Undifferentiated Peripheral Inflammatory Arthritis Research Articles

Outcomes of undifferentiated peripheral inflammatory arthritis in real-world practice. A longitudinal cohort study.

Undifferentiated peripheral inflammatory arthritis (UPIA) may have 3 different courses, including evolution to differentiated arthritis, remaining undifferentiated, and self-limited course. The purpose of this study was to provide a real-world evidence for predictors of outcomes in UPIA in a longitudinal cohort of patients. Patients enrolled in the CTDRC-UA cohort were screened for eligibility. Inclusion criteria were: (i) having synovitis in ≥ 1 joint, (ii) not meeting the criteria of any other rheumatic disease, (iii) having at least 2 visits per year, iv) included in the cohort during the period of 2004 to 2021, and (v) having active disease at cohort entry. Two hundred and three patients who met the inclusion criteria were followed up until January 2023. Medication-free remissions occurred in 42 (20.7%) cases. In 24 (11.8%) cases, the disease met the criteria of other rheumatic diseases, of which rheumatoid arthritis (RA) was the most common. In addition, joint damage occurred in 33 (16.3%) cases. Predictors of medication-free remissions were absence of comorbidity, starting a sustained remission at≤ 6months, and having no flare. Factors associated with disease evolution to RA were anti-citrullinated peptide antibody (ACPA) positivity, non-adherence to therapy, not going into sustained remission and having flare. Delay in treatment for > 3months and being ACPA positive were the predictors of joint damage. Although the majority of UIPA cases treated with step-up combination therapy with DMARDs do not progress to RA, most require continued treatment and a few achieve medication-free remissions. Key Points • Undifferentiated peripheral inflammatory arthritis (UPIA) can progress to rheumatoid arthritis in 11% of cases; and lack of sustained remission, being anti-citrullinated peptide antibody positive, non-adherence to therapy, and having flare are its predictors. • Medication-free remissions occur in 21% of patients with UPIA; and absence of comorbidity, starting a sustained remissionat ≤ 6months, and having no flare are its predictors. • Initiating treatment in the window of opportunity may lead to a better joint outcome.

Assessment of the safety, tolerability and effectiveness of first Russian generic aceclofenac in patients with undifferentiated peripheral inflammatory arthritis

To evaluate the effectiveness and tolerability of the drug in patients with undifferentiated peripheral inflammatory arthritis (UPIA). We observed 60 patients (39 women and 21 men) met G. Hazlewood et al., UPIA criteria, 2011. Patients were divided into 3 groups: with monoarthritis, oligoarthritis and polyarthritis. They took aceclofenac 100 mg twice day for 3 weeks. We noted significant decreasing in pain level according to visual analogue scale: in patients with monoarthritis by 69.3 mm (p0.001); in oligoarthritis group by 47.5 mm (p0.001), in patients with polyarthritis by 30 mm (p0.001). The life quality by the EQ-5D-5L index was improved too in all groups from 0.616 to 0.829 (p0.001). The satisfaction with the therapy was: in monoarthritis patients (80% of patients and 93% of doctors noted good results), in oligoarthritis group (53% and 39% accordingly) and polyarthritis (74% and 64% respectively). We suppose the difference was due to the fact that mono- and oligoarthritis patients suffered from initial forms of seronegative spondylarthropathy, in which the effectiveness of NSAIDs is traditionally higher; polyarthritis patients probably had debut of rheumatoid arthritis. Adverse events of therapy were mild. We noted gastrointestinal tract symptoms (dyspepsia) and increased ALT in 10 patients and increased blood pressure in 1 patient. The symptoms did not require discontinuation of therapy. Сonclusion. Post-registration observational study of first Russian generic aceclofenac (Alental, Vertex, Russia) was conducted. In UPIA patients aceclofenac therapy was most effective in mono- and oligoarthritis patients. The first Russian generic aceclofenac (Alental, Vertex, Russia) has good efficacy, tolerability and safety and can be recommended for arthritis treatment.

O14 Semi-quantitative assessment of synovial inflammation on US guided synovial membrane biopsy is contingent to disease phase, autoimmune profile and treatment response in RA: a large single center experience

Abstract Background Ultrasound (US)-guided minimally-invasive synovial tissue (ST) biopsy is a well-tolerated procedure for basic and translational studies on chronic inflammatory joint diseases as rheumatoid arthritis (RA), psoriatic arthritis (PsA) and spondyloarthritis (SpA). The aim of the study was to evaluate the utility of histopathologic criteria to differentiate US-guided ST biopsies in daily clinical care in relation to diagnosis, disease characteristics, US parameters and treatment response in a large single center ST biopsy unit. Methods 1,064 patients [545 RA, 167 PsA, 75 SpA, 199 undifferentiated peripheral inflammatory arthritis (UPIA), 18 crystal arthritis, 26 connective tissue diseases and 34 osteoarthritis (OA) respectively] who underwent US-guided ST biopsy were enrolled. US parameters (Synovial Hyperthrophy and Power Doppler signal respectively) were recorded for each biopsied joint. RA, PsA and SpA patients were stratified based on disease activity phase (naive to DMARDs, DMARDs resistant and in sustained remission, respectively). Clinical, demographic and immunological characteristics were recorded for each patient. All ST FFPE specimens were routinely processed and stained with H&E and classified by a pathologist, blinded to clinical characteristics, using the Krenn score to assess the degree of ST inflammation. Moreover, the presence/absence of lymphocytes, plasmacells, granulocytes and oedema was assessed for each ST. All naive to treatment RA were treated according to the T2T scheme and followed for at least 12 months and DAS remission rate was recorded. Results In the cohort, the distribution of synovitis score was significantly different among patients with inflammatory chronic diseases (RA, PsA, SpA and UPIA respectively) compared to OA (ANOVA Test p < 0.001). Moreover, Krenn score directly correlated with synovial hyperthrophy (R = 0.36; p < 0.001) and Power Doppler signal (R = 0.40;p<0.001) of the biopsied joint. Considering the RA cohort, naive RA showed a higher Krenn score compared to resistant RA (p < 0.001) and RA in sustained clinical and US remission (p < 0.001), directly correlating with DAS28 (R = 0.51; p < 0.001). Moreover, ACPA and RF positivity was related to the Krenn score and to ST plasmacells presence at RA onset (p < 0.05 and p < 0.001, respectively) but not at the time of DMARDs-failure or sustained remission achievement (p > 0.05 for both). Stratifying naive RA based on disease duration at ST biopsy, naive RA with symptoms duration >1 year, showed higher Krenn score compared to those with symptoms duration <3 months (p < 0.001). Finally, logistic regression analysis revealed that Krenn score higher or equal to 4.5 at baseline is an independent factor of no DAS remission achievement within 12 months [OR(95%CI):0.37(0.20-0.67)p<0.001] in naive RA. Conclusion Krenn score is a reliable tool for the semi-quantitative assessment of ST inflammation on US-guided ST biopsies being differentially distributed among various chronic inflammatory joint diseases and contingent to disease phase, autoimmune profile and therapeutic response in RA. Disclosures S. Alivernini None. B. Tolusso None. M. Gessi None. M. Gigante None. L. Petricca None. C. Di Mario None. S. Perniola None. A. Fedele None. G. Peluso None. L. Bui None. A. Capacci None. F. Federico None. G. Ferraccioli None. E. Gremese None.

Synovial Predictors of Differentiation to Definite Arthritis in Patients With Seronegative Undifferentiated Peripheral Inflammatory Arthritis: microRNA Signature, Histological, and Ultrasound Features.

Objectives: To examine synovial tissue (ST) predictors of clinical differentiation in patients with seronegative undifferentiated peripheral inflammatory arthritis (UPIA).Methods: Fourty-two patients with IgA/IgM-Rheumatoid Factor and anti-citrullinated peptide antibodies negative UPIA, naive to Disease-Modifying Anti-Rheumatic Drugs, underwent Gray Scale (GSUS) and power Doppler (PDUS) evaluation and Ultrasound (US) guided ST biopsy. CD68, CD3, CD21, CD20, and CD31 synovial expression was evaluated by immunohistochemistry. Whole ST microRNA expression was assessed using miScript miRNA PCR Array. Peripheral blood (PB) and synovial fluid (SF) IL-6, VEGF-A, and VEGF-D levels were measured by ELISA and ST TNF expression was assessed by RT-PCR. Each patient was prospectively monitored and classified at baseline and within 1 year as UPIA, Rheumatoid Arthritis (RA), Spondyloarthritis (SpA) or Psoriatic Arthritis (PsA), respectively.Results: At baseline, CD68+ cells were the most common cells within the lining layer (p < 0.001) in seronegative UPIA, directly correlating with GSUS (R = 0.36; p = 0.02) and PDUS (R = 0.55; p < 0.001). Synovial CD31+ vessels count directly correlated with GSUS (R = 0.41; p = 0.01) and PDUS (R = 0.52; p < 0.001). During the follow-up, 6 (14.3%) UPIA reached a definite diagnosis (2 RA, 2 SpA and 2 PsA, respectively). At baseline, UPIA who differentiated had higher GSUS (p = 0.01), PDUS scores (p = 0.02) and higher histological scores for CD68+ (p = 0.005 and p = 0.04 for lining and sublining respectively), sublining CD3+ cells (p = 0.002), CD31+ vessels count (p < 0.001) and higher IL-6 PB levels (p = 0.01) than patients who remained as UPIA. MiRNA PCR Array showed that among the 86 tested miRNA species, at baseline, miR-346 and miR-214 were significantly down-regulated (p = 0.02 for both) in ST of UPIA who differentiated than in patients who remained as UPIA, inversely correlating with the lining CD68+ cells IHC score (R = −0.641; p = 0.048) and CD31+ vessels count (R = −0.665; p = 0.036) and with higher baseline ST expression of TNF (p = 0.014). Finally, logistic regression analysis demonstrated that baseline GSUS and PDUS scores ≥1.5 [OR:22.93 (95%CI:0.98–534.30)] and CD31+ vessels count ≥24.3 [OR:23.66 (95%CI:1.50–373.02)] were independent factors associated with the development of definite arthritis.Conclusions: MiRNA signature, histological and US features of ST may help in the identification of seronegative UPIA with high likelihood of clinical differentiation toward definite seronegative arthritis.

Australian and New Zealand national evidence-based recommendations for the investigation and follow-up of undifferentiated peripheral inflammatory arthritis: an integration of systematic literature research and rheumatological expert opinion

To develop Australian and New Zealand (ANZ) recommendations for the investigation and follow-up of undifferentiated peripheral inflammatory arthritis (UPIA) using an evidence-based approach. Ten questions pertaining to the investigation and follow-up of patients with UPIA in daily rheumatological practice were defined by clinicians using a modified Delphi approach. A systematic literature search was conducted for each of the final questions. The results were presented to a workshop of 54 ANZ rheumatologists in May 2009. Discussions were held to develop consensus statements for each question, based on published evidence and clinical experience/expertise. Ten recommendations were made on diagnostic value of clinical features in the patient's history and examination, predictors of poor prognosis and persistence, synovial fluid analysis, serology, imaging and human leukocyte antigen B27 testing. The lack of specific research to inform recommendations presented a challenge. Dynamic discussion groups outlined individual experience in areas without good quality clinical trial evidence. The median strength of support for the final set of recommendations was 7/10 (interquartile range 6-8), ranging from 6 to 9 for individual statements. Ten ANZ recommendations for the investigation and follow-up of UPIA were formulated, based on available evidence and extensive clinical experience. The systematic literature review was of limited value while animated discussion of individual experience, with subsequent information exchange, highlighted the importance of merging clinical expertise with published literature to establish practical recommendations that can improve quality of care in rheumatology.

Porphyromonas gingivalis and the pathogenesis of rheumatoid arthritis: analysis of various compartments including the synovial tissue

IntroductionWe evaluated the presence of Porphyromonas gingivalis (Pg) DNA in the synovial tissue through synovial biopsy and in other compartments of rheumatoid arthritis (RA) patients in comparison with patients affected by other arthritides. Possible links with clinical, immunologic and genetic features were assessed.MethodsPeripheral blood (PB), sub-gingival dental plaque, synovial fluid (SF) and synovial tissue samples were collected from 69 patients with active knee arthritis (32 with RA and 37 with other arthritides, of which 14 had undifferentiated peripheral inflammatory arthritis - UPIA). Demographic, clinical, laboratory and immunological data were recorded. The presence of Pg DNA was evaluated through PCR. The HLA-DR haplotype was assessed for 45 patients with RA and UPIA.ResultsNo differences arose in the positivity for Pg DNA in the sub-gingival plaque, PB and SF samples between RA and the cohort of other arthritides. Full PB samples showed a higher positivity for Pg DNA than plasma samples (11.8% vs. 1.5%, P = 0.04). Patients with RA showed a higher positivity for Pg DNA in the synovial tissue compared to controls (33.3% vs. 5.9%, P <0.01). UPIA and RA patients carrying the HLA DRB1*04 allele showed a higher positivity for Pg DNA in the synovial tissue compared to patients negative for the allele (57.1% vs. 16.7%, P = 0.04). RA patients positive for Pg DNA in the sub-gingival plaque had a lower disease duration and a higher peripheral blood leucocyte and neutrophil count. The presence of Pg DNA did not influence disease activity, disease disability or positivity for autoantibodies.ConclusionsThe presence of Pg DNA in the synovial tissue of RA patients suggests a pathogenic role of the bacterium. The higher positivity of Pg DNA in full peripheral blood and synovial tissue samples compared to plasma and synovial fluid suggests a possible intracellular localization of Pg, in particular in patients positive for HLA-DR4.

Pain Management by Pharmacotherapy in Inflammatory Arthritis. Systematic Literature Reviews of the 3e Initiative 2010

The 3e Initiative (Evidence, Expertise, Exchange) is a multinational task force devoted to producing evidence-based recommendations for daily clinical practice in Rheumatology. It is a combination of systematically generated evidence and expert opinions of an international panel of rheumatologists. Since 2006, the 3e initiative has addressed successively the management of Ankylosing Spondylitis1, the use of Methotrexate in Rheumatoid Arthritis2, and the management of patients with Undifferentiated Peripheral Inflammatory Arthritis (UPIA)3, resulting in multinational recommendations on these topics. The 2010 3e collaboration’s objective was to elaborate recommendations on how to manage musculoskeletal pain by pharmacotherapy in inflammatory arthritis, which …

Validation of 3-dimensional ultrasound versus magnetic resonance imaging quantification of popliteal lymph node volume as a biomarker of erosive inflammatory arthritis in mice

Validation of 3-dimensional ultrasound versus magnetic resonance imaging quantification of popliteal lymph node volume as a biomarker of erosive inflammatory arthritis in mice

Algorithm for Identification of Undifferentiated Peripheral Inflammatory Arthritis: A Multinational Collaboration Through the 3e Initiative

To develop an algorithm for identification of undifferentiated peripheral inflammatory arthritis (UPIA). An algorithm for identification of UPIA was developed by consensus during a roundtable meeting with an expert panel. It was informed by systematic reviews of the literature used to generate 10 recommendations for the investigation and followup of UPIA through the 3e initiative. The final recommendations from the 3e UPIA Initiative were made available to the panel to guide development of the algorithm. The algorithm drew on the clinical experience of the consensus panel and evidence from the literature where available. In patients presenting with joint swelling a thorough evaluation is required prior to diagnosing UPIA. After excluding trauma, the differential diagnosis should be formulated based on history and physical examination. A minimum set of investigations is suggested for all patients, with additional ones dependent on the most probable differential diagnoses. The diagnosis of UPIA can be made if, following these evaluations, a more specific diagnosis is not reached. Once a diagnosis of UPIA is established, patients should be closely followed as they may progress to a specific diagnosis, remit, or persist as UPIA, and additional investigations may be required over time. Our algorithm presents a diagnostic approach to identifying UPIA in patients presenting with joint swelling, incorporating the dynamic nature of the condition with the potential to evolve over time.

Clinical Composite Measures of Disease Activity for Diagnosis and Followup of Undifferentiated Peripheral Inflammatory Arthritis: A Systematic Review

To critically appraise the validity of activity indices used in the followup of patients with undifferentiated peripheral inflammatory arthritis (UPIA). A systematic review was performed in Medline, Embase, the Cochrane Library, and abstracts presented at the 2007 and 2008 meetings of the American College of Rheumatology and European League Against Rheumatism. Selection criteria were: patients with UPIA, the assessment of instruments to evaluate disease activity, and assessment of validity of the instruments. Two reviewers screened titles and abstracts independently and collected data using ad hoc standard forms. The search yielded 179 articles and 834 abstracts, of which 4 articles and 1 abstract were included. We found no study that validated Disease Activity Score (DAS), Clinical Disease Activity Index (CDAI), or Simplified Disease Activity Index (SDAI). Included studies addressed validation of 4 questionnaires: WHO Disability Assessment Schedule (WHODAS), London Handicap Scale (LHS), Disease Repercussion Profile (DRP), and the Health Assessment Questionnaire (HAQ); and 3 indexes: RA Disease Activity Index (RADAI), McGill Range of Motion Index (McROMI), and NOAR Damaged Joint Count (NOAR-DJC). Questionnaires were self-administered and feasible; RADAI was the most feasible index. Internal consistency was studied in the questionnaires (Cronbach's α > 0.83). Responsiveness was tested in the DRP, LHS, and HAQ, but the approach to study sensitivity to change was poorly explained, with no clear intervention. Construct validity, examined by means of convergence with other instruments, was generally moderate, and slightly higher for the RADAI. No instrument of disease activity has been fully validated for use in UPIA. We found no direct evidence of what is the most useful index to follow up patients with UPIA.

The Value of Magnetic Resonance Imaging and Ultrasound in Undifferentiated Arthritis: A Systematic Review

To perform a systematic literature review of the diagnostic and prognostic value of magnetic resonance imaging (MRI) and ultrasound (US) in patients with undifferentiated peripheral inflammatory arthritis (UPIA), and to assess if MRI and US should be done at baseline and repeated, and if so, at what interval. Medline, Embase, the Cochrane Library, and abstracts presented at the 2007 and 2008 meetings of the American College of Rheumatology and European League Against Rheumatism meetings were searched for diagnostic and prognostic studies of any duration examining the ability of MRI/US to predict outcome of patients with UPIA. Sensitivity, specificity, predictive values, and positive/negative likelihood ratios (LR+/LR-) were calculated. When available, odds ratios were extracted. Quality was appraised using validated scales. Regarding MRI, 11 out of 2595 screened references were included: 2 described pure undifferentiated arthritis (UA) populations and 9, mixed populations. Bone edema (LR+ 4.5) and combination of a distinct MRI synovitis and erosion pattern (LR+ 4.8) increased probability of developing rheumatoid arthritis (RA). Absence of MRI synovitis (LR- 0.2) and absence of a distinct synovitis pattern (LR- 0) decreased probability of developing RA. Regarding US, 2 out of 2111 references were included, both mixed populations; no data could be extrapolated for UPIA. MRI bone edema and combined synovitis and erosion pattern seem useful in predicting development of RA from UPIA. The value of US in UPIA remains to be determined. The absence of MRI synovitis seems useful in excluding development of RA. No data were found about the value of repeating MRI/US. Studies evaluating MRI/US in UPIA are scarce, but current knowledge strongly encourages further testing in UA.

Diagnostic and Prognostic Value of History-taking and Physical Examination in Undifferentiated Peripheral Inflammatory Arthritis: A Systematic Review

To review the diagnostic and prognostic value of history/physical examination among patients with undifferentiated peripheral inflammatory arthritis (UPIA). We conducted a systematic review evaluating the association between history/physical examination features and a diagnostic or prognostic outcome. Nineteen publications were included. Advanced age, female sex, and morning stiffness were predictive of a diagnosis of rheumatoid arthritis (RA) from UPIA. A higher number of tender and swollen joints, small/large joint involvement in the upper/lower extremities, and symmetrical involvement were associated with progression to RA. Similar features were associated with persistent disease and erosions, while disability at baseline and extraarticular features were predictive of future disability. History/physical examination features are heterogeneously reported. Several features predict progression from UPIA to RA or a poor prognosis. Continued measurements in the UPIA population are needed to determine if these features are valid and reliable predictors of outcomes, especially as new definitions for RA and disease states emerge.

Patients Considered as Having Undifferentiated Peripheral Inflammatory Arthritis: A Systematic Review

To systematically review the differential diagnosis and minimal clinical investigation used prior to making a diagnosis of undifferentiated peripheral inflammatory arthritis (UPIA). A systematic literature search was performed for articles published between January 1950 and December 2008 in Medline and Embase, and for abstracts presented at the 2007 and 2008 meetings of the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR). Studies including defined cohorts of patients with UPIA were retrieved according to predefined inclusion/exclusion criteria. Selected studies were systematically reviewed and relevant data extracted. Baseline characteristics were also recorded to obtain a clinical picture of patients classified as UPIA. Seventy-four articles were included. Of those, 52 reported baseline characteristics. Tremendous variation existed among studies, reflecting the different inclusion/exclusion criteria used. Rheumatoid arthritis, spondyloarthropathies, osteoarthritis, crystal arthritis, connective tissue diseases, and infections were the most common diagnoses of exclusion for UPIA and made up the other subsets of patients in cohorts with mixed populations. The baseline investigation undertaken prior to diagnosis of UPIA was reported in 7 articles. History, physical examination, tender and swollen joint count, rheumatoid factor, HLA-B27, erythrocyte sedimentation rate, C-reactive protein, and radiographs of hands and feet were the only items mentioned in at least 50% of the reports. Studies of UPIA are heterogeneous. Few studies reported on the minimal clinical investigation necessary to arrive at a diagnosis of UPIA. Differential diagnosis usually consisted of the most common rheumatologic conditions but could be vast.

Diagnostic and Prognostic Value of Genetics in Undifferentiated Peripheral Inflammatory Arthritis: A Systematic Review

To evaluate the diagnostic and prognostic utility of genetic testing in undifferentiated peripheral inflammatory arthritis (UPIA). A systematic literature search was performed in Medline, Embase, the Cochrane Library, and abstracts presented at the 2007 and 2008 meetings of the American College of Rheumatology and the European League Against Rheumatism. The target studies were those evaluating diagnostic or prognostic value of genetic markers specifically in UPIA. Two reviewers independently screened titles and abstracts and reviewed included articles in detail. All data were collected using ad hoc standard forms, permitting the calculation of positive and negative likelihood ratios of each genetic marker for diagnoses of different rheumatic diseases and for the development of relevant outcomes. Of the 3109 articles retrieved, 26 original studies fulfilled criteria of the systematic review. The most frequent diagnosis tested was rheumatoid arthritis, followed by inflammatory polyarthritis, and spondyloarthropathies. The main prognostic outcome evaluated was development of erosions, followed by median Larsen score, remission, Health Assessment Questionnaire (HAQ) score, and persistent synovitis. In total, 122 genetic markers were tested. No genetic marker had a high likelihood ratio for the diagnosis of a specific rheumatic disease. The shared epitope was associated with poor prognosis (erosions, HAQ > 1, mortality, and persistent synovitis). Other genes did not predict outcome in undifferentiated arthritis. Other outcomes for persistent disease or disability were not studied in depth. In isolation, no studied genetic marker is very informative of a future diagnosis in patients with UPIA. The shared epitope has a slight association with poor prognosis of UPIA.

How to Investigate and Follow Up Undifferentiated Peripheral Inflammatory Arthritis? 3e Initiative 2008-2009: Systematic Reviews and Clinical Algorithm

The 3e (Evidence, Expertise, Exchange) Initiative in Rheumatology is a multinational effort aimed at generating evidence-based recommendations for common clinical problems. It integrates systematically generated evidence with expert opinion of a broad panel of international rheumatologists. Phases I and II of the 3e Initiative addressed, respectively, the management of ankylosing spondylitis and the use of methotrexate in rheumatoid arthritis. The objective of phase III 2008–2009 was to develop practical recommendations for management of patients with undifferentiated peripheral inflammatory arthritis (UPIA). Patients with UPIA are commonly seen in rheumatology practice and often remain without a specific diagnosis. Their management varies considerably among rheumatologists; there are no widely accepted criteria for diagnosis and no guidance on how to investigate and follow up these patients. In this international project, experts agreed to label as “undifferentiated” those patients with at least one …

Diagnostic and Prognostic Value of Antibodies and Soluble Biomarkers in Undifferentiated Peripheral Inflammatory Arthritis: A Systematic Review

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. 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. 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. Among serological tests, unanimous evidence of substantial diagnostic value exists only for anti-CCP and RF, but is scarce for other markers.

Diagnostic and Prognostic Value of Synovial Biopsy in Adult Undifferentiated Peripheral Inflammatory Arthritis: A Systematic Review

Our aim was to systematically review the literature on the diagnostic and prognostic value of synovial biopsy in undifferentiated peripheral inflammatory arthritis (UPIA) as an evidence base for generating clinical practice recommendations. The results lead to multinational recommendations in the 3e Initiative in Rheumatology. We performed a systematic literature review according to the PICO strategy (Patients, Intervention, Comparator, and Outcome). Using a designed search strategy we ran literature searches using Medline, Embase, the Cochrane Library, and abstracts presented at the 2007 and 2008 meetings of the American College of Rheumatology and European League Against Rheumatism. Articles fulfilling predefined inclusion criteria were reviewed, and quality appraisal was performed. Six publications from a total of 3265 diagnostic and 3271 prognostic studies were included, of which 2 were review articles. Data pooling was impossible because of significant clinical and statistical heterogeneity. Three themes of outcome were identified: anti-citrullinated peptide antibody (ACPA) staining in synovium, immunohistochemistry (CD22, CD38, CD68), and vascular patterns. Prognostic and diagnostic value was poor for these themes, although diagnostic trends favoring a particular diagnosis were identified. In contrast to serological ACPA testing, ACPA staining was shown not to be specific for diagnosis of rheumatoid arthritis (RA). Synovial CD22 and CD38 positivity seem to differentiate between RA and non-RA, while synovial CD38 and CD68 positivity can differentiate among RA, spondyloarthritis (SpA), and other diagnoses. Vascular patterns in undifferentiated arthritis are insufficiently specific to differentiate between SpA and RA. There is sparse evidence that synovial biopsy has diagnostic or prognostic value in patients with UPIA in clinical care. We urgently need systematic studies investigating the diagnostic and prognostic potential of synovial markers. A clear, broadly accepted, and unequivocal definition of undifferentiated arthritis is required as a starting point.

Diagnostic and Predictive Value of Acute-phase Reactants in Adult Undifferentiated Peripheral Inflammatory Arthritis: A Systematic Review

To review the available literature on the diagnostic and predictive value of acute-phase reactants in adult undifferentiated peripheral inflammatory arthritis (UPIA) as an evidence base for generating multinational clinical practice recommendations in the 3e Initiative in Rheumatology. A systematic literature search was carried out using Medline, Embase, the Cochrane Library, and abstracts presented at the 2007 and 2008 meetings of the American College of Rheumatology and European League Against Rheumatism, searching for prognostic and diagnostic markers of acute-phase reactants in adult UPIA. Articles that fulfilled predefined inclusion criteria were systematically reviewed, and the quality was appraised. Likelihood ratios (LR), sensitivity, and specificity for diagnostic and prognostic outcomes were calculated. A total of 18 publications out of 3699 identified references were included in the review. Only a small number of studies with significant heterogeneity, including different outcome measures and different cutoff values, were eligible for review, so pooling data was not possible. Overall, LR showed poor diagnostic and prognostic performance for most investigated acute-phase reactants. Available data showed some value for erythrocyte sedimentation rate in establishing a diagnosis in patients with undifferentiated arthritis; some prognostic and diagnostic value for C-reactive protein; some prognostic value for plasma viscosity in predicting persistence of arthritis; and some diagnostic value for sulfhydryl levels and matrix metalloproteinase-3 in establishing a diagnosis of rheumatoid arthritis. There is little published evidence concerning the diagnostic and predictive value of acute-phase reactants in patients with UPIA. Studies were heterogeneous, and "undifferentiated arthritis" was not well defined or was equivocally defined. The role of acute-phase reactants in diagnosing and predicting outcome in patients presenting with undifferentiated arthritis is limited.