Early response to adalimumab predicts long-term remission through 5 years of treatment in patients with ankylosing spondylitis

Pathophysiology and treatment of rheumatic disease

Response to treatment in psoriatic arthritis, the effect of age: analysis of patients receiving ustekinumab in the PsABio real-world study

Background: This post-hoc analysis of PsABio (NCT02627768) evaluated safety, effectiveness and treatment persistence in patients < 60 and ≥ 60 years of age receiving ustekinumab over 3 years. Methods: Measures included adverse events (AE), clinical Disease Activity Index for Psoriatic Arthritis (cDAPSA) low disease activity (LDA) including remission, Psoriatic Arthritis Impact of Disease-12 (PsAID-12), Minimal Disease Activity, dactylitis, nail/skin involvement and time to treatment stop. Data were analysed descriptively. Results: Overall, 336 patients < 60 and 103 ≥ 60 years received ustekinumab, with a similar gender balance. A numerically lower proportion of younger patients reported at least one AE: 124/379 (32.7%) vs 47/115 (40.9%) for patients < 60 and ≥ 60 years, respectively. Serious AEs were low (< 10%) in both groups. At 6 months, the proportion of patients with cDAPSA LDA was 138/267 (51.7%) and 35/80 (43.8%) for patients < 60 and ≥ 60 years, respectively, with the effectiveness being maintained through 36 months. PsAID-12 mean scores reduced for both groups from a baseline mean of 5.73 and 5.61 for patients < 60 and ≥ 60 years, respectively, to 3.81 and 3.88, respectively, at 6 months, and 2.02 and 3.24, respectively, at 36 months. Regarding treatment persistence, 173/336 (51.5%) vs 47/103 (45.6%) patients < 60 and ≥ 60 years, respectively, stopped or switched treatment. Conclusion: Fewer AEs were observed over 3 years for younger versus older patients with PsA. There were no clinically meaningful treatment response differences. Persistence was numerically higher in the older age group

Modulation of interleukin-23 signaling with guselkumab in biologic-naive patients versus tumor necrosis factor inhibitor–inadequate responders with active psoriatic arthritis

Objective We assessed and compared immunologic differences and associations with clinical response to guselkumab, a fully human interleukin (IL)–23p19 subunit inhibitor, in participants with active psoriatic arthritis (PsA) who were biologic-naive or had inadequate response to tumor necrosis factor inhibitors (TNFi-IR). Methods Serum biomarker levels at baseline and after treatment with guselkumab 100 mg every 8 weeks were compared between biologic-naive (n = 251) and TNFi-IR (n = 93) subgroups identified in the pooled DISCOVER-1/DISCOVER-2/COSMOS data set. Baseline biomarker levels determined by achievement of week 24 clinical responses (≥75%/90% improvement in Psoriasis Area and Severity Index [PASI 75/90], Investigator's Global Assessment [IGA] of psoriasis score 0/1 and ≥2-point improvement], ≥20% improvement in American College of Rheumatology criteria [ACR20]) were compared between prior treatment subgroups. Results Baseline IL-22, TNFα, and beta defensin-2 (BD-2) levels were significantly lower in biologic-naive than in TNFi-IR participants. With guselkumab, week 24 IL-17A, IL-17F, IL-22, serum amyloid A, C-reactive protein, IL-6, and BD-2 levels were significantly reduced from baseline in biologic-naive and TNFi-IR participants (≥1.4-fold difference, nominal P Conclusion Guselkumab modulates IL-23 signaling and provides consistent pharmacodynamic effects in both biologic-naive and TNFi-IR PsA patients. Significantly elevated baseline IL-22, TNFα, and BD-2 levels and associations between baseline IL-22, IL-17A, and BD-2 levels and skin responses to guselkumab suggest greater dysregulation of IL-23/Th17 signaling in patients with TNFi-IR

Long-term effectiveness and persistence of ustekinumab and TNF inhibitors in patients with psoriatic arthritis: final 3-year results from the PsABio real-world study

Objectives: To evaluate real-world persistence and effectiveness of the IL-12/23 inhibitor, ustekinumab or a tumour necrosis factor inhibitor (TNFi) for psoriatic arthritis over 3 years. Methods: PsABio (NCT02627768), a prospective, observational study, followed patients with PsA prescribed first-line to third-line ustekinumab or a TNFi. Persistence and effectiveness (achievement of clinical Disease Activity for PSA (cDAPSA) low disease activity (LDA)/remission and minimal disease activity/very LDA (MDA/VLDA)) were assessed every 6 months. Safety data were collected over 3 years. Analyses to compare the modes of action were adjusted on baseline differences by propensity scores (PS). Results: In 895 patients (mean age 49.8 years, 44.7% males), at 3 years, the proportion of patients still on their initial treatments was similar with ustekinumab (49.9%) and TNFi (47.8%). No difference was seen in the risk of stopping/switching; PS-adjusted hazard ratio (95% CI) for stopping/switching ustekinumab versus TNFi was 0.87 (0.68 to 1.11). In the overall population, cDAPSA LDA/remission was achieved in 58.6%/31.4% ustekinumab-treated and 69.8%/45.0% TNFi-treated patients; PS-adjusted ORs (95% CI) were 0.89 (0.63 to 1.26) for cDAPSA LDA; 0.72 (0.50 to 1.05) for remission. MDA/VLDA was achieved in 41.4%/19.2% of ustekinumab-treated and 54.2%/26.9% of TNFi-treated patients with overlapping PS-adjusted ORs. A greater percentage of TNFi-treated patients achieved effectiveness outcomes. Both treatments exhibited good long-term safety profiles, although ustekinumab-treated patients had a lower rate of adverse events (AEs) versus TNFi. Conclusion: At 3 years, there was generally comparable persistence after ustekinumab or TNFi treatment, but AE rates were lower with ustekinumab

Spondylarthropathies (including psoriatic arthritis): 244. Validity of Colour Doppler and Spectral Doppler Ultrasound of Sacroilicac Joints Againts Physical Examination as Gold Standard

Background: Sacroiliac joints (SJ) involvement is a distinctive and charasteristic feature of Spondyloarthritis (SpA) and x-ray is the test routinely used to make a diagnosis. However, x-ray reveals late structural damage but cannot detect active inflammation. The objective of this study was to assess the validity of Doppler ultrasound in SJ. Methods: Prospective blinded and controlled study of SJ, in which three populations were compared. We studied 106 consecutive cases, who were divided into three groups: a) 53 patients diagnosed with SpA who had inflammatory lumbar and gluteal pain assessed by a rheumatologist; b) 26 patients diagnosed with SpA who didn't have SJ tenderness and had normal physical examination; c) control group of 27 subjects (healthy subjetcs or with mechanical lumbar pain). All patients included that were diagnosed with SpA met almost the European Spondyloarthropathy Study Group (ESSG) classification criteria. Physical examination of the SJ included: sacral sulcus tenderness, iliac gapping, iliac compression, midline sacral thrust test, Gaenslen's test, and Patrick s test were used as gold standard. Both SJ were examined with Doppler ultrasound (General Electric Logiq 9, Wauwatosa WI, USA) fitted with a 9-14 Mhz lineal probe. The ultrasonographer was blinded to clinical data. Doppler in SJ was assessed as positive when both Doppler colour and resistance index (RI) < 0.75 within the SJ area were present. Statistical analysis was performed estimating sensitivity and specificity against gold standard. The Kappa correlation coefficient was used for reliability study. Results: 106 cases (53 female, 55 male; mean age 36 10 years) were studied. There were no statistical differences between groups related to age or sex. Physical examination of SJ was positive in 38 patients (59 sacroiliac joints). US detected Doppler signal within SJ in 37 patients (58 SJ): 33 of them were symptomatic SpA (52 SJ), one of them were asymptomatic SpA (1 SJ) and one was a healthy control (1 SJ). The accuracy of US when compared to clinical data as gold standard at subject level in the overall group was: sensitivity of 68.6% and specificity of 85.7%, positive predictive value of 70.5% and negative predictive value of 84.5%. A positive likelihood ratio of 4.8, a negative likelihood ratio of 0.36 and a kappa coefficient of 0.55 were achieved. Conclusions: Doppler US of SJ seems to be a valid method to detect active SJ inflammation. Disclosure statement: The authors have declared no conflicts of interes

Effect of guselkumab on serum biomarkers in patients with active psoriatic arthritis and inadequate response to tumor necrosis factor inhibitors: results from the COSMOS phase 3b study

Abstract Background Guselkumab is a selective interleukin (IL)-23 inhibitor targeting the IL-23p19 subunit. In the phase 3b COSMOS trial, guselkumab demonstrated efficacy in treating participants with active psoriatic arthritis (PsA) and inadequate response (IR; lack of efficacy or intolerance) to tumor necrosis factor inhibitors (TNFi). Methods Adults with active PsA (≥ 3 swollen joints,  ≥ 3 tender joints) and IR to one or two TNFi (TNFi-IR) were randomized 2:1 to guselkumab at Weeks 0, 4, then every 8 weeks (Q8W) or placebo➔guselkumab Q8W at Week 24 with possible early escape at Week 16. Levels of serum cytokines, including interferon ɣ (IFNɣ), IL-10, and tumor necrosis factor α (TNFα); T helper 17 (Th17) effector cytokines IL-17A, IL-17F, and IL-22; and acute phase proteins C-reactive protein (CRP), IL-6, and serum amyloid A (SAA), were assessed and compared with matched healthy controls; guselkumab pharmacodynamics through Week 24 were also assessed. Associations between baseline biomarker levels and 1) baseline disease activity (28-joint disease activity score using CRP [DAS28-CRP], psoriasis area and severity index [PASI], and % body surface area [BSA] affected by psoriasis) and 2) clinical response (including  ≥ 20% improvement in American College of Rheumatology criteria [ACR20] response) at Week 24 were assessed. Results Baseline serum levels of IL-6, IL-10, IL-17A, IL-17F, IL-22, TNFα, and IFNɣ were significantly higher in COSMOS TNFi-IR participants than in matched healthy controls. Baseline IL-6, CRP, and SAA levels were associated with baseline DAS28-CRP. IL-17A and IL-17F levels were associated with baseline PASI score and psoriasis BSA. Baseline swollen or tender joint counts did not associate with baseline biomarker levels. At Week 24, significant decreases from baseline in CRP, SAA, IL-17A, IL-17F, and IL-22 levels were seen in guselkumab, but not placebo-, treated participants. IL-17F and IL-22 levels at Week 24 in guselkumab-treated participants did not significantly differ from those of matched healthy controls. Guselkumab-treated participants achieving ACR20 response at Week 24 exhibited higher baseline IL-22 and IFNɣ levels versus nonresponders. Conclusions Results from COSMOS participants with active, TNFi-IR PsA suggest guselkumab reduces levels of effector cytokines associated with the IL-23/IL-17 pathway, including those associated with baseline arthritis and skin disease activity. Trial registration ClinicalTrials.gov: NCT03796858

Synthetic water soluble di-/tritopic molecular receptors exhibiting Ca2+/Mg2+ exchange

International audienceStructural integration of two synthetic water soluble receptors for Ca2+ and Mg2+, namely 1,2-bis(2-aminophenoxy) ethane-N, N, N', N'-tetraacetic acid (BAPTA) and o-aminophenol-N, N, O-triacetic acid (APTRA), respectively, gave novel di- and tritopic ionophores (1 and 2). As Mg2+ and Ca2+ cannot be simultaneously complexed by the receptors, allosteric control of complexation results. Potentiometric measurements established stepwise protonation constants and showed high affinity for Ca2+ (log K = 6.08 and 8.70 for 1 and 2, respectively) and an excellent selectivity over Mg2+ (log K = 3.70 and 5.60 for 1 and 2, respectively), which is compatible with magnesium-calcium ion exchange. While ion-exchange of a single Mg2+ for a single Ca2+ is possible in both 1 and 2, the simultaneous binding of two Mg2+ by 2 appears prohibitive for replacement of these two ions by a single Ca2+. Ion-binding and exchange was further rationalized by DFT calculations

Low rates of radiographic progression associated with clinical efficacy following up to 2 years of treatment with guselkumab: results from a phase 3, randomised, double-blind, placebo-controlled study of biologic-naïve patients with active psoriatic arthritis

Objective: Evaluate relationship between radiographic progression and clinical outcomes in post hoc analyses of patients with psoriatic arthritis (PsA) receiving up to 2 years of guselkumab therapy in the phase 3, placebo-controlled, randomised trial, DISCOVER-2. Methods: Biologic-naïve adults with active PsA (≥5 swollen joints /≥5 tender joints ; C reactive protein ≥0.6 mg/dL) were randomised to guselkumab 100 mg every 4 weeks (Q4W); guselkumab 100 mg at week 0, week 4, then every 8 weeks (Q8W); or placebo→guselkumab 100 mg Q4W (week 24). Radiographs (hands/feet) at week 0, week 24, week 52 and week 100 were scored via PsA-modified van der Heijde-Sharp (vdH-S) methodology. In these post hoc analyses, mean changes in vdH-S scores were summarised according to achievement of American College of Rheumatology 20/50/70 response; low disease activity (LDA) defined by Disease Activity in Psoriatic Arthritis (DAPSA) ≤14 or Psoriatic ArthritiS Disease Activity Score (PASDAS) ≤3.2, or minimal/very low disease activity (MDA/VLDA); and normalised physical function (Health Assessment Questionnaire-Disability Index (HAQ-DI) ≤0.5). Response rates for achieving MDA/VLDA and each component were determined among patients with and without radiographic progression (change in total vdH-S score &gt;0.5). No formal hypothesis testing was performed. Results: 664 of 739 treated patients in DISCOVER-2 continued study treatment at week 52 and were included in these analyses. Mean changes in vdH-S scores from weeks 0 to 100 among all patients in the Q4W and Q8W groups were 1.7 and 1.5, respectively. Among all guselkumab-randomised patients, those who achieved ACR20/50/70, DAPSA LDA, PASDAS LDA, MDA, VLDA and HAQ-DI ≤0.5 (normalised physical function) had smaller mean changes in vdH-S scores than did non-responders at week 52 (0.2–1.2 vs 1.7–4.1) and week 100 (0.3–1.2 vs 2.0–4.6). Relative to patients with radiographic progression, those without progression were more likely to achieve the MDA criteria related to swollen and tender joint counts, patient-reported pain and global assessment, and normalised physical function through week 100. Conclusion: In these post hoc analyses, the achievement of low levels of disease activity, including MDA, was associated with diminished rates of radiographic progression observed in patients receiving up to 2 years of guselkumab. Radiographic non-progressors were more likely to achieve patient-reported MDA criteria of minimal pain and normalised physical function compared with radiographic non-responders. Trial registration number: NCT03158285

Earlier clinical response predicts low rates of radiographic progression in biologic-naïve patients with active psoriatic arthritis receiving guselkumab treatment.

OBJECTIVE: Assess relationship between earlier clinical improvement and radiographic progression (RP) over 2 years in guselkumab-treated patients with active psoriatic arthritis (PsA). METHOD: Post hoc analyses combined data from DISCOVER-2 biologic-naïve adults with active PsA randomized to either guselkumab 100 mg every 4 weeks (Q4W) or guselkumab at W0, W4, then Q8W. Correlations (Spearman\u27s coefficient) between baseline disease parameters and total PsA-modified van der Heijde-Sharp (vdH-S) score were examined. Repeated-measures mixed models, adjusted for known RP risk factors, assessed the relationship between Disease Activity Index in PsA (DAPSA) improvement, DAPSA improvement exceeding the median or the minimal clinically important difference (MCID), or DAPSA low disease activity (LDA) at W8 and RP rate, assessed by change from baseline in vdH-S score through W100. RESULTS: Baseline age, PsA duration, CRP level, and swollen joint count, but not psoriasis duration/severity, weakly correlated with baseline vdH-S score. Elevated baseline CRP (parameter estimate [β] = 0.17-0.18, p \u3c 0.03) and vdH-S score (β = 0.02, p \u3c 0.0001) significantly associated with greater RP through W100. Greater improvement in DAPSA (β = -0.03, p = 0.0096), achievement of DAPSA improvement \u3e median (least squares mean [LSM] difference: -0.66, p = 0.0405) or \u3e MCID (-0.67, p = 0.0610), or DAPSA LDA (-1.44, p = 0.0151) by W8 with guselkumab significantly associated with less RP through W100. The effect of W8 DAPSA LDA on future RP was strengthened over time among achievers vs. non-achievers (LSM difference enhanced from -1.05 [p = 0.0267] at W52 to -1.84 [p = 0.0154] at W100). CONCLUSIONS: In guselkumab-treated patients with active PsA, earlier improvement in joint symptoms significantly associated with lower RP rates through 2 years, indicating blockade of the IL-23 pathway may modify long-term disease course and prevent further joint damage. Key Points • Greater improvement in DAPSA at Week 8 of guselkumab treatment was significantly associated with less progression of structural joint damage at 2 years in patients with active psoriatic arthritis (PsA). • Early control of peripheral joint disease activity with blockade of the IL-23 pathway may modify long-term PsA trajectory and prevent further joint damage