Systemic lupus erythematosus in the Fars Province of ... - SAGE Journals

Lupus (2008) 17, 221–227 http://lup.sagepub.com

LUPUS AROUND THE WORLD

Systemic lupus erythematosus in the Fars Province of Iran MA Nazarinia1, F Ghaffarpasand2, A Shamsdin3, AA Karimi2, N Abbasi2 and A Amiri2 1

Rheumatology Department of Shiraz University of Medical Sciences, Shiraz, Iran; 2Student Research Committee of Fasa University of Medical Sciences, Fasa, Iran; and 3Immunology Department of Fasa University of Medical Sciences, Fasa, Iran

Abstract

Clinical features of systemic lupus erythematosus (SLE) have been described from different geographical regions in the world. However, data from many Middle East countries, including Iran, are scarce. This study aims to demonstrate the demographic, clinical, and laboratory characteristics in Iranian patients with SLE. In this prospective study, all the patients referring to Shiraz educational hospitals (Nemazi–Hafez) with SLE (American College of Rheumatology criteria) during a 5-year period (2001 to 2006) were included. A complete history was taken; physical examination and routine hematological, serological, and immunological tests were done for each patient. There were 356 women and 54 men with an average age of 30.27 years at the onset of disease. Of the patients, 78% had hematological abnormalities, 65.5% had articular involvement, 54.5% had photosensitivity, and 60.5% had malar rash. Serositis occurred in 38% of patients of whom 12% had pericarditis and 26% had pleuritis. Nephritis was diagnosed in 48% of the cases and consisted always of glomerular nephritis. Biopsy-proven lupus nephritis was in most cases class IV(49.7% of all the biopsies). Oral ulcers were observed in 28% of patients. Neuropsychiatric manifestations, gastrointestinal involvement, and lymphadenopathy were observed in 31.5%, 8.3%, and 14.2% of patients, respectively. In all, 93% of patients were positive for antinuclear antibodies, whereas antidouble-stranded DNA was positive in 83% of patients. Coomb’s positive hemolytic anemia appeared in 12.4% of the cases. Rheumatoid factor was detected in 9.7% of patients, and lupus erythematosus cell was seen in 32.5% of them. In all, 196 (47.8%) patients represented hypocomplementemia. Regarding hematological manifestations, 74.5% had microcytic hypochromic anemia, 64.6% had leukopenia, and 44.6% had thrombocytopenia; 18 (4.4%) patients died during the study period of which eight (2%) died because of cardiopulmonary involvement. Generally, there was more cutaneous, serositis, and neuropsychiatric involvement in our population than other Middle East countries. Serositis was associated with poorer prognosis, and the pattern of disease in these patients was much more sever than patients without serositis (P = 0.001). This is the first study of its kind in Iran. More multicenter studies should be undertaken in Iran to describe the pattern of SLE. Lupus (2008) 17, 221–227. Key words: clinical manifestations; cutaneous characteristics; immunological features; Iran; systemic lupus erythematosus

Introduction Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with a wide spectrum of clinical and immunological abnormalities.1 There is a wide variation in the natural history of SLE among different ethnic and geographical groups.2–4 Genetic, environmental, and sociodemographic factors play important roles in the pathogenesis and expression of this disease.5–7 This multiplicity of etiological factors could Correspondence to: Fariborz Ghaffarpasand, Fasa University of Medical Sciences, Ebne Sina Square, Fasa, Iran, PO Box 7461686688. Email: [email protected] Received 1 September 2007; accepted 25 October 2007 © 2008 SAGE Publications Los Angeles, London, New Delhi and Singapore

explain the variability of disease manifestations observed not only between individuals but also between ethnic groups.2,8,9 The understanding of the distinctive manifestations and the course and outcome of SLE among different ethnic groups could lead to a better understanding of the factors that contribute to these differences and to the delivery of better medical care to these populations. Furthermore, clinical features of SLE have been described from different geographical regions in the world, with some clinical differences among different racial groups.10 The Hopkins Lupus Cohort, a prospective longitudinal study of SLE outcomes, has shown that race is a major predictor of clinical manifestations, laboratory 10.1177/0961203307086509

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and serological tests, and disease-related morbidity.11 Some studies shows that the prevalence of SLE is higher among Chinese12,13 and Asian Indian14 in comparison with Arabs.15 However, data from many Middle East countries, including Iran are scarce.

Lupus and Fars province Fars province is located in the south of Iran. This province cover 122,483 sq km with a population of just over 5.5 million mainly comprising Iranians (73.2%). Fars encompasses people of different sociocultural backgrounds living in climatic extremes with an environmental spectrum ranging from urban life in big cities, life in deserts and nomadic life to life in mountain ranges and valleys (Figure 1). For most individuals in Iran, health care is provided at government polyclinics and public hospitals. Although Iran has made advances in different fields (especially medical research in recent years), there is a lag in the field of medicine as evident by the fact that

Figure 1 Map of Iran and Fars province (study area). Lupus

the country is facing multiple problems in providing quality health care services to all its citizens due to insufficient resources and inadequate governance and management. There are two major rheumatology centers (Nemazi and Hafez hospitals) in Shiraz (center of Fars province) that are tertiary referral centers from all parts of Fars. One of these centers (Hafez hospital) has an SLE clinic. Patients from all parts of Fars diagnosed as SLE are registered in this clinic. Five rheumatologists work in this clinic. The SLE patients refer to this clinic routinely for assessing the progression of disease and to get appropriate medication. There are a few publications on SLE in the international literature from Iran. This is, to our best knowledge, the first study that aims to demonstrate the demographic, clinical, and laboratory characteristics in Iranian patients with SLE.

Patients and methods We performed a prospective study of the cases diagnosed as SLE in two tertiary referral centers (Department of Rheumatology, Nemazi and Hafez University Hospitals in Shiraz) during a 5-year period (2001–2006). Only patients with symptoms of at least one-year duration, who fulfilled at least four of the American College of Rheumatology criteria for the classification of the disease revised in 199716 and whose charts had sufficient clinical and laboratory data were included. The study was approved by the research ethics committee of Fasa University of Medical Sciences. All the patients filled the ethical testimonial form. A questionnaire was designed according to the American Rheumatism Association glossary committee.17 A blood sample was collected from each patient at the time of admission. The laboratory data including a standard hematological and immunological profile (complete blood count, erythrocyte sedimentation rate, plasma thromboplastin time (PTT), prothrombin time (PT), serum electrolytes, serum creatinine, blood urine nitrogen (BUN), serum proteins, C-reactive protein and creatine phosphokinase (CPK), and various immunological tests, including antinuclear antibodies (ANA), antibodies to doublestranded DNA (dsDNA), rheumatoid factor (RF), direct Coomb’s test, antineutrophilic cytoplasmic antibodies (ANCA), serum complements levels, and venereal disease research laboratories (VDRL) tests were assessed for each patient. Standard enzyme-linked immunosorbent assay (ELISA) was used to screen ANA, dsDNA, ANCA, and serum complements.


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Organ involvement was assessed by clinical and laboratory testing. The lupus erythematosus (LE) cell test was also performed classically. Patients with lupus nephritis (more than 3+ proteinuria or more than 500 mg/24 h proteinuria) underwent renal biopsy, and their specimens were routinely processed for standard analysis by light microscope and immunofluorescence microscope. They were analyzed and classified according to the 1982 World Health Organization (WHO) classification for lupus glomerulonephritis. Only one biopsy was performed for each patient, and the abnormal findings of urinalysis were observed simultaneously. The clinical course and the relative incidence of the various complications that ultimately resulted in morbidity and mortality were noted and compared with the results of other studies. The statistical package for social science, SPSS for Windows, Version 12 (SPSS, Chicago, IL, USA) was used for data analysis. The results were compared with various international studies.

Results In all, 410 SLE patients were studied. The patients originated from all parts of Fars province: 59% were from the centre and the south, 24% from the northwest and 17% from the northeast. Our series consisted of 54 men (13.2%) and 356 women (86.8%). The average age at SLE diagnosis was 30.27 years ranging from 3 to 78 years. The median age of the patients was 28 years. In all, 34 patients were above 50 years and 11 were below 10 years. The delay of the diagnosis was on average 6 months (ranging from 2 weeks to 28 months). Relatives of 28 patients (6.8%) had SLE. The month of May had the highest rate of disease onset with 59 (14.4%) patients. Overall, spring was the most common season in which the symptoms occured with 141 (34.4%) patients. The most common major complaints of patients were arthralgia (27%), fever (25.3%), cutaneous problems (21.7%), and renal problems (20.7%). The most common clinical features of SLE in our series were skin involvements (89.5%), hematological abnormalities (78%), arthritis or arthralgia (65.4%), fever (63.4%), lupus nephritis (47.8%), serositis (38%), neuropsychiatric manifestations (31.5%), and oral ulcers (27.8%). In all, 51 (12.4%) patients had generalized edema, whereas 122 (30%) had localized edema mostly in lower extremities (5.6%). The cumulative frequencies of systemic involvement and nonspecific manifestations of SLE in our patients are presented in Table 1 and Table 2, respectively.

The most common cutaneous manifestations were malar rash (60.5%), photosensitivity (54.4%), and discoid lupus (49%). Cutaneous manifestations found in our series are demonstrated in Table 3. Regarding hematological parameters, 44.6% of patients had thrombocytopenia, 74.6% had anemia (53.1% microcytic hypochromic anemia), 64.6% had leukopenia, and 43% had significant lymphopenia. In all, 8% of the patients presented with pancytopenia (n = 32). Coomb’s positive hemolytic anemia appeared in 12.4% of the cases. The PT and PTT were prolonged in 59% (n = 241) of patients, and prolonged Erythrocyte sedimentation rate was observed in 63% (n = 258) of them with mean time of 57 seconds. Albumin-globulin ratio was reversed in 49.7% of patients. Mean evaluated level of BUN and creatinine Table 1 The cumulative frequencies of systemic involvement in our series Clinical features

Frequencies (%)

Skin Malar rash Photosensitivity Hematological Leukopenia Thrombocytopenia Hemolytic anemia Articular Lupus nephritis Cardiopulmonary Pleuritis Pericarditis Myocarditis Neuropsychiatric Psychosis Seizures Myositis Antiphospholipid syndrome Gastrointestinal Gastrointestinal bleeding

89.5 60.5 54.5 78 64.5 44.5 12.5 65.5 48 41 26 12 3 31.5 18.5 13 17 14 8.3 5.3

Table 2 The non-specific manifestations of systemic lupus erythematosus in our series Non-specific manifestations

Frequencies (%)

Fever Edema Anorexia Weight loss Fatigue Malaise Nausea Vomiting Myalgia Diarrhea Lymphadenopathy Night sweating Dry cough Constipation

63.4 42.2 42 35.4 30.2 23.9 22.7 20.7 15 14.9 14.2 12.7 12.7 5.9 Lupus


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Table 3 Cutaneous manifestations in 410 Iranian patients with systemic lupus erythematosus

Table 4 Hematological, abnormalities in our series

Cutaneous manifestations

Frequencies (%)

Abnormalities

Frequencies (%)

Malar rash Photosensitivity Discoid lupus Hair loss Erythema Oral ulcer Facial eruption Dermal vasculitis Alopecia Raynaud’s phenomenon Telangiectasia Bullae Hives Purpura Lupus hair Skin ulcer Vaginal ulcer

60.5 54.5 49 47 35 28 27.5 22 23 21 19 11.5 11 10 6 4.5 2

Hematological Leukopenia Prolonged ESR Prolonged prothrombin time and PTT Microcytic hypochromic anemia Thrombocytopenia Lymphopenia Hemolytic anemia Pancytopenia Serological C-reactive protein (CRP) Reversed Albumin/globulin ratio Creatinine phosphokinase (CPK) Immunological Antinuclear antibody (ANA) double-stranded DNA antibody Hypocomplementemia ANCA Lupus erythematosus cell test aCL Rheumatoid factor VDLR

78 64.6 63 59 74.5 44.6 43 12.4 8 62 54.7 49.7 20 100 93 83 47.8 34 32.5 26 9.7 3.2

was 24.74 and 1.8 mg/dl, respectively. C-reactive protein was positive in 54.7% of patients and CPK in 20% of them. In all, 93% of the patients were ANA positive (n = 381). Anti-dsDNA test results were positive in 83% of patients (n = 340), whereas 3.4% of patients were positive for ANCA. A total of 107 patients (26%) represented positive anticardiolipin antibodies (aCL). But this may not be reliable because anticardiolipin antibodies were checked for 307 patients only. During the study period 58 (14%) patients suffered from antiphospholipid syndrome (APS) from which one died due to catastrophic APS. 196 (47.8%) patients represented hypocomplementemia with mean C3 & C4 level of 0.72 and 0.28 EU respectively. The RF was detected in 9.7% of patients and LE cell was seen in 32.5% of them. False positive VDRL test was observed in 3.2% (n = 13) of patients. The cumulative frequencies of hematological, serological and immunological features are presented in Table 4. Renal biopsy findings revealed that 49.7% of the cases had WHO class IV, 11.3% had class V, 20.9% had class III, 15.8% had class II and 2.3 had class I histological findings. 18 (4.4%) patients died during this period mostly because of cardiopulmonary involvement (n = 8). The causes of death in these patients are listed in Table 5.

Discussion In this present study, we describe the frequency and characteristics of the main SLE clinical and laboratory features, and the causes of death in 410 Iranian Lupus

serological,

and

immunological

ESR, Erythrocyte sedimentation rate PT, Prothrombin time PTT, Plasma thromboplastin time ANCA, Antineutrophilic cytoplasmic antibodies aCL, Anticardiolipin Antibodies VDRL, Venereal disease research laboratories

patients from Fars province are diagnosed and treated in the two tertiary referral university centres. The Iranian population is mostly composed of native Iranians. Afghans (immigrants), Kurds and Turks are the minority groups of Iran’s population. Clinical features have been described in various ethnic groups including Caucasian,2 Asian,2,4 Hispanic,2 black Americans and Africans2,18,19 Chinese,20 Arabs from the Middle East,21–25 Pakistanis,26 and Indians,27 but no literature exists on SLE features of Iranian patients. Racial differences in prevalence and

Table 5 Causes of death in 410 Iranian patients with systemic lupus erythematosus Causes of death

Cases (%)

Cardiopulmonary Myocardial infarction Tamponade Pulmonary hypertension Mitral valve insufficiency Pulmonary emboli Sepsis Renal insufficiency Central nervous system involvement Catastrophic antiphospholipid syndrome Massive gastrointestinal bleeding

8 2 2 2 1 1 4 3 1 1 1

(2) (0.5) (0.5) (0.5) (0.25) (0.25) (1) (0.7) (0.25) (0.25) (0.25)


Population

— 24 4.8 7 10.9 — — 35 37 26

—

—

98/10 31.5 43 48 10 33 87 — 37 23 83 94 54 908/92 29 26.4 18.7 5.4 8.9 41.3 12.9 22.2 13.6 12.8 96 78 58/13 42.8 — 94 — — 89 — 32 59 77 97.4 21.1 66/4 34.2 — 93 — — 93 — 62 68 90 98.6 44.3 78/10 35.4 — 92 — — 94 — 59 67 86 97.7 40.9 136/11 35.1 30 51 10 37 91 37 22 9 — 97 54 354/27 31 63 32 7 19 62 21 56 14 17 93.4 85.6 24/4 30 26 14 20 25 68 19 49 28 83 91.7 85.8 172/24 31 29 6 14 19.7 38 22 33 26 54 86 74 78/9 28.5 56 26 18 16 90.8 56.3 63.2 25.3 78 98 93 92/8 32 63 53 18 4 78 45 43 25 81 100 56 356/54 28 60.5 54.5 49 28 65.5 38 48 31.5 78 93 83

Female/Male Median age Malar rash Photosensitivity Discoid lupus Oral ulcers Arthropathy Serositis Nephritis Neuropsychiatric Hematologic Antinuclear antibody Anti-double stranded DNA antibodies Anticardiolipin antibodies

Kuwaiti (n = 108) European (n = 1000) Caucasian (n = 71) Hispanic (n = 70) AfricanAmerican (n = 88) Tunisian (n = 100) Iranian (n = 410)

Saudi (n = 87)

Pakistani (n = 196)

Indian (n = 28)

Chinese (n = 381)

English (n = 147)

LUMINA2 LUMINA2 Hopkinson3 Thumboo4 Thumboo4 Rabbani26 Alballa21 Houman15 Our series

Table 6 Frequencies of clinical and laboratory features of systemic lupus erythematosus patients among different ethnicities

LUMINA2

Cervera30

Al-Jarallah24

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features of SLE suggest that ethnic factors may be important in the expression and severity of disease.28 Incidence and prevalence of SLE in Iran and in other Middle East and Arab countries cannot be clarified for lack of national epidemiological inquiries. Age of SLE onset and sex ratio in our patients were similar to those from other racial groups.2,3,15,21–26 Relatives of 28 patients (6.8%) had SLE. Generally, approximately 10% of SLE patients have familial SLE. A high familial rate (24%) has been reported by Habib and Saliba in their study of SLE among Arabs in Israel.29 The mean duration between symptoms and diagnosis in our study was comparatively less.15,20,24,30,31 Thumboo et al. in a comparative study between Caucasians and Chinese found a similar difference with lesser mean duration of symptoms in the latter.4 Generally, there were more cutaneous, hematological, and neuropsychiatric symptoms in our population. The frequencies of major clinical and serological manifestations of our patients, compared with other populations are represented in Table 6. Articular and cutaneous manifestations were the most common symptoms in our patients and in the other reported series. Frequency of malar rash in our patients was similar to that in patients from South Africa,32 Tunisia,15 Middle East,21–25 and Asia (Vietnamese,33 Chinese,4 and Japanese34 populations) but clearly higher than in European, Indian, Pakistanis, and Senegalese patients.3,19,26,35 Rabbani et al. have reported the lowest incidence of malar rash (29%) and photosensitivity (6%).26 This difference may be due to the higher levels of sunshine in the Fars Province of Iran compared with Europe and due to the less dark skin of Iranian people compared with Pakistanis and Indians. LUMINA cohort have reported the highest level of photosensitivity in Hispanic, African-American and Caucasian population.2 Compared with other studies, the prevalence of oral ulcers in our patients was the same as Indians,4 Malayans,4 Vietnamese,33 and South African.32 Uthman et al. in a study in Lebanon found that oral ulcers complicated 40% of SLE patients, which is higher than our study.23 Houman et al. reported oral ulcers in only 4% of SLE patients, which is the lowest incidence among various studies.15 We are unable to explain these findings. Compared with others, we found a higher prevalence of hematological abnormalities in our population.23,26,32,35 Alballa et al. found the incidence of lymphopenia in an Arab population to be 70%, which is higher than that of our patients (43%).21 In comparison with several studies worldwide,20,21,23,26,31,36,37 we had the highest prevalence of thrombocytopenia (44.6%). Compared with those studies, we also had Lupus


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the highest prevalence of leukopenia (64.4%) after Arabs (83%).21 However, there was no significant difference in other hematological abnormalities such as pancytopenia. Nossent et al. in the Netherlands found that lymphopenia was present in 20% of the Caucasian population,38 suggesting that our patients lie in the middle of a spectrum between Asians and Caucasians. Even with therapeutic advances, lupus nephritis remains a major cause of morbidity and mortality39–41 particularly among patients of Hispanic42,43 and African-American ethnicity.44–46 The SLE patients with renal involvement are at a higher risk of death due to this disease.47,48 Generally, renal involvement is more common in Africans,36 Indians,27 and Chinese,49 with lesser prevalence in Caucasians,49 Puerto Ricans,31 and Arabs.14 Nearly half of our patients had renal involvement from which about 60% were grade V and grade IV on biopsy, suggesting a severe renal involvement. This is comparable with Tunisian,15 Lebanese,23 Indian,4 Malayan,4 South African,32 and Chinese.4 Renal involvement is less frequent in Pakistanis,26 Caucasians,2 and Europeans,30 whereas it is more frequent in Arabs,21 Senegalese,19 and Hispanics.2 Compared with Caucasians,30 Chinese,20 21,24 37 Arabs, Hispanics, and Puerto Ricans,31 our patients had a higher prevalence of neurological involvement with about one-third of the patients being affected. Alarcon et al.2 has described a prevalence of neurological symptoms of 67% in African-Americans. Brey et al.50 found similar incidences of seizures and psychosis among the neuropsychiatric manifestations in Caucasian SLE patients as found by us. Other studies have also found lower incidences of seizures and psychosis in patients with SLE in the Caucasian and Chinese populations.20,40 Compared with other studies, the prevalence of serositis in our patients was much higher.27,30,31,34 Badui et al.,51 in a study in Oman, found that pleural effusion complicated 40% of SLE patients with serositis, which is comparable with our study. However, Segasothy et al. found lower incidences of pleuritis and pericarditis in the Australian Caucasians and Aborigines.52 Nearly half of the deaths in our series were due to serositis. Rabbani et al. associated the infections and renal involvement with poorer prognosis.26 But in our study, patients with serositis (especially pericarditis) showed poorer prognosis, and the pattern of disease in these patients was much more severe in comparison to patients without serositis (P = 0.001). Houman et al.,15 in a study in Tunisia, found that infections were the most common cause of death in Tunisian people. Lupus

Although the level of ANA in most studies approached 100%,15,19,27,33,36,37 only 93% of our patients were found to be ANA positive, which is comparable with Indians,4 Kuwaitis,24 and Europeans.35 This may be due to technical failure because ELISA may fail to detect ANA in some cases. Rabbani et al.26 and Uthman et al.23 reported the lowest level of ANA in their series (86% and 87%, respectively). There was no difference in the prevalence of dsDNA as compared with Chinese,20 Caucasians,30 Africans,36,53 Hispanics,37 and Indians.27 Compared with the Chinese, our patients had a higher prevalence of anticardiolipin antibodies.20 Regarding aCL, it seems that Iranians mostly resemble Europeans.30 Middle East countries show much more positive aCL,15,26 whereas LUMINA reported less in African-Americans, Hispanic, and Caucasians.2 However, this may not be reliable as only 74% of our patients underwent anticardiolipin screen. This is the first study of its kind in Iran but, being a descriptive study, it cannot give statistical associations. As this study was conducted in a single province in two tertiary care hospitals, it may not represent the country and all races as a whole. More studies and preferably multicenter ones (because Iran is a very vast country and includes many races) should be held to describe the pattern of SLE.

Acknowledgment The authors wish to thank all the patients who participated in the study.

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