Recognized initially as a disease of the skin, it was named “lupus” or latin for wolf, red or erythematosus because of its inflammatory tendency and systemic was added when it was realized that it is a disease which affects most organs. Here is a diagram of which organs it affects and the probable mechanism of why it occurs.
How does lupus present to a physician?
The skin manifestation is a malar rash as given in this picture. This is an acute manifestation of cutaneous lupus.
Discoid lesions on the face of patients. Scarring occurs as well as marked photosensitivity in both these lesions. The picture on the right the lesions have become chronic.
Alopecia areata in the scalp.
A discoid lesion on the pinna of a patient is seen in this picture.
Chilblain like lesions on the toes.
Cutaneous lupus erythematosus (cutaneous LE) includes three subsets of LE-specific skin diseases:
- acute cutaneous lupus erythematosus (ACLE)
Localized ACLE (ie, malar rash, butterfly rash)
Toxic epidermal necrolysis-like ACLE
- subacute cutaneous lupus erythematosus (SCLE)
Less common variants: erythrodermic, poikilodermatous, erythema multiforme-like (Rowell syndrome), and vesiculobullous annular SCLE
- chronic cutaneous lupus erythematosus (CCLE) which includes:
- discoid lupus erythematosus (DLE), which may be generalised, localised or hypertrophic.
- lupus erythematosus tumidus (LE tumidus),
- lupus profundus (also known as lupus panniculitis),
- chilblain lupus erythematosus (chilblain LE), and
- lichenoid cutaneous lupus erythematosus-lichen planus overlap syndrome (LE-LP overlap syndrome).
Cutaneous disease is common in systemic lupus erythematosus (SLE); approximately 80 percent of patients develop skin disease at some point in their disease course. However, cutaneous LE frequently exists independently of SLE and may be two to three times more prevalent than SLE.
Always ask about the drugs that the patient is taking. Many classes of drugs have been implicated in SCLE, including antihypertensive drugs, lipid-lowering agents, proton pump inhibitors, antifungal agents, TNF-alpha inhibitors, and others. Drug-induced SCLE and idiopathic SCLE have similar clinical, histopathologic, and laboratory features and can be indistinguishable in the absence of a helpful medication history. Drug withdrawal often leads to improvement in drug-induced SCLE.
Mucosal manifestations of lupus are also commonly seen. These are ulcers and white plaques on the palate and inside the mouth. Do remember to examine the oral cavity. The oral ulcers are usually painless. Oral ulcers may be the first sign of SLE. There is no apparent association between the presence of oral ulcers and systemic activity.
Cutaneous manifestations of vascular involvement in SLE include periungual erythema, livedo reticularis, telangiectasia, Raynaud phenomenon, and vasculitis. Cutaneous vascular abnormalities occur in approximately 50 percent of patients with SLE. Bullous cutaneous lupus erythematosus (bullous CLE) is a rare and distinct complication of SLE characterized by the development of autoantibodies against type VII collagen and subepidermal blistering. Affected patients develop a vesicular or bullous eruption that may affect any body site, including oral mucosa.
Other than the mucocutaneous manifestations of systemic lupus patients commonly have constitutional symptoms such as fever (SLE should be part of the workup of pyrexia of unknown origin in a young woman of reproductive age), fatigue, weight loss, myalgia and arthralgia.
Cardiac disease among patients with SLE is common and can involve the pericardium, myocardium, valves, conduction system, and coronary arteries. Pericarditis, with or without an effusion, is the most common cardiac manifestation of SLE, occurring in approximately 25 percent of patients at some point during their disease course. Verrucous (Libman-Sacks) endocarditis is usually clinically silent, but it can produce valvular insufficiency and can serve as a source of emboli.
Raynaud phenomenon in SLE is a vasospastic process induced by cold that occurs in up to 50 percent of patients with SLE. Raynaud phenomenon is characterized by intermittent acral pallor followed by cyanosis and erythroderma. Cutaneous small-vessel vasculitis can manifest as palpable purpura, petechiae, papulonodular lesions, livedo reticularis, panniculitis, splinter hemorrhages, and superficial ulcerations.
Renal involvement is clinically apparent in approximately 50 percent of SLE patients and is a significant cause of morbidity and mortality. Several forms of glomerulonephritis can occur, and renal biopsy is useful to define the type and extent of renal involvement.
SLE-related gastrointestinal abnormalities can involve almost any organ along the gastrointestinal tract and include esophagitis, intestinal pseudo-obstruction, protein-losing enteropathy, lupus hepatitis, acute pancreatitis, mesenteric vasculitis or ischemia, and peritonitis. Symptoms may also be related to treatment and medication.
Pulmonary manifestations of SLE include pleuritis (with or without effusion), pneumonitis, interstitial lung disease, pulmonary hypertension, shrinking lung syndrome, and alveolar hemorrhage. Respiratory symptoms must also be distinguished from infection, particularly in patients on immunosuppressive therapy. The risk of thromboembolic involvement is increased in those with antiphospholipid antibodies or with lupus anticoagulant.
Neuropsychiatric involvement of SLE consists of a broad range of neurologic and psychiatric manifestations, including cognitive dysfunction, organic brain syndromes, delirium, psychosis, seizures, headache, and/or peripheral neuropathies. Other less common problems are movement disorders, cranial neuropathies, myelitis, and meningitis.
Lymph node enlargement commonly occurs in association with active SLE and usually involves the cervical, axillary, and inguinal regions. Splenomegaly can also be observed among SLE patients, particularly with active disease. Leukopenia can be due to lymphopenia and/or secondary neutropenia and generally correlates with clinically active disease. Neutropenia may also result from toxicity due to immunosuppressive medications. Mild thrombocytopenia is also a common hematologic abnormality. Rarely, severe thrombocytopenia can occur and requires treatment. Autoimmune hemolytic anemia is also relatively rare but can be severe, requiring immediate therapy.
Genetic factors in the causation of SLE.
SLE commonly results from the combined effect of variants in a large number of genes. In rare cases SLE may be associated with the deficiency of a single gene (e.g., the complement components C1q and C4). Lack of C4 has been linked to decreased elimination of self-reactive B cells (compromising negative selection), whereas lack of C1q leads to deficient elimination of necrotic (waste) material. Each allele contributes only minimally, and the cumulative effect of several genes is necessary to substantially increase the risk of SLE. Some genes have been associated with several autoimmune diseases (e.g., STAT4 and PTPN22 with rheumatoid arthritis and diabetes); others appear to increase the risk of SLE specifically.
Epigenetic changes such as DNA hypomethylation have been attributed to medications known to cause SLE. Hydralazine and procainamide inhibit DNA methylation and can induce manifestations of lupus in healthy persons. The regulatory regions of some genes known to be involved in the pathogenesis of the disease (ITGAL, CD40LG, CD70, and PPP2CA) have been reported to be hypomethylated in SLE. Smoking and exposure to ultraviolet light have been implicated in epidemiologic studies. The possibility that viruses may trigger SLE has been considered during the past 40 years. The faster seroconversion to Epstein–Barr virus (EBV) infection and higher viral load in patients with SLE than in normal subjects, the molecular similarity between EBV nuclear antigen 1 and the common lupus autoantigen Ro, and the inability of CD8+ T cells to control EBV-infected B cells suggest that viruses may contribute to the expression of lupus.
Female hormones and sex.
Hormones contribute through unknown mechanisms to the increased prevalence of SLE among women. The X chromosome may contribute independently from hormones because in castrated female and male mice that have been genetically manipulated to express XX, XO (female), XY, or XXY (male) combinations, the presence of two X chromosomes increases the severity of SLE. Among the genes known to contribute to the pathogenesis of SLE is CD40, which is located on chromosome X. Pregnancy may aggravate SLE, and although it is not clear whether rising levels of estradiol or progesterone play a role, a link between pregnancy outcome and the status of the disease at conception has been noted; in fact, the levels of these hormones are lower during the second and third trimesters in patients with SLE than in healthy pregnant women. Treatment with dehydroepiandrosterone has shown some clinical benefit.
Immune cells and cytokines.
Antigen receptor–mediated activation is altered in T and B cells from patients with SLE, and early signaling events are amplified. The T-cell receptor–CD3 complex, which recognizes and binds antigen and autoantigen and sends activation signals to the interior of the cell, is “rewired” in T cells, with the CD3-ζ chain replaced by the FcR-γ common chain. In relaying the signal intracellularly, the spleen tyrosine kinase (Syk) is used rather than the canonical 70-kD ζ-associated protein (ZAP-70).27 Lipid rafts, cholesterol-rich scaffolds that contain signaling proteins on the surface membrane of cells, are present in aggregates that are metabolically active, and their inhibition in lupus-prone mice results in a change in disease expression. Limited amounts of interleukin-2, in turn, result in poor activity of cytotoxic T cells and thus an increased risk of infection, which is a major cause of illness and death in patients with SLE. Lack of interleukin-2 also results in the suppression of activation-induced cell death and, therefore, increased longevity of autoreactive T cells in patients with SLE. Interleukin-17 is produced mainly by activated T cells and plays an important role in the immune response against certain bacteria and fungi.
In active SLE, a marked disease activity–dependent reduction in the number of naive B cells is observed, and the number of plasma cells is increased in the peripheral blood. All B-cell subgroups (B1 and B2 cells in both the follicular and marginal zones) contribute to the production of autoantibodies. B cells are central to the expression of the disease.
Antibody responses overall are lower than normal after immunization of patients with SLE against tetanus toxoid or hemophilus influenza, but the majority of patients have protective responses. Low responses are associated with SLE itself and with immunosuppressive drug treatment. Patients with SLE should always be vaccinated (but only with killed vaccines) to gain all possible protection against infections.
How does SLE cause tissue injury?
Immune complexes are central players in the tissue injury in SLE. They are formed in large amounts as antinuclear antibodies bind to the abundant nuclear material in blood and tissues, and they are not cleared promptly because the Fc and complement receptors are numerically and functionally deficient. In addition to activating complement, immune complexes may alter the function of Fc receptors.
In the kidney, immune complexes accumulate in the subendothelial and mesangial areas first, followed by deposition in the basement membrane and subepithelial areas. Immune complexes containing cationic anti-DNA antibodies and antibodies against the collagen-like region of C1q have an increased propensity to accumulate in the kidney. Anti-DNA and anti-nucleosome antibodies contribute to lupus nephritis, and anti-chromatin–chromatin immune complexes are present in the mesangium of patients with lupus nephritis.
Although the spectrum of autoantibody specificities in SLE is extensive, only a few have been shown to contribute to disease-related tissue injury.
- Anti–blood-cell antibodies that activate complement and cause cytopenias are typical.
- Anti–T-cell (CD3 and T-cell receptor) antibodies suppress interleukin-2 production.
- Anti-Ro antibodies, which may alter the function of myocytes and cells of the conduction system, have been linked to neonatal lupus and specifically to congenital heart block. The presence of anti-Ro antibodies calls for special fetal monitoring (neonatal lupus develops in only 2% of fetuses of mothers who are positive for such antibodies) and treatment.
- Some patients with SLE have antibodies against phospholipids and β2-glycoprotein 1. The presence of such antibodies is linked to thrombotic events and fetal loss in mice and is known as the antiphospholipid syndrome.
- Antiphospholipid antibodies interfere with the coagulation system (especially protein C) and the function of endothelial cells.
- Low doses of heparin (which has also been shown to inhibit complement activation) can reduce the risk of fetal loss in patients with the antiphospholipid syndrome.
Certain naturally occurring antibodies and autoantibodies (against DNA, phospholipids, histones, and ribonucleoprotein) may bind to ischemic tissues, activate complement, and cause damage. Such experimental findings may explain why some patients with SLE have disease flares after they experience a stressful event.
T cells infiltrate tissues, including the skin and the kidney, where they contribute to tissue damage.
- In the skin, keratinocytes that are exposed to ultraviolet light become apoptotic and release nuclear material, which is not cleared efficiently in patients with SLE. This nuclear material may further stimulate the immune system.
- Patients with C1q deficiency, which is rare, are particularly photosensitive.
- The expression of additional organ-specific molecules is important in determining which organ or organs are damaged.
- Expression of tumor necrosis factor receptor 1 is needed for the expression of skin disease, whereas it provides protection against kidney inflammation.
- Atherosclerosis-attributed vascular events are significantly more frequent in patients with SLE than in matched healthy persons. Several factors contribute to this increased frequency, including antibodies to lipoproteins, oxidized lipoproteins, hypertension, and the metabolic syndrome.
How does all this information help in the treatment of SLE?
Patients with SLE are treated with nonsteroidal antiinflammatory drugs, antimalarial agents, glucocorticoids, and immunosuppressive drugs, including cyclophosphamide, azathioprine, methotrexate, and mycophenolate mofetil. The choice of the drug is determined largely by the severity of the disease and the function of the involved organ.
Cyclophosphamide pulses (intravenous infusions every month or bimonthly at lower doses) are effective in the treatment of lupus nephritis, although there are serious potential side effects, including bone marrow suppression, infections, and gonadal suppression. Mycophenolate mofetil has considerable therapeutic value with few side effects, but its long-term effects with respect to the preservation of kidney function are unproven.
Blockade of BLyS with an anti-BLyS antibody results in a small but significant beneficial clinical effect within the first year of treatment in patients with mild or moderate disease. This antibody (belimumab) is approved by the Food and Drug Administration for use in the treatment of lupus.
A monoclonal antibody against the interleukin-6 receptor (tocilizumab) was judged to be promising in a phase 1 clinical trial.
Complement activation is profoundly increased in patients with SLE, and inhibition of C5 with an antibody (eculizumab), which has proved efficacious in the treatment of paroxysmal nocturnal hemoglobinuria, is being considered.
A chimeric anti-CD20 antibody (rituximab) has shown initial promise in small studies and case series involving patients with SLE, but a trial of rituximab in patients with moderate-to-severe SLE failed to reach its primary end points.
Inhibitors of the nuclear factor of activated T cells (NFAT), such as tacrolimus, may benefit patients with SLE, as should dipyridamole, which along with its antiplatelet function inhibits calcineurin-mediated NFAT activity. The mammalian target of rapamycin (mTOR), which plays a role in several key metabolic pathways, is increased in T cells of patients with SLE, and treatment of cells with rapamycin (i.e., sirolimus) corrects the signaling process.