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Objectives: In PsA management, remission and low disease activity represent preferential treatment targets. We aimed at evaluating the predictive value and clinical use of initial therapeutic response for subsequent achievement of these targets. Methods: Based on data of 216 patients enrolled in a randomized controlled trial of golimumab (GO-REVEAL), we performed diagnostic testing analyses using 3- and 6-month disease activity as tests for treatment outcomes to understand the implications of early response. In regression analyses, we estimated the probabilities for achieving at least LDA. Disease activity was measured by the disease activity index for PsA (DAPSA). Results: Three-month DAPSA levels were excellent tests for disease activity at 6 months (and at 1 year), with areas under the receiver operating characteristic curves of 0.92 (and 0.88, respectively). The estimated probability for 6-month LDA could be quantified as <22% if patients did not reach at least moderate disease activity after 3 months on golimumab. Similar data were seen for early DAPSA response: patients achieving a DAPSA 85% at 3 months had an 84% probability for 6-month LDA or REM. All results were validated in an independent trial cohort of patients treated with infliximab (IMPACT 2). Conclusion: Three months after implementation of therapy in PsA, it is already possible to evaluate the potential for accomplishing therapeutic goals. This substantiates the choice of the 3-month assessment as essential for treatment adaptations.

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The study aimed to develop evidence-based recommendations regarding the evaluation and use of biosimilars to treat rheumatological diseases. The task force comprised an expert group of specialists in rheumatology, dermatology and gastroenterology, and pharmacologists, patients and a regulator from ten countries. Four key topics regarding biosimilars were identified through a process of discussion and consensus. Using a Delphi process, specific questions were then formulated to guide a systematic literature review. Relevant English-language publications through November 2016 were searched systematically for each topic using Medline; selected papers and pertinent reviews were examined for additional relevant references; and abstracts presented at the 2015 and 2016 American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) annual scientific meetings were searched for those about biosimilars. The experts used evidence obtained from these studies to develop a set of overarching principles and consensus recommendations. The level of evidence and grade of recommendation were determined for each. By the search strategy, 490 references were identified. Of these, 29 full-text papers were included in the systematic review. Additionally, 20 abstracts were retrieved from the ACR and EULAR conference abstract databases. Five overarching principles and eight consensus recommendations were generated, encompassing considerations regarding clinical trials, immunogenicity, extrapolation of indications, switching between bio-originators and biosimilars and among biosimilars, and cost. The level of evidence and grade of recommendation for each varied according to available published evidence. Five overarching principles and eight consensus recommendations regarding the evaluation and use of biosimilars to treat rheumatological diseases were developed using research-based evidence and expert opinion.

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OBJECTIVE: To review the published literature on the performance of indirect immunofluorescence (IIF)-HEp-2 antinuclear antibody (ANA) testing for classification of systemic lupus erythematosus (SLE). METHODS: A systematic literature search was conducted in the Medline, Embase, and Cochrane databases for articles published between January 1990 and October 2015. The research question was structured according to Population, Intervention, Comparator, Outcome (PICO) format rules, and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations were followed where appropriate. Meta-regression analysis for diagnostic tests was performed, using the ANA titer as independent variable, while sensitivity and specificity were dependent variables. RESULTS: Of 4,483 publications screened, 62 matched the eligibility criteria, and another 2 articles were identified through reference analysis. The included studies comprised 13,080 SLE patients in total, of whom 12,542 (95.9%) were reported to be IIF-ANA positive at various titers. For ANA at titers of 1:40, 1:80, 1:160, and 1:320, meta-regression gave sensitivity values of 98.4% (95% confidence interval [95% CI] 97.6-99.0%), 97.8% (95% CI 96.8-98.5%), 95.8% (95% CI 94.1-97.1%), and 86.0% (95% CI 77.0-91.9%), respectively. The corresponding specificities were 66.9% (95% CI 57.8-74.9%), 74.7% (95% CI 66.7-81.3%), 86.2% (95% CI 80.4-90.5%), and 96.6% (95% CI 93.9-98.1%), respectively. CONCLUSION: The results of this systematic literature review and meta-regression confirm that IIF-ANAs have high sensitivity for SLE. ANAs at a titer of 1:80 have sufficiently high sensitivity to be considered as an entry criterion for SLE classification criteria, i.e., formally test other classification criteria for SLE only if ANAs of at least 1:80 have been found.

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BACKGROUND: The Disease Activity Index for Psoriatic Arthritis (DAPSA) is a valid and discriminative tool. Definitions of disease activity states and therapeutic response are still missing. We derived such criteria for the DAPSA. METHODS: We retrieved 30 patient profiles from an observational database including joint counts, patient pain and global activity ratings and C-reactive protein (CRP) and carried out a survey among experts to classify patients into remission (REM), low (LDA), moderate (MDA) or high (HDA) disease activity. Based on the distributions of DAPSA in each of these expert-assigned states we defined the cutpoints between groups. We performed similar analyses evaluating a clinical score (cDAPSA), omitting CRP. To define minor, moderate and major treatment response, we used Cohen's Kappa statistics and analysed agreement of DAPSA percentage change with ACR20/50/70-response in three randomised controlled trials. RESULTS: Our survey yielded a response rate of 75% (n=33). Mean DAPSA differed significantly between patients classified as REM, LDA, MDA or HDA (p<0.001). Based on the distributions of DAPSA in these groups, we propose cut-off values of ≤4 for REM, >4 and ≤14 for LDA, >14 and ≤28 for MDA and >28 for HDA. We observed best agreement with ACR20/50/70-response at DAPSA changes of 50/75/85%, reflecting minor, moderate and major improvement. CONCLUSIONS: The DAPSA constitutes a disease-specific, validated and feasible tool for PsA assessment. In this study, we provide criteria for disease activity states and treatment response. They are based on an international expert survey, and show good performance in clinical trials and observational data.

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OBJECTIVE: A systematic literature review (SLR; 2009-2014) to compare a target-oriented approach with routine management in the treatment of rheumatoid arthritis (RA) to allow an update of the treat-to-target recommendations. METHODS: Two SLRs focused on clinical trials employing a treatment approach targeting a specific clinical outcome were performed. In addition to testing clinical, functional and/or structural changes as endpoints, comorbidities, cardiovascular risk, work productivity and education as well as patient self-assessment were investigated. The searches covered MEDLINE, EMBASE, Cochrane databases and Clinicaltrial.gov for the period between 2009 and 2012 and separately for the period of 2012 to May of 2014. RESULTS: Of 8442 citations retrieved in the two SLRs, 176 articles underwent full-text review. According to predefined inclusion/exclusion criteria, six articles were included of which five showed superiority of a targeted treatment approach aiming at least at low-disease activity versus routine care; in addition, publications providing supportive evidence were also incorporated that aside from expanding the evidence provided by the above six publications allowed concluding that a target-oriented approach leads to less comorbidities and cardiovascular risk and better work productivity than conventional care. CONCLUSIONS: The current study expands the evidence that targeting low-disease activity or remission in the management of RA conveys better outcomes than routine care.

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BACKGROUND: Reaching the therapeutic target of remission or low-disease activity has improved outcomes in patients with rheumatoid arthritis (RA) significantly. The treat-to-target recommendations, formulated in 2010, have provided a basis for implementation of a strategic approach towards this therapeutic goal in routine clinical practice, but these recommendations need to be re-evaluated for appropriateness and practicability in the light of new insights. OBJECTIVE: To update the 2010 treat-to-target recommendations based on systematic literature reviews (SLR) and expert opinion. METHODS: A task force of rheumatologists, patients and a nurse specialist assessed the SLR results and evaluated the individual items of the 2010 recommendations accordingly, reformulating many of the items. These were subsequently discussed, amended and voted upon by >40 experts, including 5 patients, from various regions of the world. Levels of evidence, strengths of recommendations and levels of agreement were derived. RESULTS: The update resulted in 4 overarching principles and 10 recommendations. The previous recommendations were partly adapted and their order changed as deemed appropriate in terms of importance in the view of the experts. The SLR had now provided also data for the effectiveness of targeting low-disease activity or remission in established rather than only early disease. The role of comorbidities, including their potential to preclude treatment intensification, was highlighted more strongly than before. The treatment aim was again defined as remission with low-disease activity being an alternative goal especially in patients with long-standing disease. Regular follow-up (every 1-3 months during active disease) with according therapeutic adaptations to reach the desired state was recommended. Follow-up examinations ought to employ composite measures of disease activity that include joint counts. Additional items provide further details for particular aspects of the disease, especially comorbidity and shared decision-making with the patient. Levels of evidence had increased for many items compared with the 2010 recommendations, and levels of agreement were very high for most of the individual recommendations (≥9/10). CONCLUSIONS: The 4 overarching principles and 10 recommendations are based on stronger evidence than before and are supposed to inform patients, rheumatologists and other stakeholders about strategies to reach optimal outcomes of RA.

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In this review we provide reasons to use joint specific composite measures of disease activity for psoriatic arthritis (PsA) rather than composite scores that combine several manifestations of psoriatic disease, including skin involvement. Based on a principal component analysis, which, indeed, excluded skin involvement as a major factor in PsA, the Disease Activity index for PSoriatic Arthritis (DAPSA) was validated using clinical trial and observational data. Further, disease activity states and response criteria were recently defined. The DAPSA is simply calculated by summing swollen + tender joint counts + patient pain + patient global assessments + CRP, using 66/68 joint counts. DAPSA has meanwhile been validated in other studies and has shown to have a very high level of validity, also when compared with joint sonography. Thus, DAPSA is useful in clinical practice, clinical trials and observational studies.

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BACKGROUND: Therapeutic targets have been defined for diseases like diabetes, hypertension or rheumatoid arthritis and adhering to them has improved outcomes. Such targets are just emerging for spondyloarthritis (SpA). OBJECTIVE: To define the treatment target for SpA including ankylosing spondylitis and psoriatic arthritis (PsA) and develop recommendations for achieving the target, including a treat-to-target management strategy. METHODS: Based on results of a systematic literature review and expert opinion, a task force of expert physicians and patients developed recommendations which were broadly discussed and voted upon in a Delphi-like process. Level of evidence, grade and strength of the recommendations were derived by respective means. The commonalities between axial SpA, peripheral SpA and PsA were discussed in detail. RESULTS: Although the literature review did not reveal trials comparing a treat-to-target approach with another or no strategy, it provided indirect evidence regarding an optimised approach to therapy that facilitated the development of recommendations. The group agreed on 5 overarching principles and 11 recommendations; 9 of these recommendations related commonly to the whole spectrum of SpA and PsA, and only 2 were designed separately for axial SpA, peripheral SpA and PsA. The main treatment target, which should be based on a shared decision with the patient, was defined as remission, with the alternative target of low disease activity. Follow-up examinations at regular intervals that depend on the patient's status should safeguard the evolution of disease activity towards the targeted goal. Additional recommendations relate to extra-articular and extramusculoskeletal aspects and other important factors, such as comorbidity. While the level of evidence was generally quite low, the mean strength of recommendation was 9-10 (10: maximum agreement) for all recommendations. A research agenda was formulated. CONCLUSIONS: The task force defined the treatment target as remission or, alternatively, low disease activity, being aware that the evidence base is not strong and needs to be expanded by future research. These recommendations can inform the various stakeholders about expert opinion that aims for reaching optimal outcomes of SpA.

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PURPOSE OF REVIEW: Rheumatoid arthritis (RA) is a potentially destructive disease with profound impact on patients' function and quality of life. Newer therapeutic agents have revolutionized outcomes but have not resulted in best outcomes for all patients. In this article, we will review recent progress in the development of strategies to enhance outcomes in patients with early RA (ERA). RECENT FINDINGS: Over the past 10 years, investigators have increasingly focused on additional means for improving long-term prognosis of patients with RA by examining the effect of different strategies to reach clinical targets reflecting optimal levels of disease control. In particular, it has become apparent that patients with ERA have the best chance to reach optimal outcomes, thus normalizing function, and halting radiographic damage. Studies show that strategies including treating to a target, computerizing targets, and combining clinical and biological or imaging targets for patients are enabling more patients to achieve remission, sustained remission, and even drug-free remission. SUMMARY: Overall, the bar has been set higher in clinical research with the expectation that therapeutic approaches for all patients should be implemented to achieve high-level targeted outcomes. Studies evaluating the feasibility of implementing these in practice are needed to achieve this goal for all patients with ERA.

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BACKGROUND: Since approval of tocilizumab (TCZ) for treatment of rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA), interleukin 6 (IL-6) pathway inhibition was evaluated in trials of TCZ and other agents targeting the IL-6 receptor and ligand in various RA populations and other inflammatory diseases. This consensus document informs on interference with the IL-6 pathway based on evidence and expert opinion. METHODS: Preparation of this document involved international experts in RA treatment and RA patients. A systematic literature search was performed that focused on TCZ and other IL6-pathway inhibitors in RA and other diseases. Subsequently, incorporating available published evidence and expert opinion, the steering committee and a broader expert committee (both including RA patients) formulated the current consensus statement. RESULTS: The consensus statement covers use of TCZ as combination- or monotherapy in various RA populations and includes clinical, functional and structural aspects. The statement also addresses the second approved indication in Europe JIA and non-approved indications. Also early phase trials involving additional agents that target the IL-6 receptor or IL-6 were evaluated. Safety concerns, including haematological, hepatic and metabolic issues as well as infections, are addressed likewise. CONCLUSIONS: The consensus statement identifies points to consider when using TCZ, regarding indications, contraindications, screening, dose, comedication, response evaluation and safety. The document is aimed at supporting clinicians and informing patients, administrators and payers on opportunities and limitations of IL-6 pathway inhibition.

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BACKGROUND: Suppression of the immunoinflammatory cascade by targeting interleukin 6 (IL-6) mediated effects constitutes a therapeutic option for chronic inflammatory diseases. Tocilizumab is the only IL-6 inhibitor (IL-6i) licensed for rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA), but also other agents targeting either IL-6 or its receptor are investigated in various indications. OBJECTIVE: To review published evidence on safety and efficacy of IL-6i in inflammatory diseases. METHODS: We performed systematic literature searches in Medline and Cochrane, screened EULAR and American College of Rheumatology meeting-abstracts, and accessed http://www.clinicaltrials.gov. RESULTS: Comprehensive evidence supports the efficacy of tocilizumab in RA in DMARD-naïve patients, and after DMARD- and TNFi-failure. Randomised comparisons demonstrate superiority of tocilizumab in JIA, but not ankylosing spondylitis (AS). Other indications are currently investigated. Additional IL-6i show similar efficacy; safety generally appears acceptable. CONCLUSIONS: IL-6i is effective and safe in RA and JIA, but not in AS. Preliminary results in other indications need substantiation.

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BACKGROUND: Optimal treatment for rheumatoid arthritis (RA) after inadequate response (IR) to tumour necrosis factor α inhibitors (TNFi) remains uncertain. OBJECTIVE: To compare the efficacy and safety of biological agents after TNFi-IR. METHODS: A systematic literature search was carried out using Medline and Cochrane databases, as well as http://www.clinicaltrials.gov, and bibliographies of the retrieved literature were searched by hand. Randomised, placebo-controlled trials that enrolled patients with RA with TNFi-IR were included and American College of Rheumatology (ACR) response as primary efficacy outcome and adverse events (AEs), serious adverse events (SAEs) and serious infections (SIs) as safety measures were extracted. An indirect meta-analysis with pairwise comparisons of efficacy and safety data was then carried out using ORs or risk differences (RDs) in a random effects model. RESULTS: In four randomised controlled trials with 24 weeks' follow-up, direct comparisons of abatacept, golimumab, rituximab and tocilizumab versus placebo showed statistically significant mean ORs of 3.3-8.9 for ACR20, 5.5-10.2 for ACR50 and 4.1-13.5 for ACR70. Risks of AEs, SAEs and SIs versus placebo were non-significant. Indirect pairwise comparisons of the four biological agents showed no significant differences in ACR50 and ACR70. Golimumab had a significantly lower OR (0.56-0.59) for ACR20 but significantly fewer AEs (RD 0.13-0.18). Efficacy after one versus multiple TNFi failures did not differ significantly between the different biological agents. CONCLUSION: In patients refractory to one or more TNFi, new biological agents provide significant improvement with good safety. Lacking head-to-head trials, indirect meta-analysis enables a comparison of effectiveness and safety of biological agents with each other and shows that all biological agents have similar effects.

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OBJECTIVE: When patients present with undifferentiated peripheral inflammatory arthritis (UPIA), early diagnosis and evaluation of prognostic factors are decisive steps for therapeutic success. We reviewed published evidence on the diagnostic and prognostic performance of autoantibodies and soluble biomarkers in UPIA. METHODS: We conducted a systematic literature search covering studies published until January 2009. Additionally, we screened conference abstracts presented at European League Against Rheumatism and American College of Rheumatology meetings in 2007 and 2008. RESULTS: We included 52 full-text articles and 12 abstracts. The association of anti-cyclic citrullinated peptide antibody (anti-CCP) and rheumatoid factor (RF) with diagnosis of rheumatoid arthritis at followup is compelling, supported by positive likelihood ratios (LR+) ranging between 1.2 and 20.5 for anti-CCP and 1.1 to 13.5 for RF. The same applies to radiographic outcome. For antikeratin antibodies (AKA) and antiperinuclear factor, existing evidence suggests diagnostic usefulness; AKA also showed prognostic value. Diagnostic and prognostic evidence for other autoantibodies and for bone and cartilage biomarkers was scarce, negative, or controversial. CONCLUSION: Among serological tests, unanimous evidence of substantial diagnostic value exists only for anti-CCP and RF, but is scarce for other markers.

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BACKGROUND AND OBJECTIVES: Instruments for measuring disease activity in psoriatic arthritis (PsA) are not yet firmly established, and most of the currently employed ones have been derived for rheumatoid arthritis. Some of these instruments are based on 28 joint counts, which do not capture joints frequently affected in PsA. Therefore, the reliability and validity of DAREA (for 'Disease Activity index for REactive Arthritis'), which was originally developed for reactive arthritis and employs a 66/68 joint count, was tested in patients with PsA. METHODS: Trial data from the Infliximab Multinational Psoriatic Arthritis Controlled Trial were analysed. Results were then independently validated using an observational data set. DAREA was compared to other composite indices regarding correlations with core set variables, sensitivity to change and criterion validity. RESULTS: Good correlation of the DAREA with single items of disease activity, other composite scores (r=0.6-0.9) and physical function (Health Assessment Questionnaire; r=0.5) was found. Likewise, DAREA was at least as sensitive to change as the other indices and more so in patients with distal interphalangeal joint involvement. Additionally, DAREA correlated well with radiographic changes. CONCLUSION: The analyses of this study provide evidence of the utility and validity of the DAREA for PsA disease activity assessment. A second name should therefore be assigned to this score: DAPSA (for 'Disease Activity index for PSoriatic Arthritis').

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Treatment of rheumatoid arthritis (RA) may differ among rheumatologists and currently, clear and consensual international recommendations on RA treatment are not available. In this paper recommendations for the treatment of RA with synthetic and biological disease-modifying antirheumatic drugs (DMARDs) and glucocorticoids (GCs) that also account for strategic algorithms and deal with economic aspects, are described. The recommendations are based on evidence from five systematic literature reviews (SLRs) performed for synthetic DMARDs, biological DMARDs, GCs, treatment strategies and economic issues. The SLR-derived evidence was discussed and summarised as an expert opinion in the course of a Delphi-like process. Levels of evidence, strength of recommendations and levels of agreement were derived. Fifteen recommendations were developed covering an area from general aspects such as remission/low disease activity as treatment aim via the preference for methotrexate monotherapy with or without GCs vis-à-vis combination of synthetic DMARDs to the use of biological agents mainly in patients for whom synthetic DMARDs and tumour necrosis factor inhibitors had failed. Cost effectiveness of the treatments was additionally examined. These recommendations are intended to inform rheumatologists, patients and other stakeholders about a European consensus on the management of RA with DMARDs and GCs as well as strategies to reach optimal outcomes of RA, based on evidence and expert opinion.

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OBJECTIVE: To review the cost effectiveness of rheumatoid arthritis (RA) treatments and inform the clinical recommendations by the European League Against Rheumatism. METHODS: A systematic literature search and review of the health economic evidence on RA treatment options was performed. RESULTS: Despite diverse methodological approaches, health economic analyses are concordant: at onset of disease, traditional disease-modifying antirheumatic drugs (DMARDs) are cost effective-that is, treatment merits outweigh treatment costs. If DMARDs fail, therapeutic escalation with tumour necrosis factor alpha inhibitors (TNFi) is cost effective when standard dosing schemes are employed. If TNFi fail, rituximab or abatacept is cost effective. Economic evidence for switching TNFi remains sparse. CONCLUSIONS: The costly sequelae of insufficiently controlled RA justify intensive escalations of treatment in this disease. By maintaining function, patients are kept in the work process, reducing indirect costs. Quality of life is improved at an expense commonly accepted for chronic diseases. Effective control of disease activity seems to be a prudent use of societal resources.

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