How to Reduce Cardiovascular Morbidity and Mortality in Psoriasis and PsA


Patients with psoriatic disease have significantly higher risks of myocardial infarctionstroke, and cardiovascular mortality than does the general population, yet research consistently paints what dermatologist Joel M. Gelfand, MD, calls an “abysmal” picture: Only a minority of patients with psoriatic disease know about their increased risks, only a minority of dermatologists and rheumatologists screen for cardiovascular risk factors like lipid levels and blood pressure, and only a minority of patients diagnosed with hyperlipidemia are adequately treated with statin therapy.

In the literature and at medical meetings, Dr Gelfand and others who have studied cardiovascular disease (CVD) comorbidity and physician practices have been urging dermatologists and rheumatologists to play a more consistent and active role in primary cardiovascular prevention for patients with psoriatic disease, who are up to 50% more likely than patients without it to develop CVD and who tend to have atherosclerosis at earlier ages.

According to the 2019 joint American Academy of Dermatology (AAD)–National Psoriasis Foundation (NPF) guidelines for managing psoriasis “with awareness and attention to comorbidities,” this means not only ensuring that all patients with psoriasis receive standard CV risk assessment (screening for hypertension, diabetes, and hyperlipidemia), but also recognizing that patients who are candidates for systemic therapy or phototherapy — or who have psoriasis involving > 10% of body surface area — may benefit from earlier and more frequent screening.

CV risk and premature mortality rises with the severity of skin disease, and patients with psoriatic arthritis (PsA) are believed to have risk levels similar to patients with moderate-severe psoriasis, cardiologist Michael S. Garshick, MD, director of the cardiorheumatology program at New York University Langone Health, said in an interview.

photo of Michael Garshick
Dr Michael S. Garshick

In a recent survey study of 100 patients seen at NYU Langone Health’s psoriasis specialty clinic, only one-third indicated they had been advised by their physicians to be screened for CV risk factors, and only one-third reported having been told of the connection between psoriasis and CVD risk. Dr Garshick shared the unpublished findings at the annual research symposium of the NPF in October.

Similarly, data from the National Ambulatory Medical Care Survey shows that just 16% of psoriasis-related visits to dermatology providers from 2007 to 2016 involved screening for CV risk factors. Screening rates were 11% for body mass index, 7.4% for blood pressure, 2.9% for cholesterol, and 1.7% for glucose, Dr Gelfand and coauthors reported in 2023.

Such findings are concerning because research shows that fewer than a quarter of patients with psoriasis have a primary care visit within a year of establishing care with their physicians, and that, overall, fewer than half of commercially insured adults under age 65 visit a primary care physician each year, according to John S. Barbieri, MD, of the department of dermatology at Brigham and Women’s Hospital in Boston. He included these findings when reporting in 2022 on a survey study on CVD screening.

Dr John S. Barbieri, director of the Advanced Acne Therapeutics Clinic at Brigham and Women’s Hospital in Boston

In many cases, dermatologists and rheumatologists may be the primary providers for patients with psoriatic disease. So, “the question is, how can the dermatologist or rheumatologist use their interactions as a touchpoint to improve the patient’s well-being?” Dr Barbieri said in an interview.

Dr John S. Barbieri

For the dermatologist, educating patients about the higher CVD risk fits well into conversations about “how there may be inflammation inside the body as well as in the skin,” he said. “Talk about cardiovascular risk just as you talk about PsA risk.” Both specialists, he added, can incorporate blood pressure readings and look for opportunities to measure lipid levels and hemoglobin A1c (HbA1c). These labs can easily be integrated into a biologic work-up.

“The hard part — and this needs to be individualized — is how do you want to handle [abnormal readings]? Do you want to take on a lot of the ownership and calculate [10-year CVD] risk scores and then counsel patients accordingly?” Dr Barbieri said. “Or do you want to try to refer, and encourage them to work with their PCP? There’s a high-touch version and a low-touch version of how you can turn screening into action, into a care plan.”

Beyond traditional risk elevation, the primary care hand-off

Rheumatologists “in general may be more apt to screen for cardiovascular disease” as a result of their internal medicine residency training, and “we’re generally more comfortable prescribing… if we need to,” said Alexis R. Ogdie, MD, a rheumatologist at the Hospital of the University of Pennsylvania, Philadelphia, and director of the Penn Psoriatic Arthritis Clinic.

photo of Alexis R. Ogdie-Beatty and Joel Gelfand
Dr Ogdie and Dr Gelfand

Referral to a preventive cardiologist for management of abnormal lab results or ongoing monitoring and prevention is ideal, but when hand-offs to primary care physicians are made — the more common scenario — education is important. “A common problem is that there is under-recognition of the cardiovascular risk being elevated in our patients,” she said, above and beyond risk posed by traditional risk factors such as dyslipidemia, hypertension, metabolic syndrome, and obesity, all of which have been shown to occur more frequently in patients with psoriatic disease than in the general population.

Risk stratification guides CVD prevention in the general population, and “if you use typical scores for cardiovascular risk, they may underestimate risk for our patients with PsA,” said Dr Ogdie, who has reported on CV risk in patients with PsA. “Relative to what the patient’s perceived risk is, they may be treated similarly (to the general population). But relative to their actual risk, they’re undertreated.”

The 2019 AAD-NPF psoriasis guidelines recommend utilizing a 1.5 multiplication factor in risk score models, such as the American College of Cardiology’s Atherosclerotic Cardiovascular Disease (ASCVD) Risk Estimator, when the patient has a body surface area > 10% or is a candidate for systemic therapy or phototherapy.

Similarly, the 2018 American Heart Association (AHA)-ACC Guideline on the Management of Blood Cholesterol defines psoriasis, along with RA, metabolic syndrome, HIV, and other diseases, as a “cardiovascular risk enhancer” that should be factored into assessments of ASCVD risk. (The guideline does not specify a psoriasis severity threshold.)

“It’s the first time the specialty [of cardiology] has said, ‘pay attention to a skin disease,’ ” Dr Gelfand said at the NPF meeting.

Using the 1.5 multiplication factor, a patient who otherwise would be classified in the AHA/ACC guideline as “borderline risk,” with a 10-year ASCVD risk of 5% to < 7.5%, would instead have an “intermediate” 10-year ASCVD risk of ≥ 7.5% to < 20%. Application of the AHA-ACC “risk enhancer” would have a similar effect.

For management, the main impact of psoriasis being considered a risk enhancer is that “it lowers the threshold for treatment with standard cardiovascular prevention medications such as statins.”

In general, “we should be taking a more aggressive approach to the management of traditional cardiovascular risk factors” in patients with psoriatic disease, he said. Instead of telling a patient with mildly elevated blood pressure, ‘I’ll see you in a year or two,’ or a patient entering a prediabetic stage to “watch what you eat, and I’ll see you in a couple of years,” clinicians need to be more vigilant.

“It’s about recognizing that these traditional cardiometabolic risk factors, synergistically with psoriasis, can start enhancing CV risk at an earlier age than we might expect,” said Dr Garshick, whose 2021 review of CV risk in psoriasis describes how the inflammatory milieu in psoriasis is linked to atherosclerosis development.

Cardiologists are aware of this, but “many primary care physicians are not. It takes time for medical knowledge to diffuse,” Dr Gelfand said. “Tell the PCP, in notes or in a form letter, that there is a higher risk of CV disease, and reference the AHA/ACC guidelines,” he advised. “You don’t want your patient to go to their doctor and the doctor to [be uninformed].”

‘Patients trust us’

Dr Gelfand has been at the forefront of research on psoriasis and heart disease. A study he coauthored in 2006, for instance, documented an independent risk of MI, with adjusted relative risks of 1.29 and 3.10 for a 30-year-old patient with mild or severe disease, respectively, and higher risks for a 60-year-old. In 2010, he and coinvestigators found that severe psoriasis was an independent risk factor for CV mortality (HR, 1.57) after adjusting for age, sex, smoking, diabetes, hypertension, and hyperlipidemia.

Today, along with Dr Barbieri, Dr Ogdie, and others, he is studying the feasibility and efficacy of a proposed national, “centralized care coordinator” model of care whereby dermatologists and rheumatologists would educate the patient, order lipid and HbA1c measurements as medically appropriate, and then refer patients as needed to a care coordinator. The care coordinator would calculate a 10-year CVD risk score and counsel the patient on possible next steps.

In a pilot study of 85 patients at four sites, 92% of patients followed through on their physician’s recommendations to have labs drawn, and 86% indicated the model was acceptable and feasible. A total of 27% of patients had “newly identified, previously undiagnosed, elevated cardiovascular disease risk,” and exploratory effectiveness results indicated a successful reduction in predicted CVD risk in patients who started statins, Dr Gelfand reported at the NPF meeting.

With funding from the NPF, a larger, single-arm, pragmatic “CP3” trial (NCT05908240) is enrolling 525 patients with psoriasis at 10-20 academic and nonacademic dermatology sites across the United States to further test the model. The primary endpoint will be the change in LDL cholesterol measured at 6 months among people with a 10-year risk ≥ 5%. Secondary endpoints will cover improvement in disease severity and quality of life, behavior modification, patient experience, and other issues.

“We have only 10-15 minutes [with patients]…a care coordinator who is empathetic and understanding and [informed] could make a big difference,” Dr Gelfand said at the NPF meeting. If findings are positive, the model would be tested in rheumatology sites as well. The hope, he said, is that the NPF would be able to fund an in-house care coordinator(s) for the long-term.

Notably, a patient survey conducted as part of exploratory research leading up to the care coordinator project showed that patients trust their dermatologist or rheumatologist for CVD education and screening. Among 160 patients with psoriasis and 162 patients with PsA, 76% and 90% agreed that “I would like it if my dermatologist/rheumatologist educated me about my risk of heart disease,” and 60% and 75%, respectively, agree that “it would be convenient for me to have my cholesterol checked by my dermatologist/rheumatologist.”

“Patients trust us,” Dr Gelfand said at the NPF meeting. “And the pilot study shows us that patients are motivated.”

Taking an individualized, holistic, longitudinal approach

“Sometimes you do have to triage bit,” Dr Gelfand said in an interview. “For a young person with normal body weight who doesn’t smoke and has mild psoriasis, one could just educate and advise that they see their primary care physician” for monitoring.

“But for the same patient who is obese, maybe smokes, and doesn’t have a primary care physician, I’d order labs,” he said. “You don’t want a patient walking out the door with an [undiagnosed] LDL of 160 or hypertension.”

Age is also an important consideration, as excess CVD risk associated with autoimmune diseases like psoriasis rises with age, Dr Gelfand said during a seminar on psoriasis and PsA held at NYU Langone in December. For a young person, typically, “I need to focus on education and lifestyle … setting them on a healthy lifestyle trajectory,” he said. “Once they get to 40, from 40 to 75 or so, that’s a sweet spot for medical intervention to lower cardiovascular risk.”

Even at older ages, however, lipid management is not the be-all and end-all, he said in the interview. “We have to be holistic.”

One advantage of having highly successful therapies for psoriasis, and to a lesser extent PsA, is the time that becomes available during follow-up visits — once disease is under control — to “focus on other things,” he said. Waiting until disease is under control to discuss diet, exercise, or smoking, for instance, makes sense anyway, he said. “You don’t want to overwhelm patients with too much to do at once.”

Indeed, said dermatologist Robert E. Kalb, MD, of the Buffalo Medical Group in Buffalo, NY, “patients have an open mind [about discussing cardiovascular disease risk], but it is not high on their radar. Most of them just want to get their skin clear.” (Dr Kalb participated in the care coordinator pilot study, and said in an interview that since its completion, he has been more routinely ordering relevant labs.)

Rheumatologists are less fortunate with highly successful therapies, but “over the continuum of care, we do have time in office visits” to discuss issues like smoking, exercise, and lifestyle, Dr Ogdie said. “I think of each of those pieces as part of our job.”

In the future, as researchers learn more about the impact of psoriasis and PsA treatments on CVD risk, it may be possible to tailor treatments or to prescribe treatments knowing that the therapies could reduce risk. Observational and epidemiologic data suggest that tumor necrosis factor-alpha inhibitor therapy over 3 years reduces the risk of MI, and that patients whose psoriasis is treated have reduced aortic inflammation, improved myocardial strain, and reduced coronary plaque burden, Dr Garshick said at the NPF meeting.

“But when we look at the randomized controlled trials, they’re actually inconclusive that targeting inflammation in psoriatic disease reduces surrogates of cardiovascular disease,” he said. Dr Garshick’s own research focuses on platelet and endothelial biology in psoriasis.

Pill for Skin Disease Also Curbs Excessive Drinking


Summary: Apremilast, an FDA-approved drug for the treatment of skin conditions including psoriasis and psoriatic arthritis, triggers increased activity in the nucleus accumbens, a brain area associated with regulating alcohol intake. Apremilast reduced drinking behaviors in mouse models with a genetic risk of alcohol use disorder.

Source: Oregon Health and Science University

Researchers from Oregon Health & Science University and institutions across the country have identified a pill used to treat a common skin disease as an “incredibly promising” treatment for alcohol use disorder.

The study was recently published in the Journal of Clinical Investigation.

On average, the people who received the medication, called apremilast, reduced their alcohol intake by more than half — from five drinks per day to two.

“I’ve never seen anything like that before,” said co-senior author Angela Ozburn, Ph.D., associate professor of behavioral neuroscience in the OHSU School of Medicine and a research biologist with the Portland VA Health Care System.

The lead author is Kolter Grigsby, Ph.D., a postdoctoral fellow in the Ozburn laboratory at OHSU.

Beginning in 2015, Ozburn and collaborators searched a genetic database looking for compounds likely to counteract the expression of genes known to be linked to heavy alcohol use. Apremilast, an FDA-approved anti-inflammatory medication used to treat psoriasis and psoriatic arthritis, appeared to be a promising candidate.

They then tested it in two unique animal models that have a genetic of risk for excessive drinking, as well as in other strains of mice at laboratories across the country. In each case, apremilast reduced drinking among a variety of models predisposed to mild to heavy alcohol use. They found that apremilast triggered an increase in activity in the nucleus accumbens, the region of the brain involved in controlling alcohol intake.

Researchers at the Scripps Research Institute in La Jolla, California, then tested apremilast in people.

The Scripps team conducted a double-blind, placebo-controlled clinical proof-of-concept study involving 51 people who were assessed over 11 days of treatment.

“Apremilast’s large effect size on reducing drinking, combined with its good tolerability in our participants, suggests it is an excellent candidate for further evaluation as a novel treatment for people with alcohol use disorder,” said co-senior author Barbara Mason, Ph.D., Pearson Family professor in the Department of Molecular Medicine at Scripps.

The clinical study involved people with alcohol use disorder who weren’t seeking any form of treatment, and Mason predicts that apremilast may be even more effective among people who are motivated to reduce their alcohol consumption.

“It’s imperative for more clinical trials to be done on people seeking treatment,” Ozburn said. “In this study, we saw that apremilast worked in mice. It worked in different labs, and it worked in people. This is incredibly promising for treatment of addiction in general.”

This shows a drink in a glass
An estimated 95,000 people in the United States die every year from alcohol-related deaths, according to the National Institute on Alcohol Abuse and Alcoholism.

An estimated 95,000 people in the United States die every year from alcohol-related deaths, according to the National Institute on Alcohol Abuse and Alcoholism.

Currently, there are three medications approved for alcohol use disorder in the United States: Antabuse, which produces an acute sensitivity akin to a hangover when alcohol is consumed; acamprosate, a medication thought to stabilize chemical signaling in the brain that is associated with relapse; and naltrexone, a medication that blocks the euphoric effects of both alcohol and opioids.

Rice Bodies in Tenosynovitis Due to Psoriatic Arthritis


A 74-year-old woman presented to the infectious diseases clinic with a 4-year history of swelling of the fifth finger on the left hand. She had a history of psoriatic arthritis that had been treated with a tumor necrosis factor inhibitor and methotrexate. On physical examination of the left hand, there was redness and swelling from the metacarpophalangeal joint to the distal interphalangeal joint in the proximal and middle phalanges of the fifth digit; the redness and swelling extended across the palm, with predominant involvement in the hypothenar region (Panel A). Flexion of the fifth finger was limited. There were also nontender, mobile, subcutaneous nodules in the hypothenar region and over the proximal fifth finger. Magnetic resonance imaging of the left hand revealed tenosynovitis of all flexor tendons. A carpal-tunnel release and fifth-finger flexor tenosynovectomy were performed. After incision of the transverse carpal ligament, numerous “rice bodies” — grainlike particles that form in joints in the context of infectious or noninfectious chronic inflammation — were found in the carpal tunnel (Panel B). More rice bodies were released after the fifth-finger tendon sheaths were incised. Microbiologic and molecular studies were negative for bacteria, fungi, and mycobacteria. Histopathological testing showed papillary synovial hyperplasia with chronic inflammation and fibrinous nodules. A final diagnosis of inflammatory tenosynovitis with rice bodies associated with psoriatic arthritis was made. Treatment with oral glucocorticoids was initiated. At 6 weeks of follow-up, the patient’s symptoms had abated.

Cannabidiol treatment in hand osteoarthritis and psoriatic arthritis: a randomized, double-blind placebo-controlled trial.


ABSTRACT: Cannabidiol (CBD) is increasingly used as analgesic medication even though the recent International Association for the Study of Pain presidential task force on cannabis and cannabinoid analgesia found a lack of trials examining CBD for pain management. The present trial examines CBD as add on analgesic therapy in patients with hand osteoarthritis or psoriatic arthritis experiencing moderate pain intensity despite therapy. Using a randomized double-blind, placebo-controlled design, patients received synthetic CBD 20-30mg or placebo daily for 12 weeks. Primary outcome was pain intensity during the last 24 hours (0-100mm); safety outcomes were percentage of patients experiencing adverse events and a characterization of serious adverse events. Explorative outcomes included change in Pittsburgh Sleep Quality Index (PSQI), Hospital Anxiety and Depression Scale (HADS), Pain Catastrophizing Scale (PCS) and Health Assessment Questionnaire (HAQ-DI).One hundred and thirty-six patients were randomized 129 were included in the primary analysis. Between group difference in pain intensity at 12 weeks was 0.23mm (95%CI -9.41 to 9.90; p = 0.96). 22% patients receiving CBD and 21% receiving placebo experienced a reduction in pain intensity of more than 30mm. We found neither clinically nor statistically significant effect of CBD for pain intensity in patients with hand osteoarthritis and psoriatic arthritis when compared to placebo. Additionally, no statistically significant effects were found on sleep quality, depression, anxiety, or pain catastrophizing scores.

FDA approves Skyrizi for adults with active psoriatic arthritis


The FDA has approved AbbVie’s risankizumab-rzaa for the treatment of adults with active psoriatic arthritis, expanding its initial indication from plaque psoriasis only.

Risankizumab (Skyrizi; AbbVie, Boehringer Ingelheim), an interleukin-23 inhibitor, made its U.S. debut in 2019 for moderate-to-severe plaque psoriasis among adults who are candidates for systemic therapy or phototherapy. The new approval for PsA follows results from the KEEPsAKE 1 and KEEPsAKE 2 trials, both of which resulted in statistically greater improvements in signs and symptoms, relative to placebo, among patients who received the drug.

PatientAA_212585204
The FDA has approved AbbVie’s risankizumab-rzaa for the treatment of adults with active PsA, expanding its initial indication from plaque psoriasis only. S

“Patients often do not suspect a connection between their psoriasis skin symptoms and the joint pain, swelling and stiffness they may be experiencing, potentially leading to a delay in diagnosis and treatment of psoriatic arthritis,” Thomas Hudson, MD, senior vice president of research and development and chief scientific officer at AbbVie, said in a company press release. “We’re proud to expand the use of Skyrizi to patients with psoriatic arthritis who are living with the debilitating combination of skin and joint symptoms.”

KEEPsAKE 1 and KEEPsAKE 2 together enrolled 1,407 adults with active PsA, active plaque psoriasis or nail psoriasis, with at least 5 swollen and tender joints, including those with inadequate response, or an intolerance to, biologic therapy and/or non-biologic disease-modifying antirheumatic drugs.

Across the two phase 3 studies, risankizumab met the primary endpoint of ACR20 response at week 24, compared with placebo, and demonstrated significant improvements across several other PsA manifestations, including swollen, tender and painful joints.

“In the pivotal KEEPsAKE trials, Skyrizi demonstrated improvements across a number of psoriatic arthritis symptoms, including joint pain, enthesitis and dactylitis,” Alan J. Kivitz, MD, CPI, KEEPsAKE researcher and founder/medical director of the Altoona Center for Clinical Research, as well as the Altoona Arthritis and Osteoporosis Center, in Duncansville, Pennsylvania, said in the release. “This approval provides both dermatologists and rheumatologists with an option that helps improve skin and joint symptoms in patients with active psoriatic arthritis, alongside a quarterly dosing schedule that may fit their patients’ lifestyle.”

According to AbbVie, risankizumab maintains a dosing regimen for PsA that is consistent with its existing regimen for plaque psoriasis — a single 150 mg subcutaneous injection four times a year, after two starter doses at weeks 0 and 4. It can be administered alone or in combination with DMARDs.

The drug is part of a collaboration between AbbVie and Boehringer Ingelheim, with the former leading its global development and commercialization.

Brodalumab Boosts Response in Psoriatic Arthritis


A monoclonal antibody targeting the interleukin-17 receptor A (IL17RA) showed efficacy for the musculoskeletal components of psoriatic arthritis in a multicenter phase II study, investigators reported.

Among patients who received subcutaneous brodalumab in doses of 140 mg every 2 weeks, a 20% improvement according to the criteria of the American College of Rheumatology (ACR20) was achieved by 37% after 3 months of treatment (P=0.03), and 39% of those given 280 mg (P=0.02) compared with 18% of those receiving placebo, according to Philip J. Mease, MD, of the University of Washington in Seattle, and colleagues.

And on the Disease Activity Score in 28 joints (DAS28), both treatment groups had least-squares mean changes from baseline of -0.7 compared with placebo (P=0.002), the researchers reported in the June 12 New England Journal of Medicine.

Interleukin-17 has been implicated in the pathogenesis of psoriatic arthritis, and several agents targeting related signaling pathways are being developed.

In an earlier phase II trial evaluating brodalumab for moderate-to-severe psoriasis, more than 75% of patients experienced significant improvements on skin scores by week 12.

To further investigate the efficacy and safety of this agent for psoriatic arthritis, which affects almost one-third of patients with psoriasis, Mease and colleagues enrolled 168 patients from 29 North American sites.

The trial included a 3-month, double-blind randomized phase with the two different doses of brodalumab, followed by an open-label phase intended to last up to 5 years in which all participants receive the 280 mg dose every 2 weeks.

Patients’ mean age was 53, the majority were women, and almost all were white.

Body mass index averaged 33 kg/m2, and mean disease duration was 9 years.

All patients had at least three tender and three swollen joints and were on stable doses of background medications such as methotrexate and steroids. Half had previously received other biologic therapies.

On the Clinical Disease Activity Index, least squares mean change from baseline was -10.6 in the 140 mg group at 12 weeks, and -11.3 in the 280 mg group, compared with -4 in the placebo group (P<0.001).

And on the Psoriasis Symptom Inventory, the change in score was -8.5 in the 140-mg group and -10.9 in the 280-mg group, compared with -1.3 in the placebo group (P<0.001).

Response rates continued to rise after the initial 12-week period, with ACR20 responses seen in 51% and 64% of the original 140 mg and 280 mg groups at 6 months, and in 44% of those originally assigned to placebo.

“Although data from open-label trials need to be interpreted with caution, continued improvements beyond the primary endpoint suggest that a full clinical response among patients with psoriatic arthritis requires longer than 12 weeks, a hypothesis that must be evaluated in longer-term controlled studies,” Mease and colleagues wrote.

Adverse events were reported by 62% and 71% of the lower-dose and higher-dose brodalumab groups and by 65% of patients receiving placebo. The most common were upper respiratory tract infection, fatigue, headache, and diarrhea.

Serious adverse events during the double-blind phase included one case of abdominal pain in a patient receiving 140 mg, one case each of cholecystitis and cellulitis in the 280 mg group, and one case of cellulitis in the placebo group.

In the first year of the open-label phase, the most common adverse events included upper respiratory tract infection, disease flare, and arthralgias.

There were no serious cases of neutropenia, “an important safety outcome, since interleukin-17 is involved in neutrophil homeostasis,” the authors noted. There also were no opportunistic infections and no deaths.

The investigators concluded that “IL17RA is a potential target for the treatment of psoriatic arthritis.”

Limitations of the study included the short treatment duration and relatively small number of patients, so larger studies will be needed to more fully evaluate safety.

leflunomide in rheumatoid arthritis and psoriatic arthritis


Jones PBB et al. – Recent trials have shown that leflunomide can be used safely with biologic DMARDs, including antitumor necrosis factor agents and rituximab as part of the treatment algorithm in place of methotrexate as a cotherapy. Leflunomide has demonstrated efficacy as a monotherapy in psoriatic arthritis, and it also has a beneficial effect in psoriasis. Postmarketing studies have shown that retention on treatment with leflunomide is equal to methotrexate and superior to other DMARDs. In general, its side effect profile is acceptable compared with other DMARDS, with nausea, diarrhea, and hair fall occurring commonly, but only rarely leading to discontinuation. Liver toxicity is the most significant problem in clinical use although it is uncommon. Peripheral neuropathy, hypertension, pneumonitis, and cytopenia occur more rarely. Leflunomide is contraindicated in pregnancy and should be used with caution in women during child–bearing years. In this review, the place of leflunomide in therapy is discussed and practical advice informed by evidence is given regarding dosing regimens, safety monitoring, and managing side effects. Leflunomide remains one of the most useful of the nonbiologic DMARDs.