The current state of systemic lupus erythematosus care in the Philippines: a narrative review

Abstract

Systemic lupus erythematosus (SLE) is a multisystemic autoimmune disease of clinical importance in the Philippines. While its actual prevalence in the Philippines is unknown due to a lack of organized cohorts and community-level screening, Filipino females in the second and third decades of life are primarily affected, commonly presenting with mucocutaneous, musculoskeletal, hematologic, and renal involvements. Several risk factors have been described as influencing the development of SLE in Filipinos, including molecular/genetic, clinical, lifestyle, and environmental factors. The diagnosis of SLE in the Philippines still relies on international standards, such as the Systemic Lupus International Collaborating Clinics 2012 and the European League Against Rheumatism/American College of Rheumatology 2019 classification criteria. Similarly, the lack of published local guidelines for SLE requires Filipino practitioners to rely on international management guidelines, which now include the Asia-Pacific League of Associations for Rheumatology recommendations for the Asia-Pacific region, with management goals including the achievement of a low disease activity state, the prevention of organ damage, the prevention of flares, and the promotion of quality of life. Structural barriers still impede comprehensive lupus care in the country, manifesting as poor access to essential drugs and rheumatologists, low capacity for community-level surveillance, lacking research and guidelines in Philippine-specific nuances (i.e., common presentations and comorbidities such as tuberculosis), and education. The medical community in the country must be mobilized to ensure holistic care for SLE patients, as it is one of the most important rheumatologic conditions in the Philippines.

INTRODUCTION

Systemic lupus erythematosus, or SLE, is a multiorgan autoimmune disease characterized by the production of autoimmune antibodies toward nuclear antigens, immune complex deposition, and chronic inflammation of different organs of the body [1]. SLE is a relapsing-remitting disease with unpredictable flares in between periods of clinical quiescence of varying duration. The patterns of disease activity can be long quiescent, relapsing-remitting, and persistently active [2]. SLE remains a public health concern globally, including in the Philippines. However, there are still limited studies on SLE in the Philippines. Hence, this study synthesized the available literature on the epidemiology, diagnosis, and management of SLE in the Philippines. This narrative review paper also identified gaps in clinical management and potential areas for health research in the country.

Burden of SLE in the Philippines

The actual prevalence and incidence of lupus in Asia and the Philippines are unknown, in part due to the lack of other centralized estimation efforts aside from the Community Oriented Program for the Control of Rheumatic Diseases of the World Health Organization (WHO) and the International League of Associations for Rheumatology [3]. Prevalence approximations vary, ranging from 3 to 70 cases per 100,000 people in Asian countries [3]. In Malaysia, the estimated prevalence is 43 persons per 100,000, with immigrant Chinese having the highest rates, followed by Indians, then ethnic Malays [4]. The Asian cohort in Hawaii was also found to have a higher prevalence of SLE compared with Caucasians [4]. The incidence in Hong Kong in 2006 was 2.8 in the general population and 5.1 in females, whereas the overall incidence in Japan was 0.9 [3]. In another study, it was described that the prevalence of SLE in South Korea (20 to 26.5 per 100,000 Person-Years [PY]) was lower than that of in China (30 per 100,000 PY) and of Taiwan (67.4 per 100,000 PY), with the prevalence of SLE in North America trumping all East Asian countries at 241 per 100,000 PY, which remains consistent with previous studies [5,6]. There is a paucity of prevalence and incidence data in the Philippines due to a lack of centralized cohorts and representative epidemiologic studies. Despite this, institutional cohorts, registries, and studies provide insights into the burden of lupus in the Philippines.

Filipino females are primarily affected by SLE, with female-to-male ratios ranging from 20~30 to 1, and with common ages at diagnosis falling within the second and third decades of life [7,8]. This female preponderance is also seen in juvenile SLE in the country, which has an average age at diagnosis of 14 years old [9-12]. This is consistent with previous reports in South Korea, as analyzed by Han et al. [6], in which female-to-male ratios were found to range from 6.5:1 to 10:1. About half (52.17%) of all outpatient consults for connective tissue diseases in the Philippines are due to lupus [13]. Some of the most common initial manifestations of SLE in Filipino adults include mucocutaneous involvement (e.g., alopecia, malar rash, discoid rash, oral ulcers, etc.), seen in 59% to 86.4%, musculoskeletal impairments (e.g., arthritis) in 61.4% to 68%, hematologic derangements (e.g., anemia, thrombocytopenia, etc.) prevalent in 46% to 63.6%, and renal injury in about 47% to 74% [7,14,15]. These local findings echo results in SLE patients in Asia, with respective prevalence rates of 52% to 98% for mucocutaneous, 36% to 95% for musculoskeletal, 26% to 83.8% for hematologic, and 18% to 100% for renal involvements [14]. Similarly, juvenile SLE patients most commonly present with mucocutaneous lesions (88% to 91%), renal injury (45% to 63%), musculoskeletal complaints (41% to 67.8%), and hematologic problems (35% to 61%) [9-11]. Some of the rarer but equally serious clinical states in Filipino children with SLE are seizures seen in 34.5%, myocarditis in 23.8%, acute kidney injury in 12.6%, and blurring of vision in 10.3% [11]. SLE patients are also at higher risk for cardiovascular diseases such as myocardial infarction (MI), heart failure, and stroke, with hazard ratios ranging from 1.39 to 6.88, with the pretext that these diseases may be defined differently across countries [6].

SLE is the most common rheumatologic disease prompting admission in the Philippines [8]. During the entire course of the disease, it may lead to complications in various organs such as the kidneys (e.g., acute kidney injury, nephrotic syndrome, etc.), blood (e.g., hemolytic anemia, thrombocytopenic purpura, etc.), and mucocutaneous surfaces (e.g., oral ulcers, etc.) [7,9,11,14]. Furthermore, juvenile SLE has a mortality ranging from 10% to 25% [11]. Common causes of death in the general population aside from active lupus include septic shock and infections and cardiopulmonary complications such as myocarditis and pulmonary hypertension [6,9,11]. Several complications and risk factors during disease have also been found to increase the risk of mortality in juvenile SLE patients, including younger age at diagnosis (odds ratio [OR]: 0.89), occurrence of seizures (OR: 9), pleural effusion (OR: 6.25), myocarditis (OR: 5.89), hemolytic anemia (OR: 3.36), leukopenia (OR: 2.48), and lymphopenia (OR: 2.82) [11].

Risk factors of SLE in the Philippines

The etiology of SLE is complex. There were several risk factors associated with this diseases including genetic and immune factors, environmental exposure, socioeconomic factors, and comorbidities (Figure 1).

Figure 1.

Risk factors associated with the development of SLE. SLE: systemic lupus erythematosus, SNP: single nucleotide polymorphism, ANA: antinuclear antibody, Ro/SSA: Sjögren’s-syndrome-related antigen A autoantibodies, dsDNA: double stranded DNA.

1) Molecular and immune factors

Molecular determinants of SLE prevalence and disease burden in the Philippines primarily affect nucleic acid repair and immune responses. Single nucleotide polymorphisms (SNPs) in the genes MSH5, HLA-G-HLA-H, and DRB1-DQA1 have been identified to be associated with multiple sclerosis (MS) and SLE [16]. Additionally, the SNP rs9271366, located in the HLA-G-HLA-H region, has been suggested to have a major role in variants on the haplotype of SLE patients in the Philippines, which is concordant with other studies that analyzed Pacific populations [16,17]. SNP rs9271366 is expressed in patients with MS and can suppress immune responses mediated by natural killer cells, suggesting its involvement in autoimmune diseases [18,19]. The Philippine Genome Center has also investigated SNP rs9271366. It has been implicated in SLE patients from East Asia and Malaysia, highlighting the importance of studying this molecular factor and its interactions with other proteins in the SLE disease process in the Philippine population [20,21].

Profiling the autoantibodies in SLE patients and their first-degree relatives in the Philippines also showed differences from unaffected, unrelated controls. Antinuclear antibody (ANA) positivity was significantly higher in SLE patients and their unaffected first-degree relatives [22,23]. Anti–Sjögren’s-syndrome-related antigen A autoantibodies (Ro/SSA) and anti-double stranded DNA (anti-dsDNA) also had higher occurrences in SLE patients and first-degree relatives (4.94% for anti-Ro/SSA and 1.36% for anti-dsDNA) versus healthy, unrelated controls [22,23]. These autoantibodies, even in asymptomatic cohorts, may further be used to prognosticate overt clinical disease.

2) Clinical factors

SLE has been diagnosed in Filipinos between the ages of 5 to 71 years, and anecdotally outside this age range, with an average age of detection at 28.5±11.5 years [7]. The average interval between the clinical presentation of the disease and the diagnosis of SLE was 6.4±10.8 months in the general population [14].

One clinical risk factor for SLE flares is endometriosis, aggravating or inducing SLE flares due to suppressed cellular immunity and increased autoantibody formation [24]. Patients with endometriosis were found to have a higher risk of having SLE (OR 1.36, 95% confidence interval [CI] 1.07 to 1.73; p=0.010) [25].

Atopic diseases are also important clinical risk factors for SLE. For instance, the presence of atopic dermatitis (AD) increases the risk of developing SLE (OR 1.46, 95% CI 1.05 to 2.04; p=0.020), hypothesized to be a result of upregulating cytokine production by Th2 and Th17 cells, with a concurrent downregulation of IL-2 production by Th1 cells [26]. Similarly, allergic rhinitis (AR), a disease associated with AD, has also been identified as a risk factor for SLE (OR 1.36, 95% CI 1.08 to 1.72, p=0.009) [27]. Atopy is generally a proinflammatory state with consequent immune dysregulation attributed to Th2 cell upregulation and IgE production increase, predisposing AD and AR to autoimmune diseases such as SLE [27].

Lastly, the gut microbiome composition has also been implicated in SLE prognostication, treatment response, and disease development. The levels of Bacillales, Coprobacter, Lachnospira, and Actinobacteria were negatively correlated with SLE risk, while Bacilli, Lactobacillales, and Eggerthella were identified as possible risk factors for SLE onset [28]. These findings present opportunities for further research on novel SLE treatment modalities, such as probiotics.

3) Lifestyle and environmental factors

Lifestyle and environmental risk factors for SLE include smoking, air pollution, and silica exposure. Current smokers were found to be at more risk for developing SLE (OR 1.50, 95% CI 1.09 to 2.08) [29]. Despite the 2012 Sin Tax on cigarettes in the Philippines, the country was still third in Southeast Asia in terms of smoking prevalence in 2016 at 24%, with an inelastic demand for cigarettes [30].

Particulate matter, ozone, nitrogen dioxide, and other byproducts of air pollution were also found to induce proinflammatory states as well as DNA hypomethylation, leading to the development of autoimmune disease, demonstrable by an increased risk for elevated SLE disease activity, nephritis, decreased serum C3, and anti-dsDNA positivity [31]. Notably, fine particulate matter (PM_2.5) in the Philippines exceeds the global average set by the WHO, especially in urban centers such as Metro Manila [32].

Exposure to silica and silicates, more specifically respirable silica dust (i.e., crystalline quartz), has been established as a risk factor for SLE and other systemic autoimmune diseases such as scleroderma and rheumatoid arthritis, among others, where higher doses of exposure were found to lead to increased intensity and exposure of SLE flares [33,34]. Inhaling silica dust is more likely in occupations exposed to silica and in residences in urban areas [35].

4) Socioeconomic factors

High SLE disease activity, organ damage, and mortality were found to be higher in SLE patients from lower and impoverished socioeconomic classes, highlighting disparities in healthcare globally [36]. Mood disorders are no exception, however depression was seen to be less frequent among Filipinos with SLE despite having lower socioeconomic status compared with their Southern Californian counterparts [37]. Patients in the low-income category were found to have higher frequencies of the following alleles, HLA-DRB1*03:01 (p-value [pC]=0.002, OR=3.6, and 95% CI=1.65 to 7.98) and HLA-DRB1*04:05 (pC=0.028, OR=12.9, and 95% CI=1.32 to 124.76) while those in the high-income category had increased frequencies of high-risk alleles such as HLADRB1*07:01 (pC=0.03, OR=2.0, and 95% CI=1.11 to 3.76), as well as HLA-DRB1*11:04 (pC=0.0004, OR=5.1, and 95% CI=2.02 to 13.06), with decreased protective alleles such as HLADRB1*14:06 (pC=0.01, OR=0.3, and 95% CI=0.10 to 0.78) and HLA-DRB1*16:02 (pC=0.04, OR=0.2, and 95% CI=0.05 to 0.94) [38]. HLA-DRB1*04:05 has been identified in higher frequencies in patients of oriental descent and may be implicated among Filipino SLE patients [38].

DIAGNOSIS OF SLE IN THE PHILIPPINES

Without published local guidelines, the Philippines relies on a comprehensive clinical assessment and the application of established international guidelines to diagnose SLE. The Asia-Pacific League of Associations for Rheumatology (APLAR) also recommends using such international guidelines validated for Asia [39]. In the country, the most widely used criteria for SLE include the Systemic Lupus International Collaborating Clinics 2012 criteria, in which patients must meet at least four criteria including at least one clinical and one immunologic criterion, or have biopsy-proven lupus nephritis [40,41], as well as the European Alliance of Associations for Rheumatology/American College of Rheumatology (EULAR/ACR) 2019 criteria, in which ANA positivity is an entry criterion [42,43].

Given the variability of SLE symptoms, a definitive diagnosis often involves carefully assessing clinical features, laboratory results, and potential imaging and histopathology studies. Diagnosing SLE can be particularly challenging in early-onset cases with nonspecific symptoms, ANA-negative patients, and late-onset cases with uncommon initial manifestations. Recognizing the diverse organ involvement associated with SLE is crucial for accurate diagnosis and appropriate treatment, as no single definitive test exists. Despite the abundance of validated diagnostic criteria for lupus in the Asia-Pacific region, a gap exists in identifying pertinent diagnostic features unique and applicable to Filipino patients with lupus. Furthermore, limitations in resources and socioeconomic constraints render early detection of lupus in Filipinos vehemently challenging.

TREATMENT OF SLE IN THE PHILIPPINES

Principles of treatment

Given its protean manifestations, SLE requires a multidisciplinary management approach tailored to the unique needs of individual patients. In the Philippines, however, a local clinical practice guideline (CPG) for managing SLE has yet to be published to help address efforts to educate primary physicians on its early recognition, approach, and referral in areas of need [44].

As such, the clinical approach to SLE treatment in the country adheres to the principles recommended by the EULAR, with the following management goals highlighted in the 2019 CPG [45-47] : (1) Remission of disease symptoms and/or achievement of a lupus low disease activity state in all organ systems, (2) prevention of organ damage accrual and minimization of drug side effects, (3) prevention of flares – defined as measurable increases in disease activity leading to change in treatment – and (4) promotion of quality of life for patients with SLE. In 2021, the APLAR also published consensus recommendations for lupus in the Asia-Pacific region, which mostly also adheres to the extant guidelines from EULAR [39].

All SLE patients are advised to initiate hydroxychloroquine (HCQ), typically maintained at 4 to 5 mg/kg/day, unless there is a contraindication. Glucocorticoids are also prescribed for rapid symptom relief and dosed following disease activity, with mild SLE cases receiving oral glucocorticoids (e.g., prednisone tablet) and moderate-severe cases receiving higher doses of oral or intravenous steroids [9,46,48]. Patients with acute, organ threatening SLE are started on intravenous methylprednisolone pulse therapy (MPPT), usually ranging from 250 to 1,000 mg per day for 3 days once an infection is ruled out [46,48]. In a retrospective study of Filipino adults with SLE who underwent MPPT in a tertiary government hospital, most patients received a dose of 1,000 mg (1 g) daily for three days [48]. Immunosuppressive agents such as mycophenolate mofetil and biologics, including rituximab, have also been used in the Philippines to treat moderate-severe cases of SLE [49,50]. Additionally, unique in the Asia-Pacific region are recommendations to screen for endemic infections from pathogens such as Hepatitis B, Hepatitis C, and Mycobacterium tuberculosis (M. tuberculosis), as well as to pursue prophylaxis against Pneumocystis spp. in high-risk populations, before initiating immunosuppression [39].

Generally, all SLE patients are advised to take adjunctive measures, such as sun protection, vaccination, regular exercise, smoking avoidance, and control of body weight, blood pressure, and lipid and glucose levels [39,45]. Further studies are needed to characterize the self-management/self-care practices of Filipino patients with SLE.

Access to medications

HCQ is commonly prescribed to patients with SLE in the Philippines [14,51]. In its oral 200 mg tablet form, it is listed as an essential drug in the 8th edition of the Philippine National Formulary (PNF) [52]. A single 200 mg tablet of HCQ costs 50 PHP (0.8 USD) [53], while the national average minimum wage stands at 440 PHP (7.6 USD) per day (Table 1) [54]. During the Coronavirus disease-19 (COVID-19) pandemic, the high demand for HCQ for COVID-19 treatment may have accorded irregular supply for Filipino SLE patients, contributing to increased symptom frequency (e.g., rash and muscle pains) [51,55]. Beyond that, however, HCQ prescription patterns and adherence rates among Filipinos with SLE are unknown. Moreover, quinacrine, the EULAR 2019 guideline-recommended alternative for HCQ for patients with skin manifestations and HCQ-induced retinopathies, remains unavailable in the Philippines.

Table 1.

Commonly used drugs for systemic lupus erythematosus treatment in the Philippines

Drug class	PNF-listed drug	Retail price (drug price reference index)
Antimalarials	Hydroxychloroquine (200 mg/tab)	50 PHP (0.8 USD)
Glucocorticoids	Prednisone (10 mg/tab)	2.45 PHP (0.04 USD)
	Methylprednisolone (16 mg/tab)	8.2 PHP (0.14 USD)
	Hydrocortisone (50 mg/mL, 2 mL vial)	149.50 PHP (2.6 USD)
Immunosuppressive drugs	Methotrexate (2.5 mg/tab)	4.7 PHP (0.08 USD)
	Methotrexate (25 mg/mL, 2 mL vial)	138.5 PHP (2.4 USD)
	Azathioprine (50 mg/tab)	34.3 PHP (0.6 USD)
	Mycophenolate mofetil (500 mg/tab)	54.5 PHP (0.75 USD)
	Cyclophosphamide (1 g powder vial)	210 PHP (3.6 USD)
Monoclonal antibodies	Rituximab (10 mg/mL, 10 mL vial)	8,363 PHP (145.7 USD)

Glucocorticoids such as prednisone, methylprednisolone, and hydrocortisone are all PNF-listed and are utilized for both outpatient and inpatient SLE care in the country, especially when patients present with worsening symptoms and/or acute flare. As an alternative to glucocorticoids, which harbor high toxicities when used for prolonged periods, immunosuppressive drugs (IDs) have emerged and are used to facilitate steroid tapering while preventing disease flares. In the Philippines, IDs are usually initiated among patients with target organ involvement and/or difficult-to-manage diseases [9,11,12,20]. Methotrexate is readily available in the PNF in both oral (as a 2.5 mg tablet) and injectable forms [52]. A single 2.5 mg tablet of methotrexate costs 4.7 PHP (0.08 USD), while a 2-milliliter vial of methotrexate (25 mg/mL formulation) costs approximately 138.5 PHP (2.4 USD) [53]. Although oral azathioprine and mycophenolate mofetil are also available in the PNF, they are more expensive. Each tablet costs approximately 34.3 PHP (0.6 USD) and 54.5 PHP (0.75 USD), respectively, posing important financial challenges to patients [52,53]. Hence, when indicated, cyclophosphamide, which does not require daily dosing and is PNF-listed [52], is often used, with a single 1 g powder vial costing about 210 PHP (3.6 USD) [50,53].

Biologic agents, such as B-cell targeting agents, are considered in poorly controlled SLE despite first-line treatments. The EULAR 2019 guidelines recommend Food and Drug Administration (FDA)-approved belimumab [56]; however, it is currently unavailable in the country. Rituximab, another B-cell-depleting biologic, is being given off-label for intractable SLE cases. Anifrolumab, a human monoclonal antibody to type I interferon receptor subunit 1, was approved by the U.S. FDA in 2021 to treat moderate-to-severe SLE [57] and is now available in the Philippines. However, like rituximab, its cost remains prohibitive.

Approach to systemic manifestations of lupus

SLE is a complex, chronic, multisystemic disease with a wide range of manifestations and complications necessitating a multidisciplinary approach to management.

Lupus nephritis is one of the most serious manifestations of SLE and is a risk for developing chronic kidney disease, affecting 40% of all SLE patients [58]. This presents with urinary signs and symptoms, including hematuria, leukocyturia, and the presence of cellular casts. It may even present more overtly, as in nephrotic and nephritic syndromes or as rapidly progressing kidney failure [59]. While patients may be asymptomatic, it is recommended that all patients suspected of having SLE have a urinalysis. Once clinical evidence of nephritis is found, a consultation with a nephrologist is warranted. In the global setting, the clinical presentation of lupus nephritis has become milder with a decrease in the rapidly progressing forms, and this has been attributed to the regular assessment of renal function [60]. A renal biopsy is recommended to clinch the diagnosis of nephritis. This procedure also allows for differentiating pathological classes, assessing disease activity, and identifying non-lupus nephritis entities [46].

Renal disease remains one of the most frequent complications of SLE and brings about significant morbidity and mortality, with a five-fold increase in the standardized mortality ratio (SMR) [61,75]. Further, it confers a nine-fold increase in the risk of MI as compared to patients with SLE without it [62]. Nephritis was reported in 30% to 70% of Asian SLE patients [3], whereas in the Philippines, prevalence estimates are similar at around 45% to 74%, making renal involvement the most common cause of organ damage in SLE [9,14,15,50]. Remission was seen in 59.12%, while 8.76% progressed to end-stage renal disease [50].

SLE also affects both the central and peripheral nervous systems, presenting as neurologic symptoms such as headaches, cognitive dysfunction (i.e., memory loss, etc.), and seizures [63]. There is no specific set of criteria to diagnose neuropsychiatric SLE (NPSLE); however, it is crucial to determine whether symptoms are due to SLE or any other superimposed medical conditions such as metabolic abnormalities, infections, or drug abuse [63]. The management of NPSLE is focused on symptomatic treatment, such as providing anxiolytics and antipsychotics for psychiatric manifestations and giving antiepileptic medications for seizures [63].

The prevalence of NPSLE is reported to be between 14% to 95% [64]. In a study with 5057 SLE patients of mostly Asian ethnicity, NPSLE had a prevalence of 56%, with the most frequent syndromes being headache, mood disorders, and cognitive dysfunction [65]. NPSLE in Filipino patients occurred in 13% to 18%, with a seizure occurrence in about 7% [7,66]. Seizures are associated with poor outcomes, high rates of hospitalization, and high rates of mortality [11,66]. Depression was also found in 52% of Filipino SLE patients in one study, and suicidality was found in 15% in another study in the country [50,67]. The mental health of SLE patients in the Philippines was also greatly impacted by the COVID-19 pandemic. A study in a local government hospital showed moderate to severe stress, anxiety, and depression symptoms [68]. The presence of comorbidities such as asthma and hypertension and the presence of symptoms were significantly associated with adverse mental health among SLE patients [68].

Normochromic normocytic anemia is the most common manifestation of SLE, present in more than 50% of affected patients [41]. However, SLE can still manifest with a complex array of hematologic abnormalities, such as leukopenia, lymphopenia, and thrombocytopenia. Mild cytopenia may not require treatment but requires close monitoring [69]. However, for moderate to severe cytopenia, steroids remain the first line of treatment [69]. Persistently steroid-refractory cases may also be treated with additional strategies such as rituximab [41].

Cutaneous manifestations are classical features of SLE and may be present in more than 80% of patients with SLE [41]. The pathognomonic lesion is the butterfly malar rash, which is typically seen in 30% of patients. Other lesions include discoid rashes, livedo reticularis, and alopecia [70]. Topical agents for cutaneous lupus erythematosus are recommended as first-line therapy. Second-line drugs include methotrexate, mycophenolate, anifrolumab, and belimumab.

Variations in health systems compared with other countries

Regarding varied health systems in Asia, patients from Universal healthcare systems such as Japan have higher index ages (mean 45.2, standard deviation=13.1) (Table 2) [71]. In the Philippines, the index age is around 26.71±11.60 for both sexes. Despite the similarity in the treatment regimen between the Philippines and Japan, where topical steroids, Nonsteroidal anti-inflammatory drugs, glucocorticoids, immunosuppressants, and HCQ are commonly given in an outpatient basis, there are still higher admission rates in the Philippines. This may be attributed to the differences in the socioeconomic status of most people in the countries, and the cost of healthcare between the two countries, where belief in medication use, lack of resources, and difficulty on travelling to follow-up clinics pose a challenge to patients in developing regions, or even patients belong to minority groups in developed regions [11,71,72].

Table 2.

Comparison of systemic lupus erythematosus management between the Philippines, Japan, and USA/UK

	Philippines	Japan	USA/UK
Diagnosis	Use ACR, SLICC, and EULAR criteria
Medications used	Hydroxychloroquine, NSAIDs, glucocorticoids, immunosuppressants, biologics
Other management nuances specific to other countries		Relatively accessible biologics Lower admission rates across the spectrum of severity	Relatively accessible biologics Increased drug discovery/development (i.e., belimumab, anifrolumab, voclosporin, etc.) Formalized special care teams (i.e., frequent multidisciplinary team meetings, dedicated lupus nurses and lupus nephritis clinics) More frequent kidney biopsies prior to initiation and/or shift of treatment for lupus nephritis

ACR: American College of Rheumatology, SLICC: Systemic Lupus International Collaborating Clinics, EULAR: European League Against Rheumatism, NSAIDs: nonsteroidal anti-inflammatory drugs.

In the West, management also primarily adheres to international guidelines published by EULAR and other associations. Mild SLE is also treated with glucocorticoids, whereas moderate and severe SLE similarly require the addition of immunosuppressives and other modalities [73]. A key difference between the Philippines and the West in terms of SLE management is the relative accessibility in the latter of novel treatments for lupus, such belimumab, anifrolumab, and the novel calcineurin inhibitor voclosporin, all of which are undergoing numerous studies in the U.S. to compare their effectivity in SLE treatment versus standard of care [73], compared with the Philippines wherein costs remain prohibitive to accessing these drugs. Furthermore, a study in the UK showed that interdisciplinary care pursuits are being employed in their healthcare systems routinely, with the inclusion of trained lupus nurses, frequent multidisciplinary team meetings between rheumatologists and nephrologists, and dedicated lupus nephritis clinics and inpatient protocols [74]. Renal biopsy is also performed more frequently prior to initiating any level of nephritis treatment, as well as prior to shifting to second-line therapy [74].

PROGNOSIS OF SLE IN THE PHILIPPINES

There has been significant improvement in the survival of patients with SLE. In the past decade, the 5-year and 10-year survival estimates for adults in high-income countries were 0.95 and 0.89, respectively, while in low- and middle-income countries, they were 0.92 and 0.85 [75]. In the Asia-Pacific region, survival rates ranged from 60% to 97% at 5 years and 70% to 94% at 10 years; and survival appeared to be higher in China (Shanghai; 98% at 5 years), Hong Kong (97% at 5 years and 94% at 10 years), and South Korea (94% at 5 years) [76]. In the Philippines, lupus had a cumulative 10-year survival rate of 75%, with an average survival time of 9.84 years [15]. The most common causes of mortality are infection and disease activity, which are consistent with other Asian and local studies [11,15,77].

SLE in children presents with more severe disease, higher disease activity, greater risk of organ damage accrual, and mortality [78,79]. Filipino children with SLE have an overall 5-year mortality rate of 11.5%, of which infection was the major cause at 77% [9]. In 2022, pediatric 5-year survival in the Philippines was quoted at 80%, with a mean survival time of 9.3 years [11].

A bimodal pattern of mortality has been classically described in SLE. Deaths early in the course of the disease are associated with disease activity and infection. In contrast, deaths late in the disease are linked to MI due to atherosclerotic complications [80].

Patients with SLE have a 2-to-3-fold higher risk of MI, stroke, cardiovascular disease, and hypertension compared to the general population [81-83]. Local data in the Philippines is limited regarding the incidence and prevalence of cardiovascular disease in SLE. One study reported an 86% prevalence of echocardiographic abnormalities and a 20% occurrence of arrhythmias on electrocardiogram traces in SLE patients [84]. Of note, 3% of cardiac tamponade patients in a local hospital had SLE [85].

Infections are still among the top causes of mortality in SLE patients in the Philippines, next to disease activity [9,11,14,15]. The SMR from infection is about five-fold higher in SLE compared to the general population [61]. Patients with SLE are susceptible to infection due to intrinsic and acquired deficiencies in the immune system. In a retrospective study involving 550 Filipino patients with SLE, 51% of the cohort had at least one infectious event at some point in their course [86]. The respiratory tract (33%) and the urinary tract (23%) are the most common sites of infection, followed by skin and soft tissue infections (22%) [86]. Bacteria are the most common pathogens (79%) with M. tuberculosis comprising 21% of these infections, followed by viruses (18%), fungi (3%) and protozoa (1%) [86]. Due to endemicity, tuberculosis is still an important cause of morbidity and mortality in Filipino patients with SLE. The most prevalent manifestation of tuberculosis in SLE in the Philippines is still pulmonary, and septic arthritis is the most common extrapulmonary TB affectation [87]. COVID-19 disease may also contribute to poorer clinical outcomes for Filipinos with SLE, especially those with uncontrolled disease activity and comorbidities [88,89]. Generally, Filipino SLE patients with elevated disease activity and a history of high-dose immunosuppression were found to be particularly vulnerable to infections and subsequent mortality [86].

SOCIOECONOMIC BURDEN OF SLE IN THE PHILIPPINES

The Philippine Health Agenda for 2016 to 2022 highlights the significant financial burden imposed on families by healthcare expenditures, including those related to SLE [16]. A cost analysis of 100 pediatric SLE patients in the Philippines revealed an average annual direct cost of 162,764.81 PHP (approximately 2,821.75 USD) per patient, primarily attributable to medication costs [12]. Meanwhile, the minimum wage in the National Capital Region (NCR) in 2024 has been pegged at 610 PHP (10.47 USD) per day [54], making this annual cost sum up to 73% of the annual income of minimum wage earners in the capital, a situation that is much worse for geographically isolated and disadvantaged areas in the country.

Furthermore, studies indicate that SLE patients in the Philippines allocate a substantial portion of their income to healthcare, with up to 82% of annual income and 25% of household budgets dedicated to medical expenses. This percentage for household healthcare expenditures is beyond the World Bank threshold of 10% [90], indicating that out-of-pocket costs for SLE care in the country may impoverish Filipino households. Nephritis leading to end-stage renal disease requiring dialysis is a significant cost driver, increasing healthcare costs by 3.5 to 7 times for patients undergoing chronic hemodialysis or those post-renal transplantation [12,16].

Aside from direct costs for SLE patients, indirect expenses, structural issues, and socioeconomic disparities in healthcare pose significant barriers to effective individual- and population-based lupus interventions in the Philippines, especially for those outside of NCR. On average, the country has approximately 3.9 doctors per 10,000 population [91]. Most doctors are concentrated in NCR, with around 10.6 doctors per 10,000, in contrast to provincial regions with only about 2 doctors per 10,000 [91]. Among these doctors, there is only 1 rheumatologist per one million Filipinos, underscoring the gravity of the country’s human resource shortage for managing lupus [92].

Similarly, most of the hospital beds in the country are in the island group of Luzon, with 29% in NCR and 36% in the rest of the island group, and only 20% in Mindanao and 15% in Visayas [91]. Pressing still are the conditions in public facilities such as overcrowding, prolonged waiting, and inefficient documentation, among others, limiting access for impoverished Filipinos with SLE who consequently delay care or forego it altogether [44]. The COVID-19 pandemic also greatly affected healthcare access among SLE patients. During the pandemic, SLE patients had to use teleconsultations. In a local study, around 62.7% of SLE patients had an average of a year-long interruption in medical care [93]. Approximately 22.7% discontinued at least one of their drugs for SLE control, which resulted in lupus flares and hospitalizations among SLE patients [93]. Another local study reported interruptions in the supply of HCQ and methotrexate during the COVID-19 pandemic, which was associated with the presence of muscle pain, rash, and joint pains among SLE patients [51].

The scarcity of studies, including financial toxicity research, that assess SLE-specific direct expenses such as diagnostics and medications, as well as indirect costs including human resources and infrastructure, significantly preclude comprehensive policymaking and targeted strategies that may alleviate the financial burden on SLE patients and their families. These insights can inform policy decisions to improve affordability, ensuring that all individuals, regardless of socioeconomic status, have equitable access to essential healthcare services for lupus.

CONCLUSION

This review is a comprehensive account of the SLE situation in the Philippines. The absence of national data registries and the reliance on available institutional records magnify the difficulty in estimating the burden of SLE in the Philippines. Furthermore, local clinical practice guidelines are yet to be published. SLE and its management in the Philippines reflect the overall state of our healthcare system. Costs for SLE diagnosis, treatment, and management generally remain blatantly toxic for most Filipinos, from early detection up until managing complications. This is compounded by the almost entirely out-of-pocket financing system for healthcare in the country. Implementing the Universal Healthcare Act may potentially alleviate this burden should all stakeholders, including the medical community and the national government, undertake a comprehensive approach to lupus care. More research on the diagnosis, treatment, and prognosis of SLE in the Philippines is needed. Once the actual burden of the disease has been described and targeted, population-based interventions will be possible. We also acknowledge the structural barriers to comprehensive lupus care due to social determinants in the country and call on stakeholders to provide safe, equitable, and effective measures to control the burden of lupus in the Philippines.