What Is the Safest Drug for Psoriatic Arthritis?

No single drug earns the title of “safest” for everyone with psoriatic arthritis, because safety depends heavily on your own health profile, including whether you have risk factors for infection, heart disease, liver problems, or are planning a pregnancy. That said, when researchers compare drug classes head-to-head, most approved biologics and targeted therapies show similar rates of serious adverse events in clinical trials, and some classes stand out as particularly well tolerated in specific situations. The real question is less “which drug is safest?” and more “which drug is safest for me?”

Why the Answer Changes From Person to Person

Psoriatic arthritis drugs fall into several broad families: conventional disease-modifying antirheumatic drugs (DMARDs) like methotrexate and leflunomide; biologic DMARDs that target specific immune molecules such as TNF, IL-17, IL-12/23, or IL-23; a small-molecule oral called apremilast; and JAK inhibitors like tofacitinib and upadacitinib. Each family suppresses or redirects the immune system differently, and each brings a distinct set of trade-offs. A person with a history of recurrent infections faces different risks than someone with high cholesterol or fatty liver disease. A woman hoping to become pregnant in the next year needs a completely different calculation than a 70-year-old man with diabetes. The sections below walk through the major safety signals by drug class so you can see where the risks concentrate.

Serious Adverse Events Look Similar Across Most Biologics

One reassuring finding from multiple network meta-analyses is that, during the induction phase of treatment (roughly the first three to six months), most biologic and targeted therapies do not differ from one another in rates of serious adverse events. A systematic review comparing fourteen agents found that all were comparable to placebo for serious side effects, with secukinumab as a possible exception warranting closer monitoring.¹ A separate network meta-analysis looking at targeted DMARDs during induction confirmed that while some drugs had higher rates of overall adverse events (tofacitinib, apremilast, and high-dose ixekizumab in particular), no significant difference emerged for serious adverse events among any of the treatments studied.²

This pattern held even for newer entrants. A 2024 analysis including bimekizumab, a dual IL-17 inhibitor, found it comparable to other biologics and targeted synthetic DMARDs for serious adverse events.³ The takeaway is that when it comes to the most alarming outcomes, like hospitalization or life-threatening reactions, the drugs on the market are broadly in the same neighborhood. The meaningful safety differences show up in the specific types of problems each class is more likely to cause.

Methotrexate and Leflunomide: Liver Concerns Worth Knowing About

Methotrexate remains a common first-line treatment because it is inexpensive and familiar to rheumatologists. But people with psoriatic arthritis appear to tolerate it less well than those with rheumatoid arthritis. In a study comparing side-effect reports, roughly 45% of psoriatic arthritis patients reported methotrexate-related side effects, versus about 29% of rheumatoid arthritis patients, with nausea, vomiting, abdominal pain, and depression all more common in the psoriatic arthritis group.⁴ Liver toxicity with methotrexate has also been found to be more frequent in psoriatic arthritis than in rheumatoid arthritis.⁵

There are good reasons for the liver vulnerability. Many people with psoriatic arthritis already have metabolic syndrome, higher body mass, or fatty liver disease, all of which compound methotrexate’s hepatotoxic potential. A case report review noted that methotrexate and these underlying metabolic risk factors can act together, making liver damage more likely than either would cause alone.⁶ That said, a systematic review of randomized controlled trials found no cases of severe hepatotoxicity, treatment discontinuation from liver injury, or liver-related deaths, suggesting that with proper monitoring the risk of catastrophic liver damage remains low.⁷ Regular blood work is non-negotiable if you are on methotrexate, especially if you carry metabolic risk factors.

Leflunomide is an alternative conventional DMARD with a side-effect profile that most patients find manageable. The most common complaints are nausea, diarrhea, and hair thinning, but these rarely lead to stopping the drug. Liver toxicity is the most clinically significant risk, though it is uncommon.⁸ In a placebo-controlled trial specific to psoriatic arthritis, diarrhea and liver enzyme elevations were more common with leflunomide, but no cases of serious liver toxicity occurred.⁹ Like methotrexate, leflunomide is strictly off-limits during pregnancy.

TNF Inhibitors and Infection

TNF inhibitors (etanercept, adalimumab, infliximab, golimumab, certolizumab pegol) are among the most widely prescribed biologics for psoriatic arthritis. Their main safety concern is infection. A meta-analysis pooling data from rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis found statistically significant increases in any infection (about 20% higher), serious infection (about 40% higher), and tuberculosis (roughly two-and-a-half-fold higher) with anti-TNF therapy compared to controls.¹⁰ The tuberculosis risk is especially relevant in parts of the world where TB is endemic. In India, for instance, the concern about reactivating latent TB is a major factor in treatment decisions.¹¹

That does not mean TNF inhibitors are unsafe. With proper screening, latent TB can be identified and treated before starting therapy, and data suggest that TNF inhibitors remain effective and safe in patients who complete that chemoprophylaxis.¹² Another rare concern is demyelinating disease. Data from the British rheumatology biologics registry found that demyelination following anti-TNF therapy is uncommon, with only a marginally increased rate that disappeared in sensitivity analyses.¹³ However, an analysis of the FDA’s adverse event reporting system did find disproportionate signals for specific demyelinating disorders with certain TNF inhibitors, particularly infliximab.¹⁴ Clinicians tend to avoid TNF inhibitors in anyone with a personal or strong family history of multiple sclerosis or other demyelinating conditions.

Despite the infection signal, TNF inhibitors have decades of real-world use and remain a mainstay of treatment. In many patients the benefit clearly outweighs the risk, though it is fair to say that newer drug classes with different mechanisms avoid this particular vulnerability.

IL-17 and IL-23 Inhibitors: Newer Options With Favorable Profiles

IL-17 inhibitors (secukinumab, ixekizumab, bimekizumab, brodalumab) and IL-23 inhibitors (guselkumab, risankizumab) are increasingly popular because they combine strong efficacy with safety profiles that many rheumatologists consider among the cleanest available. They do not carry the same tuberculosis signal as TNF inhibitors, and they are not associated with the cardiovascular warnings that have complicated JAK inhibitor use.

The main nuisance side effect of IL-17 inhibitors is yeast infections, particularly oral or gastrointestinal candidiasis. A study tracking patients on various biologics found that IL-17 inhibitors and IL-23 inhibitors had similar rates of oral or gastrointestinal candidiasis, roughly five cases per thousand patient-years of treatment, which is low enough that most patients never experience it.¹⁵ IL-17 inhibitors are generally avoided in patients with inflammatory bowel disease because blocking IL-17 can worsen gut inflammation, though no new cases of IBD developed in that same study’s cohort.

IL-23 inhibitors have an even quieter safety profile. Risankizumab maintained its efficacy and tolerability through nearly five years of follow-up in a psoriatic arthritis trial, with no new safety signals.¹⁶ Real-world data from Japan also show that risankizumab had the lowest discontinuation rate among several biologics at 12 months, which is an indirect marker of tolerability, since patients who feel good on a drug tend to stay on it.¹⁷ If you are looking for a biologic with the fewest red flags across infection, cardiovascular, and liver domains, IL-23 inhibitors are a strong contender, though they are still relatively new and long-term post-marketing data continue to accumulate.

Apremilast: The Gentlest Option, With a Trade-Off in Potency

Apremilast is an oral pill that works differently from biologics. It does not suppress the immune system in the way that injectable therapies do, which gives it a remarkably clean safety record for serious events. Pooled data from three phase III trials showed that rates of major cardiac events, malignancies, and serious opportunistic infections remained very low over three years of use, with zero serious opportunistic infections reported.¹⁸ No TB reactivation, no need for TB screening before starting, and no lab monitoring required beyond baseline checks.

Five-year follow-up confirmed the pattern: the most common problems were diarrhea and nausea, usually within the first two weeks, typically resolving within a month. Depression rates stayed at or below about 2%, and no new safety concerns appeared.¹⁹ Long-term data from psoriasis trials showed the same stability over 156 weeks, with no climbing rates of cardiac events or cancer.²⁰

The catch is efficacy. Apremilast is less powerful than biologics for joint disease and skin clearance. Real-world studies consistently show that patients on apremilast are more likely to stop treatment than those on TNF inhibitors or IL-17/IL-23 inhibitors, largely because the drug does not control their disease well enough.²¹ For mild psoriatic arthritis, apremilast can be an appealing choice precisely because of its gentle safety profile. For moderate or severe disease, a drug that does not control your arthritis is not truly “safe” in any meaningful sense, since uncontrolled joint inflammation causes permanent damage.

JAK Inhibitors: Effective but Carrying a Regulatory Cloud

Tofacitinib and upadacitinib are oral JAK inhibitors approved for psoriatic arthritis. They are potent and convenient, but a large post-marketing trial in rheumatoid arthritis patients (the ORAL Surveillance study) found that tofacitinib did not meet non-inferiority thresholds compared with TNF inhibitors for major cardiovascular events and cancer in patients who already had cardiovascular risk factors.²² That finding led regulators worldwide to add boxed warnings to the class.

The picture for psoriatic arthritis specifically is murkier. A meta-analysis of trials that included psoriatic arthritis patients found no significant difference in composite cardiovascular events or blood clots between JAK inhibitors and comparators.²³ However, a separate meta-analysis found that JAK inhibitors were associated with roughly double the risk of blood clots when compared to active comparators in longer trials (12 months or more), though the signal disappeared in shorter studies.²⁴ The discrepancy largely comes down to differences in trial populations, follow-up time, and comparators studied.

Herpes zoster (shingles) is another concern with JAK inhibitors. A review of clinical trials and real-world studies found that shingles rates in tofacitinib-treated patients with psoriatic arthritis were about 1.7 per 100 patient-years, which is lower than rates seen in rheumatoid arthritis patients on the same drug, but still higher than what is typical on biologics.²⁵ If you are considering a JAK inhibitor, your doctor will likely want to assess your cardiovascular risk, blood-clot history, and shingles vaccination status first.

Cancer Risk With Biologics

Whether biologic therapy increases cancer risk is one of the more anxiety-provoking questions patients face. A national cohort study from Taiwan looked at hematologic malignancies in patients with psoriatic arthritis, psoriasis, or ankylosing spondylitis treated with biologics. It found no overall increase in blood cancers, but did identify a higher risk of lymphoid malignancies, specifically non-Hodgkin’s lymphoma, in biologic-treated patients.²⁶ Whether that reflects the biologic itself, the underlying inflammation, or the fact that people on biologics have more severe disease (and thus more immune dysregulation) is hard to untangle. Most rheumatology guidelines consider the absolute risk to be low enough that it should not prevent treatment in the vast majority of patients, though those with a prior lymphoma history need individualized assessment.

Pregnancy and Family Planning

If you are pregnant or planning a pregnancy, the safety landscape narrows considerably. Methotrexate and leflunomide are both teratogenic and must be stopped well in advance of conception. During pregnancy, the options that have the most reassuring data are certolizumab pegol (a TNF inhibitor), low-dose corticosteroids like prednisolone, sulfasalazine, and cyclosporine.²⁷

Certolizumab pegol stands out among biologics because it lacks the part of the antibody molecule that is actively transported across the placenta. A large pharmacovigilance analysis of nearly 1,400 pregnancies with maternal exposure to certolizumab found live birth rates around 88%, miscarriage rates around 10%, and a major congenital malformation rate of about 2%, all within the expected range for the general population.²⁸ Earlier pharmacovigilance data from over 1,100 pregnancies supported this, with similar malformation rates.²⁹ For someone whose psoriatic arthritis requires ongoing biologic treatment through pregnancy, certolizumab is widely regarded as the safest choice.

Older Adults and Kidney Disease

Age alone does not appear to change the safety calculation dramatically. A study comparing leflunomide outcomes in patients over 65 versus younger patients found no significant differences in adverse effects or treatment withdrawal between the two groups.³⁰ Real-world data on biologic drug survival also showed similar persistence rates in patients over 60 compared to younger patients.²¹

Kidney disease is a different story. A cohort study found that daily NSAID use was independently associated with roughly 77% higher risk of developing chronic kidney disease in psoriatic arthritis patients. Interestingly, methotrexate use was associated with a lower risk of chronic kidney disease in the same analysis, possibly because it reduces the systemic inflammation that damages kidneys over time.³¹ Diabetes, kidney stones, and high uric acid levels were also independent risk factors. If your kidney function is already reduced, your rheumatologist will likely steer you away from NSAIDs and toward drugs that do not burden the kidneys.

Vaccination While on Treatment

Whatever drug you take, staying up to date on vaccinations is one of the most practical safety steps available to you. Consensus guidelines from the National Psoriasis Foundation recommend continuing most oral and biologic therapies without modification when receiving non-live vaccines (like flu shots and COVID vaccines). For live vaccines, most biologics and oral therapies need to be paused before and after administration.³² Methotrexate is a special case: some guidelines suggest briefly holding it even for non-live vaccines to improve immune response.

There is reassuring evidence that vaccinations are both safe and effective in patients already on biologic therapy. A study of psoriatic arthritis patients receiving secukinumab found that the seasonal flu vaccine produced an adequate immune response with no disease flares and no serious adverse effects.³³ The shingles vaccine is particularly worth discussing with your doctor if a JAK inhibitor is part of your treatment plan, given the higher shingles rates in that drug class.

Drug Interactions and the Polypharmacy Problem

Many people with psoriatic arthritis take multiple medications for co-existing conditions like high blood pressure, diabetes, or acid reflux. A study examining drug interactions in 100 psoriatic arthritis patients found that 63% had polypharmacy, and there were 236 potential drug-drug interactions across the group. The majority involved methotrexate interacting with folic acid, NSAIDs, or proton pump inhibitors. TNF inhibitors had far fewer interaction concerns.³⁴ Cyclosporine, another conventional DMARD sometimes used in psoriatic arthritis, carries its own interaction burden along with the risk of hypertension with long-term use.³⁵

Biologics and IL-23 inhibitors in particular tend to have cleaner interaction profiles because they work through highly targeted immune pathways rather than broadly affecting liver enzymes or kidney clearance. If you are already on a complex medication regimen, this is worth raising with your rheumatologist, because the “safest” drug in isolation is not always the safest drug in the context of everything else you are taking.

Liver Health Deserves Extra Attention

Liver abnormalities are common in psoriatic arthritis even before treatment starts, thanks to the metabolic overlap between the disease and conditions like fatty liver. A study specifically examining liver problems in psoriatic arthritis patients found that drug-induced hepatitis and fatty liver were the most frequent causes, and that higher BMI, daily alcohol, more damaged joints, elevated inflammation markers, and use of methotrexate, leflunomide, or TNF inhibitors were all independently associated with liver abnormalities.³⁶ This does not mean you should avoid all of these drugs, but it does mean liver monitoring is especially important if you have metabolic risk factors. Apremilast, IL-17 inhibitors, and IL-23 inhibitors do not carry meaningful liver toxicity signals, making them attractive options when liver health is a priority.