Sometimes, revisiting the science and challenging old assumptions can bring new understanding to what was once ambiguous. For patients with psoriatic arthritis, we thought there were still many open questions. We wanted to reevaluate how best to treat psoriatic arthritis, so we set out to develop a new clinical trial.
Reevaluating Treatment in Psoriatic Arthritis
Reevaluating the science specific to psoriatic arthritis (PsA)
Science is never settled. For us, science is more than just an intellectual pursuit. There are real-world consequences, especially for patients. While having scientific consensus is the ideal, physicians are often required to make clinical judgments as best they can with the information available. The more we observe, question, postulate, and analyze, the more informed therapeutic choices can be, as we strive to provide better care to patients.
We felt it was time to reexamine psoriatic arthritis.
A look at the history behind psoriatic arthritis treatment
The scientific understanding of PsA has been historically linked with rheumatoid arthritis (RA) and plaque psoriasis (PsO). After all, about 1 in 3 patients with PsO will develop PsA, and both PsA and RA are characterized by pain and swelling of the joints that, if left untreated, can lead to joint destruction and physical impairment.
While we’ve come to recognize PsA as a unique condition from RA, clinical management of PsA is still influenced by RA best practices.
Questioning Established Assumptions
What evidence supported methotrexate (MTX) as part of the psoriatic arthritis treatment paradigm?
MTX has a well-established efficacy profile in RA and is the most frequently prescribed disease-modifying antirheumatic drug (DMARD). While the benefits of MTX either alone or in combination with TNF-α inhibitors have been well established in patients with RA, there is less definitive clinical data available in PsA.
In RA, MTX in combination with a biologic has become a mainstay of treatment. As biologics were being developed for PsA, background therapy with MTX was commonly permitted in pivotal studies and soon became a norm in the treatment of PsA. Because MTX was evaluated as a background therapy in PsA studies and not as a comparator arm, the efficacy of biologics in combination with MTX or versus MTX alone were never fully explored.
A Meeting of the Minds
A consensus on the outstanding science in psoriatic arthritis
We wanted to help address the knowledge gaps in PsA and better inform treatment decisions for these patients. In 2014, nearly 14 years after biologic clinical trials in PsA began, we convened with key opinion leaders in rheumatology and dermatology to see how we could contribute to helping patients with PsA.
Thought leaders agreed that there was still more to learn in PsA. What exactly is the most effective treatment paradigm for patients with PsA? And how can we better evaluate and quantify the unique symptoms of PsA in their own composite measurement?
The advisory board was clear—we should explore important questions about the PsA treatment paradigm.
Designing a study specifically for
psoriatic arthritis patients
We made it our priority to build on the science informing PsA treatment decisions. To accomplish our goal, we needed to:
- Create a separate MTX treatment arm to evaluate its effects versus a biologic
- Establish a PsA-specific composite endpoint to evaluate the unique aspects of PsA
- Power our study with a large biologic- and MTX-naïve patient population to gain clear understanding of outcomes
Bringing background MTX to the foreground
It’s not often that a drug developed prior to 1950 gets evaluated in a new, robust PsA study. Previous studies evaluating biologics in PsA allowed for background MTX use but were not designed to clearly confirm whether MTX was influencing the results.
Evaluating the unique aspects of psoriatic arthritis
We saw the research endeavor as not only an opportunity to evaluate treatment options, but also to look holistically at how psoriatic arthritis is measured.
Over the years, we’ve come to understand that features such as enthesitis, dactylitis, nail dystrophy, and psoriasis are common to patients with PsA but not RA. Yet, standard rheumatological endpoints such as ACR20/50/70* that were developed to measure disease activity in RA don’t encompass a holistic measurement of all the major components of PsA that patients experience. Endpoints like DAS28†, utilized in RA clinical trials, measure clinical characteristics of RA patients. Likewise, PsA needed its own measurement to evaluate its aspects. With guidance from key opinion leaders, we decided to include minimal disease activity (MDA).
*ACR20 = 20% improvement in American College of Rheumatology response criteria. ACR20 is a composite measure based on tender and swollen joint counts, patient’s assessment of pain, patient and physician global assessment of disease activity, patient’s assessment of physical function, and acute-phase reactant value.
†DAS28 = Disease Activity Score based on a 28-joint count (28 tender and 28 swollen).
An endpoint specifically tailored to measure psoriatic arthritis
MDA is a treatment target specifically for patients with PsA. Not only does MDA evaluate tender/swollen joint counts, but it also measures aspects unique to PsA patients, such as tender entheseal points and the Psoriasis Area and Severity Index (PASI) or Body Surface Area (BSA). Developed by the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA), MDA is reliably reproducible and works in clinical practice.
With a holistic perspective of PsA, we chose to include MDA and set forth building our clinical trial.
Finding the Right Patients
Recruitment has been a primary obstacle in previous PsA studies attempting to evaluate biologics with or without MTX. Patients need to be naïve to both biologics and MTX. Physicians hoping to treat with either didn’t need to enroll patients in a clinical trial to do so, they simply could prescribe either agent.
On top of it all, we wanted to focus our recruitment on patients naïve to biologics and methotrexate to better evaluate how biologics and MTX inhibit radiographic progression, either alone or in combination. We recruited a large number of patients to power the study in an effort to drive confidence in the results.
Now that we had decided on the three separate treatment arms, outcome measures specific to PsA, and a robust patient population, our clinical trial was in the making.
Not actual patients.
We gathered 851 psoriatic arthritis patients who had no prior exposure to MTX for PsA or any exposure to a biologic DMARD.
This site is intended for healthcare professionals only. If you are not a healthcare professional, please contact your doctor about ENBREL.
A robust clinical study tailored specifically to patients with psoriatic arthritis
A holistic approach to evaluating psoriatic arthritis treatments
outcome measureACR20at Week 24
A patient achieves minimal disease activity (MDA)
when 5 of the following 7 criteria are met:
- Tender joint count ≤1
- Swollen joint count ≤1
- Psoriasis Area and Severity Index (PASI) ≤1 or body surface area (BSA) ≤3%
- Patient pain visual analog scale (VAS) ≤15 mm
- Patient global disease activity VAS ≤20 mm
- Health Assessment Questionnaire (HAQ) Disability Index ≤0.5
- Tender entheseal points ≤1
measureACR20at Week 24
Regardless of the results, we were determined to share why we pursued the SEAM PsA study and its importance in advancing the treatment decisions for PsA patients.
SEAM PsA results
Patients on ENBREL monotherapy and ENBREL + MTX experienced similar ACR 20 responses at Week 241
- 65% and 61% of patients achieved ACR 20 with ENBREL + MTX* and ENBREL monotherapy,† respectively, vs 51% with MTX1
*P=0.005 vs MTX monotherapy.
†P=0.029 vs MTX monotherapy.
Patients on ENBREL monotherapy and ENBREL + MTX experienced similar ACR 50 and 70 responses at Week 241
Percent of patients achieving ACR 50 and 70 at Week 24
Percent of patients achieving ACR 50 and 70 at Week 24
- These comparisons were analyzed as observed and were not adjusted for multiplicity
The same percentage of patients achieved minimal disease activity (MDA) response at Week 24 with ENBREL monotherapy and ENBREL + MTX1
- 36% of patients achieved an MDA response with ENBREL + MTX and ENBREL monotherapy vs 23% with MTX (P=0.005) at Week 241
- 78% and 72% of patients achieved sPGA of clear or almost clear with ENBREL + MTX and ENBREL monotherapy, respectively, vs 66% with MTX at Week 241‡§
- The percentage of patients with a clear Leeds Dactylitis Index (LDI=0) at Week 24 was 79% (69 of 87) and 76% (68 of 89) with ENBREL + MTX and ENBREL monotherapy, respectively, vs 65% (58 of 89) with MTX1**
- The percentage of patients with a clear SPARCC Enthesitis Index (SPARCC=0) at Week 24 was 48% (85 of 179) and 53% (91 of 173) with ENBREL + MTX and ENBREL monotherapy, respectively, vs 43% (72 of 167) with MTX1††
‡Assessment was determined on a 0 to 5 (clear to severe psoriasis) scale.
§Subset of patients with BSA ≥3% at baseline.
**Among patients who had dactylitis at baseline.
††Among patients who had enthesitis at baseline.
Results from the original Psoriatic Arthritis Pivotal Study of ENBREL
24-week randomized, multicenter, double-blind, 3-period study of 205 patients with active PsA2
- Eligible patients were randomly assigned to receive placebo or ENBREL. Randomization was stratified by concomitant MTX use2
Primary efficacy endpoint and result3-5
- ACR 20 was achieved by 59% of patients with ENBREL vs 15% with placebo at Week 12 of the double-blind period (P<0.001)
Secondary efficacy endpoint and result4
- 23% of ENBREL patients and 3% of patients taking placebo achieved PASI 75 at Week 24
References: 1. Mease PJ, et al. Presented at: American College of Rheumatology Annual Meeting; October 18-24, 2018; Chicago, IL. Poster L11. 2. Mease PJ, Kivitz AJ, Burch FX, et al. Etanercept treatment of psoriatic arthritis: safety, efficacy, and effect on disease progression. Arthritis Rheum. 2004;50:2264-2272. 3. Mease PJ, Kivitz AJ, Burch FX, et al. Continued inhibition of radiographic progression in patients with psoriatic arthritis following 2 years of treatment with etanercept. J Rheumatol. 2006;33:712-721. 4. Data on file, Amgen; 1630 PsA 2 yr: August 5, 2004. 5. Data on file, Amgen; 1630 PsA 1 yr Radiographic: October 7, 2002.
Important Safety Information and Indications
Patients treated with ENBREL are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids or were predisposed to infection because of their underlying disease. ENBREL should not be initiated in the presence of sepsis, active infections, or allergy to ENBREL or its components. ENBREL should be discontinued if a patient develops a serious infection or sepsis. Reported infections include: 1) Active tuberculosis (TB), including reactivation of latent TB. Patients with TB have frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent TB before ENBREL use and periodically during therapy. Treatment for latent infection should be initiated prior to ENBREL use, 2) Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized, disease. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Empiric antifungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness, and 3) Bacterial, viral, and other infections due to opportunistic pathogens, including Legionella and Listeria.
The risks and benefits of treatment with ENBREL should be carefully considered prior to initiating therapy in patients 1) with chronic or recurrent infection, 2) who have been exposed to TB, 3) who have resided or traveled in areas of endemic TB or endemic mycoses, or 4) with underlying conditions that may predispose them to infections such as advanced or poorly controlled diabetes. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with ENBREL, including the possible development of TB in patients who tested negative for latent TB prior to initiating therapy.
Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with tumor necrosis factor (TNF) blockers, including ENBREL.
In adult clinical trials of all TNF blockers, more cases of lymphoma were seen compared to control patients. The risk of lymphoma may be up to several-fold higher in RA patients. The role of TNF blocker therapy in the development of malignancies is unknown.
Cases of acute and chronic leukemia have been reported in association with postmarketing TNF blocker use in RA and other indications. The risk of leukemia may be higher in patients with RA (approximately 2-fold) than the general population.
Melanoma and non-melanoma skin cancer (NMSC) have been reported in patients treated with TNF blockers, including ENBREL. Periodic skin examinations should be considered for all patients at increased risk for skin cancer.
In patients who initiated therapy at ≤18 years of age, approximately half of the reported malignancies were lymphomas (Hodgkin’s and non-Hodgkin’s lymphoma). Other cases included rare malignancies usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. Most of the patients were receiving concomitant immunosuppressants.
Treatment with TNF-blocking agents, including ENBREL, has been associated with rare (<0.1%) cases of new onset or exacerbation of central nervous system demyelinating disorders, some presenting with mental status changes and some associated with permanent disability, and with peripheral nervous system demyelinating disorders. Cases of transverse myelitis, optic neuritis, multiple sclerosis, Guillain-Barré syndromes, other peripheral demyelinating neuropathies, and new onset or exacerbation of seizure disorders have been reported in postmarketing experience with ENBREL therapy. Prescribers should exercise caution in considering the use of ENBREL in patients with preexisting or recent-onset central or peripheral nervous system demyelinating disorders.
CONGESTIVE HEART FAILURE
Cases of worsening congestive heart failure (CHF) and, rarely, new-onset cases have been reported in patients taking ENBREL. Caution should be used when using ENBREL in patients with CHF. These patients should be carefully monitored.
Rare cases of pancytopenia, including aplastic anemia, some fatal, have been reported. The causal relationship to ENBREL therapy remains unclear. Exercise caution when considering ENBREL in patients who have a previous history of significant hematologic abnormalities. Advise patients to seek immediate medical attention if they develop signs or symptoms of blood dyscrasias or infection. Consider discontinuing ENBREL if significant hematologic abnormalities are confirmed.
HEPATITIS B REACTIVATION
Reactivation of hepatitis B has been reported in patients who were previously infected with hepatitis B virus (HBV) and received concomitant TNF-blocking agents, including ENBREL. Most reports occurred in patients also taking immunosuppressive agents, which may contribute to hepatitis B reactivation. Exercise caution when considering ENBREL in these patients.
Allergic reactions associated with administration of ENBREL during clinical trials have been reported in <2% of patients. If an anaphylactic reaction or other serious allergic reaction occurs, administration of ENBREL should be discontinued immediately and appropriate therapy initiated.
Live vaccines should not be administered to patients on ENBREL. Pediatric patients, if possible, should be brought up to date with all immunizations prior to initiating ENBREL. In patients with exposure to varicella virus, temporarily discontinue ENBREL and consider prophylactic treatment with Varicella Zoster Immune Globulin.
Autoantibodies may develop with ENBREL, and rarely lupus-like syndrome or autoimmune hepatitis may occur. These may resolve upon withdrawal of ENBREL. Stop ENBREL if lupus-like syndrome or autoimmune hepatitis develops.
WEGENER’S GRANULOMATOSIS PATIENTS
The use of ENBREL in patients with Wegener’s granulomatosis receiving immunosuppressive agents (eg, cyclophosphamide) is not recommended.
MODERATE TO SEVERE ALCOHOLIC HEPATITIS
Based on a study of patients treated for alcoholic hepatitis, exercise caution when using ENBREL in patients with moderate to severe alcoholic hepatitis.
The most commonly reported adverse reactions in RA clinical trials were injection site reaction and infection. In clinical trials of all other adult indications, adverse reactions were similar to those reported in RA clinical trials.
In general, the adverse reactions in pediatric patients were similar in frequency and type as those seen in adult patients. The types of infections reported in pediatric patients were generally mild and consistent with those commonly seen in the general pediatric population.
The use of ENBREL in patients receiving concurrent cyclophosphamide therapy is not recommended. The risk of serious infection may increase with concomitant use of abatacept therapy. Concurrent therapy with ENBREL and anakinra is not recommended. Hypoglycemia has been reported following initiation of ENBREL therapy in patients receiving medication for diabetes, necessitating a reduction in anti-diabetic medication in some of these patients.
ENBREL is indicated for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in patients with moderately to severely active rheumatoid arthritis. ENBREL can be initiated in combination with methotrexate (MTX) or used alone.
ENBREL is indicated for the treatment of patients 4 years or older with chronic moderate to severe plaque psoriasis (PsO) who are candidates for systemic therapy or phototherapy.
ENBREL is indicated for reducing signs and symptoms, inhibiting the progression of structural damage of active arthritis, and improving physical function in patients with psoriatic arthritis (PsA). ENBREL can be used with or without MTX.
ENBREL is indicated for reducing signs and symptoms in patients with active ankylosing spondylitis.
ENBREL is indicated for reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in patients ages 2 and older.