Real-World Efficacy and Safety of Apremilast in Belgian Patients with Psoriatic Arthritis: Results from the Prospective Observational APOLO Study.

INTRODUCTION: Apremilast is approved for the treatment of psoriasis and psoriatic arthritis (PsA). Real-world evidence on the efficacy and safety of apremilast in clinical practice is limited. We assessed the use of apremilast in patients with PsA in Belgium clinical practice. METHODS: The multicentre, observational, prospective APOLO study enrolled patients with active PsA initiating apremilast in Belgium between April 2017 and December 2018. Primary outcome was PsA Response Criteria (PsARC) after 6 months of apremilast treatment. Secondary outcomes included PsA Impact of Disease 12 (PsAID12) and Health Assessment Questionnaire Disability Index (HAQ-DI). Disease-specific outcomes and patient-reported outcomes (PROs) were analysed for patients who received apremilast within 30 days prior to their study inclusion and completed at least 150 days of treatment (reference set [REF]). RESULTS: Of 107 patients enrolled in the study, 106 received at least one dose of apremilast and 69 were included in the REF. PsARC response was achieved by 43.5% of patients (30/69) in the REF at month 6; mean global and composite scores including 68-joint count for pain/tenderness (68-TJC) and 66-joint count for swelling (66-SJC) improved, and 27% and 42% of patients with 68-TJC and 66-SJC > 0 at baseline had complete joint count resolution, respectively. Mean global and composite PsAID12 and HAQ-DI scores decreased at 6 months, indicating improved quality of life. Apremilast was well tolerated and the reported adverse events were in line with the known safety profile. CONCLUSION: Results from the APOLO study indicate that treatment with apremilast in Belgian clinical practice improves the signs and symptoms of PsA as well as patient quality of life. CLINICALTRIALS. GOV IDENTIFIER: NCT03096990.

Antibodies of the immunoglobulin a isotype to novel antigens in early axial spondyloarthritis.

Introduction: There is an unmet need for biomarkers to identify patients with axial spondyloarthritis (axSpA). Increasing evidence suggest the presence of autoantibodies in a subset of axSpA patients. The aim of this study was to identify novel IgA antibodies in early axSpA patients and to determine their diagnostic potential in combination with previously determined IgG antibodies against UH (Hasselt University)-axSpA-IgG antigens. Methods: An axSpA cDNA phage display library constructed from axSpA hip synovium, was used to screen for novel IgA antibodies in plasma from early axSpA patients. The presence of these antibodies against novel UH-axSpA-IgA antigens was determined in two independent axSpA cohorts, in healthy controls and in patients with chronic low back pain. Results: We identified antibodies to 7 novel UH-axSpA-IgA antigens, of which 6 correspond to non-physiological peptides and 1 to the human histone deacetylase 3 (HDAC3) protein. IgA antibodies against 2 of these 7 novel UH-axSpA-IgA antigens and IgG antibodies against 2 of the previously identified antigens were significantly more present in early axSpA patients from the UH cohort (18/70, 25.7%) and the (Bio)SPAR cohort (26/164, 15.9%), compared to controls with chronic low back pain (2/66, 3%). Antibodies to this panel of 4 antigens were present in 21.1% (30/142) of patients with early axSpA from the UH and (Bio)SPAR cohorts. The positive likelihood ratio for confirming early axSpA using antibodies to these 4 UH-axSpA antigens was 7.0. So far, no clinical correlation between the novel identified IgA antibodies and inflammatory bowel disease could be identified. Discussion: In conclusion, screening an axSpA cDNA phage display library for IgA reactivity resulted in the identification of 7 novel UH-axSpA-IgA antigens, of which 2 show promising biomarker potential for the diagnosis of a subset of axSpA patients, in combination with previously identified UH-axSpA-IgG antigens.

Antibodies Against Three Novel Peptides in Early Axial Spondyloarthritis Patients From Two Independent Cohorts.

OBJECTIVE: This study was undertaken to identify novel autoantibodies in axial spondyloarthritis (SpA) and determine their diagnostic potential in patients with early axial SpA and controls from 2 independent cohorts. METHODS: An axial SpA complementary DNA phage display library was used to screen for novel IgG antibodies in plasma from patients with early axial SpA. The presence of these antibodies against novel peptides (i.e., peptides identified in an early axial SpA cohort from Hasselt University, designated UH-axSpA) was determined by enzyme-linked immunosorbent assay in 76 patients with early axial SpA, 75 controls with nonspecific chronic low back pain, 60 patients with rheumatoid arthritis, and 94 healthy controls from the UH cohort. Antibody reactivity to these novel peptides was further validated in 174 patients with axial SpA (of whom 79 had early axial SpA) from the University Hospitals Leuven (Bio)SPAR (Spondyloarthritis [Biologics]) cohort. RESULTS: We identified antibodies to 9 novel UH-axSpA peptides, corresponding to randomly formed peptides and to a novel axial SpA autoantigen, double homeobox protein 4. Antibodies to 3 UH-axSpA peptides with the highest positive likelihood ratio (LR) for a diagnosis of axial SpA were present in significantly more patients with early axial SpA from the UH and (Bio)SPAR cohorts (14.2% [22/155]) compared to controls with chronic low back pain (5% [4/75]), resulting in 95% specificity. The positive LR for confirming axial SpA using antibodies to these 3 UH-axSpA peptides was 2.7, which is higher than the LR obtained with the currently used laboratory marker C-reactive protein. Testing for antibodies to these 3 UH-axSpA peptides in patients with chronic low back pain increased the posttest probability of a diagnosis of axial SpA from 79% to 91%. CONCLUSION: Antibodies to 3 UH-axSpA peptides could provide a novel tool in the diagnosis of a subset of axial SpA patients.

A 12-week randomized, double-blind, placebo-controlled multicenter study of choline-stabilized orthosilicic acid in patients with symptomatic knee osteoarthritis.

BACKGROUND: The aim of this study was to assess the efficacy of choline-stabilized orthosilicic acid (ch-OSA) in patients with symptomatic knee osteoarthritis (OA). METHODS: In a multicenter, double-blind, placebo-controlled study, 211 patients with knee OA (Kellgren and Lawrence grade II or III) and moderate to moderately severe pain were randomly allocated to ch-OSA or placebo for 12 weeks. The primary outcome was the change in the WOMAC pain subscale from baseline to week 12. Secondary outcomes were changes from baseline to week 12 in WOMAC total, WOMAC stiffness, WOMAC physical function, Subject Global Assessment and levels of cartilage degradation biomarkers C-terminal telopeptide of collagen type II (CTX-II) and cartilage oligomeric matrix protein (COMP). Pre-specified subgroup analyses included the effect of gender. RESULTS: A total of 166 (120 women, 46 men) patients were included in the analysis (87 and 79 in the ch-OSA and placebo group, respectively). In the total study population, no differences were observed between the two treatment groups for the different outcomes but significant treatment x gender interactions were found. In men taking ch-OSA, a significant improvement in WOMAC total, WOMAC stiffness and WOMAC physical function as well as a lower increase in biomarker levels of cartilage degradation was observed, but not in women. The change in WOMAC pain showed a similar positive trend in men taking ch-OSA. CONCLUSION: After 12 weeks of treatment, no effect was found of ch-OSA in the total study population on clinical parameters and biomarkers, but a gender interaction was observed. In men, ch-OSA was found effective in reducing symptoms of knee OA, which was associated with a slight but significant reduction of biomarkers that are related to cartilage degradation. TRIAL REGISTRATION: The study was registered retrospectively: ISRCTN88583133 . Registration date: 2015-10-07.

Effectiveness of methotrexate with step-down glucocorticoid remission induction (COBRA Slim) versus other intensive treatment strategies for early rheumatoid arthritis in a treat-to-target approach: 1-year results of CareRA, a randomised pragmatic open-label superiority trial.

OBJECTIVES: Combining disease-modifying antirheumatic drugs (DMARDs) with glucocorticoids (GCs) is an effective treatment strategy for early rheumatoid arthritis (ERA), yet the ideal schedule and feasibility in daily practice are debated. We evaluated different DMARD combinations and GC remission induction schemes in poor prognosis patients; and methotrexate (MTX) with or without GC remission induction in good prognosis patients, during the first treatment year. METHODS: The Care in ERA (CareRA) trial is a 2-year investigator-initiated randomised pragmatic open-label superiority trial comparing remission induction regimens in a treat-to-target approach. DMARD-inexperienced patients with ERA were stratified into a high-risk or low-risk group based upon presence of erosions, disease activity, rheumatoid factor and anticitrullinated protein antibodies. High-risk patients were randomised to a COBRA Classic (MTX + sulfasalazine + prednisone step-down from 60 mg), COBRA Slim (MTX + prednisone step-down from 30 mg) or COBRA Avant Garde (MTX + leflunomide + prednisone step-down from 30 mg) scheme. Low-risk patients were randomised to MTX tight step-up (MTX-TSU) or COBRA Slim. Primary outcome was the proportion of patients in 28 joint disease activity score calculated with C-reactive protein remission at week 52 in an intention-to-treat analysis. Secondary outcomes were safety and effectiveness (ClinicalTrial.gov identifier NCT01172639). RESULTS: 98 COBRA Classic, 98 COBRA Slim (high risk), 93 COBRA Avant Garde, 47 MTX-TSU and 43 COBRA Slim (low risk) patients were evaluated. Remission was achieved in 64.3% (63/98) COBRA Classic, 60.2% (59/98) COBRA Slim (high risk) and 62.4% (58/93) COBRA Avant Garde patients at W52 (p=0.840); and in 57.4% (27/47) MTX-TSU and 67.4% (29/43) COBRA Slim (low risk) patients (p=0.329). Less adverse events occurred per patient with COBRA Slim (high risk) compared with COBRA Classic or COBRA Avant Garde (p=0.038). Adverse events were similar in MTX-TSU and COBRA Slim (low risk) patients (p=0.871). At W52, 76.0% patients were on DMARD monotherapy, 5.2% used GCs and 7.5% biologicals. CONCLUSIONS: MTX with a moderate-dose GC remission induction scheme (COBRA Slim) seems an effective, safe, low-cost and feasible initial treatment strategy for patients with ERA regardless of their prognostic profile, provided a treat-to-target approach is followed. TRIAL REGISTRATION NUMBERS: EudraCT-number 2008-007225-39 and NCT01172639; Results.

Randomized Crossover Comparison of Injection Site Pain with 40 mg/0.4 or 0.8 mL Formulations of Adalimumab in Patients with Rheumatoid Arthritis.

INTRODUCTION: Adalimumab, an anti-tumor necrosis factor antibody, is currently available in a 40 mg/0.8 mL formulation. The objective of this analysis was to evaluate injection site-related pain, safety, and tolerability of a 40 mg/0.4 mL formulation of adalimumab that had fewer excipients, a smaller volume, and a delivery presentation with a smaller gauge needle, versus the current 40 mg/0.8 mL formulation in patients with rheumatoid arthritis (RA). METHODS: Two identically designed, phase 2, randomized, single-blind, two-period crossover studies were conducted in Belgium and the Czech Republic (Study 1) and Australia, Canada, and Germany (Study 2). In both studies, adults with RA [biologic-naive or current users of 40 mg/0.8 mL adalimumab with an average injection site-related pain rating ≥3 cm on a visual analog scale (VAS; 0-10 cm)] were randomized to receive 40 mg/0.8 mL or 40 mg/0.4 mL adalimumab at visit 1. After 1-2 weeks (depending on patient medication schedule), patients received the other formulation at visit 2. A pain VAS [McGill Pain Questionnaire (MPQ-SF)] and the Draize scale were evaluated immediately after injection and 15 min postinjection. The primary endpoint was immediate pain after injection. RESULTS: 64 and 61 patients were randomized in Studies 1 and 2, respectively. Both studies found a clinically relevant and statistically significant lower immediate pain after injection for the 40 mg/0.4 mL versus the 40 mg/0.8 mL formulation. The mean difference on the VAS for the pooled data (-2.48 cm) was also clinically relevant. Most other endpoints in both studies favored the 40 mg/0.4 mL formulation, and its tolerability and safety profile were consistent with 40 mg/0.8 mL adalimumab. CONCLUSION: A 40 mg/0.4 mL adalimumab formulation was well tolerated and associated with less injection site-related pain than the 40 mg/0.8 mL adalimumab formulation. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01561313 and NCT01502423. FUNDING: AbbVie.

The isotype repertoire of antibodies against novel UH-RA peptides in rheumatoid arthritis.

BACKGROUND: Recently, autoantibodies against novel UH-RA peptides (UH-RA.1 and UH-RA.21) were identified as candidate biomarkers for patients with rheumatoid arthritis (RA) who are seronegative for the current diagnostic markers rheumatoid factor and anticitrullinated protein antibodies. Previously, screening for anti-UH-RA autoantibodies was based on measuring the immunoglobulin (Ig) G response. We aimed to investigate whether measurement of other isotypes could improve the performance of diagnostic testing. In addition, assigning the isotype profile might provide valuable information on effector functions of the antibodies. METHODS: The isotype profile of antibodies against UH-RA.1 and UH-RA.21 was studied. The IgG, IgM, and IgA classes, together with the 4 different IgG subclasses, were determined in 285 patients with RA, 88 rheumatic control subjects, and 90 healthy control subjects. RESULTS: Anti-UH-RA.1 antibodies were primarily of the IgM isotype and twice as prevalent as IgG (IgG3-dominated) and IgA. RA sensitivity when testing for anti-UH-RA.1 IgM was shown to be higher than when testing for the IgG isotype: 18 % versus 9 % sensitivity when RA specificity was set to 90 %. Within antibodies against UH-RA.21, IgG and IgA were more common than IgM. Different anti-UH-RA.21 IgG subclasses were found, with the highest prevalence found for IgG2. Combined testing for IgG and IgA slightly increased RA sensitivity of UH-RA.21-specific antibody testing to 27 % compared with solely testing for IgG (23 %). Notably, a higher number of anti-UH-RA.21 antibody isotypes was related to increased levels of erythrocyte sedimentation rate. Finally, for both antibody responses, the full antibody isotype use was demonstrated in early and seronegative disease. CONCLUSIONS: The isotype distribution of anti-UH-RA.1 and anti-UH-RA.21 antibodies was successfully outlined, and, for antibodies against UH-RA.1, we found that isotype-specific testing might have implications for diagnostic testing. The exact mechanisms by which the different antibody isotypes act still have to be unraveled.

The prevalence of vertebral fractures in spondyloarthritis: relation to disease characteristics, bone mineral density, syndesmophytes and history of back pain and trauma.

INTRODUCTION: An increased risk of vertebral fracture (VF) is one of the extra-articular manifestations of spondyloarthropathy (SpA). The prevalence of moderate to severe VFs visualized by radiography (Rx) in patients with SpA in daily practice is unknown until imaging of the full spine is available, as most VFs do not present with clinical signs and symptoms of an acute fracture. METHODS: We evaluated the prevalence of VFs (>25% loss in height) on available Rx and dual-energy X-ray absorptiometry (DXA) images in 390 consecutive patients with SpA in daily practice. We assessed their association with disease characteristics, bone mineral density, the modified Stoke Ankylosing Spondylitis Spinal Score, and history of trauma. RESULTS: Forty-six patients (11.8%) had Rx VF (56.4% men, 93.5% in the thoracic spine), and 44.5% had multiple VFs. Compared with patients without VF, patients with VF were older (52.2 vs. 47.3 years, p < 0.01; range 25-84 years), had lower femoral neck T-scores (-1.1 vs. -0.7; p < 0.05), and had a marginally higher modified Stoke Ankylosing Spondylitis Spinal Score (11.7 vs. 7.0; p = 0.06). Among patients with VFs, 15.2% had a history of trauma with acute back pain (p < 0.001 vs. no VF). The reliability of DXA for diagnosing radiographic VFs was high (κ 0.90). CONCLUSIONS: Moderate to severe VFs are found in more than 10% of patients with SpA before the age of 40 years in 5% of women and 9% in men. Most VFs are located in the thoracic region, are related to low femoral neck bone mineral density and to stiffening of the spine, and are only rarely related to trauma history. DXA is a useful alternative for diagnosing VFs.

Patients lacking classical poor prognostic markers might also benefit from a step-down glucocorticoid bridging scheme in early rheumatoid arthritis: week 16 results from the randomized multicenter CareRA trial.

INTRODUCTION: Considering a lack of efficacy data in patients with early rheumatoid arthritis (eRA) presenting without classical markers of poor prognosis, we compared methotrexate (MTX) with or without step-down glucocorticoids in the CareRA trial. METHODS: Disease-modifying antirheumatic drug-naïve patients with eRA were stratified into a low-risk group based on prognostic markers that included non-erosiveness, anti-citrullinated protein antibodies and rheumatoid factor negativity and low disease activity (Disease Activity Score in 28 joints based on C-reactive protein (DAS28(CRP)) ≤3.2). Patients were randomized to 15 mg of MTX weekly (MTX with tight step-up (MTX-TSU)) or 15 mg of MTX weekly with prednisone bridging, starting at 30 mg and tapered to 5 mg daily from week 6 (COmbinatie therapie bij Reumatoïde Artritis (COBRA Slim)). A TSU approach was applied. Outcomes assessed were DAS28(CRP)-determined remission, cumulative disease activity, Health Assessment Questionnaire (HAQ) scores and adverse events (AEs) after 16 treatment weeks. RESULTS: We analyzed 43 COBRA Slim and 47 MTX-TSU patients and found that 65.1% in the COBRA Slim group and 46.8% in the MTX-TSU group reached remission (P = 0.081). Mean ± standard deviation area under the curve values of DAS28(CRP) were 13.84 ± 4.58 and 11.18 ± 4.25 for the MTX-TSU and COBRA Slim patients, respectively (P = 0.006). More COBRA Slim patients had an HAQ score of 0 (51.2% versus 23.4%, P = 0.006) at week 16. Therapy-related AEs between groups did not differ. CONCLUSION: In patients with low-risk eRA, MTX with step-down glucocorticoid bridging seems more efficacious than MTX step-up monotherapy, with a comparable number of AEs observed over the first 16 treatment weeks. TRIAL REGISTRATION: EU Clinical Trials Register Identifier: EudraCT number 2008-007225-39 . Registered 5 November 2008.

Belgian rheumatologists' perception on eligibility of RA patients for anti-TNF treatment matches more closely Dutch rather than Belgian reimbursement criteria.

OBJECTIVES: To assess discrepancies between perception of Belgian rheumatologists on eligibility of RA patients for anti-TNF treatment and Belgian reimbursement criteria and to compare Belgian with Dutch criteria and UK guidelines. METHODS: Consecutive MTX-experienced patients with active RA were recruited from 25 private and academic rheumatology practices. Discrepancies between eligibility for anti-TNF treatment according to the rheumatologist and fulfillment of Belgian reimbursement criteria [HAQ > or =25%, tender joint count (TJC) and swollen joint count (SJC) > or =8; > or =1 erosion; failure of > or =2 DMARDs including MTX; no tuberculosis] were recorded. Reasons for failing the Belgian criteria and results of applying Dutch reimbursement criteria and UK guidelines on the dataset were analysed. RESULTS: Of 492 patients, rheumatologists considered 135 (27.4%) as eligible, whereas Belgian criteria were fulfilled for only 34 (6.9%). Positive predictive value (PPV) of rheumatologists' perception on eligibility for fulfillment of Belgian criteria was 22.9%, whereas negative predictive value (NPV) was 99.1%. The 104 patients (21.1%) considered eligible despite criteria not being fulfilled had significantly greater TJCs, SJCs, disease activity score (DAS28) and Rheumatoid Arthritis Disease Activity Index scores than the 385 patients (78.2%) in the no-discrepancy group. Number of swollen joints, HAQ and erosions mainly accounted for discrepancies. Of 492 patients, 263 (53.4%) qualified for Dutch criteria and 41 (8.3%) for UK guidelines. PPV of Belgian rheumatologists' perception was 72.6% for fulfilling Dutch criteria (NPV 49.6%) and 23.4% for UK guidelines (NPV 96.7%). CONCLUSIONS: Rheumatologists consider more RA patients eligible for anti-TNF treatment than would be reimbursed according to Belgian criteria. Dutch guidelines, based on DAS28, match more closely eligibility according to Belgian rheumatologists.

Impact of systematic implementation of a clinical case finding strategy on diagnosis and therapy of postmenopausal osteoporosis.

INTRODUCTION: Case finding for osteoporosis in postmenopausal women is advocated in guidelines of osteoporosis, but implementation is unsatisfactory. We studied, in daily practice, the impact of systematic implementation of a previously validated clinical decision rule and fracture history on referral for bone densitometry (DXA) and drug prescription for osteoporosis. MATERIALS AND METHODS: Before-after impact analysis in 41,478 consecutive consulting postmenopausal women, included by 1080 general practitioners (GPs) during 2 mo, using the osteoporosis self-assessment (OST) index (based on age and weight, indicating women at low [LR], moderate [MR], and high risk [HR] for having osteoporosis [T-score < -2.5 in spine and/or hip]) and fracture history. Relative risks (RRs) and 95% CIs were calculated between referrals before (n = 6580) and after intervention (n = 10,379) and between risk subgroups. RESULTS: Post-intervention RR for referral for DXA was 1.9 (95% CI, 1.8-2.0). Compared with LR women with prior DXA, the RR was 6.3 (95% CI, 6.0-6.6) in MR and 10.7 (95% CI, 10.0-11.4) in HR women without fracture, but similar in MR and HR women with fracture (11.4 and 11.6, respectively). New cases of osteoporosis were diagnosed in 3811 women, 96% of whom were prescribed drug treatment. Of HR women, 79% were referred for DXA. The sensitivity of a low OST index to predict osteoporosis was 92% and specificity was 16%. CONCLUSIONS: The impact of temporary systematic implementation of this case finding strategy on GP practice was high: it nearly tripled referrals for DXA, and 96% of patients found to have osteoporosis had treatment. The impact depended on OST index and fracture history. Only 79% of HR women were referred for DXA. Specificity of a low OST index to predict osteoporosis was low. This indicates the need in the GP population for case finding strategies with fewer barriers for referral for DXA and with higher accuracy for predicting osteoporosis.

The relationship among history of falls, osteoporosis, and fractures in postmenopausal women.

OBJECTIVE: To study the relative contribution of osteoporosis and falls to the occurrence of symptomatic fractures in postmenopausal women. DESIGN: Retrospective survey of current osteoporosis in relation to falls and fractures in the preceding year. SETTING: Patients of general practitioners of the area around a Belgian university. PARTICIPANTS: A total of 2649 consecutive postmenopausal women (mean age, 61y; range, 45-91y). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Current bone density measurements (single-photon absorptiometry in the forearm) were analyzed in relation to self-reported incidence of falls and fractures in the preceding year. RESULTS: Osteoporosis was found in 15% of the patients, 19% reported 1 or more falls during the preceding year, and 1.8% had a fracture during the preceding year. The age-adjusted risk for a fracture in the past 12 months for a 1 standard deviation decrease in bone density was 1.9 (95% confidence interval [CI], 1.4-2.5; P<.01). Adjusted risk for age, bone density, and body mass index (BMI) for a fracture in the past 12 months in patients who reported a fall was 6.0 (95% CI, 3.1-11.5; P<.001). Compared with women without osteoporosis and without a fall, women with osteoporosis without a fall had an age- and BMI-adjusted fracture risk of 2.8 (95% CI, 0.6-12.8; P<.10), and women with osteoporosis and a fall had an adjusted-fracture risk of 24.8 (95% CI, 6.9-88.6; P<.0001). CONCLUSIONS: Falls are a major contributing factor to the occurrence of symptomatic fractures in postmenopausal women, independent of and additive to the risk attributable to age and osteoporosis.