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Research paper
Thyroid Dysfunction in Juvenile Systemic Lupus Erythematosus: Clinical Features and Relation to Disease Activity
ABSTRACT
Objective: The aim of this study was to evaluate thyroid dysfunction and thyroid auto-antibodies (ATA) production in Juvenile Systemic Lupus Erythematosus (JSLE) patients and its relation to clinical features and disease activity.
Methodology: Thirty-seven patients and twenty-five controls were enrolled in this study. All of them were subjected to full clinical examination and routine laboratory investigations in addition to thyroid function tests (TSH, free T4) and thyroid auto antibodies (ATA) namely antithyroglobulin (ATg) and antiperoxidase (APO) antibodies detection.
Results: Auto thyroid antibodies were detected in eleven JSLE patients “four patients had antithyroglobulin (ATg), three had antiperoxidase (APO), and four had both of ATg and APO". Auto thyroid antibodies were detected in five of the control group “two had ATg, one had APO and two had both of ATg and APO. There were significant differences between JSLE patients and control groups regarding the detection of thyroid auto antibodies (P<0.05). Subclinical hypothyroidism was detected in nine ATA positive JSLE patients. Renal, neuropsychiatric and hematological manifestations (at least one of them) were significantly detected in eutohyroid JSLE patients and ATA negative JSLE patients respectively in comparison to subclinical hypothyroid JSLE patients and ATA positive JSLE patients respectively (P<0.05, P<0.01 respectively). ATg and APO levels were significantly higher in (euothyroid & subclinical hypothyroid) JSLE patients than control group (P<0.01). In subclinical hypothyroid patients ATA levels were significantly higher than euothyroid JSLE patients (P<0.01). Furthermore ATA or subclinical hypothyroidism detection had no significant relation to SLE disease activity index (SLEDAI).
Conclusion: Subclinical hypothyroidism could be detected in thyroid auto antibodies positive JSLE patients. Detection of subclinical hypothyroidism or thyroid auto antibodies did not show significant relation to disease activity but was significantly associated with less renal, neuropsychiatric and hematological complications.
KEYWORDS: Juvenile Systemic Lupus Erythematosus, Thyroid dysfunction, Thyroid auto-antibodies, Systemic Lupus Erythematosus activity index.
INTRODUCTION
Systemic Lupus Erythematosus (SLE) is an autoimmune disorder. It may be associated with other organ-specific autoimmune diseases. The detection of antibodies in this population is anticipated as B-lymphocytes over activity, which associated with autoantibody production, is an immunopatholologic feature of SLE (Arkachaisri and Lehman, 1999).
Autoimmune thyroiditis is an organ-specific disease that could be associated with production of variety of antibodies such as antinuclear antibodies, anti-double-strandedDNA, anti-Ro antibodies, anti-cardiolipin antibodies and others (Trpojevic & Djuceras, 2005 and Arbuckle et al, 2003).
Many systemic autoimmune disorders have been reported to be associated with autoimmune thyroiditis in up to 50% of the cases. These disorders included SLE, rheumatoid arthritis, Sjogren’s disease and mixed connective tissue disease (Silverman, 2002).
Worldwide, 15-17% of SLE patients were presented before 16 years with peak incidence at 10-14 years. It is rare below 4 years. Overall male to female ratio is 1:2.6 (Thomson and Hahn, 2005). Some researchers believed that childhood SLE had more organ involvement and disease severity than adult-onset disease, especially renal and neuropsychiatric diseases (Mina & Brunner, 2010 and Tapanes et al, 2000).
Thyroid auto-antibodies, namely anti-peroxides (APO) and anti-thymoglobulin (ATg) antibodies have been found in many adult SLE (Madder et al, 2007). Several studies had demonstrated clinical and laboratory autoimmune thyroiditis in adult SLE patients (El Sherif et al, 2004).
The aim of this study was to evaluate thyroid dysfunction and thyroid autoantibodies in juvenile SLE patients and its relation to clinical features and disease activity.
SUBJECTS & METHODS
Thirty seven patients (29 females and 8 males) satisfied the classification criteria for SLE (Petri, 2009) were included in the study. Thirteen of them were selected from Pediatric Department. Their ages ranged from (6-15years) and twenty four patients, with ages ranged from (9-17years), were selected from Rheumatology & Rehabilitation Department. ZagazigUniversityHospitals, Egypt, in the period from July 2009 up to August 2010. Mean ±SD of ages was (12.4±4.35). Twenty-five apparently healthy volunteers, age and sex–matched with the patients, were saved as a control group (20 females and 5 males) their ages (mean ±SD) was (12.5±3.9). Written informed consent was obtained from their parents and revised by the ethical committee.
Current medical treatment of patients included non-steroidal anti-inflammatory drugs in 17 (45.9%) patients, corticosteroids in 32 (86.4%) patients, methotrexate in 4 (10.8%) patients, antimalarials in 30 (81.1%) patients, azathioprine in 22 (59.4%) patients and cyclophosphamide in 1 (2.7%) patient.
Study protocol included demographic and clinical data related to thyroid dysfunction such as (fatigue, anxiety, diaphoresis, mode changes, bowel habits, weight changes, palpitation, tremors and exophthalmoses) were searched. Clinical hypothyroidism was defined as elevated TSHand suppressed free T4 (FT4), subclinical hypothyroidism had elevated TSH with normal FT4. Clinical hyperthyroidism was defined as suppressed TSH with elevated FT4, subclinical hyperthyroidism was defined as low TSH and normal FT4 (Diaz-Olmos et al. 2010).
Exclusion criteria: Patients who was subjected in the past to thyroid surgery , treatment with I131or thyroid hormone replacement therapy were excluded .
Disease activity was determined in patients by SLE disease activity index (SLEDAI) score. This index takes into consideration 24 variables (using clinical and laboratory parameters) representing nine organ systems. Each variable is rated as (present or absent) over 10 days before, and including the day of evaluation (Bombardier et al, 1992)
SLEDAI score is classified according to Esdiale et al (1996) into:
a- Inactive disease: If SLEDAI =6 points. b- Active disease: If SLEDAI >6 points.
The Systemic Lupus International Collaborating Clinics (SLICC) Damage Index, which has been endorsed by the American College of Rheumatology, was also used (Gladman et al, 1996).
All the following were done for all patients and control group:
1-Full medical history taking and clinical examination.
2-Routine laboratory investigations including Complete blood count (CBC), erythrocyte sedimentation rate (ESR): by Westergren method.
3-FreeT4 and TSH were measured by electrochemiluminescence immunoassay [Cobas e411,Roche,Japan]. Kits were provided form Roche diagnostics GmbH,Mannheim,Germany).
4-Serum thyroid autoantibodies measured by enzyme linked immunosorbent assay (ELISA kit, GenWay Biotech, Inc.).
The following were done for JSLE patients:
-Antinuclear antibody (ANA) and anti ds-DNA was done with the indirect immunoflorescence (The Binding site,Birmingham,UK).
-Urine analysis: To detect proteinuria, microscopic examination for pus cells , red blood cells, and casts as indication of renal affection quantitative 24 hours urinary protein excretion (turbidity assay).
-Complement C-3 by cobas integra 400(turbidimetric assay).
-Anti-Sm antibodies for patients with CNS manifestations to be differentiated from thyroid CNS manifestations.
Methods of detection of Serum thyroid autoantibodies:
Serum thyroid autoantibodies were measured by enzyme linked immunosorbent assay for the determination of autoantibodies against thyroid peroxidase (APO) and thyroglobulin (ATg) autoantibodies in human serum (ELISA kit, GenWay Biotech, Inc.).
Purified human thyroglobulin antigen is bound to the wells of a polystyrene microwell plate under conditions that will preserve the antigen in its native state.
Pre-diluted controls and diluted patient sera are added to separate wells, allowing any thyroglobulin antibodies present to bind to the immobilized antigen. Unbound sample is washed away and an enzyme labeled anti-human IgG conjugate is added to each well. A second incubation allows the enzyme labeled anti-human IgG to bind to any patient antibodies, which have become attached to the microwells. After washing away any unbound enzyme labeled anti-human IgG, the remaining enzyme activity is measured by adding a chromogenic substrate and measuring the intensity of the color that develops. The assay can be evaluated spectrophotometrically by measuring and comparing the color intensity that develops in the patient wells with the color in the control wells. The intra-assay CVs for APOand ATg were 3.5 and 2.7%, respectively, and the inter-assay CVs were 8.7 and 9.1%, respectively. Test results were considered positive if levels were greater than 50 IU/ml for APOand 100 IU/ml for ATg. Mannheim, Germany). The intra-assay coefficient of variation (CV) was 1.5–8.6%, and the inter-assay CV was 1.5–3% for TSH. The intra-assay coefficient of variation (CV) was 1.5–8.6%, and the inter-assay CV was 1.5–3% for Free T4.The reference range was 11.5–22.7 pmol/l for FT4 and 0.35–5.5 µIU/ml for TSH.
Statistical analysis
Statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS) software version 10. The relationship between categorical variables was tested by Chi-square test or by Fisher exact test. The relationship between continuous variables by "t" test and ANOVA. P values of 0.05 or less were considered statistically significant.
RESULTS
Auto thyroid antibodies were detected in eleven JSLE patients “four patients had antithyroglobulin (ATg) , three had antiperoxidase (APO), and four had both of ATg and APO”. Auto thyroid antibodies were detected in five of the control group “two had ATg, one hadAPOand two had both of ATg andAPO. A significant difference was detected between JSLE patients and control groups according to the detection of thyroid auto antibodies (P<0.05)(figure1).
Demographic and clinical data of JSLE patients were depicted in table (1). There were no significant differences between JSLE patients (euothyroid& subclinical hypothyroidism) regarding to age, sex, disease duration, SLEDAI score, SLICC score, FT4 or corticosteroids usage (p>0.05), there was highly significant difference regarding TSH level and azathioprine administration (P<0.01). There were 18(64.3%) euothyroid JSLE patients versus4 (44.4%) subclinical hypothyroid JSLE patients receiving azathioprine in treatment protocol and this difference was highly significant (P<0.01) (table1).
The analysis of SLE clinical manifestations of the 9 patients with hypothyroidism compared to the 28 patients with normal thyroid function revealed that the former group had significant lower detection of at least one major organ involvement ; hematological manifestations were found in the form of chronic hypochromic anemia (40% vs 50%), leucopenea(32% vs 52%), and mild thromobcytopenea (37 vs 47%). Lupus nephritis (27% vs 35%), neuropsychiatric lupus (45% vs 55%), (figure 2).
Comparing ATA positive versus ATA negative JSLE patients; there were 2(18.2%) patients versus 20(76.9%) patients receiving azathioprine in treatment protocol and this difference was highly significant (P<0.01) (table2), subclinical hypothyroidism was detected in 9 ATA positive JSLE patients. There was highly significant difference regarding to renal, neuropsychiatric and hematological manifestations (at least one of them) (P<0.01) (table 2).
APO and ATg levels were significantly higher in euothyroid and subclinical hypothyroid JSLE patients than control group (p<0.01). Also their levels in subclinical hypothyroid were significantly higher than euothyroid JSLE patients (P<0.05 and P<0.01 respectively) (table 3).
Sixteen patients had active disease with a SLEDAI score mean± SD (7.4±1.2), and twenty-one patients were inactive with disease activity score mean± SD (4.6±1.3). Assessment of SLE activity, using SLEDAI score, showed non significant relation with ATA & subclinical hypothyroidism detection (table 4).
DISCUSSION
In adult patients with thyroid disease, thyroid autoantibodies appeared to be involved in disease pathogenesis, but their role in JSLE population remains uncertain (Madder et al, 2007).
We evaluated thyroid dysfunction and presence of thyroid antibodies in patients with juvenile systemic lupus erythematosus and its effects on clinical features and disease activity.
In our study, thyroid autoantibodies (ATg or APO) were detected in eleven JSLE patients and that was significantly different from control group. That met with the findings of Hongo and Kato (1999) who stated that cross reactivity of anti-thyroid autoantibodies with other tissue antigens including epithelial autoantigens and cytokine imbalance are possible mechanisms of thyroid autoantibodies production in JSLE patients. Another mechanism was suggested in thyroid autoantibodies production including auto reactive T cells, HLA-dependent genetic factors has been suggested in the formation of such overlap syndromes (Bero et al, 2006).
Regarding thyroid dysfunction, we found that subclinical hypothyroidism was detected in nine ATA positive (JSLE) patients; meanwhile clinical hyperthyroidism was not detected. That met with the findings of Costa et al( 2009) study which detected higher prevalence of hypothyroidism (either clinical or sub-clinical) in the adult JSLE patients. A lower frequency was observed in two other studies carried by Ronchezel et al (2001) and Mihailova et al(1999), that may be due to the younger mean age of the patients, since an age related increase has been reported.
In the current study, autoantibodies were detected in eleven patients; subclinical hypothyroidism was diagnosed in nine of them. That met with Eberhard et al (1991)study who suggested that steroids may either depress T3 or T4 values or suppress thyroid gland inflammation. This can prevent abnormalities of the immune system or reveal low-grade thyroiditis that kept suppressed by anti-inflammatory medications.
In this study, percentages of patients receiving azathioprine in treatment of JSLE were more in eutohyroid JSLE patients and ATA negative JSLE patients than in subclinical hypothyroid JSLE patients and ATA positive JSLE patients and that was highly significant.
Renal, neuropsychiatric and hematological manifestations were significantly detected in eutohyroid JSLE patients and ATA negative JSLE patients in comparison to subclinical hypothyroid JSLE patients and ATA positive JSLE patients (P<0.01). Consistent with these findings Saleh et al (2008) study, which assessing thyroid abnormalities in adult SLE and demonstrated that the presence of thyroid dysfunction was associated with less major organ involvement, more over reinforcing this finding Tapanes et al (2000) found that JSLE patients with thyroid antibodies had a higher frequency of anti-U1RNP. This pattern of autoantibody specificity seems to be associated with a more benign form of lupus nephritis. To and Petri (2005) had also demonstrated that the presence of anti-RNP/Sm antibodies in ATA positive JSLE patients was negatively associated with renal and hematological involvements in SLE .
We suggested that there is a significant association between subclinical hypothyroidism and ATA positive JSLE patients. The underlying pathogenic mechanism for this association however isn’t clear. El-Sherif et al (2004) demonstrated that Immune complexes have been detected in kidney, skin and muscles of patients with SLE.
Since SLE is a systemic disorder that can affect any target organ it is interesting to speculate that the thyroid disorders are the result of the antithyroid activity of one of the antibodies produced in SLE. The thyroid disorder may be a result of immune injury following deposition of immune complexes. This could be verified if thyroid biopsies is performed (To and Petri, 2005).
We did not find significant relation between thyroid antibodies or subclinical hypothyroidism and disease activity which is consistent with the finding of the study done by (Ronchezel et al. 2001).
CONCLUSION
Subclinical hypothyroidism could be detected in thyroid auto antibodies positive JSLE patients. Detection of subclinical hypothyroidism or thyroid auto antibodies did not show significant relation to disease activity but was associated with less renal, neuropsychiatric and hematological complications.
REFERENCES
Arbuckle MR, McClain MT, Rubertone MV, et al: Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med., 16:1526–33,2003.
Arkachaisri T and Lehman TJA: Systemic lupus erythematosus and related disorders of childhood. Curr Opin Rheumatol., 11(5): 348-52,1999.
Bero E, Szekanecz Z, Czirjak L, et al: Association of systemic and thyroid autoimmune diseases. Clin Rheumatol., 25:240-5, 2006.
Bombardier C, Gladman DD, Urowitz MB, et al: Derivation of the SLEDAI .A disease activity index for lupus patients. The committee on progress studies in SLE. Arth Rheum.,35:630-40, 1992.
Costa LP, Bonfa E , Martinago CD, et al: Juvenile onset systemic lupus erythematosus thyroid dysfunction: A subgroup with mild disease? J Autoimmunity, 33: 121–4, 2009.
Diaz-Olmos R, Nogueira AC, Penalva DQ, et al: Frequency of subclinical thyroid dysfunction and risk factors for cardiovascular disease among women at a workplace.Sao Paulo Med J., Jan; 128 (1):18-23,2010.
Eberhard BA and Laxer RM: Presence of thyroid abnormalities in children with systemic lupus erythematosus. J Pediat., 119(2): 277-9, 1991.
El-Sherif WT, El Gendi SS, Ashmawy MM, et al: Thyroid disorders in systemic lupus erythematosus and rheumatoid arthritis patients. Egyt J Immunol., 11(2): 81-90, 2004.
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Madder R, Mishail S, Adawi M, et al: Thyroid dysfunction in patients with systemic lupus erythematosus (SLE): relation to disease activity. Clin Rheumatol., 26:1891–4, 2007.
Mihailova D, Grigorova R, Vassileva B, et al: Autoimmune thyroid disorders in juvenile chronic arthritis and systemic lupus erythematosus. Adv Exp Med Biol., 455:55–60, 1999.
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ABSTRACT
Objective: The aim of this study was to evaluate thyroid dysfunction and thyroid auto-antibodies (ATA) production in Juvenile Systemic Lupus Erythematosus (JSLE) patients and its relation to clinical features and disease activity.
Methodology: Thirty-seven patients and twenty-five controls were enrolled in this study. All of them were subjected to full clinical examination and routine laboratory investigations in addition to thyroid function tests (TSH, free T4) and thyroid auto antibodies (ATA) namely antithyroglobulin (ATg) and antiperoxidase (APO) antibodies detection.
Results: Auto thyroid antibodies were detected in eleven JSLE patients “four patients had antithyroglobulin (ATg), three had antiperoxidase (APO), and four had both of ATg and APO". Auto thyroid antibodies were detected in five of the control group “two had ATg, one had APO and two had both of ATg and APO. There were significant differences between JSLE patients and control groups regarding the detection of thyroid auto antibodies (P<0.05). Subclinical hypothyroidism was detected in nine ATA positive JSLE patients. Renal, neuropsychiatric and hematological manifestations (at least one of them) were significantly detected in eutohyroid JSLE patients and ATA negative JSLE patients respectively in comparison to subclinical hypothyroid JSLE patients and ATA positive JSLE patients respectively (P<0.05, P<0.01 respectively). ATg and APO levels were significantly higher in (euothyroid & subclinical hypothyroid) JSLE patients than control group (P<0.01). In subclinical hypothyroid patients ATA levels were significantly higher than euothyroid JSLE patients (P<0.01). Furthermore ATA or subclinical hypothyroidism detection had no significant relation to SLE disease activity index (SLEDAI).
Conclusion: Subclinical hypothyroidism could be detected in thyroid auto antibodies positive JSLE patients. Detection of subclinical hypothyroidism or thyroid auto antibodies did not show significant relation to disease activity but was significantly associated with less renal, neuropsychiatric and hematological complications.
KEYWORDS: Juvenile Systemic Lupus Erythematosus, Thyroid dysfunction, Thyroid auto-antibodies, Systemic Lupus Erythematosus activity index.
INTRODUCTION
Systemic Lupus Erythematosus (SLE) is an autoimmune disorder. It may be associated with other organ-specific autoimmune diseases. The detection of antibodies in this population is anticipated as B-lymphocytes over activity, which associated with autoantibody production, is an immunopatholologic feature of SLE (Arkachaisri and Lehman, 1999).
Autoimmune thyroiditis is an organ-specific disease that could be associated with production of variety of antibodies such as antinuclear antibodies, anti-double-strandedDNA, anti-Ro antibodies, anti-cardiolipin antibodies and others (Trpojevic & Djuceras, 2005 and Arbuckle et al, 2003).
Many systemic autoimmune disorders have been reported to be associated with autoimmune thyroiditis in up to 50% of the cases. These disorders included SLE, rheumatoid arthritis, Sjogren’s disease and mixed connective tissue disease (Silverman, 2002).
Worldwide, 15-17% of SLE patients were presented before 16 years with peak incidence at 10-14 years. It is rare below 4 years. Overall male to female ratio is 1:2.6 (Thomson and Hahn, 2005). Some researchers believed that childhood SLE had more organ involvement and disease severity than adult-onset disease, especially renal and neuropsychiatric diseases (Mina & Brunner, 2010 and Tapanes et al, 2000).
Thyroid auto-antibodies, namely anti-peroxides (APO) and anti-thymoglobulin (ATg) antibodies have been found in many adult SLE (Madder et al, 2007). Several studies had demonstrated clinical and laboratory autoimmune thyroiditis in adult SLE patients (El Sherif et al, 2004).
The aim of this study was to evaluate thyroid dysfunction and thyroid autoantibodies in juvenile SLE patients and its relation to clinical features and disease activity.
SUBJECTS & METHODS
Thirty seven patients (29 females and 8 males) satisfied the classification criteria for SLE (Petri, 2009) were included in the study. Thirteen of them were selected from Pediatric Department. Their ages ranged from (6-15years) and twenty four patients, with ages ranged from (9-17years), were selected from Rheumatology & Rehabilitation Department. ZagazigUniversityHospitals, Egypt, in the period from July 2009 up to August 2010. Mean ±SD of ages was (12.4±4.35). Twenty-five apparently healthy volunteers, age and sex–matched with the patients, were saved as a control group (20 females and 5 males) their ages (mean ±SD) was (12.5±3.9). Written informed consent was obtained from their parents and revised by the ethical committee.
Current medical treatment of patients included non-steroidal anti-inflammatory drugs in 17 (45.9%) patients, corticosteroids in 32 (86.4%) patients, methotrexate in 4 (10.8%) patients, antimalarials in 30 (81.1%) patients, azathioprine in 22 (59.4%) patients and cyclophosphamide in 1 (2.7%) patient.
Study protocol included demographic and clinical data related to thyroid dysfunction such as (fatigue, anxiety, diaphoresis, mode changes, bowel habits, weight changes, palpitation, tremors and exophthalmoses) were searched. Clinical hypothyroidism was defined as elevated TSHand suppressed free T4 (FT4), subclinical hypothyroidism had elevated TSH with normal FT4. Clinical hyperthyroidism was defined as suppressed TSH with elevated FT4, subclinical hyperthyroidism was defined as low TSH and normal FT4 (Diaz-Olmos et al. 2010).
Exclusion criteria: Patients who was subjected in the past to thyroid surgery , treatment with I131or thyroid hormone replacement therapy were excluded .
Disease activity was determined in patients by SLE disease activity index (SLEDAI) score. This index takes into consideration 24 variables (using clinical and laboratory parameters) representing nine organ systems. Each variable is rated as (present or absent) over 10 days before, and including the day of evaluation (Bombardier et al, 1992)
SLEDAI score is classified according to Esdiale et al (1996) into:
a- Inactive disease: If SLEDAI =6 points. b- Active disease: If SLEDAI >6 points.
The Systemic Lupus International Collaborating Clinics (SLICC) Damage Index, which has been endorsed by the American College of Rheumatology, was also used (Gladman et al, 1996).
All the following were done for all patients and control group:
1-Full medical history taking and clinical examination.
2-Routine laboratory investigations including Complete blood count (CBC), erythrocyte sedimentation rate (ESR): by Westergren method.
3-FreeT4 and TSH were measured by electrochemiluminescence immunoassay [Cobas e411,Roche,Japan]. Kits were provided form Roche diagnostics GmbH,Mannheim,Germany).
4-Serum thyroid autoantibodies measured by enzyme linked immunosorbent assay (ELISA kit, GenWay Biotech, Inc.).
The following were done for JSLE patients:
-Antinuclear antibody (ANA) and anti ds-DNA was done with the indirect immunoflorescence (The Binding site,Birmingham,UK).
-Urine analysis: To detect proteinuria, microscopic examination for pus cells , red blood cells, and casts as indication of renal affection quantitative 24 hours urinary protein excretion (turbidity assay).
-Complement C-3 by cobas integra 400(turbidimetric assay).
-Anti-Sm antibodies for patients with CNS manifestations to be differentiated from thyroid CNS manifestations.
Methods of detection of Serum thyroid autoantibodies:
Serum thyroid autoantibodies were measured by enzyme linked immunosorbent assay for the determination of autoantibodies against thyroid peroxidase (APO) and thyroglobulin (ATg) autoantibodies in human serum (ELISA kit, GenWay Biotech, Inc.).
Purified human thyroglobulin antigen is bound to the wells of a polystyrene microwell plate under conditions that will preserve the antigen in its native state.
Pre-diluted controls and diluted patient sera are added to separate wells, allowing any thyroglobulin antibodies present to bind to the immobilized antigen. Unbound sample is washed away and an enzyme labeled anti-human IgG conjugate is added to each well. A second incubation allows the enzyme labeled anti-human IgG to bind to any patient antibodies, which have become attached to the microwells. After washing away any unbound enzyme labeled anti-human IgG, the remaining enzyme activity is measured by adding a chromogenic substrate and measuring the intensity of the color that develops. The assay can be evaluated spectrophotometrically by measuring and comparing the color intensity that develops in the patient wells with the color in the control wells. The intra-assay CVs for APOand ATg were 3.5 and 2.7%, respectively, and the inter-assay CVs were 8.7 and 9.1%, respectively. Test results were considered positive if levels were greater than 50 IU/ml for APOand 100 IU/ml for ATg. Mannheim, Germany). The intra-assay coefficient of variation (CV) was 1.5–8.6%, and the inter-assay CV was 1.5–3% for TSH. The intra-assay coefficient of variation (CV) was 1.5–8.6%, and the inter-assay CV was 1.5–3% for Free T4.The reference range was 11.5–22.7 pmol/l for FT4 and 0.35–5.5 µIU/ml for TSH.
Statistical analysis
Statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS) software version 10. The relationship between categorical variables was tested by Chi-square test or by Fisher exact test. The relationship between continuous variables by "t" test and ANOVA. P values of 0.05 or less were considered statistically significant.
RESULTS
Auto thyroid antibodies were detected in eleven JSLE patients “four patients had antithyroglobulin (ATg) , three had antiperoxidase (APO), and four had both of ATg and APO”. Auto thyroid antibodies were detected in five of the control group “two had ATg, one hadAPOand two had both of ATg andAPO. A significant difference was detected between JSLE patients and control groups according to the detection of thyroid auto antibodies (P<0.05)(figure1).
Demographic and clinical data of JSLE patients were depicted in table (1). There were no significant differences between JSLE patients (euothyroid& subclinical hypothyroidism) regarding to age, sex, disease duration, SLEDAI score, SLICC score, FT4 or corticosteroids usage (p>0.05), there was highly significant difference regarding TSH level and azathioprine administration (P<0.01). There were 18(64.3%) euothyroid JSLE patients versus4 (44.4%) subclinical hypothyroid JSLE patients receiving azathioprine in treatment protocol and this difference was highly significant (P<0.01) (table1).
The analysis of SLE clinical manifestations of the 9 patients with hypothyroidism compared to the 28 patients with normal thyroid function revealed that the former group had significant lower detection of at least one major organ involvement ; hematological manifestations were found in the form of chronic hypochromic anemia (40% vs 50%), leucopenea(32% vs 52%), and mild thromobcytopenea (37 vs 47%). Lupus nephritis (27% vs 35%), neuropsychiatric lupus (45% vs 55%), (figure 2).
Comparing ATA positive versus ATA negative JSLE patients; there were 2(18.2%) patients versus 20(76.9%) patients receiving azathioprine in treatment protocol and this difference was highly significant (P<0.01) (table2), subclinical hypothyroidism was detected in 9 ATA positive JSLE patients. There was highly significant difference regarding to renal, neuropsychiatric and hematological manifestations (at least one of them) (P<0.01) (table 2).
APO and ATg levels were significantly higher in euothyroid and subclinical hypothyroid JSLE patients than control group (p<0.01). Also their levels in subclinical hypothyroid were significantly higher than euothyroid JSLE patients (P<0.05 and P<0.01 respectively) (table 3).
Sixteen patients had active disease with a SLEDAI score mean± SD (7.4±1.2), and twenty-one patients were inactive with disease activity score mean± SD (4.6±1.3). Assessment of SLE activity, using SLEDAI score, showed non significant relation with ATA & subclinical hypothyroidism detection (table 4).
DISCUSSION
In adult patients with thyroid disease, thyroid autoantibodies appeared to be involved in disease pathogenesis, but their role in JSLE population remains uncertain (Madder et al, 2007).
We evaluated thyroid dysfunction and presence of thyroid antibodies in patients with juvenile systemic lupus erythematosus and its effects on clinical features and disease activity.
In our study, thyroid autoantibodies (ATg or APO) were detected in eleven JSLE patients and that was significantly different from control group. That met with the findings of Hongo and Kato (1999) who stated that cross reactivity of anti-thyroid autoantibodies with other tissue antigens including epithelial autoantigens and cytokine imbalance are possible mechanisms of thyroid autoantibodies production in JSLE patients. Another mechanism was suggested in thyroid autoantibodies production including auto reactive T cells, HLA-dependent genetic factors has been suggested in the formation of such overlap syndromes (Bero et al, 2006).
Regarding thyroid dysfunction, we found that subclinical hypothyroidism was detected in nine ATA positive (JSLE) patients; meanwhile clinical hyperthyroidism was not detected. That met with the findings of Costa et al( 2009) study which detected higher prevalence of hypothyroidism (either clinical or sub-clinical) in the adult JSLE patients. A lower frequency was observed in two other studies carried by Ronchezel et al (2001) and Mihailova et al(1999), that may be due to the younger mean age of the patients, since an age related increase has been reported.
In the current study, autoantibodies were detected in eleven patients; subclinical hypothyroidism was diagnosed in nine of them. That met with Eberhard et al (1991)study who suggested that steroids may either depress T3 or T4 values or suppress thyroid gland inflammation. This can prevent abnormalities of the immune system or reveal low-grade thyroiditis that kept suppressed by anti-inflammatory medications.
In this study, percentages of patients receiving azathioprine in treatment of JSLE were more in eutohyroid JSLE patients and ATA negative JSLE patients than in subclinical hypothyroid JSLE patients and ATA positive JSLE patients and that was highly significant.
Renal, neuropsychiatric and hematological manifestations were significantly detected in eutohyroid JSLE patients and ATA negative JSLE patients in comparison to subclinical hypothyroid JSLE patients and ATA positive JSLE patients (P<0.01). Consistent with these findings Saleh et al (2008) study, which assessing thyroid abnormalities in adult SLE and demonstrated that the presence of thyroid dysfunction was associated with less major organ involvement, more over reinforcing this finding Tapanes et al (2000) found that JSLE patients with thyroid antibodies had a higher frequency of anti-U1RNP. This pattern of autoantibody specificity seems to be associated with a more benign form of lupus nephritis. To and Petri (2005) had also demonstrated that the presence of anti-RNP/Sm antibodies in ATA positive JSLE patients was negatively associated with renal and hematological involvements in SLE .
We suggested that there is a significant association between subclinical hypothyroidism and ATA positive JSLE patients. The underlying pathogenic mechanism for this association however isn’t clear. El-Sherif et al (2004) demonstrated that Immune complexes have been detected in kidney, skin and muscles of patients with SLE.
Since SLE is a systemic disorder that can affect any target organ it is interesting to speculate that the thyroid disorders are the result of the antithyroid activity of one of the antibodies produced in SLE. The thyroid disorder may be a result of immune injury following deposition of immune complexes. This could be verified if thyroid biopsies is performed (To and Petri, 2005).
We did not find significant relation between thyroid antibodies or subclinical hypothyroidism and disease activity which is consistent with the finding of the study done by (Ronchezel et al. 2001).
CONCLUSION
Subclinical hypothyroidism could be detected in thyroid auto antibodies positive JSLE patients. Detection of subclinical hypothyroidism or thyroid auto antibodies did not show significant relation to disease activity but was associated with less renal, neuropsychiatric and hematological complications.
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