lymphocytic infiltration. This infiltrate includes plasma, B and T-cells. A novel classification criterion for autoimmune POI/DOR is proposed subdividing in three distinct categories (possible, probable and confirmed) according to autoantibodies, autoimmune disease and ovarian histology. Unfortunately, up to date guidelines for the treatment of autoimmune oophoritis are not available. Strategies to POI treatment include hormone replacement and infertility therapy. Assisted conception with donated oocytes has been proven to achieve pregnancy by intra cytoplasmic sperm injection in POI women.

Menstrual and hormonal alterations in juvenile systemic lupus erythematosus.

Menstrual cycles of 30 patients with juvenile systemic lupus erythematosus (JSLE) were compared with 30 age-matched controls. The mean age of patients with JSLE and controls was similar (17.4 ± 3.2 vs 17.06 ± 2.08 years, P = 0.66). The mean menarche age was higher in JSLE than controls (13.13 ± 1.4 vs 11.56 ± 1.5 years, P = 0.0008). On the contrary, the mean maternal menarche age was similar in both groups (P = 0.62). Menstrual abnormalities and longer length cycles were more frequently observed in JSLE than controls (63% vs 10%, P = 0.0001; 23% vs 0%, P = 0.0105, respectively). The median of follicle stimulating hormone was significantly higher in patients with JSLE compared with controls (4.6 vs 3.4 IU/L, P = 0.0207), and the median of progesterone was lower (32.5 vs 70 ng/mL, P = 0.0033). The median of luteinizing hormone was lower in patients with JSLE with menstrual abnormalities versus normal cycles (2.9 vs 5.5 IU/L, P = 0.019) and both had a high percentage of decreased progesterone levels (63% vs 73%, P = 0.70). Our findings support the notion that menstrual disturbances are frequent and may be associated with pituitary dysfunction leading to a decreased progesterone production. We also reported that in spite of premature ovarian failure being a rare event in JSLE the follicular reserve seems to be low regardless of intravenous cyclophosphamide treatment.

Testicular Sertoli cell function in male systemic lupus erythematosus

OBJECTIVE To assess the testicular Sertoli cell function in male SLE patients. METHODS Thirty-four consecutive patients were prospectively selected to evaluate serum inhibin B. Clinical features, treatment, semen analysis, urological evaluation, testicular ultrasound, hormones and anti-sperm antibodies were determined. RESULTS Patients were subdivided into two groups: low serum inhibin B (Group 1, n = 8) and normal levels (Group 2, n = 26). The median sperm concentration (P = 0.024), total sperm count (P = 0.023) and total motile sperm count (P = 0.025) were lower in Group 1. Inhibin B levels were positively correlated with sperm concentration (r = 0.343), total motile sperm count (r = 0.357), and negatively correlated with follicule-stimulating hormone (FSH) (r = 0.699) and luteinizing hormone (r = 0.397). The median serum inhibin B was lower in SLE patients treated with intravenous cyclophosphamide (IVCYC) compared with those without this therapy (P = 0.031). Further evaluation of the 26 SLE patients with normal inhibin B and FSH levels revealed that medians of inhibin B/FSH ratio were lower in SLE patients with oligozoospermia compared with normozoospermia (P = 0.004). This ratio was also lower in SLE patients treated with IVCYC than those without this therapy (P = 0.04). In contrast, inhibin B serum level alone did not discriminate the later group of patients (P = 0.12). CONCLUSIONS This is the first study to identify a high frequency of testicular Sertoli cell dysfunction in male SLE associated with semen abnormalities. Further prospective studies are necessary to determine if inhibin levels and inhibin B/FSH ratio will be an earlier and useful marker of IVCYC toxicity in these patients.

Complement and antibody primary immunodeficiency in juvenile systemic lupus erythematosus patients

Objective: To evaluate the frequency of primary immunodeficiencies (PID) in juvenile systemic lupus erythematosus (JSLE) patients. Methods: Some 72 JSLE patients were analyzed for levels of immunoglobulin classes and IgG subclasses and early components of the classical complement pathway. Determination of C4 gene copy number (GCN) and detection of type I C2 deficiency (D) were also performed. Results: PID was identified in 16 patients (22%): C2D in three, C4D in three, C1qD in two, IgG2D (<20 mg/dl) in four, IgAD (<7 mg/dl) in three, and IgMD (<35 mg/dl) in three; one of these patients presented IgA, C2 and C4D. Two patients had low C4 GCN and two had type I C2D. Demographic data, family history of autoimmune disease and PID, JSLE clinical findings, occurrence of infections, disease activity and therapies were similar in patients with and without PID (p > 0.05). Remarkably, the median of Systemic Lupus International Collaborating Clinics/ACR-damage index (SLICC/ACR-DI) was significantly higher in JSLE patients with PID compared with patients without these abnormalities (p = 0.0033), likewise the high frequency of SLICC/ACR-DI > 1 (p = 0.023). Conclusions: A high frequency of PID was observed in JSLE patients, suggesting that these defects may contribute to lupus development. Our findings indicate that these two groups of PID should be investigated in severe pediatric lupus.

Bone mineral apparent density in juvenile dermatomyositis: the role of lean body mass and glucocorticoid use

Objective: To analyse bone mineral density (BMD) in juvenile dermatomyositis (JDM) and its possible association with body composition, disease activity, duration of disease, glucocorticoid (GC) use, and biochemical bone parameters, including osteoprotegerin (OPG) and receptor activator of nuclear factor κB (RANKL). Methods: Twenty girls with JDM and 20 controls matched for gender and age were selected. Body composition and BMD were analysed by dual‐energy X‐ray absorptiometry (DXA) and bone mineral apparent density (BMAD) was calculated. Duration of disease, cumulative GC, and GC pulse therapy use were determined from medical records. Disease activity and muscle strength were measured by the Disease Activity Score (DAS), the Childhood Myositis Assessment Scale (CMAS), and the Manual Muscle Test (MMT). Inflammatory and bone metabolism parameters were also analysed. OPG and RANKL were measured in patients and controls using an enzyme‐linked immunosorbent assay (ELISA). Results: A lower BMAD in the femoral neck (p<0.001), total femur (p<0.001), and whole body (p = 0.005) was observed in JDM patients compared to controls. Body composition analysis showed a lower lean mass in JDM compared to controls (p = 0.015), but no difference was observed with regard to fat mass. A trend of lower serum calcium was observed in JDM (p = 0.05), whereas all other parameters analysed, including OPG and RANKL, were similar. Multiple linear regression analysis revealed that, in JDM, lean mass (p<0.01) and GC pulse therapy use (p<0.05) were independent factors for BMAD in the hip region. Conclusions: This study has identified low lean mass and GC pulse therapy use as the major factors for low hip BMAD in JDM patients.

Inflammatory cervicovaginal cytology is associated with disease activity in juvenile systemic lupus erythematosus.

To evaluate cervicovaginal cytology in adolescents with juvenile systemic lupus erythematosus (JSLE) and to compare them to controls. Fifty-two female adolescents with JSLE (ACR criteria) were compared to 52 age-matched healthy controls. All Pap smears were evaluated by the same cytopathologist blinded to gynecology examination (Bethesda 2001). The mean age of JSLE patients and controls were similar (16.17 ± 1.94 versus 16.13 ± 2.16 years, P = 0.92). The cervicovaginal cytology was found to be similar in both groups, although sexual intercourses in the last month were less frequent in JSLE than controls (23% versus 59.6%, P = 0.0003). Only one patient (2%) with JSLE versus two controls (4%) had cervical dysplasia (LGSIL) and human papilomavirus (P = 1.0). Candida spp vaginitis was observed in seven JSLE (14%) versus none in controls (P = 0.012) and was associated with immunosuppressive drugs (P = 0.01) and high dose of prednisone (P = 0.002). Of interest, inflammatory cervicovaginal cytology was observed in 21 (60%) of patients with SLEDAI ≥ 4 and only four (23%) of those with SLEDAI < 4 (P = 0.001). Likewise, a higher frequency of inflammatory changes was also observed in virgin JSLE (57% versus 8%, P = 0.005). Our findings supports the notion that female genital tract may be a potential target organ in SLE since cervical inflammation is associated to disease activity independently of sexual activity. Lupus (2007) 16, 430—435.

Risk factors for amenorrhea in juvenile systemic lupus erythematosus (JSLE): a Brazilian multicentre cohort study

We evaluated the prevalence and clinical associations of amenorrhea in 298 female juvenile systemic lupus erythematosus (JSLE) patients (ACR criteria) followed in 12 Brazilian Paediatric Rheumatology centres. Amenorrhea was observed in 35 patients (11.7%) with a mean duration of 7.2 ± 3.6 months. The hormones were performed in 32/35 patients and none of them had FSH and LH levels above and estradiol below the normal range according to pubertal changes. JSLE patients with amenorrhea were younger (15.04 ± 2.5 versus 17.8 ± 3.1 years; P = 0.001), and had a shorter period of time between menarche and current age (3.4 ± 2.9 versus 6.7 ± 5.4 years; P = 0.001). Interestingly, the frequency, cumulative dose, number of pulses and duration of intravenous cyclophosphamide treatment were alike in patients with and without amenorrhea (P > 0.05). In contrast, patients with amenorrhea had significantly higher SLEDAI (P = 0.01) and SLICC/ACR-DI (P = 0.024) scores compared to those without this condition. Independent risk factors identified by multivariate analysis were higher SLEDAI (OR = 1.059; CI = 1.004—1.116; P = 0.034) and SLICC/ACR-DI (OR = 2.125; IC = 1.373—3.291; P = 0.001) scores. Our data suggest that in spite of immunosuppressive therapy, JSLE patients have an adequate ovarian follicular reserve and amenorrhea is particularly associated with disease activity and damage. Lupus (2007) 16, 531—536.

Oral health and the masticatory system in juvenile systemic lupus erythematosus.

Our objectives were to evaluate the oral health and the masticatory system of 48 juvenile systemic lupus erythematosus (JSLE) patients and to compare them with 48 healthy children and adolescents. Demographic data, clinical manifestations and therapies of JSLE were reviewed. The DMFT index (DMFTI), the plaque (PI) and the gingival bleeding (GI) indices, dental relationship, facial profile, clinical dysfunction and mandibular mobility indices were evaluated. The two groups were homogeneous regarding age, gender, Brazilian social-economic class and dental decay index (P > 0.05). Of note, the medians of the PI and the GI were higher in JSLE patients than in controls (61.5 versus 38.10, P = 0.003 and 26.0 versus 15.95, P = 0.014; respectively). Likewise, a linear statistical correlation was evidenced between the JSLE duration and the GI (P = 0.017, r = 0.11), cumulative dose of prednisone and the PI (P = 0.01, r = 0.385) and cumulative dose of prednisone and the GI ( P = 0.001, r = 0.471). The clinical dysfunction and mandibular mobility indices were higher in JSLE patients versus controls (P = 0.002, P = 0.025). Moreover, the median of the mandibular mobility index was higher in JSLE patients who used at least one immunosuppressive than on those who did not use this medication (P = 0.0001). These results suggest that JSLE patients had an inadequate oral hygiene, higher incidence of gingivitis and temporomandibular joint dysfunction. Lupus (2007) 16, 713—719.

Antinucleosome antibodies in patients with juvenile systemic lupus erythematosus.

Our objective was to evaluate the frequency of antinucleosome antibodies (anti-Ncs) in juvenile systemic lupus erythematosus (JSLE) comparing it to that observed for anti-DNA and to correlate the presence of these antibodies with clinical manifestations and disease activity. Anti-Ncs and anti-DNA were detected by ELISA in 74 patients with JSLE and 64 normal controls. Clinical records were reviewed. Disease activity was assessed by SLEDAI score. Anti-Ncs and anti-DNA showed sensitivity of 52.7% and 54% and specificity of 98.4% and 95.3%, respectively. Disagreement between the two assays was found in 25.7% of the cases: isolated positive Anti-Ncs in nine cases (12.2%) and isolated positive anti-DNA in 10 cases (13.5%). Agreement was found in 74.3%: both positive antibodies in 30 cases and both negative in 25. The presence of anti-Ncs was significantly associated with malar erythema, hemolytic anemia, anti-DNA and low complement levels, but not with renal manifestations. The presence of anti-Ncs was associated with a higher SLEDAI median (P < 0.001) and its titers correlated with the SLEDAI score (r = 0.504; P < 0.001). The frequency, sensitivity and specificity values were similar between anti-Ncs and anti-DNA antibodies in patients with JSLE. Nevertheless, the discordance of 25.7% between the two assays suggests that both antibodies may have a complementary diagnostic role. The association and correlation between anti-Ncs and several disease activity parameters demonstrated its usufulness in the follow-up of these patients.