Please can you give a brief introduction to the symptoms of psoriasis and who it tends to affect?
The prevalence of skin disease exceeds that of obesity, hypertension or cancer. One in three individuals in the United States suffers with a skin disease, with ~2-3% of the American population suffering from psoriasis.
The costs involved in treating these patients is believed to exceed $1B, including over $350M in prescriptions alone.
Although psoriasis primarily affects the skin and joints (psoriatic arthritis), several co-morbidities, including inflammatory bowel disease, lymphoma, obesity and metabolic syndrome are associated with psoriasis.
Psoriasis patients also suffer from significant emotional burden including depression, mood disorders and suicidal thoughts. Recent evidence also suggests that psoriasis patients have an increased risk for developing and dying of cardiovascular disease (CVD; providing further argument for aggressive treatment of skin disease as a means of intervening and preventing CVD co-morbidity. Thus the socioeconomic costs of psoriasis are significant.
Psoriasis is a chronic, autoimmune disease that appears on the skin. It occurs when the immune system sends out faulty signals that speed up the growth cycle of skin cells. Psoriasis is not contagious.
There are five types of psoriasis. The most common form, plaque psoriasis, appears as raised, red patches covered with a silvery white build-up of dead skin cells. Psoriasis can occur on any part of the body.
What is currently known about the causes of this inflammatory autoimmune disease?
The cause of psoriasis remains unknown and a strict mitigating signal or a single antigenic target for psoriasis has yet to be identified.
A combination of human and animal studies have led to the understanding that in patients with a susceptible genetic background, some stimulus, perhaps an infection, leads to a coordinated series of signaling events involving cytokines that occurs between keratinocytes, endothelial cells, T cells, macrophages and dendritic cells that once started, initiates a vicious pro-inflammatory hyperproliferative cycle.
Once initiated this cycle perpetuates sustained inflammatory responses. Intervention at several points in this cycle results in clinical resolution; however durable remission and/or permanent clearance has not been achievable.
How is our knowledge of the causes of psoriasis limited and why is it necessary to perform further research in this field?
We don’t know what causes psoriasis and there is no cure. Current psoriasis therapies are directed towards sign/symptom relief and none represent a cure for this chronic illness.
Current treatments include topical therapy, phototherapy, and systemic administration of steroids and biologics. Many of the most effective therapeutics also have the greatest adverse reactions. Moreover, psoriasis can become resistant to specific therapies over time, and subsequently treatments are periodically changed to prevent both the development of drug resistance and the occurrence of adverse reactions. Therefore an on-going need for discovery of new biological targets and novel therapeutics exists.
Whereas great advances have been made in understanding the roles of the immune system and the epidermal components of psoriasis, and despite clear indications that psychological stress exacerbates disease, the contribution and significance of the cutaneous neural system to psoriasis pathogenesis remains poorly defined.
With respect to our newest funded grant numerous observations suggest that the nervous system plays a role in psoriasis including the symmetrical distribution of plaque on the body, perhaps reflective of peripheral sensory nerve-interactions with immunomodulatory networks; the increase in nerve fibers and their neuropeptides in involved psoriatic skin, and reports of disease exacerbation and onset linked with psychological stress or following skin trauma/Koebnerization, two known cutaneous nervous system activators.
Finally, the striking finding that psoriasis undergoes remission following loss of innervation, nerve function or nervous system injury provides compelling evidence of a contributory role for nerves in sustaining disease.
Taken together, these findings have led some investigators to suggest that psoriasis may be a neurogenic disease. While nerve-mediated signaling may not be sufficient to cause psoriasis, the presence of the nerves and their derived proteins may play critical roles in the cascade of events that initiate and sustain inflammation and acanthosis and may provide novel targets for developing therapeutic strategies.
© National Psoriasis Foundation 2012 Photographs taken by: Billy Delfs Photographer
You have recently been awarded a National Institutes of Health grant to study the role of the nervous system in psoriasis. How will the study build upon your existing research?
Recently published work by our group (Ostrowski et al., J Investigative Derm, 2011) provided experimental insight into the cellular and molecular mechanisms underlying the observation that psoriasis undergoes remission following loss of cutaneous innervation; such that experimental elimination of cutaneous nerves in a mouse model of psoriasis, called the KC-Tie2 mouse, lead to significant decreases in the number of two populations of immune cells, specifically CD11c+ dendritic and CD4+ T cells, and this occurs concomitant with decreases epidermal hyperplasia.
In follow up work, we observed similar nerve-mediated effects in two additional mouse models of psoriasis, providing further support that neural contributions to cutaneous inflammation occur across multiple mouse models of hyperproliferative skin disorders.
Of particular significance is that these effects were reversed with restoration of two nerve-derived peptides, called substance P (SP) and calcitonin related gene related peptide (CGRP) signaling, and were recapitulated following pharmacological inhibition of either SP or CGRP or chemical denervation targeting the secretion of both(using Botulinum neurotoxin A; Ward et al, 2012).
Importantly, these events occurred in a neuropeptide specific manner, such that SP exerted effects on CD11c+ and CD4+ T cell numbers, whereas CGRP altered CD4+ T cell numbers and epidermal thickness (acanthosis).
How do you plan to use the grant? Is your work likely to lead to the identification of new targets for drug development?
Our innovative, high risk-high reward grant proposes to advance the technical capability for addressing the molecular mechanism connecting nerves and psoriasis pathogenesis. We will utilize our strengths using in vitro tissue culture approaches and our expertise in generating and studying murine models of psoriasis.
Upon successful completion of our proposed work, we will have (1) identified CGRP and SP as critical sensory nerve-derived factor(s) required for sustaining chronic skin inflammation, specifically acanthosis and DC and T cell infiltration; and (2) identified the cellular targets affected by nerve-derived SP and CGRP as well as the potential mechanism(s) used to direct KCs, DCs and T cell response that translates to sustaining inflammation and acanthosis in psoriasis.
These aims should provide fundamental new knowledge regarding the role and contributions of nerve-cutaneous cell interactions to psoriasis pathogenesis. These experiments will confirm and give support to ideas previously only discussed in terms of anecdotal accounts of nerve alteration affecting skin presentation in psoriasis.
Identification of new drug targets for psoriasis inflammation is another direct consequence of successful execution of the aims. Taken together, the likelihood for the project to exert a sustained, powerful influence on the field is reasonably high.
Estimates suggest that psoriasis patients generally die 7 to 10 years earlier than those without the disease. Will your research shed any light on this statistic?
Not directly. Our group has a second NIH grant that began funding in 2012 that is specifically studying the mechanisms by which chronic skin specific inflammation promotes cardiovascular disease. That body of work will shed new insight into how and why this occurs, and is examining the importance of skin-specific molecules, a specific type of circulating immune cell, and whether current biologics used to treat psoriasis will be effective at improving the cardiovascular disease co-morbidities.
The current grant looking at nerves, will only provide additional understanding of the role of nerves in sustaining skin inflammation, but may open up new avenues for treating psoriasis, and thus indirectly improve cardiovascular disease co-morbidities.
How do you think the future of psoriasis treatments will develop?
I think we (the entire community of Psoriasis researchers), are gaining a better understanding of the disease pathogenesis each and every year. As we learn more about the genetics of the disease, how the disease is initiated, how it’s sustained, we identify new cellular and molecular targets for developing treatment strategies around.
There are an amazing number of options for patients currently to help treat their disease, improve their health, and change for the better, their quality of life. I think this is only going to continue.
The new drugs for psoriasis that are coming through the pipeline of clinical trials currently are very exciting. I hope that in the future, we can identify new efficacious treatment options that are designed for patients who are reluctant to use biologics or who cannot afford them.
Where can readers find more information and keep up to date with your work?
A great resource for Psoriasis patients in the National Psoriasis Foundation webpage – www.psoriasis.org
The work my lab publishes can be followed at:
And they can always email me: Nicole.ward[AT]case.edu
About Dr Nicole Ward
A rising star in the psoriasis research field, Nicole L. Ward, PhD, tenured Associate Professor of Dermatology and Neurosciences at Case Western Reserve University School of Medicine has accomplished a great deal in her relatively young professional career.
A prolific researcher, Dr. Ward has been awarded 17 grants. Of those, three were awarded to her by the National Institutes of Health within the 2013 fiscal year. Her diverse work in psoriasis investigates the role and importance of interleukin-17C (IL-17C) in the onset and escalation of the disease; the link between psoriasis and heart attack and stroke; and finally, nervous system proteins that help sustain the skin disease. Dr. Ward has published 38 peer-reviewed manuscripts and 57 abstracts.
A respected member of the dermatology community, Dr. Ward sits on the editorial boards of the Journal of Investigative Dermatology and the International Journal of Clinical and Experimental Pathology. In 2013, she was elected to the Society for Investigative Dermatology’s Scientific Program committee. Through her career, Dr. Ward has received numerous awards for both her research and teaching.
In 1999, Dr. Ward earned her PhD in Anatomy & Neurobiology from Dalhousie University in Nova Scotia, Canada. Her subsequent post-doctoral work was conducted in the Department of Medical Biophysics and the Division of Molecular and Cell biology at the University of Toronto, Sunnybrook Research Center. Dr. Ward joined the faculty of Case Western Reserve in 2003.
© National Psoriasis Foundation 2012 Photographs taken by: Billy Delfs Photographer
Sympathetic nervous system and immune interplay: Key to metabolic regulation