IL-12p40/IL-23p40 Blockade With Ustekinumab Decreases the Synovial Inflammatory Infiltrate Through Modulation of Multiple Signaling Pathways Including MAPK-ERK and Wnt.

Background: Psoriatic arthritis (PsA) is a chronic inflammatory joint disease within the spondyloarthritis spectrum. IL-12p40/IL-23p40 blockade reduces PsA disease activity, but its impact on synovial inflammation remains unclear. Objectives: To investigate the cellular and molecular pathways affected by IL-12p40/IL-23p40 blockade with ustekinumab in the synovium of PsA patients. Methods: Eleven PsA patients with at least one inflamed knee or ankle joint were included in a 24-week single-center open-label study and received ustekinumab 45 mg/sc according to standard care at week 0, 4, and 16. Besides clinical outcomes, synovial tissue (ST) samples were obtained by needle arthroscopy from an inflamed knee or ankle joint at baseline, week 12 and 24 and analyzed by immunohistochemistry, RNA-sequencing and real-time quantitative polymerase chain reaction (qPCR). Results: We obtained paired baseline and week 12, and paired baseline, week 12 and 24 ST samples from nine and six patients, respectively. Eight patients completed 24 weeks of clinical follow-up. At 12 weeks 6/11 patients met ACR20, 2/11 met ACR50 and 1/11 met ACR70 improvement criteria, at 24 weeks this was 3/8, 2/8 and 1/8 patients, respectively. Clinical and serological markers improved significantly. No serious adverse events occurred. We observed numerical decreases of all infiltrating cell subtypes at week 12, reaching statistical significance for CD68+ sublining macrophages. For some cell types this was even more pronounced at week 24, but clearly synovial inflammation was incompletely resolved. IL-17A and F, TNF, IL-6, IL-8, and IL-12p40 were not significantly downregulated in qPCR analysis of W12 total biopsies, only MMP3 and IL-23p19 were significantly decreased. RNA-seq analysis revealed 178 significantly differentially expressed genes between baseline and 12 weeks (FDR 0.1). Gene Ontology and KEGG terms enrichment analyses identified overrepresentation of biological processes as response to reactive oxygen species, chemotaxis, migration and angiogenesis as well as MAPK-ERK and PI3K-Akt signaling pathways among the downregulated genes and of Wnt signaling pathway among the upregulated genes. Furthermore, ACR20 responders and non-responders differed strikingly in gene expression profiles in a post-hoc exploratory analysis. Conclusions: Ustekinumab suppresses PsA synovial inflammation through modulation of multiple signal transduction pathways, including MAPK-ERK, Wnt and potentially PI3K-Akt signaling rather than by directly impacting the IL-17 pathway.

Patients' and rheumatologists' perceptions on preventive intervention in rheumatoid arthritis and axial spondyloarthritis.

BACKGROUND: Individuals at risk of developing rheumatoid arthritis (RA) may benefit from lifestyle or pharmacological interventions aimed at primary prevention. The same may apply to individuals at risk of axial spondyloarthritis (axSpA). Our aim was to investigate and compare the willingness of individuals at risk of RA or axSpA and rheumatologists to initiate preventive intervention. METHODS: Individuals at risk of RA (arthralgia and anti-citrullinated protein antibodies and/or rheumatoid factor positivity without arthritis (RA-risk cohort; n = 100)), axSpA (first-degree relatives of HLA-B27-positive axSpA patients (SpA-risk cohort; n = 38)), and Dutch rheumatologists (n = 49) completed a survey on preventive intervention which included questions about disease perception, lifestyle intervention, and preventive medication. RESULTS: At-risk individuals reported willingness to change median 7 of 13 lifestyle components in the areas of smoking, diet, and exercise. In contrast, 35% of rheumatologists gave lifestyle advice to ≥ 50% of at-risk patients. The willingness to use 100% effective preventive medication without side effects was 53% (RA-risk), 55% (SpA-risk), and 74% (rheumatologists) at 30% disease risk which increased to 69% (RA-risk) and 92% (SpA-risk and rheumatologists) at 70% risk. With minor side effects, willingness was 26%, 29%, and 31% (at 30% risk) versus 40%, 66%, and 76% (at 70% risk), respectively. CONCLUSIONS: Risk perception and willingness to start preventive intervention were largely similar between individuals at risk of RA and axSpA. Although the willingness to change lifestyle is high among at-risk individuals, most rheumatologists do not advise them to change their lifestyle. In contrast, rheumatologists are more willing than at-risk patients to start preventive medication.

Sustained remission with methotrexate monotherapy after 22-week induction treatment with TNF-alpha inhibitor and methotrexate in early psoriatic arthritis: an open-label extension of a randomized placebo-controlled trial.

BACKGROUND: If TNF inhibitors are initiated in the early stages of psoriatic arthritis, this could potentially modulate disease and therefore allow us to discontinue the TNF inhibitor after achieving remission. OBJECTIVE: To investigate whether remission induced by tumour necrosis factor alpha inhibitor (TNFi) and methotrexate in patients with early psoriatic arthritis is sustained after withdrawal of TNFi. METHODS: Open-label extension of a recently published double-blind, randomized placebo-controlled trial. Patients with psoriatic arthritis fulfilling the CASPAR criteria and with active disease at baseline (swollen and tender joint count ≥ 3) were randomized to either golimumab and methotrexate or matched placebo and methotrexate. Patients in Disease Activity Score (DAS) remission at week 22 continued in the open-label extension on methotrexate monotherapy. The primary end point was the percentage of patients in DAS-CRP remission (DAS < 1.6) at week 50. RESULTS: Eight patients from the original placebo group and 18 patients from the original TNFi group continued in the extension phase. At week 50, 6 out of 8 (75%) patients from the original MTX (methotrexate) group versus 10 out of 18 (56%) patients from the original MTX+TNFi group were in DAS-CRP remission (p = 0.347). Considering the total study population, 6 out of 24 (25%) of the original MTX group versus 10 out of 26 (38.5%) of the original MTX+TNFi group were in DAS remission at week 50 (p = 0.308). CONCLUSIONS: Remission achieved by initial combination treatment with TNFi and methotrexate in early psoriatic arthritis is maintained on methotrexate monotherapy in approximately half of the patients. TRIAL REGISTRATION: Registered at Clinicaltrials.gov with number NCT01871649 on June 7, 2013.

Achieving remission in psoriatic arthritis by early initiation of TNF inhibition: a double-blind, randomised, placebo-controlled trial of golimumab plus methotrexate versus placebo plus methotrexate.

OBJECTIVES: Early initiation of effective treatment favours remission in rheumatoid arthritis, but it remains unknown if the same concept applies to psoriatic arthritis (PsA). Therefore, this study investigated whether the combination of golimumab plus methotrexate (MTX) as a first-line treatment is superior to MTX alone in inducing remission in PsA. METHODS: This investigator-initiated, multicentre, double-blind, randomised, placebo-controlled trial included 51 MTX and bDMARD-naive patients with PsA fulfilling the CASPAR criteria and with active disease at baseline (≥3 swollen joint count/tender joint count). Patients were randomised to golimumab (50 mg SC monthly)+MTX (n=26) (TNFi arm) or matched placebo+MTX (n=25) (MTX arm). MTX was started 15 mg/week and increased to 25 mg/week over 8 weeks. The primary endpoint was percentage of patients achieving Disease Activity Score (DAS) remission (<1.6) at week 22. Safety was assessed throughout the study. RESULTS: The primary efficacy endpoint was achieved by 81% in the TNFi arm versus 42 % in the MTX arm (p=0.004). This difference in DAS remission was already observed at week 8. A significant difference in favour of the golimumab+MTX arm at week 22 was also observed for other response criteria such as MDA, ACR20/50/70, disease measures and patient-reported outcomes. The occurrence rates of adverse event and treatment-emergent adverse event were similar in both arms. CONCLUSIONS: In patients with early PsA, DAS remission at week 22 was almost doubled with golimumab+MTX versus MTX alone. This double-blind, randomised, placebo-controlled study supports the concept that early initiation of TNFi in patients with PsA favours remission. TRIAL REGISTRATION NUMBER: NCT01871649.

First-degree relatives of axial spondyloarthritis patients of the pre-SpA cohort would consider using medication in a preventive setting.

To study the willingness of first-degree relatives of axial spondyloarthritis (axSpA) patients to use preventive medication. First-degree relatives of HLA-B27-positive axSpA patients (pre-SpA cohort) (n = 106) completed a survey including scenarios varying in disease risk, side effects, and treatment effect of hypothetical preventive medication and questions about their perceived risk of developing SpA and assessment of the severity of SpA. The willingness to use preventive medication was 63.2-91.5% (with 30-70% SpA risk, respectively) and declined to 27.4-51.9% respectively, when side effects might occur. On a visual analogue scale (VAS) 0-100 mm (totally disagree-totally agree) (median;range), participants were not occupied by the thought of developing SpA (23;13-39), did not assume that they will eventually develop SpA (22;14-35), and consider SpA a severe disease (66;52-78). The willingness to use preventive medication was negatively influenced by their own risk assessment of developing SpA (OR = 1.17, p = .001) and was not primarily influenced by costs and route of administration. First-degree relatives of axSpA patients with a clearly increased disease risk (70%) would largely consider using preventive medication. Their willingness roughly halved by the possible occurrence of side effects. Participants' perceived risk to develop SpA and their assessment of the severity of SpA negatively influenced the willingness to use preventive medication.

The Engagement of the Pelvic Floor Muscles to the Urethra, Does Variation in Point of Action Exist?

Purpose: Lower urinary tract dysfunction (LUTD) occurs frequently in girls and may display a spinning top urethra (STU) on voiding cysto-urethrogram (VCUG) in case of dysfunctional voiding. A STU presents as a narrowing of the urethra caused by a lack of relaxation of the pelvic floor musculature during micturition and may vary in length between the proximal and the distal urethra. Although a STU has been recognized since 1960 as a pathological entity on VCUG, no reports exist on the different levels of engagement of the pelvic floor muscles to the urethra as expressed by the varying length of the phenomenon. The aim of our study is to demonstrate the wide anatomical variation in the level of engagement of the pelvic floor musculature to the urethra. Materials and Methods: Dynamic ultrasound videos of pelvic floor musculature of 40 girls with LUTD were reassessed by three observers, looking for the level of engagement of the puborectalis muscle (PRM) to the urethra during coughing, Valsalva and hold-up maneuver. Three levels were defined, for the level of engagement of the pelvic floor to the urethra, proximal, mid, and distal. Intra- and inter-rater variability was analyzed using Cohen's kappa statistics. Results: A wide range of points of action was found on the assessed ultrasound videos. Intra- and inter-rater agreement showed different levels of conformity, varying over a wide spectrum (intra-rater kappa 0.145-0.546; inter-rater kappa -0.1030.724). Throughout the assessed videos, all not-corresponding intra-rater observations differed maximal one category. Of the not-corresponding inter-rater observations, 90% differed maximal one category. Conclusion: An anatomical variation in levels of engagement of the PRM to the urethra does exist. The clinical value of this finding, whether the point of engagement influences symptomatology or treatment success of LUTD, is currently being studied.

Brief Report: Interleukin-17 Blockade With Secukinumab in Peripheral Spondyloarthritis Impacts Synovial Immunopathology Without Compromising Systemic Immune Responses.

OBJECTIVE: Secukinumab (anti-interleukin-17A [anti-IL-17A]) is an effective therapy for ankylosing spondylitis and psoriatic arthritis, the prototypical forms of spondyloarthritis (SpA). We undertook this study to determine whether secukinumab modulates the immunopathology of target lesions without blunting systemic immune responses, using peripheral SpA as a model. METHODS: Twenty patients with active peripheral SpA were included in a 12-week open-label trial with secukinumab (300 mg once weekly from baseline to week 4 and then every 4 weeks thereafter). Outcomes included clinical response, cytokine production by peripheral blood cells using TruCulture technology, and histologic and real-time quantitative polymerase chain reaction analysis of synovial biopsy samples before and after treatment. RESULTS: All patients completed the 12-week study without severe adverse events (AEs) or severe treatment-related AEs. The efficacy end point, the number of patients meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at 12 weeks, was achieved by 13 of the 20 patients, of whom 8 achieved an ACR50 response and 5 achieved an ACR70 response, with rapid and significant improvements in all clinical disease activity measures. Clinical improvement in joint counts was associated with a histologic decrease in synovial sublining macrophages (P = 0.028) and neutrophils (P = 0.004), both of which are sensitive synovial biomarkers of inflammatory response in peripheral SpA, as well as with decreased synovial expression of IL-17A messenger RNA (mRNA) (P = 0.010) but not of tumor necrosis factor mRNA. Systemically, secukinumab treatment decreased the C-reactive protein level and the erythrocyte sedimentation rate (both P < 0.01), and also decreased matrix metalloproteinase 3 production in the TruCulture system (P < 0.05). However, with the exception of IL-17A itself, the capacity of peripheral blood cells to produce a broad panel of cytokines and chemokines upon stimulation with microbial antigens was not affected. CONCLUSION: This mechanism-of-action study in peripheral SpA indicates that clinical improvement with secukinumab treatment is paralleled by immunomodulation of inflamed target tissues without compromising systemic immune responses.