Lupus Erythematosus


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Angel Justiz Vaillant
Nicholas McClellan


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Updated:
7/2/2019 11:04:33 PM

Introduction

The acute form of systemic lupus erythematosus (SLE) differs from the chronic form. It disseminates differently, and it is highly fatal. Kaposi was the first in recognizing SLE in 1872, and then Pernet described it in 1908. Before that time SLE was considered to be a non-fatal disfiguring skin disease. It is now to be considered a chronic inflammatory disease characterized by a course of alternating exacerbations and remissions. SLE mimics other diseases, and therefore, its diagnosis may be difficult. It is a multisystemic, autoimmune disease in which the immune system produces autoantibodies against a variety of autoantigens, for example, antinuclear antibody (ANA) and anti-blood cell antibody. It affects vital organs such as kidneys, heart, central nervous system (CNS), the skin, the lungs, the joints, and the reproductive system. Clinical criteria defined by the American Rheumatism Association (ARA) define SLE, and 4 out of the 11 criteria confirm the diagnosis.[1]

Etiology

SLE is a multifactorial disease. Genetic, immunological, endocrine, and environmental factors influence the loss of immunological tolerance against self-antigens. With SLE, the pathogenic autoantibodies can cause tissue damage through multiple mechanisms including deposition of immune complexes, complement fixation, and neutrophil activation. Among genetic triggers is a mutation in the gene encoding for protein kinase Cd (PKCd). One study showed that this mutation caused monogenic SLE in the 3 siblings of an endogamous Pakistani family. They responded well to B-cell depletion using ofatumumab.[2]

Several immunological factors implicate SLE. Several studies showed the pathogenic role of T-helper, type 17 (Th17) axis, while regulatory T cells mediated protection. An environmental factor thought to prevent SLE etiology is the disturbance of gut microbiota (dysbiosis). It can lead to the development of autoimmunity. The elements and composition of gut microbiota have significant roles in human B cells (antibody production) and the homeostasis and balance of various subpopulations of helper T cells. Endocrine factors may play an essential role in the lupus etiology. These factors involve estrogens in the pathogenesis of SLE. Recently, in 2016, Xue and colleagues investigated the functions and mechanisms of 17 beta-estradiol in tumor necrosis factor-like weak inducer of apoptosis (TWEAK) expression in Lupus nephritis (LN). They concluded that 17 beta-estradiol plays a critical role in upregulating TWEAK expression in LN, possibly through an ERa-dependent pathway, that ends in kidney damage.[3] SLE is more prevalent in women than men (9:1) since female produce a large concentration of estrogens. Drugs may also trigger SLE for example, hydralazine, because they are associated with anti-histone antibodies.

Risk of SLE increases in men with Klinefelter's syndrome and mothers of boys with X-linked chronic granulomatous disease. These observations testify that there is a robust multifactorial etiology in SLE. 

Other contributing factors in the etiology of SLE include association with:

  • Complement deficiency, especially C2 and C4
  • HLA-A1, B8 and DR3 and other HLA genes
  • DQw1, DQw2 with anti-Ro
  • DQw6, 7 and 8 with antiphospholipid antibodies

Epidemiology

Around 3% of the population have an autoimmune disease. The prevalence of SLE is approximately 0.2%. The female to male ratio is 9 to 1. SLE mainly affects women of child-bearing age. African-Caribbeans and Asians are mostly affected. Individuals with HLA-B8, DR-2, and DR-3 are highly susceptible to this disease. Epstein-Barr virus (EBV) may trigger SLE. It is an environmental factor. Among identical twins, the likelihood of both twins having SLE is 24%.[4]

Pathophysiology

A type of III-hypersensitivity reaction mediates SLE. Soluble immune complexes deposit in several tissues and organs including the kidneys, the joints, the heart, the CNS, the skin, the lungs, and others. After that, the classical pathway of the complement system activates. Chemotactic factors including C3a attract neutrophils to the site of inflammation, and they release proteolytic enzymes to process the immune complexes but eventually they cause damage to surrounding organs and tissues. SLE is a complex immune disease caused in part by a reduction of the CR1 receptors on red blood cells. Some autoantibodies can penetrate the cells of patients with lupus and interfere with an intracellular target enzyme, e.g., anti-ribosomal P antibodies, anti-RNP, and anti-dsDNA antibodies. There is also evidence of complement consumption that is associated with disease activity.[5][6]

The thrombocytopenia and hemolytic anemia characteristic of SLE is often caused by antiplatelet and anti-erythrocyte antibodies. Lymphocytotoxic antibodies, which are mainly specific to T cells are found in the sera of many patients with SLE. Genetic susceptibility to the development of SLE has been demonstrated in family studies. It shows that antibody formation can be genetically determined, for example, patients with HLA-DR2 are more likely to produced anti-ds-DNA antibodies, and those with HLA-DR3 can produce more copious amounts of anti-Ro (SS-A) and anti-La (SS-B) antibodies. Besides patients with HLA-DR4 make anti-Smith antibodies. However, autoantibody production is partially suppressed by regulatory T lymphocytes that are thought to play a critical role in immunologic tolerance.[7][8][9]

Another immunopathologic finding is the association of SLE to FcRIIA polymorphism that impairs immunocomplexes binding and accumulates in the kidneys causing glomerulonephritis. This also affects other organs. 

Histopathology

The following characterize SLE histopathology:

  • Fibrinoid necrosis at the dermo-epidermal junction along with liquefactive degeneration and atrophy of the epidermis
  • Edema, small hemorrhages, and a mild infiltrate of inflammatory cells (principally lymphocytes in the upper dermis) accompanying small hemorrhages and edema
  • Fibrinoid material deposits in the dermis close to capillary blood vessels, on collagen, and in the interstitium
  • There is more mucin deposit in the reticular dermis in acute SLE than discoid lupus

In addition there are histopathologic changes in some organs and tissues for instance:

  • In the spleen can be seen the peculiar periarterial concentric fibrosis that results in a lesion known as "onion skin."
  • In the heart can be the described the verrucous endocarditis of Libman-Sacks that consists of ovoid vegetations, which form along the base of the valve.
  • A pathognomonic feature of SLE is the "hematoxylin body." It is a homogeneous globular mass of nuclear material that stains bluish purple with hematoxylin. It can be observed in the lungs, kidneys, spleen, heart, lymph nodes and serous and synovial membranes.

History and Physical

American College of Rheumatology Revised Criteria for the Classification of SLE[4]

Symptoms/Signs

  • Malar rash: Red, flat, or raised over the cheeks, sparing the nasolabial folds
  • Discoid rash: Red raised patches with keratotic scales, atrophy, and scarring may occur in older lesions
  • Photosensitivity: Presence of skin rash due to sunlight exposure
  • Oral ulcers: Painless ulcers in the mouth or nasopharyngeal areas   
  • Arthritis: Nonerosive arthritis (pain, swelling or effusion) is greater than or equal to 2 peripheral joints
  • Serositis: Pleuritis (pleuritic pain or rub or pleural effusion) or pericarditis (ECG or rub or evidence of effusion)

Disorders

  • Renal: Proteinuria (greater than 500 mg daily) persistent or cellular casts (RBC, granular, tubular, or mixed)  
  • CNS: Seizures or psychosis in the absence of an alternative explanation (e.g., drugs or metabolic disorders such as electrolyte abnormality or uremia) 
  • Hematologic: Hemolytic anemia (with reticulocytosis) or leucopenia (less than 4000/mm) on 2 or more occasions or lymphopenia (less than 1500/mm) on 2 or more occasions or thrombocytopenia (less than 100,000) in the absence of medications known to decrease platelets
  • Immunologic: Antiphospholipid antibodies present based on either an abnormal serum level of IgM or IgG anticardiolipin antibodies or a tested positive result for lupus anticoagulant or Anti-DNA antibody or anti-Sm antibody or false positive VDRL (or RPR).  
  • Antinuclear antibodies: An elevated level of ANA, in the absence of drugs known to cause "drug-induced lupus."

More than 4 criteria need to be present during observation. These criteria are 95% sensitive for the diagnosis of SLE, but only 84% specific.

In the gastrointestinal system ulceration due to vasculitis can occur in SLE. Manifestations include diarrhea, abdominal pain, and bleeding. Also, cholecystitis, pancreatitis, and chronic hepatitis may occur. In the vascular system different findings have been shown; for example, small-vessel vasculitis commonly occurs in acute SLE. Skin manifestations include splinter hemorrhages, infarctions of finger pulp, and periungual occlusions. Other vascular problems are bowel infarction, mononeuritis multiplex, and cerebrovascular accidents. 

Drug-induced lupus-like syndrome presents with arthralgias, arthritis, fever, rash, and pleurisy. Kidney and central nervous system involvement are rare. The disease usually remits when the offending drug is discontinued. The most common drugs involved in the pathogenesis of SLE are hydralazine and procainamide. The antinuclear antibodies typical of drug-induced SLE are anti-histone and anti-single-stranded DNA. 

Evaluation

The immunodiagnosis of acute systemic lupus erythematosus includes testing for autoantibodies and complement proteins, which form the mainstay of diagnosis.

  • Antinuclear antibodies (ANA) can perform by indirect immunofluorescence. Most cases of SLE show positive ANA results. Most patients show a peripheral, homogeneous, or speckled pattern. The peripheral pattern is related to double-stranded DNA, the homogeneous pattern is associated with DNA-histone complex, and the speckled is connected to the Smith antigen (a pathognomonic finding in SLE), ribonucleoprotein, SS-A, and SS-B.[10]   
  • The second step is the confirmation of the antigenic specificity. It includes testing for auto-antibodies such as anti-double-stranded DNA (dsDNA), anti-Smith, ENA, anti-cardiolipin, and anti-beta2 GP-I. A high serum level of this anti-dsDNA and anti-Smith suggests SLE. These 2 antibodies can be considered as immunological markers for SLE. Other autoantibodies present in this systemic illness are the anti-histone and rheumatoid factor.   
  • SLE can also associate with other autoimmune disorders, e.g., autoimmune thyroid disease (5% to 10%) and Sjogren syndrome (15% to 20%). Other organ-specific autoantibodies must be ruled out, including those that affect the thyroid, gastric parietal cells, anti-erythrocytes, and others clinically essential antibodies.  
  • Detection of C3 and C4, serum immunoglobulins, electrophoresis, and cryoglobulins (if Raynaud is present) are additional tests that should be done as part of the routine testing in SLE patients.   
  • Biopsies (lupus band test) shows deposits of IgG and C3/C4 along the dermo-epidermal junction in a lumpy-bumpy distribution. They may be deposits around cutaneous blood vessels. Renal biopsy may help show immune complexes deposition involving IgM, IgG, and C3/C4.

Treatment / Management

The efficacy of the drugs used in the treatment of SLE is difficult to evaluate, because of spontaneous remissions. SLE is a life-threatening disease that can evolve into a fulminant illness. Generally, depending on the disease severity, no treatment, minimal treatment (aspirin, antimalarials), or intensive treatment (cytotoxic drugs, corticosteroids) may be required.[11][12][13]

  • Mild disease can treat with non-steroidal anti-inflammatory drugs (NSAIDs).
  • Skin problems including rashes and vasculitis can manage with topical steroid creams.  
  • Antimalarials, e.g., hydroxychloroquine, can use to treat arthralgia and skin disease.   
  • Acute SLE with hemolytic anemia, CNS disease, or severe pericarditis requires urgent intravenous (IV) cyclophosphamide plus high dosage of prednisolone. 
  • Mycophenolate mofetil can use as an alternative to azathioprine or cyclophosphamide.  
  • Methotrexate can be used for arthritis.  
  • Sunblock creams are used to protect against ultraviolet (UV) light.
  • Intense immunosuppression is used in lupus nephritis. Prednisone can be used in a dosage of 1 mg/kg/d orally. High-dosage corticosteroid therapy is recommended in fulminant lupus and severe central nervous system lupus. One or more courses of "pulse" therapy (15 mg/kg/d IV for 3 days) may be useful in patients with severe disease.  
  • The patient may need kidney transplantation if the disease progresses.  
  • High blood pressure can be managed with calcium-channel blockers (e.g., nifedipine).  
  • An SLE-maintenance regimen of NSAIDs and hydroxychloroquine may be used.     
  • Neurological involvement is difficult to treat, and there is no clinical consensus; high-dose steroids can be used, but they may trigger a steroid psychosis.  
  • Plasmapheresis along with cytotoxic drugs may be used, but never alone or the disease may worsen.  
  • In pregnancy, dexamethasone can be used to treat heart problems.   
  • Intravenous immunoglobulins (IVIG) should be used with care and avoided if rheumatoid factor is present in high titer.    
  • Splenectomy may be required for thrombocytopenia.    
  • Antiphospholipid syndrome needs anti-coagulation.    
  • If the patient fails to improve with corticosteroids, immunosuppressive therapy with cytotoxic agents (including cyclophosphamide, chlorambucil, or azathioprine) is indicated, and because of serious complications (bone marrow suppression, infection, and cancer), immunosuppressive agents should be used with discretion in SLE.
  • Monoclonal antibodies including rituximab and ofatumumab have successfully been used in the treatment of many cases with acute lupus. They have caused remission of the disease.[14][15] It is a new approach in the management of SLE as the use of the anti-CD20 monoclonal antibody causes B-cell depletion[16][17]. Another new approach is the use of stem cell transplantation for severe disease, which has as a complication graft-versus-host disease.[18]

Differential Diagnosis

  • Adult-onset Still disease characterized by arthralgia, fever, lymphadenopathy, and splenomegaly but no malar rash, autoimmune blood disorders, and other organ's manifestations   
  • Behcet syndrome presents with aphthous ulcers, uveitis, and arthralgia but other systemic signs of SLE are not present.
  • Endocarditis characterized by fever, arterial emboli, arthralgia, myalgia, and a heart murmur; may be confounded with cardiac manifestations of SLE but can rule out because of the absence of SLE common autoantibodies including anti-dsDNA and anti-Smith antibodies.
  • Rheumatoid arthritis (RA) presents with morning joint stiffness lasting over 1 hour; affected joints are usually symmetric, swollen and tender. It can rule out because of positive tests for anti-cyclic citrullinated antibodies, a positive rheumatoid factor, and synovial fluid reflecting the inflammatory state. There are serological differences between these 2 problems.
  • Systemic sclerosis characterizes by decreased joint mobility, arthralgia, myalgia, Raynaud phenomenon, and skin induration. It can distinguish from SLE testing for specific antibodies.    
  • Sarcoidosis presents with fever, cough, dyspnea, fatigue, night sweats, rash, and uveitis. It shows non-caseating granuloma on chest radiography and bilateral adenopathy, which is rarely present in SLE.[19]

Prognosis

Acute SLE, if treated promptly, has a prognosis of approximately 80% survival at 15 years. It can increase the long-term risk of cardiovascular disease and osteoporosis. The prognosis varies with clinical features of the disease, in patients with renal involvement SLE may progress to renal failure and may need kidney transplantation. Here the prognosis is guarded. However, patients with mild disease have a better prognosis.

Complications

The most common SLE complications are:

  • Severe cardiovascular (e.g., pericarditis) and renal problems (glomerulonephritis)  
  • Infections  
  • Anemia   
  • Thrombocytopenia

The rheumatologist or family medicine physician must strictly monitor these complications. Hematological diseases may require blood product transfusion and dosage change of immunosuppressive drugs.

Renal failure and central nervous system lupus were leading causes of death until the advent of corticosteroids, and cytotoxic drugs. Since then the complication of therapy including atherosclerosis and cancer have become common causes of death.

Deterrence and Patient Education

Clinicians must educate patients to be compliant with immunosuppressive drugs needed to treat SLE for achieving improvement of the quality of life. Patients must also comply with the treatment of comorbidities. Psychological support should be available to carry out the necessary management of these patients.

Pearls and Other Issues

Several drugs can cause acute SLE that may improve once the patient stops taking them (within 6 months to a year). Below is a list of those drugs reported as SLE inducers:

  1. Hydralazine
  2. Quinidine
  3. Isoniazid
  4. Minocycline
  5. Procainamide

Enhancing Healthcare Team Outcomes

An interprofessional team should educate and manage patients with acute SLE. Their family physician can monitor patients with less severe form of the disease that does not involve important organ systems. Physicians should refer patients with complications, increased disease activity, or drug reactions from treatment to a rheumatologist. It is vital that the specialist coordinates closely with the patient's family physician to optimize treatment and carry out preventive health services.


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Lupus Erythematosus - Questions

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A young female presents to the clinic with complaints of a facial rash which started a few months ago and has gotten worse. She states that the rash is often itchy and is worse when she goes out in the sun. In the last few days, she has noticed generalized aches all over her body. She denies any trauma, allergies, or recent travel. She did try several over the counter products, but nothing helped. The appearance of her rash is shown in the image. Which of the following is most suggestive of her current disease?

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A 17-year-old woman presents with asthenia, low-grade fever, butterfly rash, and generalized arthritis. Laboratory tests show low C3 and C4, positive antinuclear antibody test, and a high titer of anti-dsDNA antibodies. What is the most likely diagnosis?



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Which of the following immunological markers is more likely present in a patient with acute systemic lupus erythematosus?



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Which of the following immunotherapies can be used to treat acute systemic lupus erythematosus?



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Which of the following is true about acute systemic lupus erythematosus (SLE)?



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Which is true about acute systemic lupus erythematosus?



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A 32-year-old woman complains of fatigue that has been present for the past 6 months. She also states that she has had joint pains, chest pain, and a 3 kg weight loss ever since the fatigue started. She denies recent travel, fever, or new sexual partners. She has no past medical history and takes no medications. She is sexually active with her husband of 5 years. Her mother has rheumatoid arthritis, and her father has scoliosis. Vitals: BP: 123/80 mm Hg, HR: 81 bpm, RR: 18/min, and O2: 99% on room air. On examination, she has a rash over her nose and an ulcer on her hard palate. Chest examination reveals decreased air entry in her right lung base. Her abdomen is soft, and there is no hepatosplenomegaly. Neurological examination is within normal limits. Which of the following antibody titers most likely correlates with the disease activity in this patient?



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Lupus Erythematosus - References

References

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Lam NC,Ghetu MV,Bieniek ML, Systemic Lupus Erythematosus: Primary Care Approach to Diagnosis and Management. American family physician. 2016 Aug 15     [PubMed]
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Xue L,Liu Z,Hu J,Huang J,Wen J,Liu Z, Estrogen-induced expression of tumor necrosis factor-like weak inducer of apoptosis through ERα accelerates the progression of lupus nephritis. Rheumatology (Oxford, England). 2016 Oct     [PubMed]
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Aleksandrova EN,Verizhnikova ZG,Novikov AA,Panafidina TA,Popkova TV,Lukina GV, [Clinical value of multiplex immune assay of antinuclear antibodies in systemic lupus erythematosus.] Klinicheskaia laboratornaia diagnostika. 2018;     [PubMed]
Binello N,Cancelli C,Passalacqua S,De Vito F,Lombardi G,Gambaro G,Manna R, Use of Intravenous Immunoglobulin Therapy at Unconventional Doses in Refractory Fulminant Systemic Lupus Erythematosus. European journal of case reports in internal medicine. 2018     [PubMed]
Toko H,Tsuboi H,Umeda N,Honda F,Ohyama A,Takahashi H,Abe S,Yokosawa M,Asashima H,Hagiwara S,Hirota T,Kondo Y,Matsumoto I,Sumida T, Intractable Hemophagocytic Syndrome Associated with Systemic Lupus Erythematosus Resistant to Corticosteroids and Intravenous Cyclophosphamide That Was Successfully Treated with Cyclosporine A. Internal medicine (Tokyo, Japan). 2018 Sep 15     [PubMed]
Touzot M,Terrier CS,Faguer S,Masson I,François H,Couzi L,Hummel A,Quellard N,Touchard G,Jourde-Chiche N,Goujon JM,Daugas E, Proliferative lupus nephritis in the absence of overt systemic lupus erythematosus: A historical study of 12 adult patients. Medicine. 2017 Dec     [PubMed]
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