Continuing Education Activity

Systemic lupus erythematosus is a chronic, systemic autoimmune inflammatory disease with heterogeneous clinical manifestations and multiorgan involvement. Immune dysregulation leads to autoantibody production, immune complex formation, complement consumption, and tissue inflammation, contributing to variable involvement of the skin, joints, kidneys, hematologic system, lungs, heart, nervous system, and other organs. Clinical presentations range from mild mucocutaneous and musculoskeletal disease to severe, life-threatening complications such as lupus nephritis, neuropsychiatric disease, diffuse alveolar hemorrhage, and thrombotic events associated with antiphospholipid antibodies. Diagnosis requires synthesis of clinical findings with serologic testing and, when indicated, histopathology, with careful consideration of conditions that mimic systemic lupus erythematosus. Management focuses on achieving low disease activity, preventing organ damage, and reducing morbidity and mortality through individualized therapy, commonly including hydroxychloroquine, immunosuppressive agents, and corticosteroids when necessary, while monitoring treatment-related adverse effects and comorbidities.

Participation in this continuing education activity enables the learner to recognize key clinical presentations suggestive of systemic lupus erythematosus, interpret the role and limitations of antinuclear antibody testing and more specific autoantibody assays, and select appropriate additional evaluations to assess organ involvement. The learner applies guideline-aligned treatment principles, including the foundational role of hydroxychloroquine, appropriate use of corticosteroid-sparing therapies, and escalation strategies for organ-threatening disease. The activity emphasizes risk assessment for complications, including cardiovascular disease, infections, kidney disease progression, and pregnancy-related morbidity, and highlights patient counseling on photoprotection, smoking cessation, and adherence to monitoring. Collaboration within an interprofessional team strengthens diagnostic accuracy, supports timely referrals for subspecialty input, improves medication safety through pharmacist involvement, enhances functional outcomes through therapy services, and promotes psychosocial support through behavioral health and social work engagement, collectively improving patient-centered outcomes.

Objectives:

• Differentiate systemic lupus erythematosus from other autoimmune or rheumatologic conditions with overlapping clinical presentations.
• Assess patients with suspected systemic lupus erythematosus by interpreting clinical features and laboratory findings to support an accurate diagnosis.
• Apply current evidence-based guidelines to the management of systemic lupus erythematosus, including pharmacologic and nonpharmacologic interventions.
• Collaborate effectively within the interprofessional healthcare team to coordinate monitoring, implement treatment, and provide patient education for individuals with systemic lupus erythematosus.

Introduction

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with multisystem involvement characterized by loss of immune tolerance and the development of autoantibodies. SLE preferentially affects women over men in a 9:1 ratio. Presentations are heterogeneous, may affect any organ system, and may range from mild to severe. Most patients with lupus have anti-nuclear antibodies (ANA). The European League Against Rheumatism (EULAR) and American College of Rheumatology (ACR) classification criteria, updated in 2019, serve as the most recent guide for diagnosis. Management comprises glucocorticoids, hydroxychloroquine, and traditional immunosuppressants such as methotrexate, azathioprine, mycophenolate mofetil, and cyclophosphamide. Newer targeted therapies have shown corticosteroid-sparing benefits to patients with lupus. These include targeted B-cell therapies: rituximab, obinutuzumab, and belimumab; a calcineurin inhibitor: voclosporin; and a type I interferon receptor inhibitor: anifrolumab.

Etiology

Female sex and hormonal influence are significant risk factors for SLE. Women are at higher risk of developing SLE than men, and the risk of SLE is 14-fold higher in Klinefelter syndrome (47, XXY).[2] This increased risk suggests an association with genes on the X chromosome. In mouse models, hormones are known to interfere with B-cell development, activation, and proliferation, and B cells can secrete hormones and express hormone receptors.[3] Estrogen receptors (α and β) are expressed throughout the immune system, and estrogens have been shown to stimulate B-cell production of IgA, IgG, and IgE in these models. 

Multiple environmental triggers of SLE have been identified, and the environment seems to play a role in a 2-hit hypothesis.[4] The first hit may lead to a break in tolerance and autoantibody production. In contrast, the second hit, an environmental exposure, leads to a more florid autoimmune response with clinically evident inflammation. Broadly, infections, mucosal exposures, chemicals, and the COVID-19 vaccine have had associations with the onset of SLE.[4] Ultraviolet radiation and sun exposure increase cell apoptosis and are well-known triggers of SLE flare. Several viral infections have been implicated, including Epstein-Barr virus, cytomegalovirus, and COVID-19, among others, and the underlying mechanism is thought to be molecular mimicry. Smoking is a known risk factor for SLE development. Other potential risk factors include silica exposure, air pollution, vitamin D deficiency, alfalfa sprouts, and foods containing canavanine.[1][5]

Epidemiology

Varying prevalence and incidence rates of SLE have been reported, with differences mainly attributed to population differences. The Georgia and Michigan lupus registries reported a prevalence of 72.1 to 74.4 per 100,000 persons and incidence rates of 5.6 per 100,000 person-years in primarily White and Black populations. Black populations have the highest rates, followed by Asian and Hispanic populations, and then White populations. SLE tends to have an earlier age of onset and greater disease severity in Black populations.

SLE predominantly affects women of childbearing age, with a female-to-male ratio of 9 to 1. The risk decreases after menopause. Results from studies indicated that, although rare, lupus in men tends to be more severe.[6] SLE has also been reported in pediatric and older adult populations. SLE is more severe in children than in adults, with a higher incidence of skin disease, nephritis, pericarditis, hematologic abnormalities, and hepatosplenomegaly. In older adults, SLE has more pulmonary involvement and serositis, and less Raynaud phenomenon, skin disease, nephritis, and neuropsychiatric complications.[7]

Pathophysiology

SLE arises from a multifactorial interplay of genetic susceptibility, environmental triggers, and dysregulation of both innate and adaptive immunity as noted above. Innate immune activation is a key early event. Toll-like receptor (TLR)–dependent pathways, especially TLR7 and TLR9 in plasmacytoid dendritic cells, recognize self and viral nucleic acids, leading to robust type I interferon production—a molecular hallmark of SLE. TLR–independent sensors, such as cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING), and retinoic acid-inducible gene I (RIG-I), melanoma differentiation-associated gene 5 (MDA5), further amplify interferon responses and inflammation. Neutrophils contribute by forming neutrophil extracellular traps, which are composed of DNA, histones, and proteins. Impaired clearance of neutrophil extracellular traps and apoptotic debris provides a persistent source of autoantigens, fueling autoantibody production and immune complex formation.[1][8]

T-lymphocytes and B-lymphocytes are central to the pathogenesis of SLE. Apoptotic and damaged cell-derived antigens are presented to T cells by antigen-presenting cells, triggering abnormal T-cell activation that leads to dysregulated gene expression and reduced IL-2 production, thereby impairing regulatory T-cell function. Elevated IL-6, IL-10, IL-12, and IL-23 promote mononuclear cell expansion, while increased IL-17 and IL-21 enhance T-cell proliferation. Excess interferon-γ further disrupts normal T-cell regulation. These abnormal T cells activate autoreactive B cells via CD40L and cytokine signaling, driving autoantibody production.[5][9]

B-cell activation is further amplified by toll-like receptor engagement with nucleic acid–protein complexes, the most prominent autoantigens in SLE. The resulting autoantibodies mediate tissue damage through immune complex deposition, complement activation, neutrophil recruitment, and altered cell function. Autoreactive B cells are not efficiently eliminated due to defective tolerance mechanisms and can act as antigen-presenting cells, further activating T cells. This creates a self-perpetuating cycle of B- and T-cell activation that sustains chronic autoimmunity.[1][10]

Histopathology

Tissue pathology in SLE can demonstrate a variety of aberrant immunologic mechanisms. The most common areas biopsied in SLE are the skin and the kidney. 

Skin Histopathology

On routine hematoxylin and eosin staining, SLE skin subtypes show similar findings, including lichenoid interface dermatitis with basal-layer vacuolization, apoptotic keratinocytes, periadnexal and perivascular mononuclear-cell infiltrate, epidermal atrophy, and basement membrane thickening. In discoid lupus, findings may include more hyperkeratosis, follicular plugging, and thickening of the basement membrane compared with acute or subacute cutaneous lupus.[11] Direct immunofluorescence may show deposition of IgG, IgM, IgA, and C3 along the dermal-epidermal junction.

Kidney Histopathology

Lupus nephritis (LN) can affect the glomeruli, interstitium, tubules, and blood vessels. The World Health Organization classifies lupus nephritis into 6 distinct classes, each with unique pathological features and differing clinical outcomes. Because prognosis and therapy vary by class, accurate classification is essential before initiating treatment.[12]

• Class I: Normal light microscopy and immune complex deposits by immunofluorescence and electron microscopy
• Class II: Mesangial hypercellularity, matrix expansion, and immune complex deposits
• Class III: Fewer than 50% of glomeruli display active or inactive segmental (<50% of the tuft) or global (>50% of the tuft) endocapillary or extracapillary glomerulonephritis; subendothelial deposits are usually present
• Class IV: More than 50% of glomeruli have endocapillary or extracapillary glomerulonephritis, typically with subendothelial deposits; segmental (IV-S) and global (IV-G) diffuse LN are defined by >50% of affected glomeruli having segmental and global lesions, respectively
• Class V: Capillary loop thickening in association with subepithelial immune deposits by immunofluorescence and electron microscopy
• Class VI: Greater than 90% of glomeruli are globally sclerosed [13]

History and Physical

Clinical features in SLE may vary from mild disease with only mucocutaneous involvement to severe, life-threatening disease with multiorgan involvement. Autoantibodies may help predict the disease course and clinical features. Serologic abnormalities may develop several years before the onset of clinical lupus.[14] 

Constitutional Symptoms

Constitutional symptoms, including fatigue, malaise, fever, anorexia, and weight loss, are seen in more than 90% of patients with SLE and are often the initial presenting features. While more than 40% of patients with SLE may have a lupus flare as a cause of fever, other causes include infection or thromboembolic events. SLE may be an infrequent cause of fever of unknown origin.[15]

Mucocutaneous Manifestations

More than 80% of patients with SLE have mucocutaneous involvement. SLE skin lesions may be lupus-specific, and several nonspecific lesions are also seen. Lupus-specific lesions include:

1. Acute cutaneous lupus erythematosus (ACLE), which includes localized, malar, and generalized forms 
2. Subacute cutaneous lupus erythematosus (SCLE), which includes annular and papulosquamous forms
3. Chronic cutaneous lupus erythematosus (CCLE), which includes classic discoid lupus erythematosus (DLE), hypertrophic and verrucous forms, lupus panniculitis and profundus, lupus tumidus, chilblains lupus, mucosal discoid lupus, and lichenoid discoid lupus
4. Bullous lupus

ACLE accounts for 15% of all cutaneous lupus cases and can be localized or generalized.[16] The hallmark finding in ACLE is the malar rash, also known as the butterfly rash, which is an erythematous, raised rash involving the photodistributed areas of the cheeks and nasal bridge. (See Image. Systemic Lupus Erythematosus.) The rash may be macular or papular and spares the nasolabial folds. ACLE usually has an acute onset but may last several weeks, causing induration and scaling. Acute cutaneous lupus erythematosus may spread to the forehead, chin, ears, and neck. The malar rash may also fluctuate with lupus disease activity. Other rashes in this location that must be differentiated from an ACLE malar rash include rosacea, erysipelas, seborrheic dermatitis, and perioral dermatitis. Generalized ACLE leads to widespread maculopapular or macular rash in a photodistributed pattern. ACLE lesions heal without scarring.

Subacute cutaneous lupus erythematosus is a photodistributed, widespread, nonscarring, nonindurated rash. SCLE tends to occur on the neck, upper trunk, and upper extremities, usually sparing the face. SCLE may be either papulosquamous, resembling psoriasis, or annular or polycyclic, with central clearing and peripheral scaling. The lesions may persist for several months but usually heal without scarring. The disease is associated with a positive anti–Sjögren-syndrome-related antigen A/Ro antibodies (anti-SSA/Ro) antibody result in up to 90% of cases. Subacute cutaneous lupus erythematosus can also be caused by certain drugs such as hydrochlorothiazide and proton pump inhibitors.[17][18]

DLE is the most common form of CCLE, present in approximately 20% of patients with SLE.[16] DLE may occur with or without SLE and can be localized (head and neck only) or generalized (above and below the neck). The lesions are disc-shaped erythematous papules or plaques with adherent scaling and central clearing. Discoid lupus erythematosus heals with scarring and can be associated with permanent alopecia when present on the scalp. Mucosal DLE lesions can be seen in the oral cavity, and mucosal discoid lupus erythematosus lesions tend to be painful, erythematous, round lesions with white radiating hyperkeratotic striae. Hypertrophic DLE may histologically mimic squamous cell carcinoma. Lupus panniculitis can occur above the waist and is less commonly associated with SLE. The lesions result in depressed areas, and when associated with DLE lesions overlying them, they are known as lupus profundus. Chilblain lupus presents with erythematous, tender plaques on digits. Lupus tumidus lesions are erythematous, edematous, smooth plaques without epidermal involvement.

Bullous lupus is a subepidermal bullous dermatosis mediated by autoantibodies against collagen VII. Bullous lupus lesions tend to occur on the face, upper torso, neck, and axillary flexures and do not leave scars but may leave dyspigmentation. Bullous lupus can correlate with more severe systemic lupus manifestations.[16] 

Oral ulcers are common in SLE and are often painless at first. Oral ulcers may present as gradual-onset erythema, petechiae, erosions, or ulcers involving any part of the oral cavity. The most common locations are the hard palate, the buccal mucosa, and the vermilion border.

Photosensitivity is present in SLE in more than 90% of cases. Photosensitivity is characterized by an abnormal skin reaction to ultraviolet A and ultraviolet B radiation, as well as visible light, that may last for weeks to months. Patients with photosensitivity also experience worsening of systemic symptoms with sun exposure. Alopecia in SLE may be due to DLE (scarring) or brittle, easily breaking lupus hair (nonscarring) in the temporal and parietal area.

Several other nonspecific skin manifestations are seen in SLE. These include cutaneous vasculitis (leukocytoclastic or urticarial), vasculopathy (livedo reticularis, superficial thrombophlebitis, Raynaud phenomenon, erythromelalgia, periungual erythema), urticaria, and erythema multiforme.

Musculoskeletal Manifestations

Bullous lupus is a subepidermal bullous dermatosis mediated by autoantibodies against collagen VII. They tend to occur on the face, upper torso, neck, and axillary flexures and do not leave scars but may leave dyspigmentation.[16] Bullous lupus can correlate with more severe systemic lupus manifestations. 

Oral ulcers are common in SLE and are often painless at first. They may present as gradual onset erythema, petechiae, erosions, or ulcers involving any part of the oral cavity. The most common locations are the hard palate, the buccal mucosa, and the vermilion border.

Photosensitivity is present in SLE in more than 90% of cases. It is characterized by an abnormal skin reaction on exposure to ultraviolet A and B and visible light, which may last for weeks to months. These patients also experience worsening of their systemic symptoms on sun exposure. Alopecia in SLE may be due to DLE (scarring) or the brittle, easily breaking lupus hair (nonscarring) in the temporal or parietal area. 

Several other nonspecific skin manifestations are seen in SLE. These include cutaneous vasculitis (leukocytoclastic or urticarial), vasculopathy (livedo reticularis, superficial thrombophlebitis, Raynaud phenomenon, erythromelalgia, periungual erythema), urticaria, and erythema multiforme.[19]

Musculoskeletal Manifestations

Approximately 80% to 90% of patients with SLE have musculoskeletal involvement at some point during their disease course, which may range from mild arthralgias to deforming arthritis. Lupus arthritis is typically a nonerosive, symmetrical inflammatory polyarthritis that predominantly affects the small joints of the hands, knees, and wrists, although any joint can be involved. Jaccoud arthropathy results from joint capsule and ligament laxity, leading to nonerosive deformities of the hands, including ulnar deviation and subluxation of the metacarpophalangeal joints. Usually, these deformities are reducible, although they may rarely become fixed. About 3% to 5% of patients with SLE have overlapping rheumatoid arthritis and develop more aggressive inflammatory arthritis, and another subset can develop rheumatoid arthritis-like erosive disease.[20] Avascular necrosis (with or without corticosteroid use) can occur in up to 10% of patients with SLE. 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.[21]

Hematologic and Reticuloendothelial Manifestations

The hematologic system is commonly affected in patients with SLE, with multiple manifestations. Because of SLE itself, patients may develop autoimmune hemolytic anemia, lymphopenia, or thrombocytopenia. Occasionally, the bone marrow may be targeted, leading to bone marrow failure states from myelofibrosis, aplastic anemia, and pure red cell aplasia. Anemia that is associated with SLE but not immune-mediated may be secondary to multiple causes, including iron deficiency, anemia of chronic inflammation, or medication-related causes. Leukopenia is defined as a leukocyte count less than 4000 cells/mm³, and lymphopenia is defined as a lymphocyte count less than 1500 cells/mm³. Thrombocytopenia is defined as a platelet count less than 100,000/mm³ and can be due to immune-mediated thrombocytopenia, antiphospholipid syndrome (APLS), thrombotic thrombocytopenic purpura, and non–immune-related complications such as medication-related and infection-related causes. Macrophage activation syndrome is another condition that can lead to cytopenias in patients with severe lupus manifestations.

Thrombotic complications can be found in more than 10% of patients with lupus. Antiphospholipid antibodies (anticardiolipin IgG, anticardiolipin IgM, β2 glycoprotein-1 IgG, β2 glycoprotein-1 IgM, and lupus anticoagulant) are associated with both arterial and venous clots. Shotty, nontender lymphadenopathy is common in SLE, and rare cases of histiocytic necrotizing lymphadenitis (Kikuchi-Fujimoto disease) have been reported. Splenomegaly is uncommon in SLE, whereas splenic atrophy and asplenism have been reported.[22] 

Neuropsychiatric Manifestations

There are 19 neuropsychiatric manifestations of lupus, defined by the ACR in 1999, affecting up to 20% of patients with SLE in some cohorts.[23] The most common central nervous system manifestation is intractable headache, reported in more than 50% of cases. Cerebrovascular disease may occur, contributing to mortality in up to 15% of patients. Cognitive dysfunction and focal or generalized seizures are also common. Less common CNS manifestations are movement disorders such as chorea, acute confusional states, aseptic meningitis, demyelinating disease, and transverse myelitis. Other uncommon lupus CNS manifestations include cerebral venous sinus thrombosis, posterior reversible encephalopathy syndrome, isolated optic neuritis, progressive multifocal leukoencephalopathy associated with the JC virus, and idiopathic intracranial hypertension. Peripheral nerve manifestations include peripheral neuropathy, cranial neuropathy, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, and myasthenia gravis. Psychiatric manifestations are difficult to diagnose and manage and may range from depression and anxiety to frank psychosis.

Renal Manifestations

Lupus nephritis (LN) occurs in approximately 50% of patients with SLE, with about 5% to 15% of those patients progressing to end-stage kidney disease within 10 years.[24][25] The involvement may range from mild subnephrotic proteinuria to diffuse progressive glomerulonephritis leading to chronic kidney damage. Lupus nephritis usually occurs early in the course of SLE. New-onset hypertension, hematuria, proteinuria, lower extremity edema, and elevated creatinine level should raise suspicion for lupus nephritis. Proteinuria is the best prognostic marker for kidney health, with a 1-year cutoff of 0.7 to 0.8 g/24 h predictive of good long-term renal prognosis.[26] A biopsy is crucial for establishing the presence of nephritis, determining the class, and ruling out other causes. Class I LN is characterized by mesangial immune deposits without hypercellularity and does not typically cause abnormalities in urinalysis results or creatinine. Class II LN reveals mesangial hypercellularity and is associated with mild proteinuria and hematuria on urinalysis. Class III LN is characterized by segmental disease affecting fewer than 50% of glomeruli, while Class IV affects more than 50% of glomeruli. Class III and Class IV LN may present with hypertension, elevated creatinine, hematuria, and proteinuria. Class V tends to present with nephrotic syndrome characterized by hypertension, proteinuria, and minimal hematuria, and Class VI is advanced sclerosing disease with bland sediment but proteinuria. Renal biopsy findings dictate the treatment of lupus nephritis. The prognosis varies across classes, with excellent outcomes for Classes I and II and less favorable outcomes for Classes III and IV. Class V usually carries a favorable prognosis except for complications of nephrotic syndrome, such as thromboembolism. Other renal lupus manifestations may include thrombotic microangiopathy, interstitial nephritis, lupus vasculopathy, lupus podocytopathy, and vasculitis.[27][28][27]

Pulmonary Manifestations

Pulmonary involvement affects almost 50% of patients with SLE. The main manifestations are pleural effusions and pleurisy, which mostly cause sharp chest pain with breathing.[29] Other primary pulmonary manifestations include pulmonary fibrosis, alveolitis, pneumonitis, vasculitis, diffuse alveolar hemorrhage, pulmonary hypertension, and pulmonary emboli. Shrinking lung syndrome is rare. Secondary pulmonary complications include atelectasis due to diaphragmatic dysfunction, pneumonia, drug toxicity, and pulmonary manifestations from cardiac and renal failure.

Cardiovascular Manifestations

Cardiac complications from SLE tend to occur both early and late in the disease course. Earlier manifestations are inflammatory lesions, while later reflect the onset of atherosclerotic disease and the accrual of damage. SLE may involve any layer of the heart, including the pericardium, myocardium, endocardium, and even the coronary arteries. Pericarditis is the most common cardiac manifestation. Cardiac tamponade is rare. Other complications are asymptomatic pericardial effusions, valvular heart disease, and myocarditis. Libman-Sacks endocarditis involving the mitral valve is a rare complication associated with antiphospholipid antibody syndrome. Patients with SLE, especially those predisposed to cardiac complications, have the following added factors: advanced age, hypertension, hyperlipidemia, the presence of antiphospholipid antibodies, and higher body mass index, all of which contribute to increased risk.[5][30]

Gastrointestinal Manifestations

Gastrointestinal (GI) symptoms are common among patients with lupus. Gastrointestinal symptoms may include nausea, vomiting, diarrhea, and abdominal pain, and often occur in association with medication adverse effects or infections.[31] Overall, however, gastrointestinal manifestations of the disease are less frequently encountered than other organ involvement. Serositis or peritonitis may occur, but serositis or peritonitis is typically observed in parallel with other lupus activity. Lupus enteritis is uncommon but may be associated with vascular inflammation, including vasculitis of the bowel. Protein-losing enteropathy, pseudo-obstruction, and pancreatitis are other rare manifestations. Liver function test abnormalities are commonly observed but typically associated with medication adverse effects or lupus complications, such as hemolysis, and not a primary liver disorder. Rarely, autoimmune hepatitis, primary biliary cirrhosis, or primary sclerosing cholangitis may be associated disorders. Occasionally, patients with SLE and antiphospholipid syndrome can develop Budd-Chiari syndrome, mesenteric vessel thrombosis, and hepatic veno-occlusive disease.

Pregnancy Complications

Pregnancy complications are common for patients with active lupus, and approximately 25% of patients with lupus may flare during pregnancy.[32] Beyond increasing disease activity during pregnancy, complications of the pregnancy include preterm delivery, low birthweight, preeclampsia, pregnancy loss, and a higher risk of maternal mortality. Patients with more severe SLE manifestations, such as pulmonary hypertension, severe cardiovascular disease, or cerebrovascular accident, are at very high risk of mortality during pregnancy.[33] A higher burden of disease activity at the time of conception correlates with greater lupus activity during pregnancy and adverse pregnancy outcomes. Optimizing pregnancy planning and treatment leads to better outcomes. Optimized pregnancy planning includes deliberate preconception planning, switching corticosteroid-sparing medications to those that are not teratogenic or harmful to the pregnancy, delaying conception by at least 6 months until a period of disease quiescence, and continuation of hydroxychloroquine throughout the duration of pregnancy.[34] Anti-SSA/Ro and anti-SSB/La antibodies can cross the placenta, leading to fetal heart block and neonatal lupus, which presents with a photosensitive rash, cytopenias, and transaminitis. The risk of congenital heart block and neonatal lupus is 1% to 2% for a first pregnancy, but the risk rises to 17% for subsequent pregnancies.[35][36] 

SLE patients with positive antiphospholipid antibodies (anti-cardiolipin antibodies, anti–β2-glycoprotein-1 antibodies, and lupus anticoagulant) are at high risk of spontaneous early abortions, intrauterine fetal loss, prematurity, preeclampsia, eclampsia, hemolysis, elevated liver enzymes, and low platelet count syndrome, and maternal thromboembolic events.[37]

Other Manifestations

Eye involvement is common, and keratoconjunctivitis sicca is frequently observed in SLE, with or without secondary Sjögren disease. Other ocular manifestations include retinal vasculitis, optic neuritis, uveitis, scleritis, peripheral ulcerative keratitis, and episcleritis. Patients with SLE are also more susceptible to drug-induced ocular damage, including corticosteroid-induced glaucoma or cataract and hydroxychloroquine-induced maculopathy. Ear involvement can cause sudden sensorineural hearing loss.

Classification Criteria

Classification criteria for the diagnosis of SLE have been revised multiple times. The ACR first developed SLE classification criteria in 1971 and revised them in 1982 and 1997. The 1997 ACR criteria were further revised by the Systemic Lupus International Collaborating Clinics (SLICC) group in 2012.[38] The 1997 ACR criteria required 4 out of 11 criteria for the classification of SLE. The 11 criteria included were malar rash, discoid rash, photosensitivity, alopecia, Raynaud phenomenon, oral and nasal ulcers, arthritis (nonerosive arthritis involving 2 or more peripheral joints), serositis (pleurisy or pericarditis), renal disease (proteinuria > 500 mg/d or cellular erythrocyte, granular, tubular, or mixed casts), hematologic disease (hemolytic anemia with reticulocytosis, or leukopenia < 4000/mm³ on 2 or more occasions or lymphopenia < 1500/mm³ on 2 or more occasions, or thrombocytopenia < 100,000/mm³ in the absence of medications known to decrease platelets), neurologic disease (seizures or psychosis in the absence of an alternative explanation), immunologic criteria (antiphospholipid antibodies present based on either an abnormal serum level of IgM or IgG anticardiolipin antibodies or a tested positive result for lupus anticoagulant or anti–double-stranded DNA antibody [anti-dsDNA] or anti-Smith [anti-Sm] antibody or false-positive syphilis testing results with venereal disease research laboratory [VDRL] or rapid plasma reagin [RPR]) and antinuclear antibody (ANA) positivity in the absence of drugs known to cause drug-induced lupus.

The SLICC criteria made notable changes to the 1997 ACR to improve clinical relevance. At least 1 of the 4 criteria must be clinical, and at least 1 of the 4 must be immunologic. In addition, neurologic and immunologic criteria were expanded to include new information about SLE immunology. Further, patients with biopsy-proven nephritis and positive ANA result or anti-dsDNA results could be directly classified as SLE even if they lacked any other criteria. Compared to the 1997 ACR criteria, the SLICC criteria improved sensitivity and are considered more valid and clinically relevant.

The most updated classification criteria were devised by the European League Against Rheumatism (EULAR) and ACR in 2019. The EULAR/ACR criteria are shown in Tables 1 and Table 2 and have a specificity of 93.4% and sensitivity of 96.1%, compared with 93.4% specificity and 82.8% sensitivity for the 1997 ACR criteria and 83.7% specificity and 96.7% sensitivity for the 2012 SLICC classification criteria. Each criterion is assigned a score of 2 to 10. Patients with 10 or more points and at least 1 clinical criterion are classified as having SLE.[39]

Table

Table 1. EULAR/ACR Clinical Domains and Criteria for Systemic Lupus Erythematosus.

Table

Table 2. EULAR/ACR Immunologic Domains and Criteria for Systemic Lupus Erythematosus.

Abbreviations: aCL, anticardiolipin antibodies; aPL, antiphospholipid antibodies; anti-β2GP1, anti–β2 glycoprotein 1 antibodies; LA, lupus anticoagulant.

These criteria are developed for research studies to classify patients and may not always be valid in the clinical setting. Therefore, while they can assist a clinician in suspecting a diagnosis of SLE, the criteria alone should not be considered sufficient to confirm or rule out SLE, which remains a clinical diagnosis made by an expert based on the overall clinical presentation and appropriate diagnostic test results.

Evaluation

Diagnosis of SLE is challenging, as no single clinical feature or laboratory test is diagnostic. Instead, the diagnosis is based on a constellation of signs, symptoms, and supporting laboratory findings, with imaging and histopathology often providing additional confirmation. A wide range of autoantibodies has been described in SLE, each with variable sensitivity and specificity. Some are associated with specific clinical subsets, while others correlate with disease activity.

A positive ANA test result remains the hallmark of SLE and should be the initial screening test. The gold standard method is the immunofluorescence assay, although enzyme-linked immunosorbent assay (ELISA) and multiplex assays are widely available but less sensitive. ANA positivity is observed in more than 97% of SLE cases.[40] However, its specificity is only about 20%, as ANA can also be present in other autoimmune disorders and even in healthy individuals.[41] Thus, a positive ANA finding is not diagnostic, but a negative result makes SLE highly unlikely. Rare cases of ANA-negative SLE have been reported; some of these patients are positive for Sjögren syndrome-related antigen B (anti-SSA)/Ro antibody or anti-dsDNA antibody.[42] 

ANA testing may reveal several staining patterns—speckled, homogeneous, centromere, cytoplasmic, nucleolar, and dense fine speckled. While patterns alone are not diagnostic, certain associations exist. Dense fine speckled ANA (anti-DFS70) is generally considered nonpathologic, and patients with this pattern rarely develop SLE.[43] The speckled pattern often corresponds to autoantibodies against SSA/Ro, SSB/La, Smith, or ribonucleoprotein (RNP). The homogeneous pattern is typically seen with antibodies to histones, chromatin, and dsDNA. The centromere pattern is most often linked to anticentromere antibodies in limited systemic sclerosis.[44]

In addition to SLE, ANAs can be seen in several other conditions, as noted above. More than 20% of the healthy normal population, especially women or relatives of patients with autoimmune diseases, can have a positive ANA result, although titers more than 1:320 are uncommon. Other rheumatological disorders associated with a positive ANA result include drug-induced lupus, systemic sclerosis, polymyositis and dermatomyositis, mixed connective tissue disease, Sjögren disease, rheumatoid arthritis, and juvenile idiopathic arthritis. Several other autoimmune disorders are associated with a positive ANA finding, including autoimmune hepatitis, multiple sclerosis, Hashimoto thyroiditis, and idiopathic thrombocytopenic purpura. Infections and malignant neoplasms have also been associated with a positive ANA result.

If SLE is suspected, follow-up testing for more specific autoantibodies to detect the antigen responsible for the positive ANA test results is recommended. In fact, more than 150 autoantibodies are associated with SLE.[45] These antibodies can target any molecule (nucleic acids, lipids, and proteins), organelle, plasma protein, or tissue. However, only a few have been identified as clinically relevant and are used in diagnostic testing. 

Antibodies to dsDNA can be divided into 2 groups: those reactive with denatured, single-stranded (ss) DNA and those that identify dsDNA. Notably, anti-ssDNA antibodies are considered nonspecific and may be seen either as a laboratory error or in the healthy population. Testing for antibodies to ssDNA is not recommended because the antibodies are not clinically relevant in SLE. Anti-dsDNA antibodies have more than 95% specificity for SLE but are found in only about 40% to 80% of patients with SLE. Thus, a negative anti-dsDNA result does not rule out the diagnosis of SLE. The Farr radioimmunoassay is considered the gold standard for detecting anti-dsDNA antibodies, although the assay is not frequently used. ELISA tests are available, but they carry a high risk of false-positive results. The Crithidia luciliae immunofluorescence test can confirm the presence of anti-dsDNA antibodies. Anti-dsDNA antibodies can also be seen in drug-induced lupus, primarily secondary to anti–tumor necrosis factor (anti-TNF) agents and interferon alpha. Rarely, low titers of anti-dsDNA antibodies have been reported in rheumatoid arthritis and Sjögren disease. In SLE, anti-dsDNA antibodies can correlate with disease activity and the development of lupus nephritis. However, correlations may not be consistent because some patients have elevated anti-dsDNA antibodies in minimally active or inactive lupus.

Table

Table 3. Antibodies in Systemic Lupus Erythematosus [46][47][48].

Abbreviations: aPL, antiphospholipid antibodies; dsDNA, double-stranded deoxyribonucleic acid; MCTD, mixed connective tissue disease; RNP, ribonucleoprotein; SLE, systemic lupus erythematosus; Sm, Smith; SSA, Sjögren syndrome-related antigen A; SSB, Sjögren syndrome-related antigen B; U1-RNP, uridine-rich small nuclear ribonucleoprotein U1. 

Anti-SSA/Ro and anti-SSB/La antibodies target ribonucleoprotein particles. Anti-SSA/Ro and anti-SSB/La antibodies are present in up to 90% of cases of Sjögren disease but can also be present in SLE. In SLE, they may be associated with secondary Sjögren disease and keratoconjunctivitis sicca, subacute cutaneous lupus, photosensitivity, congenital heart block, and neonatal lupus.[49]

Anti-Sm antibodies are seen in 10% to 55% of patients with SLE but have 99% specificity for SLE. Anti-Sm antibodies are more frequently observed in Black individuals with SLE. Anti-Sm antibodies in SLE are usually associated with uridine-rich small nuclear ribonucleoprotein U1 (anti-U1-RNP) antibodies, which are present in up to 20% to 40% of patients with SLE. Anti-U1-RNP antibodies are also associated with mixed connective tissue disease (MCTD). Anti-ribosomal P antibodies are highly specific for SLE, although their prevalence in SLE is less than 5%, and they may correlate with neuropsychiatric manifestations of SLE. Anti-histone antibodies are not specific to drug-induced lupus and are present in 50% to 70% of cases of SLE. Patients with SLE may also have antiphospholipid antibodies (lupus anticoagulant, anticardiolipin, and anti-β2-glycoprotein I antibodies), which are associated with thrombotic events and adverse pregnancy-related outcomes.

Complement C3 and C4 should be checked in patients with SLE or suspected SLE, and low complement levels indicate complement consumption and may correlate with disease activity. Markers of inflammation, such as the C-reactive protein and sedimentation rate, are frequently elevated, and hypergammaglobulinemia may be present in a polyclonal pattern. An assessment of organ involvement is completed by obtaining a complete blood count, liver and renal function tests, including serum creatinine, urinalysis, and urine protein quantification (24-hour urine protein, or spot urine protein/creatinine ratio). If needed, a synovial fluid aspiration may reveal a mildly inflammatory joint effusion.

Joint radiographs may demonstrate periarticular osteopenia, deformities, or subluxation, but rarely show erosions. Other diagnostic testing can be performed based on clinical manifestations. For cardiopulmonary symptoms, chest radiographs and computed tomography (CT) scans may reveal pulmonary infiltrates, pleural effusions, or other findings that correlate with symptoms. Echocardiography, an electrocardiogram, and telemetry should be performed for patients with suspected cardiac complications. A central nervous system workup with magnetic resonance imaging (MRI) and lumbar puncture should be pursued if there are symptoms of severe central nervous system dysfunction, such as meningitis, somnolence, cognitive changes, and other neurologic findings. A renal biopsy for histopathology, immunofluorescence, and electron microscopy should always be performed when lupus nephritis is suspected to help stage the disease and direct management. Other organ manifestations, such as the skin, may benefit from tissue biopsy and histopathology, especially when the underlying diagnosis is ambiguous.

Treatment / Management

Treatment of SLE focuses on preventing organ damage and achieving a low disease activity state. The therapeutic approach depends on the organ system(s) involved and the severity of the disease, ranging from minimal therapy (eg, nonsteroidal anti-inflammatory drugs (NSAIDs), antimalarials) to intensive regimens (eg, cytotoxic agents, biologics, corticosteroids). The ACR updated its management recommendations in 2025.[50] Patients with systemic lupus should be prescribed hydroxychloroquine. Hydroxychloroquine has been shown to reduce flares, improve fatigue, reduce rash, improve arthralgias and arthritis, and confer a mortality benefit.[51] 

Treatment Recommendations by Organ System

Cutaneous manifestations

Mild cutaneous manifestations can usually be treated with topical corticosteroids or topical calcineurin inhibitors such as tacrolimus. Low-potency corticosteroids should be used in sensitive areas such as the face, while higher-potency corticosteroids should be used in thicker-skinned areas such as the hands and back. Higher-potency corticosteroids increase the risk of skin atrophy and dyspigmentation. Hydroxychloroquine is the drug of choice for most cutaneous manifestations. Quinacrine can be used for hydroxychloroquine intolerance or adverse effects, or quinacrine may be added to hydroxychloroquine to augment its effect. Methotrexate may be used when hydroxychloroquine is ineffective. For severe or resistant disease, systemic corticosteroids, mycophenolate mofetil, anifrolumab, or belimumab, or lenalidomide can be considered.[50] Bullous lupus tends to respond to the addition of dapsone to standard therapies, though methotrexate, mycophenolate, azathioprine, or rituximab may also be used.[52] Chillblain lupus may be treated with topical glucocorticoids, calcineurin inhibitors, and topical nitrates, with oral therapies such as pentoxifylline, phosphodiesterase type 5 inhibitors, or calcium channel blockers as other management options.[50]

Musculoskeletal manifestations

For minor arthralgias, NSAIDs may be used. Short courses of corticosteroids can also be helpful, but for ongoing and recurrent joint pain due to inflammatory arthritis, corticosteroid-sparing medications should be the mainstay of therapy. Medications most effective for joint disease beyond hydroxychloroquine are methotrexate, mycophenolate mofetil, and azathioprine. Belimumab, rituximab, or anifrolumab can be used in refractory cases.[50][53]

Hematological manifestations

Mild cytopenias usually require no treatment unless there is concurrent lupus activity. For patients without symptoms and moderate thrombocytopenia (platelets > 30,000/μL but < 100,000/μL), observation is acceptable. For patients with symptomatic thrombocytopenia, corticosteroids with intravenous immunoglobulin (IVIG) or rituximab are recommended.[50] Patients with chronic asymptomatic thrombocytopenia less than 30,000/μL may be treated with corticosteroids, azathioprine, mycophenolate, tacrolimus, or cyclosporine, or with rituximab, belimumab, or IVIG as steroid-sparing agents. Severe or symptomatic thrombocytopenia may require intravenous pulse dose corticosteroids, mycophenolate mofetil, rituximab, cyclophosphamide, plasmapheresis, recombinant granulocyte colony-stimulating factor (G-CSF), or splenectomy.[54] Agents that stimulate thrombopoietin may also be used, but use should occur in consultation with a hematologist. Hemolytic anemia may be managed with corticosteroids, IVIG, aor rituximab. Asymptomatic leukopenia (neutropenia or lymphopenia with a cell count less than 1000/μL) does not require immunosuppressive therapy. Severe neutropenia associated with infection may be treated with G-CSF, but under the guidance of hematology. Patients may also have associated antiphospholipid syndrome (APLS) or predisposition to thrombophilia. In this case, management should be specific to antiphospholipid syndrome and include anticoagulation.

Cardiopulmonary manifestations

Pleuropericarditis typically responds to NSAIDs, colchicine, or moderate-dose corticosteroids. For recurrent pleuritis or pericarditis despite treatment with NSAIDs, colchicine, and hydroxychloroquine, the addition of mycophenolate mofetil or azathioprine is recommended.[50] Persistent pericarditis may have some evidence supporting the use of anti–interleukin 1 agents.[55] Myocarditis management comprises corticosteroids, with either cyclophosphamide, mycophenolate mofetil, or rituximab. Libman-Sacks endocarditis is treated with anticoagulation, given its association with APLS; immunosuppressive therapy may or may not have a role. Acute lupus pneumonitis requires high-dose intravenous pulse corticosteroids, while plasmapheresis and/or cyclophosphamide may be needed if diffuse alveolar hemorrhage is present.[56] Interstitial lung disease can be managed with low to moderate-dose corticosteroids with immunosuppressive agents, such as mycophenolate mofetil or rituximab. Pulmonary arterial hypertension may require vasodilator therapy. Both interstitial lung disease and pulmonary hypertension require input from and comanagement by pulmonary and cardiology. 

CNS manifestations

Accurate diagnosis and ruling out other potential causes are critical before initiating treatment for neuropsychiatric manifestations of SLE. High-dose corticosteroids, combined with immunosuppressive agents such as cyclophosphamide, azathioprine, or rituximab, are used to treat inflammatory neuropsychiatric manifestations, including optic neuritis, acute confusional state, mononeuritis multiplex, aseptic meningitis, and transverse myelitis. Lifelong warfarin is indicated in cases of thromboembolic central nervous system events associated with APLS.[50] Management of stroke should be guided by neurology clinicians. Seizures may be managed with antiepileptics plus immunosuppressive therapy, but management should be guided by neurology input. Chronic cognitive dysfunction is generally not treated with immunosuppressive therapy, although there is some controversy in the management approach.

Renal manifestations

Lupus nephritis (LN) should be confirmed by biopsy, which helps rule out other causes and classify the stage of disease. Class II LN should be treated with renin-angiotensin-aldosterone system blockade. The ACR recommends triple therapy for patients with new onset or flare of class III or IV disease. Triple therapy entails the use of glucocorticoids with either a mycophenolic acid analog plus belimumab, a mycophenolic acid analog plus a calcineurin inhibitor such as voclosporin, tacrolimus, or cyclosporin, or cyclophosphamide, according to the Eurolupus protocol, followed bymycophenolic acid analog plus belimumab.[57] For patients with class V disease, triple therapy with glucocorticoids and mycophenolic acid analog plus a calcineurin inhibitor is preferred. Tapering of corticosteroids to approximately 5 mg/day of prednisone is preferred by the 6-month mark. For refractory disease, escalation to a more intensive regimen, such as adding an anti-CD20 agent (eg, rituximab or obinutuzumab), may be considered.[58] Patients with lupus nephritis and other renal complications should always be treated in conjunction with a nephrologist. 

Pregnancy manifestations: 

Pregnancy in SLE should be planned only when the disease has been quiescent for at least 6 months, as active disease at conception or early pregnancy increases the risk of flares. Medications that may pose a risk to the fetus and pregnancy should be switched to suitable alternatives. Azathioprine may be used for any disease manifestation as a safe corticosteroid-sparing medication.[59] Ideally, patients transition medication use 4 to 6 months prior to conception, with a period of disease stability prior to conception. Hydroxychloroquine is considered safe during pregnancy, reduces disease activity and flare risk, and should be continued throughout gestation. Low-dose glucocorticoids may also be used. For patients at high risk of preeclampsia, treatment with low-dose aspirin (81 mg) is recommended starting in the first trimester.  

All patients with SLE planning pregnancy should have had testing for antiphospholipid antibodies and anti-SSA/Ro and anti-SSB/La antibodies. The presence of these antibodies modifies the management strategy in certain cases. Patients with thrombotic and/or obstetric APLS should receive therapy with heparin to improve outcomes and reduce thrombotic risk. Patients with positive antiphospholipid antibodies without a history of thrombosis or obstetric APLS could be treated with aspirin 81 mg/d to prevent preeclampsia. In women with anti-SSA/Ro or anti-SSB/La antibodies and a history of neonatal lupus, close fetal heart monitoring with weekly or biweekly echocardiography during the second trimester is recommended, but weekly if the patient has already had a prior infant with congenital heart block.[59] First- or second-degree heart block should be treated promptly with dexamethasone, though prophylactic dexamethasone is not recommended. Complete heart block is irreversible and requires a permanent pacemaker in the infant. Continuing hydroxychloroquine has been shown to decrease the risk of fetal heart block.[60]

Other treatment considerations

Patients on immunosuppressive therapy should continue treatment for at least 3 to 5 years with sustained clinical remission or low disease activity before tapering medication. Hydroxychloroquine should be continued indefinitely unless there is a contraindication or adverse event. All patients with lupus should receive regular monitoring for comorbid conditions that are more common in this population. These include infections, cardiovascular disease, osteoporosis, malignant neoplasms, and reproductive health complications.

Patient education, lifestyle measures, and emotional support are central to disease management. Patients should be counseled on the underlying disease process, the potential for organ involvement, and the importance of adherence to medications and monitoring. Stress reduction, good sleep hygiene, regular exercise, and attention to emotional and mental health should be emphasized. Smoking exacerbates SLE activity, and cessation must be strongly encouraged.

Dietary advice includes ensuring adequate vitamin D intake. Photoprotection is critical: patients should avoid direct sun exposure by scheduling activities appropriately, wearing lightweight, loose-fitting, dark clothing that covers as much skin as possible, and using broad-spectrum (ultraviolet A and ultraviolet B) sunscreens with sun protection factor (SPF) at least 70 for chemical sunscreens and at least 50 for physical-blocker sunscreens.

Differential Diagnosis

SLE is a systemic disease with multiorgan involvement, and multiple other diseases can mimic SLE.

Other Systemic Rheumatologic Autoimmune Diseases

• Drug-induced lupus may be difficult to differentiate from SLE, especially given significant overlap in clinical and serological features. Drug-induced lupus is characterized by the resolution of symptoms after drug withdrawal and lack of more severe manifestations, although autoantibodies may remain positive for several years.
• Mixed connective tissue disease is characterized by overlapping features of scleroderma, lupus, rheumatoid arthritis, and myositis, and notably has the presence of the anti-U1-RNP antibody. 
• Undifferentiated connective tissue disease is characterized by clinical and serological features suggestive of SLE or other autoimmune rheumatic diseases, with common joint involvement, but it does not fulfill established classification criteria for SLE or another defined connective tissue disease. Undifferentiated connective tissue disease can present with positive antinuclear antibodies and symptoms such as arthralgia, Raynaud phenomenon, and leukopenia, but typically lacks the organ involvement (eg, renal or neurologic) seen in SLE. A minority of patients withUndifferentiated connective tissue disease (2.9% to 13.2%) may progress to a definitive SLE diagnosis over several years, underscoring its importance in the differential diagnosis of early or incomplete SLE presentations.[61]
• Sjögren disease is typically characterized by xerophthalmia and xerostomia, decreased aqueous tear production, the presence of the anti-SSA/Ro antibody, or an abnormal minor salivary gland biopsy with a focus score ≥ 1.
• Adult-onset Still disease is characterized by arthralgia, fever, lymphadenopathy, fluctuating rash, and splenomegaly, but no malar rash, cytopenias, or renal involvement, and lacks SLE-specific autoantibodies.
• Behcet disease presents with aphthous ulcers in the oropharynx and genitals, uveitis, and arthralgia, but lacks the other systemic and serological features of SLE.
• Scleroderma, or systemic sclerosis, is characterized by sclerodactyly, swollen digits, Raynaud phenomenon, skin thickening of the extremities or face, telangiectasias, and variable internal organ involvement, such as pulmonary hypertension or interstitial lung disease.
• Rheumatoid arthritis can present with several extraarticular manifestations in addition to a polyarticular inflammatory arthritis and may be difficult to differentiate from SLE. The presence of a rheumatoid factor or cyclic citrullinated peptide antibody aids in diagnosis.
• Dermatomyositis is characterized by a photodistributed rash very similar to acute cutaneous lupus, myopathy, and abnormal muscle biomarkers, and may include other features, such as synovitis, Raynaud phenomenon, and internal organ involvement, such as interstitial lung disease. 
• Vasculitides such as granulomatosis with polyangiitis, eosinophilic polyangiitis with granulomatosis, and microscopic polyangiitis may present with rash, nephritis, hemoptysis, sinus disease, mononeuritis multiplex, and other systemic manifestations. An anti–neutrophil cytoplasmic antibody may be present. 
• Sarcoidosis may present with fever, cough, dyspnea, fatigue, night sweats, rash, or uveitis. Sarcoidosis shows noncaseating granuloma on histopathology and typically demonstrates bilateral hilar adenopathy on chest radiography.[62]

Infections

• Parvovirus B19 infection can cause fever, rash, inflammatory arthritis, and cytopenias. 
• Hepatitis B and C virus infection can be associated with arthralgia and inflammatory arthritis.
• Cytomegalovirus and Epstein-Barr virus can cause fever, fatigue, cytopenias, and transaminitis.
• Human immunodeficiency virus can cause fever, fatigue, oral ulcers, and cytopenias. 
• Syphilis can cause constitutional symptoms such as fever, headaches, weight loss, adenopathy, rash, alopecia, synovitis, and nephritis in the secondary stage.
• Infectious endocarditis, characterized by fever, arterial emboli, arthralgia, myalgia, and a heart murmur, may be confused with cardiac manifestations of SLE but can be differentiated by the absence of specific SLE-associated autoantibodies and positive blood culture results.[54]

Malignant Neoplasms

• Lymphomas, especially non–Hodgkin lymphoma, can present with fatigue, weight loss, fever, arthralgia, cytopenias, lymphadenopathy, and a positive ANA result. The more specific SLE-associated autoantibodies are absent. In older adult patients presenting with lupus-like symptoms, malignant neoplasms should be evaluated for.

Other

• Multiple sclerosis can cause neurologic disease and cranial neuropathies that can overlap with lupus. Multiple sclerosis has characteristic features on brain MRI.
• Fibromyalgia presents with fatigue, arthralgias, myalgias, xerostomia, xerophthalmia, and sometimes neurological symptoms that may mimic SLE, but lack objective markers of inflammation and signs of organ involvement. 
• Medication adverse effects, such as a delayed hypersensitivity reaction, may trigger a serum sickness response characterized by fever, rash, arthralgias, and myalgias days after exposure, mimicking a potential lupus-like presentation. 

Prognosis

Five- and eight-year survival rates in SLE are approximately 91% and 89%, respectively, but overall mortality remains 2 to 3 times higher than the general population, especially among younger patients and those with severe organ involvement. Poor prognostic factors in SLE include Black ethnicity, renal disease, male sex, younger age at onset, hypertension, low socioeconomic status, the presence of antiphospholipid antibodies, and higher overall disease activity.[63] The leading causes of morbidity and mortality in SLE are cardiovascular disease, chronic kidney disease due to lupus nephritis, and serious infections.[8] Cardiovascular disease now accounts for about half of deaths in Western cohorts, with infection and cancer also contributing significantly.[64] Of patients with lupus nephritis, about 10% progress to end-stage kidney disease.[24] For those patients with end-stage kidney disease who proceeded to transplant, approximately 16.9% died compared with 51.6% who did not receive a kidney transplant. Recurrent lupus nephritis after renal transplant is very rare.[65]

Complications

Patients with SLE are at risk for a wide spectrum of complications due to both the underlying disease process and the adverse effects of therapy. Some of these complications include:

• Accelerated atherosclerosis and increased risk of cardiovascular disease, particularly in younger patients, leading to premature cardiovascular events and cerebrovascular accidents. This risk is driven by chronic inflammation, immune dysregulation, and the presence of antiphospholipid antibodies and is further exacerbated by glucocorticoid therapy and traditional risk factors.[66]
• Increased risk for malignant neoplasms in part due to chronic inflammation, immunosuppression, and other factors. Non–Hodgkin lymphoma is associated most commonly with SLE, and there are higher rates of precancerous cervical dysplasia in SLE compared with patients without SLE.[8]
• End-stage kidney disease and dialysis dependence secondary to the progression of lupus nephritis.
• Avascular necrosis of the bone is a common occurrence, affecting approximately 28.5% of patients.[67]
• Increased risk of infections, including opportunistic (mycobacterial and fungal) and serious infections, is due to both immune dysfunction and immunosuppressive therapy (eg, glucocorticoids, cytotoxic agents, biologics). Other risk factors include active disease, kidney injury, lymphopenia, and diabetes mellitus.[33]
• Glucocorticoid-related long-term adverse effects may occur, including osteoporosis, glaucoma, cataracts, weight gain, skin striae, and diabetes mellitus, with sequelae of those complications.
• Permanent skin damage, scarring, dyspigmentation, and alopecia, particularly chronic cutaneous lupus (eg, discoid lupus), are associated with a significant reduction in quality of life, depression, and anxiety.
• Psychiatric complications are common and adversely impact health-related quality of life.
• Pregnancy-related complications may occur, such as fetal loss, preeclampsia, eclampsia, congenital heart block, and neonatal lupus, especially in women with active disease. Early menopause may also occur.[68]

Deterrence and Patient Education

Patient education is a cornerstone of SLE management. Teaching patients to recognize early signs of organ involvement can enable timely intervention and prevent complications. Emphasizing medication adherence, as well as dietary and lifestyle modifications—such as sun protection and smoking cessation—is essential. Patients should be instructed to wear sunscreen with a sun protection factor (SPF) of at least 70. Educating patients about how lupus can affect the body and its organs is important for promoting follow-up and adherence to prescribed medications and treatment plans. Connecting patients with support groups, such as through the local Lupus Foundation chapter, promotes connection and provides additional support. Stress and anxiety should be addressed with a counselor or therapist, and patients should be encouraged to adopt a healthy lifestyle, including getting adequate sleep, minimizing stress, exercising regularly, and eating a healthy diet.

Enhancing Healthcare Team Outcomes

SLE is a chronic systemic inflammatory disease that can affect any organ system, leading to accrual of damage, significantly reducing quality of life, and contributing to morbidity and mortality. An interprofessional team is essential for educating patients and coordinating care to improve outcomes. Frontline clinicians, including primary care, urgent care, and emergency care, play a role in recognizing when to consider lupus in the differential diagnosis and in ordering appropriate diagnostic tests, with a referral to rheumatology. Both rheumatologists and primary care clinicians confirm diagnoses, evaluate for disease complications, initiate and coordinate therapies, and provide longitudinal care and support. Subspecialists, including nephrologists, dermatologists, cardiologists, neurologists, pulmonologists, obstetricians and gynecologists, hematologists and oncologists, and physical medicine and rehabilitation specialists, are critical to managing disease complications and providing long-term support. Physical and occupational therapists help manage functional and physical disorders that arise from musculoskeletal, neurologic, and psychological problems, and social workers, psychiatrists, psychologists, and other behavioral health clinicians support the mental health needs of patients and their families. Nurses provide educational and symptom support, as well as point-of-care services. Pharmacists provide medication therapy support, help secure authorizations, and offer educational support to patients and clinicians. An interdisciplinary approach to patient care, with clear communication, is key to caring for these patients.

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Disclosure: William Bowers declares no relevant financial relationships with ineligible companies.

Disclosure: Marissa Blum declares no relevant financial relationships with ineligible companies.