Jessica A. Walsh

The development of candidate composite disease activity and responder indices for psoriatic arthritis (GRACE project)

Objective To develop new composite disease activity indices for psoriatic arthritis (PsA). Methods Data from routine clinic visits at multiple centres were collected in a systematic manner. Data included all domains identified as important in randomised controlled trials in PsA. Decisions to change treatment were used as surrogates for high disease activity. New indices were developed by multiple linear regression (psoriatic arthritis disease activity score: PASDAS) and empirically, utilising physician-defined cut-offs for disease activity (arithmetic mean of desirability functions: AMDF). These were compared with existing composite measures: Composite Psoriatic arthritis Disease Activity Index (CPDAI), Disease Activity for PSoriatic Arthritis (DAPSA), and Disease Activity Score for rheumatoid arthritis (DAS28). Results 161/503 (32%) subjects had treatment changes. Although all measures performed well, compared with existing indices, PASDAS was better able to discriminate between high and low disease activity (area under receiver operating curves (ROC)) curve with 95% CI: PASDAS 0.773 (0.723, 0.822); AMDF 0.730 (0.680, 0.780); CPDAI 0.719 (0.668, 0.770); DAPSA 0.710 (0.654, 0.766); DAS28 0.736 (0.680, 0.792). All measures were able to discriminate between disease activity states in patients with oligoarthritis, although area under the receiver operating curves (AUC) were generally smaller. In patients with severe skin disease (psoriasis area and severity index >10) both nonparametric and AUC curve statistics were nonsignificant for all measures. Conclusions Two new composite measures to assess disease activity in PsA have been developed. Further testing in other datasets, including comparison with existing measures, is required to validate these instruments.

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.

Effect of certolizumab pegol over ninety-six weeks in patients with axial spondyloarthritis: Results from a phase III randomized trial

Previous reports of the RAPID‐axSpA trial (NCT01087762) described the efficacy and safety of certolizumab pegol (CZP) over 24 weeks in patients with axial spondyloarthritis (SpA), including ankylosing spondylitis (AS) and nonradiographic axial SpA. We report efficacy and safety data up to week 96 of the study.

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.

Development and testing of new candidate psoriatic arthritis screening questionnaires combining optimal questions from existing tools

Several questionnaires have been developed to screen for psoriatic arthritis (PsA), but head‐to‐head studies have found limitations. This study aimed to develop new questionnaires encompassing the most discriminative questions from existing instruments.

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.

Sustained efficacy, safety and patient-reported outcomes of certolizumab pegol in axial spondyloarthritis: 4-year outcomes from RAPID-axSpA

Abstract Objective The aim was to assess the long-term safety and efficacy of certolizumab pegol over 4 years of continuous treatment in patients with axial spondyloarthritis (axSpA), including both AS and non-radiographic (nr-) axSpA. Methods RAPID-axSpA was a phase 3 randomized trial, double blind and placebo controlled to week 24, dose blind to week 48 and open label to week 204. Patients had a clinical diagnosis of axSpA, meeting Assessment of SpondyloArthritis international Society (ASAS) criteria, and had active disease. The assessed outcomes included ASAS20, ASAS40, AS DAS (ASDAS), BASDAI, BASFI and BASMI scores, along with selected measures of remission. Further patient-reported outcomes, peripheral arthritis, enthesitis, uveitis and quality-of-life measures are also reported. Results Two hundred and eighteen of 325 patients randomized (AS: 121; nr-axSpA: 97) received certolizumab pegol from week 0. Of these, 65% remained in the study at week 204 (AS: 67%; nr-axSpA: 63%). Across all outcomes, for AS and nr-axSpA, sustained improvements were observed to week 204 [week 204 overall axSpA: ASAS20: 54.1% (non-responder imputation); 83.7% (observed case, OC); ASAS40: 44.0% (non-responder imputation); 68.1% (OC); ASDAS inactive disease: 32.1% (last observation carried forward); 31.4% (OC)]. In the safety set (n = 315), there were 292.8 adverse events and 10.4 serious adverse events per 100 patient-years. No deaths were reported. Conclusion In the first study to evaluate the efficacy of an anti-TNF across both axSpA subpopulations, improvements in clinical and patient-reported outcomes at 24 and 96 weeks were sustained through 4 years of treatment, with no new safety signals. Trial registration ClinicalTrials.gov, http://clinicaltrials.gov, NCT01087762.

Onset of psoriatic arthritis during ustekinumab treatment for psoriasis: a case series of seven patients

DEAR EDITOR, Psoriasis is an inflammatory skin disease that affects approximately 2–3% of the population. Patients with psoriasis are at risk of developing psoriatic arthritis (PsA), an inflammatory arthritis with a recently estimated prevalence of 30% in patients with psoriasis. In recent years tumour necrosis factor (TNF)-a inhibitors (TNFIs) have been used to treat both psoriasis and PsA. More recently, ustekinumab, a monoclonal antibody that binds to p40, the shared subunit of interleukin (IL)-12 and IL-23, was approved for psoriasis and PsA. Clinical trials have demonstrated that ustekinumab is a safe and efficacious therapy for both psoriasis and PsA. Clinical trials for PsA of both TNFIs and ustekinumab have demonstrated that in evaluable study populations both PsA and psoriasis improve. Although not described in the literature, it is our observation in clinical practice that patients sometimes have discordant responses of their skin and joint disease, but new onset of PsA appears uncommon during treatment with TNFIs. This is a report of seven patients with well-controlled psoriasis on ustekinumab, but who experienced new-onset PsA or worsening PsA diagnosed by a rheumatologist. The following case is representative of the seven cases included in this series. Information on all of the cases can be found in Table 1. Patient 1 is a 65-year old obese white woman who was first diagnosed with psoriasis in 1982. She had no prior diagnosis of PsA. She had tried and failed multiple therapies for psoriasis, including alefacept, efalizumab and adalimumab. Following an infusion reaction to infliximab in November 2009 she was started on ustekinumab, initially at 45 mg then 90 mg every 12 weeks. Her psoriasis body surface area involvement improved from 40% to clear within 6 months of initiating ustekinumab therapy. In February 2012 she complained of joint pain and swelling in her hands. Examination was remarkable for dactylitis of the second left toe. Radiographs of her hands and feet revealed multiple erosions and pencil-in-cup deformities. Her C-reactive protein level was 2 8 mg dL . The evaluating rheumatologist diagnosed her with erosive PsA and added sulfasalazine. In July 2012 she discontinued ustekinumab and started golimumab due to persistent PsA symptoms. Over the following year the patient’s PsA symptoms improved but did not resolve, and her psoriasis worsened to body surface area involvement of 10%, which was controlled with the addition of narrowband ultraviolet B (NB-UVB). The seven patients in our series were evaluated by a rheumatologist for new-onset PsA or exacerbation of previously controlled PsA after starting ustekinumab for psoriasis. Our report demonstrates that in certain patients receiving ustekinumab, the activity of psoriasis and PsA may be discordant. There were several phenotypic similarities between the cases we evaluated. The majority of our patients were women aged over 49 years with long-standing psoriasis. All but one patient had total or near-total clearance of their cutaneous symptoms while on ustekinumab, but all seven patients experienced onset or worsening of joint symptoms during this period. Notably, five of the seven patients developed new-onset PsA, all of whom were female. Five of the seven had exposure to TNFIs prior to initiating ustekinumab, all of whom switched from a TNFI to ustekinumab. Of the seven patients, four developed peripheral-joint synovitis, five developed enthesitis, four developed dactylitis, three had radiographical changes consistent with PsA, and three had elevated inflammatory markers (Table 1). Three other case series have reported similar findings, including marked improvement of cutaneous symptoms while joint symptoms worsened. While our patients reported a later time to onset of joint symptoms (≥ 8 months), other cases reported a shorter interval (≤ 5 months). The pathogenesis by which ustekinumab could lead to new onset or worsening of PsA in certain patients remains unknown, but may be due to lack of efficacy at the doses given. Supporting this is the observation that, in one phase 3 trial, more patients in groups receiving the higher dose (90 mg) of ustekinumab achieved ACR20 responses (20% improvement in American College of Rheumatology criteria) than those in groups receiving 45-mg injections. Alternatively, articular disease may require more frequent ustekinumab dosing than cutaneous disease to achieve meaningful responses in some people. Our observations may support arguments that PsA and psoriasis involve distinct inflammatory pathways. In some patients, TNF-a inhibition may be superior for joint inflammation, and IL-12/23 inhibition may be more effective for skin inflammation. Although head-to-head trials of ustekinumab and TNFIs are lacking in PsA, improvements in joint symptoms, as measured with ACR20 responses, suggest

Early and sustained efficacy with apremilast monotherapy in biological-naïve patients with psoriatic arthritis: a phase IIIB, randomised controlled trial (ACTIVE)

Objective Evaluate apremilast efficacy across various psoriatic arthritis (PsA) manifestations beginning at week 2 in biological-naïve patients with PsA. Methods Patients were randomised (1:1) to apremilast 30 mg twice daily or placebo. At week 16, patients whose swollen and tender joint counts had not improved by ≥10% were eligible for early escape. At week 24, all patients received apremilast through week 52. Results Among 219 randomised patients (apremilast: n=110; placebo: n=109), a significantly greater American College of Rheumatology 20 response at week 16 (primary outcome) was observed with apremilast versus placebo (38.2% (42/110) vs 20.2% (22/109); P=0.004); response rates at week 2 (first assessment) were 16.4% (18/110) versus 6.4% (7/109) (P=0.025). Improvements in other efficacy outcomes, including 28-joint count Disease Activity Score (DAS-28) using C reactive protein (CRP), swollen joint count, Health Assessment Questionnaire-Disability Index (HAQ-DI), enthesitis and morning stiffness severity, were observed with apremilast at week 2. At week 16, apremilast significantly reduced PsA disease activity versus placebo, with changes in DAS-28 (CRP) (P<0.0001), HAQ-DI (P=0.023) and Gladman Enthesitis Index (P=0.001). Improvements were maintained with continued treatment through week 52. Over 52 weeks, apremilast’s safety profile was consistent with prior phase 3 studies in psoriasis and PsA. During weeks 0–24, the incidence of protocol-defined diarrhoea was 11.0% (apremilast) and 8.3% (placebo); serious adverse event rates were 2.8% (apremilast) and 4.6% (placebo). Conclusions In biological-naïve patients with PsA, onset of effect with apremilast was observed at week 2 and continued through week 52. The safety profile was consistent with previous reports. Trial registration number NCT01925768; Results.

Treatment patterns and annual biologic costs in US veterans with rheumatic conditions or psoriasis

Abstract Objective: To determine annual biologic drug and administration costs to the US Veterans Health Administration (VHA) per treated patient with rheumatoid arthritis (RA), psoriasis (PsO), psoriatic arthritis (PsA), or ankylosing spondylitis (AS) who received abatacept, adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, rituximab, tocilizumab, or ustekinumab. Methods: Adults with at least one biologic claim between January 1, 2008 and December 31, 2011 were included. Evidence of enrollment in the VHA was required from 365 days before (pre-index) to 360 days after (post-index) the date of the first biologic claim (index date). Included patients had pre-index diagnoses of RA, PsO, PsA, and/or AS. Drug costs were from Federal Supply Schedule or ‘Big Four’ in November 2014. Administration costs were VHA fixed costs for infused (