Systemic Lupus Erythematosus Molecular Cause And Clincal Effects Biology Essay


Lupus is an autoimmune disease characterized by acute and chronic inflammation of various tissues of the body. Autoimmune diseases occur when body tissues are targeted by an individual his own immune system. Characteristic of subjects with lupus is the production of abnormal antibodies by hyperactive B cells against self-antigens, abnormally activated T cells, activation of the complement system and imbalanced cytokineproduction. Lupus may affect the skin, heart, lungs, kidneys, joints, and/or nervous system. When merely the skin is involved, the condition is called cutaneous lupus erythematosus. When internal organs are involved, the condition is referred to as systemic lupus erythematosus. Although a primary cause is not described for lupus evidence suggests that immunologic abnormalities, hormonal influences, environmental triggers and the genetic settings represent the enabling environment or even the driving force behind lupus. Diagnosis of Lupus is mainly done with the use of the list of 11 criteria set by the American Rheumatism Association combined with Anti-nuclear- antibodies test. Treatment of lupus is mainly based on the health condition of the patient and how severe the disease manifests itself. Difficult about treating these patients is the lack of a permanent cure. Treatment for lupus patients is based on relieving the patient, protecting organs by decreasing inflammation and control the level of autoimmune activity in the body. Possible medicines for relieving patient condition are autoimmune-suppressors, anti-inflammatory medicines and painkillers.

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Lupus can be explained as an autoimmune disease, an autoimmune disease arises from an overactive immune response. In this case the immune system mistakes some parts of the body as a pathogen resulting in formation of antibodies against its own tissue. Lupus is the latin word for wolf, erythematosus means redness. This disease is named Lupus Erythematosus because of the characteristic symptoms of facial-rash which appears to look like a wolf bite. When researchers first examined lupus in 1828 they primarily described the skin lesions. In 1873 the dermatologist Kaposi discovered that aside from the skin itself other tissues can be affected. In 1890 sir William Osler notes the possibility how only the organs of a patient can be affected, without the combination of facial-rash. [1] 

Multiple forms of lupus erythematosus are known; if patients only appear to develop cutaneous symptoms, then he will be diagnosed with Lupus Erythematosus (LE) or cutaneous lupus. About 10% of all lupus patients have the cutaneous form of lupus. This form represents itself by the skin leasions, a red coin-shaped rash appears in these patients, mainly in the face (butterfly rash) but it may also appear on other body parts. Some symptoms of cutaneous lupus patients can be triggered by ultra violet light; therefore these patients have to limit exposure to sun light. [2] Another form of lupus is Systemic Lupus Erythematosus (SLE), in this case aside from skin rash other body parts and organs are affected as well. SLE is a complex multisystem autoimmune disease, which means that multiple immunologic abnormalities contribute tot the development of this autoimmune disease. SLE is characterised by remission and relapse and can affect nearly every organ system of the body. [3] Lupus can also be induced by drugs, this it is called Drug-Induced LE (DILE) or lupus syndrome. These patients can provoke lupus-like manifestations but there are some clear differences between SLE and lupus syndrome. [4] The main differences are found in the clinical features which will be discussed in the chapter symptoms and risk factors on page 9 of this report.

About 1 in 4000 people in Holland are suffering from lupus, especially woman are affected, the female to male ratio is 9:1. The world wide prevalence of SLE is 40-50 cases per 100.000 people. SLE is also more prevalent in African Americans and Asians than in Europeans.

Autoimmunity and SLE

The immune system has tremendous diversity and, because the repertoire of specificities expressed by the B and T cell populations is generated randomly, it is bound to include many that are specific for self components. The body must therefore establish self-tolerance mechanisms to distinguish between self and non-self determinants to avoid autoreactivity. However, all mechanisms have a risk of breakdown. The self-recognition mechanisms are no exception, and a number of diseases have been identified in which there is autoimmunity, due to production of autoantibodies and autoreactive T cells.

The spectrum of autoimmune diseases

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Autoimmune diseases may be classified as organ-specific or non-organ-specific. The common target organs in organ-specific disease include the thyroid, adrenal, stomach, and pancreas. The non-organ-specific diseases, often termed systemic autoimmune diseases, which include the rheumatological disorders, characteristically involve the skin, kidney, joints, and muscle.

Genetic factors influence the development of autoimmunity

There is an undoubted familial incidence of autoimmunity. This is largely genetic rather than environmental, as may be seen from studies of identical and non-identical twins, and from the association of thyroid autoantibodies with abnormalities of the X chromosome. Within the families of patients with organ-specific autoimmunity, not only is there a general tendency to develop organ-specific antibodies, it is also clear that other genetically controlled factors tend to select the organ that is mainly affected.

Normal subjects also posses Self-reactive B and T cells

Despite the complex mechanisms of selection of lymphocyte development, the body contains large numbers of lymphocytes, which are potentially autoreactive. Knowing that autoreactive B cells exist, the question remains whether they are stimulated to proliferate and produce autoantibodies by interaction with autoantigens or by some other means, such as non-specific polyclonal activators or idiotypic interactions. (Figure A)

Figure 1: An immune complex consisting of autoantigen (e.g. DNA) and a naturally occurring (germline) autoantibody is taken up by an antigen-presenting cell (APC), and peptides derived by processing of the idiotypic segment of the antibody are presented to Th cells. B cells that express the 'pathogenic' autoantibody can capture the complex and so can receive T cell help via presentation of the processed antibody to the Th cell. Similary, an anti-DNA-specific B cell that had endocystosed a histone_DNA complex could be stimulated to autoantibody production by histon-specific Th cells.

In organ-specific disorders, there is ample evidence for T cells responding to antigens present in the organs under attack. But in non-organ-specific autoimmunity, identification of the antigens recognized by T cells is often inadequate. True, histone-specific T cells are generated in patients with SLE and histone could play a role in the formation of anti-DNA antibodies.

Another possibility is that the T cells do not see conventional peptide antigen (possible true of anti-DNA responses), but instead recognize an antibody's idiotype (an antigenic determinant on the V region of the antibody). In this view SLE, for example, might sometimes be explained as an idiotypic disease, like the model presented in figure 1. In this scheme, autoantibodies are produced normally at low levels by B cells using germline genes. If these then form complexes with the autoantigen, the complexes can be taken up by APCs (including B cells) and components of the complex, including the antibody idiotype, presented to T cells. Idiotype-specific T cells would then help the autoantibody-producing B cells.

Cross-reactive antigens induce autoimmune Th cells

Normally, naive autoreactive T cells recognizing self epitopes are still switched on because the antigen is presented only at low concentrations on 'professional' APCs or it may be presented on 'non-professional' APCs. However, infection with a microbe bearing antigens that cross-react with the self epitopes will load the professional APCs with levels of processed peptides that are sufficient to activate the naive autoreactive T cells. Once primed, these T cells are able to recognize and react with the self epitope on the non-professional APCs because they no longer require a co-stimulatory signal, and have a higher avidity for the target due to up regulation of accessory adhesion molecules (figure 2).

Cross-reactive antigens that share B cell epitopes with self molecules can also break tolerance, but by a different mechanism. However, these 'helpless' B cells can be stimulated if the cross-reacting antigen bears a 'foreign'carrier epitope to which the T cells have not been tolerated (figure 3).

Figure 2: The inability of naive Th cells to recognize autoantigen on a tissue cell, whether because of low concentration or low affinity, can be circumvented by a cross-reacting microbial antigen at higher concentration or with higher innate affinity, together with a co-stimulator such as B7 on a 'professional' APC; these primes the Th cells (1). Due to increased expression of accessory molecules (e.g. LFA-1 and CD2) the primed Th cells now have high affinity and, because they do not require a co-stimulatory signal, they can interact with autoantigen on 'non-professional' APCs such as organ-specific epithelial cells to produce autoimmune disease (2).

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The autoimmune process may persist after clearance of the foreign antigen if the activated B cells now focus the autoantigen on their surface receptors and present it to normally resting autoreactive T cells, which will then proliferate and act as helpers for fresh B cell stimulation.

Aside from the normal 'ignorance' of self epitopes, other factors that normally restrain autoreactive cells may include, regulatory T cells, hormones (e.g steroids), cytokines (e.g. transforming growth factor β [TGFβ]) and products of macrophages. Deficiencies in any of these factors may increase susceptibility to autoimmunity.

Figure 3: The B cell recognizes an epitope present on autoantigen, but coincidentally present also on a foreign antigen. Normally the B cell presents the autoantigen, but receives no help from autoreactive Th cells, which are functionally deleted. If a cross-reacting foreign antigen is encountered, the B cell can present peptides of this molecule to non-autoreactive T cells and thus be driven to proliferate, differentiate, and secrete autoantibodies.

Immune complexes appear to be pathogenic in systemic autoimmunity. In the case of SLE, it can be shown that complement fixing complexes of antibody with DNA and other nucleosome components such as histones are deposited in the kidney, skin, joints and choroid plexus of patients, and must be presumed to produce type III hypersensitivity reactions. Cationic anti-DNA antibodies and histones facilitate the binding to heparin sulphate in the connective tissue structures. Individuals with genetic deficiency of the early classical pathway complement components clear circulating immune complexes very poorly and are unduly susceptible to the development of SLE. [5] 

The origin of SLE and it's underlying mechanisms

SLE is one of the best examples of generalized loss of tolerance. Immunologic abnormalities, hormonal influences and environmental triggers all result in anomalous immune functions. Obviously the genetic setting represents the enabling environment or even the driving force behind the entire process. [6] 

Hyperactive B cells produce a vast array of antibodies (Abs) against cytoplasmic, nuclear and other self-antigens, abnormally activated T cells and APCs, activation of the complement system and imbalanced cytokineproduction characterize SLE. Studies working on understanding the characteristics of autoantibodies in human or murine lupus have provided the basis of our current understanding regarding the autoantibody response in lupus. Isotype switching and somatic mutations and hypermutations point towards an antigen-driven response whereas many studies support the existence of only a few initial autoantigenic determinants (or peptide epitopes), which through the mechanisms of epitope spreading and clonal expansion could diversify the autoimmune response to involve even seemingly unrelated self-antigens. [7] The reason why certain autoantigens become the target of the autoimmune response remains unknown. Antigen-driven properties of B cell hyperactivity point towards an abnormal T cell-dependent immune response, placing lupus T cells at the centre of SLE pathogenesis.

T cells

Within T cells of individuals diagnosed with lupus, activation leads to increased calcium mobilization, tyrosine phosphorylation and heightened mitochondrial potentials making T cells display hyper excitability. [8] 

The phenotype of hyper excitable T cells could explain the up regulation of cycloxygenase 2 (COX-2) and CD40 ligand (CD40L). [9] 10However understanding why stimulated lupus T cells display a marked deficiency in IL-2 production remains difficult. Increased COX-2, mitochondrial hyperpolarization and decreased IL-2 production most probably help T cells escape activation-induced cell death (AICD). [11] Decreased AICD and increased CD40L can in turn account for the presence of increased numbers of T cells in the peripheral blood of SLE patients and they are able to provide increased help to B cells to produce autoantibodies.

B cells

Increased T cell help, intrinsic B cell abnormalities and violation of tolerance mechanisms are several aspects of immune dysregulation resulting in B cell hyperactivity. [12] In addition, B cell functions other than Abs production, such as antigen presentation, cytokine secretion and T cell regulation, were revisited after studies showed that it is the presence of B cells and not the presence of autoantibodies that determines the development of autoimmune disease. [13] For example, as shown in animal models, presentation of antigen by self-reactive B cells that have broken tolerance can activate T cells that had been anergic to the self-antigen. [14] In parallel, it was shown that B cells from patients with SLE display

abnormal Ca2+ and tyrosine phosphorylation kinetics following activation through their B cell receptor (BCR), which was linked to the decreased levels of the inhibitory kinaselyn. [15] Autoreactive B cells normally appear primarily in the immature and naive subsets of B cells but are restricted from entering the memory or switch populations. [16] B cells bearing the 9G4 idiotype from patients with SLE overcome a specific peripheral tolerance checkpoint, occurring during the early stages of germinal centre (GC) formation. Impaired GC exclusion led to the expansion the IgG memory and plasma cell compartments. [17] While interaction of CpG-motifs on bacterial or viral DNA with the TLR-9 receptor in cells results in IgM antibody production, in the presence of IL-10, class switching of naïve B cells is initiated and subsequent activation through their BCR or by BlyS (a cytokine that is produced by dendritic cells in response to INF-α) enables the production of T cell-independent IgG antibodies. [18] 19


T cells from patients with SLE display increased and prolonged expression of the co-stimulatory molecule CD40L, which is believed to result in the delivery of abnormal co-stimulatory signals that sustain the production of pathogenic autoantibodies. In addition, ectopic CD40L expression on lupus B cells and monocytes suggests that CD40L-CD40 interactions in SLE can also occur in a T cell-independent manner. [20] 21


The underlying pathogenetic mechanisms are thought to involve the crucial functions of complement, namely clearance of apoptotic debris(waste disposal hypothesis) and inhibition of selfreactivity. It appears that whereas early proteins of the classical complement pathway have a central role in the maintenance of immune tolerance, and thus possess a protective role against the development of SLE, in established SLE excessive activation of complement can lead us to organ damage either by directly damaging cells or by altering their function through the binding of complement factor split products to cognate receptors21.

Symptoms and risk factors of lupus

Each lupus patient has different symptoms that can range from mild to severe which often come in flares. At the onset, the symptoms of lupus are very common, the first symptoms are extreme fatigue, unexplained fever and muscle/joint pains and inflammation (arthritis). These symptoms are often mistaken as the symptoms that appear during the flu, this makes setting the right diagnose difficult. A very common symptom in lupus patients is the characteristic skin lesions/rashes across the nose and cheeks, the rash can also appear on other parts of the body. Symptoms like the rash and arthritis can worsen after sun/UV light exposure; many lupus patients are photosensitive, which means that they are really sensitive to sunlight. [22] 

Lupus syndrome can be induced by certain drugs (Drug Induced Lupus Erythematosus), such as hydralazine, procainamide, ioniazid, chlorpromazine and miocycline. Different symptoms will show in patients with lupus syndrome than in patients with LE or SLE, but there are some similarities too. The symptoms of lupus syndrome are arthralgias, arthritis, rash and fever. There is no involvement of the kidney or the central nervous system but pleural and pericardial effusions are more frequent in lupus syndrome than in SLE. Lupus syndrome is easy to treat, when a patient stops using the drugs that induces the lupus-like manifestations, the symptoms will mostly disappear.

Secondary conditions in lupus patients

Raynaud's syndrome can occur as a secondary condition in patients with lupus, it can also occur along with rheumatoid arthritis and scleroderma. Raynaud's syndrome is a disorder where the bloodflow to the extremities is reduced in phases, this phenomenon has discoloration of the fingers and toes as an effect. In patients with raynaud's syndrome extreme vasoconstriction of the peripheral blood vessels causes tissue hypoxia which has discoloration of the extremities as effect.

Also Sjogren syndrome (SS) can occur as a secondary condition in lupus patients, this is a disease where chronical inflammation of the glandula orbitaria (tear gland) and the salivary gland appears which causes a decrease in tear- and saliva secretion through which a patient suffers from dry eyes and a dry mouth. [23] 

Neonatal Lupus Erythematosus

When woman who are diagnosed with LE or SLE are having a baby there is a small chance that the child will develop lupus too. In some patients are found specific SS-A (ro) and SS-B (la) autoantibodies that can cause neonatal lupus erythematosus (NLE). NLE is an immune-mediated disease that is associated with transplacental passage of maternal IgG antibodies that are reactive to specific antigens. Infants diagnosed with NLE can have cardiac problems, abnormal haematological cells and hepatic disease. The major clinical manifestations are cutaneous lesions, cardiac problems, including congenital heart block (CHB), this may be found before or after a baby is born. It is also possible that a baby that is born to an asymptomatic mother is suffering from NLE. [24] 

Diagnosing (Systemic) Lupus Erythematosus

The diagnosis lupus is a difficult diagnosis to make, as is the case with other autoimmune diseases. The diagnosis can be made by combining criteria set by the American Rheumatism Association (ARA) [25] or the European Academy of Dermatology and Venereology (EADV) with serological testing [26] 27282930


In 1982 the ARA published a list of 11 criteria for lupus. This list was created for the purpose of comparing patients who were suspected to have lupus. The list covers a variety of symptoms from characteristic rashes to immunologic disorders as seen in table 1. A minimum of 4 criteria has to be met in order to consider the diagnosis lupus. After these indications for lupus further testing has to be done in order to make the diagnosis.



Malar rask

A rash found on the bridge of the nose and the cheeks. Looks like a butterfly.

Discoid rash

A rash which is atrophic on the inside of the rash. Red on the outside rim of the rash. The rim can also become more pigmented.


Over-sensitivity to light which can result in 1st or 2nd degree burns. Urticaria and oedema are also common.

Oral ulcers

Ulcers found in the mouth. These ulcers can also be found in the mucous membrane of the colon or vagina.


Inflammation of the joints.


Inflammation of the serosa such as pleuritis and pericarditis.

Renal disorder

Different disorders such as loss of kidney function, protein-uria more than 0.5 g per day or anemia.

Neurologic disorder

Disorders that can manifest as behavioural changes, seizures and psychosis.

Hematologic disorder

Disorders such as hemolytic anemia, leucopenia, lymphopenia, thrombocytopenia.

Immunologic disorder

The presents of high levels of autoantibodies in serum. Such as anti-DNA, anti-SM, antiphospholipid antibodies. Also abnormal serum level of lgG or lgM anticardiolipin antibodies, lupus anticoagulant or a false-positive serologic test for syphilis.

Anti nuclear antibodies (ANA)

An abnormal titer of ANA.

Table 1: ARA criteria for Lupus Erythematosus

Not all subclasses of lupus fulfill the minimum of 4 ARA criteria. In particular cutaneous lupus erythematosus does not fulfill the ARA criteria. That's why the EADV suggested a few additional criteria. The EADV criteria include the ARA criteria and a few other parameters such as vasculitis of the fingers, muscle weakness, lupus band test etcetera. The diagnosis lupus cannot be made solely by these criteria. For every EADV criteria all other possible illnesses have to be considered before the diagnosis lupus can be made. After looking at these criteria's serological testing has to be done to confirm the suspicion of lupus.

Serological testing

Anti-nuclear- antibodies (ANA) can be found in 99% of patients with lupus. This makes ANA a good diagnostic tool. In table 2 antibodies associated with lupus are depicted schematically. The diagnostic sensitivity and other associations are also described. The diagnostic sensitivity refers to amount of people with lupus who have this specific autoantibody in their serum.



% diagnostic sensitivity



Nuclear particles





Associated with nefritis


Various components of snRNPs


Associated with vasculitis, central-nerve-system-lupus (CNS-lupus)

SS-A (Ro)

Protein from scRNP particle (60-kD- and 52-kD-polypeptide)


Associated with photosensitivity, SCLE, neonatal lupus, heartblock , Sjögren

SS-B (La)



The same as SS-A (Ro)


Proteins from the ribonucleoprotein particle, ribosomal antigen


Associated with arthritis, myositis, Raynaud, swollen fingers, CNS-lupus


Cycline A, Cardiolipine.





Lamin B


Associated with autoimmune liver diseases

Ribosomal P


Associated with psychosis


Histone protein


Seen in many disorders



Seen in many disorders

Table 2: Autoantibodies associated with SLE and their autoantigens, diagnostic sensitivity and overall comments

Even though almost all patients with lupus have ANA, the type of ANA is different for every patient. As seen in table 2 the type of lupus and the type of ANA can be mildly associated with each other. For example anti-Ro is associated with subacute lupus erythematosus and neonatal lupus. While anti-Sm is associated with lupus of the central nerve system. Therefore the diagnosis of lupus and its subclasses can be made by combining EADV criteria and serological testing.

In some cases a few additional tests will be performed. For example when a patient has a high risk for developing Sjögren, because their serological testing showed a high level of anti SS-A (or SS-B) or they have symptoms that suggest this. A lip biopsy or eye exam such as Schirmer test may be performed. In lupus patients that suffer from rashes, skin biopsies can be taken for a LE cell test or immunofluorescence tests.


Treatment for lupus patients is based on relieving the patient, protecting organs by decreasing inflammation and control the level of autoimmune activity in the body. Difficult about treating these patients is the lack of a permanent cure. SLE patients have active and quite periods. Patients with SLE will need more rest during periods of active disease. a lack of sleep is a significant factor for SLE patients. There is no treatment necessary for patients with mild symptoms or simple intermittent courses of anti-inflammatory medication. [31] 3233

Treating lupus depends on the health condition of the patient and how severe the disease manifests itself. Possible medicines for relieving patient condition are autoimmune-suppressors, anti-inflammatory medicines and painkillers.

Non-steroidal anti-inflammatory drugs, also called NSAIDs reduce inflammation and pain in muscles, joints and other tissues. It works by inducing the cyclooxygenase enzyme (COX), which blocks the formation of prostaglandins. Prostaglandins stimulate pain, increase body temperature and dilatation of arteries. Most NSAIDs block COX 1 and 2. By blocking COX 1 or 2 it relieves the patient from its symptoms of inflammation and pain. Examples of NSAIDs are aspirin, ibuprofen and diclofenac. The most common side effects are stomach upset, heartburn, ulcers and skin raches. Less common side effects are swelling of the face, feet and lower legs or a sudden decrease in the amount of urine. Taking higher doses or long-term use of this drug will increase the possibility of having side effects. [34] 3536

Corticosteroids are drugs closely related to cortisol, a hormone which is naturally produced by the adrenal cortex. Cortisol plays an important part in controlling salt and water levels in the body. It also regulates carbohydrates, fat and proteins metabolism. Stress conditions of the body will induce production of cortisol, it allows the body to cope with infection, trauma, surgery or emotional problems. Corticosteroids block the immune system by blocking the production of substances that trigger allergic and inflammatory reactions, this sort of drug is more effective than NSAIDs in reducing inflammation and restoring function of the body in an active state of the disease. Corticosteroids are useful when internal organs are affected and can be given oral or injected (intramuscular or directly into inflamed joints) into the body. Corticosteroids have serious side effects, especially in high doses or long term use. They impede the function of white blood cells, which are needed to destroy foreign bodies (such as antigens) and help the immune system. Further side effects are weight gain, thinning of bones and skin, infection, diabetes, facial puffiness and necrosis in tissues of the large joints. [37] 

Antimalarial medication is found to be effective for SLE patients with fatigue, joint disease and skin involvement. Hydroxychloroquine, also named Plaquenil is such an antimalarial drug. Taking this drug will prevent the flare-ups of active periods. For lupus patients it has an anti-inflammatory effect, but the exact functionality from this drug remains unknown. Side effects are uncommon but include diarrhea, stomach upset and eye-pigment changes. Researchers discovered that Plaquenil decreases the frequency of abnormal clots in patients with (S)LE. This type of drug is used in lupus patients in combination with other treatments.

For patients with an affected skin, like LE patients, other antimalarial drugs, such as Aralen or Quinacrine can be used in combination with Plaquenil. Alternative medication for an affected skin is Dapsone or Retinoic Acid (Retin A). For more severe skin disease immunosuppressive medications are given to (S)LE patients. [38] 39

Patients with more severe manifestations of SLE, such as damage in internal organs, can be treated with immunosuppressors also called cytotoxix drugs. This type of drug suppresses the immune system so the body does not attack itself, relieving the organs from the damage. Examples are Methotrexate, Azathioprine, Chlorombucil and Cyclosporine. Side effects of this type of drug are radical; it can depress blood-cell counts and increases risks of infection and bleeding, because the immune system is off. Other side-effects are drug specific. [40] 

An alternative treatment for lupus was published in Annals of Rheumatic Diseases in 2002 by a researcher named M. Polderman from Leids Universtair Medisch Centrum. This therapy is especially for LE patients with skin disease, but can also be used for SLE patients. It is based on a study done in the USA in 1993 on mice with an autoimmune disease. The mice were radiated with UVA-1, which increases survival expectancy. For patients with lupus it is a mild treatment. The patient will be under a sun bed which radiates the body with UVA-1. UVA-1 has a less carcinogenic effect than UVA-2 and UVA-B, so the side effects will not be severe. The therapeutic effect is that the radiances penetrate to the blood vessels and cells in the blood, with an immune modulating effect. The precise mechanism remains unknown. [41] 

Patient interviews and research report VUMC

The first patient is a 56 year old woman whose diagnosis was set at the age of 37. She went to the doctor because recently her son (at that time almost a year old) was diagnosed with Neonatal Lupus. Her son's doctor told her that her son would be fine but that she should be checked out by a rheumatologist because her son got the disorder from her. At this time the patient had few symptoms like: a skin rash when after sunlight exposure and fatigue. She thought she had a sun allergy which explained the skin rash. At that time she also had two young children which explained the fatigue. But this was not the case the diagnosis was subacute lupus erythematosis and a beginning Sjögren syndrome. The patient was a little bit familiar with the diagnosis lupus because that's the diagnosis her son got. She also has a sister with a few medical problems and one of the hypothesis was that she may have an auto-immune disease but this was never confirmed. So she knew a little bit about her diagnosis but not a lot. When she got the diagnosis she was surprised because she didn't feel sick. But mostly she was relieved because she knew that her son wasn't sick he just got the symptoms from her. She thought that it was important to be checked out every now and then by a doctor because of the risk for developing systemic lupus. The doctor used serological testings (ANA, anti-Ro, anti-La), a skinbiopt and a Schirmer test to set the diagnosis subacute lupus erythematosus.

In the last 10 years the disease has developed in more limiting symptoms. Limiting symptoms like pain in the joints and more fatigue. Because of these developments the patient is less mobile. Furthermore the patient has so little energy that she has to select what activities she'll do in a day and has to take a nap sometimes twice a day to do so. The patient also had trouble sleeping which contributes to the fatigue. Trouble sleeping is characteristic property of lupus and pain. In general the patient's quality of life has decreased. She can't do normal things like her household, hobbies and sport without having pain and it is costing her a lot of energy. After the patient's children grew up she wanted to go back to work. This however was not possible due to her increase in symptoms. But she has a fighter's mentality so she says "I will not let this disease rule my life".

The patient goes threw active and calm phases. An active phase is described as a very bad time which can last for months. In this phase of the disease the patient is literally without energy, physically as well as mentally. She can't feel an active phase coming nor can she feel a calm phase coming. A calm phase is never without symptoms but the symptoms are more manageable.

The only treatment option she has is medication against the pain. For a while she used Plaquenil which is an anti-malaria drug (frequently used in lupus patients). This worked well against the skin rash but had no (or a little) effect against the pain. Therefore she started using Celebrex which is a NSAID. Additionally she had an appointment with a nurse of the rheumatology department who talked to her about accepting her limitations and dealing with the consequences of this acceptance. The use of Celebrex lowers the pain by 50% in the calm phases as well as in the active phases. She doesn't have any side effects from the medication but the pain still remains a limiting factor.

When asked if she wanted to participate in a new treatment method or research for a new treatment method she answered that she would in the hope of a cure.

The patient has a varying experience with doctors. Her first doctor, Dr. Van de Merwe, was a very kind man. Every time she went to see him he would educate her about her disease. As if he was talking to a student. Professor Beilsma was also very good at communicating. He was very clear. But a few other rheumatologists weren't so good. They couldn't communicate well to their patient. This made her feel like she wasn't being taken seriously. Furthermore it felt like routine work. Her overall experience with doctors, hospitals and the service they provide is good. But she also thinks that doctors should be more patient orientated. She thinks there should be more counseling for chronically ill patients. There should also be more patient orientated information for the patient (from doctors/hospitals). She only got a flyer with some global information about the disease from the hospital.

The patient has been to a meeting for lupus patients. She thought the meeting was very depressing. She hoped there would be people with some tips about dealing the disease better. Instead she found a bunch of whining women who were crying about how miserable their life was. Women with a lot of sad stories and self-pity, she said. So she never went back. The advise she would want to give to her partners in misfortune is that they should be experts in their own disease. That way they can ask more specific questions to doctors. They could also influence the doctor by guiding them towards a new treatment etc.

Interview with Monica Ferreiros Lopez, SLE patient (oktober 4th 2010)

Second patient is Monica Ferreiros Lopez, she is 39 years old and was diagnosed with SLE five years ago. Her first symptom was Raynauld's phenomenon and she went to visit her doctor, she was redirected to a rheumatologist right away and underwent further examination because the rheumatologist knew this was a symptom that fits SLE. The diagnosis SLE was confirmed by doing a blood test and ANA/ANF test. Before this diagnosis she did not had any lupus like symptoms, she did not get rashes from the sun for instance, but when the diagnosis once was set she realised that she had SLE flares earlier but there was always another excuse for these symptoms, like joint pains could be caused by growth spurt when she was a kid and fatigue always could have an other cause too.

At time of the diagnosis Monica was not familiar with SLE so she did some research on the internet and found frightening information on the website of the lupus patient group. Her parents reacted frightened either and her kids were very involved in everything, in a good way. Because Monica is raising her kids on her own (sometimes with help of her parents and friends) it is important for the kids to understand what is going on. Monica and her kids have found a way to deal with the disease and they speak really open about it. Sometimes that is hard to understand for other people, which is too bad. It even went this far that her kids school called the infant welfare centre because the kids where so happy and performed really well at school while their mother was sick and they should be unhappy and depressed in the schools opinion.

Symptoms Monica is suffering from are joint inflammation, pleuritis, heart rhythm problems. The symptoms of SLE come in flares, so every day can be different. A typical feature for SLE is that it has its active and calm periods; Monica only has had an active period since she was diagnosed with SLE, so she does not know if in her case calm periods can be without symptoms.

Monica has had all of the possible medications for SLE but neither of them worked well. In January of this year the diagnosis cerebral lupus was set. The cerebral lupus has caused demential syndrome, problems in reading and writing and sleeping problems. Cerebral lupus was treated by a high dose of prednisone (6 mg a day). The demential syndrome disappeared after a week of prednisone treatment. The daily restraints are vast mainly because of the prednisone, but on the other hand also because of the symptoms of SLE. Prednisone has some serious adverse effects which are the main cause of the daily restraints for Monica. Prednisone has caused for example muscle weakness through which she was not able to walk without crutches. Monica was admitted to the hospital because she had a lot of trouble with her health and the doctors were not sure if that was an effect of the prednisone or SLE itself. The conclusion was that the prednisone made her even sicker so the only solution was to finish the prednisone treatment step by step. But when the treatment slowly was reduced the demential syndrome came back. Via the lupus patient group she heard about a program in Leiden where the prednisone therapy could be reduced by using chemo therapy. The only treatments against cerebral lupus are prednisone and chemo therapy. Since June 2010 she started with chemo therapy, this is going well; to the exclusion of the hair loss the patient is feeling fine and the final two blood tests where even better than two years ago. So Monica remains with this treatment until she can stop the prednisone.

Research VUMC

Dr. Voskuyl, rheumatologist in the VUMC, told us how most research done regarding (S)LE is based on trials. These trials benefit health and well being of the patients, resulting in better medication. The VUMC in Amsterdam takes part in some of these trials. Most trials for (S)LE are combination trials, with rheumatic and arthritis patients. A lot of medication for (S)LE patients is found by accident. Medication used for other diseases in some cases also work for lupus patients, this makes it hard to find good medication for these patients, because it is not specific.

Most trials which are active now do research for so called biologicals. Over the last few years various biologicals, which are therapeutic proteins, have been brought on the market. Examples of biologicals are rituximab, which blocks CD24, and infliximab, a TNFα targetter. There are different types of biologicals which have different routes of interfering in the human body, this also makes trials complex to set up because the biologicals differ so broad from each other. The aim in the use of biologicals is lowering the disease activity and afterwards remission. Yet this is not fully obtained and studies keep going on.

Dr. Voskuyl also told us how his colleagues contacted the (S)LE patient association to find out which symptoms patients seem to bother the most. Most patients complain about being tired and having no

energy. However this is very difficult to examine, because there is no direct cause for tiredness. Research also tells us that (S)LE patients have more risk of infection than any other patient. Researchers try to find out if this is because of the medication, or the disease itself. They have discovered that the interferon pathway does not work correctly. Yet they have no good explanation or treatment to lower the risk of infection. An other discovery is that (S)LE patients have antigens in their body long before the disease manifests itself and researchers want to interfere with the disease manifestation.

Rituximab is a medicine which temporarily inhibits B-Cell formation. The B-Cells make up a great part of the adaptive immune response. B-Cells are our natural defenders against infections. A symptom of SLE is hyperactive B-Cells. Inhibition of B-Cells results in a decrease in the number of cells. This will compensate for the hyperactivity of the B-Cells. Besides Rituximab there is Belimumab which consist of a complete human monoclonal antibody. This antibody inhibits B-lymfocyt stimulation factor (BlyS). BlyS is one of the essential factors required for B-Cell stimulation. Dr. Voskuyl explained how modern medicines which are available for SLE patients are mostly based on the anti-B-Cell therapy. However Dr. Voskuyl emphasizes how stemcell therapy could become a game changer for SLE patients. Current stemcell trails still have their limitations due to the risk for the patients well being. Previous stemcell trails did achieve a cure for SLE patients. However also showed an 11% mortality after 100 days of treatment. These mortalities are mostly because of infections which arise after surgery due to the instability of the patients immune system. Dr. Voskuyl believes that as stemcell therapies evolve, SLE patients could be confronted with a remedy in the near future.


The exact cause of SLE remains difficult to understand. Multiple factors influence the tendency to develop SLE, however a exact trigger cannot be described. The presence of autoantibodies seems to play a key role. Arbuckle et al42 reported how autoantibodies are typically present many years before the diagnosis of SLE and concluded the appearance of autoantibodies in patients with SLE tends to follow a predictable course, with a progressive accumulation of specific autoantibodies before the onset of SLE, while patients are still asymptomatic. This experiment was done by evaluating serum samples obtained from 130 persons before they received a diagnosis of SLE, along with samples from matched controls. The U.S. Department of Defense Serum Repository contains more than 30 million serum samples. The stringent physical requirements of the U.S. military ensure that subjects are healthy on induction for active duty.

This experiment evaluated a prospectively assembled collection of frozen serum samples to test the hypothesis that the appearance of autoantibodies precedes the diagnosis of SLE.

A review of military medical records identified 130 persons, some formerly and some currently on active duty, who met the criteria for SLE and for whom stored serum samples obtained before diagnosis were available.

Results confirmed their hypothesis. In 115 of the 130 patients with SLE (88 percent), at least one SLE autoantibody tested was present before the diagnosis (up to 9.4 years earlier; mean, 3.3 years).42

Diagnosis of lupus has refined itself over the last years. The use of the list of 11 criteria combined with ANA test has proven itself to be trustworthy. ANAs can be found in approximately 5% of the normal population, usually in low titers. These people usually have no disease. Titers of lower than 1:80 are less likely to be significant. (ANA titers of less than or equal to 1:40 are considered negative.) Even higher titers are often insignificant in patients over 60 years of age. Ultimately, the ANA result must be interpreted in the specific context of an individual patient's symptoms and other test results. It may or may not be significant in a given individual.43

Its becoming a very intriguing question to many scientists how ANAs and other autoantibodies maintain themselves in the human body without directly activating the immune response causing autoimmune diseases.

Treatment of lupus patients is expected to bloom within the near future. As present medicines develop better ways of relieving patients from symptoms and different methods are coming together to form specialized therapies, patients dreams of a permanent cure may proof itself to be more achievable then ever thought.