ORGANUM
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with multisystem involvement and is associated with significant morbidity and mortality. A multitude of factors promote the loss of immunological tolerance against self-antigens leading to the formation of pathogenic autoantibodies that cause tissue damage through multiple mechanisms.
SLE has varying clinical presentations - from mild mucocutaneous manifestations to multiorgan and severe central nervous system involvement,
The typical SLE patient is a female between the ages of 15 and 45 years. Although SLE can occur at nearly any age, the incidence of disease clearly increases in women of childbearing age. The female-to-male ratio during these ages may be >8:1, but during childhood or after the menopause, the ratio is close to 2:1. This pattern is strongly suggestive of the involvement of sex hormones, a conclusion that is supported by studies in animal models of lupus.
African-Americans have the greatest incidence of the disease, alongside the incidence being higher in Asian and Hispanic patients in comparison to Caucasians. The disease tends to have an earlier age of onset and is more severe in African-Americans.
Although males develop SLE less frequently, their illness is not milder than in females. Men tend to have more frequent skin manifestations, cytopenias, renal disease, serositis, neurologic involvement, thrombosis, cardiovascular disease, hypertension and vasculitis than women.
SLE is more severe in children - it tends to have a higher incidence of malar rashes, nephritis, pericarditis, hematologic abnormalities, and hepatosplenomegaly. It tends to have a more insidious onset in older people and has more pulmonary involvement and serositis and less Raynaud's, Malar rash, nephritis and neuropsychiatric complications.
The pathogenesis of SLE is complex, and the understanding is evolving. A break in the tolerance in genetically susceptible individuals on exposure to environmental factors leads to the activation of autoimmunity. Cell damage caused by infectious and other environmental factors exposes the immune system to self-antigens, leading to T and B cell activation, which become self-sustained by a chronic self-aimed immune response. Cytokine release, complement activation, and autoantibody production lead to organ damage.
The pathway for immune activation, self-sustaining response and end-organ damage are as follows:
Innate immune system activation is either Toll-like receptor (TLR) dependent or independent
Cell membrane bound TLRs 2,4,6 are activated in response to extracellular DNA and RNA from dying cells
Leads to a downstream activation of molecules, which act as a transcription factor for the production of proinflammatory mediators such as IFN-b. There is downstream activation of :
Interferon regulatory family (IRF-3)
NF-kB
MAP-kinases
Endosomal TLRs 7,9 are activated by single stranded RNA and demethylated DNA, leading to interforn-alpha production and RNA binding autoantibodies such as antibodies against:
Ro
La
Sm
RNP
TLR-independent pathway is activated by intracytoplasmic RNA sensors (RIG-1, MDA-5) and DNA sensors (IF116, DAI) and leads to activiation of IRF-3 and NF-kB.
Both self and foreign DNA/RNA can lead to the activation.
NETosis has gained attention in the pathogenesis of SLE
On activation by various factors such as cytokines, activated platelets, and vascular endothelial cells, neutrophils systemically release their nuclear aggregates in the extracellular environment
These aggregates can promote interferon-alpha production by the dendritic cells, mediate thrombosis and vascular damage and severe as self-antigens for T-lymphocytes.
T-cell and B-cell play a significant role in the pathophysiology of SLE:
Apoptotic and damaged cell-derived antigens are presented to T-cells by antigen presenting cells (APCs)
T-cells in SLE display a distorted gene expression leading to the production of several cytokines:
Less IL-2, leading to altered regulatory T-cell production
Increases of some cytokines increases mononuclear cell production:
IL6
IL10
IL12
IL23
Increases of other cytokine promote increased T-cell production
IL17
IL21
Increased IFN-gamma leads to defective T-cell production
T-cells lead to the activation of autoreactive B-cells by CD40L and cytokine production, leading to autoantibody production, which is a hallmark of SLE.
Toll-like receptors on interactions with DNA and RNA lead to activation of these B-cells
Nucleic acid and protein-containing intranuclear complexes are the most prominent antigens leading to B-cell activation
These autoantibodies are pathogenic and cause organ damage by immune complex deposition, complement, and neutrophil activation
This alters cell function and leads to apoptosis and cytokine production
The autoreactive B-cells in SLE, which are stimulated by self-antigens, are not readily eliminated due to a deficiency of the process involved in the functional neutralisation of autoreactive B cells. The B-cells can also severe as antigen-presenting cells and activate T-cells by presenting internalised soluble antigens to T-cells.
As SLE is a multisystem disease with several phenotypes, clinical features may vary from a very mild disease with only mucocutaneous involvement to severe life-threatening disease with multiorgan involvement.
These symptoms are seen in more than 90% of patients with SLE and often are the initial presenting feature. Fatigue, malaise, fever, anorexia and weight loss are common. While more than 40% of patients with SLE may have a lupus flare as a cause of fever, infections must always be ruled out first. Given the immunocompromised state of patients with SLE, even if there is a clinical suspicion of first-presentation of SLE, infection must be ruled out. SLE is an infrequent cause of pyrexia of unknown origin.
More than 80% of patients with SLE suffer from mucocutaneous involvement, one the most well-known and identified clinical features.
Approx. 80-90% of patients with SLE suffer from MSK involvement at some point during their disease course and may range from mild arthralgias to deforming arthritis.
Lupus arthritis is typically a non-erosive, symmetrical inflammatory polyarthritis affecting predominantly the small joints of the hands, knees, and wrists, although any joint can be involved
Jaccoud arthropathy - a arthropathy characterised by deformities the hand secondary to joint capsule and ligament laxity - can be seen in patients with lupus arthritis. Usually these deformities are reducible, although rarely, they may become fixed.
Avascular necrosis (with or without steroid use) can occur in up to 10% of patients with SLE and is usually bilateral and involves the hip joints. Inflammatory myopathy with histopathological features similar to but less striking than polymyositis has been seen in less than 10% of SLE cases. Patients with SLE are at high risk for the development of fibromyalgia, with incidences as high as 20% reported. Rheumatoid nodules have been reported in patients with SLE.
Anemia is present in more than 50% of patients with SLE and most commonly is anaemia of chronic disease. Other causes of anaemia in SLE may be iron deficiency anemia, coombs positive autoimmune hemolytic anemia, red blood cell aplasia, and microangiopathic hemolytic anaemia, which may be associated with antiphospholipid antibody syndrome. Leukopenia secondary to neutropenia or lymphopenia is also very frequent and severe. Thrombocytopenia can be mild or severe and may be associated with antiphospholipid syndrome and autoantibodies against platelets, glycoprotein IIb/IIIa, or thrombopoietin receptor. Pancytopenia is not infrequent and may occasionally be associated with myelofibrosis. Soft non-tender lymphadenopathy is common in SLE, although rare cases of histiocytic necrotising lymphadenitis have been reported (Kikuchi-Fujimoto disease). Splenomegaly is common in SLE, while splenic atrophy and asplenism have been reported in SLE patients
Both the CNS and PNS may be involved in SLE in addition to several psychiatric manifestations, although the diagnosis can be difficult. The most common CNS manifestations is intractable headaches, reported in more than 50% of cases. Focal or generalised seizures may be seen, and are associated with disease acitvity, although they carry a favorable prognosis.
Other CNS manifestations include aseptic meningitis, demyelinating syndrome including optic neuritis and myelitis, movement disorders such as chorea and cognitive dysfunction. Patients with SLE are also at high risk for ischemic stroke. Cranial and peripheral neuropathies, mononeuritis multiplex, autonomic neuropathies, and syndromes that mimicke GBS and MG are the peripheral nervous sytem manifestations. Psychiatric manifestations are difficult to diagnose and manage and may range from depression and anxiety to frank psychosis.
The American College of Rheumatology first developed the SLE classification criteria in 1971, which was revised in 1982 and 1997. The 1997 ACR criteria was further revised by the Systemic Lupus international Collaborating clinics (SLICC) group in 2012.