2001 Skin, General Immune System Function, Human Lupus Biology
Sensitivity to sunlight, or photosensitivity, is a significant problem for lupus patients because ultraviolet (sun) light can be extremely harmful. Sunlight can trigger flares of systemic lupus, flares that affect such vital internal organs as the heart, kidneys, brain and blood. It can also lead to flares of lupus skin eruptions.
In lupus, photosensitivity most frequently presents itself as a butterfly rash over the nose and central face.
With LRI funding, Dr. Werth and her team at the University of Pennsylvania pursued innovative work in this area and eventually identified a variant of the human gene for tumor necrosis factor-alpha as a cause of photosensitivity in lupus.
“A lot of traits vary from person to person, such as eye color, hair color, and blood type. When a variant trait is present in at least one percent of the population, it's called a polymorphism,” explained Dr. Werth. “Nearly all human genes also show small differences from person to person. What's important from the standpoint of medical science is when the small genetic differences in a particular gene contribute to the development of a particular disease.”
The variants can help us identify who may be predisposed to the disease and also help us better determine why the disease develops.
With her LRI support, Dr. Werth’s crucial discovery was made.
“Our LRI-funded research project allowed us to pursue novel translational research, namely studying the effects of this polymorphism in people and in cultured cells—a type of translational research not typically funded through the NIH,” said Dr. Werth.
“Most important, we've found that a large percentage of patients with subacute cutaneous lupus erythematosus (S.C.L.E.), a highly photosensitive form of lupus, have one or even two copies of the TNF variant gene. Thus, when they are exposed to sunlight, the gene becomes overactive, a large quantity of TNF is produced, nearby skin cells undergo apoptosis, and the immune system becomes stimulated.”
Major Contribution: CLASI - Cutaneous Lupus Erythematosus Disease Area and Severity Index
Now Dr. Werth has developed a new system to measure the severity of disease—CLASI—that is “My LRI-funded work developed an interest in developing this outcome measure for cutaneous lupus,” she explained in 2010. The outcome measure is being used being used in clinical trials to assess the effectiveness of experimental treatments for lupus, even in international trials.
“Development of the CLASI helped to get development of an investigator-initiated trial of a thalidomide derivative for cutaneous lupus,” she added
CLASI also is being used in an NIH-funded prospective cutaneous (skin) lupus database that has enabled researchers to conduct studies related to the quality of life with skin lupus, as well as determine information about therapeutic needs for people with this complication.
Annual LRI research conferences were key in alerting Dr. Werth to the need for this type of structured and systematic clinical research framework. She has since set up a post-MD clinical training program that combines dermatology and internal medicine, which will in turn increase the number of specialists able to research and treat cutaneous lupus.
“The LRI grant really provided me with the unique opportunity to develop the patient-oriented research, an area that, in the past, was not typically funded by the NIH. Our findings have now led to grant funding from the NIH to support additional translational research (applying laboratory studies to patients and studying what we learn from patients in the laboratory).” – Dr. Werth
IL-12 completely blocks ultraviolet-induced secretion of tumor necrosis factor alpha from cultured skin fibroblasts and keratinocytes. Werth VP, Bashir MM, Zhang W. J Invest Dermatol. 2003 Jan;120(1):116-22.
Ultraviolet-B recruits mannose-binding lectin into skin from non-cutaneous sources. Lokitz ML, Zhang W, Bashir M, Sullivan KE, Ang G, Kwon EJ, Lin JH, Werth VP. J Invest Dermatol. 2005 Jul;125(1):166-73.
The CLASI (Cutaneous LE Disease Area and Severity Index): an outcome instrument for cutaneous lupus erythematosus. J Invest Dematol 2005 125:889-894.
Failure of physiologic doses of pure UVA or UVB to induce lesions in photosensitive cutaneous lupus erythematosus: implications for phototesting. Lokitz ML, Billet S, Patel P, Kwon EJ, Sayre RM, Sullivan KE, Werth VP. Photodermatology, Photoimmunology & Photomedicine 2006 22:290-296.
Skin involvement and outcome measures in systemic autoimmune diseases. Albrecht J, Atzeni F, Baldini C, Bombardieri S, Dalakas MC, Demirkesen C, Yazici H, Mat C, Werth VP, Sarzi-Puttini P. Clin Exp Rheumatol 2006 24 (1Suppl 40):S52-S59, 2006.
Cutaneous Lupus: Insights into Pathogenesis and Disease Classification. Werth VP. Supplement to the Hospital for Joint Disease Bulletin 2007 65:200-204.
Pathophysiology of Cutaneous Lupus Erythematosus. Lin JH, Dutz J, Sontheimer R.D., Werth VP. Clinical Reviews in Allergy and Immunology 2007 33:85-106.
The CLASI is a useful clinical instrument to separately follow activity and damage during therapy of cutaneous lupus erythematosus. Bonilla-Martinez Z, Albrecht J, Taylor L, Okawa J, Werth VP Arch Dermatol2008 144: 173-180.
The Cutaneous Lupus Erythematosus Disease Activity and Severity Index (CLASI) expansion for rheumatology and dermatology. Krathen MS, Dunham J, Gaines E, Grove G, Junkins-Hopkins J, Kim E, Kolasinski SL, Kovarik C, Kwan-Morley J, Okawa J, Propert K, Rogers N, Rose M, Thomas P, Troxel AB, Van Voorhees A, Von Feldt J, Weber AL, Werth VP. Arthritis Care & Research2008 59:338-344.
Development of outcome measures for autoimmune dermatoses. Gaines EG, Albrecht J, Werth, VP. Archives of Dermatological Research 2008 300:3-9.
QoL and disease severity in a CLE pilot study. Gaines E, Bonilla-Martinez Z, Albrecht J, Taylor L, Okawa J, Troxel AB, Werth VP Arch Dermatol (letter) 2008 144:1061-1062.
UVB and pro-inflammatory cytokines synergistically activate TNF-alpha production in keratinocytes through enhanced gene transcription. Bashir MM, Sharma M, Werth V.P. J Invest Dermatol 2009 129: 994-1001.
TNF-alpha production in the skin. Bashir MM, Sharma MR, Werth VP. Arch Derm Res 2009 301: 87-91.
Lenalidomide for the Treatment of Resistant Discoid Lupus Erythematosus. Shah A, Albrecht A, Bonilla-Martinez Z, Okawa J, Rose M, Rosenbach M, MD, Werth VP. Arch Dermatol 2009 45:303-306.
Cross-sectional analysis of a collaborative web-based database for lupus erythematosus associated skin lesions: 114 prospectively enrolled patients. Moghadam-Kia S, Chilek K, Gaines E, Costner, M, Rose M, Okawa J, Werth V. Arch Dermatol 2009 145:255-260.
The risk of ultraviolet radiation exposure from indoor lamps in lupus erythematosus. Klein RS, Werth VP. Autoimmunity Rev 2009 8:320-324.
Analysis of compact fluorescent lights for use by patients with photosensitive conditions. Klein RS, Werth VP, Dowdy JC, and Sayre RM. Photochem Photobiol 2009 85:1004-10.
Mechanistic studies of effects of UVB on the TNFa promoter. Bashir MM, Werth V.P. [Submitted for publication.]
Although it was the same year has her LRI grant award, Dr. Werth considers the NIH “Mid-Career Investigator Award in Patient Oriented Research” that she received in 2001 an extension of her LRI work. This NIH grant for patient-oriented research, in the amount of $550,000, was eventually renewed for another 5 years—at $160,000 per year. Additionally, in 2009 Dr. Werth was awarded a 2-year $42,000 NIH CTSA (Mentor) grant for examining photosensitivity in cutaneous lupus. And in 2005, she received a renewal of her $500,000 Veteran's Award Merit Grant.
In this 2002 interview, Dr. Werth describes her work in detail.
LRI: Can you describe your LRI-funded research project?
Dr. Werth: A lot of traits vary from person to person, such as eye color, hair color, and blood type. When a variant trait is present in at least one percent of the population, it's called a polymorphism. Nearly all human genes also show small differences from person to person. What's important from the standpoint of medical science is when the small genetic differences in a particular gene contribute to the development of a particular disease. These variants can help us identify who may be predisposed to the disease and also help us better determine why the disease develops. With support from the LRI, we've been studying human genetic polymorphisms that cause sensitivity to sunlight.
LRI: What have you discovered?
Dr. Werth: We've identified a variant, or polymorphism, of the human gene for tumor necrosis factor-alpha (TNF) that shows increased activity in response to sunlight. This finding is crucial because TNF had been shown by other labs to stimulate a particular pathway, called apoptosis, which kills cells. As apoptosis kills the skin cells, intracellular proteins move to the cells' surface, where they stimulate an immune reaction. The immune system makes new antibodies against these proteins and triggers further inflammation. Our LRI-funded research project allowed us to pursue novel translational research, namely studying the effects of this polymorphism in people and in cultured cells—a type of translational research not typically funded through the National Institutes of Health (NIH). Most important, we've found that a large percentage of patients with subacute cutaneous lupus erythematosus (S.C.L.E.), a highly photosensitive form of lupus, have one or even two copies of the TNF variant gene. Thus, when they are exposed to sunlight, the gene becomes overactive, a large quantity of TNF is produced, nearby skin cells undergo apoptosis, and the immune system becomes stimulated.
LRI: All LRI Novel Research Program grant recipients are doing "novel," or new, work in lupus. What is novel about your research?
Dr. Werth: A large number of laboratories are devoting substantial efforts to finding genetic polymorphisms that are associated with different diseases. True associations are very difficult to find, and most of the published work of this type has unfortunately not stood up under scrutiny by other laboratories. Our laboratory was the first to demonstrate the role of TNF polymorphisms in causing photosensitivity in lupus. Most important, an independent laboratory using a different population of lupus patients has already confirmed our discovery. The effect is real. We're now identified two genes, one involved with production of skin cell death (TNF), and the other with clearance of dying cells (mannose-binding lectin, MBL), that are involved in autoimmune photosensitivity. It's now clear that genetic susceptibility to the S.C.L.E. variant of lupus involves a combination of genes that are involved in either increasing the damage to cells caused by ultraviolet light and/or slowing the body's disposal of these damaged cells.
LRI: What other breakthroughs have you uncovered in photosensitive lupus?
Dr. Werth: We have made progress in three general areas. In addition to our findings previously referenced, we recently found more TNF production in cells from patients with photosensitive lupus relative to normal controls, suggesting that additional genetic variants are associated with increased TNF production in response to sunlight.
Second, based in part on this work, we're looked at polymorphisms of the human gene for the mannose-binding lectin (MBL), a protein involved in the disposal of dying cells. We've found that underactive variants of the MBL gene are associated with dermatomyositis, another photosensitive disease clinically similar to lupus. This discovery indicates that deficiencies in proteins involved in clearing sunlight-damaged cells, in addition to overproduction of molecules that cause damage, contribute to photosensitive autoimmune disease. These results were recently published in the Journal of Investigative Dermatology (119:1394-1399, 2002). Additionally, there is evidence that variants of MBL also contribute to problems with clearance of dead cells in some cases of systemic lupus.
Third, to see if person-to-person variations in the immune system itself could affect the response to sunlight, we found that patients with the most photosensitive forms of skin lupus have a specific polymorphism of an immune gene called HLA-DR3 that seems to work in concert with overproduction of TNF . This discovery suggests that both genes are needed to develop the type of immune response that causes photosensitive lupus. These results were recently published in the Journal of Investigative Dermatology (119:617-620, 2002).
LRI: What is the significance of your findings for lupus patients?
Dr. Werth: Our results now let us think about different categories of drugs for treatment of photosensitivity. Drugs like antimalarials and thalidomide that inhibit TNF as part of their mechanism of action are already used to treat the skin manifestations of lupus. Our findings provide a rationale to test some of the newer drugs in development that inhibit TNF. However, there is some concern about a number of side effects from these therapies, so they need to be systematically studied in large clinical trials. As we determine the combination of genetic variants that trigger photosensitivity, it may be possible to target abnormalities, such as MBL deficiency and the actions of HLA-DR3, specifically. Also, as we better understand the wavelengths of light that trigger disease, we can develop optimal sunscreens that will hopefully improve the ability to block the harmful effects of sunlight.
LRI: The LRI is often called an "incubator" for new ideas. Have your findings led to additional research projects in photosensitive lupus?
Dr. Werth: The LRI grant really provided me with the unique opportunity to develop the patient-oriented research, an area that, in the past, was not typically funded by the NIH. Our findings have now led to grant funding from the NIH to support additional translational research (applying laboratory studies to patients and studying what we learn from patients in the laboratory). There is a lot of work to do to define further genetic risk factors and refine our understanding of the mechanisms by which these genetic variants work to produce photosensitivity.
Rev. July 2010