RENEW OR SUBSCRIBE TO PPM
Subscription is FREE for qualified healthcare professionals in the US.
12 Articles in Volume 16, Issue #1
A New Look at Sphenopalatine Ganglion Blocks for Chronic Migraine
Can Weight Loss Help Reduce Psoriatic Arthritis Symptoms?
Chronic Back and Neck Pain in America 2015 Survey Results
Efficacy of Acupressure Plus Manipulation for Lumbar Disc Herniation: A Clinical Report
Is Tapentadol a Glorified Tramadol?
Letters to the Editor: Naloxone, Opioid Tolerance, Polyarthropathy
New Research Into Psoriatic Arthritis
New Technique Shows Promise as Adjunct In Chronic Pain Management
Pharmacogenetic Testing in Pain Management: Where Do We Stand?
Reinventing IM and Procedural Injections: The Sota Omoigui Short Needle Technique
Timely- versus Delayed-Use of TNFi’s: Which Approach Is Better?
Undiagnosed Atlas Subluxation in Patient with Pain and Poor Myofascial Function

New Research Into Psoriatic Arthritis

The last few years have seen a marked increase in new therapies and emerging research on the treatment of psoriatic arthritis.

Interviews with Philip J. Mease, MD, and Elaine Husni, MD, MPH

Psoriatic arthritis (PsA) is an autoimmune disorder that often presents serious clinical challenges to practitioners. The disease’s array of disabling manifestations and painful, chronic symptoms can be intermixed with comorbid health problems. Oftentimes, late diagnosis is a pressing danger, as it ratchets up the risk of permanent joint damage, severely compromising a patient’s long-term outlook.

“Part of the underdiagnosis of PsA is simply lack of knowledge and awareness among clinicians and patients that patients with psoriasis can have an immunologically-mediate arthritis condition associated with it,” noted Philip J. Mease, MD, Director of Rheumatology Research, Swedish Medical Center, and Clinical Professor at the University of Washington School of Medicine, Seattle, Washington.

National Psoriasis Foundation, 1990

 

The Warning Signs of PsA

Are Plaque Psoriasis Patients Under-evaluated?

Psoriasis occurs in 3.2% of the US population, according to current findings from the National Health and Nutrition Examination Survey.1 Of patients with psoriasis, 10% to 30% have PsA.

While this may implicate an intrinsic, pathogenic link between the 2 conditions, there is still a lack of understanding how the inflammatory T cell responses that sustain lesional skin inflammation are connected to the joint inflammation that characterizes PsA.2

Data from Corrona (Consortium of Rheumatology Investigators of North America) on the relationship between skin and joint disease was presented at the American College of Rheumatology (ACR) annual meeting, held in San Francisco, California. Researchers reported that patients in the PsA registry who had a higher percentage of skin involvement (>3% body surface area [BSA]) had worse outcomes.

Indeed, patients with >3% affected BSA were more likely to be disabled and less likely to achieve minimal disease activity (MDA), compared to patients with ≤3% BSA at enrollment. Patients with >3% affected BSA also showed slightly higher rates of comorbid health problems, including cardiovascular disease (61.25% vs. 59.4%), cancer (9.1% vs. 6.6%), and serious infections (5.1% vs. 4.4%), compared to those with ≤3% BSA, respectively.3

Even when the definition of MDA was modified, excluding BSA, the criteria still pointed to worse outcomes for patients with >3% BSA. It also should be noted that 3% BSA is a relatively low cutoff point. And yet “the extent of psoriasis lesions confers a significantly greater burden of disease in PsA,” reported Dr. Mease, a co-author of the study, which underscores the importance of effectively managing psoriasis symptoms in patients that also suffer from PsA.3

 Treating Psoriasis, While Looking Out for PsA

Use of over-the-counter (OTC) and topical treatments for psoriasis management typically is considered the first line of defense. Consistent doses of ultraviolet B (UVB) phototherapy also can improve symptoms. Doctors even are using combination approaches, pairing topical therapies with biologic agents, like disease-modifying antirheumatic drugs (DMARD’s), tumor necrosis factor inhibitors (TNFi), or interleukin inhibitors, which have been shown to be effective and safe despite the risk of adverse events associated with chronic use.4

However, while practitioners continue to pinpoint the best treatment approaches to managing psoriasis lesions, clinicians still need to be on the watch for PsA incidence, which appears to be a source of dysfunction in overall patient management. The relatively recent PREPARE trial found that 41% of psoriasis patients diagnosed with psoriatic arthritis were not previously aware that they had PsA.5 New research presented at this year’s ACR meeting further corroborate these claims.

In an analysis of 1,002 patients with psoriasis, a meager 4.3% received joint exams.6 In addition, out of those with physician-reported or patient-reported joint pain, 79.0% and 90.7% did not receive joint exams, respectively. Patients that had physician-reported joint pain but no joint examinations reported much poorer utility scores, greater activity impairment, and more severe psoriasis.

Underdiagnosis of PsA is a concerning trend, given that commonly overlooked non-specific musculoskeletal symptoms, including joint pain, fatigue, and stiffness, are typical warning signs of the preclinical PsA phase.7 Interestingly though, physicians and patients alike seem to be more interested in pain and functional activity than skin disease associated with PsA.

BioTRAC is another ongoing, prospective registry for culling data on autoimmune disease management, specifically for patients being treated with infliximab (Remicade) or golimumab (Simponi). A group of 92 patients (52.2% male; mean age 48.7; disease duration 6.8 yr) were assessed at baseline. A majority of patients (84.8%) had received past treatments of a DMARD (methotrexate; 71.7%). Patients and doctors both showed a stronger inclination towards more concern over reported pain and HAQ-DI when evaluating the global status of PsA.8,9 This could be a hopeful sign that skin symptoms are not seen as inconsequential in PsA management.

Timely Treatment Decisions

Treatment decisions need to be timely, precise—perhaps even pragmatic—to improve outcomes and inhibit the disease’s radiographic progression. However, this may be a more perplexing task than it was in the past. For decades, methotrexate (Trexall, Rasuvo, others) was the proverbial drug-of-choice for PsA, but in the last few years, the practice has seen a ballooning inventory of pharmaceutical options.

“It’s unbelievable the amount of new treatments that are available for psoriatic arthritis today,” said Elaine Husni, MD, MPH, of the Cleveland Clinic Foundation in Ohio. The litany of TNFi, phosphodiesterase-4 inhibitors (PDE4i), and emerging investigational interleukin inhibitors present a bevy of therapeutic approaches to assess.

Figuring out the most effective, responsive treatment strategies is an area of burgeoning research. “It becomes a great area of research to figure out which person should get which medication for their psoriatic arthritis,” Dr. Husni told Practical Pain Management, and fortunately for practitioners, a major update of consensus guidelines is on the way, courtesy of GRAPPA, the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis.

At the ACR meeting, the non-profit GRAPPA published an abstract of their new 2015 treatment recommendations for PsA.10 The last time the organization updated their guidelines was back in 2009,11 and given the influx of new research and approved therapies for PsA, the 2015 update could serve as a useful guidepost (Figure 1, Table 1).

“It’s an opportunity to have a consensus among health care professionals that focuses on psoriatic arthritis,” said Dr. Husni, who was part of a team of rheumatologists, dermatologists, and patient-research partners (PRP) that drafted the recommendations based on 6 separate literature reviews, using the GRADE system to stratify strong and conditional recommendations.

The large majority of GRAPPA membership voted in consensus on the treatment recommendations (87.2%) and schema (87.9%), which were organized based around the PsA’s various clinical contexts, which are known for their heterogeneity. Arthritis, spondylitis (axial disease), enthesitis, dactylitis, skin and nail disease, and related comorbidities—all were given their own management principles, with further specific information about prescribing for patients either naïve or inadequately-responding to an initial treatment.

For instance, for patients suffering from peripheral arthritis who are naïve to DMARDs, the guidelines strongly recommend starting them off with standard DMARD therapy, such as methotrexate, sulfasalazine (Azulfidine), or leflunomide (Arava), or a biologic therapy (TNFi). However, in the event that a patient is inadequately responding to the DMARD, switching to a TNFi is strongly recommended.

“We now are able to treat to target—meaning treat to a target of either low disease activity or even remission. In addition, we now have quantitative measures that can be employed in rheumatology to quantitate disease response,” noted Dr. Mease.

Typically, the first-line biologic agents are the TNFis (eg, adalimumab [Humira], etanercept [Enbrel], certolizumab [Cimzia], golimumab, or infliximab), “which have been a major part of our treatment armamentarium over the last decade,” said Dr. Mease.

Newer agents include ustekinumab (Stelera), a monoclonal antibody that targets interleukin (IL)-12 and IL-23 proteins. Ustekinumab has been found to be very effective in the treatment of psoriasis when given once every 3 months via subcutaneous injection, and has been shown to be effective in PsA. Ustekinumab is just one of the non–anti-TNF biologic therapies now available to practitioners.

A host of new research has been conducted on these drugs. In the following section, Practical Pain Management takes a look at many of these new therapies: including apremilast (Otezla), the first oral agent that inhibits the enzyme phosphodiesterase 4; secukinumab (Cosentyx), an IL-17 inhibitor that recently received approval for the treatment of PsA; and 2 investigational agents in Phase 3 clinical trials.

New and Emerging Therapies for PsA

Apremilast

Apremilast was approved in March 2014 by the Food and Drug Administration (FDA) for the treatment of PsA in adults. The following September, the FDA also approved apremilast for the treatment of moderate-to-severe plaque psoriasis (PsO). The first oral drug of its kind, apremilast could be just as valuable as it is convenient, as new extended Phase 3, randomized controlled clinical trials showed good results for the drug’s long term safety, efficacy, and improvements to patient quality of life (QoL).12-17

The patients featured in the apremilast PALACE clinical trials previously had an inadequate response to conventional DMARDs, but after taking apremilast, they showed sustained improvements past the 100-week mark. For instance, the majority of patients in the PALACE 1 trial continued to achieve ACR20/ACR50/ACR70 responses, improvements in physical function, and reduced PsO through the 156 weeks of continuous treatment.12

Upper respiratory tract infections were the only prevalent (≥5% of patients) adverse event (AE) through weeks >104 to ≤156 of taking apremilast. Otherwise, there were no new safety concerns.12 Laboratory abnormalities have been infrequent with apremilast, typically returning to baseline after continued treatment, which suggests laboratory monitoring while patients are on the medication is unnecessary.13

Apremilast appears to improve the QoL of patients in other practical ways, like enhancing work productivity, something that PsA patients otherwise stuggle with. Throughout PALACE trials 1, 2, and 3, the Work Limitations Questionnaire (WLQ) revealed that patients achieving ACR20 and ACR30 scores also experienced improved work productivity, starting as early as week 16 and sustaining into week 52 of treatment.14 Apremilast also appeared to improve fatigue levels for over 104 weeks15 and facilitate meaningful improvements in physical function for ACR30 patients.16

Enthesitis and dactylitis (inflammation of the entire digit) are painful, hallmark features of PsA that apremilast appeared to quell. Enthesitis is inflammation that occurs wherever tendons and ligaments insert into bone. Common locations include the Achilles tendon insertion at the heel, plantar fascia insertion at the heel, and patellar tendon insertions. Even the ligamentous tissue that binds the rib cage together can be inflamed, causing chest pain, said Dr. Mease.

A pooled analysis of all 3 PALACE trials showed Maastricht Ankylosing Spondylitis Enthesitis Scores (MASES) (range: 0-13) improved at week 24 of treatment by a mean change of -1.3 and -1.2 for APR 30 and APR20 patients, respectively, with a -0.9 mean change for placebo. Dactylitis count virtually depleted for many patients by week 104, with 77.5% of ACR30 patients and 72.9% of ACR20 patients decreasing their dactylitis counts down to zero.17

Secukinumab

Secukinumab is an IL-17A inhibitor approved by the FDA in January 2015 for the treatment of moderate-to-severe plaque psoriasis and more recently for PsA and ankylosing spondylitis (AS). A wide review of research was presented at the ACR meeting that presented thorough examinations of the drug’s efficacy and safety profiles in the context of PsA treatment, including a sub-analysis of the recent CLEAR clinical trials in psoriasis, which reported secukinumab actually outperforming ustekinumab, a currently approved interleukin 12/23 inhibitor.18

Of the 676 patients taking part in the study, 123 had concomitant PsA. By week 16 of treatment, secukinumab achieved a noticeably higher rate of patients achieving PASI 90, where 79.0% of patients taking subcutaneous secukinumab 300 mg achieved PASI 90 compared to the 57.6% taking ustekinumab 45 mg or 90 mg. Physical function also improved at a greater rate when patients were on secukinumab. At week 16 of treatment, change from baseline in HAQ-DI was -0.29 (-47.6%) with secukinumab compared to -0.13 (-37.7%) with ustekinumab.18

Secukinumab could be another option for patients inadequately responding to a TNFi therapy. The FUTURE 2 study presented the results of a 52-week investigation, where 397 patients were enrolled to receive the drug. While the majority of the cohort were naïve to TNFi therapy, a sizable 35% were classified as inadequately responding to TNFi therapy. Secukinumab 300 mg outperformed placebo in primary endpoints for both TNFi naïve and TNFi-resistant patients.19

Secukinumab’s safety profile appears to hold up with previous reports. One study pooled the safety data of 5 different Phase 3 studies investigating secukinumab for PsO (ERASURE, FIXTURE, SCULPTURE, FEATURE, and JUNCTURE) and 2 other studies for PsA (FUTURE 1 and FUTURE 2). Only 2.9% of the patient pool had to discontinue their treatment regimen due to AEs, which were most frequently nasopharyngitis and upper respiratory tract infections. Other known AEs, such as inflammatory bowel disease (IBD)/Crohn’s disease, infections, neutropenia, major adverse cardiac events (MACE), and malignancy, were “low in occurrence,” noted the authors of the study.20

Ixekizumab

Ixekizumab (Eli Lilly and Co.) is similar to secukinumab in that it shares a comparable mechanism of action—both inhibit IL-17A and both are different from brodalumab, which is an IL-17 receptor inhibitor.

Ixekizumab is an IgG4 monoclonal antibody that binds with high affinity and specificity to the proinflammatory cytokine IL-17A, currently under investigation for the treatment of PsA. Ixekizumab was well tolerated in patients, with no unexpected safety findings to note.21

Ixekizumab was tested side by side with adalimumab (Humira, AbbVie) in a recent Phase 3 trial with 417 DMARD-naïve PsA patients randomized for 24 weeks of treatment with adalimumab 40 mg taken once every 2 weeks, ixekizumab 80 mg taken following a 160 mg dose at week 0, or placebo. Both ixekizumab and adalimumab showed favorable signs of efficacy, outperforming placebo in ACR and PASI scores.21,22

The SPIRIT-1 trial was the big new news for this class of agents at this year’s ACR meeting, noted Dr. Mease. This is an important message because adalimumab is one of the most commonly used biologic treatment for PsA, said Dr. Mease. These studies showed that ixekizumab significantly improved quality of life, physical function, and work productivity—placing it on similar footing as adalimumab.22

Brodalumab

Brodalumab (Valeant Pharmaceuticals) is a fully human IL-17 receptor antibody formulated to block IL-17A, IL-17F, and IL-17A/F cytokines implicated in the pathogenesis of psoriasis. The results of a Phase 2 study were presented at this year’s ACR meeting, which showed strong ACR20 and ACR50 responses in patients receiving 140 or 280 mg. Outcome measures were sustained through week 108 of the study. According to the authors of the study, brodalumab’s safety profile appeared to be comparable to other biologics approved for treating PsA.

The most frequent AEs that occurred in ≥10% of all patients were nasopharyngitis, upper respiratory tract infection, psoriatic arthropathy, urinary tract infection, arthralgia, diarrhea, sinusitis, and bronchitis. No deaths occurred in the study. There was 1 laboratory report of neutropenia, 1 case of suicidal ideation, and 11 cases of oral candidiasis.23

Last updated on: June 13, 2017
Continue Reading:
Can Weight Loss Help Reduce Psoriatic Arthritis Symptoms?

Join The Conversation

Register or Log-in to Join the Conversation
close X
SHOW MAIN MENU
SHOW SUB MENU