Juvenile-Onset versus Adult-Onset Systemic Lupus Erythematosus: Different Clinical and Serological Patterns

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1 Original Article Juvenile-Onset versus Adult-Onset Systemic Lupus Erythematosus: Different Clinical and Serological Patterns Dalia Fayez Mohamed 1, Amina Badr El- Din Abdel Aziza 1, Sameh Abdel-Moteleb Hassan 1, Noha Hussein Shedid 1, Rasha Hassan El-Owaidy 2, Mohammed Abd El Moniem Teama 1 Departments of Internal Medicine, Rheumatology Division 1, Pediatrics, Rheumatology and Immunology Division 2, Ain Shams University; Egypt ABSTRACT Objectives: The aim of this study was to evaluate the differences in organ involvement, serological pattern, disease activity and damage index between juvenile-onset and adult-onset systemic lupus erythematosus (SLE) patients. Patients and Methods: 180 SLE patients (80 Adult and 80 Juvenile onsets) diagnosed according to Systemic Lupus International Collaborating Clinics (SLICC) classification criteria for SLE were included. All the patients were subjected to full history taking, clinical examination and laboratory investigations. Disease activity was assessed using Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and damage by Systemic Lupus International Collaborative Clinics/American College of Rheumatology (SLICC/ACR) damage index. Results: The most common clinical presentation among adult SLE was malar rash (75%) followed by articular manifestations (62.5%), while in juvenile articular manifestations (71.2%) followed by nephritis (67.2%) were the most common. Juvenile patients had significantly more frequent neuropsychiatric manifestations, nephritis and different hematological abnormalities. Juvenile patients had significantly more frequent class II lupus nephritis (53.2% vs 20.6%), while adult patients had significantly more frequent class III and IV (37.9% vs 8.5%). Positivity and titres of both anticardiolipin antibodies and lupus anticoagulant were significantly higher in juvenile SLE than adult. Damage was non significantly more frequent (86.3% vs 78.8%) and index significantly more higher in juveniles than adults. The cumulative dose of steroid was significantly higher in adult. Cyclophosphamide, hydroxychloroquine and azathioprine were significantly more received by adult SLE patients in comparison to juvenile patients while mycophenolate mofetil was significantly more received by juvenile SLE patients. Conclusion: Both the clinical and serological manifestations of juvenile and adult onset SLE are different. Juvenile patients present more frequently with major organs affection like the kidney, brain and blood with more and severe chronic organ damage. According to these more aggressive presentations, early and careful assessment with strict management plan and follow-up are needed in this juvenile group. [Egypt J Rheumatology & Clinical Immunology, 2016; 4(1): 15-22] Key Words: SLE, Adult, juvenile, Damage. INTRODUCTION Systemic lupus erythematosus (SLE) is a worldwide multisystem autoimmune disease of unknown etiology 1. It usually affects adults as well as adolescences and affects ten times as many women as men. It is characterized by production of autoantibodies, which result in widespread immunological abnormalities and immune complex formation. Symptoms range from rather mild manifestations such as rash or arthritis to life threatening conditions 2. Juvenile systemic lupus erythematosus is diagnosed as disease onset before 16 years of age. Patients younger than 5 years are rarely affected and the age of onset may contribute to the course of disease in terms of clinical presentation, organ involvement, and serological findings 3. Juvenile-onset systemic lupus erythematosus represents 15-20% of all SLE cases. While features of this complex chronic multisystem autoimmune disorder are highly variable, children and adolescents generally present with a more severe illness than adults and accrue greater disease damage over time 4. A better recognition of the age specific manifestations and long term complications of the disease is needed to improve its outcome 5. This study was performed to evaluate the differences in organ involvement, serological pattern, disease activity and damage indices between juvenileonset and adult-onset SLE patients. PATIENTS AND METHODS This was a case control study which included 160 SLE patients diagnosed according to Systemic Lupus International Collaborating Clinics (SLICC) classification criteria for SLE 6. They were 80 patients with adult onset and 80 patients with juvenile onset enrolled Egypt J Rheumatology and Clinical Immunology Jan 2016 Vol. 4 Issue 1 15

2 from adult Rheumatology and pediatric Immunology and Rheumatology Units of Ain Shams University Hospitals during the period from April 2014 to May Adult and juvenile onsets were defined as age of onset above and below 16 years, respectively. Adult SLE patients with disease onset before the age of 16 years and patients who were not regularly following up in the Rheumatology Units were excluded from the study. The nature of the present study was explained to all participants. Informed consent was obtained from each adult patients and care giver of each paediatric patient after explanation of the study to them. Study protocol gained approval of local ethical committee of Ain Shams University. All patients were subjected to full history taking and clinical examination. Rheumatological evaluation was completed using the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) 7. Assessment of chronic organ damage was performed uniformly with the Systemic Lupus International Collaborative Clinics/American College of Rheumatology (SLICC/ACR) Damage Index 8. Gonadal damage was removed from the assessment because of difficult detection in the peri-pubertal period. Routine laboratory investigations such as complete blood count, ESR, kidney and function tests, complete urine analysis, 24 hours urinary proteins and corrected creatinine clearance were done. Antinuclear antibodies (ANA), antidouble stranded DNA (Anti-ds- DNA) antibodies using immunofluorescence technique, anticardiolipin IgG (ACL IgG) and IgM (ACL IgM) antibodies, lupus anticoagulant (LAC) and serum complement C3 and C4 levels were detected. Renal biopsies were done only in 76 patients (out of 105 with renal involvement). Histological assessment of lupus nephritis was performed according to the classification revised by the International Society of Nephrology and the Renal Pathology Society in Statistical Analysis Data were analyzed using Statistical Program for Social Science (SPSS) version Quantitative data were expressed as mean±standard deviation (SD). Qualitative data were expressed as frequency and percentage. Independent-samples t-test of significance was used when comparing between two means. Mann Whitney U test: for two-group comparisons in nonparametric data. Chi-square (X 2 ) test of significance was used in order to compare proportions between two qualitative parameters. Multiple regressions analysis was used to test and estimate the dependence of a quantitative variable based on its relationship to one or more independent variables. <0.05 was considered significant. RESULTS The demographic data of the patients are shown in Table (1). The disease duration was significantly longer in adult in comparison to juvenile SLE patients (p 0.05). The relative incidences of different clinical manifestations in adult and juvenile patients with SLE are summarized in Table (2). The most common clinical presentation among adult SLE was malar rash (75%) followed by articular manifestations (62.5%), photosensitivity (52.5%), nephritis (51.3%), and the least manifestation was myocarditis (1.3%), while in juvenile SLE patients we found that the most common clinical presentation was articular manifestations (71.2%) followed by nephritis (67.2%), malar rash (55.7%), photosensitivity (46.2%) and the least manifestation was pleural effusion (2.5%). Comparison between both groups showed that juvenile patients had significantly more frequent neuropsychiatric manifestations (mostly seizures and psychosis) (p=0.015), nephritis (p= 0.001) and different hematological abnormalities (leucopenia, anemia, lymphopenia, neutropenia and thrombocytopenia) while adult patients had significantly more frequent malar rash (p= 0.01) and recurrent thrombosis (p=0.009). Renal biopsies were done only in 76 patients (out of 105 with renal involvement). The relative incidence of different classes of lupus nephritis among adult and juvenile patients with SLE is shown in Table (3). The most common class of lupus nephritis in adult patients is class IV, but the most common class of lupus nephritis in juvenile patients is class II. Comparison between both groups showed that adult patients had significantly more frequent class III and IV lupus nephritis while juvenile patients had significantly more frequent class II lupus nephritis. The results of urine analysis, laboratory investigations and autoantibodies of SLE patients are summarized in Table (4). Hematuria, proteinuria, urinary cast and pyuria were more frequent and 24 hour proteinuria was higher in juvenile than adult SLE patients. C3 and C4 consumptions and positive antids- DNA antibodies were significantly more frequent in juvenile than adult patients. Positivity and titres of both anticardiolipin antibodies and lupus anticoagulant were significantly higher in juvenile SLE than adult (28% vs 14%- 24% vs 11%). There was no significant difference between both groups regarding disease activity. Damage was non significantly more frequent in juvenile than adult (86.3% vs 78.8%) but significantly more severe in juvenile than adult as measured by damage index {median 2 (range, 0-7) in juvenile versus 1 (0-4) in adult}, p< (Table 5, Figure 1). Regarding individual organ damage, neuropsychiatric, 16 Egypt J Rheumatology and Clinical Immunology Jan 2016 Vol. 4 Issue 1

3 cardiovascular and renal damage were more frequent in juvenile SLE than adult with statistical significant difference (22.5% vs 7.5%, 10% vs 3.7% and 16.2 vs 6.2%, respectively) while musculoskeletal damage and diabetes were significantly more frequent in adults (8.7% vs 2.5%, 18.7% vs 7.5%, respectively) (Table 6). Multiple regression analysis was done to detect risk factors of damage in both groups showed that disease duration (p=0.035), lymphopenia (p=0.029), thrombosis (p=0.023) and neuropsychiatric manifestation (p=0.002) were risk factors for damage in adult SLE patients, while only thrombosis (p=0.041) and neuropsychiatric manifestation (p=0.038) were risk factors for damage in juvenile SLE patients. Immunosuppressive treatments of both groups are shown in Table (7). The cumulative dose of steroid was significantly higher in adults. Cyclophosphamide, hydroxychloroquine and azathioprine were significantly more received by adult SLE patients in comparison to juvenile patients while mycophenolate mofetil was significantly more received by juvenile SLE patients. Cyclosporine, IVIG and rituximab were non significantly more received by juveniles. Table 1. Demographic data of adult and juvenile patients. Age, years Sex Disease duration, years Demographic Data Adult SLE () Juvenile SLE () 29.91± ±2.13, years Male 7 (8.75%) 2 (2.5%) Female 73 (91.25%) 78 (97.5%) Female to male ratio 10:1 39:1, years 2.96± ± Table 2. Cumulative clinical manifestations of adult and juvenile patients with SLE. Clinical Data Adult SLE Juvenile SLE Malar rash 60 (75%) 44 (55.70%) Oral ulcer 32 (40%) 27 (33.75%) Polyarthralagia /arthritis 50 (62.5%) 57 (71.25%) Photosenstivity 42 (52.5%) 37 (46.25%) Alopecia 27(33.75%) 22 (27.5%) Fever 10 (12.5%) 8 (10%) Serositis 6 (7.59%) 10 (12.5%) Pleural effusion 4 (5%) 2 (2.5%) Pericardial effusion 4 (5%) 8 (10%) Neuropsychiatric 6 (7.5%) 18 (22.5%) Thromboembolic event 12 (15%) 17 (21.25%) Recurrent thrombosis 9 (11.25%) 1 (1.25%) Vasculitis 8 (10%) 14 (17.5%) Nephritis 42 (52.5%) 63 (78.8%) <0.001 Myocarditis 1 (1.3%) 3 (3.8%) Raynaud s phenomena 5 (6.3%) 6 (7.5%) Leucopenia 15 (18.75%) 26 (32.5%) Neutropenia 25 (31.25%) 59 (73.75%) <0.001 Lymphopenia 6 (7.5%) 29 (36.25%) <0.001 Anemia 48 (60%) 67 (83.75%) <0.001 Thrombocytopenia 6 (7.5%) 30 (37.5%) <0.001 Egypt J Rheumatology and Clinical Immunology Jan 2016 Vol. 4 Issue 1 17

4 Table 3. Lupus nephritis among patients with adult and juvenile lupus. Adult SLE Juvenile SLE No. % No. % Lupus nephritis % <0.001 Biopsy Class II Class III Class III, IV Class IV Class V Table 4. Laboratory parameters among patients with adult and juvenile lupus. Adult SLE Juvenile SLE Parameter Active urinary sediment 26 (32.5%) 41 (51.25%) Pus Cell (Pyuria) 22 (27.5%) 28 (35%) Red Cell (hematuria) 12 (15.4%) 24 (31.2%) Urinary cast 4 (5%) 13 (16.3%) Proteinuria 42 (51.3%) 63 (78.8%) <0.001 Creatinine clearance (mg/dl) ± ±16.83 < h urinary protein (mg)/m ± ± C3 (Consumed) 40 (50%) 49 (61.25%) C3 (mg/dl) 76.66± ± C4 (Consumed) 18 (22.5%) 31 (38.75%) C4 (mg/dl) 20.04± ± ANA (positive) 80 (100%) 80 (100%) AntiDNA (positive) 56 (70%) 67 (83.75%) Anti DNA titre 18.80± ACL antibodies (positive) 14 (17.5%) 28 (35%) ACL IgG (GPL/ml) ACL IgM (MPL/ml) 17.34± ± ± ± LAC (positive) 11 (13.75%) 24 (30%) LAC (sec) 32.65± ± Egypt J Rheumatology and Clinical Immunology Jan 2016 Vol. 4 Issue 1

5 Table 5. Disease activity and damage index of the adult and Juvenile-onset SLE patients. Adult SLE () Juvenile SLE () Parameter Median Median (Percentile 25 th -75 th ) (Percentile 25 th -75 th ) SLEDAI 8 (4-12) (6-12) 2-22 > 0.05 SLICC 1 (1-2) (1-4) 0-7 < Damage index Adult Groups Juvenile Figure 1. Damage index in adult in comparison to juvenile SLE patients. Table 6. Individual organ damage among adult and Juvenile-onset SLE patients. Organ damage Adult SLE Juvenile SLE No. % No. % Ocular damage Neuropsychiatric damage Pulmonary damage Renal damage Cardiovascular damage Peripheral vascular damage Gastrointestinal damage Musculoskeletal damage Skin damage Diabetes Malignancy Egypt J Rheumatology and Clinical Immunology Jan 2016 Vol. 4 Issue 1 19

6 Table 7. Immunosuppressive treatment among adult and Juvenile-onset SLE patients. Treatment Adult SLE () Juvenile SLE () No/ %, No/ %, Prednisolone Cumulative dose of steroid (gram) 23.68± ± <0.001 Hydroxychloroquine <0.001 Azathioprine <0.001 Cyclophosphamide Mycophenolate mofetil <0.001 Cyclosporine Intravenous immunoglobulin Rituximab DISCUSSION Approximately 15 20% of SLE patients have disease onset before adulthood 10. Clinical presentations, serological characteristics and the applied immunosuppressive treatment may differ from the adult onset form. Juvenile-onset SLE patients have a tendency to more aggressive presentation and course with higher frequencies of organ involvement and lower life expectancy than adult-onset SLE patients 11. According to the literature, incidence and prevalence of the juvenile form of SLE are affected by geographic and ethnic factors 12. Based on the literature, juvenile and adult onset lupus may be different. The sex ratio is different for juvenile SLE compared to the adult form 13. Unlike the classical ratio of 9:1 females: males that present in adults, the ratio in children is 4:3. It appears to shift toward boys 14. This observation cannot be found among our patients. Moreover, the ratio was exaggerated toward females to reach 39: 1 which may indicate that the possibility of lupus is less frequently considered in boys so they are less often diagnosed. This finding was similar to Tarr et al., who showed that the ratio in the prepubertal age group of lupus patients was more skewed toward females (24: 1) 15. In this study, some clinical manifestations occur more commonly in children with SLE. Lupus nephritis was found significantly more commonly in juveniles. This was detected in almost all comparative studies (15-18). Regarding the different histological types, when comparing both groups, focal and diffuse proliferative nephritis were significantly more common among adults as compared to juveniles, while mesangial proliferative nephritis occurred more often in juveniles. While this finding was similar Tarr et al., other studies didn t find any differences when comparing histological results 15,16,19. In our patient population, neuropsychiatric manifestations occurred more frequently in children. This observation was documented previously by some authors 17,20. Earlier studies reported that neurological involvement was the third most common cause of death in pediatric SLE 21,22, so neurological symptoms should be closely monitored. Besides renal and neuropsychiatric involvement, different hematological abnormalities were also more common among children. This was observed by Tarr et al. and Ramírez Gómez et al. during their studies 15,23. On the other hand, our patients with adult onset lupus had higher prevalence of cutaneous symptoms. While some authors documented similar observation 24, others reported that oral ulcers are more common in children than among adults 15,22 and others found no differences regarding skin symptoms 25,26. Based on the literature, frequency of serological abnormalities shows no significant difference between juvenile and adult forms 27,28. In the current study, the antinuclear antibodies were detected with similar frequency in both groups while the anti-dna antibodies were more frequently detected among children and this agrees with an earlier study done by Levy et al. 12. Regarding other antibodies, we found that antibodies against cardiolipin (IgG and IgM) and lupus anticoagulants occur more commonly in children with higher titres. These results were in agreement with Papadimitrak and Isenberg 13 although another recent study reported opposite results 15. Our results showed that C3 and C4 consumptions were significantly more common in juvenile than adult patients. This was close to another study which reported that the percentage of patients with a decreased C3 and C4 value was increased in adolescents in comparison to adults Egypt J Rheumatology and Clinical Immunology Jan 2016 Vol. 4 Issue 1

7 Some authors reported higher prevalence of organ damage in patients with pediatric SLE 16,24,28 while others found greater damage in patients diagnosed at an older age 15,30. In this study, we confirmed higher frequency of damage (although not significant) in juvenile patients with lupus with higher index in comparison to adult patients. Renal, neuropsychiatric and cardiovascular damage were detected more frequently in juveniles than adults that may be attributed to the more prevalence of renal and neuropsychiatric manifestations in children or to the lesser use of hydroxychloroquine among them which has a protective effect on renal and neuropsychiatric damage as previously documented 31,32. In both age groups, neuropsychiatric manifestations were predictor for damage. The differences between juvenile and adult onset lupus could be explained by the significant differences in the number of carried SLE risk alleles between them studied by genotyping of the SLE susceptibility gene loci. The relatively higher infection rate in childhood could be an environmental factor, while hormonal changes during pregnancy and lactation and the thymic regression with age might serve as intrinsic triggers. The immune dysregulation occurring in SLE may affect the developing organs in children, like the kidney, brain and even on the immune system 15,33. Conclusion Both the clinical and serological manifestations of juvenile and adult onset SLE are different. Juvenile patients present more frequently with major organs affection like the kidney, brain and blood with more and severe chronic organ damage. According to these more aggressive presentations, early and careful assessment with strict management plan and follow-up are needed in this juvenile group. REFERENCES 1. Essam AA., Zahraa I., Moustafa E et al. Markers of acute neuropsychatric systemic lupus erythematosus: amultidisciplinary evulation. Rheumatol Int. 2013; 33: Postal M., Costallat L. and Appenzeller S. Biological therapy in systemic lupus erythematosus. Int J Rheumatol. 2012: Hedrich CM, Zappel H, Straub S et al. Early onset systemic lupus erythematosus: differential diagnoses, clinical presentation, and treatment options. Clin Rheumatol. 2011; 30(2): Morgan TA, Watson L, McCann LJ et al.: Children and adolescents with SLE: not just little adults. Lupus. 2013; 22(12): Stichweh D, Arce E, Pascual V. Update on pediatric systemic lupus erythematosus. Curr Opin Rheumatol 2004; 16: Petri M, Orabi AM, Alarcon GS. et al. Derivation and validation of systemic lupus International Collaborating Clinics classification criteria for systemic lupus erythemateous Arthritis Rheum. 2012; 64 (8): Bombardier C, Galdman DD, Urowitz MB. Derivation of the SLEDIA disease activity index for lupus patients. The committee on prognosis studies in SLE. Arthritis Rheum. 1992; 35: Gladman D, Ginzler E, Goldsmith C. et al. The development and intial validation of the systemic Lupus International Collaborating Clinics/ American College of Rheumatology damage index for systemic lupus erythematosus. Arthritis Rheum.1996; 39: Weening JJ, D'Agati VD, Schwartz MM, et al.the classification of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol Feb. 15(2): Kamphuis S, Silverman ED. Prevalence and burden of pediatric onset systemic lupus erythematosus. Nat Rev Rheumatol 2010; 6: Hersh AO, Trupin L, Yazdany J, et al. Childhoodonset disease as a predictor of mortality in an adult cohort of patients with systemic lupus erythematosus. Arthritis Care Res (Hoboken).2010; 62: Levy DM, Peschken CA, Tucker LB, et al. Influence of ethnicity on childhood-onset systemic lupus erythematosus: Results from a multiethnic multicenter Canadian cohort. Arthritis Care Res (Hoboken) 2013; 65: Papadimitraki ED, Isenberg DA. Childhood and adult onset lupus: An update of similarities and differences. Expert Rev Clin Immunol 2009; 5: Mina R, Brunner HI. Update on differences between childhoodonset and adult-onset systemic lupus erythematosus. Arthritis Res Ther 2013; 15: Tarr T, Derfalvi B, Gyori1N, Szanto A et al. Similarities and differences between pediatric and adult patients with systemic lupus erythematosus. Lupus. 2015; 24: Brunner HI, Gladman DD, Iban ez D, Urowitz MD, Silverman ED. Difference in disease features between childhood-onset and adult-onset systemic lupus erythematosus. Arthritis Rheum 2008; 58: Hersh AO, von Scheven E, Yazdany J, et al. Differences in long term disease activity and treatment of adult patients with childhood- and adult-onset systemic lupus erythematosus. Arthritis Rheum 2009; 15: Egypt J Rheumatology and Clinical Immunology Jan 2016 Vol. 4 Issue 1 21

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