Introduction
Although SLE, a prototypical multiorgan autoimmune disease, has been studied for more than a century, its complex aetiology is incompletely understood. Genetic risk1 is strongly associated with SLE and likely interacts with environmental influences, such as infectious agents, to initiate overt clinical disease.2 Consistent with the role of genetic factors in SLE, disease severity varies between racial groups, with African-American, Hispanic and Asian patients disproportionately affected by major organ involvement.3 4 However, these populations are oftentimes under-represented in SLE research. In particular, little is known about the aetiology and pathogenesis of SLE among Filipinos, a racially diverse and heterogeneous population with Malay, Chinese, Indian and Spanish ancestries.
In the 1970s, a multiethnic survey study estimated that the prevalence of SLE among Filipino individuals in Hawaii, USA, was 19.9 per 100 000 individuals, compared with 5.8 per 100 000 in white individuals.5 The increased disease burden in Filipinos may be partially due to genetic differences, since SLE risk alleles and haplotypes in the major histocompatibility complex (MHC) region are more common and have a greater effect size in the Filipino population.6 In addition, anti-dsDNA, which is associated with renal disease, is more common among Filipino patients with SLE and their first-degree relatives (FDRs) compared with their counterparts in African-American cohorts.7 As in other populations, antinuclear antibodies, anti-dsDNA, anti-Ro/SSA and antichromatin are more common in Filipino patients with SLE compared with FDRs and healthy controls,7 but other lupus-associated autoantibodies have not been studied in the Filipino population. Endemic infections in the Philippines contribute to increased morbidity and early mortality among Filipino patients with SLE,8–10 and infections may also influence SLE pathogenesis.
Several viral pathogens have been associated with SLE in non-Filipino populations.11 To date, the strongest of these associations is with Epstein-Barr virus (EBV),12 13 a member of the herpes virus family that infects B cells and is linked to SLE through molecular mimicry,14 15 bystander activation16 and epitope spreading.17 18 The initial active EBV infection is followed by a lifelong latent infection with potential for reactivation, thus providing opportunities for both acute and long-lasting effects on the immune system.19 Latent EBV infection requires EBV nuclear antigen (EBNA)-1.20 21 Several EBNA-1 epitopes, such as PPPGRRP and (GR)x, exhibit cross-reactivity with early autoantigens in SLE, such as Sm B′ (PPPGMRPP) and Sm D1 (GR)x, respectively.22–24 Furthermore, several studies have shown an increased prevalence of antibodies against EBV early antigen (EBV-EA), a marker of EBV reactivation,25–27 as well as increased EBV viral loads28 in patients with SLE, suggesting that EBV reactivation may present a chronic immune stimulus that affects the disease course in SLE. A limited number of studies have implicated another herpes virus, cytomegalovirus (CMV), in SLE,29 30 although the effects of CMV on SLE development and autoantibody production remain unclear.31
Increased rates of EBV and CMV seropositivity have been described in patients with SLE compared with healthy controls,12 32–34 but this has not previously been examined in the Filipino population. To better understand the role of herpes virus infections in SLE among the Filipino population, we compared the seroprevalence of EBV, CMV and herpes simplex viruses (HSV-1 and HSV-2) in Filipino patients with SLE, their unaffected FDRs and unrelated healthy Filipino controls. We also evaluated the effects of herpes virus seropositivity on American College of Rheumatology (ACR) classification criteria and autoantibody positivity in Filipino patients with SLE.