Tumor necrosis factor inhibitor (TNFi) persistence and reasons for discontinuation in a predominantly male cohort with axial spondyloarthritis.

Although tumor necrosis factor inhibitors (TNFi) have favorably altered the treatment landscape for patients with axial spondyloarthritis (axSpA), there is limited data regarding TNFi persistence and reasons for discontinuation. This is an observational time-to-event study utilizing data collected for a prospective multiple-disease registry of US Veterans with axSpA treated with TNFi therapies and recruited over a 10 year period. Clinical, serological, and comorbid parameters were collected. Corporate Data Warehouse Pharmacy files provided courses of the 5 TNFi agents, and response to treatment was documented. Individual TNFi persistence was established utilizing univariate and multivariate Cox proportional models, and reasons for discontinuation were obtained by physician chart review. Two-hundred and fifty-five axSpA patients received 731 TNFi courses. A majority of patients (84.3%) had TNFi persistence at 12 months; 63.5% and 47.1% at 24 and 36 months, respectively. Compared to adalimumab, infliximab demonstrated greater persistence, certolizumab the least. Age, smoking status, BMI, comorbidity burden, inflammatory markers and HLA-B27 did not predict TNFi persistence or discontinuation. Stroke and peripheral arterial disease increased the probability of TNFi discontinuation. Secondary non-response (SNR) was the most common reason for discontinuation (46% of all courses); non-adherence (6%) and clinical remission (2%) were uncommon. Pain score at enrollment, myocardial infarction, African American race and inflammatory bowel disease (IBD) predicted TNFi response. While initial persistence of TNFi treatment was high, a large proportion of the patients discontinued initial TNFi therapy by 3 years, primarily due to loss of efficacy. While further research identifying potential predictors of TNFi discontinuation in axSpA is warranted, access to alternate disease-modifying therapies is needed.

Treatment Patterns with Disease-Modifying Antirheumatic Drugs in U.S. Veterans with Newly Diagnosed Rheumatoid Arthritis, Psoriatic Arthritis, or Ankylosing Spondylitis.

BACKGROUND: Delays in treatment for inflammatory arthritis (IA) are associated with unfavorable outcomes, including impaired quality of life, irreversible joint damage, and disability. OBJECTIVE: To characterize treatment initiation patterns in veterans with newly diagnosed rheumatoid arthritis (RA), psoriatic arthritis (PsA), or ankylosing spondylitis (AS). METHODS: ICD-9/10-CM codes and natural language processing were used to identify incident cases of RA, PsA, or AS between January 1, 2007, and December 31, 2015, in patients enrolled in the Veterans Health Administration. Patterns of treatment initiation and nontreatment with disease-modifying antirheumatic drugs (DMARDs) were assessed in the 12-month follow-up period after the incident diagnosis. Outcomes included the percentage of veterans treated with a DMARD, the mean time to the initial DMARD after diagnosis, and the percentage of veterans who accessed rheumatology care before DMARD initiation. To assess outcomes over time, veterans were grouped by year of initial IA diagnosis. Additionally, outcomes were compared between nonbiologic and biologic DMARDs and among IA subtypes (RA, PsA, and AS). Groups were statistically compared with 95% confidence intervals. RESULTS: The population consisted of 12,118 IA veterans (9,711 RA, 1,472 PsA, and 935 AS), with 91.3% males and a mean age of 63.7 years. The percentage of veterans treated with ≥ 1 DMARD (nonbiologic or biologic) during the 12-month follow-up period increased from 48.8% in 2007 to 66.4% in 2015. In veterans diagnosed with IA in 2015, DMARD treatment was more common for PsA patients (72.9%) and RA patients (68.6%) than for AS patients (28.9%). In the subset treated with a DMARD within 12 months after diagnosis, the mean time to the initial DMARD after diagnosis did not change throughout the observation period (35.5 days for RA, 43.9 days for PsA, and 59.5 days for AS). Rheumatology specialty care was accessed by 87.4% of veterans treated with a nonbiologic DMARD and 92.2% of veterans treated with a biologic DMARD, in patients diagnosed in 2015. CONCLUSIONS: DMARD treatment rates during the initial 12 months after diagnosis increased between 2007 and 2015, but nontreatment remained common, particularly in veterans with AS. The time to treatment after diagnosis was stable over time; it was shortest for RA, intermediate for PsA, and longest for AS. DMARD treatment was uncommon in veterans who did not access rheumatology specialty care. DISCLOSURES: AbbVie Pharmaceuticals and Marriott Daughters Foundation funded this study via investigator-initiated grants. Data analyses were completed by investigators independent of AbbVie and Marriott Daughters Foundation. Walker, Clewell, and Douglas are employed by, and stockholders in, Abbvie. Halwani reports grants from BMS, Kyowa Hakko Kirin, Seattle Genetics, Roche-Genentech, Miragen, Immunedesign, Takeda, Amgen, Pharmacyclics, and Abbvie. The other authors have nothing to disclose.

Rapidly Fatal Internal Carotid Artery Mycotic Aneurysm Rupture in a Rheumatoid Patient Taking a TNF-α Inhibitor: Case Report and Literature Review.

OBJECT: Tumor necrosis factor (TNF)-α inhibitors are effective at treating certain inflammatory and autoimmune disorders. They are generally safe; potential adverse events include infections (bacterial, fungal, and viral), congestive heart failure exacerbations, and the potential for demyelinating diseases and possibly certain malignancies. We present the first documented case of fungal internal carotid artery (ICA) mycotic aneurysm in a patient being treated with a TNF-α inhibitor. We also review the literature on infections with TNF-α inhibition and the management of previously reported fungal ICA mycotic aneurysm cases. CASE DESCRIPTION: A 76-year-old woman with rheumatoid arthritis, treated with etanercept and methotrexate, presented with a 2-week history of left temporal headaches. She was treated empirically for giant cell arteritis (GCA) with oral prednisone, which provided no symptom relief. She was subsequently hospitalized for a superficial temporal artery biopsy, which was negative for GCA. She returned 2 weeks later after experiencing a left thromboembolic ischemic stroke. She had an acute neurologic decline, and a head computed tomography scan showed diffuse subarachnoid hemorrhage from a ruptured left fusiform paraclinoid ICA aneurysm. She was taken emergently for a craniotomy for clip-wrapping of the aneurysm, but intraoperative ultrasound revealed poor flow in the left anterior cerebral circulation and a complete infarct of the left-sided anterior circulation. The family withdrew care and the patient died. Postmortem analysis demonstrated fungi consistent with Aspergillus invading the necrotic left ICA. CONCLUSIONS: Although fungal mycotic aneurysms of the ICA are rare, their incidence may increase with the expanded use of immunosuppressive medications. Patients with rheumatoid arthritis who take potent immunosuppression regimens may be prime candidates for mycotic aneurysms because they often have two favoring conditions: atherosclerosis and immunosuppression. These ICA aneurysms carry a high mortality rate, so early diagnosis and aggressive therapy, potentially by endovascular trapping/vessel occlusion coupled with long-term antifungal therapy, is essential.

Work productivity loss and fatigue in psoriatic arthritis.

OBJECTIVE: To explore the relationship between fatigue and work productivity loss (WPL) in people with psoriatic arthritis (PsA). METHODS: Data were collected from participants in the Utah Psoriasis Initiative Arthritis registry between January 2010 and May 2013. WPL was measured with the 8-item Work Limitations Questionnaire. Fatigue was assessed with question 1 from the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI#1), "How would you describe the overall level of fatigue/tiredness you have experienced?" and with question 1 from the Psoriatic Arthritis Quality of Life Questionnaire (PsAQOL#1) "I feel tired whatever I do." Psoriatic activity was evaluated with tender joint count (TJC), swollen joint count (SJC), dactylitis count, enthesitis count, inflammatory back pain (IBP), physician global assessment, body surface area, and psoriasis pain and itch. RESULTS: Among 107 participants, work productivity was reduced by 6.7%, compared to benchmark employees without limitations. Fatigue was reported by 54 patients (50.5%) on PsAQOL#1, and 64 (60.0%) were classified as high fatigue by BASDAI#1. TJC, SJC, enthesitis count, IBP, and depressed mood were highest or most frequent in participants reporting fatigue. After adjustments for psoriatic activity and depressed mood, WPL was associated with fatigue, as measured by PsAQOL#1 (p = 0.01) and BASDAI#1 (p = 0.002). CONCLUSION: WPL was associated with fatigue, and the association was not entirely explained by the evaluated musculoskeletal, cutaneous, or psychiatric manifestations of PsA.

Limitations in screening instruments for psoriatic arthritis: a comparison of instruments in patients with psoriasis.

OBJECTIVE: To compare the abilities of 3 validated screening instruments to predict the diagnosis of psoriatic arthritis (PsA) in patients with psoriasis. METHODS: Prior to a rheumatologic evaluation, 213 participants in the Utah Psoriasis Initiative completed the Psoriasis Epidemiology Screening project (PEST), the Toronto Psoriatic Arthritis Screen (ToPAS), and the Psoriatic Arthritis Screening and Evaluation (PASE). Previously established instrument cutoff scores were used to designate positive and negative classifications. Sensitivities and specificities were determined by comparing instrument classifications to the rheumatologist's diagnosis. Phenotypic features and alternative diagnoses were compared between participants who screened positively and negatively on each instrument. Discrepancies between the rheumatologist's examination findings and responses to specific instrument questions were compared. RESULTS: The sensitivities of PEST, ToPAS, and PASE were 85%, 75%, and 68%, and the specificities were 45%, 55%, and 50%, respectively. The instruments were less sensitive in patients with lower disease activity, fewer PsA features, and shorter disease duration. The instruments did not consistently differentiate between PsA and other types of musculoskeletal disease. Discrepancies between examination findings and responses to instrument questions occurred more frequently with ToPAS than with PEST and PASE. CONCLUSION: Sensitivities and specificities for PEST, ToPAS, and PASE were lower than previously reported. This population included patients with PsA and other types of musculoskeletal disease and may represent those most likely to complete a screening instrument and follow through with a rheumatology referral. Further analyses may enable the development of more successful screening strategies for PsA in psoriasis patients with musculoskeletal complaints.

Lower frequency of obstructive sleep apnea in spondyloarthritis patients taking TNF-inhibitors.

STUDY OBJECTIVES: Sleep disturbances, including obstructive sleep apnea (OSA), commonly limit function and quality of life in people with spondyloarthritis (SpA). Systemic inflammation has been implicated in the pathophysiology of both OSA and SpA, and suppression of inflammation with tumor necrosis factor α (TNF) inhibitors may decrease OSA severity. In this study, we compared the frequency of OSA in patients receiving and not receiving TNF-inhibitor therapy. METHODS: Data were collected from 63 consecutively screened veterans with SpA. Participant interviews, examinations, chart reviews, and referrals to the Salt Lake City Veteran Affairs (SLCVA) Sleep Center were used to obtain demographic data, comorbidities, SpA features, therapy data, and sleep study outcomes. RESULTS: OSA occurred in 76% of SpA patients. OSA was less common in patients receiving TNF-inhibitor therapy (57%), compared to patients not receiving TNF-inhibitor therapy (91%) (p = 0.01). CONCLUSIONS: OSA is underrecognized in veterans with SpA, and TNF-inhibition was associated with a lower frequency of OSA.

New paradigm for patient-reported outcomes assessment in foot & ankle research: computerized adaptive testing.

BACKGROUND: Accurately measuring, reporting and comparing outcomes is essential for improving health care delivery. Current challenges with available health status scales include patient fatigue, floor/ceiling effects and validity/reliability. METHODS: This study compared Patient Reported Outcomes Measurement Information System (PROMIS)-based Lower Extremity Physical Function Computerized Adaptive Test (LE CAT) and two legacy scales -the Foot and Function Index (FFI) and the sport module from the Foot and Ankle Ability Measure (spFAAM) -for 287 patients scheduled for elective foot and ankle surgery. We documented the time required by patients to complete the instrument, instrument precision, and the extent to which each instrument covered the full range of physical functioning across the patient sample. RESULTS: Average time of test administration: 66 seconds for LE CAT, 130 seconds for spFAAM and 239 seconds for FFI. All three instruments were fairly precise at intermediate physical functioning levels (i.e., Standard Error of Measurement < 0.35), were relatively less precise at the higher trait levels and the LE CAT maintained precision in the lower range while the spFAAM and FFI's had decreased precision. The LE CAT had less floor/ceiling effects than the FFI and the spFAAM. CONCLUSION: The LE CAT showed considerable advantage compared to legacy scales for measuring patient-reported outcomes in orthopaedic patients with foot and ankle problems. CLINICAL RELEVANCE: A paradigm shift to broader use of PROMIS-based CATs should be considered to improve precision and reduce patient burden with patient-reported outcome measuremen foot and ankle patients.

OARSI/OMERACT initiative to define states of severity and indication for joint replacement in hip and knee osteoarthritis. An OMERACT 10 Special Interest Group.

OBJECTIVE: To define pain and physical function cutpoints that would, coupled with structural severity, define a surrogate measure of "need for joint replacement surgery," for use as an outcome measure for potential structure-modifying interventions for osteoarthritis (OA). METHODS: New scores were developed for pain and physical function in knee and hip OA. A cross-sectional international study in 1909 patients was conducted to define data-driven cutpoints corresponding to the orthopedic surgeons' indication for joint replacement. A post hoc analysis of 8 randomized clinical trials (1379 patients) evaluated the prevalence and validity of cutpoints, among patients with symptomatic hip/knee OA. RESULTS: In the international cross-sectional study, there was substantial overlap in symptom levels between patients with and patients without indication for joint replacement; indeed, it was not possible to determine cutpoints for pain and function defining this indication. The post hoc analysis of trial data showed that the prevalence of cases that combined radiological progression, high level of pain, and high degree of function impairment was low (2%-12%). The most discriminatory cutpoint to define an indication for joint replacement was found to be [pain (0-100) + physical function (0-100) > 80]. CONCLUSION: These results do not support a specific level of pain or function that defines an indication for joint replacement. However, a tentative cutpoint for pain and physical function levels is proposed for further evaluation. Potentially, this symptom level, coupled with radiographic progression, could be used to define "nonresponders" to disease-modifying drugs in OA clinical trials.

Prologue: 2010 Spondyloarthritis Research and Therapy Network (SPARTAN) annual research and education meeting.

The Spondyloarthritis Research and Therapy Network (SPARTAN) is a network of health care professionals who are dedicated to research, awareness and treatment of ankylosing spondylitis and related forms of spondyloarthritis (SpA). Members meet yearly to promote research, education and treatment of SpA. The SPARTAN 2010 meeting was held on July 23 to 24 in Houston, Texas. Major presentations were given on structural bone changes in SpA, the sensitivity and specificity of magnetic resonance imaging in early SpA, mycobacterial infections in this era of modern biologic therapies and findings from the U.S. National Health and Nutrition Examination Surveys for ankylosing spondylitis, SpA and inflammatory back pain. Additional country-specific presentations on the epidemiology of SpA were provided by representatives of North America, Central America, Brazil, Argentina, Colombia and Mexico. These topics were all developed into separate contributions contained in this in-issue supplement and summarized herein.

2007 annual research and education meeting of the Spondyloarthritis Research and Therapy Network (SPARTAN).

OBJECTIVE: The Spondyloarthritis Research and Therapy Network (SPARTAN; www.spartangroup.org) was founded in 2003 by a group of North American clinicians and researchers to promote research, education, and treatment of spondyloarthritis (SpA). In past years, it has produced and disseminated United States-specific modifications of the ASsessments in Ankylosing Spondylitis (ASAS) guidelines for the use of anti-tumor necrosis factor (TNF) therapy in AS1,2. SPARTAN held its fifth annual research meeting in September 2007 in Cleveland, Ohio. Highlights of the meeting included updates on current research in SpA, including epidemiology and genetics, bone formation and inflammation, biomarkers, activation of the IL-23/IL-17 axis, and animal models. A presentation was made on basic and clinical science of inflammatory bowel disease, and an educational pre-meeting conference was specifically designed for rheumatology fellows.

Treatment of ankylosing spondylitis.

Ankylosing spondylitis (AS) is a condition characterized by inflammatory back pain and associated with considerable disability and diminished quality of life in affected individuals. The condition is undertreated in part due to a delay in diagnosis and limited therapeutic interventions. Although traditional treatment approaches (physical therapy, exercise, patient education, nonsteroidal antiinflammatory drugs) remain important components of the management of AS, the demonstrated efficacy of tumor necrosis factor-a (TNF-a) antagonists such as etanercept and infliximab have allowed clinicians to more effectively manage this condition. These targeted therapies have demonstrated rapid and consistent effectiveness in reducing the axial and peripheral symptoms of AS, slowing disease progression, and improving patient function and quality of life. Appropriate and timely use of TNF-a antagonists offers additional options for patients with active AS who are inadequately controlled with conventional treatment.

Etanercept in adult patients with early onset ankylosing spondylitis.

OBJECTIVE: To determine whether twice-weekly subcutaneous etanercept improves the signs and symptoms of adult patients with early onset ankylosing spondylitis (AS). METHODS: A retrospective analysis was performed on a subgroup of patients with AS with onset < 18 years of age from a multicenter, double-blind, placebo-controlled, randomized study of etanercept in the treatment of patients with AS. Twenty patients met criteria and are presented. RESULTS: As early as week four, 5/9 (56%) patients who received etanercept achieved an Assessments in Ankylosing Spondylitis 20% response (ASAS 20) versus only 1/11 (9%) of those who received placebo (p = 0.032). The observed ASAS 20 response continued through week 24, with 6/9 (66%) patients receiving etanercept responding, versus 2/11 of patients receiving placebo (p = 0.025). CONCLUSION: Etanercept improves signs and symptoms of early onset AS in adult patients for at least 24 weeks.

Baseline factors that influence ASAS 20 response in patients with ankylosing spondylitis treated with etanercept.

OBJECTIVE: To examine the baseline demographic and disease characteristics that might influence improvement as measured by the Assessment in Ankylosing Spondylitis Response Criteria (ASAS 20) in patients with ankylosing spondylitis (AS). METHODS: A multicenter Phase 3 study was performed to compare the safety and efficacy of 24 weeks of etanercept 25 mg subcutaneous injection twice weekly (n = 138) and placebo (n = 139) in patients with AS. The ASAS 20 was measured at multiple time points. Using a significance level of 0.05, a repeated measures logistic regression model was used to determine which baseline factors influenced response in the etanercept-treated patients during the 24-week double blind portion of the trial. The following baseline factors were used in the model: demographic and disease severity variables, concomitant medications, extra-articular manifestations, and HLA-B27 status. The predictive capability of the model was then tested on the patients receiving placebo after they had received open-label etanercept treatment. RESULTS: Baseline factors that were significant predictors of an ASAS 20 response in etanercept-treated patients were C-reactive protein (CRP), back pain score, and Bath Ankylosing Spondylitis Functional Index (BASFI) score. Although clinical response to etanercept was seen at all levels of baseline disease activity, responses were consistently more likely with higher CRP levels or back pain scores and less likely with increased BASFI scores at baseline. CONCLUSIONS: Higher CRP values and back pain scores and lower BASFI scores at baseline were significant predictors of a higher ASAS 20 response in patients with AS receiving etanercept but predictive value was of insufficient magnitude to determine treatment in individual patients.

Recombinant human tumor necrosis factor receptor (etanercept) for treating ankylosing spondylitis: a randomized, controlled trial.

OBJECTIVE: To determine the safety and efficacy of etanercept in a multicenter, randomized, placebo-controlled, double-blind trial of adults with moderate to severe active ankylosing spondylitis (AS). METHODS: Patients (n = 277) were treated with either etanercept 25 mg (n = 138) or placebo (n = 139) subcutaneously twice weekly for 24 weeks. The primary outcome measures were the percentages of patients achieving the Assessments in Ankylosing Spondylitis 20% response (ASAS20) at weeks 12 and 24. Other outcome measures included the percentage of patients achieving higher ASAS responses, and the safety of etanercept in patients with AS. All outcome measures were assessed at 2, 4, 8, 12, and 24 weeks. RESULTS: Treatment with etanercept resulted in dramatic improvement. The ASAS20 was achieved by 59% of patients in the etanercept group and by 28% of patients in the placebo group (P < 0.0001) at week 12, and by 57% and 22% of patients, respectively, at week 24 (P < 0.0001). All individual ASAS components, acute-phase reactant levels, and spinal mobility measures were also significantly improved. The safety profile of etanercept was similar to that reported in studies of patients with rheumatoid arthritis or psoriatic arthritis. The only adverse events that occurred significantly more often in the etanercept group were injection-site reactions, accidental injuries, and upper respiratory tract infections. CONCLUSION: Etanercept is a highly effective and well tolerated treatment in patients with active AS.