Psoriatic Arthritis Update

Arthur Kavanaugh, MD

Dr Arthur Kavanaugh is a Rheumatologist and a Professor of Medicine at the University of California, San Diego. At MauiDerm 2014, he provides the practicing dermatologist with an update on PsA and the latest treatment advances…

The reported estimates of the prevalence of PsA among psoriasis patients have been highly variable, i.e., six percent to 42 percent. It is currently estimated that between 20 and 30 percent of psoriasis patients also have PsA. In addition, psoriasis precedes PsA in over 85-90 percent of the cases, though we’re not sure why. Dr Kavanaugh believes that in 20 to 30 years, we may have that answer. In 2012, there were an estimated 1,600,000 PsA patients in the United States. Of those patients, about 485,000 were diagnosed and only about 345,000 received treatment. Now that we have treatment available, Dr Kavanaugh feels that healthcare providers will be seeing more of these patients. As dermatologists, it is important to remember that PsA is a serious condition; approximately 20 percent of patients with PsA will develop destructive, disabling arthritis. PsA results in radiological damage in up to 47 percent of patients at a median interval of two years. Remember that other comorbididites often exist among PsA patients; these include, metabolic syndrome, CAD, uveitis, IBD, impaired function and quality of life, and economic implications.

Recent data presented at the 2013 American College of Rheumatology, suggest that a delay in the diagnosis of PsA correlates with poor patient outcomes. A study of 283 PsA patients, fulfilling the CASPAR criteria, demonstrated that even a six-month delay from symptom onset to the first visit with a rheumatologist contributed to the development of peripheral joint erosions, sacroiliitis, and worse long-term physical function.

Diagnostic Criteria for PsA (CASPAR)

The diagnostic criteria for PsA includes an established inflammatory articular disease (joint, spine, or entheseal), plus three or more points from the following five categories:

Psoriasis
- Current-psoriatic skin or scalp disease present today (2 points)
- History-a history of psoriasis
- Family history-history of psoriasis in a first or second degree relative
- Nail Changes-typical psoriatic nail dystrophy
- A negative test for RF-by any method except latex (preferably ELISA or nephlemetry)
- Dactylitis
  - Current-swelling of a current digit
  - History –history of dactylitis
  - Radiological evidence of juxta-articular new bone formation-ill-defined ossification near joint margins (but excluding osteophyte formation) on plain X-rays of hand or foot

The CASPAR criteria are very sensitive and very specific; but, in the clinic, the question lies as to whether or not the patient has inflammatory arthritis. That is a tougher question and we don’t have a perfect answer for that. Several questionnaires and screening tests have been developed for this, such as the Psoriasis Epidemiological Screening ProjecT (PEST), Toronto Psoriatic Arthritis Screen (ToPAS), and Psoriatic Arthritis Screening and Evaluation (PASE). All of these instruments did relatively well in the development studies; however, remember that with these screening tests come trade-offs. The more sensitive an answer is, the less specific it is and vice versa. There is no perfect questionnaire and how they perform is based upon how you define them. The difficulties are the oligoarticular and differentiating osteoarthritis from inflammatory arthritis. The utilization of more sensitive imaging (ultrasound and MRI) can help to determine what is inflammatory versus what isn’t inflammatory.

GRAPPA PsA Treatment Recommendations

The chart below outlines the GRAPPA treatment recommendations; however, these guidelines are currently being updated to incorporate some of the newer treatment modalities.

Treatment choices are based on the severity of the different domains.

Clinical Pearl-PsA requires a clinician to really listen to the patient, examine the patient, and formulate and appropriate treatment plan with the patient.

We know that the data on the TNF blockers for the treatment of PsA is very positive for both joint symptoms and skin symptoms. Currently, we even have data that demonstrate the effects of TNF blockers on issues that are important to the patient, such as nail involvement, enthesitis, and dactylitis. In the past, we didn’t have we didn’t have quantifiable ways to measure these, but now we do.

Data also demonstrate that TNF inhibitors slow down the damage to the bone. Getting patients under good control allows them to be functional and go about doing the things they do in their daily life.

Certolizumab Pegol

Certolizumab Pegol (CZP) was approved for the treatment of PsA in September of 2013 and is the fifth TNF inhibitor available for the treatment of PsA. The RAPID-PsA study is important to us, as clinicians, because the researchers looked at switching, i.e., may have failed a previous TNF inhibitor. The phase III results of the 24-week, double-blind, placebo-controlled study showed that the ACR20 response at week 12 was significantly higher in the CZP 200 mg Q2W and CZP 400 mg Q4W arms versus placebo (58.0% and 51.9% vs. 24.3%) and PASI75 response at week 24 for patients with ≥ three percent psoriasis body surface area at baseline (61.6% randomized set) was 62.2 percent with CZP 200mg Q2W and 60.5 percent with CZP 400mg Q4W versus 15.1 percent with placebo. This data demonstrate that CZP is effective in PsA, including patients with prior TNF inhibitor exposure. This is very important for our patients who may not have responded to previous therapy. This data as also been confirmed in other registries; therefore, indicating that switching from one TNF inhibitor to another in PsA is a viable option.

In PsA, we don’t know whether a TNF inhibitor plus methotrexate (MTX) is additive or synergistic. In Rheumatoid Arthritis, there is data that demonstrate that even a dose of MTX as low as 10mg gets you synergy. This is something that as a practitioner, you need to negotiate with your patients.

What about obesity and weight loss?

Currently, the data on obesity are very strong and very consistent. We know that PsA patients have shown an increased prevalence of obesity. A study by Di Minno and colleagues demonstrated that within 12 months of starting a TNF inhibitor, patients with PsA achieved minimal disease activity (MDA). The prevalence of obesity was lower in the group achieving MDA. Patients who lose weight and then begin a TNF inhibitor have a much better chance of doing well, than those who are obese. When you look at the CORRONA database, a study of 392 patients starting a TNF inhibitor showed that only obesity was significantly associated with the discontinuation of treatment. This tells us that patients who are obese do not do as well on therapy and have more disease activity. This is true not only for fixed-dose treatment, but weight-based treatment, such as infliximab, as well. Obesity is inflammatory and this is a very dramatic effect. In fact, it has changed the way Dr Kavanaugh approaches his patients regarding discussing the importance of weight loss.

Biosimilar (CT-P13)

A randomized, double-blind, phase III study of 606 patients demonstrated the clinical equivalence of CT-P13 to infliximab when co-administered with MTX in patients with active rheumatoid arthritis. The results were maintained after the switch from infliximab to CT-P13 from weeks 52 to 104. CT-P13 received a favorable opinion by the EMA and is now available in Europe. CT-P13 was studied in rheumatoid arthritis and ankylosing spondylitis and because it was clinically equivalent it received approval for all of the indications for which infliximab is approved. The FDA has not yet weighed in on how it will approach biosimilar approvals; however, they are here and this is coming. Cost is a major issue, i.e., they could be available at 20-25 percent less than the branded products.

Emerging Therapies

We know that TNF inhibitors work well in GI disease, skin disease, rheumatoid arthritis, etc.. Dr Kavanaugh points out that we have made a somewhat switch from “bench to bedside” to “bedside to bench.” He states that “we are dissecting these diseases by our therapies” with hopes to find more specific treatments for specific groups of patients with these distinct diseases.

Ustekinumab (USK) was approved for PsA in September of 2013. The PSUMMIT trial included 615 adult PsA patients with active disease despite DMARD and/or NSAID therapy. Patients were randomized to receive USK 45 mg, 90 mg, or placebo at weeks 0, 4, and q12 weeks thereafter. At week 16, patients with less than five percent improvement in tender joint count and swollen joint count entered blinded early escape (placebo to USK45 mg; USK 45 mg to 90 mg; 90 mg to 90 mg). Stable concomitant MTX use was permitted but not mandated. Patients treated with prior anti-TNF agents were excluded. The primary endpoint was an ACR20 response at week 24. A significantly greater proportion of USK-treated patients (versus placebo) had an ACR20 response at week 24. Significant improvements were also observed with USK 45mg and 90 mg for ACR50/70 responses and DAS28-CRP responses at week 24 versus placebo. Through week 16, adverse events were similar between patients receiving USK and placebo with infections being the most common AE. No malignancies, serious infections, tuberculosis, opportunistic infections, or deaths occurred through week 24. PASI 75 response at week 24 also demonstrated positive efficacy among the USK 45mg and 90mg doses versus placebo.

The PSUMMIT 2 study looked at USK in patients with active PsA who were previously treated with an anti-TNF agent. This data show some improvement in ACR 20/50/70 and demonstrate that it is safe and could be modestly effective for PsA TNF inhibitor-experienced patients.

Dr Kavanaugh and his colleagues, utilizing an integrated data analysis of two phase III randomized, placebo-controlled studies, also demonstrated that USK inhibits radiographic progression in patients with active PsA.

IL-17

Genovese, et al. studied brodalumab, an anti-IL-17RA in patients with PsA. ACR20 was achieved at week 12 by 37 percent and 39 percent of patients in the 140- and 280-mg brodalumab groups, respectively, compared with 18 percent of placebo patients. The percent of ACR20 responders (observed) increased at week 24 (44%, 51%, 64%, in prior placebo, prior 140 mg, and prior 280 mg groups, respectively). The percent of ACR50 responders (observed) across all groups increased from week 12 to week 24. There were improvements in other secondary endpoints such as DAS 28, CDAI, and several components of the ACR from baseline to week 12 that continued through week 24 in all treatment groups. Adverse events were similar among all treatment groups and placebo. This demonstrates that brodalumab is associated with significant clinical response with continued improvement from week 12 to 24 and further studies of brodalumab for treatment of PsA should be conducted.

Small Molecules

Apremilast, an inhibitor of PDE4, is currently under development for the treatment of PsA. Data from the PALACE 1 study are statistically significant for the apremilast group(s) versus placebo for both ACR 20/50/70 scores and PASI75. At week 24, significantly more apremilast 20 mg BID (36%) and 30 mg BID (45%) patients achieved ACR20 versus placebo (13%). There were also significant improvements in key secondary measures (physical function, psoriasis) with both apremilast doses versus placebo.

One of the major advantages of apremilast is its safety profile. Laboratory monitoring may not be needed with this drug.

Conclusions

Since the availability of biologics, the interest in PsA has increased exponentially. This is exciting for us, as healthcare providers, and very promising for our patients. Lastly, remember the importance of tight control in early PsA. If patients are not responding the way you feel that they should be, then their management strategy needs to be modified. Data demonstrate that using a treat-to-target approach can significantly improve both joint and skin outcomes for newly diagnosed PsA patients.