Elise Oberliesen

After reviewing three clinical trials involving 1,493 people diagnosed with active psoriatic arthritis, the FDA approved Otezla (apremilast), a phosphodieasterase-4 (PDE-4) inhibitor, in March, 2014. That was welcome news for people who had been relying on injectable biologics as part of their treatment plan to reduce swollen, tender joints commonly associated with the disease.

Since apremilast is the first oral medication in this class of drugs to treat PsA, now patients have more treatment options. Until apremilast hit the market, “tumor necrosis factor inhibitors, an interleukin-12/23 inhibitor and corticosteroids” were the only treatment options available to treat PsA, according to the 

Compared to interventions or subcutaneous treatments for PsA, having this oral medication offers more convenience to patients, say some 

, who commented to NPF about the new treatment

Whether apremilast will help improve treatment adherence remains unknown, but it will be interesting to watch as more people choose this new oral treatment over their usual injectable therapies.

According to Celgene, the New Jersey-based drug manufacturer that makes apremilast, the treatment targets characteristic symptoms in people with PsA. Those include “specific disease manifestations” like inflamed fingers and toes (dactylitis), and inflammation where tendons and ligaments connect with bone (enthesitis).

“Treatment with OTEZLA resulted in improvement in dactylitis and enthesitis in patients with these pre-existing symptoms,” the company said in a 

Researchers concerned about quality of life in patients with PsA also took notice of apremilast and published findings from a randomized clinical trial that involved 204 people with active PsA. The study results, published in the 

, suggest that apremilast helped people “improve quality of life” while on the treatment.

Keep in mind, apremilast is only FDA-approved at 20 mg and 30 mg doses; however, people in the study who were prescribed 20 mg and 40 mg doses “reported significant improvements that were clinically meaningful, eg, ≥ minimum clinically important differences (MCID) in global VAS (visual analog scale) scores and FACIT-F (Functional Assessment of Chronic Illness Therapy-Fatigue) versus placebo, and significant improvements in pain VAS scores,” according to the study authors.

Compared to the placebo group, researchers concluded that “Apremilast 20 and 40 mg BID resulted in statistically significant and clinically meaningful improvements in physical and mental component summary scores and 7 and 6 SF-36 domains, respectively… Moderate-high, significant correlations were evident between SF-36 domains and other PRO (patient reported outcomes).”

Lead author Vibeke Strand, MD, FACP, Stanford University School of Medicine, said, “Essentially skin manifestations already impact HRQOL through social functioning and role emotional but also pain; but psoriatic arthritis impacts pain, physical function, role physical.”

The NPF Annual Patient Survey Panel reported that 44% of non-working people with psoriatic arthritis blame the disease for their lower quality of life—citing examples like “bodily pain and physical functioning.”

 of people surveyed reported that psoriatic arthritis affected their “overall emotional well-being.”

In clinical trials, the most common side effects of apremilast were diarrhea, nausea, and headache and elevated depression, according to an 

 statement. Risks among pregnant women and their unborn babies also are not yet known. 

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Until apremilast was approved earlier this year, patients with psoriatic arthritis had to rely primarily on injectable therapies, which contributed to less than optimal treatment adherence in many patients. 

Oral Medication Option May Lead to Improved Treatment Adherence in Patients with Psoriatic Arthritis 

Patients with psoriatic arthritis treated with certolizumab pegol (CZP), a PEGylated Fc-free anti-tumor necrosis factor (TNF), showed “rapid improvement” in symptoms related to joints, skin, enthesitis, dactylitis and nails, according to a phase 3 study published in the 

For the double-blind, controlled study, Philip J. Mease, MD, from the Swedish Medical Center and University of Washington in Seattle and his research team randomized 409 participants to receive one of two doses of CZP and compared results to a placebo group.

The study authors reported, “ACR20 response was significantly greater in CZP 200 mg Q2W and 400 mg Q4W-treated patients than placebo (58.0% and 51.9% vs 24.3% (p<0.001)) at week 12, with improvements observed by week 1.”

In total, 368 participants completed the study. By week 24, researchers observed more patients with improvement in both medication groups (CZP 200 mg and CZP 400 mg) compared to placebo, (78.3% and 77.0% vs 33.1% (p<0.001).

A significant number of study participants (70%) used combined doses of DMARDs with CZP. About 20% of both groups (placebo and combined dosages) used TNF inhibitors at some point before the study.

Mease said “the ACR responses were the same regardless of whether the patient had been previously anti-TNF-exposed.” Interestingly, many people on TNF inhibitors will eventually show decreased response rates to treatment.

“Recent studies of ustekinumab (an interleukin 12/23 inhibitor) have demonstrated this expected reduced efficacy in PsA patients with prior exposure to TNF inhibitors,” according to study authors. And for this reason, in the past, a course of TNFs would have disqualified them from study participation—until now.

Mease said this study is unique because it included people with prior anti-TNF treatment regimens—something that helped researchers fully observe treatment outcomes among patients with PsA.

“Knowing that the ACR responses in the CZP PsA study were similar in patients who had been on prior TNF inhibitor therapy gives you some confidence that in a patient who is on an anti TNF medication and is not responding adequately, then it would be reasonable to consider trying certolizumab,” said Mease.

That’s an important point considering that a fair number of people eventually stop responding to medications and will likely need other treatments. Plus, with fewer available treatments for PsA and the high prescription costs that make it hard for patients to afford them, researchers pointed out that physicians may need to “cycle through TNF inhibitors” if DMARDs stop working.

Less serious common side effects included diarrhea and headacheâ€‘â€‘3.6% CZP vs. 2.9% placebo, and 3.6% CZP vs. 1.5% placebo, respectively. 

 were nasopharyngitis and upper respiratory tract infections, at 3.6% CZP vs. 1.5% placebo; and 7.8% CZP vs. 5.1% placebo, respectively. Participants reported their symptoms as mild to moderate. In essence, at week 24, respiratory problems were reported in 21 people in the placebo group, and 38 people in both CZP dosage groups.

Also of note, researchers found that participants in the CZP groups more often showed elevated liver enzymes, compared to placebo group.

With more research in the pipeline, physicians are hopeful that new treatments for people with PsA will become available. “There are fewer options for PsA patients, with approved drugs, compared to rheumatoid arthritis,” said Mease.

Patients treated with certolizumab pegol for 24 weeks showed rapid improvement in the signs and symptoms of psoriatic arthritis. 

Phase III Trial Results Show Certolizumab Pegol Is an Effective Treatment for Psoriatic Arthritis

alk to nearly any rheumatologist and you quickly discover that new treatments for psoriatic arthritis (PsA) fail to keep pace with treatments for other diseases, such as rheumatoid arthritis. For that reason, phase 3 trials aimed at treatment for the disease garner much anticipation.

), an oral phosphodiesterase 4 inhibitor, to treat adults with active psoriatic arthritis.

Participants in a 24-week phase 3 randomized clinical trial took apremilast at 20 mg twice a day or 30 mg once a day, with other disease-modifying antirheumatic drugs (DMARDs). According to research published in the March 2014 issue of 

, people on apremilast showed symptom improvement compared to placebo.

“Significantly more apremilast 20 mg BID (31%) and 30 mg BID (40%) patients achieved ACR20 versus placebo (19%) (p<0.001), the study authors wrote.

ACR (American College of Rheumatology) 20 is the minimum score indicative of symptom improvement associated with joints. Higher ACR scores are synonymous with higher levels of improvement. Some people achieved 

. (ACR50, at 20 mg and 30 mg respectively, 14.7% and 19.9%; ACR 70, at 20 mg and 30 mg, 5.5% and 10.6%).

To assess joint symptoms and improvements, physicians used HAQ-DI score and the Short-Form Health Survey v2 Physical Functioning domain score. They also took into account their patient’s reporting of pain.

Lead study author Arthur Kavanaugh, MD, Director of the Center for Innovative Therapy at UC San Diego School of Medicine, said, “The drug can have good efficacy for some patients, and it seems to be very well tolerated.”

The results suggest that people on 30 mg showed better “response rates” compared to placebo.

Regarding the differences in dosage, Kavanaugh said, “Most of the responses were either similar or with higher doses they [patients] did a little bit better.”

He continued, “Doctors do like to play around with dosing… Might there be different doses in the future? … That remains to be seen.”

Of the 504 participants in the RCT, some were previously prescribed traditional disease-modifying antirheumatic drugs (DMARDs) and/or biologics. However, the authors noted that “Prior tumor necrosis factor blocker efficacy failures were limited to ≤10% of enrolled patients.”

To assess skin improvement, researchers used the Psoriasis Area and Severity Index (PASI). Results suggest that patients on the drug showed significant skin clearing, compared to placebo

“In patients with baseline psoriasis affecting ≥3% of the body surface area, significantly greater proportions of patients receiving either dose of apremilast achieved at least 50% reduction from baseline Psoriasis Area and Severity Index

 (PASI-50) score (apremilast 20â€…mg BID: 25/74 (33.8%), p = .0439; apremilast 30 mg BID: 41/81 (50.6%), p = .0001) and PASI-75 score (13/74 (17.6%), p = .0180; 17/81 (21.0%), p = .0040) versus placebo (PASI-50: 12/65 (18.5%); PASI-75: 3/65 (4.6%)).

Gastrointestinal symptoms were most commonly reported in people who tried the medication; other 

 included diarrhea, nausea, headache and upper respiratory tract infection. Considered a pregnancy category C drug, it is unclear how apremilast is tolerated among pregnant women or their babies.

Patients with a history of depression or suicidality should be screened, because people on apremilast showed higher rates of depression (1.0%) compared to placebo group (0.8%), according to the 

In addition, the FDA suggests monitoring for significant weight loss for people using this drug.

“If unexplained or clinically significant weight loss occurs, the weight loss should be evaluated and discontinuation of treatment should be considered. Treatment with Otezla was also associated with an increase in reports of depression compared to placebo,” states an 

When it was approved by the FDA in March 2014, apremilast became the first oral medication approved for the treatment of psoriatic arthritis (PsA). Data from clinical trials showed it to be an effective option for patients, with a safer side effect profile than currently used PsA treatments.

Apremilast and the Future of Psoriatic Arthritis Treatment

A, PsA, and Extended Oligoarthritis (CLIPPER) published in the May 2013 issue of 

, suggest etanercept is a safe and effective treatment in patients with polyarticular course juvenile idiopathic arthritis (JIA), the most common chronic rheumatic disease in children. The study results also indicated that etanercept may also be effective in patients with psoriatic arthritis and other conditions.

The trial enrolled pediatric patients with extended oligoarticular juvenile idiopathic arthritis (eoJIA), enthesitis-related arthritis (ERA), or psoriatic arthritis (PsA). Subjects in each category received a weekly dose of etanercept 0.8 mg/kg, (maximum dose of 50 mg), with an average weekly dose of 35 mg.

A large percentage (93.1%) of the children with psoriatic arthritis (n=29) achieved JIA American College of Rheumatology (ACR) 30 criteria, indicating a 30% improvement in symptoms based on the ACR composite index.

The higher the number, the better the score, said pediatric rheumatologist Nicolino Ruperto, MD, MPH, the study’s senior author. “Improving by 30% is the minimum important clinical improvement but of course improving by 70% or 90% is more desirable,” he said in an e-mail statement.

While those numbers appear favorable, Ruperto indicated the need to better understand the long-term effects of treatment on people in other rheumatic disease categories that are not as well understood.

“The efficacy and safety of etanercept in specific ILAR categories, such as extended oligoarticular JIA (eoJIA), enthesitis-related arthritis (ERA) and psoriatic arthritis (PsA) has not been studied thoroughly,” wrote the study authors.

While Ruperto did not elaborate on specifics, he emphasized the “essential” need for further data since the “chronic” nature of these diseases require ongoing drug treatment—something we know little about. This is especially true since biologic use in juvenile PsA is so new. “This is the first study [using etanercept] that has considered children with PSA,” Ruperto said.

Along similar lines, researchers from the Hospital for Sick Children Research Institute, at the University of Toronto, acknowledged this lack of understanding in a 2013 study published in 

“There are fewer reports describing the characteristics and long-term outcome of patients with JPsA than other subtypes of JIA,” the authors noted. They also said that this is partially due to a lack of consensus in the medical community, writing “As more than one classification system for JPsA has been used, it can be confusing to compare different studies and, as recently as 2008, no single classification was agreed upon or universally accepted.”

In conclusion, the Canadian researchers theorize that four main groups may make up JPsA, with similar characteristics to non-JPsA JIA in terms of symptoms, disease course, and treatment outcomes.

However, psoriasis itself may offer “little clinical relevance” in terms of treatment outcomes in youngsters with JIA, they added. “Therefore we may consider psoriasis as an extra-articular manifestation seen in JIA, similar to uveitis, rather a feature requiring a distinct classification grouping.”

Returning to the CLIPPER study, to establish an understanding of drug efficacy, researchers compared results using meta-analysis from JIA studies. They reported that compared to placebo, the results suggest that youngsters with PSA are 40.7 times more likely to improve.

“For eoJIA, ERA, and PsA categories, the ORs (95% CI) of ETN versus the historical placebo data were 26.2 (10.6 to 64.2), 15.1 (6.0 to 38.2) and 40.7 (9.4 to 176.9), respectively,” the authors wrote.

To assess drug safety in all three disease categories, researchers looked at common non-infectious side effects reported by subjects. Most commonly reported symptoms were fatigue and pyrexia, headache, and stomach pain. Comparing all three categories, the researchers found “no differences in the rates of non-infectious treatment-emergent adverse effects (TEAEs).”

Study results show that treatment with etanercept is effective and well tolerated in adolescent patients with psoriatic arthritis and other rheumatic conditions.

Elise Oberliesen

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