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Spondyloarthritis: Interleukin-17a Underlies its Pathophysiology
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PRIORITY PRESS - Annual Meeting of the American College of Rheumatology (ACR) 2015
San Francisco, California / November 6-11, 2015
San Francisco - Complex interactions between immunologic mediators, including interleukin (IL)-17a, underlie the pathogenesis of spondyloarthritis (SpA), which includes psoriatic arthritis (PsA) and ankylosing spondylitis (AS). Although the pathogenesis and clinical manifestations of SpA differ from those of rheumatoid arthritis (RA), the disease burden as reflected by pain and disability is similar between SpA and RA. Therapy directed against IL-17a has demonstrated improvements in signs and symptoms, physical function, and quality of life in PsA and AS, and these improvements are sustained over the long term.
Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec
Spondyloarthritis (SpA) is a group of genetically linked inflammatory diseases, the spectrum of which includes psoriatic arthritis (PsA) and ankylosing spondylitis (AS). Despite being progressive and debilitating diseases that have a significant negative impact on function and quality of life, PsA and AS are underrecognized in clinical practice.
The pathophysiology of SpA involves the production of cytokines, including a crucial one called interleukin (IL)-17a, by proinflammatory immune cells, which serve to activate extracellular receptors on target cells. Activation of these receptors induces clinical manifestations of SpA, such as osteoproliferation, cartilage destruction, bone erosion, enthesitis and synovitis.
IL-17a signaling acts synergistically with tumour necrosis factor (TNF)-alpha at the cell surface to regulate chronic inflammation, said Dr. Mark Genovese, Director, Rheumatology Clinic, Stanford University, Palo Alto, California. IL-17a signaling, he noted, leads to the joint inflammation and matrix destruction that are characteristic of PsA.
In PsA, IL-17a-producing cells are enriched in synovial tissue and synovial fluid, and an elevated number of IL-17a producing T cells is detected in the peripheral blood of patients with AS. In the facet joints, increased numbers of myeloid precursors and neutrophils express IL-17.
Skin and Joint Involvement in PsA is Heterogeneous
“PsA is characterized by a mixed picture across patients,” Dr. Laura Coates, Clinical Lecturer in Rheumatology, University of Leeds, England, told attendees. Clinical domains of PsA, and skin and joint manifestations are heterogeneous.
“In a majority of patients, skin and nail lesions precede the arthritis,” said Dr. Coates.
The joint damage with PsA progresses over time. Data from the Early Arthritis Cohort reveals that 27% of patients with early PsA had at least one erosion at presentation to clinic; 2 years later, 47% developed erosive disease despite active treatment in the clinic.
“Many patients experience a delay between onset of symptoms and diagnosis,” she said, and delays in diagnosis beyond 6 months have a significant negative impact on short-term and long-term outcomes in terms of worse erosive disease, worse function, and a lower rate of response to treatment at follow-up than those diagnosed earlier.
“One of the things that we use increasingly in clinic is imaging for the diagnosis and monitoring. We know that x-rays pick up typical features of PsA, but that’s often seen a lot later down the line. We want to be diagnosing people before they have erosive disease…so we’re now much more frequently using more sophisticated imaging techniques like ultrasound and magnetic resonance imaging (MRI), in particular.”
As with rheumatoid arthritis (RA), ultrasound can be useful in picking up the inflammatory activity in the spine and in the joints, and also inflammation of the entheses. Ultrasound can also be useful for monitoring disease. MRI allows direct visualization of inflammation in peripheral and axial joints and entheses.
A significant proportion of psoriasis patients seen in a dermatology clinic have undiagnosed PsA.
One tool to assist in the early diagnosis of PsA in patients with psoriasis is PEST (Psoriasis Epidemiology Screening Tool), a 5-question “yes or no” screening device. The sensitivity of the questionnaire for PsA with at least 3 positive answers is 75% to 80% and specificity is 40% to 50%.
Therapy Directed Against IL-17a
Therapies directed against IL-17a have been studied clinically for the treatment of PsA and AS, as not all patients have adequate response to TNF inhibitors or can tolerate TNF inhibitors. Secukinumab, a human monoclonal IgG1k antibody to IL-17a, has demonstrated improvements in signs and symptoms, physical function, and quality of life, and these improvements are sustained.
In a subgroup analysis of the phase 3 randomized, double-blind FUTURE 2 study, secukinumab at 150 mg or 300 mg subcutaneously was associated with sustained improvements in the signs and symptoms of PsA, function, and quality of life compared with placebo in patients who were TNF inhibitor-naïve or TNF inhibitor-exposed, reported Dr. Arthur Kavanaugh, University of California, San Diego, California. Clinical responses to secukinumab were generally greater in patients who were TNF inhibitor-naïve. For example, in the TNF inhibitor-naïve group, an American College of Rheumatology 20% (ACR20) response through week 52 was achieved by 79.4% randomized to 150 mg of secukinumab, 68.7% to 300 mg of secukinumab and 15.9% to placebo. The percentages in the TNF inhibitor-exposed group were 37.8%, 54.5%, and 14.3%, respectively. ACR50/70 responses were similarly improved through week 52 with the two higher dosages of secukinumab.
Another secondary analysis of FUTURE 2 shows improvement in fatigue with secukinumab in patients with active PsA despite treatment with anti-TNF therapy, as reported by Prof. Laure Gossec, Paris 06 University, Paris, France. An improvement in fatigue by at least 4 points on the Functional Assessment of Chronic Illness Therapy-Fatigue scale was observed at week 16 in 52% to 71% of patients treated with secukinumab.
In the FUTURE 1 study, the efficacy of secukinumab in PsA was sustained to 2 years, according to data presented by Dr. Philip Mease, Swedish Medical Center and University of Washington, Seattle, Washington. Secukinumab was superior to placebo on week 24 ACR20 response, the primary endpoint, after which patients could receive open-label secukinumab. At week 104, 66.8% of patients treated with secukinumb 150 mg and 58.6% treated with 75 mg had an ACR20 response, compared with 50.0% and 50.5% at week 24. Other clinical domains, such as resolution of dactylitis and enthesitis, scores on the Health Assessment Questionnaire Disability Index (HAQ-DI), the SF36-physical component score, PsA pain, and radiographic progression were also improved with IL-17a inhibition.
Some 78.5% of the patients remained in the study at 2 years. Nasopharyngitis and upper respiratory tract infection each occurred in about 19% of patients receiving secukinumab, back pain was reported by 8.9% and non-serious Candida infections were reported in 2.4% of patients with secukinumab over the entire 104 weeks.
In a subanalysis of patients with psoriasis and concomitant PsA who were enrolled in the CLEAR trial, a higher proportion of patients randomized to secukinumab achieved a Psoriasis Area and Severity Index (PASI) 90% response at week 16, although the difference was not statistically significant (79.0% vs. 57.6%; P=0.063) compared to ustekinumab, reported Dr. Alice Gottlieb, Tufts Medical Center, Boston, Massachusetts. The proportion of patients who achieved a clinically meaningful improvement in HAQ-DI was 34.9% in the secukinumab group and 26.5% in the ustekinumab group.