Lupus erythematosus 1

Lupus erythematosusThe Lupus erythematosus (lat. lupus "wolf," Greek. ἐρύθημα [erýtʰēma] "redness" + -ώδης [-ṓdēs] "similar to"; also Butterfly Lichen) is a systemic autoimmune disease from the group of collagenoses. "Erythematodes" (Engl. erythematosus) – "flushing" derives from the redness common in this disease (in 71% of patients). Particularly characteristic of SLE (systemic lupus erythematosus) is the so-called butterfly erythema.

Origin of the name

The name "lupus" – "wolf" derives from the possibility of facial mutilations caused by CDLE lesions [1] , physicians of earlier generations compared these lesions to wolf bites. Nowadays, thanks to modern treatment options, it rarely occurs.

Epidemiology

Nine out of ten sufferers are female due to the sex-specific signaling pathway of interferon-alpha induction [2] , so the disease is gynecotropic. In Europe, systemic lupus erythematosus occurs with an incidence of 25 to 27 new cases per 100 people per year.000 persons to. It is estimated that in Germany about 40.000 people, especially young women of childbearing age, at Lupus erythematosus. African- and Asian-descended people are strikingly more frequently affected than European ("white") people. [3] In SLE, the 5-year survival rate ranges from 50% to 95%, with worse rates found primarily in socially marginalized groups [4] . The average 10-year survival rate is 85%.

Forms and symptoms

Systemic lupus erythematosus (SLE)

Systemic lupus erythematosus (SLE, other name: Lupus erythematosus disseminatus, abbreviated LED) often begins with fever, fatigue and sensitivity to sunlight often follow. In addition, sufferers usually complain of rheumatism-like joint pain. Erythema often forms on the skin.

Overview of possible symptoms in systemic lupus erythematosus [5] [6] Frequency in % Symptom 100 Hematologic symptoms 85 Joint pain 84 General complaints (fatigue, poor performance …) 81 Skin changes 77 Renal findings 63 Joint inflammation 58 Raynaud's syndrome 54 Complaints d. Central nervous system 54 mucosal changes 47 gastrointestinal complaints 37 pleurisy 32 lymphadenopathy 29 pericarditis 17 pulmonary involvement 5 myocarditis 4 pancreatitis

It can also affect any other organ of the body (systemic = affecting all "systems"). Inflammation of the joints, heart, lungs, kidneys, and brain may develop. The danger lies in particular in multi-organ system failure.

SLE can be acute-inflammatory with severe relapses, foudroyant. In the past, this form of the disease frequently and rapidly led to death by affecting muscles, joints, brain, skin and kidneys. It has become very rare today thanks to modern treatment methods. Today, SLE is usually milder. With fewer signs of disease. There are slow-slow. Relapsing forms of progression.

There are also very mild courses in which only one or two ACR criteria are met. [1] These courses may progress to SLE after years of progression.

SLE with secondary Sjogren's syndrome

Some of those affected have an overlap with Sjogren's syndrome, which is the most common collagenosis overall. Autoantibodies against anti-SS-A (Ro) are typical. Partially also against anti-SS-B (La). A pronounced photosensitivity is present in these patients. In so-called ANA-negative lupus erythematosus, only low or no antinuclear antibodies (ANA) are detectable, but sometimes high-titer SS-A (Ro) and possibly. also called anti-SS-B (La) antibody. This is why it is important to screen for ANA subtypes when screening for collagenosis. Pregnant women with antibodies to anti-SS-A (Ro) and anti-SS-B (La) have an increased likelihood of congenital heart block in the unborn child and neonatal lupus erythematosus.

SLE with secondary antiphospholipid syndrome (APS)

In some forms (about 40% of those affected) of lupus erythematosus, antiphospholipid syndrome occurs. Antibodies are formed against phospholipid-protein complexes (anti-cardiolipin and anti-β-2-glycoprotein I antibodies as the main representatives), which is used in diagnostics, as these can be detected in immunological tests. In addition, these complexes can lead to thromboembolism, which also has a negative impact on prognosis. Female patients with APS have an increased risk of recurrent miscarriage (a characteristic of APS patients).

Drug-induced SLE

The milder course of LE, triggered by antihypertensives (such as dihydralazine), antiarrhythmics: procainamide), anticonvulsants, and antibiotics, as well as other drugs, usually improves after the drug is discontinued. Laboratory parameters for this are ANA and histone-AK.

Late-stage SLE

Since the late stage of the disease can nowadays almost always be prevented with medication, the full-blown form of SLE only occurs very rarely. The typical organ damage caused by acute SLE therefore usually occurs only in a mitigated form. Nowadays, drugs are used to avoid or reduce this damage; therefore, many patients do not reach the late stage of the disease, which used to be lethal. In addition to regular control by an experienced rheumatologist, drug treatment is also absolutely important. The possible severe organ damage caused by SLE, renal failure, nephrotic syndrome, arteriosclerosis, heart valve damage, thromboembolism, bone necrosis, neurological and psychiatric diseases, pulmonary fibrosis [1] have thus become rarer in modern times.

Chronic discoid lupus erythematosus (CDLE)

In cutaneous lupus (CDLE), only the skin is affected. The course is mild. Only about 5 % develop SLE. The skin lupus usually manifests itself in disc form ("discoid" lupus erythematosus). These skin changes show a three-phase structure:

1. At the edge there is a reddening, which turns into a 2. changes to a scaly area. The skin scales are firmly attached. After removal of a scale, a so-called "skin tag" is found on the underside of the scale. keratotic spur (paper nail phenomenon). 3. Centrally, there is tie atrophy, which becomes scarred and leads to permanent hair loss (alopecia) in hairy areas of the skin. UV light and certain drugs provoke the skin changes.

Tumorous lupus erythematosus

Lupus erythematosus tumidus is a rare variant of discoid lupus erythematosus with inflammatory tumor-like infiltrates that often appear on the face. The reddish foci are swollen, hyperthermic, and have a mottled surface due to scarring.

Subacute cutaneous lupus erythematosus (SCLE)

Subacute cutaneous lupus erythematosus is a rare form of the lupus erythematosus group. It is intermediate between chronic cutaneous and systemic lupus erythematosus and is clinically characterized by increased photosensitivity, especially to UV-B. It presents with psoriasis-like, round foci on areas of skin usually exposed to sunlight. In addition, joint and muscle pain, and rarely kidney involvement with mild symptoms have been described. In a chronic relapsing course, SCLE can heal spontaneously or turn into systemic lupus erythematosus. [7]

Neonatal LE syndrome

In the case of a maternal autoimmune disease such as systemic lupus erythematosus, the risk of miscarriage is increased to about 20%. Of the remaining 80%, only a small proportion develop neonatal lupus erythematosus. In principle, the mother's autoantibodies can cause symptoms in other organs from 16 weeks of age. The disease can be transmitted to the child via the placenta during the first week of pregnancy. Here they preferentially cause symptoms on the skin and the heart. The mother herself may well still be asymptomatic at this time. In a prospective study, skin lesions were described in 16%, AV block °III in 1.6%, elevated liver enzymes in 26%, and hematologic abnormalities in 27% of cases. [8] Symptoms in other organs such as the kidneys, lungs, nervous system or blood cells occur much less frequently. The AV block cannot be reversed even by immunosuppressive therapy. Must usually be treated with a pacemaker. Otherwise, the disease has a good prognosis, because the remaining symptoms disappear on their own as the autoantibodies passively transferred from the mother disappear. Since not all children of mothers with the corresponding autoantibodies develop symptoms, prophylactic immunosuppressive therapy is not generally indicated. However, it is recommended that in such cases, from the 16. regular ultrasound examinations of the heart of the fetus should be performed during the first week of pregnancy. If AV block °I or II is found in this case, prophylactic treatment of the mother with a steroid [9] or plasmapheresis [10] is discussed. It is important to determine SS-A/Ro and SS-B/La antibodies in the mother's blood, because they cause the changes in the heart muscle tie of the unborn child.

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Cause

The etiology of SLE as well as CDLE is largely unknown. However, viruses (such as the Epstein-Barr virus) or UV light are thought to be causative or. Trigger factors come into question. In rare cases, unusual stimuli – such as z. B. an insect bite – in genetically predisposed patients a lupus resp. trigger a relapse [11] . Apoptosis of cells occurs, resulting in the release of their nuclear components (autoantigens). This is especially true when phagocytosis of apoptotic cells is impaired, as has been described for a subset of SLE patients. [12] These cells are recognized as foreign by the misdirected immune system, and antibodies are formed against them, so-called autoantibodies. Autoantigens and autoantibodies form immune complexes. These cannot be eliminated by the mononuclear phagocytic system (macrophages). Deposit in a wide variety of locations (such as the vessel wall). Among other things, this leads to complement and platelet activation. In addition, vascular inflammation (vasculitis) develops. This results in vascular occlusion. Later the organ lesion. However, the nuclear components are also presented on the surface of various cells (such as keratinocytes). The dysregulated immune system reacts to this, and polyclonal B-cell activation and the production of further autoantibodies occur, which then leads to the destruction of the cells (s. butterfly erythema).

The cause of this pathological reaction of the immune system is unknown so far. There is a strong genetic predisposition. Family members first. Second-degree patients show an increased prevalence of SLE. [13] The probability that an SLE patient has at least one first-degree relative with SLE is reported to be 3 to 10 percent. [14] . For monozygotic twins, a common SLE disease of 57% is reported, for dizygotic twins of 5%. [13] Other autoimmune diseases also occur more frequently in the circle of relatives.

Clearance deficiency as a possible model for the development of SLE

Lupus erythematosus 1

The precise mechanism of systemic lupus erythematosus (SLE) is a multifactorial process and is still unclear. In addition to the causes already mentioned, impaired clearance of dying cells is another reason for the expression of this autoimmune disease. This refers, in addition to the increased susceptibility to apoptosis, to the impaired phagocytosis activity of monocytes or tie macrophages and granulocytes, as well as to missing or inefficient serum components.

Isolated monocytes from peripheral venous blood of SLE patients show decreased expression of the CD44 surface molecule involved in the phagocytosis process. Most of these monocytes as well as some of the "starry sky macrophages" (tingible body macrophages, TBM), which are found in the germinal centers of the lymph nodes, also clearly show a morphological difference in SLE patients: not only are they diminished and more likely to die, but they are also smaller and malformed. Serum components, such as complement factors, C-reactive protein, and some glycoproteins, are also crucial for the functioning phagocytosis process. Such components are absent or decreased or inefficient in the serum of many SLE patients.

The clearance of early apoptotic cells is an important function in the organism. If this ability is impaired and progression of apoptosis occurs, secondary necrosis of the cell occurs. From necrotic cells that have lost their membrane integrity, nuclear components become autoantigens as well as danger signals presented, which stimulates the maturation of dendritic cells (DC). Inefficient clearance" is also triggered by high apoptotic cell proliferation. Thus, an increased rate of apoptosis also triggers maturation of DC, as well as presentation of intracellular antigens to late apoptotic cells or secondary necrotic cells via their MHC molecules.

Autoimmunity may be initiated by prolonged exposure of intracellular and nuclear autoantigens of late apoptotic and secondary necrotic cells, among others. B- and T-cell tolerance to autoantigens of apoptotic cells is lost, and lymphocytes are activated by autoantigens. Inflammatory response and antibody production by plasma cells result as a typical clinical picture of SLE. In patients with chronic discoid lupus erythematosus (CDLE / skin lupus), this clearance defect has also been observed.

Lupus erythematosus 1

Accumulation in germinal centers

In healthy individuals, apoptotic lymphocytes in the germinal centers of lymph nodes are efficiently cleared by specialized phagocytes, TBM, leaving no free apoptotic and potentially autoantigenic material there. In SLE patients, due to inefficient clearance, deposition and accumulation of apoptotic material occurs there. In close proximity to the TBM, in the special microenvironment of the germinal center, follicular dendritic cells (FDC) are localized, which, in contrast to the dendritic cells (DC) matured in the bone marrow, bind the antigens on their surface and neither take them up, nor present them via MHC molecules. Autoreactive B lymphocytes, like nonautoreactive B cells, arise from somatic hypermutation of centroblasts and migrate into the light zone. Autoreactive B lymphocytes formed by chance normally do not receive survival signals by FDC and die by apoptosis. If clearance is inefficient, there is accumulation of apoptotic nuclear material in the bright zone of the germinal centers, which is fixed by FDC.

FDC loaded with deposited nuclear autoantigens may represent short-term survival signals for autoreactive B lymphocytes. Final survival signals that allow differentiation into autoantibody-producing plasma cells and into memory B cells are obtained by autoreactive B cells through interaction with autoreactive T helper cells after migration into the mantle zone. The chronic autoimmune disease SLE can be the consequence.

Investigation

CDLE (skin lupus)

In addition to the typical skin appearance, a small skin sample is often taken (biopsy) and examined for fine tie to confirm the diagnosis. Microscopic examination reveals hyperkeratosis, basement membrane enhancement and high numbers of CD4 T lymphocytes in the affected skin areas. In the course of a special examination (immunohistochemistry) dye-labeled antibodies are used, which bind to endogenous antibodies of class G (IgG). In this process, an accumulation of these antibodies along the basement membrane of the skin can be seen in the microscopic image. Since the basement membrane is located everywhere in the skin, the image of a luminous band (lupus bands) is formed.

SLE (systemic LE)

The diagnosis of systemic lupus erythematosus is based on the so-called ARA criteria (ARA stands for: American Rheumatology Association – renamed the American College of Rheumatology (ACR) in 1988). If 4 of the 11 criteria are present, the diagnosis of SLE can be made with 80 to 90 percent certainty.

ACR criteria (formerly ARA criteria)

The 11 ACR criteria (1982, revised 1997) are: [1]

1. Butterfly erythema: This refers to a circumscribed, symmetrical, bright red, flat to slightly raised redness of the cheeks that converges over the bridge of the nose. 2. CDLE- typical skin changes 3. Photosensitivity (hypersensitivity to light: after exposure to sunlight, headaches, fatigue and fever may occur – this has nothing to do with sunburn or sunstroke in this context!) 4. Erosions or ulcers of the oral mucosa 5. Joint pain and joint effusion 6. Serositis (inflammation of so-called serous membranes such as the pleura or pericardium) 7. Kidney infestation 1. More than 0.5 g protein per day in urine or 2. abnormal urinary sediments such as blood residues or urinary cylinders

1. mental diseases without known metabolic or drug-related cause as a trigger

1. Hemolytic anemia or with leukocyte counts below 4000 per mm³ of blood or with lymphocyte counts below 1500 per mm³ of blood or 2. Thrombocytopenia with platelet counts below 100000 per mm³ of blood

1. Positive LE cell sign: Hematoxylin bodies" visible in blood smears: This refers to phagocytosed nuclear remnants in leukocytes. These nuclear remnants originate from destroyed cells to which a specific autoantibody directed against deoxyribonucleoproteins, known as "LE factor", had bound. Testing for the LE cell sign is rarely performed nowadays and is of historical interest only [1]; or 2. autoantibodies against native or double-stranded DNA (anti-dsDNA-AK) or 3. Autoantibodies against complexes of certain proteins and RNA (Smith antibodies or anti-Sm-AK) 4. Autoantibodies against phospholipids (anti-phospholipid-AK)

Treatment

General

Regular examinations are necessary in order to be able to detect at an early stage the infestation of organs such as the kidneys or the heart. Since UV light aggravates the skin symptoms of lupus erythematosus, consistent sun protection is necessary.

Drugs

Drug therapy for lupus is staged and is based on the severity of symptoms, organ involvement, and efficacy in individual patients.

In mild disease, in some cases no treatment at all or only symptomatic treatment with skin creams and/or so-called NSAIDs (nonsteroidal anti-inflammatory drugs) is necessary.

The next stage is usually the basic therapeutic agent chloroquine (belonging to the DMARDs), which is also used to treat malaria, often combined with cortisone.

If these agents do not improve the condition, immunosuppressive drugs are usually used. The most common and best proven drug in the treatment of lupus is azathioprine. Also with cyclosporine A. mycophenolate mofetil are successful. In addition, cytostatic drugs such as cyclophosphamide or methotrexate are occasionally used. Thalidomide is also used under strict supervision. Sometimes some of these drugs are combined with each other, more often with cortisone.

Other treatment methods

Other treatment modalities include immunoadsorption, plasmapheresis, stem cell transplantation, immunoglobulins, and physical therapy.

Contraception

For a long time, the use of the "pill" (oral contraception) was considered dangerous in patients with lupus erythematosus, as it was feared that the estrogens contained in the pill could lead to a flare-up or worsening of the disease.

On the other hand, there are good reasons for using the "pill" especially in patients with lupus erythematosus

– Planned pregnancies have fewer complications in a phase of low disease activity (remission). – Patients with high disease activity or patients who have to take fertility-damaging (teratogenic) drugs need a reliable contraceptive method. – In patients who have to take glucocorticoids, taking the "pill" can reduce the associated bone loss and thus prevent osteoporosis. – The use of the IUD in combination with immunosuppressive therapy does not reliably protect against pregnancy and may mask inflammation of the genital tract.

In 2005, several studies [15] [16] [17] showed that in patients with inactive disease or moderate but stable disease activity, taking hormonal combination drugs is safe if phospholipid antibodies are not detectable. Patients with severe disease, blood clotting disorders or phospholipid antibodies in the blood should not take the pill not occupy.

incompatibilities

Generally known to be intolerant to carotene (especially in carrots) and anisole (especially in anise, caraway, and fennel).

Particularly noteworthy is the incompatibility with the active ingredient diclofenac (as in Voltaren), which is found in various rheumatism medications. In lupus patients, this agent can lead to a relapse of the disease up to (fatal) allergic shock. Special caution and consultation with the physician is necessary when taking the pill [18] .

History

The disease was described as early as 1872 by the Hungarian dermatologist Kaposi, but has been known at least since the Middle Ages. The term "lupus erythematosus Derives from the Latin name of an animal: "lupus is called Wolf. This refers to the fact that the face of lupus patients allegedly resembles a wolf's face after the skin damage heals due to the scar-like furrows. The name Lupus Originates from the Lombard Roger Frugardi (around 1140-1195). Frenchman Pierre Louis Alphee Cazenave (1795-1877) was the first to describe the disease in a scientifically accurate form in 1851.

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