Syntax Literate: Jurnal Ilmiah Indonesia pï¿½ISSN: 2541-0849 e-ISSN: 2548-1398

Vol. 7, No. 9, September 2022

DRUG UTILIZATION STUDY OF CORTICOSTEROID SPARING AGENT IN PEDIATRIC PATIENT WITH LUPUS NEPHRITIS (STUDY AT PEDIATRIC DEPARTMENT OF DR. SOETOMO TEACHING HOSPITAL, SURABAYA)

Chatarina Widianti, Yulistiani, Ninik Asmaningsih Soemyarso

Universitas Airlangga, Surabaya, Indonesia

Dr. Soetomo General Academic Hospital, Surabaya, Indonesia

Email: [email protected], [email protected], [email protected]

Abstract

Lupus nephritis occurs mostly in children. The main therapy used is long-term corticosteroids that can lead to organ damage, which should be treated by providing corticosteroid sparing agent; to control the underlying disease and reduce the side effects of corticosteroid therapy and facilitate tapering off. This study analyzed the drug utilization profile and the tapering off pattern of corticosteroid and corticosteroid sparing agents and identified potential adverse effects of corticosteroid sparing agents in pediatric patients with LN. The study used observational method that was analyzed descriptively on 37 patients with hospitalization period of January 2016 until December 2017. The profile of corticosteroid sparing agent in patients with LN was a combination of oral MMF and oral chloroquine. Oral cyclosporine A was added if persistent proteinuria> 1 g / day / 1.73 m2 after three months of therapy and combination of IV CPA pulse and oral chloroquine. The tapering off pattern of oral prednisone in the presence of corticosteroid sparing agent was in accordance with the Clinical Practice Guide, which was decrease of 5 mg/day every month. Actual adverse effects included leucopenia (34%), hepatotoxicity (13%), GIT disorders (45%), and several potential adverse effects. The utilization of corticosteroid sparing agent in pediatric patients with LN in Dr. Soetomo Hospital was in accordance with Clinical Practice Guide (PPK) issued by Dr. Soetomo General Hospital. Both regular monitoring of patients as well as enhanced interprofessional collaboration are required to monitor adverse effects of corticosteroid sparing agents.

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Introduction

Lupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus (SLE) characterized by the buildup of immune complexes in the glomerulus. LN is initiated by the activation of T cells and B cells that are autoreactive, resulting in potential pathogenic effects (Lech & Anders, 2013) and (Furie et al., 2014). LN therapy aims to control symptoms, reduce flares, protect the kidneys, prevent complications, and most importantly, reduce the rate of mortality (Mok, 2015). However, the primary method of LN therapy uses corticosteroids regularly in a long-term duration. This can cause resistance and side effects of hypothalamicï¿½pituitaryï¿½adrenal axis (HPA Axis) suppression that leads to organ damage (Lightstone et al., 2018). Therefore, it is necessary to give corticosteroid sparing agents after some time, namely drugs that reduces the dose (tapering off) of corticosteroids, which consequently reduces the side effects of corticosteroid therapy and control the primary disease (LN) [5, 6].

LN occurs in many children. In general, LN that begins before age 18 includes childhood-onset or pediatric lupus/juvenile SLE. According to research conducted by Tarr et al., out of 342 adult and 79 pediatric SLE patients, the prevalence of adult LN sufferers was 26.4%, while children was 39.2% (Tarr et al., 2015). Meanwhile, according to research conducted by Kamphuis and Silverman, the prevalence of SLE sufferers in children is 3.3-8.8/100,000 children, and 80% of them are female (Kamphuis & Silverman, 2010).

LN is a progressive autoimmune disease that must be treated appropriately. In autoimmune diseases, immune system sensitization occurs by endogenous proteins that are considered foreign proteins, thus stimulating the formation of antibodies or developing T cells that can react with endogenous antigens. The therapy that is generally given is immunosuppressants with the principle of suppressing the immune response. Giving corticosteroids as the primary therapy can prevent the progression of the disease quickly and effectively, but it also causes adverse side effects (Lightstone et al., 2018). Serious side effects can be inflicted on pediatric patients, such as growth retardation, failure in protein metabolism, hyperglycemia, hypertension in children, fluid retention, full moon face, gastrointestinal disorders, and osteoporosis [9].

The toxic effects of corticosteroids in long-term use or resistant patients should be reduced by providing an alternative drug (sparing agent) that also serves as immunosuppressants (Chu, Sartorelli, Katzung, Masters, & Trevor, 2007). Drugs often used as corticosteroid-sparing agents are azathioprine, mofetil mycophenolate, hydroxychloroquine, and cyclophosphamide (Indonesia, 2011).

Therapy on LN using corticosteroids requires tapering off to avoid organ damage and gives the body a chance to produce endogenous corticosteroids that are important in metabolism [11]. Tapering patterns can vary, depending on the doses that are used. Based on a research conducted by Ueda et al. [12], a decrease in doses in long-term corticosteroid use indicates lower and safer levels of relapsing in pediatric nephrotic syndrome patients. In comparison, the decrease in doses which are carried out irregularly indicates higher levels of relapse [12].

Usage of corticosteroids in a long-term therapy should be reduced gradually, starting with a decrease in the dose of corticosteroids before being discontinued [13]. Sudden discontinuation of corticosteroids will lead to impaired HPA Axis function and re-emergence of symptoms, such as anorexia, nausea, vomiting, orthostatic hypotension, and hypoglycemia [15]. This dose reduction process (tapering off) takes about 2-12 months (Chu et al., 2007). Tapering is done based on doctorsï¿½ personal views and practical experience [16]. As an example, for tapering off prednisone doses of more than 40 mg/day, a decrease of 5-10 mg every 1-2 weeks is performed until a dose of 20-40 mg/day is reached. After that, it is lowered again by 1.0-2.5 mg/day every 2-3 weeks when the dose of prednisone <20 mg/day. Low dosage is still maintained to control the disease (Indonesia, 2011).

Besides corticosteroids, other immunosuppressants also cause side effects. For example, cyclophosphamide (CPA) with large doses can cause the risk of myelosuppressive, lymphoproliferative disorders, malignancies, pancytopenia, hemorrhagic cystitis, and secondary infertility (Chu et al., 2007). Mycophenolate mofetil (MMF) can cause gastrointestinal disorders (diarrhea, nausea, or vomiting) and hematology (leukopenia, red cell aplasia) and increases the risk of cytomegalovirus (CMV) infection and progressive multifocal leukoencephalopathy (Krensky, Bennett, & Vincenti, 2011). Azathioprine (AZA) can cause bone marrow suppression, including leukopenia, thrombocytopenia, or anemia. It can also cause susceptibility to infection (particularly varicella and herpes simplex viruses), hepatotoxicity, alopecia, gastrointestinal (GI) toxicity, pancreatitis, and an increased risk of neoplasia (Krensky et al., 2011).

The numerous types of immunosuppressants given as corticosteroid-sparing agents have different working mechanisms, and consequently results in a variety of effects. Therefore, the profile and effects of corticosteroid-sparing agent for pediatric LN patients are important to be studied. This includes the type of drug given, dosage, frequency, and length of use. This study is expected to be used as additional information material for LN therapy and a reference for improved hospital drug management. In addition, health practitioners can use the results of this study as a therapeutic evaluation and supervision of drug use for patients with LN.

Research Methods

The study conducted is an observational study. The study was conducted retrospectively using data in the past. The purpose of this study was to review the profile of drug use in systemic lupus erythematosus patients with LN at the pediatric ward in Dr. Soetomo General Hospital. Analysis of research results was done descriptively. The population in this study was patients diagnosed with LN who were not accompanied by comorbid and were undergoing hospitalization in the Pediatric Unit at Dr. Soetomo General Hospital. The samples used in the study were pediatric patients diagnosed with LN and met the inclusion criteria and were limited by time during the period January 2016 to December 2017. The inclusion criteria in this study were pediatric patients with a final diagnosis of uncomplicated LN who received immunosuppressant therapy with complete data related to dose, route of administration, and frequency of administration in the Pediatric Unit at Dr. Soetomo General Hospital. A non-random sampling technique determines the sample. Sampling is performed through a retrospective method, while making sure that the desired research factors are contained in the sample data. The research sample will be obtained from patientsï¿½ medical records. The data consisted of patient demographics, including medical record number, patient initials, gender, weight, age, significant complaints, diagnosis results, accompanying diseases, and history of drug use. In addition, clinical data includes examining cytokine profiles, and drug therapy received, for example, the type, route, dose, frequency of use, and side effects that appear. From the data obtained, a descriptive analysis between the data and the results of the immune complex examination was presented. Data was presented in the form of descriptions, tables, and diagrams. Analysis of the actual and potential side effects of corticosteroid-sparing agents were presented in the form of descriptions and tables.

Result and Discussion

Patient Gender Profile

Based on the data obtained from 37 pediatric patients with LN, there were 23 female patients (62%) and 14 male patients (38%). Table 1 below shows the gender distribution diagram of a pediatric LN patients.

Table 1 Sex distribution table of pediatric LN patients that used corticosteroid sparing agents for therapy

Gender	Percentage of patients (%)
Male	38
Female	62

Patient Age Profile

According to the American Academy of Pediatrics 2012, the age in children can be classified into three categories, namely infants (0-2 years), children (2-12 years), and adolescents (12-18 years). Table 2 below showed the age profile of pediatric LN patients in the study. Most of the LN patients are classified into adolescents aged 12-18 years.

Table 2 Age distribution table of pediatric LN patients that used corticosteroid sparing agents in their therapy

Age (year)	Percentage of patients (%)
2 - < 12	32
12-18	68

Clinical Manifestations

Systemic lupus erythematosus (SLE) is an autoimmune disease with various clinical manifestations that can attack various organs, one of which is the kidneys (as in the case for LN). The initial criteria for a diagnosis of SLE were determined by the American College of Rheumatology (ACR) in 1971 but were updated in 1997. These criteria aim to classify the disease and distinguish SLE patients from healthy people. Clinical manifestations of SLE patients include skin lesions, arthritis, kidney abnormalities, neurological abnormalities, and hematological changes (Yu, Gershwin, & Chang, 2014). Data in Table 3 shows the clinical manifestation based on the ACR criteria to confirm the initial SLE diagnosis of the patients. Out of the 37 patients, these symptoms were found in 18 patients (49%), while 19 patients (51%) were not symptomatic.

Table 3 Clinical manifestation profile based on ACR criteria in pediatric LN patients *each patient can experience more than one clinical manifestation

Clinical manifestations*	Percentage of patients (%)
Not recorded	51
Discoid rash	11
Neurological disorder	33
Serosity	39
Immunological disorder	39
Photosensitivity	44
Arthritis	50
Malar rash	56
Mouth ulcer	61
Antinuclear Antibody	78
Hematological disorder	89
Kidney disorder	100

Patients suffering from LN may experience immune complex deposits in other tissues, which reflects the symptoms of SLE disease itself. Clinical manifestations can be observed from the patientï¿½s complaints at the time of hospital admission, in which the most cases are nausea, vomiting, and fever.

Corticosteroid Therapy Pattern using Sparing Agents

Immunosuppressant therapy is the primary therapy in LN with two phases, namely the induction and maintenance phases. Methylprednisolone (MP) Pulse is used every 2-4 weeks in the induction phase as many as six cycles combined with corticosteroid sparing agents, namely CPA Pulse or MMF and cyclosporin A. Based on the guideline, patients who use MMF as a corticosteroid sparing agent in the maintenance phase will be lowered slowly to reach the lowest dose to maintain remission conditions. On the other hand, patients who use CPA as a corticosteroid sparing agent will undergo therapy for 24 months. Of the 37 patients, the complete data of dose lowering and duration of sparing agents was not found in eight patients.

Steroid administration needs to be combined with sparing agents (MMF, calcineurin inhibitors (CNI), and cyclophosphamide) to minimize long-term steroid side effects. The recommended combinations are (1) steroids + MMF ï¿½ CNI; and (2) steroids + CPA. Oral MMF begins simultaneously as MP pulse at a dose of 600 mg/m²/dose every 12 hours (15-23 mg/kg/dose every 12 hours) with a maximum dose of 1 g per 12 hours. In addition, oral cyclosporine A may be added if there is a persistent proteinuria > 1 g/day/1.73 m² after three months of therapy with normal serum creatinine. The protocol of LN therapy using corticosteroid sparing agents based on Clinical Practice Guideline can be seen in Table 4.

Table 1 Corticosteroid sparing agent protocol for therapy in pediatric LN patients

Therapeutic Patterns	Corticosteroid sparing agent	Dosage and Frequency	Dosage and Frequency of Administration	Dosage Suitability	Length of Therapy	Information	Number of patients (percentage)
Therapeutic Patterns	Corticosteroid sparing agent	Book	Dosage and Frequency of Administration	Dosage Suitability	Length of Therapy	Information	Number of patients (percentage)
Steroids + MMF and/ or Cyclosporine A
Induction Phase (6 months)	MMF	600 mg/m²/dose every 12 hours (15-23 mg/kg/dose every 12 hours)¹	15-23 mg/kg/dose every 12 hours	Appropriate	Every day	It starts with MP pulse.	4 (11 %)
	Cyclosporin A	3-6 mg/kg/day (dose every 12 hours) to achieve cyclosporine A blood levels of 150-200 μg/L1	3-6 mg/kg/day (dose every 12 hours)	Appropriate	3-6 months and terminated when complete remission is stamped	Added if there is persistent proteinuria >1 g/day/1.73m²after three months of therapy with normal serum creatinine
	Chloroquine	3 mg/kg/day¹	3 mg/kg/day	Appropriate	Every day	Given for one month each cycle
Maintenance phase	MMF	600 mg/m²/dose every 12 hours (15-23 mg/kg/dose every 12 hours)¹		Appropriate	Every day	Lowered dose slowly to the lowest dose that can maintain remission conditions	1 (3 %)
	Cyclosporin A	Lowered dose slowly¹		Appropriate	Until remission is reached	Lowered dose slowly until remission, considered to be discontinued
	Chloroquine	3 mg/kg/day¹	3 mg/kg/day	Appropriate	Every day	Given for one month each cycle
Steroids + CPA
Induction Phase (6 months)	CPA Pulse	500-1000 mg/m² ²	500-1000 mg/m²	Appropriate	Given every 4 weeks as many as 6 cycles	To suppress the progressivity of the underlying disease	12 (32 %)
Induction Phase (6 months)	Chloroquine	3 mg/kg/day	3 mg/kg/day	Appropriate	Every day	Given for one month each cycle	12 (32 %)
Maintenance phase (24 months)	CPA Pulse	500-1000 mg/m² ²	500-1000 mg/m²	Appropriate	every 3 months for 24 months	To suppress the progressivity of the underlying disease	20 (54 %)
Maintenance phase (24 months)	Chloroquine	3 mg/kg/day	3 mg/kg/day	Appropriate	Every day	Given for one month each cycle	20 (54 %)

\MMF = Mycophenolate mofetil; CPA = Cyclophosphamide

¹Clinical Practice Guideline of Pediatric Unit at Dr. Soetomo General Hospital

² Bircan and Kara [20]

According to the National Institute of Health (NIH) in 2003, the use of a combination of oral prednisone with CPA pulse IV provides better kidney protection, reduces the incidence of relapsing, and prevents the onset of CKD and ESRD compared to prednisone monotherapy alone [21]. In addition, chloroquine is also given to prevent and reduce the spread of lupus disease to other organs, help reduce the incidence of flares, and help modulate the immune system by preventing plasmacytoid dendritic cell activation, so it is recommended for long-term therapy in lupus patients.

Oral Prednisone Usage Profile and Tapering Off Pattern

Oral prednisone is used after the patient gets MP pulse IV for maintenance so that there are no flares or recurrences. Oral prednisone is used daily and tapering off so that there is no steroid withdrawal effect without tapering off from one of the corticosteroids sparing agents. The profile of oral prednisone and its tapering off pattern can be seen in Table 5.

Table 2 Profile of oral prednisone use and tapering off patterns

Number Patient	BW (kg)	Dosage and Frequency	Grant Time	Sparing Agent
8	36,9	1 x 20 mg	0.5 months	Cyclophosphamide
8	36,9	1 x 15 mg	0.5 months	Cyclophosphamide
10	48	1 x 50 mg	0.5 months	Cyclophosphamide
		1 x 45 mg	0.5 months
		1 x 40 mg	1 month
		1 x 35 mg	0.5 months
		1 x 30 mg	0.5 months
11	58	1 x 20 mg	1 month	Cyclophosphamide
		1 x 15 mg	1 month
		1 x 10 mg	1 month
		1 x 5 mg	0.5 months
		1 x 5 mg (AD)	1.5 months
23	43	1 x 40 mg	0.5 months	Cyclophosphamide
23	43	1 x 35 mg	0.5 months	Cyclophosphamide
29	32,4	1 x 35 mg	1 month	Cyclophosphamide
29	32,4	1 x 30 mg	1 month	Cyclophosphamide
31	36,5	1 x 35 mg	1 month	Cyclophosphamide
31	36,5	1 x 30 mg	1 month	Cyclophosphamide
32	29	1 x 30 mg	0.5 months	Cyclophosphamide
32	29	1 x 25 mg	0.5 months	Cyclophosphamide
37	19,5	1 x 15 mg	1 month	Cyclophosphamide
		1 x 10 mg	1 month
		1 x 5 mg	1 month
		1 x 5 mg (AD)	1 month

BW = body weight; AD = alternating dose

¹ Oral prednisone begins at a dose of 0.5-1 mg/kg/day and then gradually lowered by 5mg/day within one month after administration of MP pulse and depends on disease activity.

²Dose of 1 prednisone tablet = 5 mg; AD Alternate dose (not taken every day but one day)

Potential and Actual Side Effects of Corticosteroid Sparing Agent

Side effects are a drug problem often experienced by pediatric LN patients who uses corticosteroid sparing agent therapy. In this study, the actual side effects of corticosteroid sparing agents were seen from clinical data or lab data after the drug was given. In contrast, potential side effects are seen based on libraries and can potentially occur in all patients who use corticosteroid sparing agents. However, not all the data were written in medical records. In addition, all side effects that occur can overlap with the activity of LN. The potential side effects of corticosteroid sparing agent can be seen in Table 6.

Table 6. Actual and potential side effects on the use of corticosteroid sparing agents during LN therapy

Types of corticosteroid sparing agents	Side Effects	Number of patients		Recommendations
		Potential Side Effect	Actual Side Effect
Cyclophosphamide	Leucopenia	-	14	- Routine WBC monitoring²
(n = 32)				- Reduce the cumulative dose of CPA²
	Hepatotoxicity	-	5	Monitoring ALT/AST²
	Risk of infection	32	-	- Maintaining personal and environmental hygiene²
				- Avoiding leukopenia²
	Gastrointestinal disorders (nausea, vomiting, diarrhea)	32	-	Provide anti-vomiting therapy
	Hemorrhagic cystitis	32	-	Increase the frequency of bowel movements, drink plenty of water, and
				Using diuretic therapy²
MMF	Gastrointestinal disorders (nausea, vomiting, diarrhea)	-	1	Divide the daily dose by 2 or 3 times²
(n = 5)	Leucopenia	-	1	- The daily dose does not exceed two grams²
				- Monitoring of white blood cells every week in the first month of administration
	Risk of infection	5	-	- Maintaining personal and environmental hygiene
				- Avoiding leukopenia²
Chloroquine	Gastrointestinal disorders (nausea, vomiting, diarrhea)	-	8	Administration of drugs with food, split into 2 doses¹
(n = 32)	Retinal toxicity (retinopathy)	32	-	Essential eye examination before or within one year of the start of treatment

Cyclosporin A	Nephrotoxicity	2	-	Monitoring serum creatinine levels every 4-6 weeks, if increased by 25%, lower the dose by 20%
(n = 2)	Neurological symptoms (tremors, headaches)	2	-
	Hirsutism and gum hypertrophy	2	-

WBC = white blood cells; ALT = alanine transaminase; AST = aspartate transaminase; MMF = mycophenolate mofetil

¹Marmor et al. [22]

² Moroni et al. [23]

Based on the patientï¿½s demographic data in Table 1, it is shown that female pediatric LN patients are higher than male (62% vs 38%). These results agree with previous literature results. According to Hermansen et al. [24], LN are more prevalent in females than males. According to Sinha and Raut [6], 80% of LN patients are women. One of the factors that affect is hormonal factors. In females, higher estrogen concentration aids the expression of autoimmune phenotypes, such that more autoreactive B cells can attack other lymphocytes. Thus, females are more susceptible to SLE [14].

In Table 2, it is shown that the age distribution of pediatric LN patients is mostly in the age range of 12-18 years (adolescent category) and there were no patients aged below 5 years. These results also agree with previous research, which stated that the average onset of SLE appearance is at the ages of 11 and 12 years, and rarely at the age of <5 years [25]. Furthermore, the number of patients in the adolescent age range is associated with the influence of the onset of steroid sex hormones that play a role in the pathogenesis of lupus [26].

Clinical manifestations in pediatric SLE patients vary. In general, nonspecific symptoms appear, such as feelings of unwellness and weakness, pain, episodic fever, anorexia, nausea, weight loss, and the butterfly-shaped redness of the face for several weeks or months [29]. For initial diagnosis in SLE patients, 11 criteria have been established by the American College of Rheumatology in 1997, in four criteria must at least be met. The eleven criteria are 1) malar rash, 2) discoid rash, 3) photosensitivity, 4) mouth ulceration, 5) arthritis, 6) serositis, 7) kidney abnormalities, 8) neurological disorders, 9) hematological abnormalities, 10) immunological abnormalities, and 11) positive antinuclear antibodies (Yu et al., 2014). In Table 3, the most common clinical manifestations are kidney and hematological disorders. Clinical manifestations could overlap with disease activity and the side effects of immunosuppressant therapy.

The therapy for LN is divided into two phases: induction phase, helps control the disease by inducing the cure/cessation of disease flares. At this stage, diseases that threaten organ damage and life should be treated seriously. The second phase is maintenance phase, in which the patient is kept from experiencing relapse and controlling the disease by avoiding inflammation and damage [6].

WBC = white blood cells; ALT = alanine transaminase; AST = aspartate transaminase; MMF = mycophenolate mofetil

¹Marmor et al. [22]

² Moroni et al. [23]

The induction phase lasts six months based on the Clinical Practice Guideline of Dr. Soetomo General Hospital. Patients will receive MP Pulse therapy as much as six cycles (every 2-4 weeks) at a dose of 10-30 mg/kg/day (maximum 1 gram) for three consecutive days. The procedure of making MP pulse IV is MP 500 mg or 1000 mg dissolved in NaCl 0.9% 100 ccs and given within 1-3 hours (Indonesia, 2011). MP dose used includes pulse or supraphysiological (>250 mg/day) doses administered to achieve rapid therapeutic effects and reduce long-term side effects [30]. In Table 6, we can see the number of patients undergoing induction therapy on various cycles. However, there are limitations to the data because the therapy cycle of some patients is not written in medical records.

After the induction phase is complete, therapy is continued with long-term therapy (maintenance phase). Corticosteroid sparing agent is still used but has been lowered dose to reduce the side effects caused and maintain the condition of remission [31]. In the maintenance phase, patients continue to use oral prednisone every day with an initial dose of 0.5-1 mg/kg/day, and the dose is decreased every month. Prednisone can be converted into a daily interval dose if proteinuria drops to <0.3 mg/day/1.73 m² to the lowest dose that can maintain remission conditions. In patients taking CPA as a corticosteroid sparing agent, the maintenance phase runs for 24 months. Patients will receive CPA Pulse every three months, then be discontinued. For patients taking MMF as a corticosteroid sparing agent, oral MMF will be lowered slowly until it reaches the lowest dose that can maintain remission conditions and should not be stopped.

The primary therapy in LN is by using large doses of corticosteroids in a long-term duration to suppress the excessive immune response that causes LN. This can cause resistance and side effects of HPA Axis suppression to lead to organ damage [4, 32]. Therefore, it is necessary to give corticosteroid sparing agent from time to time. Inflammatory lesions in LN are acute and can return to normal with corticosteroid sparing agent therapy [31]. If LN patients experience relapse while undergoing therapy protocols, it should be reinduced, by repeating the therapy protocol from the beginning. The pattern of corticosteroid sparing agent therapy given to pediatric LN patients in this study refers to Soetomoï¿½s 2017 ï¿½Clinical Practice Guidelineï¿½ and can be seen in Table 4.

The most appropriate way to reduce side effects from this high steroid is to slowly lower the dose of oral prednisone (tapering off) and use the lowest effective dose (Moroni, Depetri, & Ponticelli, 2016). In this study, tapering off prednisone doses was already applied regarding the applicable Clinical Practice Guideline. Oral prednisone begins at a dose of 0.5-1 mg/kg/day daily. It is gradually lowered by 5 mg/day within one month after administration of MP pulse and depending on disease activity. Corticosteroid administration for more than two weeks can cause adrenal suppression. The time it takes for the HPA Axis to return to normal functioning is 2-12 months, and cortisol levels can return to normal after 6-9 months. If the dose is lowered too quickly, the withdrawal symptoms will arise, which can be more severe. In steroid deficiency, the symptoms also appear at normal or even high cortisol levels, which indicate steroid dependence [15].

Based on the reference used in Dr. Soetomo General Hospital, a decrease in oral prednisone dose is carried out for 6-12 months. It can be converted into a daily interval dose if proteinuria drops to <0.3 mg/day/1.73 m² and normal serum levels of C3 and C4. The minimum dose to maintain remission conditions is given as an alternate dose (AD), i.e., corticosteroid administration every 48 hours [34]. Daily corticosteroid administration causes HPA axis suppression in most patients, and alternate dose therapy is relatively safer. Prednisone in the morning aims to mimic the bodyï¿½s physiological system that produces high endogenous cortisol in the morning and decreases throughout the day, thus equating to regular hypothalamic stimulation. Thus, patients can feel the effectiveness of therapy with minimal side effects [35]. The tapering pattern of oral prednisone can be seen in Table 5. From this table, it appears that a reduction in oral prednisone doses of 5 mg/day was performed monthly.

After administering MP pulse IV, patients are also given sparing agents in the form of CPA pulse IV or MMF + cyclosporin A. Regular administration of high doses of CPA IV (3-6 monthly cycles or every two weeks as much as 0.5-1.0 g/ m²) is an alternative to overcome the toxicity of oral CPA administration [36]. In other studies, it was said that the effectiveness of MMF and CPA is equally significant, but MMF provides fewer side effects than CPA (Lech & Anders, 2013). CPA is given at a dose of 500-1000 mg/m²/day each month in the induction phase. To maintain a state of remission, Intravenous CPA administration along with the use of prednisolone indicates a cumulative dose and lower recurrence rate [20]. Before being given CPA, patients receive premedication in the form of ondansetron IV or metoclopramide IV to overcome complaints of nausea and vomiting related to the side effects of CPA IV and furosemide IV to overcome the occurrence of fluid retention. Rehydration is done with the administration of 5% dextrose or NaCl 0.9% as much as 750 ccs within 3 hours (250 cc/hour) to prevent complications in the form of hemorrhagic cystitis. CPA is given in 250 cc NaCl 0.9% for 1-2 hours followed by administration of MESNA (sodium 2-mercaptoethanolsulphate) at 20% of the dose of CPA IV in NaCl 0.9% 50 cc IV drip for 15 minutes (Indonesia, 2011).

Mofetil mycophenolate and mycophenolic sodium are pre-drugs of mycophenolic acid (MPA) and are hydrolyzed by esterases into MPA. MPA administration was found to have lower side effects than CPA (Lech & Anders, 2013). Oral MMF can be given daily starting at the same time as MP pulse at a dose of 600 mg/m² every 12 hours (maximum 1 gram every 12 hours with a half-life of 8-16 hours). MMF and MPS are both hydrolyzed into active mycophenolic acid in the body. The difference is that the MMF form is made in film-coated tablets and causes gastrointestinal side effects. At the same time, mycophenolate sodium has been modified into a form of enteric coated tablet that causes few gastrointestinal side effects [37]. The preparation of coated tablets require the drug to be taken as a whole, therefore in some cases, the administration of MMF to patients are given at different doses. For example, patient A receives 500 mg MMF (1 tablet) in the morning, while at night 1000 mg (2 tablets) are given because MMF cannot be given at a daily dose of 2 x 750 mg.

American College of Rheumatology (ACR) and European Alliance of Associations for Rheumatology (EULAR) also recommend adjuvant therapy such as chloroquine for long-term treatment of LN. Based on existing research, in addition to antimalarial therapy, the use of chloroquine is also renoprotective. Chloroquine is a weak base that can penetrate lipid cell membranes and is centered on acidic cytoplasmic vesicles [38]. Changes in the acidic atmosphere inside the lysosome cause internalization defects. This leads to damage to the function of macrophages or antigen-presenting cells and modification of immune response effectors with decreased levels of proinflammatory cytokines IL-1, IL-6, and TNF [38]. Since there is an activation of type I IFN system in SLE patients that is suspected to be triggered by dysregulation of TLRs signaling, chloroquine can weaken this signaling process that plays a role in LN pathogenesis and helps reduce the incidence of kidney and non-renal flares [31, 39]. The difference in using chloroquine as an antimalarial and adjuvant therapy in LN lies in its dose. The dose of chloroquine as an antimalarial is 500 mg orally given once a week, while the dose used for LN therapy is 3 mg/kg/day and can be used daily starting from induction phase therapy. This study found that oral chloroquine was given to LN patients in the form of diphosphate with a daily frequency of 1 x with an equivalent dose of 150 mg of chloroquine base.

When giving corticosteroid sparing agents to children, the potential side effects need to be monitored regularly. Long-term use of corticosteroids generally causes Cushingï¿½s syndrome, which are characterized by weight gain, redistribution of adipose tissue, and fat accumulation especially on the face (full moon face). Cushingï¿½s syndrome may occur 1-2 months after the start of corticosteroid therapy and depends on the dose given and the length of therapy. These side effects are reversible and may go away after stopping the use of corticosteroids. To prevent withdrawals, a slow reduction in the dose of corticosteroids (tapering off) can be done. In some LN patients, the use of low doses of prednisone 5-7.5 mg/day and other corticosteroid sparing agents have maintained remission conditions (Moroni et al., 2016).

In using CPA, side effects can include leukopenia, hepatotoxic, gonad toxicity, cystitis hemorrhage, and increased risk of infection. The risk of malignancy and infertility may also increase at cumulative doses. In patients who receive CPA therapy, routine WBC monitoring should be done to avoid leukopenia because CPA can inhibit bone marrow activity (Moroni et al., 2016). In addition, CPA metabolic results in acrolein excreted through the kidneys can induce toxic effects on the bladder epithelium, thus causing hemorrhage cystitis, fibrosis of the bladder, and bladder cancer. In a study conducted by Houssiau et al. [40], the risk of bladder cancer was 3.6 times greater in patients receiving >36 g of CPA compared to patients who received <36 g of CPA or did not receive CPA at all. In another retrospective research, it was also stated that from 1018 patients treated with CPA, less than 2% of patients had hemorrhagic cystitis after ten months of CPA, and 0.19% experienced the development of bladder cancer (Yilmaz et al., 2015).

Patients are asked to drink plenty of fluids or use diuretic therapy to reduce CPA side effects, so CPA is more comfortable to give in the morning. Another additional therapy to reduce urotoxicity is mercaptoethanesulfonate (MESNA), which binds to acrolein and prevents direct contact with the urogenital (Moroni et al., 2016). Generally, the dose of CPA given to children is not more than the maximum cumulative dose of 250 mg/kg (e.g., 2 mg/kg/day for 18 weeks). In men, CPA will induce oligospermia or permanent azoospermia. While in women, amenorrhea and ovarian failure can be experienced by patients who use CPA for the long term, especially in women over the age of 30 years (Moroni et al., 2016). In addition, CPA can cause an increase in serum transaminases because it can induce a decrease in cholinesterase activity. However, the disorder will usually disappear after CPA is stopped. Therefore, serum transaminase monitoring is required, and if the level is less than 200 U/I, then CPA should be discontinued (Moroni et al., 2016).

For the usage of MMF, side effects that often arise are gastrointestinal disorders (nausea, vomiting, diarrhea), leukopenia, and an increased risk of infection (especially sepsis due to cytomegalovirus) (Krensky et al., 2011). Side effects increase with the amount of dose given can be overcome by dividing the dose of MMF in a day into 2-3 divided doses (Moroni et al., 2016).

Cyclosporine A is calcineurin inhibitor (CNI) used when patients experience persistent proteinuria >1 g/day/1.73 m² after three months of induction therapy, with normal serum creatinine. Cyclosporin A binds to cyclophilin in the cytosol, an isomerase enzyme that plays a vital role in protein formation. This barrier to isomerase activity is thought to be responsible for its immunosuppressant activity. Cyclophilin is part of immunophilin, a protein that binds to immunosuppressants [42]. In addition to its immunosuppressive effects, cyclosporine A can be used to treat proteinuria because it is a selective afferent constrictor, thereby lowering capillary pressure on the glomerulus. Common side effects are nephrotoxic neurological symptoms such as tremors and headaches, hirsutism, and gum hypertrophy. In our study, two patients used cyclosporine A. The value of proteinuria in one patient cannot be observed, while in the other, the value was 4+ (> 1000 mg/dL).

From the results of our study, it is recommended to regularly monitor the pediatric LN patients for the side effects that can arise from the usage of corticosteroid sparing agents and other drug therapies. In addition, an increased interprofessional collaboration between pharmacists and other health workers needs to be done. It is important for pharmacists to improve their knowledge on patients related to corticosteroid sparing agent drugs in pediatric LN patients so that optimal therapy can be achieved as well as to minimize drug-related problems for patients.

Conclusion

Corticosteroid sparing agent in pediatric LN patients is oral MMF and oral chloroquine with steroids, and under certain conditions may be added cyclosporine A oral and combination CPA pulse and oral chloroquine with steroids.

In the 6-month induction phase, oral MMF is started at the same time as MP pulse at a dose of 600 mg/m2/12hours (15-23 mg/kg/12 hours), and under certain conditions, cyclosporine A oral at a dose of 3-6 mg/kg/day every 12 hours. CPA pulse is given intravenously at a dose of 500-1000 mg/m2 every four weeks as many as six cycles. In the maintenance phase, MMF dose will be lowered slowly until the patient reach a state of remission and should not be stopped. In patients taking cyclosporine A, it is lowered slowly until it reaches remission and will be considered for discontinuation. While in the use of CPA pulse, will be given intravenously every three months for 24 months, then discontinued.

The pattern of tapering off oral prednisone and corticosteroid sparing agent used daily follows applicable clinical practice guidelines, namely a decrease in prednisone of 5 mg/day each month to a minimum dose that can maintain a state of remission. Meanwhile, tapering off corticosteroid sparing agents was not found in the study.

The side effects for each corticosteroid sparing agents are mentioned in the following: For the use of cyclophosphamide, they are leukopenia (14%) and hepatotoxicity (13%). For the use of MMF, they are gastrointestinal (GIT) disorders (20%) and leukopenia (20%). For the use of chloroquine, it is GIT disorder (25%). In comparison, potential side effects on the use of CPA are the risk of infection, GIT disorders and hemorrhagic cystitis. For MMF it is the risk of infection. In addition, for the use of chloroquine is retinal toxicity, while for the use of cyclosporine A is nephrotoxicity.

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