The Wolf Within: Understanding Systemic Lupus Erythematosus

 What is lupus or SLE?

Systemic Lupus Erythematosus or SLE also called lupus is an autoimmune disease involving multiple organs, characterized by a vast array of autoantibodies, particularly antinuclear antibodies (ANAs), in which injury is caused mainly by deposition of immune complexes.

Why called lupus?

The term "lupus" is derived from the Latin word for "wolf". It was originally used to describe a skin rash that resembles the bite of a wolf. The characteristic rash of systemic lupus erythematosus (SLE) is called a "butterfly rash" because it spreads across the cheeks and bridge of the nose, resembling the wings of a butterfly. However, the term "lupus" is now used to refer to the entire disease, not just the rash.

Prevalence of lupus 

The prevalence of systemic lupus erythematosus (SLE) varies widely depending on the population and geographic region studied. According to a recent systematic review and meta-analysis of 136 studies, the global prevalence of SLE was estimated to be 50-200 cases per 100,000 people, with a higher prevalence in women (9:1 female-to-male ratio) and in non-Caucasian populations. In the United States, the estimated prevalence of SLE is approximately 72-200 cases per 100,000 people, and it is more common in African American, Hispanic, and Asian populations than in Caucasian populations

The spectrum of antibodies in SLE

Anti-nuclear antibodies (ANA): These antibodies are directed against the cell nucleus and are present in approximately 95% of patients with SLE. ANA can target different nuclear antigens, including double-stranded DNA (dsDNA), histones, nucleosomes, and extractable nuclear antigens (ENAs) such as Ro, La, Sm, and RNP.

Anti-dsDNA antibodies: These antibodies specifically target double-stranded DNA and are considered highly specific for SLE. Anti-dsDNA antibodies can be present in up to 70% of patients with active SLE and are associated with disease activity, renal involvement, and lupus nephritis.

Anti-phospholipid antibodies (aPL): These antibodies are directed against phospholipids and phospholipid-binding proteins and are present in up to 30-40% of patients with SLE.

Antibodies against the phospholipid- B2-glycoprotein complex also bind to cardiolipin antigen, used in syphilis serology, and therefore lupus patients may have a false-positive test result for syphilis. 

 aPL are associated with an increased risk of thrombosis, pregnancy loss, and other clinical manifestations such as livedo reticularis and thrombocytopenia.

Anti-erythrocyte antibodies: These antibodies are directed against red blood cells and can cause hemolytic anemia in patients with SLE.

Anti-platelet antibodies: These antibodies can cause thrombocytopenia in patients with SLE.

Anti-neutrophil cytoplasmic antibodies (ANCA): These antibodies are present in a subset of patients with SLE and can be associated with vasculitis and other organ manifestations.

The presence and levels of these autoantibodies can vary between patients with SLE and can help in the diagnosis, classification, and monitoring of disease activity and organ involvement.

Pathogenesis of SLE

SLE pathogenesis involves a combination of genetic, environmental, and immunological factors. Genetic predisposition plays a significant role in the development of SLE. Studies have identified over 100 genetic loci that are associated with SLE, and it is estimated that up to 70% of the risk for SLE is due to genetic factors. These genetic loci are involved in the regulation of immune system function, including the production of cytokines, chemokines, and other immune system proteins.

Environmental factors also contribute to the development of SLE. Exposure to ultraviolet radiation, certain medications, infections, and other environmental triggers can activate the immune system and cause inflammation. In addition, hormonal factors, such as estrogen, have been implicated in the development of SLE, as the disease is more common in women than men.

The pathogenesis of SLE is characterized by the production of autoantibodies that target a variety of self-antigens, such as nuclear components, red blood cells, and platelets. These autoantibodies form immune complexes that deposit in tissues, leading to inflammation and tissue damage.

The immune system abnormalities in SLE are multifaceted, involving both innate and adaptive immune responses. In the early stages of the disease, dendritic cells and macrophages become activated and release pro-inflammatory cytokines,such as interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-α). These cytokines stimulate B cells to produce autoantibodies and activate T cells.

In SLE, T cells are also activated and contribute to the pathogenesis of the disease. CD4+ T cells differentiate into various subsets, including Th1, Th2, Th17, and T follicular helper (Tfh) cells. Th1 cells produce cytokines, such as interferon-gamma (IFN-γ) and IL-2, that promote inflammation and autoimmunity. Th2 cells produce cytokines, such as IL-4, IL-5, and IL-13, that are involved in allergic responses and can contribute to tissue damage in SLE. Th17 cells produce IL-17, which is involved in the recruitment of immune cells to sites of inflammation.

B cells are also important players in the pathogenesis of SLE. In response to activation by T cells and other signals, B cells produce autoantibodies that target self-antigens. In addition, B cells can present antigens to T cells and produce cytokines, such as IL-10, that can modulate immune responses.

The deposition of immune complexes in tissues leads to inflammation and tissue damage in multiple organs, including the skin, joints, kidneys, and central nervous system.

Organs involved in SLE

Skin: Skin involvement is one of the most common manifestations of SLE, affecting up to 70% of patients. The skin lesions can be variable and include a butterfly-shaped rash on the face, discoid lesions on the scalp and other parts of the body, and photosensitivity. The lesions can be erythematous, scaly, and atrophic. Histologically, the lesions show interface dermatitis with hyperkeratosis, acanthosis, and lymphocytic infiltrates.

Joints: Joint involvement is common in SLE, with up to 90% of patients experiencing joint pain and stiffness. The joints affected are typically the small joints of the hands and feet. The synovium can become inflamed, leading to synovitis and erosions of the bone and cartilage. Histologically, the synovium shows synovial hyperplasia, lymphocytic infiltration, and fibrin deposition.

Kidneys: Renal involvement is a serious complication of SLE and can lead to renal failure. Up to 50% of patients with SLE have some degree of renal involvement. The most common histological finding is diffuse proliferative glomerulonephritis, which is characterized by glomerular hypercellularity, capillary wall thickening, and subendothelial deposits. The deposits are composed of immune complexes, complement, and fibrin. This can lead to progressive glomerular damage, with fibrosis and sclerosis.

Heart: Cardiovascular involvement is a significant complication of SLE, and can include pericarditis, myocarditis, and coronary artery disease. Pericarditis is the most common cardiac manifestation, with inflammation of the pericardium leading to chest pain and a friction rub on examination. Myocarditis can occur, leading to impaired cardiac function. Histologically, the heart can show lymphocytic infiltration and fibrinoid necrosis.

Lungs: Lung involvement in SLE can include pleuritis, pleural effusions, and interstitial lung disease. Pleuritis can cause chest pain and shortness of breath, and may be accompanied by pleural effusions. Interstitial lung disease can cause cough, dyspnea, and impaired gas exchange. Histologically, lung involvement can show lymphocytic infiltrates, interstitial fibrosis, and alveolar damage.

Understanding the gross morphology of the organs affected in SLE can aid in the diagnosis and management of this complex disease.

Clinical features

Skin and Mucous Membranes: SLE can affect the skin and mucous membranes, leading to a wide range of skin lesions. These can include a butterfly-shaped rash on the face, discoid lesions on the scalp and other parts of the body, and photosensitivity. Other skin manifestations can include alopecia, oral ulcers, and Raynaud's phenomenon.

Joints and Muscles: Joint involvement is common in SLE, with up to 90% of patients experiencing joint pain and stiffness. The joints affected are typically the small joints of the hands and feet, although larger joints can also be involved. Muscle pain and weakness can also occur, particularly in the proximal muscles of the arms and legs.

Cardiovascular System: Cardiovascular involvement is a significant complication of SLE, and can include pericarditis, myocarditis, and coronary artery disease. Pericarditis is the most common cardiac manifestation, with inflammation of the pericardium leading to chest pain and a friction rub on examination. Myocarditis can occur, leading to impaired cardiac function. Coronary artery disease can also occur, leading to angina or myocardial infarction.

Lungs: Lung involvement in SLE can include pleuritis, pleural effusions, and interstitial lung disease. Pleuritis can cause chest pain and shortness of breath, and may be accompanied by pleural effusions. Interstitial lung disease can cause cough, dyspnea, and impaired gas exchange.

Kidneys: Renal involvement is a serious complication of SLE and can lead to renal failure. Up to 50% of patients with SLE have some degree of renal involvement. Symptoms can include proteinuria, hematuria, and decreased urine output.

Nervous System: SLE can affect the nervous system, leading to a range of symptoms. These can include headaches, seizures, cognitive dysfunction, and peripheral neuropathy. Psychiatric symptoms can also occur, including anxiety, depression, and psychosis.

Hematological System: SLE can affect the hematological system, leading to anemia, leukopenia, and thrombocytopenia. This can result in fatigue, increased susceptibility to infections, and bleeding or bruising.

Gastrointestinal System: SLE can affect the gastrointestinal system, leading to symptoms such as abdominal pain, nausea, vomiting, and diarrhea. These symptoms can be caused by inflammation of the intestines or by side effects of medications used to treat SLE

Diagnostic criteria

The diagnosis of systemic lupus erythematosus (SLE) is based on a combination of clinical features, laboratory tests, and imaging studies. There are several diagnostic criteria that have been established for SLE, including the American College of Rheumatology (ACR) criteria and the Systemic Lupus International Collaborating Clinics (SLICC) criteria.

ACR criteria for SLE: The ACR criteria were developed in 1982 and have been widely used in clinical practice. A patient is considered to have SLE if they meet at least 4 of the following criteria:

Malar rash: butterfly-shaped rash over the cheeks and nose

Discoid rash: scaly, raised patches on the skin

Photosensitivity: skin rash in response to sunlight

Oral ulcers: mouth sores, usually painless

Arthritis: inflammation and pain in two or more joints

Serositis: inflammation of the lining around the lungs or heart

Renal disorder: abnormal urine findings or kidney biopsy results

Neurological disorder: seizures or psychosis

Hematological disorder: anemia, leukopenia, or thrombocytopenia

Immunological disorder: positive antinuclear antibody (ANA) test or other autoantibodies.

SLICC criteria for SLE: The SLICC criteria were developed in 2012 and include additional clinical features that were not included in the ACR criteria. A patient is considered to have SLE if they meet at least 4 of the following criteria, with at least one clinical and one immunological criterion, or biopsy-proven lupus nephritis with positive ANA or anti-dsDNA antibodies:

Acute cutaneous lupus: a rash that develops rapidly and resolves within a few weeks

Chronic cutaneous lupus: discoid rash, photosensitivity, or subacute cutaneous lupus

Oral ulcers: as described in ACR criteria

Arthritis: as described in ACR criteria

Serositis: as described in ACR criteria

Renal disorder: as described in ACR criteria

Neurologic disorder: as described in ACR criteria

Hematologic disorder: as described in ACR criteria

Immunologic disorder: as described in ACR criteria, plus anti-Smith or anti-phospholipid antibodies, or low complement levels.

It is important to note that these criteria are not intended to be used as a definitive diagnosis of SLE, but rather as a guide to aid in the diagnostic process. Clinical judgment and expertise are essential in interpreting these criteria and making a diagnosis of SLE

Treatment of SLE

The management of systemic lupus erythematosus (SLE) involves a multidisciplinary approach, including rheumatologists, nephrologists, dermatologists, and other specialists as needed. The management of SLE aims to control disease activity, prevent organ damage, and improve quality of life. The treatment plan for SLE varies depending on the severity of the disease, organ involvement, and individual patient factors.

Non-pharmacological management: Non-pharmacological management of SLE includes patient education, lifestyle modifications, and monitoring for potential complications. Patients with SLE should avoid excessive sun exposure, maintain a healthy diet, and engage in regular exercise. Patients should also be advised to quit smoking and limit alcohol consumption. Counseling and support groups can also be helpful in managing the emotional and psychological impact of the disease.

Pharmacological management: Pharmacological management of SLE involves the use of medications to control disease activity and prevent organ damage. The choice of medication depends on the severity of the disease, organ involvement, and individual patient factors. Commonly used medications for SLE include:

Nonsteroidal anti-inflammatory drugs (NSAIDs): NSAIDs are used to relieve pain and inflammation associated with arthritis and pleurisy.

Antimalarials: Antimalarials such as hydroxychloroquine are used to treat skin and joint symptoms of SLE, and to prevent disease flares.

Glucocorticoids: Glucocorticoids such as prednisone are used to control disease activity in patients with moderate to severe SLE. They are usually given in high doses initially and tapered over time to minimize side effects.

Immunosuppressants: Immunosuppressants such as azathioprine, mycophenolate mofetil, and cyclophosphamide are used to control disease activity and prevent organ damage in patients with severe SLE. These medications are associated with potential side effects and require close monitoring.

Biologic agents: Biologic agents such as belimumab are used to treat patients with refractory SLE who have not responded to other medications. Belimumab is a monoclonal antibody that targets B cells and reduces disease activity.

Surgical management: Surgical management of SLE may be necessary in patients with severe organ involvement, such as renal failure or cardiovascular disease. Procedures may include kidney transplantation or cardiac surgery

Monitoring: Patients with SLE require regular monitoring for disease activity and potential complications. This includes monitoring of disease activity with laboratory tests, physical exams, and imaging studies. Patients may also require monitoring of potential medication side effects, such as glucocorticoid-induced osteoporosis or immunosuppression-related infections.

In summary, the management of SLE is complex and requires a multidisciplinary approach. Non-pharmacological management, pharmacological management, surgical management, and monitoring are all important components of the treatment plan. The goal of treatment is to control disease activity, prevent organ damage, and improve quality of life for patients with SLE.

Summary

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that can affect various organs and systems in the body. It is characterized by periods of disease activity (flares) and remissions, and its symptoms can range from mild to severe. The cause of SLE is not fully understood, but it is believed to be a combination of genetic and environmental factors. Women are more commonly affected than men. The diagnosis of SLE is based on clinical and laboratory criteria, and management involves a multidisciplinary approach, including non-pharmacological and pharmacological interventions to control disease activity, prevent organ damage, and improve quality of life. With appropriate treatment, many people with SLE are able to manage their symptoms and lead productive lives.