Systemic Lupus Erythematosus - SLE

 Systematic Lupus Erythematosus - SLE

OUTLINE

• Introduction
• Epidemiology
• Aetiology
• Pathogenesis
• Clinical manifestation
• Diagnosis
• management
• Differential diagnosis
• Prevention
• Prognosis
• Conclusion
• References

Introduction

• Systemic Lupus Erythematosus (SLE) is a multisystem autoimmune inflammatory disorder characterized by the production of antibodies to components of the cell nucleus.
• It is a connective tissue disorder
• It is marked by periods of exacerbation and remissions
• Occurs predominantly in women of childbearing age
• It has a diverse array of clinical manifestations and consequently, is often difficult to diagnose
• Ethnic considerations it is more common in the African Americans compared to Caucasians

Epidemiology of Systemic Lupus Erythematosus

• SLE occurs worldwide but the prevalence varies from country to country
• The prevalence is influenced by gender, race and age
• In USA 1: 2000 with highest prevalence in African American and Afro Caribean women 1: 250-500
• UK 1: 10 000
• China 1: 1 000
• 5.28 of 1,250 rheumatology cases seen over 6 yrs in a Nigeria rheumatology clinic in Lagos, Nigeria Adelowo O Etal 2018
• Over 91 of 30 patients with Autoimmune connective tissue disorder in a dermatology/rheumatology clinic in Port Harcourt (Mercy E Etal 2015
• Male to Female ratio is 1: 9
• The peak age at onset is 14-45yrs in women of childbearing age

Table 1

SLE in Different Black African Populations ( Adapted from Bae, Fraser, Living Arthritis Rheum.1999;41:2091 2099)

AETIOLOGY OF SLE

• The aetiology of SLE remains unknown and is clearly multifactorial
• Many observations suggest the role of
• Genetics
• Hormonal triggers
• Immunologic
• Environmental factors

GENETIC FACTORS

• The following observations are compatible with a genetic role in the pathogenesis of SLE:
• There is a high concordance rate (24 58%) of SLE in monozygotic twins
• Familial aggregation is seen in 5 13% of 1 st and 2 nd degree relatives with SLE
• 27% of 195 children of mothers with lupus had a positive test for antinuclear antibodies
• The most common genetic predisposition is found at the major histocompatibility locus (MHC) HLA DR2 and HLA DR3
• GWAS has identified 30 40 gene loci with polymorphism that predispose to SLE
• Other genes that have been implicated involve those associated with interferon alfa pathway and deficiency of complement components(C1q, C2, C4)
• A combination of susceptibility genes, or presence of susceptibility genes plus absence of protective ones are required to permit disease development
• The female sex is permissive for SLE

ENVIRONMENTAL FACTORS

• INFECTIONS
• Viruses Eg EBV, CMV
• Mycoplasma
• ULTRAVIOLENT LIGHT

• UV may stimulate keratinocytes to secrete more IL 1, IL 3, IL 6, GM CSF, TNF alpha
• UV light may also increase the degree of systemic autoimmunity by interfering with antigen processing by activation of macrophages.
• UV decreases T Cell DNA methylation
• Silica dust
• Drug induced lupus
• Tobacco smoking
• No apparent association between SLE and use of Hair dyes, occupational solvent exposure or the use of
• pesticides
• studies of alcohol use and SLE concluded that moderate alcohol consumption had a protective effect.

HORMONAL

• The etiologic role of hormones in SLE may be related to their effects in immune responsiveness.
• OESTROGEN:
• Effect of oestrogen on the immune system
• Stimulates thymocytes CD 8+ and CD 4+ T cells, B cells, macrophages, the release of certain cytokines and the expression of both HLA and endothelial cell adhesion molecules (VCAM, ICAM)
• Estrogen also causes increased macrophage proto-oncogene expression of both HLA and enhanced adhesion of peripheral mononuclear cells to endothelium.
• Estradiol reduces apoptosis of self-reactive B cells thus promoting selective maturation of autoreactive B cells with high-affinity anti-DNA
• The use of Estrogen containing contraceptive agents is associated with 50% increased risk of developing SLE
• Early onset of menarchy and administration of estrogen in postmenopausal women doubles risk
• Treatment of women with clinically stable SLE with OCP for 1yr does not increase disease flares
• SLE has been observed in some males with klinefelter syndrome
• In women with SLE, plasma levels of the following hormones are decreased; testosterone, progesterone and DHEA while estradiol and prolactin are increased.
• Breast feeding may decrease risk of SLE
• Androgens t end to be immunosuppressive
• Both progesterone and high levels of estrogen promote a Th2 response, which favors autoantibody productions
• Lupus flares have been associated with hyperprolactinemia
• Abnormalities of the HPA axis may also exist among those with SLE. Patients appear to have an abnormal reaction to stress

PATHOPHYSIOLOGY

• Genetic, hormonal and environmental factors that increase the probability of development of SLE are likely to act on the immune system to induce autoimmunity and consequent tissue inflammation and damage.

DEFECTIVE APOPTOSIS

• Apoptosis is programmed cell death, this process that to the ordered destruction of cells, avoiding the release of intracellular contents into the extracellular microenvironment, where they have an inflammatory effect
• Under normal circumstances, apoptotic cells are engulfed by macrophages in the early phase of apoptotic cell death without inducing inflammation or the immune response
• The increased rate of apoptosis in SLE would theoretically increase the chance of leakage of intracellular antigens that may trigger an autoimmune response or participate in the formation of immune complexes
• The reasons for the defective clearance of apoptotic cells is associated with defects of the early complement proteins such as C2, C4 or C1q

LOSS OF SELF TOLERANCE

• Failure to adequately clear apoptotic cells exposes nuclear antigens (in the form of nucleosomes ) to the immune system
• Self antigens (nucleosomes) are recognized by the immune system in surface blebs of apoptotic cells
• The innate immune response is first activated and results in augmented APC capacity(TLR pattern) and successful generation of an antigen-specific adaptive immune response

• Immune cell activation is accompanied by increased secretion of pro-inflammatory type 1 and 2 interferons, TNF alfa,IL 17 and B cell maturation/survival cytokines, B lymphocyte stimulator and IL 10
• Upregulation of genes induced by IFN is a genetic ‘ signature’ in peripheral blood cells of 50 60% of SLE patients
• Lupus T and NK cells fail to produce enough IL 2 and TGF beta to induce and sustain regulating CD4+ and CD8+ T cells

Autoantibody production and immune complex deposition

• The result of the abnormalities in the immune tolerance is sustained production of autoantibodies
• Autoreactive T cells provide help to B cells which produce large quantities of autoantibodies, which form immune complexes
• Circulating immune complexes are not adequately cleared and become deposited in tissues
• The immune complexes deposited in tissues elicit inflammation via activation of complement leading to release of cytokine, chemokines , vasoactive petipdes , oxidants and proteolytic enzymes
• Most SLE patients have autoantibodies for 3yrs or more before the first symptoms of the disease

TISSUE INJURY

• Production of pro-inflammatory and pro-fibrotic cytokines lead to irreversible tissue damage
• In the setting of chronic inflammation, accumulation of growth factors and products of chronic oxidation contribute to irreversible tissue damage including fibrosis/sclerosis in lungs and other tissues

Clinical Features

CLINICAL FEATURES AMONG 66 NIGERIAN SLE PATIENTS

Adapted Adelowo OO,Oguntona S. Clin Rheumatol . 2009.28;6:699-703

CONSTITUTIONAL SYMPTOMS

• Fever
• Fatigue
• Headache
• Weightloss
• Generalised arthralgia and myalgias,

MUCOCUTANEOUS MANIFESTATIONS

• MALAR RASH:
• An erythematous facial rash with a ‘ butterfly’ distribution across the malar and nasal prominences and sparing the nasolabial folds
• Seen in 30 60% of patients
• Often triggered by sun exposure
• Photosensitivity can also be demonstrated diffusely in other areas of the body

Malar Rash

MUCOCUTANEOUS MANIFESTATION DISCOID LUPUS

• These are erythermatous plaques with central scarring and maybe covered with scale
• Seen in in 25% of patients
• Involves the scalp or the face and ears and maybe associated with alopecia
• Discoid lesions can be present in the absence of systemic involvement

Discoid Lupus

Alopecia in Lupus

Subacute Cutaneous Lupus Erythematosus

• Consists of scaly red or circular flat red-rimmed lesions
• Patients with these manifestations are exquisitely photosensitive
• Most have antibodies to Ro(SSA)

Others

• Oral ulcers                                                                          
• Livedo reticularis
• Vasculitic ulcers
• Raynaud’s phenomenon
• Splinter haemorrhage
• Lupus panniculitis
• Acute cutaneous lupus

MUSCULOSKELETAL

• Arthritis
• Arthritis are among the most common clinical features of SLE, occur in 85%
• Arthritis is polyaticular , symmetrical, episodic and flitting in nature
• Jaccoud’s arthropathy  - a chronic, deforming, non-erosive arthropathy Synovitis often the earliest sign and affect 90%

• Osteoporosis - from SLE itself or from steroid therapy
• Osteonecrosis - usually avascular necrosis
• Myositis - characterized muscle weakness, elevated creatinine kinase level.
• Glucocortoid therapies and anti-malaria therapy can cause muscle weakness

Jaccoud's Arthropathy

RENAL SYSTEM

• Renal involvement is seen in 30% of patients
• It is a poor prognostic indication
• Renal pathology is due to immune complex deposition or in situ formation of those complexes in the glomeruli
• Because nephritis is asymptomatic in most Lupus patients urinalysis should be ordered in any person suspected of having SLE
• Renal biopsy is recommended for every SLE patient with clinical evidence of nephritis
• The International Society of Nephrology(ISN) and Renal pathology society(RPS) classified lupus nephritis

Neuropsychiatric Manifestation of Systemic Lupus Erythematosus

Neuropsychiatric

PNS

• Acute inflammatory demyelinating polyradiculoneuropathy Gullain-Barre syndrome)
• Autonomic disorder
• Mononeuropathy , single/multiplex
• Myasthenia gravis
• Neuropathy
• Plexopathy
• Polyneuropathy

GASTROINTESTINAL MANIFESTATIONS

• This is uncommon
• Mesenteric vasculitis
• Dysphagia
• Mouth ulcers
• Peritonitis
• Bowel infarction
• pancreatitis
• autoimmune hepatitis

PULMONARY

• Pleuritis /pleural effusion
• Pulmonary infiltrates/Discoid atelectasis
• Acute lupus pneumonitis
• Chronic interstitial pneumonia
• Pulmonary hemorrhage
• Shrinking lung syndrome
• Restrictive lung disease

Chest Xray of the Shrinking-lung syndrome

CARDIAC MANIFESTATIONS

• Pericarditis infrequently leads to cardiac tamponade
• Libman Sacks endocarditis
• Cardiac failure
• Cardiac arrhythmias
• Valvular heart disease
• Coronary artery disease

Libman-Sacks Endocarditis, Gross

Raynaud's Phenomenon

HEMATOLOGIC

• Hemolytic anemia reticulocytes
• Leukopenia --<4,000/mm* on 2 or more occasions
• Lymphopenia --<1,500/mm* on 2 or more occasions
• Thrombocytopenia --<100,000/mm* in the absence of offending drugs
• Elevated ESR

OCULAR

• Sicca syndrome  Sjogren's syndrome)
• Conjunctivitis
• Photophobia
• Retinal vasculitis and optic neuritis are serious manifestations blindness can develop over days to weeks
• Monocular blindness transient or permanent

Sicca Syndrome

RECTICULOENDOTHELIAL

• Lymphadenopathy diffused lymphadenopathy, nodes are often non tender
• Hepatosplenomegaly

ANTIPHOSPHOLIPID SYNDROME

• Characterised by recurrent arteriolar or venous thrombosis
• Recurrent pregnancy losses
• Thrombocytopenia
• Positive Anti cardiolipin Ab /lupus Anti coagulant

DIAGNOSIS OF SYSTEMIC LUPUS ERYTHEMATOSUS

• A criterion for the classification of patients with SLE was developed by the American College of Rheumatology (ACR) In 1982 and updated in 1997 diagnosis was made if 4 out of the 11 criteria were present.
• In 2012 The Systemic Lupus International Collaborating Clinic (SLICC) group revised and validated the ACR classification, they classified a person as having SLE in the presence of biopsy-proven Lupus Nephritis with ANA or ds DNA antibodies or if 4 of the diagnostic criteria including at least 1 clinical and immunologic criterion have been satisfied

AUTO ANTIBODIES

• Autoantibodies usually appear for a long time before the development of symptoms
• ANA - Sensitivity is 95% not diagnostic without clinical features
• Anti dsDNA - High specificity, sensitivity is 70%
• Anti Sm - most specific antibody for SLE, only 30 40% sensitivity
• Anti SSA (Ro) or Anti SSB (La) - present in 15% of patients with SLE and other connective tissue diseases such as Sjogren syndrome, associated with Neonatal lupus
• Anti Ribosomal P - Uncommon antibodies that may correlate with the risk for CNS disease, including increased hazards of psychosis
• Anti RNP included with anti Sm , SSA and SSB in the extractable nuclear antigen profile may indicate mixed connective tissue disease with overlap syndrome, Scleroderma and myositis
• Anti Cardiolipin
• Lupus anti coagulant
• Direct Coombs test
• Anti Histone

LAB INVESTIGATIONS OF SLE

• CBC with differential leukopenia, anemia, thrombocytopenia
• ESR and CRP elevated
• Serum creatinine
• Urinalysis with urine microscopy
• Complement level C3 and C4
• Liver function test
• Creatinine kinase assay
• Spot protein/spot creatinine ratio

RADIOLOGIC STUDIES

• JOINT RADIOLOGY Shows periarticular osteopenia and soft tissue swelling without erosions
• CHEST RADIOGRAPH/CT scan of the Chest To monitor international lung disease and to assess for pneumonitis, pulmonary emboli and alveolar hemorrhage
• ECHO Used to assess for pericardial effusion, pulmonary hypertension, verrucous Libman Sacks endocarditis
• BRAIN MRI/MRA Used to evaluate for central nervous system lupus white changes, vasculitis or stroke

ECHO findings in Libman Sacks Endocarditis

OTHER INVESTIGATIONS

• Arthrocentesis
• Lumbar puncture
• Renal biopsies
• Skin biopsies lupus skin rash often demonstrates inflammatory infiltrates at the dermo-epidermal junction and vacuolar change in the basal columnar cells. Discoid lesions demonstrate more significant skin inflammation with hyperkeratosis, follicular plugging, edema, and mononuclear cell infiltration at the dermo-epidermal junction

Photomicrography of Lupus Nephritis

MANAGEMENT OF SYSTEMIC LUPUS ERYTHEMATOSUS

• The multisystemic nature of SLE requires involvement of consultations from various specialties rheumatologists, Neurologists, Cardiologist, nephrologists, Pulmonologist, Gastroenterologist, dermatologist, hematologist
• Patient Education and Counseling is important to stay off triggers eg. UV light
• There’s actually no cure for SLE, but medications have been made available for the management of this disease

MEDICATIONS

NSAIDs

• Useful analgesics/anti-inflammatory agents particularly for arthritis and arthralgia
• Has been found to cause NSAID induced aseptic meningitis, elevated serum transaminases, HTN, renal dysfunction, and increased risk of MI

ANTIMALARIAL

• Eg ; Hydrochloroquine , chloroquine and quinacrine
• They reduce dermatitis, arthritis, and fatigue
• Hydrochloroquine is given at doses ranging from 200 400mg/day, Chloroquine 250mg/ day,Quinacrine 100mg/day

CORTICOSTEROIDS

• They are the cornerstone In the treatment of SLE
• Therapeutic protocols vary from pulse to high dose (0.5 1gm/kg/day) to medium (0.2 0.5mg/kg/day) and low (0.1 0.2mg/kg/day) doses and are variably used for induction of remission of flares and maintenance remission
• Frequently SLE patients are maintained at a low dose of <10mg/day of Prednisolone for years

IMMUNOSUPPRESSIVE AGENTS

CYCLOPHOSPHAMIDE

• Standard treatment for severe organ involvement in SLE
• Also shown to be effective in the treatment of lupus nephritis and CNS involvement
• Maybe administered IV (Pulse 500 1000mg) or orally (1 2mg/kg)

AZATHIOPRINE

• It’s a steroid-sparing agent,widely used for treatment of a spectrum of SLE manifestations (skin, serositis, hematology
• Used in the active SLE or in th maintenance phase of severe SLE
• Administered at a daily dose of 1 2mg/kg but doses of up to
• 2.5mg/kg/day has also been used



METHOTREXATE

• At doses of up to 15 20mg/week they seem to be effective in the treatment of articular manifestations refractory to treatment my steroids and antimalarial, but also in the treatment of serositis , cutaneous manifestations in the case of moderately sever SLE
• Available data has shown that 75 80% of patients treated for skin manifestations respond to methotrexate
• Intrathecal methotrexate has been used in the treatment of neuropsychiatric involvement

MYCOPHENOLATE MOFETIL

• Indicated in moderate to severe disease renal, cutaneous, hematologic,and neurologic) resistant to other immunosuppressive drugs with doses ranging from 1500 2000mg daily
• Case reports has confirmed its efficacy in treating hematologic manifestations, particularly thrombocytopenia and hemolytic anemia

LEFLUNAMIDE 

• Well established in the treatment of RA and psoriatic arthritis as well as in treatment of SLE

BIOLOGIC DMARD THERAPY

• BELIMUMAB - A monoclonal antibody, a B lymphocyte stimulator specific inhibitor. Found to reduce disease activity and decrease the number of flares and steroid use in patients with SLE
• RITUXIMAB (Anti CD20) - used in treatment of RA,Sjogrens , dermatophytosis
• EPRATIXUMAB(Anti CD22
• LJP-394 ( Abetimus sodium)

INTRAVENOUS IMMUNOGLOBULIN

• Dosage may vary from 2g/kg/day to 1gm/kg/day for 2 5 consecutive days ,once a month to 0.4g/kg/day for 5days once a month
• Has been used in treatment of mild to moderate disease and also lupus nephritis
• Beneficial results have been obtained in the treatment of hematologic manifestations, serositis and pregnancy losses

NEWER THERAPIES

• Fludarabine
• Inhibition of co-stimulatory molecules

Hematopoietic stem cell transplant

Plasma exchange

ADJUVANT THERAPY

• Vitamin D Supplementation
• Sunscreen agents

SPECIAL CONDITIONS THAT REQUIRE ADDITIONAL Rx

• CRESCENTRIC LN; High dose cyclophosphamide+ high dose corticosteroids for induction
• MEMBRANOUS LN Alternate day glucorticoids + cyclophosphamide or MM or cyclosporine
• Pregnancy and lupus
• Antiphospholipid syndrome
• Lupus dermatitis
• Microvascular thrombotic crisis

DRUG INDUCED LUPUS

• Classically associated with hydralazine, isoniazid, procainamide, quinidine, minocycline, D penicillamine
• Anti histone antibodies are present in more than 75% of patients
• Male to female ratio is equal
• Nephritic and CNS abnormalities are rare
• Normal complement and antibodies to anti-single-stranded DNA
• Symptoms usually resolve with stopping the drug

PREGNANCY AND LUPUS

• Fertility rate is normal
• Fetal loss is increased 2 3 fold in women with SLE
• Fetal demise is higher in mothers with high disease activity, anti phospholipid antibodies and or active nephritis
• Active SLE in pregnant women should be controlled with hydrochloroquine and if necessary prednisolone at the lowest effective doses for the shortest duration
• Neonatal lupus is a distinct entity that occur in infants of mothers with or without a diagnosis of SLE. It is characterized by cutaneous lesions and congenital heart block in the infant and the presence of antibodies

DIFFERENTIAL DIAGNOSIS OF SLE

RHEUMATIC

• Rheumatoid Arthritis
• Sjogren’s syndrome
• systemic sclerosis
• Dermatomyositis

NONRHEUMATIC

HIV

• endocarditis
• viral infections
• hematologic malignancies, multiple sclerosis, vasculitis
• Overlap syndrome

PREVENTION

• Smoking cessation
• Avoid UV exposure
• Avoid estrogen therapy
• Family planning
• Aggressive BP and lipid control
• Medication related steroid complications ( Ca , Vit D, Bisphosphonates)
• Diet modification low fat diet

PROGNOSIS

• Unpredictable course
• Prognosis is better for isolated skin and musculoskeletal disease, worse for renal and CNS
• 10 year survival rate exceeds 85%
• Most patients die from infection probably due to suppressed immunity
• Major causes of mortality are lupus nephritis, CCF and pulmonary HTN

SUMMARY

• SLE is a chronic inflammatory, multisystemic, autoimmune disease
• The cause is unknown
• it could have phases of worsening symptoms that alternate with periods of mild symptoms
• Diagnosis is based on a combination of symptoms and laboratory test
• SLE currently has no cure, but various forms of treatment have been made available

REFERENCES

• Longo. D. L, Kasper, D. L, Jmeson , J. L 19 th edition Harrisons Principles of Internal Medicine. New York; Macgraw hill , 2015
• Lee. G, Andrew I. S, ( eds ) Goldmann Cecil Medicine, 25 th edition. New York, Saunders Elsevier 2016
• Alagappan , R. Manual of Practicl Medicine 4 TH ed. New Delhi;Jaypee Brothers Medical publisher
• Kumar. P, Clark M. Clinical medicine 8 th edition. London: Elsevier printing press 2012
• Adewale . O, Oguntona S. A, Patterns of systemic lupus erythermatosus among Nigerians, Clinical Rheumatology, March 2009
• MEDSCAPE

Download Systemic Lupus Erythematosus pptx slide