More work needed to advance understanding of genetics in psoriasis

It is well known that psoriasis is a complex, multifactorial disease for which the genetic background plays a key role.

However, little is known about the extent to which genetics determines disease severity and treatment outcomes.

Since 2007, researchers have worked to identify psoriasis genetic mutations through family studies and genome-wide association studies performed on cohorts of large numbers of psoriasis cases and controls. Those studies helped pave the way for better understanding of disease biology, with the identification of more than 80 genetic loci associated with disease susceptibility. Additional associations have been discovered between psoriasis and a variety of human leukocyte antigen (HLA) genes, among others.

Genetic variations associated with psoriasis present a complex scenario in psoriasis, Mona Ståhle, MD, professor of dermatology and venereology in the department of medicine at Karolinska Institute in Stockholm, Sweden, said during an interview with Healio Psoriatic Disease.

“What is now emerging as a new and exciting scenario is the realization that not only coding sequences in the human genome are important. In fact, the noncoding regions, previously thought to be just junk DNA, are actually critical in regulating the expression and function of genes,” Ståhle said. “However, while these gene variations are important, psoriasis is a complex disease interacting with the environment which can exert so-called epigenetic effects. There will be a lot more to understand, and it will be challenging but rewarding to know how cigarette smoking or other environmental triggers influence the expression of genes and the onset and course of psoriasis.”

Healio Psoriatic Disease spoke with experts about the most recent study findings in the role of genetics in the susceptibility and severity of psoriasis, how genetics affect treatment and the research that is still needed.

Susceptibility

Research has provided key insights into the biology of psoriasis.

“Tremendous progress has been made in genetic research in common diseases such as psoriasis as a result of advances initiated by the Human Genome Mapping Project. Studies performed have provided great insights into the important mechanisms driving psoriasis,” Jonathan Barker, MD, FRCP, professor of clinical dermatology at St. John’s Institute of Dermatology at King’s College London said during an interview with Healio Psoriatic Disease. “By far, the most important mechanisms in the genetics of psoriasis are immunological. Still, there is a requirement for continued research to fully identify the psoriasis genetic map and that work is currently ongoing.”

Barker said he and colleagues recently identified more than 100 genetic loci across the human genome that are associated with psoriasis.

“That research was conducted as a part of the International Psoriasis Council and is not yet published but we are edging towards completing the genetic map of psoriasis. We still have a long way to go,” he said.

Proton Rahman, MD, rheumatologist and genetic epidemiologist at St. John’s Newfoundland, said a lot has happened recently in research regarding the genomics of psoriasis.

“We now know that we can assess the heritability of psoriasis to identify strong genetic factors related to the disease,” Rahman told Healio Psoriatic Disease. “That being said, psoriasis is a multifactorial disease in which genes and the environment interact, so it’s not solely a genetic disease to be solved. Psoriasis is complex.”

According to Anne M. Bowcock, PhD, the Norman Orentreich, MD Professor of Dermatology Research at the Icahn School of Medicine at Mount Sinai, clinical research has plateaued in recent years and more research is needed on the genetics of the disease.

“There once were many genome-wide association studies in psoriasis, but they require larger and larger numbers of patients and controls. Research has just hit a plateau right now,” Bowcock said during an interview with Healio Psoriatic Disease. “We certainly now know of many risk factors with very small effects, including those affecting the immune system and the skin barrier, but it is hard to know how this all fits together. Our group identified one gene (CARD14) that is responsible for a familial form of psoriasis, and interestingly, its strongest pattern of expression is in the skin itself (the keratinocyte), suggesting that many GWAS findings could be modifying larger genetic effects manifesting in the keratinocyte.”

Ståhle said psoriasis is clearly a genetic disease and many patients have a family member with the disease.

“Psoriasis today is not such a bad autoimmune disease to have,” she said. “I tell my patients, if you wish for one autoimmune disease, you may wish for psoriasis because we have more effective therapies now than we do for many other autoimmune diseases. It isn’t a hindrance for children to inherit the disease because with effective therapy, patients can, for the most part, forget about the disease.”

Severity

Experts agreed that more work is needed to better understand the role of genetics in disease severity.

“We are beginning to stratify disease severity based on genetics with certain known risk factors,” Rahman said. “For instance, the age of onset. If a patient has allele HLA-Cw6, which is the strongest value that predisposes risk for psoriasis, usually their psoriasis is going to start at a much earlier age. Their disease is also likely to be more severe and have more skin involvement compared with someone who is HLA-Cw6-negative.”

Some carriers of HLA-Cw6 may additionally experience longer delays in the development of psoriatic arthritis, Rahman added.

“A challenge of psoriasis is that about 20% to 30% of people go on to develop psoriatic arthritis, typically within about 7 to 10 years after psoriasis onset,” he said. “But psoriatic arthritis is delayed among those with HLA-Cw6. This suggests there are certain risk factors that are clinically and importantly associated with HLA-Cw6.”

While the notion of psoriasis stratified by age of disease onset is correct regarding HLA-Cw6-positive genotype, this finding may not help inform the disease course, according to Ståhle and Axel Svedbom, PhD, researcher in the department of medicine at Karolinska Institute.

In a letter to the editor published in August in the Journal of the American Academy of Dermatology, Ståhle and Svedbom wrote, “Nonpustular psoriasis may have two distinct forms: early-onset disease [< 40 years], characterized by high prevalence of family history, HLA-Cw6-positive genotype, and severe clinical course, and late-onset disease [> 40 years], characterized by low prevalence of family history, HLA-Cw6-negative genotype, and mild clinical course. This dichotomy was originally found in an investigation based on hospitalized patients only, limiting generalizability.”

To address this limitation, researchers examined data from the Stockholm Psoriasis Cohort including 509 patients with plaque psoriasis who had complete data on family history and HLA-Cw6 status.

Researchers found that compared with patients with late-onset psoriasis, a greater proportion of those with early-onset disease were HLA-Cw6-positive (15% vs. 48%; P < .001) and had a positive family history (42% vs. 61%; P < .001). Conversely, researchers observed no difference in disease severity between the two groups, with severe disease observed in 20% of those with late-onset disease vs. 21% with early-onset disease.

Results of another study by Ståhle and colleagues showed patients with psoriasis were more likely to go on to develop severe disease if they had plaque phenotype and interleukin (IL)-23 involvement at baseline.

Researchers pooled data from the Stockholm Psoriasis Cohort to better define the clinical course of disease and potential indicators for long-term outcomes among 721 patients with recent-onset psoriasis. Patients had psoriasis for less than 1 year and were aged 15 years or older.

Results of the study, published in 2021 in JAMA Dermatology, showed a cumulative incidence for severe psoriasis in 21% of patients at median follow-up of 9.6 years. Moreover, more than half of patients (52%; 95% CI, 41%-64%) with plaque phenotype, above-median disease activity and scalp lesions at onset were more likely to develop severe disease later in life. Researchers additionally identified smoking (HR = 1.7; 95% CI, 1.1-2.63) and activating genes in the IL-23 pathway (OR = 1.55; 95% CI, 1.14-2.11) as prognostic factors for disease severity.

“The findings of this cohort study suggest combinations of clinical characteristics at onset and activating genes in the IL-23 pathway are significantly associated with the clinical course of psoriasis. Patients within those categories merit specialist referral and closer follow-up,” the researchers wrote.

Pustular psoriasis is another disease type that involves a unique mode of genetic inheritance, Rahman said.

“Certain patients with pustular psoriasis may have one gene or a set of genes that cause their disease to be quite severe,” Rahman said. “We know of certain disease manifestations that are associated with either onset or coexistence of other illnesses or even a different type of psoriasis altogether.”

Ståhle said patients with the IL-36 receptor antagonist mutation eventually develop pustular psoriasis.

“This is different from the complex scenario of common psoriasis. This involves more of a dominant trait,” Ståhle said. “Knowing that a patient with the IL-36 associated mutation develops pustular psoriasis led to the development of spesolimab [Spevigo, Boehringer Ingelheim], which has almost reached the market, where we saw that patients who had this dangerous genetic variant experienced good efficacy with this treatment on clinical trial, which has really been a game changer.”

Ståhle said further data are needed to identify which genes determine early- or late-onset disease or whether someone will have severe or mild psoriasis.

“These are important questions that we will need answered and we are only in the beginning of understanding them now,” she said. “There are a few genes that we know are associated with severe disease, but we usually don’t genotype patients in the clinic — only in research cohorts. We would like to identify those at risk for severe disease so that we can intervene early.”

There are indications that early intervention could alter the disease trajectory, Ståhle added.

“If we intervene early with treatment, we may be able to prevent severe disease in patients,” she said. “There are two ongoing trials that are testing this hypothesis, and preliminary data from one of those trials are encouraging.”

Treatment

More data are also needed on the role of genetic markers in predicting treatment response.

“We currently cannot use genetics in general to determine which treatments patients can and should receive nor can we tell who will respond to treatments,” Bowcock said.

However, research is underway.

A study published in The New England Journal of Medicine showed that intravenous spesolimab dosed at 900 mg reduced pustules and increased skin clearance among a cohort of 53 patients with generalized pustular psoriasis. The findings additionally showed the agent was associated with a favorable safety profile compared with placebo.

“This is a fantastic step forward in untangling a psoriasis phenotype and we will see a lot more of this type of research in the future,” Ståhle said.

Another treatment area under development is targeting HLA-Cw6.

“HLA-Cw6 is one of the best predictors of treatment response in patients with psoriasis,” Rahman said. “Patients who are HLA-Cw6-positive achieve better clinical response with the monoclonal antibody, ustekinumab [Stelara, Janssen], whereas those who are HLA-Cw6-negative tend to do better with adalimumab [Humira, AbbVie]. We have these very specific examples of where genetics may provide some help with treatment response, and overall, this is a fantastic area of research underway.”

Other treatments target the CARD14 mutation.

“While we currently cannot use genetics to determine the therapies patients should receive or know who will respond, there is some evidence with CARD14,” Bowcock said. “A few studies have shown patients with a common variant in CARD14 respond well to TNF inhibitors, but the data are not clear cut.”

Certain children with psoriasis who have CARD14 mutations have responded well to ustekinumab, she added.

“When we identified CARD14 years ago, one of the patients we investigated was a child with generalized pustular psoriasis who had not responded well to any therapies,” Bowcock said. “She had a de novo mutation in CARD14, and she responded well to treatment with ustekinumab, which is used to treat plaque psoriasis and targets the IL-23/IL-17 pathway. However, mild to severe CARD14 cases will respond variably to therapies and often to traditional therapies.”

Barker said he is hopeful that more research will lead to more treatment advancements in the future.

“A better understanding of disease biology has led to greater knowledge and new treatment options,” he said. “Research has allowed for treatments that impact the immune system in a highly specific way. Some of which have turned out to be highly effective and were entirely predicted by genetic knowledge.”

Research needs

Experts with whom Healio Psoriatic Disease spoke said the future of psoriasis is headed toward a precision medicine approach.

“We really want a paradigm of precision medicine in psoriasis, but we are not clinically there yet,” Rahman said. “We need to stratify patients carefully. Phenotyping is very important to identify precise genetic variants with a particular disease entity.”

Ståhle agreed.

“The field needs more precision medicine so that we can know how to better choose treatments for each patient and also what to expect from treatment,” Ståhle said. “We currently don’t fully understand why one patient fares better on a treatment compared with another. We need more phenotypical profiling when it comes to genes, the expression of genes and also the interaction with the environment.”

Bowcock said more research is needed in general to better understand the genetic contribution of psoriasis.

“I personally would love to understand the full genetic contribution to psoriasis — how it all fits together. The treatments that we have right now work very well, but they are biologics and injections, so they are very expensive. Patients prefer topical therapies but there’s not many of those that are effective,” she said. “We also need to know what truly determines disease severity. As for complex traits, knowing what the actual risk factors are would be helpful because whenever we find an association, there are many variants in a region and we need to know what those variants are doing. Little by little they are being elucidated, but slowly.”

Barker agreed.

“By understanding the science of psoriasis better, we will be able to better identify individuals at risk not only for common psoriasis, but at risk for severe disease and institute treatment much earlier,” he said. “This all goes back to genetic biomarkers. We know there are some genetic markers that hold promise. There is also the new genetic technology, polygenic risk score, which we are rather hoping that we can apply to individuals with psoriasis to identify those we wish to treat earlier to prevent long-term sequelae ofdisease.”

Rahman said collaboration is needed across the board.

“We know that psoriasis involves genetics, but we are especially looking to tease out the issue that genetics and the environment play a role together,” he said. “This will require a large cohort of patients to be studied in a very collaborative manner because for any one particular institution, it is not possible to obtain the number of patients needed or to have an index genetic analysis because the investigation is quite expensive. Therefore, collaboration will be key.”

More research is also needed among other ethnic groups, Rahman added.

“We need to go beyond the white and Asian populations in psoriasis genetics. Those populations have been exclusively studied in a large-scale manner,” he said. “We need multiethnic cohorts particularly in underrepresented groups, because genetic associations for those groups are not necessarily the same as those previously studied. All of this will require a large amount of investment in terms of funds to conduct these studies properly. Again, this must be done in a collaborative manner so that the data that is generated can be shared amongst all.”

Despite the research needs, the field has significantly evolved over the years, according to Ståhle.

“I have been a dermatologist since 1979, a time when patients with psoriasis were committed to hospitals for long periods of time for all types of treatments,” she said. “Having psoriasis was more like having a full-time job back then. I am happy to say that the field has definitely come a long way, but there is still so much more work to do.”

• References:
• Bachelez H, et al. N Engl J Med. 2021;doi:10.1056/NEJMoa2111563.
• Capon F. Int J Mol Sci. 2017;doi:10.3390/ijms18122526.
• Dand N, et al. Acta Derm Venereol. 2020;doi:10.2340/00015555-3384.
• Svedbom A, et al. JAMA Dermatol. 2021;doi:10.1001/jamadermatol.2021.0734.
• Svedbom A, et al. J Am Acad Dermatol. 2022;doi:10.1016/j.jaad.2022.07.050.

• For more information:
• Jonathan Barker, MD, FRCP, can be reached at jonathan.barker@kcl.ac.uk.
• Anne M. Bowcock, PhD, can be reached at anne.bowcock@mssm.edu.
• Proton Rahman, MD, can be reached at prahman@mun.ca.
• Mona Ståhle, MD, can be reached at mona.stahle@ki.se.