Psoriasis: symptoms and recent research
There have been several interesting advances in the study of psoriasis recently, including the analysis of a genetic component (1,2), the effectiveness of psoriasin as a target for therapy (4), an examination of the T-cell–driven immune response observed during flare-ups (6), and the report of positive results in a Phase II clinical trial for treatment of plaque psoriasis symptoms (7-9). This review includes a background on the symptoms and manifestations of psoriasis, along with a brief description of current advances in this field.
What is Psoriasis?
Psoriasis is a chronic, non-contagious autoimmune disease that affects the skin and joints. It commonly causes red, scaly patches to appear on the skin. The scaly patches caused by psoriasis, called psoriatic plaques, are areas of inflammation and excessive skin production. Skin rapidly accumulates at these sites and takes on a silvery-white appearance. Plaques frequently occur on the skin of the elbows and knees, but can affect any area.
The disorder is a chronic recurring condition that varies in severity from minor localized patches to complete body coverage. Fingernails and toenails are frequently affected. Psoriasis can also cause inflammation of the joints, which is known as psoriatic arthritis. Ten to fifteen percent of people with psoriasis have psoriatic arthritis.
The cause of psoriasis is not known, but it is believed to have a genetic component. Factors that may aggravate psoriasis include stress, withdrawal of systemic corticosteroid, excessive alcohol consumption, and smoking. There are many treatments available, but because of its chronic recurrent nature psoriasis is a challenge to treat.
Psoriasis is probably one of the longest known illnesses of humans and simultaneously one of the most misunderstood. Some scholars believe psoriasis to have been included among the skin conditions called tzaraat in the Bible. In more recent times psoriasis was frequently described as a form of leprosy. While psoriasis may have been visually, and later semantically, confused with leprosy, it was not until 1841 that the condition was finally given the name ''psoriasis''; the name is derived from the Greek word ''psora'' which means ''to itch''.
Genetic Component to Psoriasis: CARD14
The first gene linked to the common form of Psoriasis has been identified by scientists led by a group at Washington University School of Medicine in St. Louis. This research is published May 4 in two separate papers in The American Journal of Human Genetics.1,2
Like other common diseases, psoriasis runs in families and has been thought to have a genetic component, but it's been difficult to pin down the genes involved. Using the latest DNA technology to sequence all of a patient's genes, the authors uncovered a rare CARD14 mutation in a large family of northern European descent in which plaque psoriasis was prevalent. They also found the mutation in the one-third of family members who had developed psoriatic arthritis, suggesting that the same rare mutation can play a role in both conditions. The scientists also identified another rare CARD14 mutation in an extended family from Taiwan that had a large number of plaque psoriasis cases.
The researchers also found a CARD14 mutation in a 3-year-old girl with a severe case of pustular psoriasis, a rare form of psoriasis. Neither of the girls' parents had mutations in CARD14, indicating that the rare mutation was not inherited but had occurred spontaneously. This is significant because it tells us that CARD14 mutations alone are enough to lead to psoriasis, possibly after an early trigger such as an infection.
The scientists showed that in specialized skin cells called keratinocytes, mutations in CARD14 increase the activity of NF-kappaB, a protein that turns on genes. This protein increases the production of certain signaling molecules that attract inflammatory cells to the skin, unleashing a vicious cycle of inflammation that is so notable in psoriasis. Psoriasis affects the life cycle of skin cells, causing them to mature rapidly in just a few days and accumulate to form thick, scaly patches. Interestingly, in psoriasis patients with CARD14 mutations, the researchers found the gene's activity was increased in the skin's upper layers, which may explain the flakiness that characterizes the condition.3
Psoriasin as a Target for Therapy
An important component of Psoriasis is the psoriasin protein (S100A7), which is abundant in psoriasis-affected skin but rarely in normal skin. The same protein is also assumed to be a factor in the development of breast cancer. In a study on cultured skin cells, researchers have illustrated that the interaction between psoriasin, oxygen free radicals, and vascular endothelial growth factors (VEGF) leads to significantly increased cell division and growth of new blood vessels.4 When the formation of psoriasin was blocked, the expression of VEGF also decreased.
Previous studies in mice have shown that angiogenesis inhibitors reduce not only neovascularization but also inflammation and excessive cell division. Attempts to inhibit the growth factor VEGF have resulted in unwanted side effects because it exists in normal tissue where it contributes to wound healing. The researchers propose that since psoriasin is expressed specifically only in diseased psoriatic skin, that inhibitors against this protein may be highly selective and effective against the disease, and that the risk for side effects would be minimal. Currently, palliative treatments such as vitamin D, cortisone, light and low doses of chemotherapeutics are used. More recently, some antibody-based drugs are being investigated; however they are very expensive and not free from side effects.5
A Fully Human anti-IL17A Monoclonal Antibody as Therapy for Psoriasis
Novartis has announced positive results from three Phase II trials showing that AIN457 (secukinumab) produced a quick and significant improvement of symptoms in patients with moderate-to-severe plaque psoriasis.7-9
In one study, 81% of patients receiving AIN457 150mg subcutaneously once a month experienced at least a 75% improvement of psoriasis signs and symptoms as measured by PASI (Psoriasis Area and Severity Index) vs 9% for placebo at week 12 (p<0.001).7 In another study, results also showed that 83% of patients who were given an intravenous starting dose of AIN457 experienced at least a 75% improvement of symptoms vs. 10% for placebo.8 A third study showed that receiving AIN457 in the first month was beneficial to 55% of patients vs. 2% for placebo at week 12 (p<0.001).9
These data suggest that AIN457 could potentially bring about a considerable improvement in the lives of patients with moderate-to-severe plaque psoriasis by producing a rapid response and substantial relief of symptoms. AIN457 is a fully human, targeted monoclonal antibody that specifically and rapidly binds to and neutralizes interleukin-17A (IL-17A), an inflammatory cytokine implicated in a number of immune-mediated diseases, including psoriasis. The Phase III program for these potential indications has already commenced.
- Jordan,C.T. at al., PSORS2 is Due to Mutations in CARD14. The American Journal of Human Genetics, 2012; DOI: 10.1016/j.ajhg.2012.03.012
- Jordan,C.T et al., Rare and Common Variants in CARD14, Encoding an Epidermal Regulator of NF-kappaB, in Psoriasis. The American Journal of Human Genetics, 2012; DOI: 10.1016/j.ajhg.2012.03.013
- ScienceDaily (Apr. 19, 2012) First Gene Linked to Common Form of Psoriasis Identified http://www.sciencedaily.com/releases/2012/04/120419121436.htm
- Shubbar, E. et al., Psoriasin (S100A7) increases the expression of ROS and VEGF and acts through RAGE to promote endothelial cell proliferation. Breast Cancer Research and Treatment (2011); DOI: 10.1007/s10549-011-1920-1925.
- ScienceDaily (Jan. 10, 2012) New Hope for Better Treatment of Psoriasis http://www.sciencedaily.com/releases/2012/01/120110114448.htm
- Eyerich, S. et al., (2011) N Engl J Med 365: 231-238.
- Kapp K.A. et al. 'Secukinumab efficacy and safety preliminary results from a phase II subcutaneous dose-ranging study in the treatment of moderate-to-severe plaque psoriasis.' Presented at: 20th Congress of the European Academy of Dermatology and Venereology; 20-24 October, 2011; Lisbon, Portugal. Oral presentation FC01.5.
- Papp K.A. et al. 'Secukinumab, a novel fully human antibody to interleukin-17A, in the treatment of moderate-to-severe plaque psoriasis: Efficacy and safety interim results from a phase II intravenous induction dose-ranging study.' Presented at: 20th Congress of the European Academy of Dermatology and Venereology; 20-24 October, 2011; Lisbon, Portugal. Oral presentation FC01.7.
- Rich P.A. et al. 'Secukinumab, a new fully human monoclonal anti-Interleukin-17A antibody, in the treatment of moderate-to-severe plaque psoriasis: Interim efficacy and safety data from a phase II regimen-finding trial.' Presented at: 20th Congress of the European Academy of Dermatology and Venereology; 20-24 October, 2011; Lisbon, Portugal. Oral presentation FC01.
Selected Psoriasis Related Antigens and Antibodies
|C1340-03B||CARD4 (Caspase recruitment domain 4, NOD1, Nod1, Caspase recruitment domain family member 4)||Pab||Gt x||Hu|
|C1340-04A||CARD 6 (CARD containing inhibitor of Nod1 and Cardiak-induced NF-kB activation, Caspase recruitment domain family, member 6, Caspase recruitment domain protein 6, CINCIN1)||Pab||Gt x||Hu|
|C1340-08||CARD17 (Caspase Recruitment Domain Family, Member 17, INCA, Inhibitory Caspase Recruitment Domain Protein)||Pab||Gt x||Hu|
|C1350-01C||CARD 9 (Caspase recruitment domain family member 9 )||Pab||Rb x||Hu|
|C5820-01A||CLAN (CARD 12, CARD LRR and NACHT containing protein 1, CARD LRR and NACHT containing protein, Caspase recruitment domain containing protein 12, CLAN 1, CLAN A, CLAN, CLAN B, CLAN C, CLAN D, Clan protein, CLAN1, CLANA, CLANB, CLANC, CLAND, CLR 2.1, CLR2.1, ICE protease activating factor, IPAF, NLR family CARD domain containing 4, NLRC 4, NLRC4)||Pab||Rb x|
|C5820-01B||CLAN (NLR Family CARD Domain-containing Protein 4, CARD, LRR, and NACHT-containing Protein, Clan Protein, Caspase Recruitment Domain-containing Protein 12, Ice Protease-activating Factor, Ipaf, NLRC4, CARD12, CLAN1, IPAF, UNQ6189/PRO20215)||Pab||Rb x||Hu|
|C5820-01C||CLAN (NLR Family CARD Domain-containing Protein 4, CARD, LRR, and NACHT-containing Protein, Clan Protein, Caspase Recruitment Domain-containing Protein 12, Ice Protease-activating Factor, Ipaf, NLRC4, CARD12, CLAN1, IPAF, UNQ6189/PRO20215)||Pab||Rb x||Hu|
|C5820-01D||CLAN (NLR Family CARD Domain-containing Protein 4, CARD, LRR, and NACHT-containing Protein, Clan Protein, Caspase Recruitment Domain-containing Protein 12, Ice Protease-activating Factor, Ipaf, NLRC4, CARD12, CLAN1, IPAF, UNQ6189/PRO20215)||Pab||Rb x||Hu|
|I0610-11B||Ice Protease Activating Factor (IPAF, Caspase Recruitment Domain Containing Protein 12, CARD12, CARD LRR and NACHT Containing Protein 1, CLAN1, CLANA, CLANB, CLANC, CLAND, Clan Protein, CLR2.1, NLR Family CARD Domain Containing 4, NLRC4, UNQ6189/PRO20215)||Pab||Rb x||Hu|
|I0610-12||Ice Protease Activating Factor (IPAF, Caspase recruitment domain containing protein 12, CARD12, CARD LRR and NACHT Containing Protein 1, CLAN1, CLANA, CLANB, CLANC, Clan Protein, CLR2.1, NLR Family CARD Domain Containing 4, NLRC4)||Pab||Rb x|
|I0620-06||Iceberg (Caspase-1 Inhibitor Iceberg, Caspase Recruitment Domain Family Member 18, Caspase Recruitment Domain-containing Protein 18, CARD18, pseudo-ICE, UNQ5804/PRO19611)||Pab||Gt x||Hu|
|S0051-85F||S100A7 (Protein S100-A7, Psoriasin, S100 Calcium-binding Protein A7, PSOR1, S100A7C)||Pab||Gt x||Hu|
|S0051-85H||S100A7 (Protein S100-A7, Psoriasin, S100 Calcium-binding Protein A7, PSOR1, S100A7C)||Mab||Mo x||Hu|
|S0051-85J||S100A7 (Protein S100-A7, Psoriasin, S100 Calcium-binding Protein A7, PSOR1, S100A7C)||Mab||Mo x||Hu|
|M1203-04H||Macrophage, Monocyte Chemotactic Protein-1, aa24-99, Recombinant, Human (MCP-1, Chemokine C-C Motif Ligand 2, CCL2, GDCF-2, HC11, HSMCR30, JE, MGC9434, Monocyte Chemoattractant Protein 1, Monocyte Chemotactic and Activating Factor, Monocyte Chemotactic Protein 1, Monocyte Secretory Protein JE, Small inducible cytokine A2, SCYA2, Small Inducible Cytokine Subfamily A Cys-Cys Member 2, SMC-CF)|
|M1203-02H||Macrophage, Monocyte Chemotactic Protein-1 (MCP-1, CCL2, JE)||Mab||Mo x||Hu|
|I8439-04B||Interleukin 17, Recombinant, Human (IL-17, CTLA8, IL-17A, Interleukin-17A precursor, Cytotoxic T-lymphocyte-associated antigen 8)|
|I8439-10D||Interleukin 17, Recombinant, Human (IL-17, CTLA8, IL-17A, Interleukin-17A precursor, Cytotoxic T-lymphocyte-associated antigen 8) (Human 293 Cells)|
|I8439-04L||Interleukin 17 (IL-17, CTLA8, IL-17A, Interleukin-17A Precursor, Cytotoxic T-lymphocyte-associated Antigen 8)||Mab||Rt x||Mo|
|I8439-04L1||Interleukin 17 (IL-17, CTLA8, IL-17A, Interleukin-17A Precursor, Cytotoxic T-lymphocyte-associated Antigen 8) (Biotin)||Mab||Rt x||Mo|
|I8439-04P||Interleukin 17 (IL-17, CTLA8, IL-17A, Interleukin-17A Precursor, Cytotoxic T-lymphocyte-associated Antigen 8)||Pab||Rb x||Mo|
|I8439-04P1||Interleukin 17 (IL-17, CTLA8, IL-17A, Interleukin-17A Precursor, Cytotoxic T-lymphocyte-associated Antigen 8) (Biotin)||Pab||Rb x||Mo|