Lupus and the Skin: Manifestations, Causes, Treatments, and Research Horizons

1. Introduction
2. Manifestations (Indications) of Lupus
3. Skin Lesions Associated with Cutaneous LE
4. Causes of Lupus
5. Lupus Testing
6. Treatments
7. Research Horizons

Skin is relevant to and reflective of disease. Lupus Erythematosus (LE) is a difficult disease to classify in terms of skin findings because it can cause many different types of skin lesions, and the challenge is to determine how these lesions come about, how they fit together, and how best to treat them. By understanding the basis of these skin lesions, scientists can develop more effective therapies.

Manifestations (Indications) of Lupus

Lupus can have systemic manifestations or cutaneous manifestations. Rheumatologists have developed a list of eleven criteria based on clinical observations and laboratory test results that are used to diagnose Systemic Lupus Erythematosus (SLE). Of the eleven criteria, four are skin findings:

• Malar rash
• Discoid lesions
• Photosensitivity
• Oral ulcers

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Hard Palate Ulcer

Cutaneous Lupus Erythematosus, or skin lupus, can exist with or without systemic manifestations. The most second most common initial presentation of lupus is a skin rash or other skin lesion—a clinical presentation that affects 70-80% of lupus patients at some point in their lives. Almost half of all lupus patients with a skin lesion will have some degree of debilitation or vocational handicap because of it.

Rheumatologists have broken down cutaneous LE into specific and non-specific skin lesions. Specific skin lesions are those that are only associated with LE patients, whereas non-specific skin lesions could be found in patients with LE but could also be the result of another disease. LE specific lesions fall into one of three categories:

1. Acute Cutaneous LE (ACLE) often presents as a “butterfly rash”. The butterfly rash has an abrupt onset and can last for hours or days, and usually heals without scarring. Typically, it is localized on the face, but it could occur anywhere on the body. Variations of this rash have been observed, including bullous formations or blisters. Systemic manifestations are common with ACLE.
   
   
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   Examples of a Butterfly Rash
   
   
   
2. Subacute Cutaneous LE (SCLE) occurs in one of three forms: annular, psoriasiform, or a combination of each.
   
   Annular, or ring-like, lesions commonly appear on the chest area but could also occur in other areas of the body. Symmetric in shape, these lesions are extremely sensitive to the sun but will heal without scarring. A large percentage of patients who have annular lesions will also have systemic findings.
   
   Psoriasiform lesions are thick and scaly, similar in formation and appearance to psoriasis, and usually appear on the knees but could also develop in other areas of the body.
   
   
3. Chronic Cutaneous LE (CCLE) is the third main category of specific skin lesions in lupus. Under this umbrella are several sub-types, including: discoid, hypertrophic, lupus profundus, lupus tumidus, and chillblains.
   
   
   • Discoid lupus (DLE) is the most common form of chronic cutaneous lupus. It typically begins as a sharply demarcated, scaly lesion that evolves into a larger scarring plaque with atrophy or loss of skin. Follicular involvement is a prominent feature, causing scales in follicles and hair loss. Ranging from mild to severe, DLE predominantly occurs on the head or neck, particularly on the scalp and around the ears, but can also occur on other areas on the body, including the inside of the mouth. Systemic manifestations can occur in some patients with DLE.
     
     
     
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     Examples of discoid rash in lupus erythematosus. This rash occurs in patients with systemic lupus and with discoid lupus.
     
     
     
   • Hypertrophic lupus (HLE) causes a raised bump similar to a wart and usually develops at sites of trauma.
     
     
   • Lupus profundus (LEP) is a deep dermal or subcutaneous nodule. The overlying skin may be attached to lesions but will usually heal without scarring. It typically affects the upper arms but may develop on the head, chest, or legs.
     
     
   • Lupus tumidus (LET) presents as indurated plaques (hardened patches) or broad lesions that are slow to heal. Less is known about this form of chronic cutaneous lupus, and physicians will often take a biopsy to find out if the lesion has the typical features of lupus lesions before making a diagnosis.
     
     
   • Chilblains lupus is associated with itchy, cold sensations in the extremities and toes as well as painful, dark red swelling.

There are many LE non-specific skin conditions as well. Some of the more common conditions are:

• Alopecia, or thinning hair.
  
  
  
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  Hair loss, particularly frontal, with short, broken hairs, is common.
  
  
  
• Telangiectasia are dilated blood vessels
  
  
• Vasculitis is severe inflammation of blood vessels
  
  
• Raynaud’s Phenomenon constricts the blood vessels in the fingers, toes, ears, and nose, causing these areas to become extremely cold. Unlike chilblains, Raynaud’s can cause permanent damage to the skin when left untreated.

Lupus is a complex, multi-factorial autoimmune disease. While the immune system is poised to tackle unfamiliar pathogens, sometimes it misfires and attacks the body’s own tissues, ultimately causing an autoimmune disease. Little is known about why this happens, but in general, it is believed that both genetic and environmental factors play a significant role.

Genetic Factors

Lupus is a complex disease not only because there are genetic and environmental factors, but also because the autoimmune response is likely determined by more than one gene. Susceptibility to lupus is associated with the human leukocyte antigen genes (HLA), a system of genes involved in regulating the immune system. HLA genes and proteins are important in controlling the immune response as well as the autoimmune response. Precisely how these genes operate in lupus is still unknown.

There is also mounting evidence suggesting that there are disturbances in the several pathways of the immune system, but it is difficult to identify the genes that are responsible for these disturbances and understand how they orchestrate the disease process. The challenge is filling in the gaps of how the genes and environmental factors work together to cause the immune disregulation that leads to autoimmunity.

Environmental Factors

While some individuals may be genetically predisposed to developing lupus, it is believed that something in the environment actually triggers the autoimmune response. Unknown are the specific environmental factors that cause this response. Stress, a viral infection, or a reaction to certain medications may be to blame.

Take monozygotic twins, for example. These twins originate from the same zygote, and although the twins are genetically identical, it may be that only one of them develops lupus. Because these twins have the same genes, which clearly are predisposing, environmental factors must be playing a role.

Laboratory Tests for Cutaneous LE:

Anti-nuclear antibodies are proteins generated by the immune system in response to components in the nucleus, or command center, of cells. These antibodies are found more often in the blood of patients with acute cutaneous lupus than in the other forms of cutaneous lupus.

Double stranded DNA antibody, RO/SSA antibody, and other specific antibodies have also been found in patients with acute cutaneous lupus as well as subacute cutaneous lupus.

The lupus band test is another method used to identify skin lesions caused by lupus. In this test, a biopsy is stained and antibodies that have deposited into the skin will illuminate under a microscope.

A tissue section will also provide insight into the pathology of a skin lesion. Lupus lesions will appear scaly, exhibit degeneration between the epidermis and the dermis, and exhibit inflammation caused by an increase in the number of lymphocytes.

Treatments for cutaneous lupus are determined by the severity of each case. It is a dynamic process, and one strategy doesn’t work for everyone. Tailored and individualized therapy, following the course of disease in a given patient, is often required.

Topical treatments are among the more common treatments, and they include steroid creams, ointments or intralesional injections, retinoids, and sunscreens.

Antimalarials and immunosuppressives have also proven to be effective in many individuals. Immunosuppressive agents such as methotrexate, azothioprine, cyclophosphamide are often useful in severe and/or difficult cases. These agents, however, target the immune system broadly and can be associated with significant side effects.

Clinical trials are currently underway world-wide to explore the use of new immunomodulatory forms of therapy, the so-called 'biologics', which target specific components of the immune system and promise less general compromise of general immune function.

Innovative tools continually emerge that help scientists better understand lupus and its skin findings at the molecular level. One example is the gene chip, which allows researchers to look at thousands of genes at one time from samples of lupus tissue and blood. By comparing the samples of healthy tissue and blood to samples from a lupus patient, scientists can identify variations in gene expression and disruptions in pathways based on noted patterns.

Recent work has revealed that expression patterns of certain sets of genes in lupus skin and blood are very similar, yet distinct from healthy skin and blood. Many of the genes that are expressed in lupus patients play a role in their immune system’s response as well as other processes. By understanding lupus at the molecular level—the pathways and exact genes that are disrupted—scientists can better understand the process of disease and develop more precise therapies.

SLE Workshop at HSS