A Study on Clinical Manifestations, Treatment Pattern and Outcome in Systemic Lupus Erythematosus Patients in Tertiary Care Hospital.

 

  Sowmya Annavarapu¹,  Merry Raphael¹, Dr. Vijayanarayana K², Dr. Girish Thunga², Dr. Sreedharan N²

¹Student, Department of Pharmacy Practice, MCOPS, Manipal University, Manipal-576104

²Associate Professor, Department of Pharmacy Practice, MCOPS, Manipal University, Manipal-576104

 

ABSTRACT:

Introduction: Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder. Its expression is greatly influenced by the combined effect of genetic, environmental, demographic and geographical factors. The treatment is highly individualized depending on the development of clinical features. Objective: To study the treatment pattern and disease progression using appropriate disease activity indices. Material and Methods: A retrospective observational study was conducted in a tertiary care teaching hospital of South India. As per the study criteria, data was collected from 2010 to 2012. SLEDAI and ECLAM scores were calculated at the first and last admission for comparing the treatment given with the disease progression. Data analysis was done using SPSS 20.0. Wilcoxon non parametric test was used to compare scores at the first admission and last admission. Results: A total of 93 patients were included in the study. The mean age of onset was 29.3±8.5 years with female to male ratio of 15:1.9. Most common clinical features were arthritis (74.3%), fever (71.4%) and malar rash (52.9%). Involvement of cardiovascular and respiratory system was found to be less common. During the treatment period and last follow up steroids, hydroxychloroquine and immunosuppressants were given in different combinations. Out of which, a combination of steroids, hydroxychloroquine and immunosuppressant’s (44.1%) was the most highly prescribed. The most commonly used drugs were methyl prednisolone (89.2%), hydroxychloroquine (69.9%) and cyclophosphamide (38.7%). A statistical significance was observed (at p=0.0001) in the disease activity indexes of last admission when compared to first admission. Conclusion: There was a statistically significant improvement (at p=0.0001) in the SLEDAI and ECLAM disease activity scores from first admission to the last follow up with the treatment given in our hospital which included steroids, hydroxychloroquine and immunosuppressant’s in single or combinations of two or more.

 

 

 

INTRODUCTION:

“Systemic lupus erythematosus (SLE) is an autoimmune disease in which organs and cells undergo damage initially mediated by tissue-binding autoantibodies and immune complexes”¹. It is one of the Rheumatic diseases with highest mortality rates². Globally, its prevalence ranges from 20 to 70 per 100,000 people per year³.A point prevalence in India is of 3.2 per 100,000 (95% CI = 0-6.86 per 100,000). India has a reported prevalence of SLE that ranges from 14 to 60 per 100,000. ⁴ The expression of disease depends on various factors such as genetic, hormonal and environmental factors. Although multiple genes contribute to susceptibility of SLE, the major his to compatibility gene is most important.^1,5,6 Females are more prone to SLE and it is more pronounced in reproductive age group due to the hormonal factors⁷. Environmental factors include sunlight (i.e., ultraviolet light), drugs, chemicals such as hydrazine (found intobacco) and aromatic amines (found in hair dyes), diet and infection with viruses or    bacteria^{1, 5, 6}.

 

The assessment of SLE can be done using systematic clinical assessment, routine lab tests and standardized measures of disease activity. The standardized measures used to access disease activity include SLE Disease Activity Index (SLEDAI), the European Consensus Lupus Activity Measurement (ECLAM), the British Isles Lupus Assessment Group (BILAG), the Lupus Activity Index (LAI) and the Systemic Lupus Activity Measure (SLAM) which are valid, reliable and comparable. These scoring systems help to measure the Lupus disease activity to determine effectiveness of the therapy and to assess the health status of SLE patients. This is done by comparing the outcome measures before and after the treatment, thereby managing the disease in a better way.^8,9,10

 

SLE is a disease which includes remission, relapse and flare ups throughout the life of the patients. The development of various clinical features in the disease period is individualized^{8, 11, 12}. Treatment, duration of therapy, route of administration and dosage of the medications are also highly individualized based on the symptoms, organ involvement and disease severity. Patients are treated according to the clinical manifestations they develop with different drugs like steroids, immunosuppressant’s etc. European league against rheumatism (EULAR) and American college of rheumatology (ACR) guidelines are the standard recommendations available for the management of SLE⁹. and mortality due to SLE has many reasons such as poor control of the disease and medication’s side effects. The presence of traditional risk factors like sedentary lifestyle, obesity, hypercholesterolemia and non-traditional risk factors like renal impairment, high homo cysteine levels, chronic inflammation and low density lipid oxidation plays an important role in the management of the disease^{13, 14}.

 

The disease necessitates the adjunctive treatments to control the risk factors for developing cardiovascular and renal disorders. The drugs used to treat SLE they sometimes can be fatal e.g.: fatal infections in patients receiving potent immunosuppressive medications. As SLE is a rare disease, outcome of the treatment and the survival rates may vary across countries due to educational background, medical systems, socioeconomic factors and cultural differences. Due to the complexities of its presentation it poses a great challenge for physicians to identify the clinical manifestation, complications and treatment options to reduce the morbidity and mortality. This necessitates a need to conduct more studies on SLE.

 

AIMS AND OBJECTIVES:

To study the treatment pattern and disease progression using appropriate disease activity indices.

 

MATERIAL AND METHODS:

A retrospective observational study was conducted in a tertiary care teaching hospital of South India. Ethical approval was obtained from the Institutional Ethics Committee (IEC) of the hospital. Data was collected from medical record section by International Classification of Diseases (ICD) which codes for SLE- ICD code 10 from 2010-2012 in a suitable designed case record form. In-patients diagnosed with SLE, aged 18 years and above were enrolled in the study excluding ppregnant women. All the patient related data includes demographics, types of Lupus, clinical manifestations, treatment pattern, outcome of the treatment and statistical analysis of the data. Treatment outcome was assessed using Disease activity indexes namely Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and European Consensus Lupus Activity Measurement (ECLAM) scores which were calculated at the first admission and last admission for comparing the treatment given with the disease progression. The median of these scores were calculated and compared. Data was analyzed using SPSS 20.0. Wilcoxon non parametric test was used to compare scores at the first admission and last admission.

 

RESULTS:

One hundred and thirty two patients with SLE were treated in our hospital during 2010 to 2012. Among them 93 patients were enrolled into the study based on the inclusion and exclusion criteria. Among them 70 cases were newly diagnosed cases.

 

1. Demographic Characteristics of all Patients:

The demographic details of all patients admitted were presented in Table 1. The mean age of 93 patients was 30.60 ± 8.83 years. A high proportion of the study population was females who constituted 93.5 % (15:1.9). The average age of onset of the disease was 29.3±8.5 years. Among the various co-morbid conditions observed in SLE patient’s hypertension was seen in 6.5% followed by hypothyroidism 5.4%.

 

Table 1: Tabular representation of demographic details of all patients

S. No	Patient Demographics	(n=93)
1	Age Mean age ± SD, years Mean age at onset ± SD, years	30.60 ± 8.83 29.27 ± 8.52
2	Gender Males, n (%) Females, n (%)	6 (6.5) 87 (93.5)
3	Social habits Alcohol, n (%)	1 (1.1)
4	Family history, n (%)	8 (8.6)
5	Co-morbidities No, n (%) Hypothyroidism, n (%) Severe left ventricular dysfunction, n (%) Hypertension, n (%) Avascular necrosis of hip, n (%) Pulkochs, n (%) dyslipidaemias, n (%) Acute deep vein thrombosis, n (%)	75 (80.65%) 5 (5.4%) 1 (1.1%) 6 (6.5%) 1 (1.1%) 1 (1.1%) 3 (3.2%) 1 (1.1%)

 

2. Categorization of study population into different types of Lupus:

Distribution of patients among various types of lupus was tabulated below in Table 2. Among the various types of lupus, SLE was found in majority of the patients (98.9%).

 

Table 2: Tabular representation based on various types of lupus

S. No	Type of lupus	n (%)
1	SLE	88 (94.6%)
2	SLE + BLE	1 (1.1%)
3	Disseminated DLE	1(1.1%)
4	SLE with discoid lupus	3 (3.2%)

 

3. Clinical signs and symptoms of SLE patients at first presentation:

Clinical manifestations at first presentation were given in Table 3. Arthritis was the most common presentation by the patients (74.3%), followed by fever (71.4%) and malar rash (52.9%). Lupus nephritis was seen in 32.4% of patients at first presentation. Proteinuria was seen in 45.7% of patients. 

 

4. Pattern of Lupus nephritis (LN) stages in SLE patients:

Patients were categorized into different stages of LN. 54.3% as first presentation 61.3% at first admission and 53.8% at the last admission were under normal stage (Table 4). Among the other stages diffuse proliferative stage was observed in majority of the patients (18.6% as first presentation 19.4% at first admission and 22.6% at the last admission).

 

Table 3: Tabular representation of initial clinical manifestations in SLE patients

S. No	Clinical signs or symptoms	n (%)
1	Mucocutaneous manifestations
	Malar rash	37(52.9%)
	Discoid rash	3(4.3%)
	Oral ulcers	25(35.7%)
	Photosensitivity	23(32.9%)
	Alopecia	22(31.4%)
2	Musculoskeletal manifestations
	Arthritis	52(74.3%)
3	Hematologic manifestations
	Autoimmune hemolyticanemia	9(12.9%)
	Leucopenia	3(4.3%)
	Thrombocytopenia	14(20%)
	Pancytopenia	6(8.6%)
	Bicytopenia	1(1.4%)
	Iron deficiency anemia	3(4.3%)
	Anemia of chronic disease	2(2.9%)
	Anti-phospholipid antibody syndrome	3(%)
4	Neurologic manifestations
	Seizures	4(5.7%)
	Head ache	4(5.7%)
	Psychosis	3(4.3%)
	Depression	2(2.9%)
	CNS lupus	1(1.4%)
5	Pulmonary manifestations
	Pleural effusion	3(4.3%)
	Lupus pneumonitis	1(1.4%)
6	Renal manifestations
	Proteinuria	32(45.7%)
	Elevated serum creatinine	12(17.1%)
7	Cardiologic manifestation	3(4.3%)
8	Vasculitis
	CNS vasculitis	3(4.3%)
	Cutaneous vasculitis	1(1.4%)
	Mesenteric vasculitis	1(1.4%)
9	Infections
	Cellulitis	4(5.7%)
	Respiratory tract infection	1(1.4%)
	Urinary tract infection	5(7.1%)
	Urosepsis	1(1.4%)
10	Fever	50(71.4%)
11	Fatigue	5(7.1%)
12	Anorexia	11(15.7%)
13	Loss of weight	13(14%)

 

 

Table 4: Tabular representation based on various stages of LN in  SLE patients

S. No	Stage of lupus nephritis	Number of patients , n (%) as first presentation n=70	Number of patients , n (%) at first admission n=93	Number of patients , n (%) at last admission n=93
1	Normal	45 (54.3)	57 (61.3)	50 (53.8)
2	Mesengial	5 (7.1)	5 (5.4)	6 (6.5)
3	Focal proliferative	3 (4.3)	6 (6.5)	11 (11.8)
4	Diffuse proliferative	13 (18.6)	18 (19.4)	21 (22.6)
5	Membranous	3 (4.3)	6 (6.5)	5 (5.4)
6	Nephrotic syndrome	1 (1.4)	1 (1.1)	0 (0)

 

 

5. Drugs used to treat SLE during the treatment period:

Various drugs used to treat SLE are tabulated below in Table 5. During the treatment period methyl prednisolone was used in 89.2% of patients followed by hydroxychloroquine in 69.9%.

 

Table 5: Tabular representation of various drugs used in SLE patients

 

6. Induction Therapy in Lupus Nephritis:

Among the 93 patients 36 patients had lupus nephritis (Table 6). The pattern of induction therapy given to them is presented in table 11. Cyclophosphamide was used in 92% of LN patients of SLE.

 

Table 6: Tabular representation based on the induction therapy of LN in SLE patients

 

7. Maintenance Therapy in Lupus nephritis:

Among the 36 LN patients of SLE, during the time of last follow up they were in the induction phase (27.7%) (Table 7). Most of the patients who were in maintenance therapy were receiving methyl prednisolone (33.3%).

 

Table 7: Tabular representation based on the maintenance therapy of LN in SLE patients

S. No	Treatment Given	n (%), n=36
1	Azathioprine	8(22.2%)
2	Mycophenolatemofetil	6(16.6%)
3	Methyl prednisolone	12(33.3%)
4	Induction phase at the last follow up	10(27.7%)

 

8. Combination of drugs used to treat SLE:

The various combinations used in SLE patients were presented in Table 8. Among the different combinations used steroids + hydroxychloroquine + immunosuppressant’s combination contributes its usage in 44.1% of SLE patients followed by steroids + hydroxychloroquine (22.6%).

 

Table 8: Tabular representation of various combinations used by SLE patients

S. No	Combinations used	n (%)
1	Steroids + Steroids	13(14%)
2	Hydroxychloroquine + Hydroxychloroquine	3(3.2%)
3	Steroids + Hydroxychloroquine	21(22.6%)
4	Steroids + Hydroxychloroquine + immunosuppressants	41(44.1%)
5	Steroids  + immunosuppressants	14(15.1%)
6	Hydroxychloroquine + immunosuppressants	1(1.1%)

 

9. Outcome of the Treatment:

The outcome of the treatment was assessed using SLEDAI and ECLAM scoring indexes comparing baseline and score at the last admission (Table 9). The scores of the disease activity indexes were analyzed using Wilcoxon signed rank test. Values are presented in Median ± IQR.

 

Table 9: Tabular representation of disease activity indexes

S. No	Name of the disease activity index	Index score at first admission (Median ± IQR)	Index score at last admission (Median ± IQR)
1	SLEDAI	14 ± 9	6 ± 6 *
2	ECLAM	6 ± 2	3± 2 *

*Statistical significance (P=0.0001)

 

There was a statistically significant improvement (at p=0.0001) in the SLEDAI and ECLAM disease activity scores from first admission to the last follow up with the treatment given in our hospital which included steroids, hydroxychloroquines and immunosuppressant’s in single or combinations of two or more.

 

DISCUSSION:

Our study of ninety three patients described the clinical profile of SLE patients at their first presentation and its treatment pattern and outcomes. SLE was predominant among female patient with female: male ratio 15:1. Most of the Asian studies (2006)¹⁵ have reported female to male ratio ranging from 7:1 to 28:1. Similar study by Malaviya et al (1988)¹⁶ showed a ratio of 8:1. This increased occurrence of SLE among females may be attributed to differences in the metabolism of sex hormones and/or gonadotropin-releasing hormone⁷.  The mean age of onset of SLE was 29.3 ± 8.5 in our study which is similar to a study (28.7 years) conducted by Paudyal BP et al (2012)¹⁷. The median age of onset was 27± 13.5 years in our study. Malaviya et al (1988)¹⁶ and Vaidya et al (1997)¹⁸ noted a median age of onset at 24 and 26 years respectively. These results show the occurrence of SLE in child bearing age. Clinical presentation reported in different Indian studies indicates the regional variations. In general, cutaneous, musculoskeletal, oral mucosal, hematological, and renal manifestations were more frequent than pulmonary, cardiovascular and neuropsychiatric in our lupus population. Arthritis (74.3%) was the most common presentation found in our study followed by fever (71.4%) and malar rash (52.9%). These findings were similar to the other south Indian Studies conducted by Kosarajuet al (2010)¹⁹.

 

Renal involvement in lupus is a major cause of morbidity and mortality. Nephritis in SLE is more common in eastern India when compared to south and North India^19,20. Renal involvement in our study population was observed in 32.4% which is comparable with other south Indian studies^19,21. The incidence of renal involvement was higher in our study when compared to other Indian studies. Neurological manifestations (17%) in our study subjects were a bit higher when compared to other studies^{19, 21}. In contrast a study done by Malaviya et al (2010) ¹⁶ in Indian populations had reported an increased rate of 60% Hematologic manifestations in our patients were different when compared to other studies. In our study thrombocytopenia (20%) was found in more number of patients which is similar to the study conducted by Renusaigal et al (2012)²² who reported 33.3%.  Kosaraju et al (2010)¹⁹ reported only one hemolyticanemia in their study but in our study we found 12.9%. Sachin Ratanlal Agarwal et al (2013)²³ reported lymphopenia in 48.3% of their study population which was not found in our study.

 

Steroids were the most commonly used drug in our study. Majority of the patients had taken steroids in one or the other form during the treatment period. Among the steroids, methyl prednisolone was prescribed to most of the patients. IV methyl prednisolone was used in 20 patients in our study. A study conducted by David Isenberg et al (1982)²⁴, showed that the treatment with IV methyl prednisolone is safe and can be used especially when moderate doses of corticosteroid do not show the response. In our patients hydroxychloroquine was one of the most commonly used drugs. It was used in 69.9% of the patients. hydroxychloroquine usage reduces the disease flares and active SLE and it is suggested by the PLUS study conducted by Nathalie Costedoat Chalumean et al (2013)²⁵.

 

 

Immunosuppresants were used in 60.3% of patients with different manifestations and it showed good outcome as indicated by the reduction of scores by 0.57% and 0.5% in SLEDAI and ECLAM indexes respectively. A systemic review conducted by Peqo Reigosa et al (2013)²⁶ demonstrated the efficacy and safety of immunosuppressant’s in non-renal SLE which stands as a support for our study. In our study lupus nephritis patients were treated with Cyclophosphamide (35.5%), Mycophenolatemofetil (2.2%), and mycophenolic acid (1.1%) as induction therapy. Mycophenolatemofetil (8.6%), Azathioprine (6.5%) and methyl prednisolone (12.9%) were used as maintenance therapy. We observed a decrease in the disease assessment score which showed the treatment to be effective. A study conducted in north India also showed favorable outcome by immunosuppressant’s in LN patients of SLE¹⁶.

 

Mycophenolatemofetil was prescribed in 2.2% of patients as induction therapy and in 6.5% of patients as maintenance therapy in LN. A meta-analysis conducted by Liu et al (2010)²⁷ shows that Mycophenolatemofetil is superior to Cyclophosphamide for inducing renal remission, and had a significant advantage over Cyclophosphamide for reducing ESRD or death. However in our study most of the LN patients were prescribed with Cyclophosphamide. Rivera et a l(2010)²⁸ conducted a study which indicated Mycophenolatemofetil is safe and effective in LN patients. At the time of last follow up 41.9% were using hydroxychloroquine, 60.2% were using steroids, and 17.2% were using immunosuppressants mostly in combination of two or more. A study conducted in Nepal by Paudyal et al (2010)¹⁷ reported that 93% were taking antimalarials, 90% were taking steroids, and 9% were taking immunosuppressive agents at the time of last follow up. Some of the patients had no drug treatment for SLE during the last follow up due to complete remission and stable disease. This indicates the effectiveness of the treatment in our population.

 

The comparison of disease activity indexes showed a significant improvement in patients with the treatment given from the baseline in our hospital. This was shown through a significant reduction in the scores from first admission to the last follow up. SLEDAI was used by Badsha et al (2002)²⁹ to find the disease activity and the scores were reduced when compared to initial scores which were similar to our study. A study conducted by Swaak et al (1999)³⁰also used SLEDAI and ECLAM indexes to assess the disease activity which showed active disease in most of their study population but it was conducted in patients with disease duration of 10 years.

 

 

CONCLUSION:

The prevalence of SLE was more predominant in female patients and the common clinical manifestations were arthritis, fever and malar rash. The severity of the disease was assessed using SLEDAI and ECLAM disease activity indexes for the treatment given. The disease activity indexes showed a significant improvement in patients with the treatment given from the baseline in our hospital. Therapy included mostly steroids, hydroxychloroquines and immune-suppressants in single or combinations of two or more. Owing to its ability to cause serious complications and chronicity the early detection, diagnoses, early initiation of therapy and adherence to the therapy might help in improving the prognosis and delaying serious systemic involvement.

 

LIST OF ABBREVIATIONS:

1.        SLE- Systemic lupus erythematosus

2.        SLEDAI- SLE Disease Activity Index

3.        ECLAM- European Consensus Lupus Activity Measurement

4.        BILAG- British Isles Lupus Assessment Group

5.        LAI- Lupus Activity Index

6.        SLAM - Systemic Lupus Activity Measure

7.        EULAR- European league against rheumatism

8.        ACR- American college of rheumatology

9.        IEC- Institutional Ethics Committee

10.     ICD- International Classification of Diseases

11.     BLE- Bullous Lupus Erythematosus

12.     LN- Lupus nephritis

13.     IQR- Interquartile Range

 

ACKNOWLEDGEMENT:

The authors would like to acknowledge Manipal University, Kasturba Hospital, Manipal, Manipal College of Pharmaceutical Sciences for providing the necessary facility to conduct the study.

 

CONFLICT OF INTEREST:

There is no conflict of interest among the authors.

 

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Accepted on 17.03.2017           © RJPT All right reserved