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Hematological presentation in systemic lupus erythematosus and its relationship with disease activity

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Hematological presentation in systemic lupus erythematosus and its relationship with disease activity

Eśin Beyan a; Cen?iz Beyan b; Mustafa Turan c

a Department of Internal Medicine, Numune Education and Research Hospital,

Ankara, Turkey

b Department of Hematology, Gulhane Military Medical Academy, Etlik, Ankara,

Turkey

c Department of Medical Ecology and Hydroclimatology, Gulhane Military Medical

Academy, Ankara, Turkey Online Publication Date: 01 June 2007 To cite this Article: Beyan, Eśin, Beyan, Cen?iz and Turan, Mustafa (2007) 'Hematological presentation in systemic lupus erythematosus and its relationship with disease activity', Hematology, 12:3, 257 - 261 To link to this article: DOI: 10.1080/10245330701214145 URL: http://dx.doi.org/10.1080/10245330701214145 PLEASE SCROLL DOWN FOR ARTICLE Full terms and conditions of use: http://www.informaworld.com/terms-and-conditions-of-access.pdf This article maybe used for research, teaching and private study purposes. Any substantial or systematic reproduction, re-distribution, re-selling, loan or sub-licensing, systematic supply or distribution in any form to anyone is expressly forbidden. The publisher does not give any warranty express or implied or make any representation that the contents will be complete or accurate or up to date. The accuracy of any instructions, formulae and drug doses should be independently verified with primary sources. The publisher shall not be liable for any loss, actions, claims, proceedings, demand or costs or damages whatsoever or howsoever caused arising directly or indirectly in connection with or arising out of the use of this material.

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Hematological presentation in systemic lupus erythematosus and its relationship with disease activity

ES ´IN BEYAN1, CENG ´ IZ BEYAN2, & MUSTAFA TURAN3

1Department of Internal Medicine, Numune Education and Research Hospital, Ankara, Turkey, 2Department of Hematology,

Gulhane Military Medical Academy, Etlik, 06010 Ankara, Turkey, and 3Department of Medical Ecology and Hydroclimatology, Gulhane Military Medical Academy, Ankara, Turkey

(Received 5 September 2006; accepted 1 December 2006)

Abstract Abnormalities of hematological system are very common in systemic lupus erythematosus (SLE). The aim of the study is to evaluate hematological findings in patients with SLE at the time of referral and their relationship with disease activity and

• rgan involvement.

The study was carried consecutive 115 patients, including 20 males and 85 females. Most of the cases had anemia at the time of presentation due to various etiologies. Anemia of chronic disease was seen in 46% and it was the most common encountered picture. The rate of hemolytic anemia was 28%, and Coombs’ positivity rate was 22% among our patients. Leukopenia (,4.0 £ 109/l), neutropenia (,1.8 £ 109/l), and lymphopenia (,1.5 £ 109/l) rates were 57, 20, and 82%,

• respectively. Thrombocytopenia was seen in 40% for ,150 £ 109/l, 26% for ,100 £ 109/l, and 8% for ,50 £ 109/l. Of our

patients, 10% had antiphospholipid syndrome (APS) at the time of diagnosis. Increased fibrinogen levels were observed in 35% without relating to disease activity. The rates of C3 and C4 hypocomplementemia were 86 and 64%, respectively, and both are closely correlated with the disease activity. Moreover, C3 hypocomplementemia was more prominent in cases with renal or serosal involvement. Leukopenia and hyperfibrinogenemia were more common in patients with skin/mucosal

• involvements. C3 hypocomplementemia, APS and elevated IgG levels were more common in our patients with renal
• involvement. SLE should be kept in mind while evaluating patients with mentioned hematological findings, especially in those

with accompanying organ involvements. Keywords: Anemia, blood cells, leukopenia, lupus erythematosus, systemic, thrombocytopenia

Introduction Systemic lupus erythematosus (SLE) is a chronic inflammatory disease, which can affect the skin, joints, kidneys, lungs, nervous system, serous membranes and/or other organs of the body. Abnormalities of hematological system are very common in SLE. The aim of the present study is to determine hematological disturbances in patients with SLE at the time of referral and their relationship with disease activity and organ involvement. Methods The study was carried on a group of consecutive 115 patients, including 20 males and 85 females, who were treated for SLE in our center. The mean age of the patients was 28.94 ^ 8.46 years (mean ^ SD) (range 16–56). All patients were fulfilled the American College of Rheumatology (ACR) 1982 revised criteria for the classification of SLE [1]. The mean disease age

• f the patients (duration between the first symptom/

sign occur and the diagnosis date) was 1 year (range: 1 week–8 years). The systemic lupus erythematosus disease activity index (SLEDAI) was developed by the consensus of experts as a global assessment of lupus disease activity [2]. Evaluation of SLE disease activity was based on the SLEDAI. According to SLEDAI scores, SLE patients were divided into two groups: Those with SLEDAI scores #10 and those with SLEDAI scores

ISSN 1024-5332 print/ISSN 1607-8454 online q 2007 Informa UK Ltd. DOI: 10.1080/10245330701214145

Correspondence: C. Beyan, Department of Hematology, Gulhane Military Medical Academy, Etlik, 06010 Ankara, Turkey. Tel: 90 312 304 41 01. Fax: 90 312 304 41 00. E-mail: cbeyan@yahoo.com

Hematology, June 2007; 12(3): 257–261

Downloaded By: [ANKOS Consortium] At: 07:38 21 January 2008 $11 [3]. Mild to moderate disease is associated with SLEDAI scores #10 whereas SLEDAI scores $11 are associated with greater disease activity [3]. Forty patients had mild to moderate disease activity and 75 patients had severe disease activity regarding their SLEDAI scores. Organ involvement was defined using criteria proposed by Lim et al. [4]. Antiphospholipid syndrome (APS) was diagnosed using definition by Alarcon-Segovia [5]. Chi-square and Fisher’s exact tests were applied in statistical analysis. An a level of 0.05 was considered to be statistically significant. Statistical analysis was performed MS Excel XP software. Results Hematological findings at the time of diagnosis of the SLE patients are presented in Table I. Organ involvements of the SLE patients are presented in Table II. Hematological findings of the patients correlated with the disease activity are presented in Table III. Organ involvement correlated with the hematologi- cal findings are presented in Table IV. Discussion PatientswithSLEfrequentlydevelopabnormalitiesinall three blood cell lines. They may also have thrombophi- lia, an increased propensity to develop thromboembolic disease. Anemia is a frequent occurrence in SLE. Multiple mechanisms contribute, including inflammation, renal insufficiency, dietary insufficiency, and hemo- lysis [6–9]. Most of our cases (93%) had anemia at the time of presentation and was considered multifactor-

• ial. The most frequent cause of anemia in SLE is

suppressed erythropoiesis from chronic inflammation (anemia of chronic disease) [7,8]. The rate of anemia

• f chronic disease among our patients was 46% and it

was the most common encountered picture. Iron deficiency anemia is not rare in SLE, especially among teenagers or young women. Iron deficiency anemia cases were comprise 17% of our cases and all of them were females of reproductive age. However, iron deficiency anemia in our patients and anemia related to vitamin B12 deficiency, which was diagnosed in few cases was not directly attributed to SLE, as it mirrored that encountered commonly in the general popu-

• lation. The rate of hemolytic anemia was 28%, and

Coombs’ positivity rate was 22% among our patients. Overt autoimmune hemolytic anemia (AIHA) and/or a positive direct Coombs’ test has been noted in approximately 10% of patients with SLE [6,7,10]. The higher rate observed in our study sample may be explained by the delayed in referral of the patients for

• review. This reflects the lack of health insurance cover,

so that most of the cases were referred at a rather late period of their disease. As a result, more severe cases including AIHA were seen at the time of their initial presentation for investigation of their disease. Leukopenia is common in SLE. A white blood cell count of less than 4.5 £ 109/l has been noted in approximately 50% of patients [6,7]. A white blood cell count below 4.0 £ 109/l (the ACR criteria) occurs

Table I. Hematological abnormalities and their frequency in patients at the time of referral. Abnormality Frequency Anemia 103/115 (89.56%) Iron deficiency 19/115 (16.52%) Vitamin B12 deficiency 4/115 (3.48%) Anemia of chronic disease 53/115 (46.09%) Hemolytic anemia* 32/115 (27.83%) Coombs’ positive 25/115 (21.74%) Coombs’ negative 7/115 (6.09%) Abnormalities of white blood cells 99/115 (86.09%) Leukopenia (,4.0 £ 109/l)* 66/115 (57.39%) Neutropenia (,1.8 £ 109/l) 23/115 (20.00%) Lymphopenia (,1.5 £ 109/l)* 94/115 (81.74%) Anemia or abnormalities of white blood cells 113/115 (98.26%) Thrombocytopenia (,100 £ 109/l)* 30/115 (26.09%) Thrombocytopenia (,150 £ 109/l) 46/115 (40.00%) Cytopenia 115/115 (100.00%) Antiphospholipid syndrome 11/115 (9.56%) Decreased fibrinogen 6/115 (5.22%) Elevated fibrinogen 40/115 (34.78%) C3 hypocomplementemia 99/115 (86.09%) C4 hypocomplementemia 74/115 (64.35%) Elevated IgG 72/115 (62.61%) Decreased IgG 4/115 (3.48%) Elevated IgA 27/115 (23.48%) Decreased IgA 1/115 (0.87%) Elevated IgM 22/115 (19.13%) Decreased IgM 2/115 (1.74%) * Included in revised ACR criteria for SLE classification. Table II. Organ involvements. Skin/mucosal involvement 96/115 (83.48%) Malar rash 72/115 (62.60%) Discoid rash 21/115 (18.26%) Alopecia 67/115 (58.26%) Oral ulcer 50/115 (43.48%) Musculoskeletal involvement 98/115 (85.22%) Arthralgia 98/115 (85.22%) Myalgia 35/115 (30.43%) Arthritis 63/115 (54.78%) Renal involvement 51/115 (44.35%) Proteinuria 38/115 (33.04%) Hematuria 35/115 (30.43%) Presence of casts 13/115 (11.30%) Decreased creatinine clearance (#70 ml/min) 20/115 (17.39%) Serositis 38/115 (33.04%) Pleuritis 23/115 (20.00%) Pericarditis 29/115 (25.22%) Central nervous system involvement 8/115 (6.96%) Seizures 6/115 (5.22%) Psychosis 4/115 (3.48%)

• E. Beyan et al.

258

Downloaded By: [ANKOS Consortium] At: 07:38 21 January 2008 in only 15–20% of patients [6,11]. Lymphopenia (less than 1.5 £ 109/l), especially involving suppressor T cells, has been observed in 20–75% of patients, particularly during active disease [6,12]. Leukopenia (,4.0 £ 109/l), neutropenia (,1.8 £ 109/l), and lym- phopenia (,1.5 £ 109/l) rates were 57.39, 20.00 and 81.74%, respectively, among our patients. These findings reveal that white blood cell abnormalities are more common in our population than those reported in the literature. Mild thrombocytopenia (platelet counts between 100 £ 109/l and 150 £ 109/l) has been noted in 25– 50% of patients; while counts of less than 50 £ 109/l

• ccur in only 10% [6,7,11]. Thrombocytopenia was

noted in 40% for ,150 £ 109/l, 26% for ,100 £ 109/l, and 8% for ,50 £ 109/l in our cases. Between 34 and 42% of SLE patients have the APS. Of our patients, 10% had APS at the time of diagnosis. Ames et al. reported that fibrinogen levels of SLE patients were higher than those seen in healthy controls; however, they claimed that this observation is not related to the disease activity [13]. Increased fibrinogen levels were observed in 35% of our patients without relating to disease activity. Serum complement levels, as measured by assays for C3, or C4 are often depressed in patients with SLE, and may correlate with disease activity. Complement levels are especially low if there is kidney

• involvement. The rates of C3 and C4 hypocomple-

mentemia were 86 and 64%, respectively, and both are closely correlated with the disease activity. Moreover, C3 hypocomplementemia was more prominent in cases with renal or serosal involvement. The skin and mucous membranes are symptomati- cally involved, to some extent, in over 80% of patients with SLE [14–18]. The classic acute butterfly rash appears in approximately one-half of the patients. Chronic discoid lesions develop in up to 25% of patients with SLE [16]. Hair loss occurs in a majority of patients with SLE at some time during their illness [19]. Mucous membrane involvement occurs in 25– 45% of patients with SLE [20,21]. The oral lesions of lupus demonstrate the typical histopathology of skin lesions, including deposits of immunoglobulin and complement at the dermal–epidermal junction [22]. Skin/mucosal involvement was observed in 83%, malar rash in 63%, discoid rash in 18%, alopecia in 58% and

• ral ulcers in 43% of the patients. The observance rates

are similar with those published in the literature. No significant difference observed in our patients with oral ulcers considering immunoglobulin and complement levels in sera. Leukopenia and hyperfibrinogenemia were more common in patients with skin/mucosal involvement, and hyperfibrinogenemia was prominent in patients with oral ulcers. A PubMed search reveals that there is no published study on these findings.

Table III. Hematological findings of the patients that correlated with their disease activity. Abnormality Mild/moderate SLEDAI (n ¼ 40) Severe SLEDAI (n ¼ 75) p values Anemia 32 71 0.018* Coombs’ negative hemolytic anemia 5 2 0.048* Lymphopenia (,1.5 £ 109/l) 28 66 ,0.05† C3 hypocomplementemia 25 74 2.39 £ 1027* C4 hypocomplementemia 18 56 ,0.01† * Fisher’s exact test; † Chi-square test. Table IV. Organ involvements of the patients that correlated with their hematological findings. Abnormality Organ involvement p values Anemia Renal involvement 0.037 Anemia Serositis 0.047 Coombs’ positive hemolytic anemia Serositis ,0.05 Leukopenia Skin/mucosal involvement ,0.05 Antiphospholipid syndrome Renal involvement 0.046 Proteinuria 0.030 Hyperfibrinogenemia Skin/mucosal involvement ,0.01 Oral ulcer ,0.05 C3 hypocomplementemia Renal involvement 0.023 Proteinuria 0.049 Hematuria 0.017 C3 hypocomplementemia Serositis 0.049 Pericarditis 0.047 Elevated IgG Renal involvement ,0.05 Proteinuria ,0.01 Decreased creatinine clearance ,0.05

Hematological presentation of SLE 259

Downloaded By: [ANKOS Consortium] At: 07:38 21 January 2008 Involvement of the musculoskeletal system is extremely common in patients with SLE. Arthralgia has been noted in up to 95% of patients with SLE. Arthritis has been noted in 15–50% of patients with SLE [23–26]. Myalgias, muscle tenderness, or muscle weakness occur in up to 70% of patients with SLE [27]. Musculoskeletal involvement and arthralgia was

• bserved in 85%, arthritis in 55% and myalgia in 30%
• f our cases and they are relevant with those published

in the literature. No significant relationship was

• bserved between musculoskeletal involvement and

hematological findings at the time of diagnosis. Renal involvement is common in SLE. An abnormal urinalysis with or without an elevated plasma creatinine concentration is present in approxi- mately 50% of patients at the time of diagnosis. The most frequently observed abnormality is proteinuria (80%); while approximately 40% have hematuria. However, an elevated plasma creatinine concentration develops in approximately 30% of all patients with

• SLE. The rate of renal involvement was 44%,

proteinuria was 33%, hematuria was 30%, and decreased creatinine clearance was 17% in our patients, similar those reported in the published

• studies. C3 hypocomplementemia, APS, and elevated

IgG levels were more common in our patients with renal involvement. Most patients with lupus nephritis have an immune complex-mediated glomerular dis-

• ease. The pattern of glomerular injury seen in SLE is

related to the site of formation of the immune deposits [28–34]. As a result, activation of complement with the generation of the chemoattractants C3a and C5a results in the influx of neutrophils and mononuclear

• cells. These findings may explain why C3 hypocom-

plementemia and elevated IgG levels were observed in

• ur patients with renal involvement. Additionally, it

was argued that APS, which is more frequent in SLE patients with renal involvement, may be responsible for the observed renal pathology itself. As Bhandari et al. postulated, “In those lupus patients with an associated circulating anticoagulant there may be a tendency to develop thrombi and crescents, leading to further sclerosis and more aggressive deterioration in glomerular function. However, a complex interrelationship between intra-capillary glomerular thrombi, circulating anticoagulants and lupus nephri- tis probably exists” [35]. This argument may explain the mechanism of increased amount of APS in patients with renal involvement. Serositis involving the pleura and/or pericardium

• ccurs in 20–50% of SLE patients at some time

during the course of their disease [36]. At the time of presentation, serosal involvement was 33%, pleural effusion was 20%, and pericardial effusion was 25% in

• ur cases. Lupus effusions are characterised by low

complement levels, as well as in our cases. Neurologic and psychiatric symptoms occur in 10– 80% of patients, either prior to the diagnosis of SLE or during the course of their illness [37–40]. Seizures develop in approximately 15–20% of patients with SLE [41]. Organic psychosis occurs in approximately 5% of patients with SLE. These symptoms were

• bserved in 7% of our patients, whereas seizures
• bserved in 5% and psychosis in 3%. No significant

relationship was observed between neurological and hematological findings. As a result, anemia, leukopenia, thrombocytopenia

• r other hematological abnormalities may occur alone
• r in combination at the onset of SLE. Anemia and

white cell abnormalities were observed in almost all cases at the time of diagnosis. SLE should be kept in mind while evaluating patients with mentioned hematological findings, especially in those with accompanying organ involvements. References

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Hematological presentation of SLE 261

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