Acute calcium pyrophosphate crystal arthritis is associated with an increased rate of hip and knee joint surgery.

OBJECTIVE: Acute calcium pyrophosphate (CPP) crystal arthritis is a distinct manifestation of calcium pyrophosphate crystal deposition (CPPD). No studies have specifically examined whether acute CPP crystal arthritis is associated with progressive structural joint damage. The objective of this retrospective cohort study was to evaluate the relative rate of hip and knee joint arthroplasties as an estimate of structural joint damage accrual, in a population of patients with acute CPP crystal arthritis. METHODS: Data were collected from Waikato District Health Board (WDHB) to identify an acute CPP crystal arthritis cohort with clinical episodes highly characteristic of acute CPP crystal arthritis. Data on hip and knee joint arthroplasties were collected from the New Zealand Orthopaedic Association's Joint Registry. The rate of arthroplasties in the cohort was compared with the age-ethnicity-matched New Zealand population. Additional analysis was performed for age, obesity (BMI) and ethnicity. RESULTS: The acute CPP crystal arthritis cohort included 99 patients; 63 were male and the median age was 77 years (interquartile range, 71-82). The obesity rate was 36% with a median BMI of 28.4 kg/m2 (interquartile range, 25.8-32.2), comparable to the New Zealand population. The standardized surgical rate ratio in the cohort vs the age-ethnicity-matched New Zealand population was 2.54 (95% CI: 1.39, 4.27). CONCLUSION: Our study identified a considerable increase in the rate of hip and knee joint arthroplasties in patients with episodes of acute CPP crystal arthritis. This suggests CPP crystal arthritis may be a chronic condition, leading to progressive joint damage.

Paraneoplastic sacroiliitis.

A man in his early 70s presented with stiffness and aching in the shoulder and pelvic girdles. His C reactive protein level was elevated at 116 mg/L, leading to an initial diagnosis of polymyalgia rheumatica. Treatment with prednisone at 20 mg/day provided limited improvement and relapses recurred despite concomitant immunosuppressive agents. Extensive investigations failed to reveal an underlying aetiology.Five years later, gross painless haematuria led to the detection of an invasive papillary urothelial carcinoma. A review of the staging CT scan revealed findings compatible with bilateral erosive sacroiliitis, which had developed since his initial presentation. Radical cystoprostatectomy provided temporary relief but after a further 9 months, symptoms relapsed, and metastatic spread was discovered.Paraneoplastic sacroiliitis is a rare clinical entity; and to the best of our knowledge, this is the first reported case associated with a solid tumour.

The 2023 ACR/EULAR Classification Criteria for Calcium Pyrophosphate Deposition Disease.

OBJECTIVE: Calcium pyrophosphate deposition (CPPD) disease is prevalent and has diverse presentations, but there are no validated classification criteria for this symptomatic arthritis. The American College of Rheumatology (ACR) and EULAR have developed the first-ever validated classification criteria for symptomatic CPPD disease. METHODS: Supported by the ACR and EULAR, a multinational group of investigators followed established methodology to develop these disease classification criteria. The group generated lists of candidate items and refined their definitions, collected de-identified patient profiles, evaluated strengths of associations between candidate items and CPPD disease, developed a classification criteria framework, and used multi-criterion decision analysis to define criteria weights and a classification threshold score. The criteria were validated in an independent cohort. RESULTS: Among patients with joint pain, swelling, or tenderness (entry criterion) whose symptoms are not fully explained by an alternative disease (exclusion criterion), the presence of crowned dens syndrome or calcium pyrophosphate crystals in synovial fluid are sufficient to classify a patient as having CPPD disease. In the absence of these findings, a score >56 points using weighted criteria, comprising clinical features, associated metabolic disorders, and results of laboratory and imaging investigations, can be used to classify as CPPD disease. These criteria had a sensitivity of 92.2% and specificity of 87.9% in the derivation cohort (190 CPPD cases, 148 mimickers), whereas sensitivity was 99.2% and specificity was 92.5% in the validation cohort (251 CPPD cases, 162 mimickers). CONCLUSION: The 2023 ACR/EULAR CPPD disease classification criteria have excellent performance characteristics and will facilitate research in this field.

The 2023 ACR/EULAR classification criteria for calcium pyrophosphate deposition disease.

OBJECTIVE: Calcium pyrophosphate deposition (CPPD) disease is prevalent and has diverse presentations, but there are no validated classification criteria for this symptomatic arthritis. The American College of Rheumatology (ACR) and EULAR have developed the first-ever validated classification criteria for symptomatic CPPD disease. METHODS: Supported by the ACR and EULAR, a multinational group of investigators followed established methodology to develop these disease classification criteria. The group generated lists of candidate items and refined their definitions, collected de-identified patient profiles, evaluated strengths of associations between candidate items and CPPD disease, developed a classification criteria framework, and used multi-criterion decision analysis to define criteria weights and a classification threshold score. The criteria were validated in an independent cohort. RESULTS: Among patients with joint pain, swelling, or tenderness (entry criterion) whose symptoms are not fully explained by an alternative disease (exclusion criterion), the presence of crowned dens syndrome or calcium pyrophosphate crystals in synovial fluid are sufficient to classify a patient as having CPPD disease. In the absence of these findings, a score>56 points using weighted criteria, comprising clinical features, associated metabolic disorders, and results of laboratory and imaging investigations, can be used to classify as CPPD disease. These criteria had a sensitivity of 92.2% and specificity of 87.9% in the derivation cohort (190 CPPD cases, 148 mimickers), whereas sensitivity was 99.2% and specificity was 92.5% in the validation cohort (251 CPPD cases, 162 mimickers). CONCLUSION: The 2023 ACR/EULAR CPPD disease classification criteria have excellent performance characteristics and will facilitate research in this field.

EULAR/eumusc.net standards of care for rheumatoid arthritis: cross-sectional analyses of importance, level of implementation and care gaps experienced by patients and rheumatologists across 35 European countries.

OBJECTIVE: As part of European League against Rheumatism (EULAR)/European Musculoskeletal Conditions Surveillance and Information Network, 20 user-focused standards of care (SoCs) for rheumatoid arthritis (RA) addressing 16 domains of care were developed. This study aimed to explore gaps in implementation of these SoCs across Europe. METHODS: Two cross-sectional surveys on the importance, level of and barriers (patients only) to implementation of each SoC (0-10, 10 highest) were designed to be conducted among patients and rheumatologists in 50 European countries. Care gaps were calculated as the difference between the actual and maximum possible score for implementation (ie, 10) multiplied by the care importance score, resulting in care gaps (0-100, maximal gap). Factors associated with the problematic care gaps (ie, gap≥30 and importance≥6 and implementation<6) and strong barriers (≥6) were further analysed in multilevel logistic regression models. RESULTS: Overall, 26 and 31 countries provided data from 1873 patients and 1131 rheumatologists, respectively. 19 out of 20 SoCs were problematic from the perspectives of more than 20% of patients, while this was true for only 10 SoCs for rheumatologists. Rheumatologists in countries with lower gross domestic product and non-European Union countries were more likely to report problematic gaps in 15 of 20 SoCs, while virtually no differences were observed among patients. Lack of relevance of some SoCs (71%) and limited time of professionals (66%) were the most frequent implementation barriers identified by patients. CONCLUSIONS: Many problematic gaps were reported across several essential aspects of RA care. More efforts need to be devoted to implementation of EULAR SoCs.

Soluble ST2 and CXCL-10 may serve as biomarkers of subclinical diastolic dysfunction in SLE and correlate with disease activity and damage.

OBJECTIVE: Subclinical myocardial dysfunction has been reported to occur early in systemic lupus erythematous (SLE). The study aim was to search for biomarkers of subclinical myocardial dysfunction which may correlate with disease activity in SLE patients. METHODS: This is a prospective, controlled, cross-sectional study of 57 consecutive patients with SLE and 18 controls. Serum samples were obtained to determine serum soluble ST2 (sST2), CXCL-10 and high-sensitivity troponin (hs-troponin) levels. All participants underwent an echocardiographic tissue Doppler study. RESULTS: sST2, CXCL-10 and hs-troponin levels were higher in patients with higher SLE disease activity (SLEDAI). sST2 and CXCL-10 levels were higher in patients with more disease damage as measured by the SLE damage index. Measures of diastolic dysfunction, as assessed by echocardiographic tissue Doppler negatively correlated with log CXCL-10: including E/A; E/e'lateral and E/e'septal, while E/e' positively correlated with CXCL-10. Diastolic dysfunction parameters also correlated with log sST2 levels, a negative correlation was seen with E/e'lateral and a positive correlation was seen with E/e'. Systolic dysfunction parameters positively correlated with hs-troponin: LVED, LVES, IVS, LVMASS and LVMASS index. In a multivariate analysis, sST2 and CXCL-10 were found to be significantly different in SLE vs. healthy controls, independent of each other and independent of cardiovascular risk factors. CONCLUSIONS: Soluble ST2 and CXCL-10 are markers of disease activity and accrued damage in SLE and may serve as sensitive biomarkers for detection of subclinical diastolic dysfunction, independent of traditional cardiovascular risk factors.

Immunogenicity and safety of vaccination against seasonal influenza vaccine in patients with psoriatic arthritis treated with secukinumab.

OBJECTIVE: To assess the immunogenicity and safety of vaccination against seasonal influenza in psoriatic arthritis (PsA) patients treated with secukinumab versus healthy controls (HC). METHODS: PsA patients administered secukinumab for ≥3 months and HC received the Sanofi Pasteur vaccine composed of 3 antigens (H3N3, H1N1, and B) and underwent clinical and laboratory assessments on the day of vaccination and 4-6 weeks later. Immunogenicity of the vaccine was evaluated by hemagglutination inhibition assay against those 3 antigens. Responders to each antigen were defined by a 4-fold increase in the antigen titer or by seroconversion in patients whose baseline level was <1/40. RESULTS: Thirty-two consecutive PsA patients treated with secukinumab for ≥3 months comprised the study group, 10 of whom received concomitant conventional synthetic disease-modifying drugs, mostly methotrexate. There were 17 age- and gender-matched HC (median age 48.5 years, 6 females). The geometric mean titers of each antigen increased significantly in both groups. The number of responders in each group was similar for H3N2 and H1N1, and significantly higher for B/Brisbane in the PsA group. The proportion of patients with a seroprotective level (a titer >1/40) was high and similar in both groups. There was no correlation between the response rate and age, gender, or selected parameters of disease activity (tender/swollen joint counts, Leeds enthesitis index, physician and patient global assessment, psoriasis area severity index, and C-reactive protein). No disease exacerbation was observed following the vaccination. No serious adverse effects were observed in both groups during the study period. CONCLUSION: Secukinumab treatment does not affect the humoral response to influenza vaccine of patients with PsA.

Prevalence of high-sensitivity cardiac troponin T in real-life cohorts of psoriatic arthritis and general population: a cross-sectional study.

Patients with psoriatic arthritis (PsA) are at increased risk of cardiovascular disease (CVD). High-sensitivity cardiac troponin T (hs-cTnT) is a novel biomarker of CVD. The objective of this study is to determine the prevalence of circulating hs-cTnT in patients with PsA compared to the general population and to characterize a PsA subset with detectable hs-cTnT. A cross-sectional analysis of serum hs-cTnT levels was performed in 116 consecutive patients with PsA and the Tel-Aviv Medical Center Inflammatory Survey cohort of the general population (n = 6052) as a control group. The level and prevalence of hs-cTnT (ng/L) were similar in the entire study population: 4.94 ± 4.4, 30.2% in PsA, 5.17 ± 6.7, 34.2% and 5.38 ± 4.3, 37.9% in unmatched and matched control groups according to age, gender and cardiovascular risk factors, respectively. Factors associated with detectable hs-cTnT in PsA included male gender (p = 0.002), age (p = 0.007), hypertension (p < 0.001), diabetes mellitus (p < 0.001), and smoking (p = 0.001). Axial disease, present in 25% of patients with PsA, was significantly associated with detectable hs-cTnT (p = 0.004). This association remained significant after adjusting for age, gender and traditional cardiovascular risk factors. No correlation between hs-cTnT levels and disease characteristics, PsA activity indices, C-reactive protein levels, or treatments for PsA was found. In summary, serum hs-cTnT was detectable in about the third of the PsA and control cohorts. In PsA, axial disease was significantly associated with detectable hs-TnT, warranting a particular attention to cardiovascular risk assessment in this sub-group. The role of hs-cTnT as a biomarker for CVD in PsA should be further investigated in prospective studies.

Adenine-(methoxy)-ethoxy-Pα,α-dithio-triphosphate inhibits pathologic calcium pyrophosphate deposition in osteoarthritic human chondrocytes.

Nucleotide pyrophosphatase/phosphodiesterase-1 (NPP1) inhibitors have been suggested as a potential treatment for calcium pyrophosphate dihydrate (CPPD) deposition disease. Here, we targeted the development of improved NPP1 inhibitors based on acyclic mimics of Pα,α-phosphorodithioate-substituted adenine nucleotides, 7-10. The latter were obtained in a facile two-step synthesis from adenine-(methoxy)ethanol. Among analogs 7-10, adenine-(methoxy)ethoxy-Pα,α-dithio-triphosphate, 8, was the most potent NPP1 inhibitor both with purified enzyme (IC50 0.645 µM) and in osteoarthritic human chondrocytes (IC50 0.033 µM). Furthermore, it efficaciously (10-fold vs. control) inhibited ATP-induced CPPD in human articular chondrocytes. Importantly, 8 was a highly selective NPP1 inhibitor which showed only minor inhibition of NPP3, CD39 and CD73, and did not inhibit TNAP (tissue nonspecific alkaline phosphatase) activity in human chondrocytes. Furthermore, 8 did not activate P2Y1,2,6 receptors. Analog 8 was not toxic to cultured chondrocytes at 100 µM. Therefore, 8 may be suitable for further development as a drug candidate for the treatment of CPPD arthritis and other NPP1-related diseases.

Structure-activity relationship study of NPP1 inhibitors based on uracil-N1-(methoxy)ethyl-ß-phosphate scaffold.

Overexpression of ecto-nucleotide pyrophosphatase-1 (NPP1) is associated with diseases such as calcium pyrophosphate dihydrate deposition disease, calcific aortic valve disease, and type 2 diabetes. In this context, NPP1 inhibitors are potential drug candidates for the treatment of these diseases. The present study focuses on the analysis of the structure-activity relationship of NPP1 inhibitors based on acyclic uracil-nucleotides. For this purpose, we synthesized acyclic uridine-monophosphate analogs, 10-11, uridine-diphosphate analogs, 12-14, and uridine-Pα,α-dithio-triphosphate analogs, 15-17. We evaluated their inhibitory activity and selectivity towards NPP1, -3, NTPDase1, -2, -3, and -8, and P2Y2,4,6 receptors. Analogs 16 and 17 were the most selective and potent NPP1 inhibitors (Ki 0.94 and 0.73 µM, respectively) among the tested molecules. Analogs 10-17 had only minute effect on uracil-nucleotide responding P2Y2,4,6 receptors. Analog 17 (100 µM) displayed 96% inhibition of NPPase activity in osteoarthritic human chondrocytes. Analogs 14-17 displayed weak inhibitory effect on alkaline phosphatase activity at equimolar concentrations in human chondrocytes. All tested analogs showed no toxicity at human chondrocytes. We concluded that ribose-ring to chain transformation, as well as the type of the nucleobase, are parameters of minor significance to NPP1 inhibition, whereas the major parameter is Pα-dithio-substitution. In addition, the length of the phosphate chain also significantly affects inhibition. Overall, the experimental results were well reproduced by molecular docking. A correlation was observed between the activities of the compounds and the number of H-bonds and salt bridges formed between the inhibitors and NPP1 binding site residues. Uracil-N1-(methoxy)ethyl-ß-Pα,α-dithio, Pß,γ-methylene tri-phosphate, 17, was identified as the most potent, selective, and non-toxic NPP1 inhibitor among the tested analogs, and may be used as a lead structure for further drug development.

Correction to: Identification of adenine-N9-(methoxy)ethyl-ß-bisphosphonate as NPP1 inhibitor attenuates NPPase activity in human osteoarthritic chondrocytes.

The original version of the article unfortunately contained an error.

Association of Serum Tocilizumab Trough Concentrations with Clinical Disease Activity Index Scores in Adult Patients with Rheumatoid Arthritis.

OBJECTIVE: To determine whether serum trough concentrations of tocilizumab (TCZ) administered as a fixed-dose subcutaneous (SC) injection for the treatment of rheumatoid arthritis (RA) are associated with disease activity responses. METHODS: We analyzed datasets from the Israeli branch of the multinational TOZURA study, which evaluated a weekly subcutaneous TCZ treatment regimen in a real-life clinical setting. Generalized estimating equations (GEE) were used to evaluate associations between the TCZ levels and the study outcomes. Linear models and GEE were used to evaluate associations between patient characteristics and TCZ levels. RESULTS: A significant association between the TCZ concentrations and the change in the Clinical Disease Activity Index (CDAI) score was observed. In a multivariate binary GEE model, every increase of 10 µg/ml in the concentration of TCZ was associated with being in a state of CDAI remission or low disease activity (OR 1.41) versus a moderate/high disease activity state. An OR of 1.52 was associated with being in a state of Health Assessment Questionnaire-Disability Index remission. In univariate linear models, there was an inverse association between body mass index (BMI) and improvement in the CDAI score, and the BMI score was associated with lower TCZ concentrations. Patients who weighed > 100 kg had lower TCZ concentrations. CONCLUSION: In the first 24 weeks of treatment with SC TCZ injections, TCZ concentrations were associated with clinical improvement, while body weight and BMI were inversely associated with TCZ concentrations. Personalizing the dose of SC TCZ to body weight may improve outcomes of clinical disease activity in patients with RA.

Identification of adenine-N9-(methoxy)ethyl-ß-bisphosphonate as NPP1 inhibitor attenuates NPPase activity in human osteoarthritic chondrocytes.

Overproduction of extracellular diphosphate due to hydrolysis of ATP by NPP1 leads to pathological calcium diphosphate (pyrophosphate) dihydrate deposition (CPPD) in cartilage, resulting in a degenerative joint disease that today lacks a cure. Here, we targeted the identification of novel NPP1 inhibitors as potential therapeutic agents for CPPD deposition disease. Specifically, we synthesized novel analogs of AMP (NPP1 reaction product) and ADP (NPP1 inhibitor). These derivatives incorporate several chemical modifications of the natural nucleotides including (1) a methylene group replacing the Pα,ß-bridging oxygen atom to provide metabolic resistance, (2) sulfonate group(s) replacing phosphonate(s) to improve binding to NPP1's catalytic zinc ions, (3) an acyclic nucleotide analog to allow flexible binding in the NPP1 catalytic site, and (4) a benzimidazole base replacing adenine. Among the investigated compounds, adenine-N9-(methoxy)ethyl-ß-bisphosphonate, 10, was identified as an NPP1 inhibitor (Ki 16.3 µM vs. the artificial substrate p-nitrophenyl thymidine-5'-monophosphate (p-Nph-5'-TMP), and 9.60 µM vs. the natural substrate, ATP). Compound 10 was selective for NPP1 vs. human NPP3, human CD39, and tissue non-specific alkaline phosphatase (TNAP), but also inhibited human CD73 (Ki 12.6 µM). Thus, 10 is a dual NPP1/CD73 inhibitor, which could not only be of interest for treating CPPD deposition disease and calcific aortic valve disease but may also be considered for the immunotherapy of cancer. Compound 10 proved to be a promising inhibitor, which almost completely reduces NPPase activity in human osteoarthritic chondrocytes at a concentration of 100 µM.

Inhibition of nucleotide pyrophosphatase/phosphodiesterase 1: implications for developing a calcium pyrophosphate deposition disease modifying drug.

Objectives: Calcium pyrophosphate deposition (CPPD) is associated with osteoarthritis and is the cause of a common inflammatory articular disease. Ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (eNPP1) is the major ecto-pyrophosphatase in chondrocytes and cartilage-derived matrix vesicles (MVs). Thus, eNPP1 is a principle contributor to extracellular pyrophosphate levels and a potential target for interventions aimed at preventing CPPD. Recently, we synthesized and described a novel eNPP1-specific inhibitor, SK4A, and we set out to evaluate whether this inhibitor attenuates nucleotide pyrophosphatase activity in human OA cartilage. Methods: Cartilage tissue, chondrocytes and cartilage-derived MVs were obtained from donors with OA undergoing arthroplasty. The effect of SK4A on cell viability was assayed by the XTT method. eNPP1 expression was evaluated by western blot. Nucleotide pyrophosphatase activity was measured by a colorimetric assay and by HPLC analysis of adenosine triphosphate (ATP) levels. ATP-induced calcium deposition in cultured chondrocytes was visualized and quantified with Alizarin red S staining. Results: OA chondrocytes expressed eNPP1 in early passages, but this expression was subsequently lost upon further passaging. Similarly, significant nucleotide pyrophosphatase activity was only detected in early-passage chondrocytes. The eNPP1 inhibitor, SK4A, was not toxic to chondrocytes and stable in culture medium and human plasma. SK4A effectively inhibited nucleotide pyrophosphatase activity in whole cartilage tissue, in chondrocytes and in cartilage-derived MVs and reduced ATP-induced CPPD. Conclusion: Nucleotide analogues such as SK4A may be developed as potent and specific inhibitors of eNPP1 for the purpose of lowering extracellular pyrophosphate levels in human cartilage with the aim of preventing and treating CPPD disease.

Expression levels of selected genes can predict individual rheumatoid arthritis patient response to tumor necrosis factor alpha blocker treatment.

OBJECTIVES: Rheumatoid arthritis (RA) patients have many therapeutic options; however, tools to predict individual patient response are limited. The Genefron personal diagnostic kit, developed by analyzing large datasets, utilizes selected interferon stimulated gene expressions to predict treatment response. This study evaluates the kit's prediction accuracy of individual RA patients' response to tumor necrosis alpha (TNFα) blockers. METHODS: A retrospective analysis was performed on RA patients reported in published datasets. A prospective analysis assessed RA patients, before and 3 months after starting a TNFα blocker. Clinical response was evaluated according to EULAR response criteria. Blood samples were obtained before starting treatment and were analyzed utilizing the kit which measures expression levels of selected genes by quantitative real time polymerase chain reaction (PCR). ROC analysis was applied to the published datasets and the prospective data. RESULTS: The Genefron kit analysis of retrospective data predicted the response to a TNFα blocker in 53 of 61 RA patients (86.8% accuracy). In the prospective analysis, the kit predicted the response in 16 of 18 patients (89% accuracy) achieving a EULAR moderate response, and in 15 of 18 patients achieving a EULAR good response (83.3% accuracy). ROC analysis applied to the two published datasets yielded an AUC of 0.89. ROC analysis applied to the prospective data yielded an AUC of 0.83 (sensitivity - 100%, specificity - 75%) The statistical power obtained in the prospective study was .9. CONCLUSION: The diagnostic kit predicted the response to TNFα blockers in a high percentage of patients assessed retrospectively or prospectively. This personal kit may guide selection of a suitable biological drug for the individual RA patient.

Magnetic resonance imaging in diffuse idiopathic skeletal hyperostosis: similarities to axial spondyloarthritis.

Diffuse idiopathic skeletal hyperostosis (DISH) is a non-inflammatory condition that involves calcification and ossification of the spinal ligaments and entheses. While, characteristic magnetic resonance imaging (MRI) lesions of the spine in patients with axial spondyloarthritis, another enthesitis-related disease, have been described and defined, there is a paucity of information regarding the MRI findings in DISH. The aim of this study was to describe the MRI findings of patients with DISH. We collected computed tomography studies with findings characteristic of DISH and that also had corresponding and concurrent MRI studies of the spine. For each patient, sagittal T1-weighted and STIR MRI sequences were evaluated for anterior/posterior vertebral corners of bone marrow edema (BME) and fat deposition. In total, we assessed 156 vertebral units in 10 patients that had both radiographic evidence of DISH and available MRI studies of the spine. Lesions consistent with BME corners were detected in five patients, and in three of them, three separate sites were involved, a finding that is suggestive of axial spondyloarthritis (SpA) according to the ASAS/OMERACT consensus statement. Fat deposition corners were detected in eight patients and in seven of them, several sites were involved. Spinal MRI lesions that are characteristic of axial SpA were commonly observed in a cohort of patients with DISH. This bears relevance to cases with diagnostic uncertainty and may imply overlapping pathogenetic mechanisms for new bone formation in both SpA and DISH. Further study is indicated to better characterize the similarities and differences between the MRI lesions of DISH and SpA.

Harnessing the natural inhibitory domain to control TNFα Converting Enzyme (TACE) activity in vivo.

Dysregulated activity of A Disintegrin And Metalloproteinase 17 (ADAM17)/TNFα Converting Enzyme (TACE) is associated with inflammatory disorders and cancer progression by releasing regulatory membrane-tethered proteins like TNFα, IL6R and EGFR ligands. Although specific inhibition of TACE is thought to be a viable strategy for inflammatory disorders and for malignancies treatment, the generation of effective inhibitors in vivo has been proven to be challenging. Here we report on the development of a protein inhibitor that leverages the endogenous modulator of TACE. We have generated a stable form of the auto-inhibitory TACE prodomain (TPD), which specifically inhibits in vitro and cell-surface TACE, but not the related ADAM10, and effectively modulated TNFα secretion in cells. TPD significantly attenuated TACE-mediated disease models of sepsis, rheumatoid arthritis (RA) and inflammatory bowel disease (IBD), and reduced TNFα in synovial fluids from RA patients. Our results demonstrate that intervening with endogenous ADAM sheddase modulatory mechanisms holds potential as a general strategy for the design of ADAM inhibitors.

Longterm Efficacy of an Antipneumococcal Polysaccharide Vaccine among Patients with Autoimmune Inflammatory Rheumatic Diseases.

OBJECTIVE: To estimate the longterm humoral response of an antipneumococcal polysaccharide vaccine (PPSV23) in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), or inflammatory bowel disease (IBD)-associated spondyloarthropathy (SpA), and the effect of demographic and clinical factors and treatment on the longterm efficacy of the vaccine. METHODS: A total of 145 consecutive patients treated with biologics [tumor necrosis factor-α (TNF-α) or interleukin 6 (IL-6) receptor inhibitors] or methotrexate (MTX) participated in this study. Fifteen were excluded because of absent information regarding their vaccination status (n = 9) or because of technical problems in obtaining their serum sample (n = 6). They were diagnosed with RA (n = 63, 48.5%), PsA (n = 29, 22.3%), AS (n = 28, 21.5%), or IBD-associated SpA (n = 3, 2.3%). Their mean age was 54.6 years, and 61.5% were women. Data were collected on the timing of vaccination, demographic and clinical characteristics, and treatment, and patients' serum antipneumococcal antibody levels were tested. RESULTS: Two-thirds of the patients (67.7%) had received PPSV23 45 months (mean) earlier. Treatment included TNF-α inhibitors (73.9%), IL-6 receptor inhibitors (13.1%), or MTX without a biological treatment (13%). The uptake of vaccination was significantly higher in the older population (> 65 yrs). Vaccinated patients had significantly higher antibody levels compared with vaccine-naive patients. The antibody levels had been preserved after 10 years. MTX use, but not biologics, was associated with significantly lower antibody levels. CONCLUSION: The longterm efficacy of the PPSV23 vaccination seems to be preserved among patients with RA, PsA, AS, and IBD-associated SpA for at least 10 years. Efficacy is slightly impaired by MTX, but it is not affected by biologics. These findings suggest that revaccination after 5 years might not be needed for all, and testing the antibody titers should be considered to identify those who may benefit from revaccination.

Ultrasound assessment of enthesis thickening in psoriatic arthritis patients treated with adalimumab compared to methotrexate.

The objective of the study was to combine ultrasonographic (US) with clinical findings for comparing the effect of adalimumab (ADA) to methotrexate (MTX) on the thickness of tendons and enthesis in psoriatic arthritis (PsA) patients. Forty-three consecutive PsA patients were examined at baseline and after 6 and 12 weeks of treatment with ADA or MTX. The US assessment included thickness measurement of the extensor (ET) and flexor tendons (FT) of the second and third finger of both hands, plantar aponeurosis (PA) and the Achilles tendon (AT) bilaterally. Disease activity (DA) was assessed by the number of tender (TJ) and swollen joints (SJ), the number of inflamed enthesis (IE), pain assessment (PAI), and patient (PDAI) and physician (PHDAI) disease activity evaluations by visual activity score (VAS). Nineteen patients received MTX and 24 patients received ADA. All DA parameters improved in both groups. A decrease in thickness of tendons and enthesis was observed only in the ADA group, reaching a level of significance for the left AT (p = 0.01), left PA (p = 0.007), the second left FT (p = 0.04) and the third ET (p = 0.04). ADA patients showed a trend towards a better response to treatment compared to MTX patients that reach significance at week 6 of treatment for the thickness of left AT (p = 0.04), left PA (p = 0.03), the number of TJ (p = 0.0136), PAI (p = 0.0028), and PDAI (p = 0.029). ADA treatment for PsA compared to MTX significantly improved signs of DA and several US parameters. US assessment of enthesis can be an additional useful tool in the monitoring of psoriatic enthesopathy.

Immunogenicity and safety of vaccination against seasonal 2012 influenza virus among patients with psoriatic arthritis and psoriasis.

OBJECTIVES: We aimed to assess the immunogenicity and safety of vaccination against seasonal influenza in psoriatic arthritis (PsA) and psoriasis (Pso) patients. METHODS: Patients with PsA or Pso and healthy controls were vaccinated with the Sanofi Pasteur vaccine recommended by the WHO in 2012. Clinical and laboratory assessments were performed on the day of the vaccination and 4-6 weeks later. The immunogenicity of the vaccine was evaluated by haemagglutination inhibition assay. RESULTS: The study included 63 consecutive PsA patients and 4 Pso patients (mean age 50.1, 37 females, 30 males, 55.2% treated with tumour necrosis factor alpha blockers [TNF-α], 31.3% on disease-modifying anti-rheumatic drugs [DMARDs]) and 30 healthy controls. The geometric mean titers increased significantly in all participants for each of the subtypes tested. A substantial and similar proportion of patients in both groups responded to the vaccine. The response rate was not affected by parameters such as age, gender, disease activity or the use of TNF-α blockers or DMARDs. There were no significant changes in the patients' 68 tender and 66 swollen joint counts, dactylitis, PASI, global evaluation of the patient and physician and ESR, while there was a rise in CRP levels. CONCLUSIONS: Vaccination against seasonal influenza is safe and induces an appropriate response in patients with PsA, similar to healthy controls.