Efficacy and safety of upadacitinib in patients with ankylosing spondylitis refractory to biologic therapy: 1-year results from the open-label extension of a phase III study.

BACKGROUND: Upadacitinib, a Janus kinase inhibitor, has demonstrated efficacy and an acceptable safety profile in patients with ankylosing spondylitis (AS) in the phase III SELECT-AXIS programs. We report the 1-year efficacy and safety in patients with AS and an inadequate response to biologic disease-modifying antirheumatic drugs (bDMARD-IR) from the SELECT-AXIS 2 study. METHODS: Patients ≥ 18 years with active AS who met the modified New York criteria for AS and were bDMARD-IR received double-blind upadacitinib 15 mg once daily (QD) or placebo for 14 weeks. Patients who completed 14 weeks could enter an open-label extension and receive upadacitinib 15 mg QD for up to 2 years. Efficacy endpoints included the percentage of patients achieving ≥ 40% improvement in Assessment of SpondyloArthritis international Society response (ASAS40), Ankylosing Spondylitis Disease Activity Score (ASDAS) low disease activity (LDA), and ASDAS inactive disease (ID); and change from baseline in total and nocturnal back pain, and Bath Ankylosing Spondylitis Functional Index (BASFI). Subgroup analyses (bDMARD lack of efficacy versus intolerance, and prior tumor necrosis factor inhibitor [TNFi] versus interleukin-17 inhibitor [IL-17i] exposure) were conducted. Binary and continuous efficacy endpoints were assessed using non-responder imputation with multiple imputation (NRI-MI) and as observed (AO) analyses; and mixed-effects model repeated measures (MMRM) and AO, respectively. Safety was assessed based on adverse events. Data through week 52 are reported. RESULTS: Of 420 randomized patients, 366 (continuous upadacitinib: n = 181; placebo to upadacitinib: n = 185) completed 52 weeks of treatment. At week 52, in the continuous upadacitinib and placebo to upadacitinib groups, ASAS40, ASDAS LDA, and ASDAS ID were achieved by 66% and 65%, 57% and 55%, and 26% and 25% (all NRI-MI); and change from baseline in total back pain, nocturnal back pain, and BASFI was -4.5 and -4.3, -4.6 and -4.4, and -3.6 and -3.5 (all MMRM), respectively. No new safety risks were identified. Subgroup analyses were consistent with the overall study population. CONCLUSIONS: Upadacitinib 15 mg QD demonstrated sustained improvement up to 52 weeks in bDMARD-IR patients with AS. Efficacy was generally similar in patients with lack of efficacy versus intolerance to bDMARDs and prior TNFi versus IL-17i exposure. TRIAL REGISTRATION: NCT02049138.

Efficacy and safety of upadacitinib for active ankylosing spondylitis refractory to biological therapy: a double-blind, randomised, placebo-controlled phase 3 trial.

OBJECTIVES: To evaluate the efficacy and safety of upadacitinib, a Janus kinase inhibitor, in patients with active ankylosing spondylitis (AS) with an inadequate response (IR) to biological disease-modifying antirheumatic drugs (bDMARDs). METHODS: Adults with active AS who met modified New York criteria and had an IR to one or two bDMARDs (tumour necrosis factor or interleukin-17 inhibitors) were randomised 1:1 to oral upadacitinib 15 mg once daily or placebo. The primary endpoint was Assessment of SpondyloArthritis international Society 40 (ASAS40) response at week 14. Sequentially tested secondary endpoints included Ankylosing Spondylitis Disease Activity score, Spondyloarthritis Research Consortium of Canada MRI spine inflammation score, total back pain, nocturnal back pain, Bath Ankylosing Spondylitis Functional Index, Bath Ankylosing Spondylitis Metrology Index and Maastricht Ankylosing Spondylitis Enthesitis Score. Results are reported from the 14-week double-blind treatment period. RESULTS: A total of 420 patients with active AS were randomised (upadacitinib 15 mg, n=211; placebo, n=209). Significantly more patients achieved the primary endpoint of ASAS40 at week 14 with upadacitinib vs placebo (45% vs 18%; p<0.0001). Statistically significant improvements were observed with upadacitinib vs placebo for all multiplicity-controlled secondary endpoints (p<0.0001). Adverse events were reported for 41% of upadacitinib-treated and 37% of placebo-treated patients through week 14. No events of malignancy, major adverse cardiovascular events, venous thromboembolism or deaths were reported with upadacitinib. CONCLUSION: Upadacitinib 15 mg was significantly more effective than placebo over 14 weeks of treatment in bDMARD-IR patients with active AS. No new safety risks were identified with upadacitinib. TRIAL REGISTRATION NUMBER: NCT04169373.

Safety of ixekizumab in patients with psoriatic arthritis: data from four clinical trials with over 2000 patient-years of exposure.

OBJECTIVES: Ixekizumab, a high-affinity monoclonal antibody that selectively targets interleukin 17A (IL-17A), has shown significant efficacy in the treatment of psoriatic arthritis (PsA) and sustained long-term clinical response without unexpected new safety outcome for an IL-17A inhibitor. Here, we report the updated safety profile of ixekizumab up to 3 years in patients with PsA. METHODS: This is an integrated safety analysis from four clinical trials in patients with PsA who received at least one dose of ixekizumab. Treatment-emergent adverse events (TEAEs) and selected adverse events (AEs) exposure-adjusted incidence rates (EAIRs) per 100 patient-years up to 3 years of exposure are reported. RESULTS: A total of 1401 patients with a cumulative ixekizumab exposure of 2247.7 patient-years were included in this analysis. The EAIR of patients with ≥1 TEAE was 50.3 per 100 patient-years and most TEAEs were mild to moderate in severity. Serious AEs were reported by 134 patients (EAIR=6.0). The most reported TEAEs were nasopharyngitis (EAIR=9.0) and upper respiratory tract infection (EAIR=8.3). Infections in general and injection site reactions were the most common TEAEs; the incidence rates of serious cases were low (EAIR ≤1.2). The EAIRs of malignancies (EAIR=0.7), inflammatory bowel disease (EAIR=0.1) including ulcerative colitis and Crohn's disease, depression (EAIR=1.6), and major adverse cerebro-cardiovascular events (EAIR=0.5) were low. As assessed, based on year of exposure, incidence rates were decreasing or constant over time. CONCLUSIONS: In this analysis, the overall safety profile and tolerability of ixekizumab are consistent with the known safety profile in patients with PsA. No new or unexpected safety events were detected. TRIAL REGISTRATION NUMBER: NCT01695239, NCT02349295, NCT02584855, NCT03151551.

Tofacitinib for the treatment of active ankylosing spondylitis in adults.

INTRODUCTION: Ankylosing spondylitis, also known as radiographic axial spondyloarthritis, is a complex, immune-mediated inflammatory disorder most commonly involving the spine including the sacroiliac joints. AREAS COVERED: Complex pathogenesis of axial spondyloarthritis involving genetic, environmental, and both innate and adaptive immune systems. Treatment options for ankylosing spondylitis. Pharmacologic properties, efficacy, and safety of tofacitinib, a JAK inhibitor. Data regarding efficacy of approved JAK inhibitors in the treatment of ankylosing spondylitis, including tofacitinib, upadacitinib, and filgotinib. EXPERT OPINION: Current treatment options of ankylosing spondylitis include NSAIDs, TNFi, and IL-17i. JAK inhibitors present a new class of therapy that has shown efficacy in the treatment of active ankylosing spondylitis in adults. While it has not been directly compared to alternative therapies, tofacitinib has been shown to be effective in both phase II and phase III trials for the treatment of ankylosing spondylitis. While these trials did not show any significant difference from placebo in terms of safety, the ORAL Surveillance study showed tofacitinib to be inferior to TNFi when comparing adverse events. Thus, tofacitinib presents a viable treatment option for the management of AS, however shared decision-making regarding risks and benefits will be important.

Axial Spondyloarthritis in the Chiropractic Care Setting: A Systematic Literature Review.

ABSTRACT: Diagnosis of axial spondyloarthritis (axSpA), an immune-mediated inflammatory disease, is commonly associated with chronic inflammatory back pain (IBP) and often occurs years after initial onset of clinical symptoms. Recognition of IBP is important for timely referral of patients with suspected axSpA to a rheumatologist. Patients with all types of back pain are treated in chiropractic care, but the proportion of patients with undiagnosed axSpA is unknown. This systematic literature review investigated the presence of axSpA in patients treated by chiropractors and identified the chiropractor's role in axSpA diagnosis, referral, and management. A PubMed search was conducted using the following search strings: "chiropract*" AND ("sacroiliac" OR "back pain" OR "spondyloarthritis" OR "ankylosing spondylitis"); English language, since 2009; and (chiropractic OR chiropractor) AND (ankylosing spondylitis OR axial spondyloarthritis), with no date limits. Of 652 articles identified in the searches, 27 met the inclusion criteria. Although back pain was identified as a common reason for patients seeking chiropractic care, there was no mention of axSpA, ankylosing spondylitis, or the distinction between mechanical and IBP. Data from relevant articles suggested that the majority of patients seeking chiropractic care have lower back pain, whereas no articles reported axSpA in this patient population. The near absence of any identified articles on axSpA in chiropractic care may be due to underrecognition of axSpA, resulting in delayed rheumatology referral and appropriate management. Better awareness and increased use of validated screening tools could reduce diagnostic delay of axSpA in chiropractic care.

Axial spondyloarthritis in the USA: diagnostic challenges and missed opportunities.

Axial spondyloarthritis (axSpA) is a chronic inflammatory rheumatic disease that primarily affects the sacroiliac joints and spine. Delayed or inadequate treatment may decrease quality of life and lead to poor long-term outcomes, including irreversible loss of spinal function. In this review, we discuss clinical practice related to axSpA within the USA, including prevalence, diagnosis, reasons for delayed/missed diagnosis, and suggestions for making early diagnosis. The US population prevalence of axSpA (0.9-1.4%) is higher than the diagnostic prevalence (0.2-0.7%). Although the estimated diagnostic delay for axSpA is 14 years in the USA, the disease can be identified earlier if appropriately preselected patients are quickly referred to rheumatologists. Only 37% of patients with ankylosing spondylitis in the USA are diagnosed by rheumatologists; the remaining 63% are diagnosed by primary care (26%), chiropractic/physical therapy (7%), orthopedic surgery (4%), pain clinics (4%), acute care (3%), and other settings (19%). To help reduce diagnostic delay, non-rheumatologist-healthcare professionals are urged to refer patients with back pain and ≥ 1 of 3 SpA features (HLA-B27 positivity, current inflammatory back pain, or x-ray/MRI evidence of sacroiliitis) to a rheumatologist. Prevalence and diagnosis rates of axSpA are disparate in the USA due to the lack of awareness and knowledge among non-rheumatologists. Progress has been made in identifying hurdles causing diagnostic delays. Public health initiatives are needed to guide primary care physicians, physical therapists, chiropractors, and other specialists seeing patients with chronic back pain on methods for suspecting or identifying axSpA and early referral to rheumatologists.

Complementary medicine for axial spondyloarthritis: is there any scientific evidence?

PURPOSE OF REVIEW: Majority of patients with axial spondyloarthritis (axSpA) report use of complementary and alternative medicine (CAM) therapies before and even after the diagnosis, due to perceived efficacy and wide-spread belief that these modalities lack side effects. In this review, we describe the available scientific evidence for the CAM therapies in axSpA. RECENT FINDINGS: Clinical trials of the CAM therapies in axSpA are generally hampered by small sample size, short duration, difficulties in blinding, lack of control groups and strong placebo effect. Nonetheless, exercise programs like Pilates and mind-body techniques such as Tai Chi may have favorable effect on the disease activity and function. Although not yet confirmed, the modulation of the microbiome with the help of probiotics or fecal transplant has face validity given the evolving scientific rationale. Diet has only limited role in the management of axSpA. Deep tissue massage, omega-3 fatty acids and Stanger bath were found to be useful in small studies. CAM therapies are not always entirely well tolerated, particularly the manipulative techniques like chiropractic and Tui-na in patients with advanced disease and osteoporosis. There are no trials of yoga in axSpA despite the wider acceptance and use of yoga as an effective mind-body technique. SUMMARY: Larger and better quality clinical trials of CAM therapies are needed to confirm their efficacy and safety in the management of axSpA and to include them in the 'mainstream' medicine.

Ankylosing spondylitis diagnosis in US patients with back pain: identifying providers involved and factors associated with rheumatology referral delay.

This study aimed to identify providers involved in diagnosing ankylosing spondylitis (AS) following back pain diagnosis in the USA and to identify factors leading to the delay in rheumatology referrals. The Truven Health MarketScan® US Commercial Database was searched for patients aged 18-64 years with back pain diagnosis in a non-rheumatology setting followed by AS diagnosis in any setting during January 2000-December 2012. Patients with a rheumatologist visit on or before AS diagnosis were considered referred. Cox regression was used to determine factors associated with referral time after adjusting for age, sex, comorbidities, physician specialty, drug therapy, and imaging procedures. Of 3336 patients included, 1244 (37 %) were referred to and diagnosed by rheumatologists; the others were diagnosed in primary care (25.7 %), chiropractic/physical therapy (7 %), orthopedic surgery (3.8 %), pain clinic (3.6 %), acute care (3.4 %), and other (19.2 %) settings. Median time from back pain diagnosis to rheumatology referral was 307 days and from first rheumatologist visit to AS diagnosis was 28 days. Referred patients were more likely to be younger (hazard ratio [HR] = 0.986; p < 0.0001), male (HR = 1.15; p = 0.0163), diagnosed with uveitis (HR = 1.49; p = 0.0050), referred by primary care physicians (HR = 1.96; p < 0.0001), prescribed non-steroidal anti-inflammatory drugs (HR = 1.55; p < 0.0001), disease-modifying antirheumatic drugs (HR = 1.33; p < 0.0001), and tumor necrosis factor inhibitors (HR = 1.40; p = 0.0036), and to have had spinal/pelvic X-ray prior to referral (HR = 1.28; p = 0.0003). During 2000-2012, most patients with AS were diagnosed outside of rheumatology practices. The delay before referral to rheumatology was 10 months; AS diagnosis generally followed within a month. Earlier referral of patients with AS signs and symptoms may lead to more timely diagnosis and appropriate treatment.

The "knowns" and "unknowns" of biologic therapy in ankylosing spondylitis.

Since the first biologic agent was tested in the treatment of ankylosing spondylitis (AS), the ability of these therapies to dramatically improve the clinical symptoms and signs of the disease was very evident. Over the past decade, 4 tumor necrosis factor-alpha inhibitors have been approved by the Food and Drug Administration for the treatment of AS. Published data include randomized controlled trials, registries and observational studies. Guidelines have also been developed for the use of biologics in AS. Although a lot is known about the use of biologics in the AS, several "unknowns" remain. Whether these agents can alter the natural history of AS if started very early in the course or whether they can prevent extra-articular manifestations are among the important unanswered questions. Most of the data summarized in this review relate to tumor necrosis factor-alpha inhibitors, and other biologic agents that have been studied are included, as well. This review also summarizes what questions remain about the use of biologics in AS and what type of studies will be required to answer them.

Impaired growth hormone secretion in fibromyalgia patients: evidence for augmented hypothalamic somatostatin tone.

OBJECTIVE: To determine whether female fibromyalgia (FM) patients exhibit a normal growth hormone (GH) response to an acute exercise stressor, and to assess the importance of somatostatin tone in the generation of this GH response. METHODS: Twenty female FM patients were compared with 10 healthy female controls. All subjects exercised to volitional exhaustion on a treadmill. A standard metabolic cart was used to monitor pulse, blood pressure, electrocardiography, oxygen uptake, carbon dioxide output, anaerobic threshold, and maximal workload. Blood was drawn for GH and cortisol measurements 1 hour before exercise, immediately before exercise, immediately after exercise, and 1 hour after exercise. One month later, testing that was exactly similar was performed, except all subjects were given pyridostigmine bromide (Mestinon; 30 mg orally) 1 hour before exercise. RESULTS: Compared with controls, FM patients failed to exhibit a GH or cortisol response to acute exercise (P = 0.003). After administration of pyridostigmine, 1 hour before exercise, the GH levels of FM patients increased 8-fold (P = 0.001), to a value comparable with that of controls. Pyridostigmine did not increase the cortisol response to exercise in FM patients. Pyridostigmine alone did not stimulate GH secretion in FM patients, nor did it improve exercise-induced GH secretion in controls. FM patients with normal insulin-like growth factor 1 (IGF-1) levels had an impaired GH response to exercise. CONCLUSION: Three new findings are reported: 1) FM patients have a reduced GH response to exercise, 2) pyridostigmine reverses this impaired response, and 3) defective GH secretion in FM can occur in patients with normal IGF-1 levels. Because pyridostigmine is known to reduce somatostatin tone, it is surmised that the defective GH response to exercise in FM patients probably results from increased levels of somatostatin, a hypothalamic hormone that inhibits GH secretion.