MANAGEMENT AND CLINICAL OUTCOME OF SYSTEMIC LUPUS ERYTHEMATOSUS PATIENTS ; AT NEPHROLOGY UNIT , ZAGAZIG UNIVERSITY HOSPITALS : A ONE YEAR STUDY

Amir M. El Okely MD1, Adel A.M. Ghorab MD1, Eman H. Abdelbary MD2 and Mahmoud M. Magdy Mahmoud MSc1. 1. Nephrology unit, Internal Medicine Department, Faculty of Medicine, Zagazig University, Egypt. 2. Pathology Department, Faculty of Medicine, Zagazig University, Egypt. ...................................................................................................................... Manuscript Info Abstract ......................... ........................................................................ Manuscript History

In both regimens corticosteroid was used as follow: As an initial dose of iv methylprednisolone (0.5-1 gm/day) for 3 days at the beginning of treatment followed by oral prednisone up to 1 mg/kg, tapering according to clinical response over 6-12 months.
All patients with (LN) of any class are treated with hydroxychloroquine (maximum daily dose of 6-6.5 mg/kg ideal body weight), unless they have a specific contraindication to this drug Ruiz-Irastorza et al., (2010) (30).
Azathioprine or MMF were used as maintenance therapy after induction and clinical outcomes were compared among different classes (Complete remission, Partial remission, Deterioration or Non-response and ESRD). Patients were selected according to the following criteria: Inclusion criteria:-1. Adult patients with (LN) who all were admitted at Nephrology unit. 2. Age more than 18 years. 3. Both sexes. 4. Patients consent to share in the study.

Methods of Study:-
All subjects of the study were subjected to the following:-1. Thorough history and full clinical examination. 2 3. Assessment of the disease activity by SLEDAI-2K scores. Definitions of response to therapy in (LN) according to KDIGO guidelines:-Complete response: Return of S.Cr to previous baseline, plus a decline in the 24 hours urinary protein to less than 500 mg/day. Partial response: Stabilization, or improvement of S.Cr, but not to normal, plus a more than 50% decrease in 24 hours urinary protein. If there was nephrotic-range proteinuria (24 hours urinary protein more than 3 g/day), improvement requires a more than 50% reduction in 24 hours urinary protein and a 24 hours urinary protein less than 3 g/day.
Deterioration: There is no definition of deterioration in (LN) to define treatment failure that has been tested prospectively as an indication to change in initial therapy. A sustained 25% increase in SCr is widely used but has not been validated. (KDIGO 2012) (29) Statistical analysis:-All data were collected, tabulated and statistically analyzed using SPSS 20.0 for windows (SPSS Inc., Chicago, IL, USA), MedCalc 13 for windows (MedCalc Software bvba, Ostend, Belgium) and Microsoft Office Excel 2010 for windows (Microsoft Cor., Redmond, WA, USA). Quantitative data were expressed as the mean ± SD & median (range), and qualitative data were expressed as absolute frequencies ''number''& relative frequencies (percentage). Continuous data were checked for normality by using the Shapiro Walk test. The independent Student t-test was used to compare two groups of normally distributed data. The Mann-Whitney U was used to compare two groups of non normally distributed data. The One way ANOVA test was used to compare more than two groups of normally distributed data. The Kruskal Wallis H test was used to compare more than two groups of non normally distributed data. The Post hoc test for multiple comparisons was done by using Tamhane's T2 method. The percentages of categorical variables were compared using the Chi-square test or Fisher's exact test when appropriate. Spearman's coefficient was calculated to assess relationship between study parameters, a (+) sign indicate a direct correlation & a (-) sign indicates an inverse correlation, while values near to 1 indicate a strong correlation and values near 0 indicate a weak correlation. To determine predictors for subclinical hypothyroidism, univariate logistic regression was done. The backward multivariate logistic regression analysis model was done using any predictor with p<0.2 in the univariate analysis. All tests were two sided. p < 0.05 was considered statistically significant (S), p < 0.001 was considered highly statistically significant (HS), and p ≥ 0.05 was considered non statistically significant (NS). Table (1) showed demographic criteria recorded regarding all our patients as Age, gender, BMI, biopsy class, hypertension, positive ANA, positive Anti ds-DNA, reduced C3 -C4 level, SLE duration in months, basal serum creatinine, 24 hours urine protein , e-GFR and serum albumin.

Results:-
It showed that class IV (LN) is the most common class among all our patients and nearly 51.6% of our patients had hypertension.
There was no significant difference among the different classes of (LN) regarding urine volume/day, ESR, CRP, Hemoglobin level. Serum creatinine, liver enzyme, TSH, serum bilirubin, SLE duration, SLEDAI-2k and FBS, But there was a significant difference among different groups regarding 24 hrs Urinary protein on admission being the highest in class (V-III/IV) (LN) and a significant difference regarding serum albumin being the lowest in class (V-III/IV) (LN) as illustrated in table (2).
Comparison between the number of patients in each group -of the 3 classes of (LN) -who received induction by either oral MMF or iv Cyclophosphamide showed that the highest number of patients receiving iv CYC or oral MMF being in class IV (LN), however this did not show any statistically significant difference. As showed in Table (3). The mucocutaneous, musculoskeletal, hematological and constitutional manifestations represented the highest percentage of manifestations up on which patients sought medical advice and were diagnosed as SLE patients. As illustrated in figure (1) We found that proteinuria, hypertensive emergency and nephritis flare were the 3 most common causes of admission of SLE cases in our unit and its percent is shown in figure (2). We found that 31.3% of patients achieved CR, 45.3% achieved PR and 20.3% were non responders. As regards CR, it was significantly different among the 3 groups being the highest in class III (LN) reaching 47.6%, While PR was much noticed in class V-III/IV (LN), however it failed to establish a significant difference among other groups. Failure of treatment did not show any statistically significant difference among the 3 groups of patients table (4).
Table (5) shows that 9.4% of patient developed complications caused by treatment, while 10.9% developed ESRD and 17.2 % died during the study -(2 of our patients died by unknown causes 3 weeks after starting treatment) -. However none of the 3 parameters of poor outcome showed a significant difference among the 3 classes of (LN).
There was no significant difference between the use of oral MMF or iv Cyclophosphamide, regarding CR or PR, However regarding non responders, a statistically significant difference was noticed as the number of non responders was higher in the CYC arm than the MMF arm reaching 30% of patients in the CYC group, facing only 4.2 % in the MMF arm which can be applied as a point of superiority of MMF over iv CYC, Table (6) and table (7).
Table (8) shows rates of response between males and females with no significant difference; however despite being non significant our male patients showed a higher response rate either CR or PR than females.

Table (9)
shows the difference between responders and non responders regarding SLEADI-2K showing a significant difference being higher in the non responders group.
While Table (10) shows a comparison between responders and non responders regarding demographic, clinical and investigational features. Base line e-GFR showed a significant difference among the 3 groups of responders being the lowest in the non responders & the highest in CR. The higher the e-GFR, the better the response. The same did SLE duration in months which showed significant difference among patients being the lowest in CR & The highest in the non responders. The longer SLE duration is associated with a poorer outcome.

Discussion:
Systemic Lupus Erythematosus (SLE) is a multisystem autoimmune disorder with a broad spectrum of clinical presentations. It can virtually involve any self structure of the body and exhibits a large spectrum of clinical manifestations including cutaneous and joint diseases, renal diseases, hematological involvements and In this study the predominance of female sex was similar to all western studies (Hsu et al., 2011)   Regarding comparative levels of proteinuria & serum albumin between different classes of (LN) , proteinuria was higher in the mixed Class ( V+ III/IV) than other 2 groups reaching 7.6 ± 2.6 g/day & serum albumin was reduced than other 2 groups reaching 2.2 ± 0.6 g/dl, this comes in consistency with Ikeuchi et al., (2016) (14) who reported proteinuria of 5.0 (2.2-6.6) g/day which was higher than pure Class III/IV and a serum albumin of 2.4 ±0.7 g/dl which was lower than pure Class III/IV. In this study, we could not find a statistically significant difference in response between males & females. In fact, the response rate ( either PR or CR ) was surprisingly higher in males than in females reaching {85.7%(6/7) in males & 75.4% (43/57) in females}, although this can be supported by Laura et al., (2016) (9) who stated that" Male sex was not associated with ESRD incidence", this is not in concordance with other studies as Yi et al., (2015) (8) who stated that "the disease severities and organs damage (especially renal impairment) of (LN) in male patients are higher than those of female patients, which was consistent with other studies". This difference can be attributed to the small sample size in our study.
In this study patients with high SLEDAI-2K score developed poorer outcome than those with low score, this correlates with Yi et al., (2015) (8) who reported that 30.9 % patients with SLEDAI score >20 developed ESRD during follow-up.
In this study the response was influenced by SLE duration in months significantly. The shorter the duration the better the response. For patients who achieved CR, the SLE duration in months mean was 17.2 ± 6.8, while those who were considered non responders the SLE duration in months mean was 25.3 ± 8.7. These results are similar to the previously reported, suggesting that delayed (LN) development tends to progress in tandem with renal damage compared to the good therapeutic response that (LN) typically manifests at SLE onset Takahashi et al., (2009) (7). However, this come in contrast with The Spanish study in which the onset time of (LN) during the course of SLE did not affect the outcome of renal function Galindo-Izquierdo et al., (2016) (6).

Conclusion:-
In conclusion, the results of our study revealed the high prevalence of class IV (LN) among SLE patients, the little superiority of MMF over cyclophosphamide in induction of remission and the better outcome of class III lupus nephritis over other classes.
Given the poor outcome of (LN) among SLE patients, depending on the class of the biopsy , our findings suggest that future studies are warranted with special stress on the mixed class of (V-III/IV) (LN) with the consensus on international definitions of remission and treatment failure beside the introduction of new drugs and local guidelines based on clinical trials.