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Objective Investigate effects of gender on disease characteristics and treatment impact in patients with psoriatic arthritis (PsA). Methods PsABio is a non-interventional European study in patients with PsA starting a biological disease-modifying anti-rheumatic drug (bDMARD; ustekinumab or tumour necrosis factor inhibitor [TNFi]). This post-hoc analysis compared persistence, disease activity, patient-reported outcomes and safety between male and female patients at baseline and 6 and 12 months of treatment. Results At baseline, disease duration was 6.7 and 6.9 years for 512 females and 417 males respectively. Mean (95% CI) scores for females versus males were: clinical Disease Activity Index for Psoriatic Arthritis (cDAPSA), 32.3 (30.3;34.2) versus 26.8 (24.8;28.9); Health Assessment Questionnaire-Disability Index (HAQ-DI), 1.3 (1.2;1.4) versus 0.93 (0.86;0.99); total Psoriatic Arthritis Impact of Disease-12 (PsAID-12) score, 6.0 (5.8;6.2) versus 5.1 (4.9;5.3), respectively. Improvements in scores were smaller in female than male patients. At 12 months, 175/303 (57.8%) female and 212/264 (80.3%) male patients achieved cDAPSA low disease activity, 96/285 (33.7%) and 137/247 (55.5%), achieved minimal disease activity (MDA), respectively. HAQ-DI scores were 0.85 (0.77;0.92) versus 0.50 (0.43;0.56), PsAID-12 scores 3.5 (3.3;3.8) versus 2.4 (2.2;2.6), respectively. Treatment persistence was lower in females than males (p = Conclusions Before starting bDMARDs, females had more severe disease than males and a lower percentage reached favourable disease states, with lower persistence of treatment after 12 months. A better understanding of the mechanisms underlying these differences may improve therapeutic management in females with PsA. Trial registration ClinicalTrials.gov, https://clinicaltrials.gov, NCT02627768

Purpose As bone formation is associated with psoriatic arthritis (PsA), positron emission tomography (PET) using a 18F-Fluoride tracer may enable sensitive detection of disease activity. Our primary aim was to determine the feasibility of whole-body 18F-sodium fluoride PET-CT in clinically active PsA patients to depict new bone formation (as a reflection of disease activity) at peripheral joints and entheses. Our secondary aim was to describe 18F-sodium fluoride findings in the axial skeleton. Methods Sixteen patients (female 10/16, age 50.6 ± 8.9 years) with PsA fulfilling CASPAR criteria or with a clinical diagnosis of PsA according to the treating rheumatologist and with ≥ 1 clinically active enthesitis site were included. Of each patient, a whole-body 18F-sodium fluoride PET-CT scan was performed. All scans were scored for PET-positive lesions at peripheral joints, enthesis sites and the spine. Clinical disease activity was assessed by swollen/tender joint count 44, enthesitis according to MASES and SPARCC scores. Results Out of 1088 evaluated joints, 109 joints showed PET enhancement, mainly in the interphalangeal and metatarsal joints of the feet (14/109, 12.9%) and the distal interphalangeal joints of the hands (14/109, 12.9%). PET positivity was found at 44/464 enthesis sites, mainly at the patella tendon insertion (11/44, 25%) and quadriceps tendon insertion (10/44, 22.7%). Of the PET-positive joints and enthesis sites, respectively 18.2% and 29.5% were clinically positive; 81.8% and 70.5% of the PET-positive joints and entheses respectively were clinically asymptomatic. In 11 patients, ≥ 1 axial PET-positive lesion was observed, mainly in the cervical spine. Conclusions New molecular bone formation was observed on 18F-sodium fluoride PET-CT scans, in all domains in which PsA disease activity can be observed, with a substantial part showing no clinical symptoms. Clinical trial registration EudraCT: 2017-004,850-40, registered on 13 December 2017.

ObjectivesEarly 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.MethodsThis 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 (ResultsThe 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.ConclusionsIn 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 numberNCT01871649.

We read with great interest, the work of Goncalves et al 1 submitted in response to our article,2 comparing potential treatment targets for patients with psoriatic arthritis in real world data. Our study showed considerable overlap between these targets, whether or not they included a laboratory measure of inflammation such as a C reactive protein (CRP). We concluded that ‘Inclusion of laboratory markers seems unnecessary’. This Brazilian study also used data from a real-life clinic cohort rather than a randomised controlled trial setting but only compared the two versions of the disease activity in PsA (DAPSA), with or without …

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 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.

International audience; 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.

We thank the authors for the interest in our paper and are grateful for the opportunity to respond to the points raised.1 We agree that there is a clear distinction between composite measures of psoriatic arthritis such as disease activity in PsA (DAPSA) and composite measures of psoriatic disease such as minimal or very low disease activity (MDA/VLDA) and the PsA disease activity score (PASDAS). As the Vienna group rightly point out, these measures differ in terms of the components included, but not due to disagreement within the outcome measure community as suggested in the letter. The choice of components for each composite measure was decided using different methodology in the development of each one, thus resulting in different measures. We believe that this variation in scores is one reason for the need to compare such scores in different populations to establish the optimal measure or measures for psoriatic arthritis (PsA). Indeed when the DAPSA was originally suggested, it was because the same components used in the disease activity in reactive arthritis (DAREA) were identified in a principal component analysis (PCA) in PsA. Interestingly in this analysis, the variables tested were taken from the Outcome mesaures in Rheumatology (OMERACT) PsA domains and therefore DAPSA was not, a priori, designed specifically to be a unidimensional composite measure. The fourth component identified in the PCA was the psoriasis area and severity index (PASI) highlighting the importance of skin in PsA despite the fact that patients had a low baseline mean PASI of only 3.3. While PASI was not included in the DAPSA as the eigenvalue was 0.949 and therefore just under the threshold of 1,2 it is interesting to imagine how the results may have differed if …

Objective.Physician’s global assessment (PGA) of disease activity is a major determinant of therapeutic decision making. This study assesses the reliability of the PGA, measured by means of 0–100 mm visual analog scale (VAS), and the additional use of separate VAS scales for musculoskeletal (PhysMSK) and dermatologic (PhysSk) manifestations in patients with psoriatic arthritis (PsA).Methods.Sixteen centers from 8 countries enrolled 319 consecutive patients with PsA. PGA, PhysMSK, and PhysSk evaluation forms were administered at enrollment (W0) and after 1 week (W1). Detailed clinical data regarding musculoskeletal (MSK) manifestations, as well as dermatological assessment, were recorded.Results.Comparison of W0 and W1 scores showed no significant variation (intraclass correlation coefficients were PGA 0.87, PhysMSK 0.86, PhysSk 0.78), demonstrating the reliability of the instrument. PGA scores were dependent on PhysMSK and PhysSk (p < 0.0001) with a major effect of the MSK component (B = 0.69) compared to skin (B = 0.32). PhysMSK was correlated with the number of swollen joints, tender joints, and presence of dactylitis (p < 0.0001). PhysSk scores were correlated with the extent of skin psoriasis and by face, buttocks or intergluteal, and feet involvement (p < 0.0001). Finally, physician and patient assessments were compared showing frequent mismatch and a scattered dot plot: PGA versus patient’s global assessment (r = 0.36), PhysMSK versus patient MSK (r = 0.39), and PhysSk versus patient skin (r = 0.49).Conclusion.PGA assessed by means of VAS is a reliable tool to assess MSK and dermatological disease activity. PGA may diverge from patient self-evaluation. Because MSK and skin/nail disease activity may diverge, it is suggested that both PhysMSK and PhysSk are assessed.

Background With expanding therapeutic possibilities for treatment of psoriatic arthritis (PsA) it will be increasingly important to determine residual disease and define when to adjust treatment. The rationale behind treatment decisions in current daily clinical practice and the relationship with residual disease activity has not been investigated. The aim of this study was to assess current clinical practice on defining residual disease and subsequent treatment decisions made in PsA patients. Methods This cross-sectional study scored disease activity and treatment decisions prospectively in 142 consecutive PsA patients visiting the outpatient clinic for routine follow up. Disease activity parameters were scored by patient and the treating rheumatologist; the rheumatologist additionally registered his opinion on the presence of remaining disease activity despite current treatment (further mentioned as remaining disease) and subsequent treatment decisions. Results Two thirds (90/142) of patients had remaining disease activity according to the treating rheumatologist. Almost half (46%) of these patients had moderate to high disease activity according to the clinical Disease Activity Index for Psoriatic Arthritis (cDAPSA). Residual disease activity was determined by joint disease and pain rather than by active psoriasis. Demographic and clinical features were similar between groups with or without residual disease. Among patients with remaining disease activity, 74% were treated with either a conventional synthetic disease-modifying anti-rheumatic drug (csDMARD) only or a first TNF-inhibiting biological agent, suggesting opportunities for treatment modification. However, treatment adjustment was initiated in only 21 (23%) of the 90 patients with residual disease. When comparing patients with remaining disease activity with and without treatment adjustment, we found no differences in objective disease activity measures, such as joint counts and patient scores. These data suggest that treatment is not adjusted in a large majority of patients with residual disease activity, although options for treatment changes are available. Conclusions Remaining disease activity is present in almost two thirds of patients with PsA when scored by the treating rheumatologist, but triggers treatment adjustment in only a minority. Further research to understand why disease activity does not lead to treatment adjustment is required to enable implementation of treatment strategies in clinical practice.

Objective Biological therapies, which include antitumour necrosis factor-α and T-cell inhibitors, are potentially effective treatments for psoriatic arthritis (PsA) but are costly and may induce a number of side effects. Response to treatment in PsA is variable and difficult to predict. Here, we sought to identify a panel of protein biomarkers that could be used to predict which patients diagnosed with PsA will respond to biologic treatment. Methods An integrated discovery to targeted proteomics approach was used to investigate the protein profiles of good and non-responders to biological treatments in patients with PsA. Reverse-phase liquid chromatography coupled to tandem mass spectrometry was used to generate protein profiles of synovial tissue obtained at baseline from 10 patients with PsA. Targeted proteomics using multiple reaction monitoring (MRM) was used to confirm and prevalidate a potential protein biomarker panel in 18 and 7 PsA patient samples, respectively. Results A panel of 107 proteins was selected, and targeted mass spectrometry MRM assays were successfully developed for 57 of the proteins. The 57 proteins include S100-A8, S100-A10, Ig kappa chain C fibrinogen-α and γ, haptoglobin, annexin A1 and A2, collagen alpha-2, vitronectin, and alpha-1 acid glycoprotein. The proteins were measured simultaneously and confirmed to be predictive of response to treatment with an area under the curve of 0.76. In a blinded study using a separate cohort of patients, the panel was able to predict response to treatment. Conclusions The approach reported here and the initial data provide evidence that a multiplexed protein assay of a panel of biomarkers that predict response to treatment could be developed. Trial registration number ISRCTN23328456.

Objective.Serum 14-3-3η is a novel joint-derived proinflammatory mediator implicated in the pathogenesis of rheumatoid arthritis (RA). In our study, we assessed the diagnostic utility of 14-3-3η and its association with standard clinical and serological measures.Methods.A quantitative ELISA was used to assess 14-3-3η levels. Early (n = 99) and established patients with RA (n = 135) were compared to all controls (n = 385), including healthy subjects (n = 189). The sensitivity, specificity, positive and negative predictive values of 14-3-3η, and the likelihood ratios (LR) for RA were determined through receiver-operator curve analysis. The incremental value of adding 14-3-3η to anticitrullinated protein antibody (ACPA) and rheumatoid factor (RF) in diagnosing early and established RA was assessed.Results.Serum 14-3-3η differentiated established patients with RA from healthy individuals and all controls (p < 0.0001). A serum 14-3-3η cutoff of ≥ 0.19 ng/ml delivered a sensitivity and specificity of 77% and 93%, respectively, with corresponding LR positivity of 10.4. At this cutoff in early RA, 64% of patients with early RA were positive for 14-3-3η, with a corresponding specificity of 93% (LR+ of 8.6), while 59% and 57% were positive for ACPA or RF, respectively. When ACPA, RF, and 14-3-3η positivity were used in combination, 77 of the 99 patients (78%) with early RA were positive for any 1 of the 3 markers. Serum 14-3-3η did not correlate with C-reactive protein, erythrocyte sedimentation rate, or Disease Activity Score, but patients who were 14-3-3η-positive had significantly worse disease.Conclusion.Serum 14-3-3η is a novel RA mechanistic marker that is highly specific, associated with worse disease, and complements current markers, enabling a more accurate diagnosis of RA.

PurposePsoriatic arthritis is a systemic inflammatory and chronic autoimmune disorder that can be treated using biologic therapies that involves targeting of biomolecules such as tumour necrosis factor alpha (TNF-α), interleukins (IL) IL-17 and IL-23. Although 70% psoriatic arthritis patients who receive the TNF-α therapy respond well and get treated successfully, however 30% of patients show either no response or limited clinical improvement. Biomarkers that could predict response to anti-TNF-α therapy in individual patients would help to avoid unnecessary use of expensive biologics in potentially non-responding patients where they are unlikely to be effective. This would enable alternative treatments targeting other biologics to be explored within the relatively narrow (timeframe) window of therapeutic opportunity available. Experimental designPatient synovial tissue samples from two clinical studies were used for (Difference In Gel Electrophoresis) gel-based proteomics to identify changes in protein expression in response to anti-TNF-α treatment. Subsequently multiplexed multiple-reaction-monitoring (MRM) measurements were used to support verification of potential biomarkers.ResultsA number of differences in synovial protein expression were observed between patients who responded or did not respond to anti-TNF-α alpha treatment. A total of 119 protein spots changed significantly (p

Background: There is a need for biomarkers to screen the effectiveness of (novel) therapeutic agents for psoriasis at an early stage. Objective: We aimed to determine which of the changes in psoriatic skin correlates best with clinical improvement 4 weeks after effective adalimumab therapy. Methods: Twenty-two psoriatic arthritis patients were randomized to receive adalimumab or placebo. T cell numbers and markers of innate immunity were estimated in lesional and nonlesional skin biopsies at baseline and after 4 weeks of treatment. Results: CD161+ and elastase+ dermal cells in lesional skin were significantly reduced upon 4 weeks of successful adalimumab treatment compared with placebo. Conclusion: Early improvement of psoriasis lesions during adalimumab therapy is associated with a marked reduction of infiltrated dermal CD161+ T cells and elastase+ neutrophils, suggesting that these parameters could be used as biomarkers to monitor early changes after active treatment in small proof-of-concept studies of short duration.

Objective To investigate the safety, tolerability, pharmacokinetics, and efficacy of apilimod mesylate, an oral interleukin-12 (IL-12)/IL-23 inhibitor, in patients with rheumatoid arthritis (RA). Methods We performed a phase IIa, randomized, double-blind, placebo-controlled proof-of-concept study of apilimod, in combination with methotrexate, in 29 patients with active RA (3:1 ratio of apilimod-treated to placebo-treated patients) in 3 stages. Patients received apilimod 100 mg/day or placebo for 4 weeks (stage 1) or 8 weeks (stage 2). In stage 3, patients received apilimod 100 mg twice a day or placebo for 8 weeks, with an optional extension of 4 weeks. Clinical response (Disease Activity Score in 28 joints [DAS28] and American College of Rheumatology [ACR] criteria) was assessed throughout; synovial tissue samples collected at baseline and on day 29 (stages 1 and 2) or day 57 (stage 3) were stained for cellular markers and cytokines for immunohistochemistry analysis. Results While only mild adverse events were observed in stages 1 and 2, in stage 3, all patients experienced headache and/or nausea. Among apilimod-treated patients (100 mg/day), there was a small, but significant, reduction in the DAS28 on day 29 and day 57 compared with baseline. ACR20 response was reached in only 6% of patients on day 29 and 25% of patients on day 57, similar to the percentage of responders in the placebo group. Increasing the dosage (100 mg twice a day) did not improve clinical efficacy. Consistent with clinical results, apilimod did not have an effect on expression of synovial biomarkers. Of importance, we also did not observe an effect of apilimod on synovial IL-12 and IL-23 expression. Conclusion Our results do not support the notion that IL-12/IL-23 inhibition by apilimod is able to induce robust clinical improvement in RA.

ObjectiveC-C chemokine receptor type 5 (CCR5), a chemokine receptor expressed on T cells and macrophages, and its ligands are found in inflamed synovial tissue (ST) of patients with rheumatoid arthritis (RA). The rationale for testing CCR5 blockade in patients with RA was supported by the effects of a CCR5 antagonist in collagen-induced arthritis in rhesus monkeys. The effects of CCR5 blockade in patients with active RA were explored.MethodsIn this phase Ib randomised, placebo-controlled trial, treatment with an oral CCR5 inhibitor (SCH351125) in patients with active RA was evaluated. Clinical efficacy was assessed using European League Against Rheumatism and American College of Rheumatology response criteria. ST biopsies were taken before and after 28 days of treatment, and analysed for CCR5+ cells. In a subset of patients, MRIs of an inflamed joint were obtained before and after treatment.ResultsIn all, 32 patients were included; 20 received SCH351125 and 12 placebo. Three patients who received SCH351125 did not complete the study due to adverse events; none of these were serious. No improvement was observed in the active treatment group compared to placebo. Results were consistent for clinical evaluation, ST analysis and MRI.ConclusionThis proof of concept study does not support the use of CCR5 blockade as a therapeutic strategy in patients with active RA.

Objective Some patients with rheumatoid arthritis (RA) exhibit lymphocyte aggregates in the synovium. This study was undertaken to address whether the presence of lymphocyte aggregates before treatment could serve as a biomarker for the clinical response to tumor necrosis factor (TNF) blockade, and to confirm whether the aggregation of synovial lymphocytes is reversible after anti-TNF treatment. Methods Synovial tissue biopsy samples were obtained from 97 patients with active RA before the initiation of infliximab treatment. Lymphocyte aggregates in the synovial tissue were counted and also graded for size. Logistic regression analysis was performed to identify whether the presence of lymphocyte aggregates could be a predictor of the clinical response at week 16. Furthermore, the effects of TNF blockade on lymphocyte aggregates were compared between patients with RA and patients with psoriatic arthritis (PsA). Results Fifty-seven percent of RA synovial tissue samples contained lymphocyte aggregates, and 32% of the patients had large aggregates. Aggregates were found in 67% of clinical responders compared with 38% of nonresponders. The presence of aggregates at baseline was a highly significant predictor of the clinical response to anti-TNF treatment (R2 = 0.10, P = 0.008). Positivity for lymphocyte aggregates increased the power to predict the clinical response (R2 = 0.29), when analyzed in a prediction model that included baseline disease activity evaluated by the Disease Activity Score in 28 joints, anti–cyclic citrullinated peptide antibody positivity, and synovial TNFα expression. There was a reduction in lymphocyte aggregates after anti-TNF antibody therapy in both RA and PsA. Conclusion RA patients with synovial lymphocyte aggregates have, on average, a better response to infliximab treatment than those with only diffuse leukocyte infiltration. Moreover, the aggregation of synovial lymphocytes is reversible after anti-TNF antibody treatment.

Objective.To describe the expression and diagnostic use of 14-3-3η autoantibodies in early rheumatoid arthritis (RA).Methods.14-3-3η autoantibody levels were measured using an electrochemiluminescent multiplexed assay in 500 subjects (114 disease-modifying antirheumatic drug-naive patients with early RA, 135 with established RA, 55 healthy, 70 autoimmune, and 126 other non-RA arthropathy controls). 14-3-3η protein levels were determined in an earlier analysis. Two-tailed Student t tests and Mann-Whitney U tests compared differences among groups. Receiver-operator characteristic (ROC) curves were generated and diagnostic performance was estimated by area under the curve (AUC), as well as specificity, sensitivity, and likelihood ratios (LR) for optimal cutoffs.Results.Median serum 14-3-3η autoantibody concentrations were significantly higher (p < 0.0001) in patients with early RA (525 U/ml) when compared with healthy controls (235 U/ml), disease controls (274 U/ml), autoimmune disease controls (274 U/ml), patients with osteoarthritis (259 U/ml), and all controls (265 U/ml). ROC curve analysis comparing early RA with healthy controls demonstrated a significant (p < 0.0001) AUC of 0.90 (95% CI 0.85–0.95). At an optimal cutoff of ≥ 380 U/ml, the ROC curve yielded a sensitivity of 73%, a specificity of 91%, and a positive LR of 8.0. Adding 14-3-3η autoantibodies to 14-3-3η protein positivity enhanced the identification of patients with early RA from 59% to 90%; addition of 14-3-3η autoantibodies to anticitrullinated protein antibodies (ACPA) and/or rheumatoid factor (RF) increased identification from 72% to 92%. Seventy-two percent of RF- and ACPA-seronegative patients were positive for 14-3-3η autoantibodies.Conclusion.14-3-3η autoantibodies, alone and in combination with the 14-3-3η protein, RF, and/or ACPA identified most patients with early RA.

We aimed to investigate the early changes in expression of C-type lectin domain family 9, member A (CLEC9A), a C-type lectin that is specifically expressed by the CD141(+) dendritic cell subset that is involved in cross-presentation to CD8(+) T cells, by evaluating gene and/or protein expression in three different compartments [skin, synovial tissue (ST) and serum] after short-term adalimumab treatment in PsA patients compared with placebo. Patients with active PsA and psoriasis were randomized to receive adalimumab or placebo for 4 weeks. Synovial and skin biopsies were obtained before and after 4 weeks of treatment and serum samples 4 weeks, 12 weeks and 1 year after treatment. Skin and serum from healthy donors were used as control. CLEC9A expression was assessed by immunohistochemistry, double immunofluorescence using terminal deoxynucleotidyl transferase 2'-deoxyuridine 5'-triphosphate nick-end labelling (TUNEL), quantitative PCR and ELISA. CLEC9A expression was significantly higher in psoriatic skin compared with healthy donor. In psoriatic skin and PsA ST, CLEC9A(+) cells were in close proximity to TUNEL(+) cells. SF CLEC9A levels were significantly lower compared with paired PsA serum. Adalimumab treatment did not affect CLEC9A serum level and skin expression. However, ST CLEC9A protein expression was significantly decreased after adalimumab treatment compared with the placebo group while CLEC9A gene expression remained unchanged. There was a positive correlation between T cell numbers and ST CLEC9A protein expression. CD141(+) cell numbers and chemokine (C motif) receptor 1 expression were not affected with adalimumab treatment. Altogether, the present study suggests that the downregulation of synovial CLEC9A might be associated with a novel mechanism by which anti-TNF therapy might reduce CD8-mediated inflammation in PsA patients

Introduction Psoriatic arthritis (PsA) is an inflammatory joint disease associated with psoriasis. Alefacept (a lymphocyte function-associated antigen (LFA)-3 Ig fusion protein that binds to CD2 and functions as an antagonist to T-cell activation) has been shown to result in improvement in psoriasis but has limited effectiveness in PsA. Interleukin-20 (IL-20) is a key proinflammatory cytokine involved in the pathogenesis of psoriasis. The effects of alefacept treatment on IL-20 expression in the synovium of patients with psoriasis and PsA are currently unknown. Methods Eleven patients with active PsA and chronic plaque psoriasis were treated with alefacept (7.5 mg per week for 12 weeks) in an open-label study. Skin biopsies were taken before and after 1 and 6 weeks, whereas synovial biopsies were obtained before and 4 and 12 weeks after treatment. Synovial biopsies from patients with rheumatoid arthritis (RA) (n = 10) were used as disease controls. Immunohistochemical analysis was performed to detect IL-20 expression, and stained synovial tissue sections were evaluated with digital image analysis. Double staining was performed with IL-20 and CD68 (macrophages), and conversely with CD55 (fibroblast-like synoviocytes, FLSs) to determine the phenotype of IL-20-positive cells in PsA synovium. IL-20 expression in skin sections (n = 6) was analyzed semiquantitatively. Results IL-20 was abundantly expressed in both PsA and RA synovial tissues. In inflamed PsA synovium, CD68+ macrophages and CD55+ FLSs coexpressed IL-20, and its expression correlated with the numbers of FLSs. IL-20 expression in lesional skin of PsA patients decreased significantly (P = 0.04) 6 weeks after treatment and correlated positively with the Psoriasis Area and Severity Index (PASI). IL-20 expression in PsA synovium was not affected by alefacept. Conclusions Conceivably, the relatively limited effectiveness of alefacept in PsA patients (compared with anti-tumor necrosis factor (TNF) therapy) might be explained in part by persistent FLS-derived IL-20 expression.

Objective.During OMERACT 8, delegates selected patient global assessment (PGA) of disease as a domain to be evaluated in randomized controlled trials in psoriatic arthritis (PsA). This study assessed the reliability of the PGA, measured by means of 0–100 mm visual analog scale (VAS), and the additional utility of separate VAS scales for joints (PJA) and skin (PSA).Methods.In total, 319 consecutive patients with PsA (186 men, 133 women, mean age 51 ± 13 yrs) were enrolled. PGA, PJA, and PSA were administered at enrolment (W0) and after 1 week (W1). Detailed clinical data, including ACR joint count, Psoriasis Area and Severity Index (PASI), and Hospital Anxiety and Depression Scale, were recorded.Results.Comparison of W0 and W1 scores showed no significant variations (intraclass correlation coefficients for PGA 0.87, PJA 0.86, PSA 0.78), demonstrating the reliability of the instrument. PGA scores were not influenced by patient anxiety or depression, but were dependent on PJA and PSA (p = 0.00001). PJA was dependent on the number of swollen and tender joints (p < 0.00001). PSA scores were influenced by the extent of skin psoriasis and by hand skin involvement (p = 0.00001). Joint and skin disease were found not to correlate in terms of disease activity as evidenced by the swollen joint count compared to PASI (r = 0.11) and by the PJA compared to PSA (r = 0.38).Conclusion.PGA assessed by means of VAS is a reliable tool related to joint and skin disease activity. Because joint and skin disease often diverge it is suggested that in some circumstances both PJA and PSA are also assessed.

BACKGROUND: There is growing interest in soluble biomarkers that could be used on the group level for screening purposes in small proof of principle studies during early drug development. We investigated early changes in serum levels of several candidate biomarkers involved in cartilage and bone metabolism following the initiation of adalimumab as a prototypic active treatment in psoriatic arthritis (PsA) compared to placebo. MATERIALS AND METHODS: Twenty-four PsA patients were randomized to receive either adalimumab 40 mg s.c. every other week or placebo for 4 weeks, followed by an open label extension phase. Serum samples were obtained at baseline and after 4 and 12 weeks of treatment and analyzed for levels of CPII and PINP (synthesis of type II and type I procollagen), melanoma inhibitory activity (MIA) (chondrocyte anabolism), matrix metalloproteinase (MMP)-3, C2C and cartilage oligomeric matrix protein (COMP) (type II collagen degradation), osteocalcin (OC) (bone formation), NTX-I and ICTP (both type I collagen degradation). RESULTS: After 4 weeks, there was a significant decrease in serum MMP-3 levels in adalimumab-treated patients (P

Alefacept, a LFA-3/IgG1 fusion protein, interferes with the activation and proliferation of T cells by binding to the CD2 receptor on their surfaces. The clinical efficacy of this drug has been demonstrated in chronic plaque psoriasis. We performed a single-center, open-label study to investigate the immunohistochemical effects in psoriatic lesional skin. A group of 11 patients with plaque psoriasis all received 12 weekly doses of 7.5 mg alefacept intravenously. Skin biopsies were obtained at baseline and on days 8, 43 and 92, and were evaluated by digital image analysis after immunohistochemical staining. After completion of treatment, 8 out of the 11 patients experienced a reduction in PASI of 50% or more compared to baseline. Immunohistochemical analysis displayed a gradual decrease in the number of cutaneous T cells during therapy, with a significant reduction in epidermal CD8(+) cells and dermal CD4(+) cells on day 92. Patients with a reduction in PASI of 50% or more after therapy had a clearance of effector/memory T cells from the epidermis, in contrast to patients with a reduction in PASI of less than 50%. These findings support the hypothesis that effector/memory T cells play a prominent role in the pathogenesis of psoriasis, and that alefacept is capable of reducing these cells in lesional psoriatic skin

Objective To investigate whether alefacept (a fully human lymphocyte function–associated antigen 3 [LFA-3]/IgG1 fusion protein that blocks the LFA-3/CD2 interaction) is able to reduce the signs and symptoms of joint inflammation in patients with active psoriatic arthritis (PsA). Methods Eleven patients with active PsA were treated with alefacept for 12 weeks in an open-label and explorative study. Clinical joint assessment and laboratory assessments were performed at baseline and after 4, 9, 12, and 16 weeks of treatment. Serial synovial tissue (ST) biopsy specimens from an inflamed index joint (knee, ankle, wrist, or metacarpophalangeal joint) were obtained by arthroscopy at baseline and after 4 and 12 weeks of treatment. Results At the completion of treatment, 6 of 11 patients (55%) fulfilled the Disease Activity Score (DAS) response criteria. Nine patients (82%) fulfilled the DAS response criteria at any point during the study. There was a statistically significant reduction in CD4+ lymphocytes (P < 0.05), CD8+ lymphocytes (P = 0.05), and CD68+ macrophages (P < 0.02) in the ST after 12 weeks of treatment compared with baseline. The ST and peripheral blood of those patients fulfilling the DAS response criteria contained more CD45RO+ cells at baseline and displayed a significant reduction in these cells compared with nonresponding patients. Conclusion The changes in ST, together with the improvement in clinical joint scores, after treatment with alefacept support the hypothesis that T cell activation plays an important role in this chronic inflammatory disease. Furthermore, since alefacept, a T cell–specific agent, led to decreased macrophage infiltration, the data indicate that T cells are highly involved in synovial inflammation in PsA.

Background TNFα blockers have had a significant impact on the management of psoriatic arthritis (PsA). Despite their effectiveness, patient response is heterogeneous, underscoring the need for markers to assist in therapy selection for likely responders. The 14-3-3 family of proteins represents intracellular chaperones that regulate various biological processes. The η (eta) isoform, is detectable in the synovial fluid and serum of patients with arthritis, is up-regulated by TNFα and correlates with measures of clinical improvement in rheumatoid arthritis (RA). Objectives To study the serum levels of 14-3-3η in PsA patients in relationship to clinical response to adalimumab therapy. Methods Serum 14-3-3η levels of 24 patients (15 males and 9 females) with active PsA fulfilling the CASPAR classification criteria were measured before receiving adalimumab therapy for either 8- or 12-weeks. Clinical assessment included: SJC68, PASI, HAQ, CRP, ESR, DAS28 and ACR response. Two-tailed Mann-Whitney U-tests were run to compare differences between ACR50 responders and non-responders. Pearson correlations were generated to determine relationships between 14-3-3η and clinical variables. Contingency and regression analyses were performed to identify which variables were predictors of an ACR50 response. Receiver operating characteristic (ROC) curves were used to examine differential expression for response and to determine the accuracy of the regression model. Results Baseline 14-3-3η serum concentrations were significantly higher in ACR50 responders (0.46ng/ml) versus non-responders (0ng/ml, p=0.02) delivering a ROC AUC of 0.75, p=0.04. Consistent with published data [1] median CRP levels were also higher in ACR50 responders; 18.3mg/l versus 5.0mg/l in non-responders, p=0.05. There were no statistically significant differences in any other clinical variables between the two response groups. Across the entire cohort, 14-3-3η titres correlated moderately with CRP levels at baseline (r=0.429, p=0.03). No correlations with other clinical measures were observed. Regression analysis revealed that 14-3-3η titres were predictive of an ACR50 response delivering a significant likelihood ratio (LR) of 5.53 (p=0.018), an odds ratio (OR) of 4.62 with a ROC AUC=0.75. Similarly, a contingency analysis showed that 14-3-3η positivity reflected likelihood of ACR50 response to adalimumab therapy [LR=5.83 p=0.016; OR=8.56 and a relative risk (RR) of 3.27]. Combining 14-3-3η positivity with CRP titres strengthens the model wherein the ROC AUC for CRP as a single variable is 0.74, LR=5.86 (p=0.015) while combining the two markers delivers a ROC AUC of 0.86, LR=10.3 (p=0.006) increasing the prediction value of CRP nearly 2-fold when 14-3-3η is added. The PPV and NPV for CRP are 0.35 and 0.65 whereas with 14-3-3η they are 0.54 and 0.46, respectively. Conclusions Serum 14-3-3η titres and positivity both predict ACR50 response to adalimumab therapy in PsA patients. 14-3-3η sero-positivity when taken together with CRP titres significantly improves prediction of response. References F Van den Bosch et al. Effectiveness of adalimumab in treating patients with active psoriatic arthritis and predictors of good clinical responses for arthritis, skin and nail lesions. Ann Rheum Dis 2010;69:394-399 Disclosure of Interest A. Marotta Shareholder of: Co-founder, A. Kuijk: None Declared, W. Maksymowych: None Declared, P. Tak: None Declared

Background The 14-3-3 protein family consists of seven highly conserved isoforms described as intracellular chaperones based on their ability to bind to a multitude of functionally diverse proteins. One isoform, 14-3-3η, is detected extracellularly in arthritis, behaves as an extracellular ligand which induces factors that contribute to joint damage and is expressed at higher levels in patients with erosive rheumatoid arthritis (RA). 14-3-3η levels correlate strongly with those of MMP-1 and MMP-3 in synovial fluid and serum further characterizing its biological expression and association with rheumatologic disease processes. Objectives To explore 14-3-3η levels in erosive compared to non-erosive Psoriatic Arthritis (PsA) patients and its relationship with clinical variables. Methods Sera of 24 patients (15 males and 9 females) with active PsA fulfilling the CASPAR classification criteria were evaluated for 14-3-3η concentrations using an investigational-grade 14-3-3η ELISA. Presence of 14-3-3η noted positivity for the biomarker. Of the 24 patients, as per radiographic assessment, 12 had erosive and 12 had non-erosive PsA. Clinical assessment included: SJC68, PASI, HAQ, CRP, ESR, DAS28. Two-tailed Mann-Whitney U-tests were run to compare group differences. Pearson correlations were generated to examine relationships between 14-3-3η and other clinical variables. Regression and contingency analyses were performed to identify which variables were associated with joint damage. Results Median 14-3-3η serum concentrations were significantly higher in the erosive (0.23ng/ml) than non-erosive (0ng/ml) patients (p=0.026). Sixty-seven (67) % of the erosive patients were positive for 14-3-3η compared to 17% in the non-erosive group. As shown in Table 1 below, both groups were balanced in terms of their clinical characteristics. Across the whole cohort, 14-3-3η titres correlated moderately with CRP (r=0.429, p=0.03) and did not correlate with other clinical variables (DAS28, ESR, HAQ, PASI and SJC68), further underscoring its independence with other disease markers. Regression analysis revealed that 14-3-3η was independently associated with erosive status [likelihood ratio (LR) of 4.26 (p=0.039), an odds ratio of (OR) of 3.71 with an ROC AUC=0.74] while the other clinical variables did not, nor did they enhance 14-3-3η’s predictive utility. Contingency analysis evaluating the relationship between 14-3-3η positivity and erosive status demonstrates that 14-3-3η positivity reflects joint damage; delivering a LR=6.5 (p=0.013), a relative risk (RR) of 2.8 with an OR of 10. Conclusions Extracellular 14-3-3η, which can be readily measured in patient serum, serves as an independent marker of joint damage in this PsA cohort. Taken together with the observed differences in expression in erosive RA, 14-3-3η should be further investigated as a promising candidate biomarker of joint damage. Disclosure of Interest A. Marotta Shareholder of: Co-founder, A. Kuijk: None Declared, W. Maksymowych: None Declared, P. Tak: None Declared

Psoriatic arthritis (PsA) is a chronic inflammatory arthropathy associated with psoriasis that affects the peripheral joints, spine, and entheses. Most patients with PsA present with peripheral synovitis of the oligoarticular or polyarticular subtype. As one of the targets of this disease, studies on the synovium may provide insight into the mechanisms involved in this condition. Key findings from the available studies comparing synovial tissue of PsA and rheumatoid arthritis patients are discussed in this review. Also, changes in the synovial infiltrate, expression of proinflammatory cytokines and adhesion molecules, and vascularity in synovial tissue after treatment with various medications are addressed. Finally, a model for proof-of-principle study design using serial synovial biopsies is described, which could be used to predict clinical (in)efficacy in early clinical trial design in PsA.

BackgroundPsoriatic arthritis (PsA) recommendations state that the target of treatment should be remission or low disease activity (LDA). We used a real-life dataset to compare different potential targets.Methods250 patients with PsA considered in an acceptable disease state according to their rheumatologist were included. Targets for remission were the Disease Activity Index for Psoriatic Arthritis (DAPSA) and clinical DAPSA (cDAPSA) remission (≤4), very low disease activity (VLDA) and Psoriatic Arthritis Disease Activity Score ≤1.9. LDA targets analysed were the DAPSA ≤14, cDAPSA ≤13, minimal disease activity (MDA) and adjusted MDA targets: MDAjoints with both tender joint count (TJC) and swollen joint count (SJC) mandated, MDAskin (psoriasis area and severity index (PASI) mandated) and MDAjoints&skin with TJC, SJC and PASI mandated.ResultsComparison of the several candidate targets demonstrates that VLDA is achieved by the lowest proportion of patients and includes patients with the lowest residual disease activity compared with the other remission targets. The modified MDA measures are the most stringent targets for LDA in terms of residual disease on joints, psoriasis and enthesitis within patients achieving the target. In both remission and LDA, the inclusion of C reactive protein did not show an added value. The exclusion of a skin domain, as in the DAPSA measures, resulted in negligence of skin disease and a negative impact on the quality of life in some patients.ConclusionsThe different remission and LDA targets show us significant overlap between measures, but these measures targeting the same definition do differ in terms of allowance of residual disease. Inclusion of laboratory markers seems unnecessary, although exclusion of a skin domain may result in psoriasis not being assessed resulting in residual impactful skin disease.