5

CHAPTER 1INTRODUCTION1.1. BackgroundSystemic lupus erythematosus (SLE) is a chronic, often life-long, autoimmune disease. SLE may affect various parts of the body, but it most often manifests in the skin, joints, blood, and kidneys. Women are more commonly affected than men and the disease is primarily diagnosed in patients aged 15 to 45 years. The name describes the disease where Systemicis used because the disease can affect organs and tissue throughout the body. Lupusis Latin for wolf. It refers to the rash that extends across the bridge of the nose and upper cheekbones and was thought to resemble a wolf bite. Erythematosusis from the Greek word for red and refers to the color of the rash.1There is varying epidemiologic information regarding systemic lupus erythematosus among countries in Asia. Prevalence rates usually fall within 30-50/100,000 population.2 The clinical classification for systemic lupus erythmatosus is based on the American College of Rheumatology 1997 revised criteria for classification of systemic lupus erythematosus. The classification is based on 11 criteria. For the purpose of identifying patients in clinical studies, a person is defined as having SLE if any 4 or more of the 11 criteria are present, serially or simultaneously, during any interval of observation.3Treatment of SLE is tailored to the individual, being based on specific disease manifestations and tolerability. For all patients, sunscreen and avoidance of prolonged direct sun exposure and other ultraviolet light may help control disease. Hydroxychloroquine (5-7 mg/kg/day) is recommended for all individuals with SLE if tolerated. Corticosteroids are a mainstay for treatment of significant manifestations of SLE.4Theprognosishasimprovedwithearlierrecognitionandimprovedmanagement.The five-yearsurvivalrateisover90%.5

1.2. ObjectiveThe aim of this study is to explore more about the theoretical aspects on systemic lupus erythematosus, and to integrate the theory and application of systemic lupus erythematosus cases in daily life.

CHAPTER 2LITERATURE REVIEW

2.1. DefinitionSystemic lupus erythematosus (SLE) is a clinically heterogeneous disease which is autoimmune in origin, and characterized by the presence of autoantibodies directed against nuclear antigens. It is, by definition, a multi-system disease, and patients can present in vastly different ways.6

2.2 EpidemiologyThere is varying epidemiologic information regarding systemic lupus erythematosus among countries in Asia. Prevalence rates usually fall within 30-50/100,000 population. Incidence rates, as reported from three countries, varied from 0.9/100,000 to 3.1% per annum.2 More than 90% of cases of SLE occur in women, frequently starting at childbearing age.7,8 The use of exogenous hormones has been associated with lupus onset and flares, suggesting a role for hormonal factors in the pathogenesis of the disease.9 The female-to-male ratio peaks at 11:1 during the childbearing years.10 Common manifestations include mucocutaneous lesions (seen in 52-98% of patients) and arthritis/musculoskeletal complaints (36-95%). Antinuclear antibodies were generally positive in 89-100% of patients, except for two studies. Renal involvement ranged from 18% to 100% with most articles reporting this in >50% of their patients. Discoid lesions, serositis, and neurologic involvement were the least frequently seen symptoms.2

2.3. Risk Factors2.3.1GeneticsGenetic susceptibility to lupus is inherited as a complex trait and studies have suggested that several genes may be important. In particular an interval on the long arm of chromosome 1, 1q2324, is linked with SLE in multiple populations. Clinically it is widely accepted that active SLE is characterised by elevated erythrocyte sedimentation rates but normal C-reactive protein (CRP) levels. Both CRP and complement as well as serum amyloid P protein are important in clearing apoptotic cell debris and the genes for CRP have been mapped to chromosome 1, 1q2324, the so-called pentraxin locus. Russell and colleagues examined the inheritance of polymorphisms at the pentraxin locus in a family-based association study of SLE and found strong linkage disequilibrium within each of the CRP and serum amyloid P genes.11 They demonstrated that an allele of CRP 4 was associated with SLE. Furthermore there were two haplotypes that were significantly associated with reduced basal CRP expression: CRP 2 and CRP 4 and an allele of CRP 4 was associated with ANA production. Thus the authors proposed a genetic explanation of the link between low CRP levels, antinuclear autoantibody production and the contribution of these to the development of human SLE. Another large study of individuals and multi-case families with SLE suggested that a single nucleotide polymorphism (SNP) within the programmed cell death 1 gene (PDCD1) is associated with the development of lupus in both European and Mexican populations. The authors showed that the associated allele of this SNP alters a binding site for a transcription factor located in an intronic enhancer, suggesting a mechanism through which it can contribute to the development of SLE.12

2.3.1GenderAbout 90% of lupus patients are women, most diagnosed when they are in their childbearing years. Hormones may be an explanation. After menopause, women are only 2.5 times as likely as men to contract SLE. Flares also become somewhat less common after menopause in women who have chronic SLE.1

2.3.2AgeMost people develop SLE between the ages of 15 - 44. About 15% ofpatients experience the onset ofsymptoms before age 18.1

2.3.4Environmental TriggersIn genetically susceptible people, there are various external factors that can trigger symptoms (flares). Possible SLE triggers include:Viruses.Epstein Barr virus (EBV) has also been identified as a possible factor in the development of lupus. EBV may reside in and interact with B cells. Gross et al 13 found a high frequency of EBV infected B cells in lupus patients compared to controls and these infected cells are predominantly memory B cells. There was no relationship with immunosuppressive therapy and furthermore patients with active lupus flares had more infected cells than patients with quiescent disease. Although other studies have suggested a causative role for EBV in SLE, these authors are more cautious and despite their findings of increased frequencies of infected cells, increased viral loads, and viral gene expression, they have not interpreted this as directly implicating EBV in the development of SLE and argue that it is also possible that the immune dysregulation of SLE may result in aberrant EBV expression. In contrast, studies in a mouse model found that direct introduction of the whole EBV nuclear antigen 1 protein can elicit IgG antibodies to Sm and to double-stranded DNA (dsDNA) thus supporting a putative role for EBV in the development of lupus. The paradox remains that although 90% of the adult population are infected by EBV, the prevalence of SLE remains low emphasising the multi-factorial nature of the pathogenesis of SLE.

Sunlight.Ultraviolet (UV) rays found in sunlight are important SLE triggers. UV light is categorized as UVB or UVA depending on the length of the wave. Shorter UVB wavelengths cause the most harm.1

Smoking.Smoking may be a risk factor for triggering SLE and can increase the risk for skin and kidney problems in women who have the disease.1

Chemicals.While no chemical has been definitively linked to SLE, occupational exposure to crystalline silica has been studied as a possible trigger. (Silicone breast implants have been investigated as a possible trigger of autoimmune diseases, including SLE. The weight of evidence to date, however, finds no support for this concern.) Some prescription medications are associated with a temporary lupus syndrome (drug-induced lupus), which resolvesafter these drugs are stopped.1

Hormone Replacement Therapy.Premature menopause, and its accompanying symptoms (such as hot flashes), is common in women with SLE. Hormone replacement therapy (HRT), which is used to relieve these symptoms, increases the risk for blood clots and heart problems as well as breast cancer. It is not clear whether HRT triggers SLE flares. Women should discuss with their doctors whether HRT is an appropriate and safe choice. Guidelines recommend that women who take HRT use the lowest possible dose for the shortest possible time. Women with SLE who have active disease, antiphospholipid antibodies, or a history of blood clots or heart disease should not use HRT.1

Oral Contraceptives. Female patients with lupus used to be cautioned against taking oral contraceptives (OCs) due to the possibility that estrogen could trigger lupus flare-ups. However, recent evidence indicates that OCs are safe, at least for women with inactive or stable lupus. Women who have been newly diagnosed with lupus should avoid OCs. Lupus can cause complications in its early stages. For this reason, women should wait until the disease reaches a stable state before taking OCs. In addition, women who have a history of, or who are at high risk for, blood clots (particularly women with antiphospholipid syndrome) should not use OCs. The estrogen in OCs increases the risk for blood clots.1

2.4. Classification1997 Update of the 1982 American College of Rheumatology revised criteria for classification of systemic lupus erythematosus1. Malar RashFixed erythema, flat or raised, over the malar eminences, tending to spare the nasolabial folds

2. Discoid rashErythematous raised patches with adherent keratotic scaling and follicular plugging; atrophic scarring may occur in older lesions

3. PhotosensitivitySkin rash as a result of unusual reaction to sunlight, by patient history or physician observation

4. Oral ulcersOral or nasopharyngeal ulceration, usually painless, observed by physician

5.Nonerosive arthritisInvolving 2 or more peripheral joints, characterized by tenderness, swelling, or effusion

6.Pleuritis or pericarditis1. Pleuritis--convincing history of pleuritic pain or rubbing heard by a physician or evidence of pleural effusionOR2. Pericarditis--documented by electrocardigram or rub or evidence of pericardial effusion

7. Renal disorder1. Persistent proteinuria > 0.5 grams per day or > than 3+ if quantitation not performedOR2. Cellular casts--may be red cell, hemoglobin, granular, tubular, or mixed

8.Neurologic disorder1. Seizures--in the absence of offending drugs or known metabolic derangements; e.g., uremia, ketoacidosis, or electrolyte imbalanceOR2. Psychosis--in the absence of offending drugs or known metabolic derangements, e.g., uremia, ketoacidosis, or electrolyte imbalance

9.Hematologic disorder1. Hemolytic anemia--with reticulocytosisOR2. Leukopenia--< 4,000/mm3on 2 occasionsOR3. Lyphopenia--< 1,500/ mm3on 2 occasionsOR4. Thrombocytopenia--