JOURNHL Of MIUTRAV PHRRMnCO-MCDICINC N°7-201«
EFFECT OF INTRAVENOUS CYCLOPHOSPHAMIDE PULSE THERAPY ON NEPHROPATHY OF SYSTEMIC LUPUS
ERYTHEMATOSUS
Nguyen Minh Nui'; Nguyen Ngoc Chau'
Nguyen Thi Phi Nga'; Nguyen Due Cong"; Doan Van De' SUMMARY
Nephhtls and kidney failure are the leading cause of mortality In systemic lupus erythematosus (SLE). The effect of Intravenous cyclophosphamide pulse therapy on nephropathy In 12 SLE patients was evaluated after 1, 3 and 6 months. The results Indicated that clinical manifestations Including fever arthritis, and peripheral edema were improved significantty. The concentration of hemoglobin as well as total serum protein and albumin Increased significantly while urine protein/24 hours decreased cleady. The stage of kidney failure was stable during 6 months Side effect was observed In two cases of uterus cervical papilloma. These results provided evidences of beneficial effect of Intravenous cyclophosphamide pulse therapy on Improvement of nephropathy In SLE patients. Our results also supptjrted a prominent role of cyclophosphamide In the management of severe, life-threatening manifestations of SLE.
* Key words: systemic lupus erythematosus; cyclophosphamide, nephropathy.
INTRODUCTION
Systemic lupus erythematosus is a systemic autoimmune disease that can affect several organs of the body. As occurs in other autoimmune diseases, the immune system attacks the body's cells and tissue, resulting in systemic inflammation and tissue damage.
Nephropathy including nephritis and end- stage kidney failure is the leading cause of mortality in SLE [1]. So far, there is no effective cure for SLE. In present, SLE is treated mainly with immunosuppression including cyclophosphamide, corticosteroids and other supplementary symptomatic controls. Corticosteroids therapy was frequently administered with beneficial effect. However, it causes several adverse effects, such as Gushing syndrome, gastrointestinal hemorrhages, immune deficiency and neurological disorders.
Cyclophosphamide has been attracted by physicians all over the word in the past decade because of its potential effects.
Cyclophosphamidehas come to assume an increasingly prominent role in the management of severe, life-threatening manifestations of SLE, particulariy in case of corticosteroid-refractory SLE. intennittent, intravenous pulse cyclophosphamide has become the standard of treatment of diffuse proliferative lupus nephritis [2], and there is now substantial clinical literature to suggest an indication for intermittent cyclophosphamide therapy in most other forms of serious lupus affecting major organ systems, in particular lupus vasculitis and acute central nervous system manifestations. However, the effect of cyclophosphamide on SLE nephropathy needs further investigation. This study aims to evaluate the effect of cyclophosphamide in the management of lupus nephritis by comparison of clinical manifestations and laboratory tests before and after intravenous cyclophosphamide pulse therapy. We also discuss potential complications of the dmg
* 103 Hospital
" Thong Nhat Hospital
Corresponding author: Nguyen Minh Nui ([email protected])
JOURNRl OF MIUTRRV PHARMRCO-MdMCINe N°7-2014 SUBJECTS AND METHODS
1. Subjects.
Total 12 female SLE patients (age:
29.14 ± 5.28 years) were diagnosed defnitely based on 11 criteria issued by American Rheumatology Association (ARA) [3] as following:
- Malar rash: Fixed erythema, flat or raised, over the malar eminences.
- Discoid rash: Erythematous circular raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring may occur.
- Photosensitivity: Exposure to ultraviolet light causes rash.
Oral ulcers: Includes oral and nasopharyngeal ulcers, observed by physician.
- Arthritis: Nonerosive arthritis of h«o or more peripheral joints, with tenderness, swelling or effusion.
Serositis: Pleuritis or pericarditis documented by ECG or rub or evidence of effusion.
- Renal disorder: Proteinuria > 0.5 g/d or 3+ or cellular casts,
- Neurologic disoreier. Seiaires or psychosis without other causes.
- Hematologic disorder. Hemolytic anemia or leukopenia (< 4,000/L) or lymphopenia (< 1,500/L) orthrombocytopenia(< 100,000/L) in the absence of offending drugs.
- Immunologic disorder: Anti-dsDNA, anti-Sm, and/or anti-phospholipid.
- Antinuclear antibodies: An abnormal titer of ANA by immunofluorescence or an equivalent assay at any point in time in the absence of drugs known to induce ANAs.
Abbreviations: ANA: antinuclear antibodies; dsDNA: double-strand DNA;
ECG: electrocardiography.
All 12 patients had at least 4 of these criteria. Because we focused on nephropathy, so all selected patients had proteinuria
> 0.5 g/day. These patients suffered from kidney failure from stage I to stage ilia.
2. Cyclophosphamide.
Cyclophosphamide (trade name: Cytoxan, bottle 1 g for injection) supplied by USP, IS a synthetic immune depressant Its chemical structure belongs to the nitrogen mustards. Cyclophosphamide was diluted in 200 ml glucose solution 5%, and then administered intravenously (IV) in 30 minutes with dose of 10 mg/kg body weight Pulse therapy of cyclophosphamide was indicated once a month in continuous 6 months. In order to minimize adverse effects of cyclophosphamide, all the patients were administered intravenously 40 mg methylprednisolone (trade name. Solu- Medrol, USP), orally 1.2 g potassium chloride before using cyclophosphamide, then followed by 20 mg furosemide IV to enhance excretion of the drug.
3. Data analysis.
Clinical symptoms were assessed before and after treatment, including: fever, arthritis, edema, hair loss and vomiting. Comparison between pre- and post-treatment was performed using chi-square test.
Latxjratory measurements were perfonned before and after 1, 3 and 6 months treatment.
Including: hematology test, serum urea, creatinin, total semm protein, albumin, and proteinuria. Data was compared between pre- and post-treatment by repeated measures one way analysis of variance (ANOVA).
All statistical analyses were performed using the SPSS software package (ver.
19, IBM Corporation, Annonk, NY, USA).
Any differences were considered statistically significant with p < 0.05.
79
JOURNAL OF MILITARV PHARMACO-MCDICIN« N°7-2014 RESULTS 1, Modification of symptoms.
TaWe 1: Comparison of symptoms between pre- and post-treatment by IV cyclophosphamide pulse therapy. Data was presented by the number of patients and the corresponding percentage.
SYMPTOM
Fever Edema Arthritis hlair loss Vomiting
PRE-TREATMENT
9 (75%) 12 (100%) 11 (91.7%) 6 (50%) 3 (25%)
POST-TREATMENT 1 MONTH 3 (25%) 6 (50%) 6 (50%) 6 (50%) 3 (25%)
POST-TREATMENT 3 MONTHS 0 ( 0 % ) "
2 (16.7%) • 2 (16.7%) * 7 (58.3%) 4 (33.3%)
POST-TREATMENT 6 MONTHS 0 (0%) **
2 (16 7%) • 2(16.7%)*
8 (66 7%) 3 (25%)
* and ": significant difference from pre-treatment with p < 0.05 andp < 0.01 respectively (chi-square test)
Fever decreased significantly 3 to 6 months after treatment as compared with pre- treatment (chi-square test, p < 0.01). Peripheral edema and arthritis also decreased significantly from 3 to 5 months after treatment as compared with pre-treatment (chi- square test, p < 0.05).
2. Changes of laboratory indices.
Table 2: Comparison of hematology indices between pre- and post-treatment by IV cyclophosphamide pulse therapy.
LABORATORY INDEX RBC (mil/L)
Hb(g/L) WBC (G/L)
PLC (G/L)
PRE-TREATMENT 3.04 ± 0,34 87,26 + 4,36 6,43 + 2,34 128,46 ±28,34
POST-TREATMENT 1 MONTH 3,24 ± 0,43 91,43+5,43 5,92 + 1,88 112,37± 16,43
POST-TREATMENT 3 MONTHS 3,43 ± 0,38 96,21 ± 6,34*
7,12 ±2,47 124,18 ±23,78
POST-TREATMENT 6 MONTHS 3,28 ± 0,47 92,48 ± 6,21 6,14 ± 2 1 2 118,65±31,82 (Data was presented by mean ± SEM. ': significant difference from pre-treatment with p < 0.05. RBC: red blood cell; Hb: hemoglobin; WBC: white blood cell; PLC:
platelet cell).
All hematology indices were not significantly different, except the concentration of hemoglobin increased significantly after treatment 3 months (repeated measures ANOVA, p < 0.05)
JOURNAL OF MIUTAfiV PHARMflCO-MCDICIN« N°7-2014 Table 3: Comparison of serum urea, creatinin and transaminase enzymes between pre- and post-treatment. Data was presented by mean + SEM.
LABORATORY INDEX Urea (mmol/L) Crea (^mol/L) SCOT (U/L) SGPT (U/L)
PRE-TREATMENT 12,46 f 3,24 164,28±24,16 29,86± 9,43 3 1 , 2 6 ± 1 1 , 2 3
POST-TREATMENT 1 MONTH 11,92 ± 4 , 5 6 156,58 + 25,14
33,52 ± 7,23 36,45 ± 9,46
POST-TREATMENT 3 MONTHS 13,21 ± 4 , 0 1 154,35 ± 3 0 , 1 2
35,72 ± 9,34 34,21 ± 1 2 , 2 4
POST-TREATMENT 6 MONTHS 12,03 ± 4 , 1 6 150,24 + 22,17
34,56 ± 8,42 37,62 ±10.68
Serum concentration of urea did not change during 6 months while serum concentration of creatinin tends to reduce slightly, however, these changes were not statistically slgnificanL The hivo transaminase enzymes (SCOT and SGPT) increased slightly but not statistically significant
I I
Figure 1: Comparison of serum concentration of total protein and albumin between pre- and post-treatment.
(*: significant difference from pre-treatment with p <0.05).
Botli protein and albumin increased significantly from 1 month after cyclophosphamide treatment and the effect was stable during 6 months.
3 5 -8'2iL>
pre-treatrr
. - - "-
:.:.. Mz h
lent post-treatment 1 month
+ * - *
ZJ*--fi
post~lreatmet)t 3 po&t-treatment 6 months months•
• protein
Figure 2: Comparison of proteinuria/24h between pre-and post-treatment by IV cyclophosphamide.
(Dafa wens presented bymean + SEfi/l. ** ***; significant difference from pre-treatment with p < 0.01; 0.001 respectively). •
The proteinuria/24h decreased significantly from the first month to the sixth month.
81
JOURNRL OF MILITARV PHRRMACO-M«DICINe N°7-e014
3. A d v e r s e effect.
There were h«o patients suffering from papilloma of uterus cervix vi/hich was found at the sixth month after therapy. Stages of ranal failure of all 12 patients were not changed during 6 months of observation.
DISSCUSION
Cyclophosphamide is an immune depressant of all<ylating agents.
Cyclophosphamide blocks the production of the deoxyribonucleic acid (DNA) in cells. This prevents cells from dividing, leading to cell death. Some of the cells affected by this medication are immune ceils. These play a key role in autoimmune diseases such as SLE, rheumatoid arthritis, scleroderma or vasculitis. The present study has provided evidence that cyclophosphamide IV pulse therapy have beneficial effects on SLE nephritis as well as potential side effect. Cyclophosphamide treatment improved both clinical manifestation and laboratory indices which suggested that systemic inftammation and kidney damages were controlled and progressive lesions in SLE might be prevented. The increases of serum protein and albumin were consistent with the decrease of proteinuria/24h after 1 month treatment, and the effect was stable 6 months later.
These improvements may due to the functional recover of glomenilus membrane from reduced sedimentation of immune
complex. Our results were consistent with previous study that cyclophosphamide may become a potential agent for wide indication of treating variety form of SLE [4]. A recent study indicates that the mechanism of cyclophosphamide effect relate to lympho B activation [5] that is different to the way of corticosteroid. This difference may develop more effective when combination of cyclophosphamide and corticosteroid in treatment of SLE, particulariy in management of severe, life- threatening manifestations.
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