Childhood Systemic Lupus Erythematosus : A Tertiary Care Centre Experience

Introduction: Systemic lupus erythematosus (SLE) is a chronic immunologic disorder with multisystem manifestations. Even more awareness is required to diagnose the disease at younger age. Objective of this study was to explore clinico-laboratory manifestations and management of SLE in children at Tribhuvan University Teaching Hospital (TUTH). Materials and Methods: The study was retrospective hospital based study conducted from 15th July, 2008 to 14th July, 2014. Medical charts of all children and adolescent (6- 16years of age) with SLE admitted at TUTH were reviewed for analysis of data. Results: The total number of patients was 33, with 28(84.8%) girls and 5 (15.2%) boys. The mean age of diagnosis was 12.12 (SD 1.89). Facial puffiness (27.3%) and arthralgia (24.2%) were the commonest presentations at disease onset. The most frequent clinical features during the entire course of illness were edema (78.9%), anemia (69.7%) and fever (66.7%). Twenty three (69.6%) patients underwent renal biopsy in which class IV was the commonest lupus nephritis. The commonly used drugs after prednisolone were intravenous cyclophosphamide, intravenouse methylprednisolone and mycophenolate mofetil. Total 17 (51.5%) patients went into remission. Two patients died due to active lupus and four due to sepsis. Conclusion: Lupus nephritis was the commonest feature at disease onset, at the time of diagnosis and throughout the disease course among Nepalese children with SLE. The most frequently used medications were prednisolone and iv cyclophosphamide. Infection and active lupus were the leading causes of complications and death. J Nepal Paediatr Soc 2015;35(2):111-116


Introduction
S ystemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by mul system infl amma on 1 .Flares of the illness can involve any organ system.Diagnosis of SLE o en is not made un l years a er onset of symptoms and so alternate ini al diagnoses are frequent.Making a mely diagnosis of SLE and ensuring appropriate early treatment may prevent devasta ng long-term outcomes.The clinical presenta on between adult and childhood SLE is similar in many ways.However, features such as mucocutaneous, renal, hematological and neuropsychiatric involvement may be more common in childhood SLE 2 .This ar cle reviews common clinical features and complica ons of SLE in Nepalese children.The study also briefl y addresses available treatment op ons and outcomes.

Materials and Methods
This study was done in Tribhuvan University Teaching Hospital (TUTH) which is a ter ary care hospital in Nepal.The study was carried out a er ge ng proposal approved by Ins tu onal Review Board of TUTH.Medical records of childhood SLE cases from 15 th July, 2008 to 14 th July, 2014 were obtained.All pa ents with childhood SLE fulfi lled American College of Rheumatology 1982 revised criteria for the classifi ca on of systemic lupus erythematosus 3 .Detail clinical informa ons regarding mucocutaneous, cardiac, pulmonary, musculoskeletal, haematological, renal and neuropsychiatric manifesta ons etc were recorded in a proforma along with other relevant demographic profi le.Laboratory data such complete blood count (CBC), urine rou ne, culture and 24 hour urine protein excre on, an bodies such as an nuclear an body(ANA), double stranded deoxyribosenucleic acid (ds DNA), renal func on tests, chest X-rays, ultrasound abdomen etc done in each pa ent were recorded.Renal biopsy reports of those who underwent such procedure were also obtained.Treatments given a er the diagnosis of the disease were recorded.Disease remission/ progression on the basis of physical examina ons and CBC, proteinuria, crea nine, ds DNA tre etc were also recorded as they came for follow up and medica ons.The inves ga ons were performed monthly if pa ent has ac ve lupus, otherwise done 3 to 6 monthly depending on disease ac vity.The dura on of follow up was considered from the me of diagnosis un l the pa ent's last hospital visit.The outcome was classifi ed as 4

Results
The total number of childhood SLE was 33.Among them, female to male ra o was 5.6:1 (28 girls, 5 boys).The mean age of appearance of fi rst symptom was 11.9 years (SD 1.97).The mean age of diagnosis was 12.12 years (SD 1.89).There was an average diff erence of 3-4 months from the appearance of fi rst symptom to the diagnosis of SLE.The presen ng clinical symptoms of children with SLE at disease onset are listed in Table  Urine rou ne microscopy for protein showed that more than half of the pa ents (57.6%) had ≥ 3 + albumin.24 hour urinary protein measurement showed nephro c range pro enuria in 18 (54.5%) of the pa ents where as nonnephro c range pro enuira was observed in 12 (36.4%) of the pa ents.Three pa ents had no proteinuria.Gross haematuria was seen in 13 pa ents (39.4%).Almost half of the pa ents (45.5%) had microscopic hematuria.Granular casts was seen in three pa ents.10 pa ents (30.3%) developed azotemia during disease process.Haemodialysis was performed in 6 pa ents of which one pa ent's dialysis modality was later converted to con nuous ambulatory peritoneal dialysis (CAPD).Urine pus cells ≥ 5 hpf was seen in 11 pa ents (33.3%) out of which fi ve developed urosepsis showing Escherichia coli as culture posi ve.
Out of 23 (69.6%) pa ents, eight pa ents underwent renal biopsy at the fi rst admission in TUTH.Remaining pa ents underwent biopsy in subsequent admissions.The various stages of lupus nephri s (LN) based on the World Health Organiza on (WHO) classifi ca on criteria for LN are as shown in the Table 5.More than half of the pa ents were in class IV.Nephro c range proteinuria and hypertension was observed in all pa ents of class IV and V of LN.

Treatment modalities
Various drugs used in the management and diff erent treatment regimens with outcomes are discussed and summarized below in Table 6 and Table 7.All pa ents received oral prednisolone at some stage of their disease.Four pa ents received non steroidal infl ammmary drugs (NSAIDS) and one pa ent received methotrexate for joint pain.These pa ents later needed other immunosuppressive drugs for ac ve disease.IV methyl prednisolone was given to 13 pa ents during their illness for severe disease ac vity (azotemia).The number of pulse methyl prednisolone doses ranged up to 6 cycles with most pa ents receiving 3 cycles.Pulse iv cyclophosphamide used ranged to 12 cycles (six monthly cycle and six 3 monthly cycle).Twenty four pa ents (72.7%) had iv cyclophosphamide of which 5 pa ents went on remission with monthly iv cyclophosphamide.MMF was used who did not respond even with 3 cycles of iv cyclophosphamide.Five out of 9 pa ents (who did not respond to iv cyclophosphamide) on MMF went into remission.One pa ent received tacrolimus as disease fl ared up a er 3 months of MMF, and s ll has ac ve lupus nephri s.Azathioprine was given in two pa ents as maintainence therapy even when they respond to monthly 6 cycles of iv cyclophosphamide as their preference to oral medica on and they went into remission.An malarial drug was used in 24 pa ents.
Ninteen pa ents (57.6%) developed hypertension and received various medica ons to lower their BP.The most common an hypertensive drug used was enalapril followed by nifedepine and then furosemide.

Clinical Outcomes: Follow Up
The follow up period ranged from few days to a maximum of fi ve years.Three pa ents requested referral to other center.Three pa ents who are greater than 15 years old now are visi ng Adult Nephrology OPD in TUTH.Among them, one is on con nuous ambulatory peritoneal dialysis and two are on remission.Two pa ents were lost to follow up.Remaining pa ents are s ll on regular follow up to Pediatric OPD.Total 17 pa ents (51.5%) were on remission.Longest hospital stay was 37 days and minimum 36 hours.
Total six pa ents (18.1%) died during the six year study period.Six pa ents needed PICU care of which four pa ents requiring mechanical ven la on expired.Parents of two cri cally ill pa ents requested for no resuscitate status (DNR) and were not admi ed in PICU, eventually later expired.Two pa ents died due to ac ve lupus (acute renal failure leading to pulmonary edema) and four due to sepsis.

Discussion
Childhood onset SLE is a rare disease but is reported to be compara vely severe than adults in Asians, Africans and Americans 5,6 .Thirty three cases were encountered over the last 6 years (2008-2014) period in TUTH.Thirty one (93.9%) of these cases was referral from outside the Kathmandu valley.The mean age at the me of onset of symptoms was 11.9 years while at diagnosis was 12.1 years.This mean age of diagnosis is similar to other studies conducted in various centres 7,8 .The rela ve high mean age of presenta on could be largely because of under repor ng or delayed referral to our center.The female to male ra o was 5.6:1 which is consistent with the study done in Oman 9 .This is in contrast with study conducted by Gulay et al in Philipines and Budhathoki et al in Dharan, Nepal showing female: male ra o of 10:1 10,11 .Only in 18% pa ents, correct diagnosis was made at the ini al presenta on in this study.The diagnosis was based on clinical and laboratory parameters fulfi lling revised criteria of 1997 American College of Rheumatology for the classifi ca on of SLE 3 .Since SLE has myriad systemic symptoms, diff eren al diagnosis could be various.Among various cons tu onal symptoms, we had fever and malar rash in 18 (54.5%) of children.These fi gures are in accordance with lupus literature and other studies done in Asian countries 1,9,12,13 .Hematological manifesta on was one of the common laboratory abnormality 23(69.7%)which was in the form of anemia, leucopenia and thrombocytopenia.This is similar to studies conducted in Kuwait, Oman and China 8,9,13 . .In this study, renal involvement in the form of edema 19 (57.8%) and hematuria 7(21.2%) was present at the me of diagnosis.The spectrum of renal involvement in diff erent ethnici es of Asian origin are as shown in the studies-China 76.6%, Oman 64% and Kuwait-29% 8,9,13 .These variabili es could be because of referral pa ern, ethnic diversity etc. Rheumatological presenta on was in the form of arthralgia/arthri s in 15 (45.4%) children which is similar to study conducted by Carian B Gulay et al in Philipino children 10 .Mucocutaneous involvement was seen in 18(54.5%) in the form of malar rash.Other presenta ons were alopecia, photosensi vity, mucosal ulcera on, Raynaud's phenomenon, vasculi c rash and rarely discoid rash.This is in accordance with study done by Agarwal et al in Indian children and Bastug et al in Turkish children 4,14 .Serosal involvement was in the form of pericardi s/eff usion 5(15.1%) and pleural eff usion 9(27.3%).In contrary to studies conducted in India and Canada, neuropsychiatric presenta ons are minimal in our study which evolved from 3%-15% during the clinical follow up 15,16 .The symptoms were headache, psychosis and seizures due to cerebral vasculi s as shown by MRI head of pa ents.
ANA and an ds DNA was found in 100% and 91% respec vely which is similar to lupus literature and other studies in Asian subcon nent and Western world 1,10,12,17 .Because of economic constraints, other immunological inves ga ons like C3,C4 were not rou nely sent but were found to be low amongst those sent.23(69.6%)pa ents underwent renal biopsy during their course to hospital admission.In the ini al years of these children's admission, renal biopsy was done in every pa ent irrespec ve of renal involvement which was later on indicated especially to pa ents showing features of nephri s and is now a specifi c indica on for renal biopsy 18 .In few pa ents, renal biopsy was not performed as they opted to go to other center for treatment, some planned for biopsy but were lost to follow up etc.Among those whose renal biopsy was done, majority 13(56.5%)were in WHO class IV, followed by 4 (17.4%) in class II.The occurrence of histological pa ern of renal disease in Asian countries shows 39-69% in class IV followed by other classes as ours 9,19 .
While trea ng these pa ents we adopted standard protocol (KDIGO) for WHO class III, IV and V with iv cyclophosphamide 500-750 mg/m 2 body surface area monthly for six pulses and then three monthly for 18 months and six monthly for 36 months 20 .MMF was kept a er ini al three cycles of cyclophosphamide who did not show features of remission or to those who showed at least par al remission (50% reduc on in proteinuria and or 50% reduc on in crea nine value) and aff ordable to bear the cost of MMF.MMF as a promising op on in trea ng lupus nephri s who are refractory to cyclophosphamide is also shown in a study done in Florida 21 .In this study also, fi ve pa ents who did not respond even with three cycles of iv cyclophosphamide went to remission only a er receiving MMF.Cor costeroid (prednisolone) was started at 60mg/m 2 /day to start and tapered to 10 mg daily during remission.Our strategy was to keep steroid by at least 0.3mg/kg even when the pa ent was in complete remission.Intravenous methylprednisolone was used in 3-5 day pulse in cases of rapidly progressive glomerlonephri s and in pa ents with suspected lupus fl are.Hydroxychloroquine was used in 24 (72%) pa ents irrespec ve of renal involvement.Azathioprine was used in few pa ents who were unaff ordable to MMF and as a maintenance therapy in those pa ents who wish to have oral drug rather than iv cyclophosphamide.Methotrexate was given to a pa ent who had persistent joint pain.Suppor ve drugs like enalapril and other an hypertensives were used when necessary.
Infec on and ac ve lupus were the leading causes of complica on and death in childhood SLE and our observa ons were also similar in this study 14,19 .

Conclusion
Childhood SLE is o en diffi cult to diagnose.Pa ents may have varied features sugges ve of SLE as well as other disease.One should suspect SLE even if classical criteria are not fulfi lled and follow such pa ents closely.The most common clinical manifesta on at disease onset, at the me of diagnosis and during the en re course of illness in this study was lupus nephri s.It was followed by joint pain,fever and malar rash as common features in presenta on.Prednisolone and iv cyclophosphamide were the most frequently used medica on.Mycophenolate mofe l seems to be eff ec ve to those who are refractory to iv cyclophosphamide.Infec on and ac ve lupus were the leading causes of complica on and death.More studies with large number of pa ents will further clarify the scenario of childhood SLE improving its management in Nepal.
: a) Remission (normal urinalysis, blood pressure, serum crea nine, no extra renal symptoms) b) Ac ve disease (proteinuria > 0.5g/day, microscopic hematuria >5 red cells per high power fi eld, hypertension, extra renal manifesta ons) c) Death d) Lost to follow-up.SPSS program 17.0 was used for sta s cal analysis.

Table 2 :
Ini al diagnosis made in children with SLE

pa ents were from outside the valley. Need of criteria, mainly laboratory fi ndings to be fulfi lled to diagnose a case of SLE and thus the easy availability of such facility in
Kathmandu Valley may have a ributed to most referrals and late diagnosis ll the pa ents reached TUTH.Late diagnosis led to severe presenta ons of disease.The clinical characteris cs of children with SLE are listed in Table 3 and hematological with immunological fi ndings at the me of diagnosis are shown in Table 4.

Table 3 :
Clinical features at the me of diagnosis and during the disease course

Table 4 :
Hematological and Immunological fi ndings at the me of diagnosis

Table 5 :
WHO Histopathologic fi ndings on renal biopsy

Table 6 :
Various drugs used in treatment

Table 7 :
Treatment regimens and outcomes