Parts of this article (those related to new drug possibilities) need to beupdated. Please help update this article to reflect recent events or newly available information.(December 2023)
Medical condition
Lupus
Other names
Systemic lupus erythematosus (SLE)
Young woman with the distinctivebutterfly rash that many individuals with lupus experience
There is no cure for SLE,[1] but there are experimental and symptomatic treatments.[7] Treatments may includeNSAIDs,corticosteroids,immunosuppressants,hydroxychloroquine, andmethotrexate.[1] Although corticosteroids are rapidly effective, long-term use results in side effects.[8]Alternative medicine has not been shown to affect the disease.[1] Men have higher mortality.[9] SLE significantly increases the risk ofcardiovascular disease, with this being the most common cause of death.[6] While women with lupus have higher-risk pregnancies, most are successful.[1]
Rate of SLE varies between countries from 20 to 70 per 100,000.[2] Women of childbearing age are affected about nine times more often than men.[6] While it most commonly begins between the ages of 15 and 45, a wide range of ages can be affected.[1][2] Those ofAfrican,Caribbean, andChinese descent are at higher risk than those ofEuropean descent.[6][2] Rates of disease in the developing world are unclear.[10]
SLE is one of several diseases known as "the great imitator" because it often mimics or is mistaken for other illnesses.[12] SLE is a classical item indifferential diagnosis,[13] because SLE symptoms vary widely and come and go unpredictably. Diagnosis can thus be elusive, with some people having unexplained symptoms of SLE for years before a definitive diagnosis is reached.[14]
Common initial andchronic complaints includefever,malaise,joint pains,muscle pains, andfatigue. Because these symptoms are so often seen in association with other diseases, these signs and symptoms are not part of the diagnostic criteria for SLE. When occurring in conjunction with other signs and symptoms, however, they are considered suggestive.[15]
Lupus patches on the cheek, ear, and scalpWidespread lupus patches across the face with anepithelioma
As many as 70% of people with lupus have some skin symptoms. The three main categories of lesions are chronic cutaneous (discoid) lupus, subacute cutaneous lupus, and acute cutaneous lupus. People withdiscoid lupus may exhibit thick, red scaly patches on the skin. Similarly, subacute cutaneous lupus manifests as red, scaly patches of skin but with distinct edges. Acute cutaneous lupus manifests as a rash. Some have the classicmalar rash (commonly known as thebutterfly rash) associated with the disease.[17] This rash occurs in 30–60% of people with SLE.[18]
Hair loss,mouth and nasal ulcers, and lesions on the skin are other possible manifestations.[19]
Muscles and bones
The most commonly sought medical attention is forjoint pain, with the small joints of the hand and wrist usually affected, although all joints are at risk. More than 90 percent of those affected will experience joint or muscle pain at some time during the course of their illness.[20] Unlikerheumatoid arthritis, lupus arthritis is less disabling and usually does not cause severe destruction of the joints. Fewer than ten percent of people with lupus arthritis will develop deformities of the hands and feet.[20] People with SLE are at particular risk of developing osteoarticulartuberculosis.[21]
A possible association betweenrheumatoid arthritis and SLE has been suggested,[22] and SLE may be associated with an increased risk ofbone fractures in relatively young women.[23]
Blood
Anemia is common in children with SLE[24] and develops in about 50% of cases.[25] Low platelet count (thrombocytopenia) and low white blood cell count (leukopenia) may be due to the disease or a side effect of pharmacological treatment. People with SLE may have an association withantiphospholipid antibody syndrome[26] (a thrombotic disorder), wherein autoantibodies to phospholipids are present in their serum. Abnormalities associated with antiphospholipid antibody syndrome include a paradoxical prolongedpartial thromboplastin time (which usually occurs in hemorrhagic disorders) and a positive test for antiphospholipid antibodies; the combination of such findings have earned the term "lupus anticoagulant-positive". Another autoantibody finding in SLE is theanti-cardiolipin antibody, which can cause a false positive test forsyphilis.[27]
Heart
SLE may causepericarditis (inflammation of the outer lining surrounding the heart),myocarditis (inflammation of the heart muscle), orendocarditis (inflammation of the inner lining of the heart). The endocarditis of SLE is non-infectious, and is also calledLibman–Sacks endocarditis. It involves either themitral valve or thetricuspid valve.Atherosclerosis also occurs more often and advances more rapidly than in the general population.[28][29]
Steroids are sometimes prescribed as an anti-inflammatory treatment for lupus; however, they can increase one's risk for heart disease, high cholesterol, and atherosclerosis.[30]
Painless passage ofblood orprotein in the urine may often be the only presenting sign of kidney involvement. Acute or chronic renal impairment may develop withlupus nephritis, leading to acute or end-stagekidney failure. Because of early recognition and management of SLE with immunosuppressive drugs or corticosteroids,[35] end-stage renal failure occurs in less than 5%[36][37] of cases, except in the black population, where the risk is many times higher.
Neuropsychiatric syndromes can result when SLE affects thecentral orperipheral nervous system. TheAmerican College of Rheumatology defines 19 neuropsychiatric syndromes in systemic lupus erythematosus.[39] The diagnosis of neuropsychiatric syndromes concurrent with SLE (now termed as NPSLE),[40] is one of the most difficult challenges in medicine, because it can involve so many different patterns of symptoms, some of which may be mistaken for signs of infectious disease or stroke.[41]
Neurological disorders contribute to a significant percentage of morbidity and mortality in people with lupus.[47] As a result, the neural side of lupus is being studied in hopes of reducing morbidity and mortality rates.[39] One aspect of this disease is severe damage to the epithelial cells of theblood–brain barrier. In certain regions, depression affects up to 60% of women with SLE.[48]
While most pregnancies have positive outcomes, there is a greater risk of adverse events occurring during pregnancy.[50] SLE causes an increased rate of fetal deathin utero andspontaneous abortion (miscarriage). The overall live-birth rate in people with SLE has been estimated to be 72%.[51] Pregnancy outcome appears to be worse in people with SLE whose disease flares up during pregnancy.[52]
Medications for treatment of SLE can carry severe risks for female and male reproduction.Cyclophosphamide (also known as Cytoxan), can lead to infertility by causingpremature ovarian insufficiency (POI), the loss of normal function of one's ovaries prior to age forty.[54]Methotrexate can cause termination or deformity in fetuses and is a commonabortifacient, and for men taking a high dose and planning to father, a discontinuation period of 6 months is recommended before insemination.[55]
Some studies have found thatvitamin D deficiency (i.e., a lowserum level ofvitamin D) often occurs in patients with SLE and that its level is particularly low in patients with more active SLE.[58][59] Furthermore, 5 studies reported that SLE patients treated with vitamin D had significant reductions in the activity of their disease.[60] However, other studies have found that the levels of vitamin D in SLE are not low, that vitamin D does not reduce their SLE's activity, and/or that the vitamin D levels and responses to vitamin D treatment varied in different patient populations (i.e., varied based on whether the study was conducted on individuals living in Africa or Europe). Because of these conflicting findings, the following middle ground has been proposed for using vitamin D to treat SLE:a) patients with SLE that have 25-hydroxyvitamin D2 plus 25-hydroxyvitamin D3serum levels less than 30 ng/ml should be treated with vitamin D to keep these levels at or above 30 ng/ml or, in patients having major SLE-related organ involvement, at 36 to 40 ng/ml and b) patients with 25-hydroxyvitamin D2 plus 25-hydroxyvitamin D3 levels at or above 30 ng/ml should not be treated with vitamin D unless they have major SLE-related organ involvement in which case they should be treated with 25-hydroxyvitamin D2 plus 25-hydroxyvitamin D3 to maintain their serum vitamin D levels between 36 and 40 ng/ml.[61]
Mutations in a wide range of other genes do not by themselves cause SLE but two or more of them may act together, act in concert with environmental factors, or act in some but not other populations (e.g., cause SLE in Chinese but not Europeans) to cause SLE or an SLE-like syndrome but do so in only a small percentage of cases.[63][72] The development of a genetically-regulated trait or disorder that is dependent on the inheritance of two or more genes is termedoligogenic inheritance orpolygenic inheritance.[73][74]
SLE is regarded as aprototype disease due to the significant overlap in its symptoms with other autoimmune diseases.[75]
Patients with SLE have higher levels ofDNA damage than normal subjects, and several proteins involved in the preservation ofgenomic stability showpolymorphisms, some of which increase the risk for SLE development.[76] DefectiveDNA repair is a likely mechanism underlying lupus development.[77]
Drug-induced SLE
Drug-induced lupus erythematosus is a (generally) reversible condition that usually occurs in people being treated for a long-term illness. Drug-induced lupus mimics SLE. However, symptoms of drug-induced lupus generally disappear once the medication that triggered the episode is stopped.[13][78] While there are no established criteria for diagnosing drug-induced SLE, most authors have agreed on the following definition: the afflicted patient had a sufficient and continuing exposure to the drug, at least one symptom compatible with SLE, no history suggestive of SLE before starting the drug, and resolution of symptoms within weeks or months after stopping intake of the drug. TheVigiBase drug safety data repositor diagnosed 12,166 cases of drug-induced SLE recorded between 1968 and 2017. Among the 118 agents causing SLE, five main classes were most often associated with drug-induced SLE. These drugs wereantiarrhythmic agents such asprocainamide orquinidine;antihypertensive agents such ashydralazine,captopril, oracebutolol;antimicrobial agents such asminocycline,isoniazid,carbamazepine, orphenytoin; and agents that inhibit the inflammation-inducing actions ofinterferon ortumor necrosis factor.[79]
Non-systemic forms of lupus
Discoid (cutaneous) lupus is limited to skin symptoms and is diagnosed by biopsy of rash on the face, neck, scalp or arms. Approximately 5% of people with DLE progress to SLE.[80]
Pathophysiology
SLE is triggered by environmental factors that are unknown. In SLE, the body's immune system produces antibodies againstself-protein, particularly againstproteins in the cell nucleus. These antibody attacks are the immediate cause of SLE.[13][81][82]
People with SLE have intense polyclonal B-cell activation, with a population shift towards immature B cells. Memory B cells with increasedCD27+/IgD—are less susceptible to immunosuppression. CD27-/IgD- memory B cells are associated with increased disease activity and renal lupus. T cells, which regulate B-cell responses and infiltrate target tissues, have defects in signaling, adhesion, co-stimulation, gene transcription, and alternative splicing. The cytokines B-lymphocyte stimulator (BLyS), also known asB-cell activating factor (BAFF), interleukin 6, interleukin 17, interleukin 18, type I interferons, andtumor necrosis factor α (TNFα) are involved in the inflammatory process and are potential therapeutic targets.[6][85][86]
There are correlations between the apoptotic rates of lymphocytes and disease activity.
Necrosis is increased in T lymphocytes.
Tingible body macrophages (TBMs) – largephagocytic cells in thegerminal centers of secondarylymph nodes – expressCD68 protein. These cells normally engulf B cells that have undergone apoptosis aftersomatic hypermutation. In some people with SLE, significantly fewer TBMs can be found, and these cells rarely contain material from apoptotic B cells. Also, uningested apoptotic nuclei can be found outside of TBMs. This material may present a threat to the tolerization of B cells and T cells.Dendritic cells in the germinal center may endocytose such antigenic material and present it to T cells, activating them. Also, apoptotic chromatin and nuclei may attach to the surfaces offollicular dendritic cells and make this material available for activating other B cells that may have randomly acquiredself-protein specificity through somatic hypermutation.[88] Necrosis, a pro-inflammatory form of cell death, is increased in T lymphocytes, due to mitochondrial dysfunction,oxidative stress, and depletion of ATP.[89]
Clearance deficiency
Clearance deficiency
Impaired clearance of dying cells is a potential pathway for the development of this systemicautoimmune disease. This includes deficient phagocytic activity, impaired lysosomal degradation, and scant serum components in addition to increasedapoptosis.[90]
SLE is associated with defects in apoptotic clearance, and the damaging effects caused by apoptotic debris. Early apoptotic cells express "eat-me" signals, of cell-surface proteins such as phosphatidylserine, that prompt immune cells to engulf them. Apoptotic cells also expressfind-me signals to attract macrophages and dendritic cells. When apoptotic material is not removed correctly by phagocytes, they are captured instead by antigen-presenting cells, which leads to the development of antinuclear antibodies.[6]
Monocytes isolated fromwhole blood of people with SLE show reduced expression ofCD44 surface molecules involved in the uptake of apoptotic cells. Most of the monocytes and tingible body macrophages (TBMs), which are found in thegerminal centres oflymph nodes, even show a definitely different morphology; they are smaller or scarce and die earlier. Serum components likecomplement factors,CRP, and someglycoproteins are, furthermore, decisively important for an efficiently operating phagocytosis. With SLE, these components are often missing, diminished, or inefficient.[90]
Macrophages during SLE fail to mature theirlysosomes and as a result have impaired degradation of internalized apoptotic debris, which results in chronic activation ofToll-like receptors and permeabilization of the phagolysosomal membrane, allowing activation of cytosolic sensors. In addition, intact apoptotic debris recycles back to the cell membrane and accumulate on the surface of the cell.[91][92]
Recent research has found an association between certain people with lupus (especially those withlupus nephritis) and an impairment in degradingneutrophil extracellular traps (NETs). These were due toDNAse1 inhibiting factors, or NET protecting factors in people's serum, rather than abnormalities in the DNAse1 itself.[93] DNAse1 mutations in lupus have so far only been found in some Japanese cohorts.[94]
The clearance of early apoptotic cells is an important function in multicellular organisms. It leads to a progression of the apoptosis process and finally to secondarynecrosis of the cells if this ability is disturbed. Necrotic cells release nuclear fragments as potentialautoantigens, as well as internal danger signals, inducing maturation ofdendritic cells (DCs) since they have lost their membranes' integrity. Increased appearance of apoptotic cells also stimulates inefficient clearance. That leads to the maturation of DCs and also to the presentation of intracellular antigens of late apoptotic or secondary necrotic cells, via MHC molecules.[95]
Autoimmunity possibly results from the extended exposure to nuclear and intracellular autoantigens derived from late apoptotic and secondary necrotic cells. B andT cell tolerance for apoptotic cells is abrogated, and thelymphocytes get activated by these autoantigens;inflammation and the production of autoantibodies byplasma cells is initiated. A clearance deficiency in the skin for apoptotic cells has also been observed in people with cutaneous lupus erythematosus (CLE).[95]
Germinal centers
Germinal centres in a person with SLE and controls (schematic). Red: CD68 in tingible body macrophages; black: TUNEL positive apoptotic cells. 1) Healthy donors with florid germinal centres show giant tingible body macrophages (TBM) containing ingested apoptotic cells and no uningested apoptotic cells outside the TBM. 2) People with follicular lymphoma show small tingible body macrophages (TBM) containing few ingested apoptotic cells however, there are no uningested apoptotic cells outside the TBM. 3) Some with SLE (1) show a lack of TBM and many uningested apoptotic cells decorating the surfaces of spindle-shaped cells, presumably follicular dendritic cells (SLE 1). 4) Some people with SLE show TBM containing few ingested apoptotic cells and many uningested apoptotic cells outside the TBM (SLE 2). However, about 50% of people with SLE show rather normal germinal centre.
In healthy conditions, apoptotic lymphocytes are removed ingerminal centers (GC) by specialized phagocytes, thetingible body macrophages (TBM), which is why no free apoptotic and potential autoantigenic material can be seen. In some people with SLE, a buildup of apoptoticdebris can be observed in GC because of an ineffective clearance of apoptotic cells. Close to TBM,follicular dendritic cells (FDC) are localised in GC, which attach antigen material to their surface and, in contrast tobone marrow-derived DC, neither take it up nor present it viaMHC molecules.[96]
AutoreactiveB cells can accidentally emerge duringsomatic hypermutation and migrate into the germinal center light zone. Autoreactive B cells, maturated coincidentally, normally do not receive survival signals by antigen planted onfollicular dendritic cells and perish by apoptosis. In the case of clearance deficiency, apoptotic nuclear debris accumulates in the light zone of GC and gets attached to FDC.[96]
This serves as a germinal centre survival signal for autoreactive B-cells. After migration into themantle zone, autoreactive B cells require further survival signals from autoreactive helper T cells, which promote the maturation of autoantibody-producing plasma cells and B memory cells. In the presence of autoreactiveT cells, a chronicautoimmune disease may be the consequence.[96][97]
Anti-nRNP autoimmunity
Anti-nRNPautoantibodies tonRNP A andnRNP C initially targeted restricted,proline-richmotifs. Antibody binding subsequently spread to otherepitopes. The similarity andcross-reactivity between the initial targets ofnRNP andSm autoantibodies identifies a likely commonality in cause and a focal point for intermolecular epitope spreading.[98]
Micrograph showingvacuolar interface dermatitis, as may be seen in SLE.H&E stain.Micrograph of asection of human skin prepared for directimmunofluorescence using an anti-IgG antibody. The skin is from a person with systemic lupus erythematosus and shows IgG deposits at two different places. The first is a bandlike deposit along the epidermalbasement membrane ("lupus band test" is positive); the second is within the nuclei of theepidermal cells (antinuclear antibodies are present).
Laboratory tests
Antinuclear antibody (ANA) testing and anti-extractable nuclear antigen (anti-ENA) form the mainstay ofserologic testing for SLE. ANA testing for lupus is highly sensitive, with the vast majority of individuals with Lupus testing positive; but the test is not specific, as a positive result may or may not be indicative of Lupus.[100]
Several techniques are used to detect ANAs. The most widely used is indirectimmunofluorescence (IF). The pattern of fluorescence suggests the type of antibody present in the people's serum.Direct immunofluorescence can detect deposits of immunoglobulins and complement proteins in people's skin. When skin not exposed to the sun is tested, a positive direct IF (the so-calledlupus band test) is evidence of systemic lupus erythematosus.[101]
ANA screening yields positive results in many connective tissue disorders and other autoimmune diseases, and may occur in normal individuals. Subtypes of antinuclear antibodies includeanti-Smith and anti-double strandedDNA (anti-dsDNA) antibodies (which are linked to SLE) andanti-histone antibodies (which are linked to drug-induced lupus). Anti-dsDNA antibodies are highly specific for SLE; they are present in 70% of cases, whereas they appear in only 0.5% of people without SLE.[13]
Laboratory tests can also help distinguish between closely related connective tissue diseases. A multianalyte panel (MAP) of autoantibodies, including ANA, anti-dsDNA, and anti-Smith in combination with the measurement ofcell-bound complement activation products (CB-CAPs) with an integrated algorithm has demonstrated 80% diagnostic sensitivity and 86% specificity in differentiating diagnosed SLE from other autoimmune connective tissue diseases.[102] The MAP approach has been further studied in over 40,000 patients tested with either the MAP or traditional ANA testing strategy (tANA), demonstrating patients who test MAP positive are at up to 6-fold increased odds of receiving a new SLE diagnosis and up to 3-fold increased odds of starting a new SLE medication regimen as compared to patients testing positive with the tANA approach.[103]
Thelupus erythematosus (LE) cell test was commonly used for diagnosis, but it is no longer used because theLE cells are only found in 50–75% of SLE cases and they are also found in some people with rheumatoid arthritis, scleroderma, and drug sensitivities. Because of this, the LE cell test is now performed only rarely and is mostly of historical significance.[106]
Diagnostic criteria
Some physicians make a diagnosis based on theAmerican College of Rheumatology (ACR) classification criteria. However, these criteria were primarily established for use in scientific research, including selection forrandomized controlled trials, which require higher confidence levels. As a result, many people with SLE may not meet the full ACR criteria.[107]
Criteria
The American College of Rheumatology (ACR) established eleven criteria in 1982,[108] which were revised in 1997[109] as a classificatory instrument to operationalise the definition of SLE in clinical trials. They were not intended to be used to diagnose individuals and do not do well in that capacity. For the purpose of identifying people for clinical studies, a person has SLE if any 4 out of 11 symptoms are present simultaneously or serially on two separate occasions.
Discoid rash (red, scaly patches on skin that cause scarring); sensitivity = 18%; specificity = 99%.[110]
Serositis:Pleurisy (inflammation of the membrane around the lungs) orpericarditis (inflammation of the membrane around the heart);sensitivity = 56%;specificity = 86% (pleural is more sensitive; cardiac is more specific).[110]
Arthritis: nonerosive arthritis of two or more peripheral joints, with tenderness, swelling, or effusion; sensitivity = 86%; specificity = 37%.[110]
Photosensitivity (exposure to ultraviolet light causes rash, or other symptoms of SLE flareups); sensitivity = 43%; specificity = 96%.[110]
Blood—hematologic disorder—hemolytic anemia (lowred blood cell count),leukopenia (white blood cell count<4000/μL),lymphopenia (<1500/μL), orlow platelet count (<100000/μL) in the absence of offending drug; sensitivity = 59%; specificity = 89%.[110] Hypocomplementemia is also seen, due to either consumption of C3[111] and C4 by immune complex-induced inflammation or to congenitally complement deficiency, which may predispose to SLE.
Renal disorder: More than 0.5 g per dayprotein in urine or cellularcasts seen in urine under a microscope; sensitivity = 51%; specificity = 94%.[110]
Immunologic disorder: Positiveanti-Smith, anti-ds DNA,antiphospholipid antibody, or false positiveserological test forsyphilis; sensitivity = 85%; specificity = 93%.[110] Presence of anti-ss DNA in 70% of cases (though also positive with rheumatic disease and healthy persons).[112]
Some people, especially those withantiphospholipid syndrome, may have SLE without four of the above criteria, and also SLE may present with features other than those listed in the criteria.[114][115][116]
Recursive partitioning has been used to identify more parsimonious criteria.[110] This analysis presented two diagnostic classification trees:
Simplest classification tree: SLE is diagnosed if a person has an immunologic disorder (anti-DNA antibody, anti-Smith antibody, false positive syphilis test, or LE cells) ormalar rash. It has sensitivity = 92% and specificity = 92%.
Full classification tree: Uses six criteria. It has sensitivity = 97% and specificity = 95%.
Other alternative criteria have been suggested, e.g. the St. Thomas' Hospital "alternative" criteria in 1998.[117]
Treatment
There is no cure for Lupus. The treatment of SLE involves preventing flares and reducing their severity and duration when they occur.[118]
Hydroxychloroquine was approved by theFDA for lupus in 1955.[119] Hydroxychloroquine is a first line agent for SLE and is associated with reduced mortality, complications and disease activity. Hydroxychloroquiine is associated with a 54% reduction in mortality due to SLE.[120][121] It is recommended that all people with SLE be on hydroxychloroquine regardless of disease activity due to its well documented benefits, unless there are contraindications to its use.[121] Contraindications to hydroxychloroquine include allergy to the medication or significant retinal disease (as hydroxychloroquine may worsen retinopathy). Regular eye exams are recommended for those on hydroxychloroquine chronically due to this rare risk.[121] The prevalence of retinal toxicity for those on the medication was 2% at 10 years.[121]
Treatment can includecorticosteroids and anti-malarial drugs. Certain types of lupus nephritis such as diffuse proliferative glomerulonephritis require intermittent cytotoxic drugs. These drugs includecyclophosphamide andmycophenolate. Cyclophosphamide increases the risk of developing infections, pancreas problems, high blood sugar, and high blood pressure.[122]
Some drugs approved for other diseases are used for SLE 'off-label'. In November 2010, an FDA advisory panel recommended approvingbelimumab (Benlysta) as a treatment for the pain and flare-ups common in lupus. The drug was approved by the FDA in March 2011.[123][124]
In terms of healthcare utilization and costs, one study found that "patients from the US with SLE, especially individuals with moderate or severe disease, utilize significant healthcare resources and incur high medical costs."[125]
Medications
Due to the variety of symptoms and organ system involvement with SLE, its severity in an individual must be assessed to successfully treat SLE. Mild or remittent disease may, sometimes, be safely left untreated. If required,nonsteroidal anti-inflammatory drugs andantimalarials may be used. Medications such asprednisone,mycophenolic acid andtacrolimus have been used in the past.[126]
Disease-modifying antirheumatic drugs
Disease-modifying antirheumatic drugs (DMARDs) are used preventively to reduce the incidence of flares, the progress of the disease, and the need for steroid use; when flares occur, they are treated withcorticosteroids. DMARDs commonly in use are antimalarials such ashydroxychloroquine andimmunosuppressants (e.g.methotrexate andazathioprine). Hydroxychloroquine is an FDA-approved antimalarial used for constitutional, cutaneous, and articular manifestations. Hydroxychloroquine has relatively few side effects, and there is evidence that it improves survival among people who have SLE.[119]Cyclophosphamide is used for severeglomerulonephritis or other organ-damaging complications.Mycophenolic acid is also used for the treatment of lupus nephritis, but it is not FDA-approved for this indication, and FDA is investigating reports that it may be associated with birth defects when used by pregnant women.[127] A study involving more than 1,000 people with lupus found that people have a similar risk of serious infection with azathioprine and mycophenolic acid as with newer biological therapies (rituximab andbelimumab).[128][129]
Immunosuppressive drugs
In more severe cases, medications that modulate the immune system (primarily corticosteroids andimmunosuppressants) are used to control the disease and prevent recurrence of symptoms (known as flares). Depending on the dosage, people who require steroids may developCushing's syndrome, symptoms of which may includeobesity, puffy round face,diabetes mellitus, increased appetite, difficulty sleeping, andosteoporosis. These may subside if and when the large initial dosage is reduced, but long-term use of even low doses can cause elevatedblood pressure andcataracts.[130]
Numerous new immunosuppressive drugs are being actively tested for SLE. Rather than broadly suppressing the immune system, as corticosteroids do, they target the responses of specific types of immune cells. Some of these drugs are already FDA-approved for treatment ofrheumatoid arthritis, however due to high-toxicity, their use remains limited.[119][131]
Analgesia
Since a large percentage of people with SLE have varying amounts ofchronic pain, stronger prescriptionanalgesics (painkillers) may be used if over-the-counter drugs (mainlynonsteroidal anti-inflammatory drugs) do not provide effective relief. Potent NSAIDs such asindomethacin anddiclofenac are relatively contraindicated for people with SLE because they increase the risk of kidney failure and heart failure.[119]
Pain is typically treated withopioids, varying in potency based on the severity of symptoms. When opioids are used for prolonged periods, drug tolerance, chemical dependency, and addiction may occur. Opiate addiction is not typically a concern since the condition is not likely to ever completely disappear. Thus, lifelong treatment with opioids is fairly common for chronic pain symptoms, accompanied by periodic titration that is typical of any long-term opioid regimen.[132]
Avoiding sunlight in SLE is critical since ultraviolet radiation is known to exacerbate skin manifestations of the disease.[135] Avoiding activities that induce fatigue is also important since those with SLE fatigue easily and it can be debilitating. These two problems can lead to people becoming housebound for long periods of time. Physical exercise has been shown to help improve fatigue in adult with SLE.[135] Drugs unrelated to SLE should be prescribed only when known not to exacerbate the disease. Occupational exposure tosilica,pesticides, andmercury can also worsen the disease.[85] Recommendations for evidence based non-pharmacological interventions in the management of SLE have been developed by an international task force of clinicians and patients with SLE.[135]
Kidney transplantation
Kidney transplants are the treatment of choice forend-stage kidney disease, which is one of the complications oflupus nephritis, but the recurrence of the full disease is common in up to 30% of people.[136]
Antiphospholipid syndrome
Approximately 20% of people with SLE have clinically significant levels of antiphospholipid antibodies, which are associated withantiphospholipid syndrome.[137] Antiphospholipid syndrome is also related to the onset of neural lupus symptoms in the brain. In this form of the disease, the cause is very different from lupus: thromboses (blood clots or "sticky blood") form in blood vessels, which prove to be fatal if they move within the bloodstream.[114] If the thromboses migrate to the brain, they can potentially cause astroke by blocking the blood supply to the brain.
If this disorder is suspected in people, brain scans are usually required for early detection. These scans can show localized areas of the brain where blood supply has not been adequate. The treatment plan for these people requires anticoagulation. Often, low-doseaspirin is prescribed for this purpose, although for cases involving thrombosis anticoagulants such aswarfarin are used.[138]
While most infants born to mothers who have SLE are healthy, pregnant mothers with SLE should remain under medical care until delivery. However, SLE in the pregnant mother poses a higher risk ofneonatal lupus,intrauterine growth restriction, pretermmembrane rupture,preterm birth, andmiscarriage.[139]Neonatal lupus is rare, but identification of mothers at the highest risk for complications allows for prompt treatment before or after birth. In addition, SLE can flare up during pregnancy, and proper treatment can maintain the health of the mother longer. Women pregnant and known to haveanti-Ro (SSA) oranti-La antibodies (SSB) often have echocardiograms during the 16th and 30th weeks of pregnancy to monitor the health of the heart and surrounding vasculature.[140]
No cure is available for SLE but there are many treatments for the disease.[1]
In the 1950s, most people diagnosed with SLE lived fewer than five years. Today, over 90% now survive for more than ten years, and many live relatively symptom-free. 80–90% can expect to live a normal lifespan.[142] Mortality rates are however elevated compared to people without SLE.[143]
Prognosis is typically worse for men and children than for women; however, if symptoms are present after age 60, the disease tends to run a more benign course. Early mortality, within five years, is due to organ failure or overwhelming infections, both of which can be altered by early diagnosis and treatment. The mortality risk is fivefold when compared to the normal population in the late stages, which can be attributed to cardiovascular disease from accelerated atherosclerosis, the leading cause of death for people with SLE.[119] To reduce the potential for cardiovascular issues, high blood pressure and high cholesterol should be prevented or treated aggressively. Steroids should be used at the lowest dose for the shortest possible period, and other drugs that can reduce symptoms should be used whenever possible.[119]
Epidemiology
The global rates of SLE are approximately 20–70 per 100,000 people. In females, the rate is highest between 45 and 64 years of age. The lowest overall rate exists in Iceland and Japan. The highest rates exist in the US and France. However, there is not sufficient evidence to conclude why SLE is less common in some countries compared to others; it could be the environmental variability in these countries. For example, different countries receive different levels of sunlight, and exposure to UV rays affects dermatological symptoms of SLE.[2]
Certain studies hypothesize that a genetic connection exists between race and lupus which affects disease prevalence. If this is true, the racial composition of countries affects disease and will cause the incidence in a country to change as the racial makeup changes. To understand if this is true, countries with largely homogenous and racially stable populations should be studied to better understand incidence.[2] Rates of disease in the developing world are unclear.[10]
The rate of SLE varies between countries, ethnicity, and sex, and changes over time.[138] In the United States, one estimate of therate of SLE is 53 per 100,000;[138] another estimate places the total affected population at 322,000 to over 1 million (98 to over 305 per 100,000).[144] In Northern Europe the rate is about 40 per 100,000 people.[13] SLE occurs more frequently and with greater severity among those of non-European descent.[144] That rate has been found to be as high as 159 per 100,000 among those of Afro-Caribbean descent.[138] Childhood-onset systemic lupus erythematosus generally presents between the ages of 3 and 15 and is four times more common in girls.[145]
While the onset and persistence of SLE can show disparities between genders, socioeconomic status also plays a major role. Women with SLE and of lower socioeconomic status have been shown to have higher depression scores, higher body mass index, and more restricted access to medical care than women of higher socioeconomic statuses with the illness. People with SLE had more self-reported anxiety and depression scores if they were from a lower socioeconomic status.[146]
Race
There are assertions that race affects the rate of SLE. However, a 2010 review of studies that correlate race and SLE identified several sources of systematic and methodological error, indicating that the connection between race and SLE may be spurious.[147] For example, studies show that social support is a modulating factor which buffers against SLE-related damage and maintains physiological functionality.[147] Studies have not been conducted to determine whether people of different racial backgrounds receive differing levels of social support.[147]If there is a difference, this could act as a confounding variable in studies correlating race and SLE.
Another caveat to note when examining studies about SLE is that symptoms are often self-reported. This process introduces additional sources of methodological error. Studies have shown that self-reported data is affected by more than just the patient's experience with the disease- social support, the level of helplessness, and abnormal illness-related behaviors also factor into a self-assessment. Additionally, other factors like the degree of social support that a person receives, socioeconomic status, health insurance, and access to care can contribute to an individual's disease progression.[147][148]
Racial differences in lupus progression have not been found in studies that control for the socioeconomic status [SES] of participants.[147][149] Studies that control for the SES of its participants have found that non-white people have more abrupt disease onset compared to white people and that their disease progresses more quickly. Non-white patients often report more hematological, serosal, neurological, and renal symptoms. However, the severity of symptoms and mortality are both similar in white and non-white patients. Studies that report different rates of disease progression in late-stage SLE are most likely reflecting differences in socioeconomic status and the corresponding access to care.[147] The people who receive medical care have often accrued less disease-related damage and are less likely to be below the poverty line.[149] Additional studies have found that education, marital status, occupation, and income create a social context that affects disease progression.[147]
Sex
SLE, like many autoimmune diseases, affects females more frequently than males, at a rate of about 9 to 1.[9][138]
Hormonal mechanisms could explain the increased incidence of SLE in females. The onset of SLE could be attributed to the elevatedhydroxylation ofestrogen and the abnormally decreased levels ofandrogens in females. In addition, differences inGnRH signalling have also been shown to contribute to the onset of SLE. While females are more likely to relapse than males, the intensity of these relapses is the same for both sexes.[16]
In addition to hormonal mechanisms, specific genetic influences found on the X chromosome may also contribute to the development of SLE. The X chromosome carries immunologic genes likeCD40L, which can mutate or simply escape silencing byX-chromosome inactivation and contribute to the onset of SLE.[150][151] A study has shown an association betweenKlinefelter syndrome and SLE. XXY males with SLE have an abnormal X–Y translocation resulting in the partial triplication of thePAR1 gene region.[152] Research has also implicatedXIST, which encodes along non-coding RNA that coatsthe inactive member of the pair of X chromosomes in females as part of aribonucleoprotein complex, as a source of autoimmunity.[153]
Changing rate of disease
The rate of SLE in the United States increased from 1.0 in 1955 to 7.6 in 1974. Whether the increase is due to better diagnosis or an increased frequency of the disease is unknown.[138]
History
A historical drawing of lupus erythematosus as it was once considered as a non-fatal disfiguring skin disease[154]
The history of SLE can be divided into three periods: classical, neoclassical, and modern. In each period, research and documentation advanced the understanding and diagnosis of SLE, leading to its classification as anautoimmune disease in 1851, and to the various diagnostic options and treatments now available to people with SLE. The advances made by medical science in the diagnosis and treatment of SLE have dramatically improved the life expectancy of a person diagnosed with SLE.[155]
Etymology
There are several explanations ventured for the term lupus erythematosus.Lupus isLatin for "wolf",[156][5] and inMedieval Latin was also used to refer to a disease of the skin,[157] and "erythematosus" is derived fromἐρύθημα, Ancient Greek for "redness of the skin". All explanations originate with the reddish, butterfly-shaped malar rash that the disease classically exhibits across the nose and cheeks. The reason the term lupus was used to describe this disease comes from the mid-19th century. Many diseases that caused ulceration or necrosis were given the term "lupus" due to the wound being reminiscent of a wolf's bite. This is similar to the naming oflupus vulgaris or chronic facial tuberculosis, where the lesions are ragged and punched out and are said to resemble the bite of a wolf.[158]
Classical period
The classical period began when the disease was first recognized in the Middle Ages. The term lupus is attributed to 12th-century Italian physicianRogerius Frugard, who used it to describe ulcerating sores on the legs of people.[159] No formal treatment for the disease existed and the resources available to physicians to help people were limited.[160]
Neoclassical period
The neoclassical period began in 1851 when the skin disease which is now known asdiscoid lupus was documented by the French physician,Pierre Cazenave. Cazenave termed the illness lupus and added the word erythematosus to distinguish this disease from other illnesses that affected the skin except they were infectious.[161] Cazenave observed the disease in several people and made very detailed notes to assist others in its diagnosis. He was one of the first to document that lupus affected adults from adolescence into the early thirties and that facial rash is its most distinguishing feature.[162]
Research and documentation of the disease continued in the neoclassical period with the work ofFerdinand von Hebra and his son-in-law,Moritz Kaposi. They documented the physical effects of lupus as well as some insights into the possibility that the disease caused internal trauma. Von Hebra observed that lupus symptoms could last many years and that the disease could go "dormant" after years of aggressive activity and then re-appear with symptoms following the same general pattern. These observations led Hebra to term lupus a chronic disease in 1872.[163]
Kaposi observed that lupus assumed two forms: the skin lesions (now known as discoid lupus) and a more aggravated form that affected not only the skin but also caused fever, arthritis, and other systemic disorders in people.[164] The latter also presented a rash confined to the face, appearing on the cheeks and across the bridge of the nose; he called this the "butterfly rash". Kaposi also observed those patients who developed the butterfly rash were often afflicted with another disease such as tuberculosis, anemia, or chlorisis which often caused death.[162] Kaposi was one of the first people to recognize what is now termed systemic lupus erythematosus in his documentation of the remitting and relapsing nature of the disease and the relationship of skin and systemic manifestations during disease activity.[165]
The 19th century's research into lupus continued with the work ofSir William Osler who, in 1895, published the first of his three papers about the internal complications oferythema exudativum multiforme. Not all the patient cases in his paper had SLE but Osler's work expanded the knowledge of systemic diseases and documented extensive and critical visceral complications for several diseases including lupus.[162] Noting that many people with lupus had a disease that not only affected the skin but many other organs in the body as well, Osler added the word "systemic" to the term lupus erythematosus to distinguish this type of disease from discoid lupus erythematosus.[166]
Osler's second paper noted that reoccurrence is a special feature of the disease and that attacks can be sustained for months or even years. Further study of the disease led to a third paper, published in 1903, documenting afflictions such as arthritis, pneumonia, the inability to form coherent ideas, delirium, and central nervous system damage as all affecting patients diagnosed with SLE.[162]
Modern period
The modern period, beginning in 1920, saw major developments in research into the cause and treatment of discoid and systemic lupus. Research conducted in the 1920s and 1930s led to the first detailed pathologic descriptions of lupus and demonstrated how the disease affected the kidney, heart, and lung tissue.[167] A breakthrough was made in 1948 with the discovery of the LE cell (the lupus erythematosus cell—a misnomer, as it occurs with other diseases as well). Discovered by a team of researchers at theMayo Clinic, they discovered that the white blood cells contained the nucleus of another cell that was pushing against the white cell's proper nucleus.[168]
Noting that the invading nucleus was coated with antibody that allowed it to be ingested by a phagocytic or scavenger cell, they named the antibody that causes one cell to ingest another the LE factor and the two nuclei cell result in the LE cell.[169] The LE cell, it was determined, was a part of ananti-nuclear antibody (ANA) reaction; the body produces antibodies against its own tissue. This discovery led to one of the first definitive tests for lupus since LE cells are found in approximately 60% of all people diagnosed with lupus.[170] The LE cell test is rarely performed as a definitive lupus test today as LE cells do not always occur in people with SLE and can occur in individuals with other autoimmune diseases. Their presence can help establish a diagnosis but no longer indicates a definitive SLE diagnosis.
The discovery of the LE cell led to further research and this resulted in more definitive tests for lupus. Building on the knowledge that those with SLE had auto-antibodies that would attach themselves to the nuclei of normal cells, causing the immune system to send white blood cells to fight off these "invaders", a test was developed to look for the anti-nuclear antibody (ANA) rather than the LE cell specifically. This ANA test was easier to perform and led not only to a definitive diagnosis of lupus but also many other related diseases. This discovery led to the understanding of what is now known as autoimmune diseases.[171]
To ensure that the person has lupus and not another autoimmune disease, theAmerican College of Rheumatology (ACR) established a list of clinical and immunologic criteria that, in any combination, point to SLE. The criteria include symptoms that the person can identify (e.g. pain) and things that a physician can detect in a physical examination and through laboratory test results. The list was originally compiled in 1971, initially revised in 1982, and further revised and improved in 2009.[172]
Medical historians have theorized that people withporphyria (a disease that shares many symptoms with SLE) generated folklore stories of vampires and werewolves, due to the photosensitivity, scarring, hair growth, and porphyrin brownish-red stained teeth in severe recessive forms of porphyria (or combinations of the disorder, known as dual, homozygous, or compound heterozygous porphyrias).[173]
Useful medication for the disease was first found in 1894 whenquinine was first reported as an effective therapy. Four years later, the use ofsalicylates in conjunction with quinine was noted to be of still greater benefit. This was the best available treatment until the middle of the twentieth century when Hench discovered the efficacy ofcorticosteroids in the treatment of SLE.[173]
Research
A study called BLISS-76 tested the drugbelimumab, a fully humanmonoclonal anti-BAFF (or anti-BLyS) antibody.[124] BAFF stimulates and extends the life ofB lymphocytes, which produce antibodies against foreign andself-protein.[174] It was approved by the FDA in March 2011.[123] Genetically engineered immune cells are also being studied in animal models of the disease as of 2019.[175]
In September 2022, researchers at theUniversity of Erlangen-Nuremberg published promising results using genetically altered immune cells to treat severely ill patients. Four women and one man received transfusions ofCAR T cells modified to attack theirB cells, eliminating the aberrant ones. The therapy drove the disease into remission in all five patients, who have been off lupus medication for several months after the treatment ended.[176][177]
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