Lupus in the developing world – is it any different?

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<ul><li><p>4evident. While the poorer outcome in developing countries is partly related to inherent geneticdifferences, better outcomes can be achieved if new initiatives are undertaken to define the bur-</p><p>1521-6942/$ - see front matter 2008 Elsevier Ltd. All rights reserved.</p><p>Best Practice &amp; Research Clinical RheumatologyVol. 22, No. 4, pp. 643655, 2008</p><p>doi:10.1016/j.berh.2008.05.003available online at http://www.sciencedirect.com* Corresponding author. Tel./Fax: 27 11 938 8738.E-mail address: tikly.mohammed01@gmail.com (M. Tikly).den of disease, increase public awareness, and establish algorithms for diagnosis and treatmentbased on the available resources and local health-care delivery systems.</p><p>Key words: lupus; epidemiology; Africa; Asia; Latin America.in the developing world and is a major cause of morbidity and mortality. Discoid lupus and lym-phopenia are frequent clinical features of SLE in patients of African extraction. Thrombotic com-plications and associated anti-phospholipid antibodies are less common in the Chinese and BlackAfrican SLE patients than in Caucasian patients. High frequencies of antibodies to extractablenuclear antigens, especially anti-Sm and anti-U1RNP, have been reported in SLE patients inmany developing countries. Infections, including tuberculosis, are among the most importantcauses of comorbidity and mortality in SLE across all regions of the developing world. Witha few exceptions, survival rates for SLE patients in developing countries are substantially lowerthan those reported in industrialized countries, with early death from infection and active dis-ease. The bimodal pattern of mortality observed in many industrialized countries, is also lessLupus in the developing world is it any</p><p>different?</p><p>Mohammed Tikly* FRCP, PhDProfessor and Head</p><p>Division of Rheumatology, Department of Medicine, Chris Hani Baragwanath Hospital and</p><p>University of the Witwatersrand, P.O. Bertsham 2013, South Africa</p><p>Sandra V. Navarra MD, FPCP, FPRAProfessor and Head</p><p>Section of Rheumatology, Clinical Immunology and Osteoporosis, University of Santo Tomas, Manila, Philippines</p><p>Systemic lupus erythematosus (SLE) is known to occur in all populations across the globe. Inmany respects SLE is similar across regions in its spectrum of clinical features, but the severityof the disease and comorbidity are appreciably different in the developing and industrializedworlds. Although data on the prevalence of SLE among Africans and Asians living in the tropicsare limited, SLE is reportedly more common and more severe in people of African and Asianextraction living in industrialized countries. Renal disease is especially common in SLE patients</p></li><li><p>Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease withprotean manifestations, ranging from relatively minor skin and joint symptoms to se-</p><p>644 M. Tikly and S. V. Navarravere life-threatening major organ involvement such nephritis and neuropsychiatriccomplications. The disease occurs in all populations, but the prevalence, spectrumand severity of the disease varies across the globe.1</p><p>In this paper we review the published literature of SLE in the developing world,highlighting the reported differences in epidemiology, clinico-serological features, co-morbidity, and outcome compared to the industrialized Western world. Two obviousbut very important caveats to this discussion need to be emphasized. Firstly, thedeveloping world does not constitute a homogeneous population with respect togeography, ethnicity, environmental factors, or socio-economic conditions. What isperhaps common to all of the developing world which includes Africa, Latin Americaand most of Asia is that majority of people are non-Caucasian, reside mainly inwarmer tropical or subtropical regions of the southern hemisphere, and live underpoor socioeconomic conditions. Secondly, SLE has not been researched to anywherenear the same extent in developing countries as in the industrialized world. Hence,while many of the reported differences probably reflect true biological differencesdue to a combination of genetic, environmental and socioeconomic factors, at leastsome of the apparent differences are simply a reflection of lack of good researchdata on SLE in the developing world.</p><p>EPIDEMIOLOGY</p><p>Over the past 5060 years there has been a rise of more than ten-fold in the annualincidence of SLE in industrialized Western countries.1 This temporal increase in SLE isthought to be due to both a true increase in incidence, related to exposure to envi-ronmental factors, and increased recognition of the disease. The epidemiology of SLEin the developing world remains largely unknown. Where formal epidemiological stud-ies have been undertaken, the occurrence of SLE has been found to be within therange reported in industrialized countries or higher. The annual incidence has been es-timated to be as high 8.7/100 000 in a Brazilian study in the tropical urban area of NatalCity2, and prevalence rates (per 100 000) of 12. 2 in Black South Africans3, 19.3 in Sau-dis4, 60 in the southern Chinese of Hong Kong5, and as high as 159 in Puerto Ricans6</p><p>have been reported.One of the enigmas of the epidemiology of SLE is that it is rarely seen in rural tropical</p><p>areas of Africa and Asia710, yet people of African and Asian extraction living in indus-trialized countries have amongst highest prevalence rates of SLE in the world.1,11 Not-withstanding the fact that SLE is probably under-diagnosed in many parts of rural Africaand Asia, where facilities to do even the basic indirect immunofluorescence antinuclearantibody (ANA) test are often not available12, many experts hypothesize that there is anSLE prevalence gradient. Racial admixture, as in the case of African Americans13, andenvironmental factors such as smoking, viral infections and silica are thought toincrease the risk of SLE in people of African or Asian extraction living in industrializedcountries.14 By contrast, tropical infections, in particular malaria, appear to conferprotection against SLE.15</p><p>SLE primarily affects women in the child-bearing years, and is estimated to be 912times more common in women than in men.1 Paediatric SLE, although rare, has beenobserved in several developing countries.1618 The mean age of disease onset appearsto be lower in developing countries. As in the case of rheumatoid arthritis, this mightbe a reflection of the lower overall life expectancy in the developing world.19,20</p></li><li><p>Alternatively, elderly-onset SLEmight be underdiagnosed because of its less florid clinicaland serological expression.21 There is also a suggestion that female preponderance of</p><p>Lupus in the developing world 645SLE is greater in developing countries (Table 1), which may be due to factors extraneousto the biology of the disease, such as differences in accessibility to health-care services.</p><p>CLINICAL AND SEROLOGICAL FEATURES</p><p>Studies from Western industrialized countries consistently show that the severity andburden of SLE is greatest in non-Caucasian ethnic groups of African and Asian extrac-tion.1,22,23 The clinical spectrum (Table 1), autoantibody profile, and comorbidity ofSLE in the developing world are not dissimilar to those in non-Caucasian SLE patientsliving in industrialized countries.</p><p>Renal disease</p><p>Perhaps the most outstanding clinical feature of SLE in the developing world is the highprevalence and severity of lupus nephritis, which impacts directly on morbidity andmortality (see below). Most studies from developing countries report lupus nephritisin at least one third of patients, and studies from South East Asia have shown that asmuch as 6469.3% of patients have renal disease24,25 compared to 27.9% in a study ofa 1000 European SLE patients.26 Moreover, a large proportion of patients have renaldisease at presentation, frequently as the presenting feature of SLE.20,27,28 At biopsy,proliferative glomerulonephritis (WHO class III and IV) is a common histological find-ing20,29, which apart from increasing the risk of end-stage renal disease (ESRD), is as-sociated with proteinuria and nephrotic syndrome in some populations.2931 In a Thaistudy of 569 patients with lupus nephritis, 43.6% of patients had nephrotic-range pro-teinuria and 58.0% had a creatinine clearance </p></li><li><p>Table 1. Demographic characteristics and frequency of key clinical features of systemic lupus erythematosus in developing countries.</p><p>Region Africa Asia Latin America27</p><p>Country/ethnic group RSA20 Tunisia40 Saudia88 Pakistan89 India61 Malaysia90 Singapore91 Hong Kong5 Philippines92 White Mestizo ALA</p><p>Year of publication 2007 2004 2007 2004 1997 1997 1998 2003 2006 2004</p><p>Sample size 226 100 86 196 1366 539 472 709 115 507 537 152</p><p>Mean age of onset (years) 34 32 24 31 24 26 31 30 31 30 28 26</p><p>Female:male ratio 18:1 11.5:1 10:1 7.2:1 8:1 12.5:1 11.8:1 e 28:1 9:1</p><p>Clinical features (%)</p><p>Photosensitivity 39 53 22 6 48 26 25e31 35 45 60 52 59</p><p>Malar rash 58 63 37 29 58.5 61e76 45e60 56 70 63 59 63Discoid rash 41 18 7 6 7 3 5e10 12 49 11 10 20</p><p>Oral ulcers 39 e 17 20 55 24 25e31 11 49 41 43 40</p><p>Arthralgia/arthritis 70 78 68 38 85 36e50 51e61 84 64 94 93 94</p><p>Serositis 18 e 27 22 22 6e13 7e21 19 23 e e ePleurisy e 29 19 e e e e e e 24 21 21</p><p>Pericarditis e 18 18 e e e e e e 16 16 26</p><p>Nephritis 44 43 61 33 73 50e74 18e54 50 80 44 58 55</p><p>Neuropsychiatric 16 25 19 26 27 23 4e14 6 24 e e eSeizures _ 6 10 e e e e 3 e 8 9 7</p><p>Psychosis e 20 e e e e e 3 e 3 5 4</p><p>Haemolytic anaemia e 6 14 e 1 19 e 20 3 13 12 10Leukopenia e e 24 22 12 24e39 e 32 23 40 43 47</p><p>Lymphopenia e 50 62 e e e e e e 51 64 70</p><p>Thrombocytopenia 13 12 16 26 7.5 16e30 e 25 10 19 18 23</p><p>ANA positive 99 100 95 86 96 93 97 e e 99 96 99</p><p>RSA, Republic of South Africa; ALA, African-Latin American; ANA, antinuclear antibody.</p><p>646</p><p>M.Tikly</p><p>andS.</p><p>V.Navarra</p></li><li><p>Lupus in the developing world 647Americans; this is thought to be related to lower prevalence of anti-phospholipidantibodies (aPLs) and less frequent use of the oral contraceptive pill or hormonereplacement therapy in the Chinese.41 A peculiar feature of anti-phospholipid antibodysyndrome (APS) in patients of African extraction is the frequent occurrence of IgAanti-cardiolipin antibodies or IgG anti-b2-glycoprotein-1 antibodies in the absence ofthe traditional aPL-associated APS, namely, IgG and IgM isotypes of aCL and lupusanticoagulant.4244 There is little evidence to suggest that the frequency, spectrumand severity of neuropsychiatric complications of SLE manifestations in developingcountries are any different from those in the industrialized world.</p><p>Organ damage</p><p>Only a few studies have addressed irreversible organ damage and comorbidity in SLE</p><p>Figure 1. Melanonychia and discoid lupus in a Black patient with systemic lupus erythematosus.patients from developing countries. Using the Systemic Lupus International Collabo-rating Clinics/American College of Rheumatology (SLICC/ACR) damage index (SDI),the GLADEL study group in Latin America found that patients of African extractionscored significantly lower SDI scores than Whites and Mestizos, even though the for-mer group had higher disease activity and more renal disease. Moreover, they foundthat lower socioeconomic status and lack of medical cover was associated with higherSDI scores. There appears to be no consistent pattern of organ damage in developingcountries, although the musculoskeletal system (osteonecrosis, osteoporosis), centralnervous system and renal system appear to be most commonly affected.6,27,45,46 Stud-ies in Mexicans and American Hispanics suggest that Hispanics are at increased risk ofpremature gonadal failure47,48, although no such inter-ethnic differences wereobserved in the GLADEL study.27 Accelerated atherosclerosis and coronary arterydisease, which is widely reported in Caucasian patients with SLE, appears to be lessof an issue in the developing world except in India. Asian Indians generally have an in-herent metabolic predisposition to the development of early atherosclerosis. Bhattet al have found Asian Indian SLE patients to have significantly thicker carotidintimo-media and more plaque formation than age-matched controls49, as well as</p></li><li><p>clinical evidence of peripheral vascular disease in a over a quarter of the patients thatthey studied.50</p><p>648 M. Tikly and S. V. NavarraAutoantibodies</p><p>No striking inter-ethnic differences in the frequency of ANA, anti-dsDNA antibody, andanti-nucleosome antibody positivity have been observed.51,52 However, numerousstudies suggest that the frequency of other specific antinuclear antibodies and aPL(see above) vary with ethnicity and geographical location, which may explain some ofthe inter-ethnic differences in clinical manifestations in SLE. Anti-Sm antibodyfrequencies are increased in non-Caucasian and Caucasian patients living in LatinAmerica20,27,39,53,54, with one study showing the frequency of anti-Sm antibodies tobe five-fold higher in French West Indian SLE patients than mainland French patients.53</p><p>Similar high frequencies (&gt;40%) of anti-U1RNP antibodies have been found in LatinAmericans27, Tunisians40, Vietnamese55, and Black South Africans.54 In the latter twostudies, patients with anti-U1RNP antibodies were more likely to have overlap features.High anti-Ro antibodies frequencies (&gt;60%) have been observed in the southernChinese5 and Black South African SLE patients.54 Teh et al found Malaysian ChineseSLE patients to have an increased frequency of anti-ribosomal P protein antibodies(38%) compared to Caucasian (13%) and Afro-Caribbean (20%) patients, although thepresence of these antibodies was not associated with neuropsychiatric manifestationsin the former group.56 At least some of the above differences relate to variations in assaytechniques and lack of standardization.</p><p>Differential diagnosis</p><p>Drug-induced lupus from drugs such as hydralazine, isoniazid, and procainamide is animportant differential diagnosis of SLE in Caucasians but is almost non-existent inBlacks.57 In addition to conditions like rosacea and polymorphic photosensitive skinreactions mimicking SLE, lupus vulgaris is an important differential diagnosis in non-Caucasian populations living in tuberculosis-endemic countries.</p><p>CO-MORBIDITY OF INFECTIONS</p><p>Infections are among themost important causes of morbidity andmortality in SLE acrossall regions.58 Several series in developing countries rank infections as either first or sec-ond to SLE disease activity as a cause or contributor to mortality (Table 2).19,20,27,40,5962</p><p>This susceptibility to infection may be explained by several intrinsic and acquired defectsin the immune system related to the disease itself or to the immunosuppressive thera-pies.20,63,64 Among the genetic factors, mannose-binding lectin (MBL) deficiency is asso-ciated with increased risk of infection, and low levels of MBL have been demonstrated inChinese lupus patients.65 Furthermore, the low-MBL-producing haplotype LX has beenobserved with higher frequency among Filipino lupus patients than in healthy controls.66</p><p>A broad spectrum of infections has been repo...</p></li></ul>