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INTRODUCTION  —  Systemic lupus erythematosus (SLE) is a chronic autoimmune disease of unknown cause that can affect virtually any organ of the body. Immunologic abnormalities, especially the production of a number of antinuclear antibodies (ANA), are a prominent feature of the disease.

Patients present with variable clinical features ranging from mild joint and skin involvement to life-threatening kidney, hematologic, or central nervous system involvement. The clinical heterogeneity of SLE and the lack of pathognomonic features or tests pose a diagnostic challenge for the clinician. To complicate matters, patients may present with only a few clinical features of SLE, which can resemble other autoimmune, infectious, or hematologic diseases.

The diagnosis of SLE is generally based on clinical and laboratory findings after excluding alternative diagnoses. In the absence of SLE diagnostic criteria, SLE classification criteria are often used by clinicians as guidance to help identify some of the salient clinical features when making the diagnosis. Serologic findings are important in suggesting the possibility of SLE, with some antibodies (eg, anti-double-stranded deoxyribonucleic acid [anti-dsDNA] and anti-Smith [anti-Sm]) highly associated with this condition.

The clinical manifestations and an approach to the diagnosis of SLE will be reviewed here. Separate topic reviews related to SLE in adults include the following:

● (See "Overview of the management and prognosis of systemic lupus erythematosus in adults" .)

● (See "Epidemiology and pathogenesis of systemic lupus erythematosus" .)

● (See "Drug-induced lupus" .)

The diagnosis and treatment of specific clinical manifestations of SLE are discussed separately:

● (See "Overview of cutaneous lupus erythematosus" .)

● (See "Arthritis and other musculoskeletal manifestations of systemic lupus erythematosus" .)

● (See "Lupus nephritis: Diagnosis and classification" .)

● (See "Lupus nephritis: Therapy of lupus membranous nephropathy" .)

● (See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis" .)

● (See "Hematologic manifestations of systemic lupus erythematosus" .)

● (See "Gastrointestinal manifestations of systemic lupus erythematosus" .)

● (See "Coronary artery disease in systemic lupus erythematosus" .)

● (See "Non-coronary cardiac manifestations of systemic lupus erythematosus in adults" .)

● (See "Neurologic and neuropsychiatric manifestations of systemic lupus erythematosus" .)

● (See "Manifestations of systemic lupus erythematosus affecting the peripheral nervous system" .)

The approach to contraception and pregnancy in females with SLE is covered separately:

● (See "Approach to contraception in women with systemic lupus erythematosus" .)

● (See "Pregnancy in women with systemic lupus erythematosus" .)

CLINICAL MANIFESTATIONS

Major clinical features and organ involvement

Constitutional symptoms  —  Constitutional symptoms such as fatigue, fever, and weight loss are present in most patients with systemic lupus erythematosus (SLE) at some point during the course of the disease.

● Fatigue – Fatigue is the most common complaint, occurring in 80 to 100 percent of patients, and can sometimes be disabling. Its presence is not clearly correlated with other measures of disease activity and is more frequently associated with depression, sleep disturbances, and concomitant fibromyalgia [ 1-5 ].

● Fever – Fever can be a manifestation of active disease and is seen in over 50 percent of patients with SLE [ 6 ]. However, in clinical practice, distinguishing fever associated with a lupus flare from other causes of fever, such as infection, a drug reaction, or malignancy, can be difficult. Clinically, there are no specific features that definitively distinguish fever due to SLE from fever due to other causes. The history may be helpful in determining the cause of the fever. As an example, fever in the setting of moderate or high doses of glucocorticoids should lead one to strongly suspect new infection, particularly if other signs of active disease are not present. Fever that does not respond to nonsteroidal antiinflammatory drugs (NSAIDs), acetaminophen , and/or low to moderate doses of glucocorticoids should raise the suspicion of an infectious or drug-related etiology, since most fevers due to active SLE will remit with use of these agents [ 7 ]. In addition, a low white blood cell (WBC) count in the setting of fever would be more consistent with lupus activity rather than infection. Infection should clearly be ruled out in a patient with SLE presenting with fever.

Serious infections are a major cause of morbidity among patients and should be considered in all immunocompromised SLE patients with fever. (See 'Clinical manifestations' above.)

● Myalgia – Myalgia is also common among patients with SLE, whereas severe muscle weakness or myositis is relatively uncommon. Myalgia and muscle weakness are discussed in more detail separately. (See "Arthritis and other musculoskeletal manifestations of systemic lupus erythematosus", section on 'Muscle involvement' .)

● Weight change – Weight changes are frequent in patients with SLE and may be related to the disease or to its treatment. Weight loss often occurs prior to the diagnosis of SLE. Unintentional weight loss may be due to decreased appetite, side effects of medications (particularly diuretics and occasionally hydroxychloroquine ), and gastrointestinal disease (eg, gastroesophageal reflux, abdominal pain, peptic ulcer disease, or pancreatitis) (see "Gastrointestinal manifestations of systemic lupus erythematosus" ). Weight gain in SLE may be due to salt and water retention associated with hypoalbuminemia (eg, due to nephrotic syndrome or protein-losing enteropathy) or, alternatively, due to increased appetite associated with the use of glucocorticoids. (See "Overview of heavy proteinuria and the nephrotic syndrome" and "Gastrointestinal manifestations of systemic lupus erythematosus", section on 'Protein-losing enteropathy' .)

Arthritis and arthralgias  —  Arthritis and arthralgias occur in over 90 percent of patients with SLE and are often one of the earliest manifestations [ 8 ]. Arthritis, with demonstrable inflammation, occurs in 65 to 70 percent of patients and tends to be migratory, polyarticular, and symmetrical. The arthritis is moderately painful, usually does not cause erosion, and is rarely deforming ( picture 1A-B ). However, occasionally patients with SLE also develop a deforming erosive arthritis, which is similar to that of rheumatoid arthritis (RA) [ 9 ]. The clinical characteristics and management of arthritis and arthralgias in SLE are discussed in detail elsewhere. (See "Arthritis and other musculoskeletal manifestations of systemic lupus erythematosus", section on 'Joint involvement' .)

Mucocutaneous involvement  —  Most patients develop skin and mucous membrane lesions at some point during the course of their disease. There is tremendous variability in the type of skin involvement in SLE. The most common lesion is a facial eruption that characterizes acute cutaneous lupus erythema (also known as "the butterfly rash") that presents as erythema in a malar distribution over the cheeks and nose (but sparing the nasolabial folds) that appears after sun exposure ( picture 2A-B ). Some patients may develop discoid lesions, which are more inflammatory and which have a tendency to scar ( picture 3A-B ). Photosensitivity is also a common theme for skin lesions associated with SLE. The various cutaneous manifestations of SLE are presented in detail separately. (See "Overview of cutaneous lupus erythematosus" .)

Many patients develop oral and/or nasal ulcers, which are usually painless in contrast to herpetic chancre blisters. Nasal ulcers may lead to nasal septal perforation. Nonscarring alopecia is also observed in many SLE patients at some point during the course of their disease. Scarring alopecia can occur in patients with discoid lupus erythematosus. (See "Overview of cutaneous lupus erythematosus", section on 'Discoid lupus erythematosus' .)

Cardiac involvement and vascular manifestations  —  A variety of cardiac and vascular abnormalities can occur in patients with SLE.

● Cardiac disease among patients with SLE is common and can involve the pericardium, myocardium, valves, conduction system, and coronary arteries. Pericarditis, with or without an effusion, is the most common cardiac manifestation of SLE, occurring in approximately 25 percent of patients at some point during their disease course [ 10 ]. Verrucous (Libman-Sacks) endocarditis is usually clinically silent, but it can produce valvular insufficiency and can serve as a source of emboli ( picture 4 ). Myocarditis is uncommon but may be severe. Patients with SLE also have an increased risk of coronary artery disease. (See "Non-coronary cardiac manifestations of systemic lupus erythematosus in adults" and "Coronary artery disease in systemic lupus erythematosus" .)

Neonatal lupus, which can occur in babies of women with SLE expressing anti-Ro/SSA and anti-La/SSB, can cause heart block of varying degrees that may be noted in utero and/or that may present as congenital heart block and is discussed separately. (See "Neonatal lupus: Epidemiology, pathogenesis, clinical manifestations, and diagnosis" .)

● Raynaud phenomenon – Raynaud phenomenon in SLE is a vasospastic process induced by cold that occurs in up to 50 percent of patients with SLE ( picture 5 ) [ 6 ]. Raynaud phenomenon is characterized by intermittent acral pallor followed by cyanosis and erythroderma [ 11 ]. Raynaud phenomenon is discussed in detail separately. (See "Clinical manifestations and diagnosis of Raynaud phenomenon" .)

● Vasculitis – Estimates of the prevalence of vasculitis among SLE patients from large cohorts range from 11 to 36 percent [ 12 ]. The clinical spectrum of vasculitis in the setting of SLE is broad due to the potential for inflammatory involvement of vessels of all sizes. Small vessel involvement is the most common, often manifesting as cutaneous lesions; however, medium- and large-vessel involvement have also been observed. Cutaneous small-vessel vasculitis can manifest as palpable purpura, petechiae, papulonodular lesions, livedo reticularis, panniculitis, splinter hemorrhages, and superficial ulcerations (see "Evaluation of adults with cutaneous lesions of vasculitis" ). As an example, a large series of 670 SLE patients identified vasculitis among 11 percent of patients [ 13 ]. Cutaneous lesions were the main clinical presentation of vasculitis, present in 89 percent of patients. The remaining 11 percent of patients with vasculitis had visceral involvement (eg, peripheral nerves, lung, pancreas, and kidney).

Other specific types of vasculitic involvement in SLE include mesenteric vasculitis, hepatic vasculitis, pancreatic vasculitis, coronary vasculitis, pulmonary vasculitis, and retinal vasculitis, as well as vasculitis of the peripheral or central nervous system. A few cases of aortitis, similar to that seen in Takayasu arteritis, have been reported [ 14 ]. (See "Overview of cutaneous lupus erythematosus" and "Gastrointestinal manifestations of systemic lupus erythematosus", section on 'Autoimmune hepatitis' and "Gastrointestinal manifestations of systemic lupus erythematosus", section on 'Acute pancreatitis' and "Gastrointestinal manifestations of systemic lupus erythematosus", section on 'Mesenteric vasculitis/ischemia' and "Manifestations of systemic lupus erythematosus affecting the peripheral nervous system" and "Retinal vasculitis associated with systemic disorders and infections", section on 'Systemic immune-mediated causes' .)

● Thromboembolic disease – Thromboembolic disease can complicate SLE, particularly in the context of antiphospholipid antibodies. Although the precise mechanism is unknown, thromboembolic disease can affect both the venous and arterial circulations [ 15,16 ]. As an example, in a large observational cohort of 554 newly diagnosed SLE patients followed for a median of 6.3 years, an arterial thrombotic event (ATE) occurred in 11 percent, a venous thrombotic event (VTE) occurred in 5 percent, and the estimated 10-year risks were 10 percent for VTE, 26 percent for ATE, and 33 percent for any thrombotic event [ 16 ]. Antimalarials may be protective for the development of thromboembolic disease in SLE [ 17 ].

Kidney involvement  —  Kidney involvement is clinically apparent in approximately 50 percent of SLE patients and is a significant cause of morbidity and mortality [ 18 ]. Thus, periodic screening for the presence of lupus nephritis with urinalyses, quantitation of proteinuria, and estimation of the glomerular filtration rate is an important component of the ongoing management of SLE patients. Several forms of glomerulonephritis can occur, and kidney biopsy is useful to define the type and extent of kidney involvement. The clinical presentation of lupus nephritis is highly variable, ranging from asymptomatic hematuria and/or proteinuria to nephrotic syndrome and rapidly progressive glomerulonephritis with loss of kidney function. Some patients with lupus nephritis also have hypertension. (See "Lupus nephritis: Diagnosis and classification" .)

Gastrointestinal involvement  —  Gastrointestinal symptoms are common in SLE patients, occurring in up to 40 percent of patients. The majority of gastrointestinal symptoms are caused by adverse medication reactions and viral or bacterial infections [ 19 ]. SLE-related gastrointestinal abnormalities can involve almost any organ along the gastrointestinal tract and include esophagitis, intestinal pseudo-obstruction, protein-losing enteropathy, lupus hepatitis, acute pancreatitis, mesenteric vasculitis or ischemia, and peritonitis. The gastrointestinal manifestations of SLE are discussed in detail elsewhere. (See "Gastrointestinal manifestations of systemic lupus erythematosus" .)

Pulmonary involvement  —  During the course of their disease, many patients develop symptoms secondary to pulmonary involvement of SLE. Pulmonary manifestations of SLE include pleuritis (with or without effusion), pneumonitis, interstitial lung disease, pulmonary hypertension, shrinking lung syndrome, and alveolar hemorrhage. Respiratory symptoms must also be distinguished from infection, particularly in patients on immunosuppressive therapy. The risk of thromboembolic involvement is increased in those with antiphospholipid antibodies or with lupus anticoagulant. (See "Pulmonary manifestations of systemic lupus erythematosus in adults" .)

Neurologic and neuropsychiatric involvement  —  Neuropsychiatric involvement of SLE consists of a broad range of neurologic and psychiatric manifestations, including stroke, seizures, cognitive dysfunction, delirium, psychosis, and/or peripheral neuropathies. Other less common problems are movement disorders, cranial neuropathies, myelitis, and meningitis. (See "Neurologic and neuropsychiatric manifestations of systemic lupus erythematosus" and "Manifestations of systemic lupus erythematosus affecting the peripheral nervous system" .)

Thromboembolic events, often in association with antiphospholipid antibodies or with lupus anticoagulant, may occur in a substantial minority (20 percent) of patients with SLE [ 20 ]. Arterial thromboemboli may cause focal neurologic problems, such as stroke or seizures and/or more diffuse cognitive defects [ 20 ]. (See "Clinical manifestations of antiphospholipid syndrome" .)

Hematologic abnormalities  —  Hematologic abnormalities are common in SLE, and all three blood cell lines can be affected. Anemia of chronic disease (also called anemia of inflammation and anemia of chronic inflammation) is the most common type of anemia among patients with SLE. Leukopenia is common in SLE patients, occurring in approximately 50 percent of patients [ 21 ]. Leukopenia can be due to lymphopenia and/or secondary neutropenia and generally correlates with clinically active disease. Neutropenia may also result from toxicity due to immunosuppressive medications. Mild thrombocytopenia is also a common hematologic abnormality. Rarely, severe thrombocytopenia can occur and requires treatment. Autoimmune hemolytic anemia is also relatively rare but can be severe, requiring immediate therapy. A more detailed discussion of the hematologic manifestations of SLE is presented separately. (See "Hematologic manifestations of systemic lupus erythematosus" .)

Lymph node enlargement commonly occurs in association with active SLE and usually involves the cervical, axillary, and inguinal regions. Splenomegaly can also be observed among SLE patients, particularly with active disease. (See "Hematologic manifestations of systemic lupus erythematosus", section on 'Lymphadenopathy' .)

Ophthalmologic involvement  —  Any structure of the eye can be involved in SLE, with keratoconjunctivitis sicca being the most common manifestation as a result of secondary Sjögren's disease [ 22 ] (see "Clinical manifestations of Sjögren's disease: Exocrine gland disease" ). The next most common pathologic condition involving the eye in lupus patients is retinal vasculopathy in the form of cotton wool spots. (See "Retinal vasculitis associated with systemic disorders and infections", section on 'Systemic immune-mediated causes' .)

Other less common ophthalmologic manifestations of SLE include optic neuropathy, choroidopathy, episcleritis, scleritis, and anterior uveitis (iritis, iridocyclitis). (See "Optic neuropathies", section on 'Systemic autoimmune disease' and "Episcleritis" and "Clinical manifestations and diagnosis of scleritis" and "Uveitis: Etiology, clinical manifestations, and diagnosis", section on 'Systemic inflammatory diseases' .)

Orbital tissues such as the lacrimal gland (typically resulting in sicca), extraocular muscles, and other orbital tissues may also be involved in SLE, leading to pain, proptosis, lid swelling, and diplopia [ 23 ]. In addition, there are specific ocular toxicities secondary to medications seen in patients with SLE, including glucocorticoid-induced glaucoma and retinal toxicity due to antimalarial therapy.

Other associated conditions and complications  —  A number of comorbid medical conditions that are related to either the underlying disease or therapy can occur in patients with SLE.

● Immunodeficiencies – Hereditary angioedema is a rare genetic disorder primarily caused by a defect in the C1 inhibitor. It can be associated with some inflammatory and autoimmune disorders, including SLE [ 24 ]. (See "Hereditary angioedema (due to C1 inhibitor deficiency): Pathogenesis and diagnosis" .)

Patients with other forms of complement deficiency like C2 also have forms of SLE. Often the manifestations depend on whether such deficiencies are homozygous. Patients with complete C4 deficiency and C1q deficiency often present with SLE [ 25 ]. Inherited C4 deficiency is discussed in detail separately (see "Inherited disorders of the complement system", section on 'C4 deficiency' ). Acquired low immunoglobulin levels can also be observed in patients with SLE [ 26 ].

● Antiphospholipid syndrome – Antiphospholipid antibodies are detected in 40 percent of patients with SLE [ 27 ]. However, the development of antiphospholipid syndrome is much less common. (See "Diagnosis of antiphospholipid syndrome" and "Clinical manifestations of antiphospholipid syndrome" .)

● Fibromyalgia – Patients with SLE, as well as several other systemic rheumatic diseases, have a higher prevalence of fibromyalgia than the general population [ 28 ]. (See "Arthritis and other musculoskeletal manifestations of systemic lupus erythematosus", section on 'Fibromyalgia' .)

● Osteonecrosis – The estimated risk of osteonecrosis, which can present with severe joint pain among patients with SLE, varies widely, ranging from 3 to 40 percent [ 29 ]. The increased risk is thought to be related to the underlying disease as well as the concomitant use of glucocorticoids. (See "Arthritis and other musculoskeletal manifestations of systemic lupus erythematosus", section on 'Osteonecrosis' .)

● Osteoporosis – Osteoporosis is a common complication of SLE and is discussed in detail separately. (See "Arthritis and other musculoskeletal manifestations of systemic lupus erythematosus", section on 'Osteoporosis' .)

● Infection – Serious infectious complications, especially of the skin, respiratory, and urinary systems, develop in up to 50 percent of SLE patients [ 6,30-33 ]. A large cohort from a Medicaid database of 33,565 SLE patients, 7113 of whom had lupus nephritis, found that the incidence rate (per 100 person-years) of serious infections requiring hospitalization was 10.8 in the SLE cohort and 23.9 in the lupus nephritis subcohort [ 34 ]. A large majority of infections (approximately 80 percent) are due to pathogenic bacteria [ 33 ]. Opportunistic infections, including those due to fungi, can be related to the use of immunosuppressive therapy and are a common cause of death [ 35-38 ]. Consequently, ascribing fever to SLE in an immunocompromised patient should be done only after reasonable efforts have been made to exclude infection.

Risk factors for infection include active SLE disease [ 39 ], long-term disease damage, neutropenia, lymphopenia, hypocomplementemia, hypogammaglobulinemia, kidney involvement, neuropsychiatric manifestations, and the use of glucocorticoids and other immunosuppressive drugs [ 33,40 ]. In nationwide cohort study, risk for infection was increased in Black Americans and for male sex; antimalarials have been found to be protective [ 34 ]. Viral infections are also common, including parvovirus B19 (which can cause a lupus-like syndrome), Epstein-Barr virus, cytomegalovirus, varicella-zoster virus, and human papillomavirus. Mycobacterial infections, including non-tuberculosis, have been noted to be more frequent in patients with SLE [ 30,33 ].

● Other autoimmune diseases – There is an increased prevalence of thyroid disease among patients with SLE, usually in the form of Hashimoto's thyroiditis. Myasthenia gravis has also been reported to co-occur in patients with SLE. There is a high prevalence of autoimmune diseases among relatives of patients with SLE [ 41-43 ]. (See "Clinical manifestations of myasthenia gravis", section on 'Epidemiology' .)

When to suspect SLE  —  The initial diagnosis of systemic lupus erythematosus (SLE) depends on the manner of presentation and the exclusion of alternative diagnoses. Given the heterogeneity of clinical presentations, there are some patients for whom the constellation of presenting clinical features and supportive laboratory studies makes the diagnosis of SLE relatively straightforward. By contrast, there are others who present with isolated complaints or infrequent disease characteristics and represent more of a diagnostic challenge. Demographics should also be taken into account when evaluating a patient for SLE, since it occurs primarily in young women of childbearing age. In addition, SLE occurs more commonly in certain racial and ethnic groups, particularly Black, Asian, and Hispanic populations compared with White populations [ 44 ]. (See "Epidemiology and pathogenesis of systemic lupus erythematosus", section on 'Epidemiology' .)

As an example, the diagnosis of SLE is more likely to be present in a young woman who develops fatigue, arthralgia, and pleuritic chest pain and is found to have hypertension, a malar rash, a pleural friction rub, several tender and swollen joints, and mild peripheral edema. Laboratory testing may reveal leukopenia, anemia, an elevated serum creatinine, hypoalbuminemia, proteinuria, an active urinary sediment, hypocomplementemia, and positive tests for antinuclear antibodies (ANA), including those to double-stranded DNA (dsDNA) and the Smith (Sm) antigen. By contrast, another patient may present with fatigue and arthralgias without evidence of organ involvement in the setting of a positive ANA test. Such patients may or may not subsequently develop characteristic multisystem features of SLE in the following months or years. (See 'Clinical manifestations' above.)

Thus, the initial evaluation requires a careful history and physical exam, along with selected laboratory testing to identify features that are characteristic of SLE or that suggest an alternative diagnosis. Patients presenting with symptoms for a shorter duration of time will need close follow-up, as the frequency with which various features of SLE are observed differs according to stage of disease [ 45-49 ].

History and physical examination  —  We perform a thorough medical history, with particular attention to the following symptoms and signs:

● Constitutional symptoms, such as fever, fatigue, lymphadenopathy, or weight loss

● Photosensitive skin lesions, such as a malar rash

● Painless oral or nasal ulcers

● Hair loss that is patchy or frontal/peripheral

● Raynaud phenomenon

● Joint pain or swelling, which can be migratory or symmetrical

● Dyspnea or pleuritic chest pain suggestive of serositis

● Chest pain suggestive of pericarditis

● Lower-extremity edema

● Neurologic symptoms, such as seizures or psychosis

● Recurrent miscarriages (see "Pregnancy in women with systemic lupus erythematosus" )

● Exposure to medications associated with drug-induced lupus (see "Drug-induced lupus" )

Given the broad range of clinical manifestations of SLE, it is helpful to consider the various features according to frequency at disease onset ( table 1 ).

A complete physical examination is indicated, since any organ system can be involved in SLE. Pertinent physical examination findings include the following:

● Skin lesions consistent with a malar rash or discoid lesions

● Scarring or nonscarring patchy alopecia

● Oral or nasopharyngeal ulcers, nasal septal perforation

● Polyarticular arthritis, which is often symmetric

● Subluxation at the metacarpophalangeal joints and rheumatoid-like swan neck deformities in the hands

● Decreased or abnormal breath sounds that may indicate a pleural effusion, pneumonitis, or interstitial lung disease

● Lower-extremity edema and hypertension

Laboratory testing  —  We obtain the following routine laboratory tests, which may provide diagnostically useful information:

● Complete blood count and differential may reveal leukopenia, mild anemia, and/or thrombocytopenia

● Elevated serum creatinine may be suggestive of kidney dysfunction

● Urinalysis with urine sediment may reveal hematuria, pyuria, proteinuria, and/or cellular casts

● Serum protein electrophoresis may demonstrate a hypergammaglobulinemia that is suggestive of a systemic inflammatory process

In addition to the routine laboratories described above, we perform the following laboratory tests, which support the diagnosis of SLE if abnormal:

● ANA (ideally by indirect immunofluorescence testing)

● Anti-double-stranded DNA (anti-dsDNA)

● Antiphospholipid antibodies (lupus anticoagulant [LA], immunoglobulin [Ig] G and IgM anticardiolipin [aCL] antibodies, and IgG and IgM anti-beta2-glycoprotein [GP] 1)

● C3 and C4 or CH50 complement levels

● Erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP) levels

● Urine protein-to-creatinine ratio

The ANA test is positive in virtually all patients with SLE at some time in the course of their disease (see "Measurement and clinical significance of antinuclear antibodies" ). If the ANA is positive, one should test for other specific antibodies, such as anti-dsDNA, anti-Smith (anti-Sm), Ro/SSA, La/SSB, and U1 ribonucleoprotein (RNP), which are described further below. In some labs, a positive ANA test by indirect immunofluorescence will automatically result in testing for such additional ANA that are often present in patients with SLE. However, a positive ANA must also be interpreted in the setting of other clinical and laboratory findings. Almost 15 percent of the population in the United States has been found to have a positive ANA of at least 1:80 by indirect immunofluorescence, but only 10 percent have a true autoimmune disorder [ 50 ]. A more detailed discussion related to measurement and interpretation of ANA testing can be found elsewhere. (See "Measurement and clinical significance of antinuclear antibodies" .)

● Anti-dsDNA and anti-Sm antibodies are highly specific for SLE, but anti-Sm antibodies lack sensitivity [ 51,52 ]. Anti-dsDNA and anti-Sm antibodies are seen in approximately 70 and 30 percent of patients with SLE, respectively. (See "Antibodies to double-stranded (ds)DNA, Sm, and U1 RNP" .)

● Anti-Ro/SSA and anti-La/SSB antibodies are present in approximately 30 and 20 percent of patients with SLE, respectively; however, both antibodies are more commonly associated with Sjögren's disease [ 51 ]. (See "The anti-Ro/SSA and anti-La/SSB antigen-antibody systems" .)

● Anti-U1 RNP antibodies are observed in approximately 25 percent of patients with SLE, but they also occur in patients with other conditions, and high levels are almost always present in patients with mixed connective tissue disease (MCTD) [ 51,52 ]. (See "Antibodies to double-stranded (ds)DNA, Sm, and U1 RNP" .)

● Antiribosomal P protein antibodies have a high specificity for SLE but low sensitivity for SLE. They also lack specificity for involvement of a particular organ system or disease manifestation. (See "Antiribosomal P protein antibodies", section on 'Clinical utility of antiribosomal P antibodies' .)

If the initial ANA test is negative but the clinical suspicion of SLE is high, then additional antibody testing may still be appropriate. This is partly related to the differences in the sensitivity and specificity among the methods used to detect ANA. A more detailed discussion on the techniques used to detect ANA and the reasons behind some of the variability in test results is presented separately. (See 'ANA-negative lupus' below.)

Additional information regarding the interpretation of abnormalities of the ESR and CRP in patients with SLE can be found elsewhere. (See "Overview of the management and prognosis of systemic lupus erythematosus in adults", section on 'Laboratory evaluation' .)

We perform the following additional laboratory tests in selected patients:

● Rheumatoid factor and anti-cyclic citrullinated peptide antibodies – In patients with predominant arthralgias or arthritis, rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP) antibodies may help exclude a diagnosis of rheumatoid arthritis (RA). RF has less diagnostic utility, since 20 to 30 percent of people with SLE have a positive RF. Anti-CCP antibodies, however, have a much higher specificity for RA and may be more useful for distinguishing the arthritis associated with RA. (See "Biologic markers in the assessment of rheumatoid arthritis", section on 'Rheumatoid factors' and "Biologic markers in the assessment of rheumatoid arthritis", section on 'Anti-citrullinated peptide antibodies' .)

● Serologic studies for infection – In patients with a brief history (eg, less than six weeks) of predominant arthralgias or arthritis, we perform serologic testing for human parvovirus B19. We also perform serologic testing for hepatitis B virus and hepatitis C virus in patients with multisystemic clinical findings. In areas endemic for Lyme disease, we may send serologic studies for Borrelia as well. Testing for Epstein-Barr virus infection may also be indicated in the appropriate clinical setting. (See "Diagnosis of Lyme disease" and "Viral arthritis: Causes and approach to evaluation and management" .)

● Creatine kinase – An elevated creatine kinase (CK) may reflect myositis, which is relatively uncommon in patients with SLE. Myositis may also suggest an alternative diagnosis, such as MCTD, polymyositis, or dermatomyositis.

● 24-hour urine collection – If the spot urine protein-to-creatinine ratio is above 0.05 g/mmol, then a 24-hour urine collection should be performed, as the spot urine collection may not reflect the true amount of proteinuria [ 53 ]. (See "Assessment of urinary protein excretion and evaluation of isolated non-nephrotic proteinuria in adults", section on '24-hour versus spot urine collection' .)

Additional testing in selected patients  —  Biopsy of an involved organ (eg, skin or kidney) is necessary in some cases. Typical histologic findings in various organs in SLE are discussed in topic reviews devoted to the particular sites of involvement. (See "Lupus nephritis: Diagnosis and classification" and "Overview of cutaneous lupus erythematosus" .)

Other tests that may be necessary are typically dictated by the clinical presentation and associated differential diagnostic possibilities. Examples include:

● Electrocardiography in the assessment of chest pain that may be due to pericarditis or to myocardial ischemia

● Tests to assess for pulmonary embolism in a patient with pleuritic chest pain and dyspnea

● Diffusing capacity for carbon monoxide to assess for suspected pulmonary hemorrhage and to estimate the severity of interstitial lung disease

Diagnostic imaging may be valuable but is not routinely obtained unless indicated by the presence of symptoms, clinical findings, or laboratory abnormalities. Examples include:

● Plain radiographs (eg, of swollen joints; unlike affected joints in RA, erosions are observed infrequently in SLE [ 54 ]).

● Musculoskeletal ultrasonography (eg, of painful joints to detect synovitis and tenosynovitis in the hands and wrists [ 55,56 ]).

● Kidney ultrasonography (eg, to assess kidney size and to rule out urinary tract obstruction when there is evidence of kidney impairment).

● Chest radiography (eg, for suspected pleural effusion, interstitial lung disease, cardiomegaly).

● Echocardiography (eg, for suspected pericardial involvement, to assess for a source of emboli, or noninvasive estimation of pulmonary artery pressure; and for evaluation of suspected valvular lesions, such as verrucae).

● Computed tomography (CT; eg, for abdominal pain, suspected pancreatitis, interstitial lung disease).

● Magnetic resonance imaging (MRI; eg, for focal neurologic deficits or cognitive dysfunction).

CLASSIFICATION CRITERIA  —  Several classification criteria have been developed for systemic lupus erythematosus (SLE) as a means of categorizing patients for inclusion in research studies. These criteria can be useful for clinicians in systematically documenting key disease features, but their imperfect sensitivity and specificity limit their use for diagnostic purposes.

● 2019 EULAR/ACR criteria – The European Alliance of Associations for Rheumatology (EULAR; formerly known as European League Against Rheumatism)/American College of Rheumatology (ACR) classification criteria for SLE were developed to improve detection of early- or new-onset SLE as well as improve the sensitivity and specificity compared with previous criteria ( table 2A-B ) [ 57,58 ]. The classification for SLE requires the presence of a positive antinuclear antibodies (ANA) as an entry criterion. Additive criteria consist of seven clinical (ie, constitutional, hematologic, neuropsychiatric, mucocutaneous, serosal, musculoskeletal, renal) and three immunologic (ie, antiphospholipid antibodies, complement proteins, SLE-specific antibodies) categories, each of which are weighted from 2 to 10. Patients are classified as having SLE with a score of 10 or more points. In the validation cohort, which included patients with early disease, the EULAR/ACR criteria had a sensitivity of 96.1 percent and a specificity of 93.4 percent, compared with the 96.7 percent sensitivity and 83.7 percent specificity of the Systemic Lupus International Collaborating Clinics (SLICC) criteria and the 82.8 percent sensitivity and 93.4 percent specificity of the ACR criteria.

The performance of the EULAR/ACR classification criteria was evaluated using the combined derivation and validation cohorts consisting of 1197 patients with SLE and 1074 patients without SLE, but with a variety of conditions mimicking SLE, and reported a sensitivity and specificity of a positive ANA of 99.5 and 19.5 percent, respectively [ 59 ]. The sensitivities of the specific criteria items were highly variable, but the specificities were more consistently high (eg, at least 80 percent).

● 2012 SLICC criteria – In 2012, the SLICC proposed classification criteria that were developed to address inherent weaknesses of the 1997 ACR classification criteria ( table 3 ) [ 60 ]. As an example, one of the major limitations of the 1997 ACR criteria is that patients with biopsy-confirmed lupus nephritis could still fail to fulfill criteria. Other concerns regarding the ACR criteria included the possible duplication of highly correlated cutaneous features (such as malar rash and photosensitivity), the lack of inclusion of other cutaneous manifestations (such as maculopapular or polycyclic rash), and the omission of many neurologic manifestations of SLE (such as myelitis). The ACR criteria also did not include relevant immunologic information such as low serum levels of complement components.

Classification as having SLE by the SLICC criteria requires either that a patient satisfy at least 4 of 17 criteria, including at least 1 of the 11 clinical criteria and one of the six immunologic criteria, or that the patient has biopsy-proven nephritis compatible with SLE in the presence of ANA or anti-double-stranded DNA (anti-dsDNA) antibodies.

The SLICC criteria were validated by analysis of 690 patients with SLE or other rheumatic diseases. In this initial validation testing, the SLICC revised criteria had greater sensitivity but lower specificity than the 1997 ACR classification criteria (sensitivity of 97 versus 83 percent and specificity of 84 versus 96 percent, respectively).

Despite the improved sensitivity compared with the ACR criteria, the SLICC criteria might delay the diagnosis of SLE in a significant number of patients, and some patients might not be classified at all. These situations were demonstrated in a study in which patients with SLE from two large cohorts were grouped according to whether the SLICC criteria were met before, at the same time as, or after the ACR criteria, and the groups were then compared [ 61 ]. Among the patients diagnosed later with the SLICC criteria, in the majority of cases, the delay was due to the fact that the combination of malar rash and photosensitivity both fall within the acute cutaneous SLE category and thus only count as one criterion.

● 1997 ACR criteria – The classification criteria that were developed by the American Rheumatism Association (ARA, now the ACR) for the classification of SLE were established by cluster analyses, primarily in academic centers and in White American patients [ 62-64 ].

The patient is classified with SLE using the ACR criteria if four or more of the manifestations are present, either serially or simultaneously, during any interval of observations ( table 3 ) [ 62,63 ]. A positive lupus erythematosus cell test, used in older criteria, was replaced by the presence of antiphospholipid antibodies [ 62 ]. When tested against other rheumatic diseases, these criteria have a sensitivity and specificity of approximately 96 percent.

DIAGNOSIS  —  The diagnosis of systemic lupus erythematosus (SLE) is based upon the judgment of an experienced clinician who recognizes characteristic constellations of symptoms and signs in the setting of supportive serologic studies after excluding alternative diagnoses. This is often challenging due to the great variability in the expression of SLE. Although the classification criteria were designed for research purposes, many clinicians refer to aspects of these criteria when making the diagnosis of SLE. (See 'Classification criteria' above.)

In the absence of existing "diagnostic criteria," we describe our general approach to the diagnosis that takes into consideration the strengths of the 1997 American College of Rheumatology (ACR) criteria, the 2012 Systemic Lupus International Collaborating Clinics (SLICC) criteria ( table 3 ), or the 2019 European Alliance of Associations for Rheumatology (EULAR)/ACR classification criteria ( table 2A ). (See 'Classification criteria' above.)

Note that our general diagnostic approach does not adequately address the myriad manifestations or subtleties of some clinical features, nor does it substitute for clinical judgment. Thus, it is often appropriate to refer the patient in whom the diagnosis of SLE is suspected to a rheumatologist with experience in this disease [ 65 ].

Our diagnostic criteria

Definite SLE  —  After excluding alternative diagnoses, we diagnose SLE in the patient who fulfills the 1997 ACR criteria, the 2012 SLICC criteria ( table 3 ), or the 2019 EULAR/ACR criteria ( table 2A ). As previously mentioned, the ACR criteria require that a patient satisfy at least 4 of 11 criteria. The SLICC criteria require either that a patient satisfy at least 4 of 17 criteria, including at least 1 of the 11 clinical criteria and one of the six immunologic criteria, or that the patient has biopsy-proven nephritis compatible with SLE in the presence of antinuclear antibodies (ANA) or anti-double-stranded DNA (anti-dsDNA) antibodies. According to the EULAR/ACR criteria, a patient can be classified as having SLE if they have a positive ANA ≥1:80 and score 10 or more points. This number has been shown to be valid in a number of cohorts. (See 'Classification criteria' above.)

Probable SLE  —  There are patients who do not fulfill the classification criteria for SLE but in whom we still diagnose the disorder. These patients include those presenting with an inadequate number of ACR or SLICC criteria or those who have other SLE manifestations not included in either classification criteria.

As a loose guide, we diagnose SLE in patients who have two or three of the ACR or SLICC criteria, along with at least one other feature that may be associated with but is not specific for SLE. Some of these features include the following [ 66 ]:

● Optic neuritis, aseptic meningitis

● Glomerular hematuria

● Pneumonitis, pulmonary hemorrhage, pulmonary hypertension, interstitial lung disease

● Myocarditis, verrucous endocarditis (Libman-Sacks endocarditis)

● Abdominal vasculitis

● Elevated acute phase reactants (eg, erythrocyte sedimentation rate [ESR] and C-reactive protein [CRP])

Possible SLE  —  We consider SLE a possible diagnosis in individuals who have only one of the ACR/SLICC criteria, in addition to at least one or two of the other features listed above. Other terms that have been used to describe patients with probable or possible SLE include incipient or latent lupus, which has been defined as patients who have three or fewer of the ACR or SLICC criteria [ 67 ].

In general, patients with either probable or possible SLE are managed similarly to patients with SLE and treated according to their predominant symptoms and manifestations. Over time, the symptoms in these patients may persist, evolve into definite SLE or a related connective tissue disorder, or even resolve. In addition, these patients may develop positive serology over time and become more clearly diagnosable as SLE. However, patients treated with high doses of prednisone may "lose" their antibodies, and it may be more difficult to diagnose the underlying disease.

Undifferentiated connective tissue disease  —  Other patients who have even fewer features suggestive of SLE may be classified as having undifferentiated connective tissue disease (UCTD). This term is used to describe patients with signs and symptoms suggestive of a systemic autoimmune disease but who do not meet the ACR criteria for SLE or another defined connective tissues disease [ 68 ]. (See "Undifferentiated systemic rheumatic (connective tissue) diseases and overlap syndromes" .)

Case series have been published that summarize the outcome of patients who have UCTD at presentation [ 69-73 ]. Up to one-third of patients have all symptoms and signs disappear over a 10-year follow-up period. Anywhere from 40 to 60 percent of patients continue to exhibit their initial clinical features, while 5 to 30 percent evolve and meet classification criteria for a definite disease, such as SLE, rheumatoid arthritis, scleroderma, or an inflammatory myopathy (myositis) [ 69-73 ] (see "Undifferentiated systemic rheumatic (connective tissue) diseases and overlap syndromes" ). Thus, patients with UCTD should be followed carefully, encouraged to report new symptoms, and have periodic laboratory testing to assess for the emergence of new clinical features or laboratory findings. Appropriate testing should include the laboratory testing described above. (See 'Laboratory testing' above.)

ANA-negative lupus  —  ANA-negative SLE has been recognized since the 1970s but was later shown to be influenced by the testing methods used to detect ANA. At that time, it was estimated that about 5 percent of patients with SLE were ANA-negative by indirect immunofluorescence [ 74 ]. However, this negative finding occurred because sera were tested using rodent, not human, tissues as the substrate for the indirect immunofluorescence test for ANA [ 75 ]. By comparison, anti-Ro/SSA antibodies were found in many of these patients when a human cell line extract was used as the substrate for anti-Ro/SSA antibody testing.

The subsequent substitution of human epithelial type 2 (Hep-2) cells (a human cell line) for rodent tissue sections in the indirect immunofluorescence ANA assay has resulted in even fewer SLE patients with negative ANA by indirect immunofluorescence. Nevertheless, on rare occasions, the presence of anti-Ro/SSA antibodies may suggest a systemic autoimmune disease despite the presence of a negative ANA indirect immunofluorescence. As an example, in one study in Sweden, among 4025 sera tested for ANA, 64 patients with negative ANA by indirect immunofluorescence had anti-Ro/SSA antibodies [ 76 ]. Of these 64 patients, 12 had SLE and 5 had cutaneous lupus erythematosus.

The clinician should understand the technique used to detect the ANA, since this can influence the result. As an example, a negative ANA by indirect immunofluorescence is clinically useful as it dramatically decreases the likelihood of SLE. On the other hand, in a patient with a strong clinical suspicion for SLE and a negative ANA result by a solid-phase assay, the test should be repeated using indirect immunofluorescence method with Hep-2 cells, given the increased risk of a false-negative result for the initial ANA test by solid-phase assay. A detailed discussion of the methods used to detect ANA is presented separately. (See "Measurement and clinical significance of antinuclear antibodies" .)

Other factors that may also influence ANA negativity in SLE patients include disease duration and treatment exposure [ 77 ]. In our experience, the frequency of ANA-negative SLE is lower in patients presenting at an early stage of their disease. In addition, SLE patients who have longstanding disease and/or have undergone treatment may lose ANA reactivity and become serologically negative over time.

DIFFERENTIAL DIAGNOSIS  —  Given the protean manifestations of systemic lupus erythematosus (SLE), the differential diagnosis is correspondingly broad. While it is beyond the scope of this review to provide a comprehensive list of all possible alternative diagnoses, we present several here.

● Rheumatoid arthritis – Early rheumatoid arthritis (RA) may be difficult to distinguish from the arthritis of SLE, since both conditions cause joint tenderness and swelling ( table 4 ). Features such as swan neck deformities, ulnar deviation, and soft tissue laxity, which are observed in later stages of RA in patients with more destructive disease, can also be seen in some patients with SLE. However, an important distinguishing features is that the joint deformities in SLE are often reducible and infrequently erosive on plain radiographs.

Some extraarticular RA manifestations, including serositis, sicca symptoms, subcutaneous nodules, anemia, and fatigue, are other features that may also be observed in SLE. These features are more common in RA patients with more severe or advanced disease. Serologic abnormalities, such as the presence of anti-cyclic citrullinated peptides (CCP), are more supportive of the diagnosis of RA and can help distinguish the diseases. It should be recognized that the antinuclear antibodies (ANA) may be positive in up to one-half of patients with RA. Conversely, rheumatoid factor (RF) may be present in approximately one-third of SLE patients. Also, anti-CCP can be present in 5 to 10 percent of patients with SLE [ 78 ]. (See "Diagnosis and differential diagnosis of rheumatoid arthritis" .)

● Rhupus – The term rhupus has been used to describe patients with overlapping features of both SLE and RA. Whether rhupus is clinically and immunologically a distinct entity, a true overlap of SLE and RA, or a subset of patients with SLE remains a matter of debate. In addition to having serologies consistent with both SLE and RA, some patients classified as rhupus may have an erosive arthropathy that is atypical for SLE. (See "Undifferentiated systemic rheumatic (connective tissue) diseases and overlap syndromes" .)

● Mixed connective tissue disease – Mixed connective tissue disease (MCTD) is characterized by overlapping features of SLE, systemic sclerosis (SSc), and polymyositis (PM), and by the presence of high titers of antibodies against U1 ribonucleoprotein (RNP). However, the diagnosis of MCTD is often complicated, since many of its characteristic features occur sequentially, often over a period of years. In addition, some patients with MCTD may evolve into another connective tissue disease, including SLE, during the clinical course [ 79 ]. (See "Mixed connective tissue disease" .)

● Undifferentiated connective tissue disease – As mentioned above, patients with undifferentiated connective tissue disease (UCTD) have signs and symptoms suggestive of a systemic autoimmune disease but do not satisfy the classification criteria for a defined connective tissue disease such as SLE or MCTD. These patients may have symptoms such as arthritis and arthralgias, Raynaud phenomenon, and serologic findings that are difficult to distinguish from early phases of SLE. The majority of patients with UCTD maintain an undefined profile and have a mild disease course [ 80 ]. (See "Undifferentiated systemic rheumatic (connective tissue) diseases and overlap syndromes" .)

● Systemic sclerosis – The coexistence of Raynaud phenomenon and gastroesophageal reflux is typically observed in SSc; however, these findings are nonspecific and may be seen in patients with SLE or healthy individuals. By contrast, sclerodactyly, telangiectasia, calcinosis, and malignant hypertension with acute kidney failure are more consistent with SSc rather than SLE. Further, a positive ANA is present in most patients with SSc, while other serologies, such as anti-double-stranded DNA (anti-dsDNA) and anti-Smith (anti-Sm) antibodies that are more specific for SLE, are not commonly observed in SSc. Correspondingly, patients with SSc commonly express antibodies to an antigen called Scl-70 (topoisomerase I) or antibodies to centromere proteins. Distinguishing SSc from SLE can be particularly difficult in cases in which there is overlap of these diseases, such as in MCTD. (See "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults" .)

● Sjögren's disease – Patients with Sjögren's disease may have extraglandular manifestations that can be observed in SLE, such as neurologic and pulmonary abnormalities. However, patients with Sjögren's disease should have objective signs of keratoconjunctivitis sicca and xerostomia and characteristic findings on salivary gland biopsy that are not typical of SLE. Patients with Sjögren's disease commonly express antibodies to Ro and La antigens. Also, some patients may have SLE with associated Sjögren's disease. (See "Diagnosis and classification of Sjögren’s disease" .)

● Vasculitis – Patients with medium- and small-vessel vasculitides, such as polyarteritis nodosa, granulomatosis with polyangiitis, or microscopic polyangiitis, may present with overlapping features of SLE, including constitutional symptoms, skin lesions, neuropathy, and kidney dysfunction. However, patients with these types of vasculitides are usually ANA-negative. Rather, these patients frequently display antibodies to neutrophil cytoplasmic antigens. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis" and "Clinical manifestations and diagnosis of polyarteritis nodosa in adults" .)

● Behçet syndrome – Oral aphthae are present in almost all patients with Behçet syndrome and may be observed in patients with SLE. Other overlapping features include inflammatory eye disease, neurologic disease, vascular disease, and arthritis. However, the oral aphthae in Behçet syndrome are typically painful, and patients with Behçet syndrome are more commonly male and ANA-negative. Also, vascular involvement of any size (small, medium, large) is more commonly a feature of Behçet syndrome than SLE. (See "Clinical manifestations and diagnosis of Behçet syndrome" .)

● Dermatomyositis and polymyositis – Patients with SLE can present with a low-grade myositis, whereas patients with dermatomyositis (DM) and PM generally demonstrate more overt proximal muscle weakness. A positive ANA is observed in approximately 30 percent of patients with DM and PM, compared with almost all patients in SLE. Patients with DM may have characteristic skin findings, including Gottron's papules, a heliotrope eruption, and photodistributed poikiloderma (including the shawl and V signs). Clinical findings characteristic of SLE, such as oral ulcers, arthritis, nephritis, and hematologic abnormalities, are absent in DM and PM. Patients with DM or PM may also express myositis-specific antibodies, such as anti-Jo-1. (See "Clinical manifestations of dermatomyositis and polymyositis in adults" .)

● Adult-onset Still's disease – Some of the clinical manifestations observed in adult-onset Still's disease (AOSD), such as fever, arthritis or arthralgias, and lymphadenopathy, are not unusual for patients with SLE. However, patients with AOSD often present with a leukocytosis rather than the leukopenia observed in SLE, and they are typically negative for ANA. Markedly elevated serum ferritin concentrations are also more frequently observed in AOSD. (See "Clinical manifestations and diagnosis of adult-onset Still's disease" .)

● Kikuchi disease – Kikuchi disease is a benign and usually self-limited form of histiocytic-necrotizing lymphadenitis. Clinical features at presentation include lymphadenopathy, fever, myalgias, arthralgias, and, less commonly, hepatosplenomegaly. Associations with SLE have been reported, but the clinical course is usually favorable, with spontaneous remission often occurring within four months. The diagnosis of Kikuchi disease is based on a lymph node biopsy, which reveals a histiocytic cellular infiltrate. (See "Kikuchi disease" .)

● Serum sickness – Many of the clinical features observed in serum sickness, such as fever, lymphadenopathy, cutaneous eruptions, and arthralgias, are often observed in SLE. Furthermore, during severe episodes, complement measurements including C3 and C4 can be depressed, as in SLE. Unlike SLE, however, ANA are typically negative, and the course tends to be self-limited. (See "Serum sickness and serum sickness-like reactions" .)

● Fibromyalgia – Patients with SLE may present with generalized arthralgias, myalgias, and fatigue, much like patients with fibromyalgia. However, other characteristic features of SLE, such as a photosensitive rash, arthritis, and multisystem organ involvement, are absent. However, fibromyalgia occurs more commonly in patients with systemic rheumatic diseases than in the general population. Concomitant fibromyalgia has been reported in at least 22 percent of patients with SLE [ 81 ]. (See "Clinical manifestations and diagnosis of fibromyalgia in adults" and "Overview of chronic widespread (centralized) pain in the rheumatic diseases", section on 'Systemic lupus erythematosus and Sjögren's disease' .)

● Infections – Several viral infections can produce signs and symptoms present in SLE, including cytomegalovirus and Epstein-Barr virus. In addition, Epstein-Barr virus infection may lead to a positive ANA [ 82,83 ]. Human parvovirus B19 can cause flu-like symptoms and hematologic abnormalities such as leukopenia and thrombocytopenia, which can be observed in SLE, and patients may present with arthralgias or arthritis.

Other viral infections that may present with multisystem involvement include human immunodeficiency virus (HIV), hepatitis B virus, and hepatitis C virus. However, serologic assays can be diagnostic for many of these viruses. Some bacterial infections such as Salmonella or tuberculosis should also be considered, if appropriate.

● Multiple sclerosis – Although rare, patients with SLE can present with cranial neuropathies that must be distinguished from multiple sclerosis (MS). Unilateral optic neuritis and pyramidal syndrome, with lesions detected by MRI suggesting dissemination in space and time, are characteristic of MS. (See "Evaluation and diagnosis of multiple sclerosis in adults" .)

● Malignancies – Leukemia or myelodysplastic syndromes may present with hematologic and constitutional symptoms similar to those observed in SLE. However, monoclonal expansion of B and T cells (as assessed by immunophenotyping), monocytosis, or macrocytosis can distinguish these malignancies from SLE. Patients with lymphoma also typically have additional findings such as splenomegaly, lymphadenopathy, or increased lactate dehydrogenase levels. Patients with angioimmunoblastic T cell lymphoma may be distinguished by findings on an excisional tissue biopsy, most commonly a lymph node.

● Thrombotic thrombocytopenic purpura – Although both patients with thrombotic thrombocytopenic purpura (TTP) and SLE may have fever and thrombocytopenia, patients with TTP also have microangiopathic hemolytic anemia, acute kidney insufficiency, fluctuating neurologic manifestations, and/or low levels of ADAMSTS13. (See "Diagnosis of immune TTP" .)

● Other – Some patients with psychiatric disorders (eg, bipolar disorder, substance use disorders) are thought to have SLE on the basis of a positive ANA and leukopenia that may actually be drug- or medication-induced. Thus, these patients should be evaluated for other clinical features consistent with SLE. (See "Drug-induced lupus" and "Drug-induced neutropenia and agranulocytosis" .)

SOCIETY GUIDELINE LINKS  —  Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Systemic lupus erythematosus" .)

INFORMATION FOR PATIENTS  —  UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5 th to 6 th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10 th to 12 th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

● Basics topics (see "Patient education: Lupus (The Basics)" )

● Beyond the Basics topics (see "Patient education: Antinuclear antibodies (ANA) (Beyond the Basics)" and "Patient education: Systemic lupus erythematosus (Beyond the Basics)" )

SUMMARY AND RECOMMENDATIONS

● Clinical manifestations – Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with a wide range of clinical and serologic manifestations that can affect virtually any organ. The disease course is often marked by remissions and relapses and may vary from mild to severe. (See 'Introduction' above.)

Major clinical manifestations of SLE include the following:

• Constitutional symptoms – Constitutional symptoms, such as fatigue, fever, and weight loss, are present in most patients with SLE at some point during the course of the disease. (See 'Constitutional symptoms' above.)

• Arthritis and arthralgias – Arthritis and arthralgias occur in over 90 percent of patients with SLE and are often one of the earliest manifestations. (See 'Arthritis and arthralgias' above.)

• Mucocutaneous involvement – Many patients also have skin and/or mucous membrane lesions. (See 'Mucocutaneous involvement' above.)

• Cardiovascular involvement – Cardiac disease among patients with SLE is common and can involve the pericardium, myocardium, valves, conduction system, and coronary arteries. Several vascular abnormalities, including Raynaud phenomenon, vasculitis, microvascular angina, and thromboembolic disease, can also be observed. (See 'Cardiac involvement and vascular manifestations' above.)

• Kidney involvement – Kidney involvement is clinically apparent in approximately 40 percent of patients and is a significant cause of morbidity and mortality. (See 'Kidney involvement' above.)

• Gastrointestinal involvement – Gastrointestinal abnormalities can involve almost any organ along the gastrointestinal tract. However, the majority of symptoms are related to adverse medication reactions or infection. (See 'Gastrointestinal involvement' above.)

• Pulmonary involvement – Pulmonary manifestations of SLE include pleuritis (with or without effusion), pneumonitis, interstitial lung disease, pulmonary hypertension, shrinking lung syndrome, and alveolar hemorrhage. (See 'Pulmonary involvement' above.)

• Neuropsychiatric involvement – Neuropsychiatric involvement of SLE consists of a broad range of neurologic and psychiatric manifestations, including cognitive dysfunction, organic brain syndromes, delirium, psychosis, seizures, headache, and/or peripheral neuropathies. (See 'Neurologic and neuropsychiatric involvement' above.)

• Hematologic abnormalities – Hematologic abnormalities can include anemia, leukopenia, and thrombocytopenia. Lymphadenopathy and splenomegaly can also be observed. (See 'Hematologic abnormalities' above.)

● Evaluation – As part of the medical history and physical examination, we pay particular attention to the following symptoms and signs (see 'Evaluation' above):

• Photosensitive skin lesions, such as a malar rash or discoid lesions

• Painless oral or nasal ulcers

• Hair loss that is patchy or frontal/peripheral

• Raynaud phenomenon

• Joint pain or swelling, which can be migratory or symmetrical

• Symptoms of serositis/pericarditis

• Fatigue/aching/fever

We also ask about exposure to medications associated with drug-induced lupus (eg, hydralazine ). (See "Drug-induced lupus" .)

● Laboratory testing – We obtain a complete blood count and differential as well as serum creatinine level and urinalysis. We also test for antinuclear antibodies (ANA; and if positive, other specific autoantibodies, such as anti-double-stranded DNA [anti-dsDNA] and anti-Smith [anti-Sm]), antiphospholipid antibodies, C3 and C4 or CH50 complement levels, erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP) levels, and the urine protein-to-creatinine ratio. (See 'Laboratory testing' above.)

● Additional testing in selected patients – Additional studies, such as diagnostic imaging or biopsy of an involved organ, may be necessary; such testing is dictated by the clinical presentation and associated differential diagnostic possibilities. (See 'Additional testing in selected patients' above.)

● Classification criteria – Classification criteria have been developed for SLE as a means of categorizing patients for study purposes. These criteria can be useful for clinicians in systematically documenting key disease features. (See 'Classification criteria' above.)

● Diagnosis – In the absence of existing "diagnostic criteria," our general approach to the diagnosis of SLE is as follows (see 'Our diagnostic criteria' above):

• Definite SLE – After excluding alternative diagnoses, we diagnose SLE in the patient who fulfills the 1997 American College of Rheumatology (ACR) criteria, the 2012 Systemic Lupus International Collaborating Clinics (SLICC) classification criteria ( table 3 ), or the 2019 European Alliance of Associations for Rheumatology (EULAR)/ACR criteria ( table 2A ). (See 'Definite SLE' above and 'Classification criteria' above.)

• Probable SLE – There are patients who do not fulfill the classification criteria for SLE but in whom we still diagnose the disorder. These patients include those presenting with an inadequate number of ACR or SLICC criteria or those who have other SLE manifestations not included in either classification criteria. (See 'Probable SLE' above.)

As a loose guide, we diagnose SLE in patients who have two or three of the ACR or SLICC criteria, along with at least one other feature that may be associated with but is not specific for SLE. Some of these features include:

- Optic neuritis, aseptic meningitis

- Glomerular hematuria

- Pneumonitis, pulmonary hemorrhage, or pulmonary hypertension, interstitial lung disease

- Myocarditis, verrucous endocarditis (Libman-Sacks endocarditis)

- Abdominal vasculitis

- Raynaud phenomenon

- Elevated acute phase reactants (eg, ESR and CRP)

• Possible SLE – We consider SLE a possible diagnosis in individuals who have only one of the ACR/SLICC criteria, in addition to at least one or two of the uncommon features listed above. (See 'Possible SLE' above.)

• Undifferentiated connective tissue disease – Other patients who have even fewer features suggestive of SLE may be classified as undifferentiated connective tissue disease (UCTD). (See 'Undifferentiated connective tissue disease' above.)

• ANA-negative SLE – Less than 5 percent of patients with SLE are negative for ANA as detected by indirect immunofluorescence. (See 'ANA-negative lupus' above.)

ACKNOWLEDGMENT  —  The UpToDate editorial staff acknowledges Peter Schur, MD, who contributed to an earlier version of this topic review.

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• Published: 23 June 2023

Environmental risk factors of systemic lupus erythematosus: a case–control study

• Rania H. Refai   ORCID: orcid.org/0000-0002-9524-1346 1 ,
• Mohammed F. Hussein   ORCID: orcid.org/0000-0003-3775-6226 2 ,
• Mamdouh H. Abdou 2 &
• Anna N. Abou-Raya 3  

Scientific Reports volume  13 , Article number:  10219 ( 2023 ) Cite this article

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• Rheumatology
• Risk factors

Systemic lupus erythematosus (SLE) is a complicated chronic autoimmune disorder. Several genetic and environmental factors were suggested to be implicated in its pathogenesis. The main objective of this study was to examine how exposure to selected environmental factors was associated with SLE risk to support the development of disease preventive strategies. A case–control study was conducted at the Rheumatology outpatient clinic of Alexandria Main University Hospital, in Alexandria, Egypt. The study sample consisted of 29 female SLE patients, and 27 healthy female controls, who matched the cases on age and parity. Data were collected by a structured interviewing questionnaire. Blood levels of lead, cadmium, and zinc of all participants were assessed by flame atomic absorption spectrometry. The multivariate stepwise logistic regression model revealed that five factors showed significant association with SLE, namely living near agricultural areas, passive smoking, blood lead levels ≥ 0.075 mg/L, and exposure to sunlight (odds ratio (OR) 58.556, 95% confidence interval (CI) 1.897–1807.759, OR 24.116, 95% CI 1.763–329.799, OR 18.981, 95% CI 1.228–293.364, OR 9.549, 95% CI 1.299–70.224, respectively). Whereas walking or doing exercise were significantly protective factors (P = 0.006). The findings of this study add to the evidence that SLE can be environmentally induced. Preventive measures should be taken to address the environmental risk factors of SLE.

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Introduction

Systemic lupus erythematosus (SLE) is a chronic rheumatic autoimmune disorder that could be manifested by many symptoms. It is a multi-system disease that may involve nearly any organ resulting in serious organ complications and even death 1 , 2 . It predominantly affects women in the child-bearing ages 3 . SLE was suggested to be a condition of multifactorial etiology; including genetics, hormones, and environmental exposures.

It is currently known that different environmental factors could trigger SLE onset and flares in genetically susceptible individuals 4 , 5 . Owing to the increasing prevalence and overall SLE burden, efforts have been made to recognize these genetic and non-genetic factors 6 .

The role of the environment was more prominent by the fact that SLE concordance among identical monozygotic twins is below 25% 7 . In addition, the contribution of environmental factors to SLE risk has been evaluated to constitute 56% 8 .

Smoking, silica dust, UV radiation, infections, stress, air pollution, pesticides, and heavy metals are the major environmental risk factors having some evidence for association with SLE 9 .

In recent years, heavy metal pollution has become a significant health issue; continuous exposure to low levels of these toxic trace elements may result in bioaccumulation and produce a wide variety of biological effects on human beings 10 .

Lead and cadmium are known to pose serious risks to human health. Toxicity of these agents is evidenced by being identified in the top 10 environmental hazards by the Agency for Toxic Substances and Disease Registry 11 .

Environmental sources of lead include inhalation of airborne dusts containing lead and ingestion through food or water contaminated by lead. Old deteriorating household paints, and lead use in some traditional medicines and cosmetics can also be a source of lead exposure 12 . In addition, active and passive smoking were found to be associated with increased blood lead levels 13 .

Cadmium is present in cigarette smoke, air, food, and water. It can enter human bodies through inhalation, ingestion and dermal contact 14 .

Experimental studies of lead and cadmium exposure in rodent models proposed that metals may play a causative role in SLE 15 , 16 . There is relatively little data pertaining to lead or cadmium exposure with the risk of SLE in humans; exposure to stained or leaded glass as a hobby was found to be more common among SLE cases than controls 17 .

Trace elements such as zinc play a crucial role in growth and development of all organisms. Zinc is the second most abundant trace metal in the human body after iron, but zinc cannot be stored and has to be taken up daily via food to guarantee sufficient supply. However, it was stated that zinc excess as well as zinc deficiency may result in severe disturbances in immune cell numbers and activities leading to immune dysfunction 18 .

A study by Sahebari et al. 19 found that serum Zn values were lower in SLE patients than healthy age and sex-matched controls. On the other hand, zinc-deficient diets retarded autoantibody production and enhanced survival in mice 20 . In their review, Constantin et al. 21 advised to restrict consumption of some minerals such as zinc and sodium.

As the data about the relation between environmental risk factors and SLE in Egypt are lacking and the incidence is increasing, the present study was proposed to determine the association between some environmental exposures with SLE risk; in order to assess the extent to which SLE is environmentally induced.

Estimation of SLE risk in relation to some socio-demographic characteristics

Analysis of data regarding the socio-demographic characteristics revealed that patients and controls were similar in terms of demographic background, no statistical significant difference between cases and controls except for the education level, the occupation, and the residence near agricultural areas (Tables 1 , 2 ).

Regarding the educational level, there was a statistically significant difference between cases and controls (P < 0.05). The percentage of illiterate cases was (31%) and constituted more than double their percentage in the control group (14.8%). Also, the percentage of cases with higher education was only (3.4%), which is very low compared to controls (14.8%). The findings showed that females with SLE who were in the primary or preparatory educational level were significantly more likely to be at risk of SLE (OR 14.67, 95% CI 1.16–185.23) compared to controls.

With regard to occupation, there was a statistically significant difference between cases and controls (P < 0.05), the majority of cases were housewives (86.2%) compared to (33.3%) in the controls group.

Estimation of SLE risk in relation to some lifestyle factors

Lack of physical activity, exposure to domestic animals, or to sun light showed significant results (Table 3 ). As regards walking and physical activity, a high proportion of SLE patients (89.7%) do not like to walk or perform any physical activity compared to (40.7%) in the control group.

Sedentary lifestyle increased SLE risk by 12.61 folds (OR 12.61, 95% CI 3.05–52.17). Dealing with domestic animals was another risk factor that was tested in the current study; the results showed that 58.6% of cases were exposed to animals more than controls (29.6%). This may be because 48.3% of cases live in rural areas compared to 7.4% of controls. There was a statistically significant increase in SLE risk when dealing with farm animals (sheep, chicken) (OR 3.36, 95% CI 1.11–10.19).

Results about UV radiation exposure and SLE risk showed a statistically significant increase of SLE risk (OR 13.714, 95% CI 3.768–49.920).

Estimation of SLE risk in relation to some indoor environmental risk factors

The risk values for the association between some indoor environmental exposures and SLE were statistically not significant except for the type of drinking water, the filled tube cooker as the fuel used at home, and passive smoking (Table 4 ); 62.1% of SLE patients use tap water for drinking compared to 22.2% of controls, meanwhile, the majority of controls (74.1%) use filtered water compared to 37.9% of cases. The use of filtered water for drinking was assumed to have protective effects against SLE.

A statistically significant difference (X 2  = 16.021, P = 0.001) between cases and controls with regard to fuel used at home, where 79.3% of cases reported the use of gas cylinders compared to 25.9% of controls. The use of gas cylinders constituted 10.95 times more risk to SLE than the use of natural gas pipes (OR 10.95, 95% CI 3.16–38.01).

Regarding passive smoking at home, which was assessed by the number of active smokers who were residing in the same house, (62.1%) of cases were exposed to Environmental Tobacco Smoke (ETS) versus (29.6%) of controls, there was a statistically significant difference between cases and controls with regard to exposure to ETS (OR 3.886, 95% CI 1.273–11.861).

Moreover, SLE risk increased with the increase in the number of cigarettes smoked per day (the risk was 2.96 and 10.36 times for light and heavy passive smoking (OR 2.96, 95% CI 0.9–9.75; OR 10.36, 95% CI 1.1–97.69 respectively). A significant trend for risk was noticed with increased passive smoking (X 2 for trend = 5.87, P = 0.015) concluding that ETS may be an important risk factor for SLE.

Estimation of SLE risk in relation to a family history of any auto-immune disease

The study found a statistically significant difference between cases and controls regarding the family history of any auto immune disease as illustrated in (Table 5 ), 33.3% of controls had surprisingly a family history of an auto immune disease including SLE compared to 3.4% of cases.

Estimation of SLE risk in relation to hormonal factors

The findings of the present study showed the prevalence of menstrual disorders and hormonal disturbances among SLE patients as demonstrated in Table 5 . Early menopause was present in (31%) of SLE patients compared to (0%) of controls, irregular menstrual cycle was prevalent in (40%) of SLE patients compared to (8%) of controls, (37.9%) of cases used hormonal therapy compared to (11.1%) of controls, and (31%) of cases had problems in uterus versus (7.4%) of controls.

There was a statistically significant increase in SLE risk with early menopause, menstrual irregularities, use of hormonal therapy, and presence of problems in uterus (OR 31.26, 95% CI 1.7–575.54; OR 7.67, 95% CI 1.3–45.29; OR 4.889, 95% CI 1.19–20.13; OR 5.625, 95% CI 1.09–29.03 respectively).

Estimation of SLE risk in relation to blood levels of lead, cadmium and zinc

As shown in (Table 6 ), the range of values of blood lead levels (Pb) in the cases group was very extensive from minimum 0.0237 mg/L to maximum 0.6951 mg/L and it is higher than the range of values in the controls group. The median concentration of blood lead in the cases group (0.115 ± 0.165) was significantly higher than in the controls group (0.067 ± 0.077). There were significantly higher blood lead levels in the cases group compared to the controls group (U = 210, P = 0.003).

After categorization of the levels of blood lead in the sample, the SLE risk associated with blood lead levels ≥ 0.09 mg/L was higher and statistically significant (OR 7.71, 95% CI 1.85–32.21) in comparison with subjects having blood lead levels < 0.05 mg/L. A statistically significant trend was computed (Chi-square trend for odds =  7.77, P value = 0.005) showing that the more the increase in blood lead level, the more the chance of SLE occurrence.

The median levels of blood cadmium (Cd) in cases group (0.059 ± 0.102 mg/L) were significantly higher than in the controls group (0.017 ± 0.042 mg/L) as U = 216, P = 0.004.

As presented in (Table 6 ), the level of blood cadmium in the sample was categorized into groups, females having blood cadmium levels from 0.03 to less than 0.07 and ≥ 0.07 mg/L blood had 6.68 and 4.45 times more risk to develop SLE in comparison with females having blood cadmium levels < 0.03 mg/L blood and the risks for these upper two categories were statistically significant (95% CI 1.58–28.29; 1.18–16.8 respectively). The observed increased trend was found to be statistically significant (X 2 trend for odds = 4.98, P = 0.026).

Regarding blood zinc levels (Zn), the median concentration of zinc in the controls group (2.275 ± 0.707 mg/L blood) was lower than the median concentration of zinc in the cases group (2.660 ± 0.970 mg/L blood), but the median blood zinc values in the cases and controls groups did not differ significantly (U = 290.5, P > 0.05).

Pearson’s correlation coefficient was calculated to demonstrate the relationship between lead and cadmium blood levels with each other and yielded a result of r = 0.548, P = 0.002, portraying a positive, moderate, linear, and significant correlation between lead and cadmium blood levels for the cases group (Fig.  1 ), whereas a non-significant correlation was observed in the controls group (r = 0.123, P = 0.542).

Correlation between blood lead and cadmium levels for cases and controls (Rheumatology outpatient clinic, Alexandria University Hospital, Alexandria, 2020). Performed through SPSS version 21.

Analysis of risk factors affecting SLE risk by stepwise logistic regression

A multivariate stepwise logistic regression model was built in order to determine which of these predictors really contribute to predicting SLE risk, and exclude those who do not.

Negelkerke R Square suggests that the model explains 78.4% of the variance in the outcome. The accuracy of the model was 87.5%, depicting that the model can correctly classify 87.5% of the cases. The sensitivity and specificity of the model were calculated, and they were 86.2%, and 88.9%, respectively.

As illustrated in (Table 7 ), the final model revealed that only five factors showed significant association with SLE. The risk was highest for subjects living near agricultural areas with an OR of 58.556 (95% CI 1.897–1807.759), followed by subjects exposed to passive smoking with an OR of 24.116 (95% CI 1.763–329.799), then subjects having blood lead levels ≥ 0.075 mg/L who were 18.981 times (95% CI 1.228–293.364) more likely to have SLE than those having blood lead levels < 0.075 mg/L, followed by subjects exposed to the sunlight who were at increased risk of SLE by 9.549 (95% CI 1.299–70.224). Whereas walking or doing exercise were significantly protective against SLE (P = 0.006); the table demonstrated a negative B coefficient (− 5.246) which indicates that a decrease in the walking and exercise is associated with a greater likelihood of SLE risk.

The current study purpose was to gain insights into the etiology of SLE and some possible risk factors.

The statistically significant difference between cases and controls regarding the education level assumes that lower education level—which is an indicator of socioeconomic status—may constitute a risk for SLE. That is similar to other studies that showed the association between lower education level and SLE onset and flare 22 , 23 .

The distribution of the study sample according to the residence area revealed that 48.3% of cases reported living near agricultural areas compared to 7.4% of controls, with 11.67 times more SLE risk (OR 11.67, 95% CI 2.32–58.6) compared to those not living near these areas. This may be attributed to some environmental exposures such as exposure to sunlight and pesticides used in agriculture, in addition to lower socioeconomic status, lower educational level, and poverty. This finding is in accordance with Pons-Estel et al. (2012) who concluded that rural residence was associated with high levels of disease activity at diagnosis and with renal disease occurrence in a Latin American multi-ethnic cohort (OR 1.65, 95% CI 1.06–2.57; OR 1.77, 95% CI 1.00–3.11) 24 .

Our data showed an increase of SLE risk due to sedentary lifestyle which is in accordance with a cross sectional study that showed that a high proportion of SLE patients were physically inactive with a long daily sedentary time 25 .

The statistically significant increase in SLE risk when dealing with animals or birds was in the same line with a case control study in Southern Sweden that reported a statistically significant difference between cases and controls regarding close contact with sheep 26 . This was not in the same line with the results of a recent study which supported the idea that exposures related to childhood farm residence and livestock farming may decrease susceptibility to developing SLE and that contact with livestock may confer protection against SLE 27 .

Current study findings support the role of sun exposure as a trigger for SLE, adding evidence to experimental and human studies that have shown that it can trigger disease onset and induce disease flares in SLE patients 26 , 28 , 29 .

ETS as a risk factor for SLE was not enormously previously discussed except for a cross sectional study of Brazilian SLE patients that assessed the association between smoking and SLE and confirmed that never smokers confer a 22% relative SLE risk reduction compared to ever smokers (including second hand smokers) 30 .

In addition, data from a cohort of SLE patients and controls suggested that secondhand smoke during childhood may be a risk factor for SLE (OR 1.81, 95% CI 1.13–2.89) 31 . Whereas, a US prospective cohort study concluded that Early-life exposure to cigarette smoke due to mothers’ or fathers’ smoking did not increase the risk of adult-onset SLE (RR 0.9, 95% CI 0.6–1.4; RR 1.0, 95% CI 0.8–1.3 respectively) 32 .

Our data revealed that the highest proportion of the study patients (96.6%) had negative family history of SLE. This supports the great contribution of other risk factors rather than the genetic factors in the development of SLE; suggesting the influence of environmental triggers on disease expression 8 , 17 . This finding was in line with a study that reported that autoimmune diseases in family members have not been associated with SLE 33 . On the other hand, a previous case control study reported the prevalence of auto-immune disease in first degree relatives in cases more than controls (53% vs 39%) and stated that a family history of any auto-immune disease was associated with increased risk of SLE (OR 6.8, 95% CI 1.4–32) 26 . This finding is also in contrast with other previous studies that stated that family history of an auto immune disease in first degree relatives (parents or siblings) was associated with increased SLE risk 34 , 35 .

The results of the current study regarding SLE risk in relation to hormonal factors was in concordance with a cohort study that revealed that menstrual irregularity was associated with an increased SLE 36 . In the same line comes a cross sectional study of 61 SLE patients, in which 49.2% of the patients had menstrual irregularities, of which 60% had sustained amenorrhoea (premature menopause) compared to the control group (16.7%) 37 . Moreover, a cross sectional study (N = 87) showed menstrual alterations in 37.9% of SLE patients and amenorrhea in 11.5% of patients which was higher than the general population 38 . Additionally, an increased SLE risk was reported in the NHS (Nurses’ Health Study) with the use of estrogen replacement therapy 39 . Moreover, a population‐based nested case control study found that the current use of COCs (Combined Oral Contraceptives) was associated with an increased SLE risk (RR 1.54, 95% CI 1.15–2.07) 40 .

Other studies contradicted the findings of the current study and stated that the use of HRT (Hormone Replacement Therapy) in postmenopausal SLE women did not appear to increase the rate of lupus flares and appeared to be well tolerated and safe in postmenopausal SLE patients 41 , 42 .

Data from experimental studies suggested that heavy metals may enhance systemic autoimmunity or accelerate disease progression in experimental models of lupus and that co-exposure to certain heavy metals may increase the risk associated with other exposures 5 .

Detailed studies on SLE onset and flares with reference to lead, cadmium, and zinc are scanty. Therefore, the current study was conducted to evaluate the role of lead, cadmium, and zinc in SLE. All blood samples were found to have lead, cadmium, and zinc concentrations.

It was observed that the median blood lead levels in the cases group as well as the controls group in this study were higher than the CDC permissible range of less than 5 µg/dL of lead in children and adults (0.05 mg/L) and this is indicative of the extent of environmental lead pollution 43 . It was also noticed that the median blood cadmium levels for both cases and controls in this study were higher than the WHO permissible range of 0.03–0.12 µg/dL of Cd 44 . This suggests more protection measures to be taken into consideration in order to avoid the toxic effects of lead and cadmium.

It was observed that the median blood zinc levels were not consistent with reference ranges of zinc in blood (70–120 µg/dL) 45 , requiring further consideration of zinc levels to avoid overdose and toxicity.

In contrast to the current study is a recent similar case control study that reported that SLE diagnosis was associated with lower serum Zn (P = 0.003), and Pb (P = 0.020) 46 . Other studies reported similar results 47 , 48 . However, some studies did not observe a significant difference in serum Zn concentrations between SLE patients and healthy controls which is similar to the finding of the present study 49 , 50 .

A case control study reported a positive correlation between lead and cadmium blood levels for the exposed group (ρ = 0.39, P = 0.023) which was consistent with the finding of the current study, whereas blood zinc levels correlated negatively with both lead (ρ = − 0.41, P = 0.015) and cadmium blood levels (ρ = − 0.44, P = 0.009). In addition, no correlations between the studied metals were found in the control group and the study suggested that zinc insufficiency is more likely to occur in cases of combined exposure to cadmium and lead, because of competition between similar ions for receptors involved in absorption, transport, storage or function, and this would explain the negative correlation in the controls group between zinc blood levels with either lead and cadmium levels 51 .

Limitations of the study

The potential of case control studies for recall bias and misclassification error; as most exposure information were based on self-reported history so some inaccuracies can be expected. The design of the study also limited the ability to ascribe causal relationships to the associations detected and to control for all potential confounders.

Absence of genetic information for participants, so the potential effects of genetic heterogeneity on the association between risk factors and SLE risk could not be determined.

Human population is rarely exposed to a single agent over time, and there may be a significant delay between exposure and the onset of the disease.

The small sample size may make it difficult to determine if a particular outcome is a true finding and in some cases no difference between the study groups is reported.

Conclusion and recommendations

To date, our knowledge about the etiology of SLE is still unclear and limited; genetic and environmental interactions were suggested.

From the present case control study, it is concluded that the risk portion attributed to unsafe and unhealthy environment was found to be quite significant, showing how the environment can play an important role in SLE occurrence.

Exposure to potential environmental risk factors specifically heavy metals should not be under-estimated. Hence, there is an urgent need for interventions to reduce environmental risk factors exposure in order to achieve substantial public health gains.

Increasing the awareness of patients about the environmental pollutants and the ways to protect their health is necessary. As well as the awareness of health care providers about environmental risk factors, so they can advise the patients about the ways of reduction of exposure to environmental hazards. Educational awareness programs to patients and their family should be carried out through media and non-governmental organizations (NGOs) to raise their knowledge about environmental hazards and how to minimize the sources of their exposure and their consequent negative impacts.

Additional experimental and epidemiological studies are required to determine the causative role of several environmental exposures, to confirm data from case control studies.

This case control study was conducted at the Rheumatology outpatient clinic of Alexandria Main University Hospital. The Inclusion criteria were female patients diagnosed with idiopathic SLE according to SLICC criteria 52 . The controls included healthy females who accompanied the SLE patients who came from remote rural areas in their visit to the Rheumatology outpatient clinic. The cases and controls were matched for age and parity.

Exclusion criteria included (1) male SLE patients “they were excluded mainly to avoid gender bias that may affect the results due to the hormonal effect. Besides, the disease affects mainly females”; (2) drug-induced Lupus; (3) overlap syndrome as lupus and rheumatoid arthritis; (4) any other rheumatic diseases; (5) coexisting morbidity not related to SLE, e.g. diabetes, hypertension; (6) cancer; (7) dementia or psychosis; (8) intake of nutritional supplements in the 6 months prior to the blood collection.

Sample size

Based on a previous case control study, the mean of serum Zinc among systemic lupus erythematosus (SLE) was 700.61 ± 135.91 and among controls was 860.45 ± 123.74, using an alpha error of 0.05 and power 98% 48 . The minimum required sample size was estimated to be 46 adults, 23 for each group, which was increased to 56 adults, 29 cases and 27 controls. The sample size was calculated using G. Power software.

Data collection methods and tools

A pre-designed pre-coded structured interviewing questionnaire was used to collect data from all participants (cases and controls). It included personal and socio-demographic data, data about occupation, lifestyle factors, the medical history, the smoking history including exposure to passive smoking, and some possible indoor environmental risk factors aiming to ascertain exposure to some environmental risk factors suspected to affect SLE risk. Regarding the evaluation of poor water quality, the participants were asked about the availability and quality of drinking water, any problems concerning drinking water (clarity, taste, smell), the type of drinking water pipes (with or without lead) by asking them whether they are old or newly installed, and the drinking water source (filtered, bottled, or tap water). Whereas for sun exposure, they were asked about the daily exposure to the sun, duration of exposure, wearing of protective clothes, and use of sunscreen, as well as whether there is an occupational sun exposure. Concerning the evaluation of sedentary lifestyle, they were questioned whether they perform any physical activity and the duration per week, whether they prefer walking or taking the car, and the duration of watching TV.

Questions of the questionnaire were taken from similar previously validated Arabic and English research questionnaires 26 , 53 . In addition, it was assessed by an expert at the faculty of medicine, Alexandria University. The English version of the questionnaire underwent a forward and back translation by native speakers whom are experts in public health.

Laboratory investigation

A blood sample (5 mL) was drawn from each participant to measure blood levels of lead, cadmium, and zinc. The samples were transferred into heparinized collection tubes. Cadmium, lead, and zinc were extracted from the blood samples using the conventional wet acid digestion method using concentrated nitric acid (HNO 3 ). A blank using deionized water instead of blood was done for each batch of analysis for comparison 44 , 54 . The digested samples were filtered and were subjected to elemental analysis using flame atomic absorption spectrophotometer (Shimadzu model AA-6650) at the central laboratory of the High Institute of Public Health (HIPH), Alexandria University.

Statistical design

SPSS version 21 was used for data entry and analysis. Qualitative variables were described through number and percentages of cases. For quantitative continuous variables, tests of normality were done. Mean and standard deviation (mean ± SD) were calculated if the variable follows normal distribution, and median and interquartile range (median ± IQR) if it does not follow normal distribution. “Pearson’s Chi-square test (X 2 )” was used to calculate significant differences between cases and controls for the categorical data. If the assumptions were violated, “Fisher’s exact test” (if 2*2 table) or “Monte Carlo test” (if m*n table) were used.

Differences between the means of the two groups were examined using independent t test for the continuous, normally distributed variables. The Mann–Whitney–Wilcoxon non-parametric test (U), for the continuous, non-normally distributed variables. Odds ratio (OR) was calculated to measure SLE risk. Increasing trends in SLE risk concerning some risk factors were tested using “Chi-square for trend”. Pearson’s correlation coefficient was used to test the association between quantitative variables.

A multivariate stepwise logistic regression analysis was used to see if there were significant associations between specific exposures and SLE and to adjust for some potential confounders. Negelkerke R 2 was calculated to tell the amount of variation in SLE risk which is explained by the model.

Ethical approval

Approval of the Ethics Committee of the High Institute of Public Health for conducting the research was obtained. Approval for conducting the study at the Rheumatology Outpatient Clinic of Alexandria Main University Hospital was obtained from the hospital outpatient clinics director after a formal written request for that. The study was performed in accordance with the ethical standards in the Declaration of Helsinki. A written informed consent was taken from all study participants after explanation of the purpose and benefits of the research. Anonymity and confidentiality were ensured. All methods were performed in accordance with the relevant guidelines and regulations.

Data availability

The datasets used and/or analyzed during the current study are not publicly due to privacy and ethical concerns but are available from the corresponding author on reasonable request.

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Rania H. Refai

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Conceptualization and design of the work: R.R., M.H., M.A., and A.A.; methodology: R.R., M.H., and M.A.; selection of cases and controls: A.A.; data analysis: R.R., and M.H.; data curation: R.R., and M.H.; writing—original draft preparation, R.R.; writing—review and editing: R.R., M.H., M.A., and A.A.; visualization: R.R. All authors read and approved the final submitted revised manuscript and agreed both to be personally accountable for the author's own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature.

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Refai, R.H., Hussein, M.F., Abdou, M.H. et al. Environmental risk factors of systemic lupus erythematosus: a case–control study. Sci Rep 13 , 10219 (2023). https://doi.org/10.1038/s41598-023-36901-y

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Lupus and the Liver: A Case Study

Affiliations.

• 1 Miscellaneous, Nova Southeastern University Dr. Kiran C. Patel College of Osteopathic Medicine, Fort Lauderdale, USA.
• 2 Immunology, Nova Southeastern University Dr. Kiran C. Patel College of Osteopathic Medicine, Fort Lauderdale, USA.
• 3 Rheumatology, Nova Southeastern University Dr. Kiran C. Patel College of Osteopathic Medicine, Fort Lauderdale, USA.
• PMID: 31646136
• PMCID: PMC6805037
• DOI: 10.7759/cureus.5477

Systemic lupus erythematosus (SLE) is an autoimmune disorder with a wide range of systemic manifestations. Though skin, renal, joint, and hematologic involvement are often associated with SLE, hepatitis is not a common manifestation. While clinically significant hepatopathy in SLE is rare, asymptomatic hypertransaminasemia has been seen in up to 60 percent of SLE patients during the course of their disease and is generally attributed to viral hepatitis, hepatotoxic drugs, or alcohol use. A diagnosis of lupus hepatitis is largely considered a diagnosis of exclusion. There has been a correlation between the presence of ribosomal P autoantibodies with the incidence of lupus hepatitis. Generally, lupus hepatitis responds well to therapy with prednisone, although cases refractory to corticosteroids and conventional immunosuppressants have been described. In these cases, treatment with mycophenolate mofetil has been shown to be effective. Here, we present the case of a 15-year old female who presented with a new diagnosis of SLE with an incidental elevation of her liver function tests (LFTs) and a subsequent finding of hepatomegaly with fatty infiltration.

Keywords: lupus; lupus hepatitis; systemic lupus erythematosus (sle).

Copyright © 2019, Patel et al.

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• Case Reports

• Case Report
• Open access
• Published: 15 April 2024

Systemic lupus erythematosus combined with Wilson’s disease: a case report and literature review

• Zhenle Yang 1 , 2   na1 ,
• Qian Li 1 , 2   na1 ,
• Suwen Liu 1 , 2 ,
• Zihan Zong 1 , 2 ,
• Lichun Yu 1 , 2 &
• Shuzhen Sun 1 , 2  

BMC Pediatrics volume  24 , Article number:  253 ( 2024 ) Cite this article

Metrics details

Systemic lupus erythematosus (SLE) and Wilson’s disease (WD) are both systemic diseases that can affect multiple organs in the body. The coexistence of SLE and WD is rarely encountered in clinical practice, making it challenging to diagnose.

Case report

We present the case of a 9-year-old girl who initially presented with proteinuria, haematuria, pancytopenia, hypocomplementemia, and positivity for multiple autoantibodies. She was diagnosed with SLE, and her blood biochemistry showed elevated liver enzymes at the time of diagnosis. Despite effective control of her symptoms, her liver enzymes remained elevated during regular follow-up. Laboratory tests revealed decreased serum copper and ceruloplasmin levels, along with elevated urinary copper. Liver biopsy revealed chronic active hepatitis, moderate inflammation, moderate-severe fibrosis, and a trend towards local cirrhosis. Genetic sequencing revealed compound heterozygous mutations in the ATP7B gene, confirming the diagnosis of SLE with WD. The girl received treatment with a high-zinc/low-copper diet, but her liver function did not improve. Upon recommendation following multidisciplinary consultation, she underwent liver transplantation. Unfortunately, she passed away on the fourth day after the surgery.

Conclusions

SLE and WD are diseases that involve multiple systems and organs in the body, and SLE complicated with WD is rarely encountered in the clinic; therefore, it is easy to misdiagnose. Because penicillamine can induce lupus, it is not recommended. Liver transplantation is indicated for patients with liver disease who do not respond to medical treatment with WD. However, further research is needed to determine the optimal timing of liver transplantation for patients with SLE complicated with WD.

Peer Review reports

Wilson’s disease (WD) is a rare autosomal-recessive disorder characterized by defective biliary excretion of copper, with a reported prevalence of 1:30,000–50,000 [ 1 ]. This defect leads to the progressive accumulation of copper in various organs and tissues, particularly the liver, corneas, kidneys, heart, and nervous system. Systemic lupus erythematosus (SLE), a multisystem autoimmune inflammatory disease, can affect any organ in the body. However, there is limited literature focusing on the coexistence of WD and SLE. In this case report, we report the occurrence of SLE and WD in a 9-year-old girl to improve the understanding of the coexistence of these two conditions.

In October 2019, a 9-year-old girl presented to our centre with a complaint of red-coloured urine lasting for 1 week. She had no accompanying symptoms, such as rash, jaundice, oliguria, joint swelling, fever, or neurological symptoms, or a significant family history. Urinalysis revealed the presence of more than 80% dysmorphic red blood cells along with proteinuria but no crystalluria or bacterial growth. Her total leucocyte count was 2.02 × 10^9/L, her haemoglobin level was 10.5 g/dl, her platelet count was 105 × 10^9/L (within the range of 150–300), her aspartate aminotransferase (AST) level was 116 U/L (normal range: 10–40), her alanine aminotransferase (ALT) level was 145 U/L (normal range: 10–40), her serum alkaline phosphatase level was 334 U/L (normal range: 140–560), her blood urea level was 5.2 mmol/L (normal range: 2.8–7.4), her serum creatinine level was 48.0 µmol/L (normal range: 40–80), her serum albumin level was 25.7 g/L (normal range: 40–55), her cholesterol level was 3.02 mmol/L (normal range: 3.6–6.2), her serum bilirubin level was 4.98 µµmol/L (normal range: 3.5–23.5), and her complement C3 level was 0.2 g/L (normal range: 0.8–1.8). Anti-nuclear antibody (ANA) and anti-double-stranded DNA antibody (anti-dsDNA) tests were positive. Abdominal ultrasound revealed no abnormalities. A kidney biopsy was performed to determine the renal pathology. We detected IgA(+), IgG(+), C3(+), F+(−), IgM(++), and C1q(++) by immunofluorescence. Under light microscopy, we detected two cases of focal segmental sclerosis with balloon adhesions and one case of cell-fibrous neoplasm formation in 26 glomeruli. Diffuse light-moderate proliferation was present in the mesangial zone. There was no thickening of the glomerular basement membrane (GBM). Podocyte swelling, swelling of epithelial cells and focal fibrosis of the renal interstitium were observed. The patient was diagnosed with SLE and lupus nephritis (LN). She was regularly followed up at the outpatient department, and her symptoms were effectively controlled with methylprednisolone, hydroxychloroquine (HCQ), and mycophenolate mofetil (MMF), except for her persistently elevated liver enzymes.

During her routine annual health checkup conducted in February 2022, her serum biochemistry still showed abnormalities in hepatic function: AST, 105 U/L; ALT, 61 U/L; and GGT, 138 U/L. However, the results of urine analysis, complete blood count, renal function tests, multiple autoantibody tests, and complement component analysis were within normal limits. The cause of the abnormal hepatic function remained unexplained, as her SLE Disease Activity Index (SLEDAI) score was 0. She exhibited no signs of abdominal distension, anorexia, or yellow staining of the skin or mucous membranes. She denied using any medications or substances that could have detrimental effects on the liver, and she had no history of infectious disease or neurological disturbances. Physical examination revealed no abnormalities in the abdomen or nervous system. Additionally, the patient tested negative for a range of autoimmune liver disease antibodies, hepatitis viruses, Epstein‒Barr virus, cytomegalovirus, and tumour markers during the follow-up. To investigate whether abnormal hepatic function was induced by medication, we advised her parents to discontinue the use of HCQ and MMF. However, the total leucocyte count decreased to 2.06 × 109/L, the complement C3 level decreased to 0.63 g/L, and the anti-dsDNA antibody level increased to 178.61 IU/ml (0-100), owing to which MMF and HCQ were discontinued after three weeks. Serum biochemistry still revealed elevated liver enzymes: AST level: 144 U/L; ALT level: 105 U/L; and GGT level: 159 U/L. Serum ceruloplasmin and tumour marker tests were also conducted. Interestingly, there was a significant decrease in serum ceruloplasmin (< 9.5 mg/dl; normal range 20–60 mg/dl), but there were no Kayser–Fleischer (K-F) rings in either eye. Therefore, serum copper and urinary copper were measured, and laboratory tests revealed that the serum copper level decreased (1.45 µmol/L; normal range 12.6–23.6 µmol/L), while the urinary copper level increased (213 µg/24 h; normal range 15–30 µg/24 h). MRI was performed to evaluate the patient’s liver. Liver MRI revealed that the liver was plump, and multiple nodules with long T1 and short T2 abnormal signals were observed in the liver parenchyma. Liver biopsy and gene sequencing were subsequently conducted. Liver biopsy sample analysis demonstrated a trend towards chronic active hepatitis, moderate inflammation, moderate-severe fibrosis, and local cirrhosis (Fig.  1 ). The liver was negative for copper content. Sequencing (Fig.  2 ) revealed that the patient (proband) had compound heterozygous mutations in ATP7B. The maternally inherited mutation (c.2333(exon8)G > T, p.R788L) was previously reported to be pathogenic, and the paternally inherited mutation (c.1817(exon5)T > G, p.V606G) was likely pathogenic according to the American College of Medical Genetics (ACMG) guidelines (2019). Consequently, a final diagnosis of SLE with WD was made. Due to the potential induction of lupus by penicillamine use, the patient was treated with a high-zinc/low-copper diet, and the amount of methylprednisolone was increased because of the reactivation of her SLE. The total leucocyte count decreased to 6.73 × 109/L, the complement C3 level increased to 0.85 g/L, and the anti-dsDNA antibody level decreased to 145.32 IU/ml (0-100); unfortunately, her liver function did not improve. Upon recommendation following multidisciplinary consultation, the patient underwent liver transplantation; however, she tragically passed away on the fourth day after surgery despite having a good clinical situation before surgery.

Liver biopsy sample from the patient. a and b: Inflammation and interface hepatitis in the portal area, hepatocyte steatosis, and bridging fibrosis. c, d, and e: Hepatocyte swelling, lipid droplets of varying sizes within some hepatocytes, the presence of cholesterol crystals, and dense collagen fibre deposition in the portal area accompanied by lymphocyte and plasma cell infiltration

Sequence analysis of ATP7B in the family. The patient had compound heterozygous mutations in ATP7B: the maternally inherited mutation was c.2333(exon8)G > T, p.R788L, while the paternally inherited mutation was c.1817(exon5)T > G, p.V606G

SLE is a chronic, systemic autoimmune disease that primarily affects young women. SLE is characterized by a complex and heterogeneous clinical presentation, with the potential to involve multiple organs and tissues throughout the body. The liver is an important target organ in SLE. Reports indicate that 25-50% of SLE patients may experience liver abnormalities during the course of the disease [ 1 ]. Although the role of SLE in the development of asymptomatic liver disease is still debated, many experts recognize that SLE often leads to subclinical liver dysfunction, known as lupus hepatitis [ 2 ]. Lupus hepatitis is a nonspecific reactive liver disease primarily caused by complement deposition and vasculitis-induced organic damage in the liver [ 3 , 4 ]. Lupus hepatitis is frequently associated with SLE flares or clinical activity, and it can be diagnosed only by ruling out secondary causes of liver involvement [ 2 ]. In the reported case, the patient was diagnosed with SLE and presented with asymptomatic elevation of liver enzymes. We ruled out drug-induced liver injury, fatty liver disease, autoimmune liver disease, and viral hepatitis, suggesting that the asymptomatic increase in liver enzymes was likely due to SLE itself. However, despite active treatment for SLE and improvements in other symptoms, the asymptomatic increase in liver enzymes persisted for more than 2 years, which prompted us to actively search for the underlying cause.

Previous studies have indicated that drug-induced liver injury is a major cause of abnormal liver function in SLE patients, with an occurrence rate of approximately 31% in SLE patients with liver dysfunction [ 5 ]. SLE patients are prone to drug-induced liver injury due to their high levels of oxidative stress [ 6 ]. Nonsteroidal anti-inflammatory drugs (NSAIDs), azathioprine, and methotrexate are the most common drugs associated with liver injury, followed by cyclophosphamide and leflunomide. HCQ, MMF, cyclosporine, tacrolimus, and corticosteroids rarely cause liver injury. In most cases, drug-induced liver dysfunction is mild and transient, and liver function can usually recover with a dose reduction or discontinuation of the medication [ 7 , 8 ]. Although HCQ and MMF rarely cause liver damage, we recommended discontinuing these medications to prevent drug-induced liver injury. However, after the discontinuation of these medications, the patient’s liver function did not improve. Instead, the SLE itself became active.

Autoimmune hepatitis (AIH) is a chronic liver disease of unknown aetiology characterized by a T-cell-mediated immune response against liver self-antigens, leading to hepatocyte necrosis and inflammation. Diagnosis is based on elevated serum transaminases, increased levels of IgG, the presence of autoantibodies (ANA, anti-smooth muscle antibodies, and anti-liver-kidney microsome type 1 antibodies), and histological findings in liver biopsy samples, such as interface hepatitis and lymphoplasmacytic infiltrates [ 9 ]. The occurrence rate of AIH in SLE patients with liver dysfunction is approximately 5-10% [ 10 , 11 ]. In the patient whose case is reported here, AIH-related antibodies were negative, but the liver biopsy sample showed pathological features similar to those of AIH, although they were nonspecific.

SLE patients receiving immunosuppressive therapy are more susceptible to viral infections, which can result in liver dysfunction [ 10 ]. The patient was screened for hepatitis B virus, hepatitis C virus, Epstein‒Barr virus, herpes simplex virus, varicella-zoster virus, and human immunodeficiency virus, and the results of all these tests were negative.

WD is a rare autosomal recessive disorder characterized by copper metabolism dysfunction due to mutations in the ATP7B gene. The resulting copper toxicity primarily affects the liver and brain [ 12 ]. WD is classified into different types based on symptoms, including hepatic, neurological, mixed, and other types. In adolescents, the hepatic type has a greater occurrence rate than the other types. The liver manifestations in WD patients can vary, ranging from asymptomatic elevation of liver enzymes to significant liver cirrhosis (compensated or decompensated) or acute liver failure. Reports indicate that 18-23% of WD patients experience asymptomatic elevation of liver enzymes [ 13 ]. Similarly, the most common liver manifestation in SLE patients is asymptomatic elevation of liver enzymes, which was the main reason for the delayed diagnosis of our patient. However, in SLE patients who respond well to effective treatment, liver function abnormalities typically improve. Therefore, in SLE patients with well-controlled disease who present with unexplained elevation of liver enzymes, the possibility of WD should be considered.

K-F rings are a typical ophthalmic manifestation of WD. Reports indicate that K-F rings are present in nearly 100% of patients with neurological WD, 40-50% of patients with hepatic involvement, and 20-30% of asymptomatic patients [ 14 ]. In our patient, there were no K‒F rings in either eye. Therefore, the absence of K-F rings does not exclude the diagnosis of hepatic WD. Serum ceruloplasmin measurement is a safe and simple screening test for WD. However, importantly, serum ceruloplasmin can also be decreased in diseases such as Menkes disease, nephrotic syndrome, protein-losing enteropathy, and various chronic liver diseases. Additionally, in 5-15% of WD patients, ceruloplasmin levels may be normal or only slightly lower than the normal range [ 15 ]. In the patients with WD treated at our centre, decreased ceruloplasmin levels were detected at the time of diagnosis. However, the presence of LN in the patient who presented with nephrotic syndrome led us to consider that the decreased ceruloplasmin levels may be related to significant protein loss due to LN, which was also a factor contributing to the delayed diagnosis. The measurement of 24-hour urinary copper excretion may be the best screening test for WD, and a value exceeding 100 µg in a 24-hour urine collection has diagnostic value for WD [ 16 ]. Therefore, in patients suspected of having hepatolenticular degeneration, serum ceruloplasmin and 24-hour urinary copper excretion should be examined. Especially in patients with significant proteinuria and decreased ceruloplasmin levels where the cause of the decrease cannot be distinguished due to protein loss, further clarification can be achieved through 24-hour urinary copper excretion.

Autoimmune antibodies and autoimmune disorders have been reported in patients with WD. These include ANAs, antiphospholipid antibodies and, rarely, even anti-double-stranded DNA [ 17 , 18 ]. Antczak-Kowalska M et al. reported that the presence of all studied autoantibodies was greater in WD patients than in healthy individuals [ 19 ]. The role of autoantibodies in the pathogenesis of WD is unclear but may be related to a bystander phenomenon. Several autoimmune disorders have been reported in patients with WD, including SLE, myasthenia gravis and inflammatory bowel disease. Penicillamine use is associated with an increased risk of autoimmune diseases. In our study, the patient had no history of oral penicillamine use.

The treatment of WD includes drug therapy, symptomatic therapy, diet therapy, and liver transplantation. Penicillamine is commonly used as the first-line treatment for acute and/or symptomatic WD [ 12 ]. However, penicillamine is not recommended for patients with coexisting WD and SLE due to the potential for the induction of lupus. Because WD was not induced by penicillamine use in our patient, we reviewed other reports of WD with SLE not induced by penicillamine use and identified ten other patients in addition to our patient [ 17 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 ]. Among these patients, six received therapy with intravenous sodium dimercaptopropane sulfonate and/or oral zinc sulfate, which led to an improvement in WD symptoms [ 20 , 23 , 24 , 25 , 26 , 27 ]. In one patient, penicillamine was initially prescribed but was changed to oral zinc due to worsening central nervous system symptoms after two weeks; however, the patient unfortunately passed away 41 days after admission [ 17 ]. Plasma exchange was used to treat fulminant liver failure in another patient, but the patient died five days after admission [ 21 ]. One patient was treated with penicillamine for 5 years, and the treatment was changed to tetraethylene teramine dihydrochloride. Liver transplantation was performed due to liver fibrosis. The patient is currently free of SLE and has normal liver enzyme levels according to the report [ 28 ]. Our patient underwent liver transplantation three months after being diagnosed with WD because her liver enzymes remained abnormal despite receiving oral zinc. Liver transplantation is a curative option because it replaces the affected liver, provides normal ATP7B protein, restores normal biliary copper excretion (preventing disease recurrence), and facilitates the removal of copper from extrahepatic sites where it may be toxic [ 29 ]. Liver transplantation is indicated for patients with liver disease who do not respond to medical treatment, who have fulminant or advanced liver failure, and/or who have significant portal hypertension [ 30 ]. With advancements in liver transplantation technology, the clinical indications for WD patients receiving liver transplantation have expanded, leading to satisfactory outcomes. Studies in which large databases were analysed have reported one-year and five-year survival rates of approximately 90% in WD children who underwent liver transplantation [ 31 , 32 ]. There are very few cases of liver transplantation in patients with SLE.

described worldwide. Barthel et al. first reported the use of liver transplantation in three patients with SLE; two did very well, and one experienced hyperacute rejection [ 28 ]. Lian EC et al. and F Zazzetti et al. each reported a patient with SLE; both patients underwent transplantation because of liver failure, did not have SLE reactivation and had good long-term survival [ 33 , 34 ]. These reports show that patients with SLE are capable of undergoing liver transplantation without experiencing SLE reactivation and have good long-term survival. Our patient died four days after liver transplantation. More cases of liver transplantation in patients with SLE are necessary to determine the optimal timing of liver transplantation for patients with SLE, including patients who have SLE complicated by WD.

SLE and WD are both systemic diseases that can affect multiple organs in the body. The coexistence of SLE and WD is rarely encountered in clinical practice, which can lead to challenges in its diagnosis. Importantly, penicillamine, a commonly used treatment for WD, is not recommended for patients with coexisting SLE due to its potential to induce lupus. Liver transplantation is considered for patients with WD who do not respond to medical treatment. However, further research is needed to determine the optimal timing of liver transplantation for patients with SLE complicated by WD.

Data availability

Data is provided within the manuscript.

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Zhenle Yang and Qian Li contributed equally to this work.

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Department of Pediatric Nephrology and Rheumatism and Immunology, Cheeloo College of Medicine, Shandong Provincial Hospital, Shandong University, Jinan, 250021, P. R. China

Zhenle Yang, Qian Li, Suwen Liu, Zihan Zong, Lichun Yu & Shuzhen Sun

Department of Pediatric Nephrology and Rheumatism and Immunology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, P. R. China

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ZY and QL wrote the main manuscript text, SL, ZZ and LY collected data and prepared Figures 1-2, SS coordinated and supervised data collection, and critically reviewed the manuscript for important intellectual content. All the authors read and approved the final version of the manuscript.

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Yang, Z., Li, Q., Liu, S. et al. Systemic lupus erythematosus combined with Wilson’s disease: a case report and literature review. BMC Pediatr 24 , 253 (2024). https://doi.org/10.1186/s12887-024-04713-2

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Volume 42, Issue 10, October 2013

Systemic lupus erythmatosus When to consider and management options

The prevalence of SLE can vary greatly depending on race, disease definition and method of validation, but is generally accepted as a rare disease, affecting less than 0.1% of the population. 2–4 In Australia, SLE is more common and more severe in Indigenous Australians and descendants from South-East Asia. 5,6 It is nine times more common in females. 7 Generally speaking, SLE has a relapsing and remitting nature where patients experience episodes of symptom exacerbation interspersed with periods of relatively low disease activity.

Clinical presentation and diagnosis

While the clinical presentation of SLE can be quite diverse because the disease can affect virtually any organ system, patients typically present with symptoms relating to joint, skin or mucosal inflammation, or with a varying degree of haematological abnormality or constitutional features. 8 In some cases, patients may present with more serious and potentially life-threatening renal, neurological or cardiopulmonary complications. 9 Since the disease most commonly affects women of childbearing age, it is a diagnosis that should be considered when such a patient presents with symptoms relating to multiple systems.

Most SLE manifestations are the result of chronic inflammatory response at the affected end organ, which can be demonstrated using laboratory, imaging or histological measures. However, the lack of a gold standard test to confirm diagnosis often results in delays or misdiagnosis.

The Systemic Lupus Erythematosus International Collaborating Clinics (SLICC) group has recently proposed a revised classification criteria, 10 which hopes to replace the 1997 American College of Rheumatology criteria, 11 to improve on the sensitivity and specificity ( Table 1 ). These criteria are useful and give consistency in the classification of the disease, mainly for the purpose of research and surveillance. For clinicians, these criteria also serve as a good guide and reminder of the spectrum of disease, but, in clinical practice, many patients can present in a more forme fruste or atypical state.

Common clinical manifestations

Constitutional.

Constitutional manifestations such as malaise, fatigue, fever and weight loss affect most patients at some time during their disease. They are, however, non-specific, and other non-SLE or non-rheumatological conditions (eg. infection and malignancy) can present the same way. Fibromyalgia is commonly observed in patients with SLE, but is considered a non-inflammatory complication of the disease. More sinister constitutional symptoms such as fever and weight loss warrant investigation before being attributed to lupus.

Musculoskeletal

Up to 95% of patients with SLE have intermittent arthritis. 12 The most common presentation is a symmetrical polyarthritis, affecting hands, wrists and knees. The degree of swelling is less prominent than seen in rheumatoid arthritis. Tenosynovitis is a relatively common musculoskeletal manifestation. 13 Joint deformities are uncommon, as are erosive changes on X-rays. 14 Myalgia is also a common manifestation, even though true myositis is relatively rare.

Cutaneous manifestations

The spectrum of cutaneous manifestations of lupus erythematosus (LE) is broad, but the most classical forms associated with systemic LE are the acute malar and chronic discoid lupus erythematosus (DLE) rash. Both can be quite photosensitive in nature. 15,16

Acute malar rash is a slightly raised erythematous rash of the face, particularly cheeks and nose, with nasolabial sparing, known as the ‘butterfly’ rash. A worsening of the rash usually accompanies a flare of systemic disease. Sometimes a more generalised form over the body is present.

DLE are characterised by slightly raised, scaly lesions that have a potential to scar. They can be found commonly on the scalp and face, and less commonly over the limbs and trunk. Only 5% of people with DLE have SLE, but conversely among individuals with SLE, 20% will have DLE. 17

Subacute cutaneous lupus erythematosus is another lupus-specific rash. It is a common skin manifestation in drug-induced lupus. The rash is extremely photosensitive. The two main variants look as their names suggest: papulosquamous looks psoriasiform, and annular polycyclic gives a characteristic ring pattern.

Other cutaneous manifestations such as alopecia, oral ulcers, Raynaud’s phenomenon, urticaria, lichen planus, vasculitis or nail fold infarcts are LE non-specific, but they often present at times when patients experience increased lupus disease activity.

Renal manifestations

Lupus nephritis (LN) is one of the more serious manifestations, and contributes significantly to mortality. It occurs in 30–50% of SLE patients during their disease course. 18,19 It is important to recognise that LN can be relatively ‘silent’, and symptoms are often driven by other organ involvement or non-specific constitutional symptoms. Renal involvement can be missed if urinalysis is not performed. Definitive diagnosis and information on prognosis can be obtained by renal biopsy, but presence of glomerular haematuria, proteinuria or casts, are the key features of LN.

Haematologic manifestations

The most frequent haematological manifestation of SLE is anaemia. 20 This is usually due to chronic inflammation, but sometimes an autoimmune haemolytic anaemia can be demonstrated. Leukopenia, such as lymphopenia or less commonly neutropenia, is also well recognised, but it rarely predisposes to infections. Thrombocytopenia may also be a recurring feature.

Serosal manifestations

Pleural and pericardial inflammation can occur during active SLE. 21 They can present as pleuritic chest pain, when associated with pleurisy or pericarditis. Less commonly, the presence of pleural or pericardial effusion may present with pleuritic chest pain with or without exertional dyspnoea. This symptom adds robustness to the criteria for identifying SLE. Other cardiopulmonary manifestations such as interstitial lung disease, pulmonary hypertension or Libman–Sacks endocarditis are less common complications of the disease.

Common immunological manifestations

Antinuclear antibodies.

The antinuclear antibodies (ANA) test is the serological hallmark of SLE. Up to 98% of patients with SLE will have a positive ANA, 22 making it highly sensitive and useful as a screening test. A negative ANA makes SLE very unlikely and other diagnoses should be sought to explain symptoms.

Both titre and pattern are relevant. A titre of 320 or greater is considered clinically significant. 23 Low-titre ANA can be found in an otherwise healthy population ( Table 2 ). 24 The most common patterns observed in SLE are homogenous and speckled pattern while other patterns may be associated with other connective tissue disease. While the titre of ANA can fluctuate over time, it is not useful to repeat ANA testing unless there is still a question regarding the diagnosis. The finding of a positive ANA must be taken into context of the clinical manifestations. A positive ANA in the absence of the clinical features associated with connective tissue disease may be irrelevant. The test has generally poor specificity, and many autoimmune or non-autoimmune conditions can also be associated with a positive ANA ( Table 2 ).

Other autoantibodies

Antibodies to double-stranded DNA (dsDNA) are specific for SLE. In some patients, an increase in anti-dsDNA titre may signify onset of disease flare. 25 Other autoantibodies, available on the extractable nuclear antigen-testing panel, can also be associated with SLE or other connective tissue diseases. Antibodies to Sm (anti-Smith), for example, are highly specific autoantibodies in SLE.

While antiphospholipid antibodies are not specific for SLE, they are part of the immunological abnormalities that can be associated with pregnancy morbidities and thrombotic complications. Testing should include anticardiolipin antibodies, lupus anticoagulant and anti-β2 glycoprotein 1.

Complements

Tissue deposition of immune complexes can fix complement in the classical pathway, and therefore results in a reduction of serum complement levels. C3 and C4 can be measured readily, and are now part of the SLICC classification criteria for SLE. 10 Complement levels are also used to gauge disease activity. 26

Systemic lupus erythematosus is a chronic inflammatory condition driven by a dysfunctional immune system. Sometimes patients are able to report known triggers, such as ultraviolet or hormonal exposure. Avoidance of these triggers would be sensible in preventing flares.

The overall aim of therapy is to control disease activity. Mild activity can be managed with non-steroidal anti-inflammatory drugs (NSAIDs) or low-dose steroids, but more severe manifestations require prompt treatment with moderate-to-high doses of steroids to minimise organ damage. Steroid-sparing immunosuppressive medications should be considered early to prevent steroid-related morbidities.

Hydroxychloroquine is an effective treatment in SLE, especially for arthritis and rash. Furthermore, it has a protective effect in reducing damage accrual in the long term, and confers a survival benefit in SLE patients. Hydroxychloroquine is well tolerated and, when dosed appropriately, ocular toxicity is very rare. 27

A range of immunosuppressive medications has been used as a steroid-sparing agent in SLE, such as cyclophosphamide and mycophenolate for lupus nephritis, although azathioprine and methotrexate are used commonly. Belimumab, which is a human monoclonal antibody that inhibits the activation of B-cells by interfering with a protein necessary for B-cell activity, has recently been approved by the Australian Therapeutic Goods Administration for treatment of moderately severe SLE. 28 This therapy is currently not easily accessed, as it has not been listed on the Pharmaceutical Benefits Scheme.

Other general measures that should be considered in SLE patients include cardiovascular risk reduction and optimisation of bone protection. Patients with SLE are at significantly increased risk of premature atherosclerosis, 29 so smoking cessation and control of hypertension, dyslipidemia, obesity and hyperglycaemia are strongly recommended. Strategies to prevent osteoporosis should be considered in most patients because many are likely to require long-term glucocorticoid therapies.

Specialist referral to a rheumatologist is important to establish the diagnosis, to gauge disease activity and severity, and to guide disease management. However the role of the general practitioner (GP) is also imperative for the optimal management of this chronic disease. By better understanding the disease process and management, GPs can help patients comprehend the complexity of disease pathogenesis and priorities in treatment. GPs, working with the treating specialist, play a key part in the monitoring and management of the disease and associated co-morbidities. Furthermore, they are also well placed to offer patients ongoing support and counselling, especially for those who may find coping with a chronic disease difficult.

The case studies (see below) demonstrate the range and breadth of diagnostic challenges that can occur due to SLE.

Case study 1

A medical student, aged 24 years, presented with a 3-month history of fatigue and arthralgia. She has occasional mouth ulcers and alopecia. She has a photosensitive rash on her face. Investigation results:

• ANA 640 homogenous, positive anti-Ro, ESR 30, lymphopenia, low C3
• Normal urinary sediment and negative for protein.

She was diagnosed with SLE, and treated with NSAIDs as required and hydroxychloroquine.

Case study 2

A 35-year-old mother of two, presented with 6-month history of fatigue, lethargy and arthralgia. She has had intermittent episodes of chest pain with one presentation to emergency department without a specific cause found. She has now noticed increased swelling in her legs with puffy eyes. Investigation results:

• Urinary protein to creatinine ratio 0.38 (normal 0.02), MSU showed glomerular red cells, ESR 40, albumin 32
• ANA 1280 homogenous, positive anti-dsDNA and anti-Sm, low C3 and C4.

She was diagnosed with SLE, with renal biopsy showing Class IV lupus nephritis. She was treated with pulsed steroids and commenced on mycophenolate.

Case study 3

A sales executive, aged 48 years, presented with a prolonged episode of chest pain and was found to have acute coronary syndrome when she presented to emergency department. She was a non-smoker and had no relevant family history. Her background history included two episodes of pericarditis in her twenties, intermittent arthralgia and occasionally a low platelet count was noted. She also had two previous miscarriages. Investigation results:

• ANA 320 homogenous, positive anti-dsDNA, ESR 25, low neutrophil and platelet counts, low C3/4, normal urine sediment and no proteinuria
• Coronary angiogram found an irregular LAD with greater than 70% stenosis in the mid portion which was treated with thrombolysis, and a stent was inserted.

She was diagnosed with SLE, but current presentation was probably not due to active disease. She was started on hydroxychloroquine. In the next few months, she had an exacerbation of joint pain and was found to have synovitis at her wrists. Methotrexate was added to control her symptoms.

SLE is a multi-system autoimmune disease that is characterised by mostly chronic inflammatory effects on a variety of organs. Diagnosis of SLE can be challenging, but is based on demonstration of a number of clinical manifestations as well as immunological abnormalities. Referral to a rheumatologist is strongly recommended to assist with the diagnosis and make treatment recommendations. Management of SLE depends on the level of disease activity and can include general measures, NSAIDs and steroids. Immunosuppression is often required and specific targeted therapy is on the horizon.

Competing interests: Alberta Yik-Bun Hoi is on the Advisory Board of Bristol-Myers Squibb and Janssen-Cilag. She has received payments for lectures from Mundipharma, Janssen-Cilag, UCB, Pfizer, Abbott and Bristol-Myers Squibb. Provenance and peer review: Commissioned; externally peer reviewed.

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Also in this issue: Diagnostic challenges

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Lupus Case Scenario: Patient History and Presentation

Anne E. Winkler, MD, PhD, MACP: Let’s go ahead and switch gears a little bit and start talking about a hypothetical case. And even though it’s hypothetical, I will tell you I’ve had patients just like this. So, this is a 24-year-old Afro American computer programmer. She was referred to rheumatologist for a sensitive rash and joint pain. On exam, she had a rash in the Malar regions of the face and forearms, she was tendering in some of the small joints of the hands and the wrist. Normal blood pressure, labs did show however a low C3 of 63, elevated double stranded DNA antibody of over 300, her UPCR was 0.2 and she was initially treated with hydroxychloroquine and leflunomide. Again, pretty typical kind of scenario we would start. She comes back and every three months she’s getting UPCR which of course, we’re big on these days because we know already because young woman of color, low C3, high double stranded DNA antibody, she’s at high risk for lupus nephritis and on a routine visit, because again, I’ve seen this happen, no other symptoms that maybe some fatigue. Her UPCR now is four, so obviously she’s developed lupus nephritis. Kind of if you can comment a little bit on what you think and how you would approach this patient.

Kristi V. Mizelle, MD, MPH, FACR : Yeah, I’d like to actually take it back to the initial presentation. So when I see a patient, and the concern is potentially for lupus, most- a lot of people ask, well, what’s the ANA? That’s the first thing we want to know. And yes, the ANA is important. But I’d also want to get a little bit more of a history, I’d also want to see what the examination findings are. These are very important things because there’s some things that can mimic manifestations of lupus that we have to make sure that we are clearly seeing things that look like lupus. For example, patient presents with malar rash, OK, a lot of people have rosacea, a lot of rosacea is called malar rash. So it’s very important to understand the difference between rosacea and malar rash, looking for if there’s fine capillaries present? Does it spare the nasal labial folds? Is it raised, is it painful, or uncomfortable on the face? Those things are very important because we may be chasing something that’s not necessarily a Lupus manifestation. And so it’s important to distinguish those things when we do see patients. For example, you mentioned she had some joint pain. Well, joint pain in and of itself is not enough to make a Lupus diagnosis and patients can have arthralgias, but diagnostic and classification criteria actually speak to inflammatory arthritis. Is there synovitis at the joints? When we examine the joints and do X-rays, is there erosion? If there’s erosion, then that makes us take a step back and say maybe this isn’t truly lupus because lupus very rarely, usually does not cause erosions at the joints. So, we have to make sure that we’re very clear in our clinical approach and that we’re very detail oriented as we take the history, because on its face when you give this presentation for an initial visit with the patient, oh, it’s like lupus, slam dunk. But I can’t tell you the number of patients who’ve come in and I’ve had similar findings, and I say, you know what? These things are not technically meeting what I would expect the criteria to be in order for us to say it’s truly a manifestation of lupus. And so we have to have our minds open. I’ve had patients come in with an ANA one 180, one to 160 and have joint inflammation and we check their inflammatory markers as well as their lupus and rheumatoid arthritis studies and they have a high CCP or they have discoid lupus that’s biopsy proven, but no ANA, and then they have inflammatory joint changes with erosions. I have some patients who have discoid lupus and an seropositive erosive rheumatoid arthritis. So, we have to make sure we understand the diagnosis because we have to- that then is so-

Anne E. Winkler, MD, PhD, MACP: You just froze again, you have a patient with seropositive, I think is where you stopped.

Kristi V. Mizelle, MD, MPH, FACR : Seropositive rheumatoid arthritis. We have to make sure that we’re very clear on our initial diagnosis before we start running and putting on treatments, because our treatment could directly flow from what the diagnosis is and we may treat or choose inappropriately as far as choice of drug if we don’t have the right diagnosis. When that patient presents to me, like you said, and I’d probe on some of those things that she kind of came in with. She’s got a very good history with UV light exposure, which can sometimes activate or be a trigger potentially for lupus. The history sounds like it could work, a young woman of reproductive age sounds like it could work, African American, increased likelihood, because African Americans have an increased risk of lupus as compared to other races and ethnicities. A lot of those things are suggestive, but we still have to make sure we do the work to understand clearly, do the various manifestations meet what we would expect as sort of the clinical and or laboratory findings that would speak more to a Lupus diagnosis? Getting the right diagnosis, super, super important. I can’t tell you how many patients I’ve seen who were evaluated by other rheumatologist and come in and I say, I want to start from the beginning. Let’s make sure we have the right diagnosis. We’re just going to go back and rethink it all. Let’s go get the old labs. Let’s go back and take the history. And then let’s come back and see are we arriving at the same point, same diagnosis? If we are, great. If we’re not, OK, well, what is it that we think is going on? And what would we do differently based upon that? It’s important to be a good diagnostician when we’re thinking about lupus patients and to take the time to be detailed. When you present that case, to me, the first thing is, let’s make sure we got the right diagnosis.

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A rebuttal letter as regards: A more detailed description of study methods could be needed—comments on “Clinico-serological associations of urinary activated leukocyte cell adhesion molecule in systemic lupus erythematosus and lupus nephritis”

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Ding H, Lin C, Cai J, Guo Q et al (2020) Urinary activated leukocyte cell adhesion molecule as a novel biomarker of lupus nephritis histology. Arthritis Res Ther 22(1):122

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Ye Z, Ding H, Lin C et al (2019) 164 Urinary ALCAM as a novel biomarker for renal pathology in lupus nephritis. Lupus Science & Medicine 6(1). https://doi.org/10.1136/lupus-2019-lsm.164

Fanouriakis A, Kostopoulou M, Andersen J, Aringer M et al (2024) EULAR recommendations for the management of systemic lupus erythematosus: 2023 update. Ann Rheum Dis 83(1):15–29

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Amer, A.S., Moneam, S.M.A., Hashaad, N.I. et al. A rebuttal letter as regards: A more detailed description of study methods could be needed—comments on “Clinico-serological associations of urinary activated leukocyte cell adhesion molecule in systemic lupus erythematosus and lupus nephritis”. Clin Rheumatol (2024). https://doi.org/10.1007/s10067-024-06954-z

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A Rare Case with Systemic Lupus Erythematosus Manifested by two Different Neurologic Entities; Guillain Barre Syndrome and Posterior Reversible Encephalopathy Syndrome

Firdevs ulutaş.

1 Department of Rheumatology

Veli Çobankara

Uğur karasu.

2 Department of Internal Medicine

Ismail Hakkı Akbudak

3 Department of Intensive Care Unit, Faculty of Medicine, Pamukkale University, Denizli, Turkey

Systemic lupus erythematosus (SLE) is an immune-mediated, lifelong disease characterized by quite heterogeneous neuropsychiatric manifestations. Herewith, we report the first rare co-incidental case with posterior reversible encephalopathy syndrome (PRES), Guillain Barre Syndrome (GBS), and (SLE). The coexistence of these neurological conditions in SLE patients could lead to delayed diagnosis and treatment due to this rare coalescence and clinical diversity. Currently, there are no specific, diagnostic radiological or laboratory biomarkers for neurological involvement in SLE. Awareness and, early recognition of neuropsychiatric involvements of the disease are important for timely appropriate treatment. Delayed treatment may cause permanent damage, poor prognosis, long term morbidity, and even death.

INTRODUCTION

Systemic lupus erythematosus (SLE) is an immune-mediated, lifelong disease. Vasculitis of small vessels, deposition of immune complexes, and autoantibody production and deposition in various organs play a role in the disease pathogenesis. Neuropsychiatric manifestations of SLE, including headaches, seizures, psychosis, and delirium, are quite heterogeneous and may occur at the onset of lupus or later in the course of the disease. The frequency of neurologic involvement ranges between 12%–95% in SLE patients. 1 Peripheral nervous system involvement is in less than 10% of all nervous system manifestations. 2 The simultaneous prevalence of SLE with Guillain Barre Syndrome (GBS) has been reported to be between 0.6% and 1.7%, whereas the prevalence of posterior reversible encephalopathy syndrome (PRES) is 0.69% in SLE. 3 The coexistence of PRES and GBS in SLE patients has not been reported in the past. Prompt diagnosis and treatment of patients can be delayed due to this rare coalescence and clinical diversity. Also, many confusing clinical conditions including hypertensive and uremic encephalopathy, delirium, use of cytotoxic drugs, ischemic or haemorrhagic cerebrovascular events, and infections may have added to the neurological involvement. 4 Although it is difficult to find overlapping effects of predisposing factors in these patients, making the distinction of the above clinical conditions is very important for treatment modalities. In the literature, this is the first educational case where GBS and PRES occurred together in an SLE patient.

CASE REPORT

A 39-year-old man with a previous history of urogenital infection one year ago, was admitted to the inpatient clinic of Neurology at Pamukkale University, Denizli. He complained of acute onset lower extremity pain, numbness and progressive weakness, stiffness in the ankles, and walking instability for the previous two weeks. At presentation, he was afebrile and normotensive. He was unable to stand alone. He had no malar rash, no oral ulcers, no weight loss, no alcohol or illicit drug use, and no high-risk sexual behaviour. On physical exam, the muscle strength in his legs was 3/5 proximally and 2/5 distally and his deep tendon reflexes were absent. The pattern in the distal limbs resembled acute onset symmetric ascending paraparesis. Bilateral axillary and inguinal 1–2 cm superficial lymphadenopathies were noted. Cerebrospinal fluid and nerve conduction studies showed albuminocytologic dissociation and findings of dysautonomic inflammatory demyelinating polyneuropathy, respectively. He was firstly treated with standard therapies including intravenous immunoglobulin (IVIG) and plasmapheresis sessions for the diagnosis of Guillain Barre Syndrome, but did not respond well to these therapies. Brain and whole spine magnetic resonance imaging was normal and inguinal excisional lymph node biopsy resulted in reactive lymphoid hyperplasia. Serum angiotensin converting enzyme (ACE) level was normal, and no lymph node or parenchymal involvement was detected in lung tomography. After excluding sarcoidosis, infections, malignancies, and antiphospholipid antibody syndrome, he was diagnosed as SLE with the presence of symmetrical arthralgia and positive immunological markers including positive antinuclear antibody, anti-dsDNA antibody, anti-Smith antibody, and anti-SSA antibody with low complement levels, meeting the minimum 4 of 11 classification criteria created by the American College of Rheumatology. Laboratory tests revealed no hematological or renal involvement. Intravenous pulse methylprednisolone (1000 mg per day, 5 consecutive days) and cyclophosphamide (1000 mg single dose per month) were given. After intensive immunosuppressive treatments, he had tonic clonic seizures and severe headaches. Hypertension was observed (160/110). Concurrent infections and cerebrovascular insults were excluded. His brain magnetic resonance imaging (MRI) was consistent with hyperintense white matter vasogenic edema, predominantly the right side of the posterior brain on T2 weighted images ( Figure 1 ). He was treated with antiepileptic and antiedema therapies. Parenteral antihypertensive agents were titrated for adequate blood pressure control. Post-treatment, complete resolution of vasogenic edema was observed on fluid-attenuated inversion recovery (FLAIR) MRI images ( Figure 2 ). Thus the diagnosis of Posterior Reversible Encephalopathy Syndrome (PRES) was made. Despite aggressive intensive care management, no clinical improvement was seen and the patient subsequently died as a result of the neurological insult.

T2 weighted image of brain MRI

39-year-old man with systemic lupus erythematosus, presenting with headache and seizures after cytotoxic treatment and hypertension. Hyperintense lesions, posterior subcortical right side predominant vasogenic white matter edema is seen indicating PRES.

FLAIR MRI; complete resolution of vasogenic edema after supportive treatments

This is the first original educational case where GBS and PRES occurred together in an SLE patient. Only 15 cases with PRES and GBS have been reported in the recent literature, with the vast majority of patients being female and older than the age of 55. 5 PRES can develop in association with autoimmune diseases like SLE, GBS, and polyarteritis nodosa. Although the association between PRES and GBS are poorly understood, underlying possible mechanisms leading to PRES in GBS patients may include dysautonomia, autoimmunity, IVIG therapy, and activation of the sympathetic nervous system. Dysautonomic cardiac and cerebrovascular complications of GBS include tachy-bradycardia, hypo-hypertension, and PRES, respectively. 6 The rare coexistence of PRES and GBS has also been reported after spinal surgery, 7 in association with hyponatremia and IVIG therapy 8 and head injury. 9

The 75% of patients with SLE can present with many different neuropsychiatric manifestations from headache to stroke throughout the course of the disease. 10 In patients with GBS, autoantibodies target peripheral nervous system cells. As a result, damaged nerves cannot transmit signals from the brain to the muscles. Many studies showed that antecedent viral or bacterial infectious agents like Campylobacter play a role in the etiology and may trigger autoimmune peripheral neuropathy. The recent cases of GBS and SLE in the literature were treated successfully with a combination of IVIG, corticosteroids, plasma exchange, and/or intravenous cyclophosphamide (CyC). The response rate of treatments was stated as 77.4% of patients with different types of peripheral nervous system involvement. 11 Although multiple clinical trials demonstrated the significant benefits of intravenous immunoglobulin and plasma exchange for the treatment of GBS, our patient did not respond to initial treatment modalities and his clinical condition worsened. 12 During the intensive immunosuppressive treatment including CyC and pulse steroid, he developed posterior reversible encephalopathy syndrome (PRES). This was first described in 1996 by Hinchey. 13 This neuroradiological disease is characterized by classical symptoms like headache, altered mental function, visual symptoms, vomiting, seizures, and with typical bilateral posterior subcortical brain edema on magnetic resonance imaging. PRES is completely reversible with supportive treatments and does not require immunosuppressive drugs. The rate in SLE patients was 18% in a case series of 120 patients with PRES and patients diagnosed with SLE and PRES were analyzed retrospectively. Concurrent hypertension, treatment with high dose steroids, and CyC have also been reported as risk factors. 14 CyC is a mainstay drug for neurolupus and lupus nephritis and may trigger PRES via direct endothelial cytotoxic effects at the blood brain barrier. 15 In another study, renal insufficiency and high SLE Disease Activity Index (SLEDAI) were also shown to be risk factors for the development of PRES. 16 Cui Hw et al. stated that SLE patients with PRES had more early disease onset with predominantly seizures, and higher mortality rates than controls. 17 Severe hypertension disrupts the autoregulation of brain blood flow. Also, interleukin-6 (IL-6)-related inflammation and endothelial damage are thought to cause hyperperfusion induced vasogenic edema and brain injury in SLE, which show a high mortality rate. 18 Male gender, atypic presentation with GBS, early disease onset, and unresponsiveness to previous treatment modalities were poor prognostic factors for our patient.

Herewith, we report the first rare coincidental case with PRES, GBS, and SLE. Underlying possible conditions in this patient were not clear. The underlying autoimmune diseases including SLE and GBS, concurrent hypertension, the use of cyclophosphamide (CyC), and IVIG may be predisposing causes for the development of PRES. We did not have a chance for further distinction due to the lethal outcome of the disease. Nevertheless, we surmise that cyclophosphamide-related PRES developed rather than active lupus disease. The patient already had been treated with intensive immunosuppressive drugs for active disease.

CONCLUSIONS

Currently, there are no specific, diagnostic radiological or laboratory biomarkers for neurological involvement in SLE. Awareness and early recognition of neuropsychiatric involvements of the disease are important for timely and appropriate treatment. Delayed treatment may cause permanent damage, poor prognosis, long term morbidity, and even death. We hope that this case could raise awareness of atypical presentations of neuropsychiatric involvement in SLE patients.

CONFLICT OF INTEREST

The authors declare no conflict of interest.

LRA Announces Partners on the First Anniversary of the Lupus Landmark Study

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April 11, 2024

The Lupus Research Alliance (LRA) and its clinical research affiliate Lupus Therapeutics (LT) are pleased to announce the group of industry partners working together on the implementation of the Lupus Nexus. The Lupus Nexus, one of LRA’s most ambitious and groundbreaking endeavors, is a first-of-its-kind lupus registry, biorepository, and data exchange platform that aims to accelerate lupus research and translation.

The Lupus Nexus comprises four infrastructure components: the Lupus Landmark Study (LLS); Clinical Coordinating Center; Biorepository; and the Data Repository, Exchange, and Analysis (DREAM) platform.  Launched last year, the Lupus Landmark Study is a prospective, longitudinal study that will recruit about 3,500 persons living with lupus over 5 years. The LLS will be a rich source of longitudinal patient data (clinical and patient reported) and linked biospecimens, which will allow investigators to address emerging questions in lupus research. Importantly, the raw data from all analyses conducted on the biospecimens will be deposited into the DREAM platform, creating a deep and comprehensive dataset over time.

“As a highly heterogeneous disease that affects each person differently and has few treatment options, there is an urgent need to understand the underlying disease mechanism of lupus to guide the development of personalized treatments,” noted Teodora Staeva, Ph.D., Chief Scientific Officer at the Lupus Research Alliance. “The Lupus Nexus will accelerate lupus research and drug development by providing not only access to highly curated longitudinal samples and data but by creating an unique information exchange ecosystem.”

“We are proud to have engaged such a superb cadre of top companies in their respective fields,” noted Devon D. Kelly, Director, Lupus Nexus, LRA. “Working in concert, this team of partners is furnishing all the behind-the-scenes nuts and bolts needed for the Lupus Nexus, building a resource for researchers around the world to exchange information and collaborate in a way never before possible.”

Watch this video to hear from Devon Kelly , Director of the Lupus Nexus at LRA, about how the Lupus Nexus and the Lupus Landmark Study will make a difference in the lives of people with lupus.

Lupus Nexus Partners

Each of the following six partners are providing specific expertise to build and maintain the Lupus Nexus.

The LLS Clinical Study partner Embleema is working with the clinical trial sites recruiting for the Lupus Landmark Study, to provide operational resources that include an electronic data entry system for clinical site coordinators to enter patient data and ask any questions. The LLS Biorepository partner Azenta Life Sciences is managing the biospecimens collected in the Landmark Study, providing each study site with kits to collect biospecimens from patients and then processing, storing, and maintaining an electronic inventory of all the samples submitted.

Two companies are supplying their testing technology to allow sites to monitor disease activity among study participants. DxTerity Diagnostics, Inc. is providing their Autoimmune Profile (AIP) Test, which measures the levels of various immune genes to help monitor patients’ lupus disease activity and response to treatment. Progentec Diagnostics, Inc. is providing their Disease Activity Index (DAI) informed by a set of 10 unique immune mediators that characterize lupus disease activity and assesses risk for active disease, as well as their Flare Risk Index (FRI), which measures levels of a unique set of 11 immune proteins to determine the risk of imminent clinical disease flare in the next 12 weeks.

The Data Repository, Exchange & Analytics Platform (DREAM) Platform is being deployed on Amazon Web Services (AWS) and will be built by two companies providing their research software expertise. Lifebit is developing the platform to organize the data and create the knowledge-exchange portal which researchers will use to access data, conduct groundbreaking research, and share their discoveries. Sano Genetics’ tech-forward solution to drive meaningful community engagement will allow study participants to view their own clinical and research data. The company’s software will also create an interactive online community for people living with lupus and others interested in making a difference in the lupus community.

Together these six partners are building the infrastructure to enable scientists to access critically needed data from people with lupus who represent the wide diversity of the disease. The project promises to help scientists better understand the complex heterogeneity of lupus and to facilitate the development of more effective ways to diagnose, monitor, predict progression and treat people with lupus.

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Rare condition caused patient to see ‘demonic’ faces, says study on ‘visual disorder’

It sounds like the stuff of horror films — but for people who are afflicted with a rare disorder , it’s a terrifying reality.

A condition called prosopometamorphopsia (PMO) causes facial features to appear distorted, according to researchers from Dartmouth College in Hanover, New Hampshire.

A study published in The Lancet revealed that a 58-year-old man reported seeing faces as distorted or "demonic" for 2½ years.

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"The patient stated that the distortions — severely stretched features of the face, with deep grooves on the forehead, cheeks and chin — were present on every person's face he encountered, but he reported no distortions when looking at objects, such as houses or cars," the researchers wrote in the findings.

The patient did not see those same distortions when looking at two-dimensional faces on printed paper or digital screens.

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Still, despite the distortions, the patient reported that he was able to recognize people.

After the researchers showed the man some images on a screen of a person, they then had him compare the images with that same person’s actual face. 

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The patient provided feedback on the differences he perceived between the two — and the researchers used computer software to edit the photograph to capture what he was seeing.

"Through the process, we were able to visualize the patient’s real-time perception of the face distortions," said Antonio Mello, a PhD student in psychological and brain sciences at Dartmouth who worked on the study, in a press release.

Dr. Jonathan Tiu, a neurologist and assistant professor of neurology at Hackensack Meridian School of medicine in New Jersey, was not involved in the study but reviewed the findings.

"Fascinatingly, the patient highlighted in the recent Lancet case report was still able to recognize everyone he was looking at," Tiu told Fox News Digital.

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"This suggests that the brain's way of visually ‘displaying’ faces, and the brain's ability to recognize a person's face, might be occurring in two different parts of the brain."

The name of the disorder, prosopometamorphopsia, comes from "prosopo" (the Greek word for face, prosopon) and "metamorphopsia," which refers to perceptual distortions.

Tiu described PMO as a "very rare visual disorder " that causes a person to see visual distortions of facial features.

"This can include a twisting or stretching of someone's eyes or a visual ballooning of that person's chin, or they might even see features where they shouldn't be, like seeing that person's teeth hover over their lips," he said.

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Experts don't fully understand how PMO occurs and who is more likely to experience it.

"It is thought that an injury to specific parts of facial processing networks in the brain, whether it be from a stroke or tumor, can produce the symptoms of PMO," Tiu said.

The condition has also been known to occur as an effect of migraines or seizures, but sometimes it comes on without any identifiable cause.

PMO is very rare, with fewer than 100 documented cases, according to the neurologist.

There are different types of PMO, as noted in a separate article published by senior author Brad Duchaine, a professor of psychological and brain sciences at Dartmouth.

The two most common types are full-face prosopometamorphopsia (full-face PMO) and hemi-prosopometamorphopsia (hemi-PMO), he noted.

Most cases last only a few days or weeks.

Some patients, however, continue seeing the distortions for years.

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Among the people who have had PMO, it is common for them to have been misdiagnosed at some point, the researchers stated in the study findings.

"We’ve heard from multiple people with PMO that they have been diagnosed by psychiatrists as having schizophrenia and put on anti-psychotics , when their condition is a problem with the visual system," Duchaine said in the release.

"And it’s not uncommon for people who have PMO to not tell others about their problem with face perception because they fear others will think the distortions are a sign of a psychiatric disorder," he added.

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For those who have the condition, the optimal treatment should be tailored to the underlying cause of the symptom, Tiu noted.

In one study from 2021 that reviewed 81 individuals with PMO, the authors found that there was full or virtually full recovery in more than half of the reported cases, he pointed out.

"Of those who recovered, the PMO resolved quickly within days to weeks," Tiu said. 

"However, some patients took years to recover, and in a group of patients, the symptoms did not demonstrate any improvement."

The study authors concluded that the facial processing networks that involve PMO may be in a part of the brain that has generally good potential for recovery, Tiu added.

The Dartmouth researchers expressed hope that this latest study will help raise awareness of the rare but impactful condition.

As Duchaine added, "It’s a problem that people often don’t understand."

Fox News Digital contacted the researchers for additional comment.

For more Health articles, visit www.foxnews.com/health . 

Original article source: Rare condition caused patient to see ‘demonic’ faces, says study on ‘visual disorder’