Clinical and biochemical manifestations of systemic lupus erythematosus at first diagnosis within Chinese patients

Bankground: The objective of this paper was to describe the first symptoms associated with systemic lupus erythematosus (SLE), including clinical manifestations, laboratory findings, prognoses, differences between men and women at the time of first diagnosis of SLE. Methods : We enrolled 223 patients with initial diagnosis of SLE. Their initial symptoms, demographic, clinical and laboratory dataprognoses and causes of death were analyzed retrospectively. Clinical manifestations and laboratory profiles were compared between male and female patients. Results: Compared with female patients, male patients had an earlier age of onset, a higher incidence of neuropsychiatric involvements, a lower incidence of leukocytopenia , and a higher score of SLE Disease Activity Index (SLEDAIat diagnosis. Fever and malar rash were most frequent presentations at onset of SLE. The most common clinical manifestation at first diagnosis was fever, followed by arthralgia, malar rash, Raynaud ’ s phenomenon, arthritis. The liver function abnormalities included increased ALT,AST,ALP and γ-GGT.ANA were found in 100% of patients, followed by anti-dsDNA(LIA) in 72.1%, anti-Ro60 in 67.8%, anti-Ro52 in 62.3%, anti-nucleosomes in 55.7%. Conclusions: We identified clinical and serological manifestations of Chinese SLE patients at first diagnosis. Male patients showed a distinctive manifestation including younger age of onseta higher incidence of CNS manifestations, a higher score of SLEDAI compared to females.


Background
Systemic lupus erythematosus(SLE) is a chronic autoimmune disease involving various organs and systems.Management of SLE is vastly complicated owing to the considerable variabilities in the clinical and laboratory manifestations, disease courses, and prognoses, particularly on the grounds of sex 1 .Accordingly, the timely diagnosis of patients with SLE is often delayed 2, 3 .The care of SLE patients also has its challenges owing to the considerable sex-specific variabilities in the clinical and laboratory.Especially, a notable impact upon woman of childbearing age are most susceptible 1, 4 .
Ninety-three percent of SLE patients survive over 5 years from diagnosis 5 , of which infection, lupus encephalopathy, atherosclerosis and pulmonary hypertension are the most frequent causes of death 6, 7 .Few studies, however, have reported on the cause of death in SLE patients followed up from their initial diagnoses.To the contrary, research on the clinical and biochemical features accumulating over the course of diseases are abundant 1, 8, 9 .Whilst a snapshot of the clinical and biochemical manifestations at onset of SLE has been described 10 ,no studies have yet reported on a cohort of Chinese SLE patients.
The present study was aimed to outline the clinical and biochemical manifestations first diagnosis of Chinese patients with SLE, which deepened our understanding on the prognosis.We also compared the differences in these parameters between male and female patients.

Patients
A cohort of 223 patients suffered from SLE with the first diagnosis, attending the department of rheumatology and immunology of first affiliated hospital to Bengbu medical college between January 2012 and December 2015, were enrolled and retrospectively analyzed.All patients were fulfilled the American College of Rheumatology revised classification criteria for SLE in 1997 11 .Patients' medical records were collected, of which the following data were extractedsex; the first clinical symptoms associated with SLE; age at disease onset defined as age when symptoms were first presented; age at the time of first diagnosis of SLE, duration between the presentation of clinical symptoms associated with the onset of SLE and the formal diagnosis of SLE; organ involvements; concomitant diseases(s); SLE Disease Activity Index(SLEDAI score; clinical and laboratory manifestations; causes of death.

Clinical outcomes
The clinical manifestations included: fatigue; fever; arthritis; arthralgia; malar rash; discoid rash; alopecia; photosensitivity; oral ulcer; raynaud , s phenomenon; vasculitis of hands; limbs rash and organ involvements of cardiac, lung, hematologic, renal, digestive and central nervous systems.Fever was considered when body temperature was 37.3℃ without other causes.
Pulmonary hypertension and intestinal pseudo-obstruction(IPO) were also noted within SLE patients at the time of diagnosis.Disease activity was evaluated by SLEDAI scoring, with a significantly lower score in females than males(P=0.048).

Laboratory findings at the time of first diagnosis of SLE
In addition to clinical manifestations, an array of laboratory tests pertaining to 51 indices of hematological, hepatic, digestive, immunological, renal, and urinary profiles were determined at the time of first diagnosis of SLE(Table 2).Hematologic abnormalities were noted within the majority of SLE patients at the time of first diagnosis.Anemia was the most common hematological manifestation noted within the cohort of 223 Chinese patients(82.7%),followed by lymphopenia(72.1%),hypoeosinophilia(52.8%),leukocytopenia(45.1%),and thrombocytopenia(23.0%).
There were 7 SLE patients(3.2%) with hemolytic anemia at time of their first diagnosis.
The prevalence of proteinuria of >0.5 /d and ≥3+ within SLE patients at the time of first diagnosis were 45.1% and 16.6%, respectively.Meanwhile, the prevalence of pyuria was 33.3%, followed by hematuria(21.3%),elevatedserum creatinine(5.4%),and finally casts in urine(0.5%).There was no significant difference in the prevalence of renal involvements within males and females.

Discussion
In the present study, there were ~21 incidences of SLE in females per male at the time of first diagnosis, which differed somewhat from the ~10 female to 1 male case reported elsewhere 1, 9, 15-17 .On the other hand, three studies observed an approximate 18 to 23 SLE diagnoses within female for every male diagnosis.18, 19 .The mean age at the onset of SLE was 34.14±13.07,whichwas in accordance with previous studies 9, 10 .Furthermore, in consolidation with previous studies, the average age at onset of SLE was younger in men than in women of our cohort 1 .The mean duration between the onset of symptoms associated with SLE and diagnoses was longer than data reported within other studies 1, 9, 20 .
The most frequent manifestations at onset of SLE are typically of musculoskeletal or mucocutaneous involvements 1 .In juvenile SLE, pallor and fever tend to present first 21 .
Within our cohort, malar rash and fever were the most common initial presentations (17.9%), followed by arthralgia(17.5%),arthritis(9.4%),and renal involvements(9.4%).The prevalence of fever at onset of SLE is highly discrepant within the literature, with the percentage of male and female SLE patients being 41.5% in men and 43.9% in women 20 , whilst Choi et al. observed fever within 28% of patients at the onset of SLE(28%) 10 .Fever may develop within SLE patients due to an immunological response to active disease or infection, or as part of bodily reactions to the treatment.44.4% of cohort had fever at the time of SLE diagnosis, which may attribute to the underlying disease activities.By temperature, a moderate fever was most frequent (38.1-39°C), followed by mild (37.3-38°C) and severe (>39°C) fever.Though, it should be noted that it was not possible to determine all fevers, which may have skewed the results in a manner unseen thus far.
Arthritis or arthralgia are common presentations at diagnosis of SLE 10 and late-onset lupus 22, 23 .But the occurrence rate of arthritis and arthralgia in our patients was less than that was reported in the aforementioned studies.Cutaneous involvement is also frequently reported in SLE patients, of which malar rash and photosensitivity are the most common 1 .Our study showed that malar rash was frequent cutaneous manifestations at time of SLE diagnosis, followed by Raynaud ' s phenomenon and alopecia, whilst discoid rash was rare.Less than 20% of SLE patients were reported to have pericarditis at first diagnosis 9, 23 .Myocarditis had also been observed in patients at diagnosis of SLE 23 , the prevalence of which was similar with our cohort.Pulmonary involvement, pleuritis, ILD, and pulmonary hypertension were observed within our patients, as also described by Catoggio et al 23 .
Hematological abnormalities are commonly observed within SLE patients.Aleem et al.
previously observed anemia, lymphopenia and leukopenia at time of diagnosis within 63%, 40%, and 30%of SLE patients, respectively 24 .Our study showed that 82.7% of Chinese patients with a first diagnosis of SLE had anemia, whilst 72.1% had lymphopenia and 52.8% had hypoeosinophilia.Mononucleosis or monocytopenia was presented around 9% of our patients.The occurrence of thrombocytopenia was not less common, and 23% patients presented thrombocytopenia.Renal involvements are commonly reported at initial diagnosis of SLE, such as renal lesions, proteinuria, hematuria, pyuria, and elevated serum creatinine 10 .Proteinuria, defined as the urinary excretion of > 0.5 grams protein per day, was the most common disorder within the present cohort.Of the renal abnormalities, 45.1% of patients had pyuria and hematuria, whilst casts in urine were rare.
Liver biochemical abnormalities in patients with SLE are typically attributed to obesity, hypertension, and the hepatotoxic effects of therapeutic medication 25 .But it may also be due to the autoimmunity inherent to SLE 26 .Our study showed that elevated serum ALT, AST, ALP, and γ-GGT were presented within 14.9,16.5,19,4,22% of the present cohort, respectively.We had strong confidence that, since infection and drug confounders were excluded, these abnormalities were solely due to SLE.Elevated TBIL resulting from SLE was rare in our patients.Elsewhere, the prevalence of neuropsychiatric SLE(NPSLE)reportedly ranged from 21% to 95% in SLE patients 27 , but we found, by contrast, a prevalence of 4.5% in our study.
Eudy et al. observed that elevated CRP was associated with a greater prevalence of flares in SLE patients, and may therefore be predictive for disease activity 28 .The prevalence of elevated CRP was 43.6% in our cohort.Raised ESR is also associated with disease activity and organ-specific activity in SLE 29 , and is particularly common within SLE patients (~79%) at the time of diagnosis 24 .The prevalence of elevated ESR was 78.3% within the present study.The mean SLEDAI score of disease severity was 9.53,which was classified as a moderate activity 30  positive for ANA at the onset of SLE 10 .We also found that >50% of patients had positivity for the anti-nucleosomes, anti-Sm and anti-U1snRNP.The positivity of anti-dsDNA was variable and highly dependent upon the detection method used.Anti-Ro52 and anti-Ro60 were frequent in 62.3% and 67.8% of SLE patients, respectively.Only Choi et al. reported the presence of anti-Ro52 at diagnosis of SLE 10 .
The primary causes of death in SLE patients have changed over time.Whilst lupus activity has decreased over time, co-mortality from infections are now most common within SLE patients 7 .Our data showed that the primary cause of death within SLE was lupus activity.Anti-ds-DNA and anti-nucleosome play a major role in the pathogenesis of lupus nephritis 31 , but our results showed that anti-Ro52 also correlated with LN.
Furthermore, anti-U1RNP in cerebrospinal fluid(CSF) is typically associated with NPSLE 32 , whereas we found that anti-U1snRNP in serum was associated with NPSLE.
Whilst male patients tend to develop identical clinical and biochemical manifestations of SLE compared with female patients, males tend to exhibit a higher renal involvement, pleurisies and serositis, thrombocytopenia 17 .Furthermore, our data showed that SLE onsets at a younger age within males, and, at diagnosis, tended to have a higher prevalence of vasculitis of the hands, CNS manifestations, a lower rate of leukocytopenia, and a higher SLEDAI score compared to women.Hematuria was higher in men, but not statistically significant.
The present study outlined the clinical manifestations and laboratory features, and their relative prevalence within 223 Chinese patients, at diagnosis of SLE.We acknowledge that there are many limitations of this study, including the limited number of patients, and of males in particular.Additionally, this was performed in a single center.
A larger-scale, multicenter study is needed to clarify the feature s of Chinese patients at initial diagnosis of SLE.

Conclusions
We identified that fever and malar rash were the most common first symptoms associated with SLE; that fever, arthralgia and malar rash were the most frequent clinical manifestations within SLE at the time of first diagnosis; that the cause of death in SLE patients at diagnosis was lupus activity; that male patients had a higher score of SLEDAI and a lower incidence of leukocytopenia.

Abbreviations
To the contrary, aberrant low serum ALB was noted in72.9% of SLE patients at the time of their diagnosis.Elevated TBIL was relatively uncommon which was only found in 2.0% of 196 patients.There was no difference in the prevalence of abnormal liver-function tests within male and female patients of SLE(Table2).Inflammatory markers, most notably CRP and ESR, were detected in many SLE patients at first diagnosis (Table2).ESR was elevated in the majority of SLE patients (78.3%), with the mean level at 55.87±32.12mm/h.The mean level of CRP was 8%) of the 223 enrolled SLE patients died during the course of the study; the causes of which are presented in Table4.Three patients succumbed to complications associated with active SLE, whereas the other one patient died from pulmonary hypertension and cardiac failure.The duration between diagnosis and SLE-rated deaths were < 6 months.There was no difference in death prevalence between men and women (Table2).Overall, the vast number of autoantibodies determined had no significant correlations with NPSLE or lupus nephritis.Anti-U1snRNP, however, was negative indicator for NPSLE(OR=0.187;P=0.047), and anti-Ro/SSA52 antibody was associated with lupus nephritis(OR=2.424;P=0.006).
Many parameters of liver function were considered abnormal.Serum ALT,AST, ALP, γ-GGT, and GLB were elevated at first diagnosis of SLE(14.9,16.5,19.4,22.0, and 29.8% prevalence, respectively).immunoglobulinlevelsand the presence of 18 autoantibodies at SLE diagnosis (Table3).At the time of initial diagnosis of SLE, 100% of SLE patients were tested positive for ANA, whereas 52.1% were positive for anti-dsDNA (IIF), rising to 72.1% if determination was via LIA.Anti-histones antibodies and anti-nucleosomes were positive in 55.9 and 55.7% of SLE patients sampled.Of the extractable nuclear antibodies, anti-Ro/SSA60 antibodies were the most prevalent (67.8%), followed by anti-Ro/SSA52 (62.3%), anti-U1snRNP (55.5%), anti-Sm in (55.4%), anti-ribosomal P0 (44.4%), anti-La/SSB (27.9%), anti-MPO (3.5%), anti-Scl70 (1.3%), and anti-PR3 (0).None of the SLE patients were positive for the anti-Jo1 .Rheumatoid factor was elevated in 50.5% (46/91)of SLE patients, whereas the anti-CCP antibody was present in only 4.6% of those sampled.Anti-phospholipid antibodies were observed at diagnosis in a subset of patients, including aCL(13.2%) and anti-β2GP1 (21.12%).There was no significant difference in the aforementioned autoantibodies within male and female patients.Serum IgG, IgA, and IgM were elevated in 71.0, 48.0, and 3.1% of SLE patients, respectively, and decreased in 2.4, 0.4, and 7.2%.Neuropsychiatric and renal involvements were associated with a worse prognosis 13, 14 ,and as such we analyzed that the correlation between the presence of autoantibodies at the time of first SLE diagnosis and neuropsychiatric systemic lupus erythematosus (NPSLE) or lupus nephritis.