Serologie - Artritis

Publicatiedatum: 13-04-2026

Beoordeeld op geldigheid: 13-04-2026

Uitgangsvraag

Welke autoantilichamen moeten worden bepaald bij patiënten die zich presenteren met artritis om reumatoïde artritis (on)waarschijnlijk te maken?

Aanbeveling

Bepaal bij patiënten die zich presenteren met artritis verdacht voor RA zowel anti-CCP als RF.

Beschouw een positieve uitslag op 1 van de 2 testen als optimaal sensitief om een patiënt met (toekomstige) RA te identificeren, maar houd hierbij rekening met fout-positieve test-uitslagen, met name voor RF.

Overwegingen

Balans tussen gewenste en ongewenste effecten

In totaal zijn er drie systematische reviews (totaal 65 individuele studies) beschreven die de plaats van RF, anti-CCP, RF en anti-CCP, RF en/of anti-CCP, anti-CarP en anti-MCV voor het stellen van de diagnose reumatoïde artritis (RA) hebben beschreven bij patiënten met artritis.

De beschreven resultaten zijn voornamelijk gebaseerd op retrospectieve studies (waaronder een groot gedeelte case-control studies) en zijn uitgevoerd in heterogene studiepopulaties. Daarnaast verschilden de assays en de bijbehorende afkappunten tussen de studies of werden deze niet beschreven. Tenslotte was er een gebrek aan toepasbaarheid, doordat in alle studies reeds gediagnosticeerde patiënten met RA werden opgenomen. De bewijskracht voor de beschreven uitkomstmaten (sensitiviteit en specificiteit) zijn gegradeerd met een GRADE zeer laag.

Hoewel er vanuit de literatuursamenvatting geen harde conclusies getrokken kunnen worden wat betreft de diagnostische waarden van de onderzochte populatie, werd wel gezien dat de specificiteit bij de testen aanmerkelijk hoger ligt dan de sensitiviteit. Dit duidt op een groter vermogen van de test om RA aan te tonen vergeleken met het vermogen om bij patiënten RA uit te sluiten. Uitzondering hierop is, vanwege de lage specificiteit, de test voor RF. Daarnaast werd een grotere spreiding van de specificiteit gezien bij de diagnostische waarde van RF en anti-CCP samen vergeleken met een van de twee biomarkers. Voor de sensitiviteit was dit omgekeerd. Zoals benoemd kunnen hier echter geen definitieve conclusies aan verbonden worden.

Concluderend moet bij bovenstaande getallen bedacht worden dat de genoemde studies veelal niet de meest-relevante situatie hebben onderzocht: namelijk patiënten met (ongedifferentieerde) artritis zonder diagnose die zich voor de eerste keer presenteren bij een reumatoloog. In plaats daarvan is gebruik gemaakt van groepen patiënten die (mogelijk al geruime tijd) een duidelijke reumatologische diagnose hadden. Het lijkt aannemelijk dat hierdoor de sensitiviteit van de diverse testen wordt overschat vergeleken met de praktijk bij patiënten met nieuwe artritis zonder diagnose het geval zou zijn. Immers, uit diverse cohorten van patiënten met “vroege” RA is bekend dat ongeveer 50% anti-CCP-positief is, i.p.v. rond de 70% zoals in deze studies werd gevonden (de Rooy, 2011; Krol, 2015). Bovenstaande studies geven daarom geen uitsluitsel over de diagnostische waarde in de meest relevante situatie voor Nederland. Om deze reden is er aanvullend literatuur-onderzoek verricht naar ongedifferentieerde artritis: zie onder.

Anti-MCV en anti-CarP

Met betrekking tot de nieuwe antilichamen anti-MCV en anti-CarP: deze bepalingen worden veelal in Nederlandse ziekenhuizen/praktijken niet standaard verricht. Uit de literatuur blijkt (met wederom de kanttekening dat dit veelal niet is onderzocht bij vroege ongedifferentieerde artritis) dat anti-MCV een vergelijkbare sensitiviteit heeft met anti-CCP maar wellicht iets lagere specificiteit. Anti-CarP heeft van alle antilichamen de laagste sensitiviteit. Hiermee lijken deze antistoffen vooralsnog geen meerwaarde te hebben voor het stellen van de diagnose RA.

RF en anti-CCP

Bij nadere betrachting van de traditionele antilichamen RF en anti-CCP, blijkt uit een vergelijking van de opties:

A) bepaling van zowel RF als anti-CCP: indien beide negatief zijn, dan levert dit de hoogste sensitiviteit op, dus kan RA met enige zekerheid worden uitgesloten. Indien men een patiënt pas als positief beschouwt indien beide testen positief zijn, is de sensitiviteit daarentegen laag, dus dit is mogelijk een te “strenge” interpretatie waarmee men (seropositieve) RA-patiënten ten onrechte niet als zodanig zou herkennen. Beschouwt men 1 positieve test als voldoende (dus óf RF óf anti-CCP) dan levert dit een redelijk goede sensitiviteit op.

B) bepaling alleen anti-CCP: heeft een redelijk hoge specificiteit en een hogere sensitiviteit dan optie A waarbij beide testen positief moeten zijn.

C) bepaling van alleen RF: lagere specificiteit, met wellicht een iets hogere sensitiviteit dan de bepaling van alleen anti-CCP.

Uiteindelijk is doorslaggevend om bij het aanvragen van de test te bedenken wat de vraagstelling precies is. Op basis van bovenstaande getallen zou men kunnen concluderen dat indien de vraag alleen luidt of er sprake is van RA, men zou kunnen volstaan met alleen een anti-CCP-test.

Hierbij moet bedacht worden dat dit een iets lagere sensitiviteit heeft dan wanneer men zowel anti-CCP als RF laat bepalen, en 1 positieve test als voldoende beschouwt: op deze manier detecteert men zoveel mogelijk RA-patiënten. Deze laatste situatie gaat echter weer gepaard met een duidelijk lagere specificiteit, dus er zullen dan ook patiënten bijzitten met een positieve antilichaam-test die uiteindelijk geen RA hebben.

Aanvullende literatuur bij ongedifferentieerde artritis (IA/UA):
Als aanvulling op de samenvatting van de literatuur vindt de werkgroep het van belang om de waarde van serologische markers bij patiënten met ‘ongedifferentieerde artritis’ te beschrijven. Er is een oriënterende search uitgevoerd in PubMed waarbij de volgende termen zijn gehanteerd: 'undifferentiated arthritis' AND 'prediction model' AND ('anti-CCP' or ''rheumatoid factor'). In totaal zijn vijf artikelen gevonden die informatie beschrijven over de voorspellende waarde van serologische markers voor de ontwikkeling van RA bij patiënten met ongedifferentieerde artritis (Chen, 2013; Ha, 2012; Kuriya, 2009; Li, 2019; van der Helm-van Mil, 2007). Deze studies laten zien dat zowel anti-CCP als RF een voorspellende factor kunnen zijn voor het ontwikkelen van RA bij patiënten met ongedifferentieerde artritis. Details per studie zijn hieronder weergegeven:

In de studie van Chen (2013) ontwikkelde 44/218 (20%) van de patiënten met ongedifferentieerde artritis RA twee jaar na het ‘baseline’ bezoek. De voorspellende waarde van anti-CCP was hoger dan die van RF. De combinatie van beiden was hoger in vergelijking met alleen anti-CCP of RF.
In de studie van Ha (2012) ontwikkelde 32/164 (20%) van de patiënten met ongedifferentieerde artritis RA 6 maanden na het ‘baseline’ bezoek. De voorspellende waarde van anti-CCP was hoger dan die van RF. In het uiteindelijke predictiemodel zijn beide variabelen opgenomen.
In de studie van Kuriya (2009) ontwikkelde 80/105 (76%) van de patiënten met ongedifferentieerde artritis RA 6 maanden na het ‘baseline’ bezoek. De variabele anti-CCP en RF waren beide geassocieerd met de ontwikkeling van RA.
In de studie van Li (2019) ontwikkelde 21/217 (10%) van de patiënten met ongedifferentieerde artritis RA 2 jaar na het ‘baseline’ bezoek. De voorspellende waarde van anti-CCP was hoger dan die van RF. De studie beschrijft dat anti-CCP een onafhankelijke voorspeller voor het ontwikkelen van RA is.
In de studie van der Helm-van Mil (2007) ontwikkelde 177/570 (31%) van de patiënten met ongedifferentieerde artritis RA 2 jaar na het ‘baseline’ bezoek. De voorspellende waarde van anti-CCP was hoger dan die van RF. In het uiteindelijke predictiemodel zijn beide variabelen opgenomen, waarbij aan een positieve anti-CCP-test meer punten werden toegekend dan aan een positieve RF-test.

Concluderend komt uit de literatuur over ongedifferentieerde artritis eenzelfde beeld naar voren als uit de eerder beschreven getallen (in tabel 1) bij patiënten met een duidelijke reumatologische diagnose. Anti-CCP en RF hebben allebei voorspellende waarde voor het ontwikkelen van reumatoide artritis, waarbij de waarde van anti-CCP hoger is dan die van RF.

Waarden en voorkeuren van patiënten (en eventueel hun naasten/verzorgers)

Voor het bepalen van autoantistoffen (in dit geval: anti-CCP en mogelijk ook RF) is een bloedafname noodzakelijk die over het algemeen toch zou plaatsvinden. Anti-CCP en RF kunnen uit dezelfde bloedbuis worden bepaald. Het is belangrijk om patiënten goed te informeren over het te verrichten onderzoek.

Kostenaspecten

De kosten van bepaling van anti-CCP2 en RF zijn relatief laag en spelen geen grote meerwaarde in de besluitvorming.

Gelijkheid ((health) equity/equitable)

De interventie levert geen verschil in gezondheidsgelijkheid op.

Aanvaardbaarheid:

Ethische aanvaardbaarheid

De diagnostiek lijkt aanvaardbaar voor de betrokkenen. Er zijn geen ethische bezwaren die een rol kunnen spelen bij het uitvoeren van de diagnostische tests.

Duurzaamheid

Bij de verschillende diagnostische test zijn er geen belangrijke duurzaamheidsaspecten die een rol spelen.

Haalbaarheid

De diagnostiek is haalbaar. De diagnostiek is over het algemeen al standaardzorg in de dagelijkse praktijk.

Rationale van de aanbeveling: weging van argumenten voor en tegen de interventies

Bij patiënten met (ongedifferentieerde) artritis hebben zowel anti-CCP als RF voorspellende en diagnostische waarde voor de uiteindelijke diagnose reumatoïde artritis. De hoogste sensitiviteit wordt behaald door beide autoantistoffen te bepalen en bij één positieve uitslag de patiënt als seropositief te beschouwen. De hoogste specificiteit wordt behaald wanneer beide testen negatief zijn.

Eindoordeel:

Sterke aanbeveling voor doen.

Onderbouwing

Achtergrond

In patients presenting to a rheumatologist with arthritis, it is common practice to perform both an IgM rheumatoid factor-test and a test for anti-cyclic citrullinated peptide antibodies. However it is unclear:

what the exact predictive value of these tests is for the diagnosis of rheumatoid arthritis;
whether it makes sense to perform both tests instead of one;
whether there is an additive value of performing other autoantibody-tests such as measuring anti-carbamylated protein antibodies (anti-CarP) or anti-Mutated Citrullinated Vimentin (anti-MCV).

This specifically applies to the setting and timing when these autoantibody tests are most frequently requested: upon the first presentation of a patient with arthritis to a rheumatologist. The goal in this setting is to diagnose or exclude rheumatoid arthritis (RA) in a timely fashion, because when RA is found to be present, an early start of treatment has been shown to lead to better disease outcomes.

Conclusies / Summary of Findings

Anti-CCP and RF compared to classification criteria

Very low GRADE

Evidence is inconclusive about the diagnostic values of anti-CCP and RF for RA diagnosis in patients with arthritis, using the classification criteria as reference.

The sensitivity of anti-CCP and RF for RA diagnosis in patients with arthritis ranges from 33% to 80%, using classification criteria as reference.

The specificity of anti-CCP and RF for RA diagnosis in patients with arthritis ranges from 89% to 100%, using classification criteria as reference.

Source: (Sun, 2014)

Anti-CCP or RF compared to classification criteria

Very low GRADE

Evidence is inconclusive about the diagnostic values of anti-CCP or RF for RA diagnosis in patients with suspected RA, using the classification criteria as reference.

The sensitivity of anti-CCP or RF for RA diagnosis in patients with arthritis ranges from 52% to 90%, using classification criteria as reference.

The specificity of anti-CCP or RF for RA diagnosis in patients with arthritis ranges from 66% to 96%, using classification criteria as reference.

Source: (Sun, 2014)

Anti-MCV compared to classification criteria

Very low GRADE

Evidence is inconclusive about the diagnostic values of anti-MCV for RA diagnosis in patients with suspected RA, using classification criteria as reference.

The sensitivity of anti-MCV for RA diagnosis in patients with arthritis ranges from 37% to 95%, using disease controls as reference.

The specificity of anti-MCV for RA diagnosis in patients with arthritis ranges from 59% to 98%, using disease controls as reference.

Source:(Zhu, 2019)

Anti-CCP compared to classification criteria

Very low GRADE

Evidence is inconclusive about the diagnostic values of anti-CCP for RA diagnosis in patients with arthritis, using classification criteria as reference.

The sensitivity of anti-CCP for RA diagnosis in patients with arthritis ranges from 47% to 90%, using disease controls as reference.

The specificity of anti-CCP for RA diagnosis in patients with arthritis ranges from 33% to 99%, using disease controls as reference.

Source: (Zhu, 2019)

RF compared to classification criteria

Very low GRADE

Evidence is inconclusive about the diagnostic values of RF for RA diagnosis in patients with arthritis, using classification criteria as reference.

The sensitivity of RF for RA diagnosis in patients with arthritis ranges from 50% to 98%, using disease controls as reference.

The specificity of RF for RA diagnosis in patients with arthritis ranges from 18% to 91%, using disease controls as reference.

Source: (Zhu, 2019)

Anti-CarP compared to classification criteria

Very low GRADE

Evidence is inconclusive about the diagnostic values of anti-CarP for RA diagnosis in patients with arthritis, using the classification criteria as reference.

The sensitivity of anti-CarP for RA diagnosis in patients with arthritis ranges from 36% to 49%, using classification criteria as reference.

The specificity of anti-CarP for RA diagnosis in patients with arthritis ranges from 79% to 100%, using classification criteria as reference.

Source: (Li, 2019)

Samenvatting literatuur

Description of studies

Sun (2014) performed a meta-analysis to assess the diagnostic accuracy of combined tests of anti-cyclic citrullinated peptide (anti-CCP) antibody and rheumatoid factor (RF) in the diagnosis of RA. A systematic literature research was performed of the database Medline between January 2000 and January 2013. Studies were included if they were observational studies without an intervention imposed by researchers; evaluated the diagnostic accuracy of serum anti-CCP antibody and RF in the same participant group; and provided sufficient data to calculate the diagnostic accuracy when both anti-CCP antibody and RF were positive or either anti-CCP antibody or RF was positive. The 1987 ACR criteria or the 2010 ACR/EULAR criteria were used as the diagnostic reference test. A total of 24 studies were included in the final analysis. These included a total of 8,320 patients of which 44% were RA patients. The control group consisted of healthy controls or patients with other rheumatic diseases. To evaluate heterogeneity among the studies a threshold effect analysis and meta-regression was used. The methodological quality was assessed according to 14 standard items from the QUADAS. Data from the 24 studies were summarized using a random-effect model, to estimate sensitivity, specificity, positive likelihood ratio (LR), negative LR, and diagnostic odds ratio (DOR). About 80% of the studies did not specifically mention whether the final diagnosis was blinded to the interpretation of index tests and vice versa. Furthermore, it was unclear in 71% of the studies whether any uninterpretable data were reported and in 62% of the studies if any participants withdrew.

Zhu (2019) performed a meta-analysis to assess the diagnostic values of anti-mutated citrullinated vimentin (anti-MCV) in the diagnosis for rheumatoid arthritis (RA), compared to anti-cyclic citrullinated peptide (anti-CCP) and rheumatoid factor (RF). To do so, the diagnostic accuracy, including sensitivity, specificity, and the area under the curve (AUC), was compared between anti-MCV, anti-CCP and RF in RA diagnosis against a disease control group (other rheumatic diseases). The ACR classification criteria of 1987 or 2010 were the reference standard. A systematic literature research was performed of the databases Medline, EMBASE, Cochrane Library and Web of Science up to August 2018. Details about inclusion and exclusion criteria are available in the evidence tables. A total of 25 studies, including a total of 9,113 patients (49% RA), achieved the inclusion criteria. Information about the number of participants, age, and male/female distribution is available in the evidence tables. Overall, the information shows a diverse and heterogenic study population. QUADAS-2 was applied to evaluate the quality of the included studies. The primary outcomes were the sensitivity and specificity of the antibody test for the diagnosis of RA. About half of the studies showed a high risk for patient selection because of the case-control design. In addition, around half of the studies presented an unclear risk for flow and timing. Nearly all the studies demonstrated a low risk among all three categories of the concerns regarding applicability.

Li (2019) performed a systematic review and meta-analysis to assess the diagnostic accuracy of anti-carbamylated protein (anti-CarP) antibodies in RA. A systematic literature research was performed of the databases PubMed, EMBASE, Cochrane Library, Web of Science, and Scopus for studies published before January 2019. Studies were included if they examined the diagnostic accuracy of anti-CarP, provided sufficient data to calculate the sensitivity and specificity, included patients diagnosed with RA based on the international classification criteria, healthy controls, and patients with other diseases who were not going to develop RA, and enrolled at least 50 RA patients and 10 controls. A total of 16 studies were included, with a total study population of 10,697 patients (45% RA). The studies were assessed with the QUADAS-1 and 2 tool and a bivariate mixed effects model was used to estimate the diagnostic indexes across studies. The primary outcomes were the sensitivity, specificity, and likelihood ratios (LRs), and diagnostic odds ratio (DOR) of the anti-CarP antibody. A limitation of the included studies is the case-control design, and it was unclear whether the anti-CarP antibody assay was assessed while blinded to the reference standard.

Results

Anti-CCP and RF compared to classification criteria

A total of 22 studies (n = 7,272, 45% RA) within the systematic review by Sun (2014), reported on the outcomes sensitivity and specificity for anti-CCP and RF versus classification criteria. Due to absence of data on detailed number of true positives (TP), false positives (FP), true negatives (TN) and false negatives (FN) in the article by Sun (2014), no forest plots could be developed for these outcomes. For more details, see Figure 3 and Table 2 in the study article by Sun (2014).

Sensitivity

Pooled analysis showed a sensitivity of 57% (95%CI: 55% to 59%) with a range of 33% to 80% for the individual studies. See Figure 3 in study article by Sun (2014).

Specificity

Pooled analysis showed a specificity of 96% (95%CI: 96% to 97%) with a range of 89% to 100% for the individual studies. See Figure 3 in study article by Sun (2014).

Anti-CCP or RF compared to classification criteria

A total of 13 studies (n = 4,345, 46% RA), within the systematic review by Sun (2014), reported on the outcomes sensitivity and specificity for anti-CCP or RF versus classification criteria. Due to absence of data on detailed number of TP, FP, TN and FN in the article by Sun (2014), no forest plot could be developed for these outcomes. For more details, see Figure 3 and Table 2 in the study article by Sun (2014).

Sensitivity

Pooled analysis showed a sensitivity of 78% (95%CI: 76% to 80%) with a range of 52% to 90% for the individual studies. See Figure 3 in study article by Sun (2014).

Specificity

Pooled analysis showed a specificity of 82% (95%CI: 81% to 84%) with a range of 66% to 96% for the individual studies. See Figure 3 in study article by Sun (2014).

Anti-CCP compared to classification criteria

A total of 24 studies (n = 7,217, 51% RA), within the systematic review by Zhu (2019), reported on the outcomes sensitivity and specificity for anti-CCP versus classification criteria. Due to absence of data on detailed number of TP, FP, TN and FN in the article by Zhu (2019), no forest plot could be developed for these outcomes. For more details, see Figure 3 and Table 1 in study article by Zhu (2019).

Sensitivity

Pooled analysis showed a sensitivity of 71% (95%CI: 64% to 77%) with a range of 47% to 90% for the individual studies. See Figure 5 in study article by Zhu (2019).

Specificity

Pooled analysis showed a specificity of 95% (95%CI: 94% to 97%) with a range of 33% to 99% for the individual studies. See Figure 5 in study article by Zhu (2019).

RF compared to classification criteria

A total of sixteen studies (n = 3,538, 56% RA), within the systematic review by Zhu (2019), reported on the outcomes sensitivity and specificity for RF versus classification criteria. Due to absence of data on detailed number of TP, FP, TN and FN in the article by Zhu (2019), no forest plot could be developed for these outcomes. For more details, see Supplementary Figure 5 and Table 1 in study article by Zhu (2019).

Sensitivity

Pooled analysis showed a sensitivity of 77% (95%CI: 68% to 84%) with a range of 50% to 98% for the individual studies. See Supplementary Figure 5 in study article by Zhu (2019).

Specificity

Pooled analysis showed a sensitivity of 73% (95%CI: 63% to 82%) with a range of 18% to 91% for the individual studies. See Supplementary Figure 5 in study article by Zhu (2019).

Anti-MCV compared to classification criteria

A total of 25 studies (n = 8,601, 49% RA), within the systematic review by Zhu (2019), reported on the outcomes sensitivity and specificity for anti-MCV versus classification criteria. Due to absence of data on detailed number of TP, FP, TN and FN in the article by Zhu (2019), no forest plot could be developed for these outcomes. For more details, see Figure 3 and Table 1 in study article by Zhu (2019).

Sensitivity

Pooled analysis showed a sensitivity of 71% (95%CI: 64% to 77%) with a range of 37% to 95% for the individual studies. See Figure 3 in study article by Zhu (2019).

Specificity

Pooled analysis showed a specificity of 89% (95%CI: 85% to 92%) with a range of 59% to 98% for the individual studies. See Figure 3 in study article by Zhu (2019).

Anti-CarP compared to classification criteria

A total of sixteen individual studies, within the systematic review by Li (2019) reported on the outcomes sensitivity and specificity for anti-CarP versus classification criteria. See Figure 1 in study article by Li (2019).

Sensitivity

Pooled analysis showed a sensitivity of 43% (95%CI: 41% to 45%) with a range of 36% to 49%. See Figure 1 in study article by Li (2019).

Specificity

Pooled analysis showed a specificity of 94% (95%CI: 92% to 96%) with a range of 79% to 100%. See Figure 1 in study article by Li (2019).

Level of evidence of the literature

The evidence for all analyzed tests came from diagnostic accuracy studies and therefore starts at GRADE level “high”:

Anti-CCP and RF compared to classification criteria
Anti-CCP or RF compared to classification criteria
Anti-CCP compared to classification criteria
RF compared to classification criteria
Anti-MCV compared to classification criteria
Anti-CarP compared to classification criteria

The level of evidence regarding the outcome measure sensitivity was downgraded by -3 levels to very low because of study limitations (large proportion of case-control studies resulting in high risk of patient selection, no cut-off points provided, -2 levels for risk of bias) and conflicting results (confidence intervals of effect estimate vary largely among individual studies, -1 for inconsistency). Next there was limitation of applicability (established RA patients included, bias due to indirectness).

The level of evidence regarding the outcome measure specificity was downgraded by -3 levels to very low because of study limitations (large proportion of case-control studies resulting in high risk of patient selection, no cut-off points provided, -2 level for risk of bias); and applicability (established RA patients included, -1 level for indirectness).

For an overview of the level of evidence for each test, see Table 2 below.

Table 2. Level of evidence for the sensitivity and specificity of each included test/comparison

Test	Reference	Sensitivity in % (95% CI)	Specificity in % (95% CI)	Level of evidence
Anti-CCP and RF	Classif. crit	57 (55-59) (when both tests positive)	96 (96-97) (when both tests negative)	Very low
Anti-CCP or RF	Classif. crit	78 (76-80) (when 1 of 2 tests positive)	82 (81-84) (when 1 of 2 tests negative)	Very low
Anti-CCP	Classif. crit	71 (64-77)	95 (94-97)	Very low
RF	Classif. Crit	77 (68-84)	73 (63-82)	Very low
Anti-CarP	Classif. Crit	43 (41-45)	94 (92-96)	Very low
Anti-MCV	Classif. Crit	71 (64-77)	89 (85-92)	Very low

Zoeken en selecteren

A systematic review of the literature was performed to answer the following question:

What are the diagnostic values of IgM RF, anti-CCP2, anti-CarP, anti-MCV or IgM RF and anti-CCP2 combined compared to the reference standard (classification criteria) in the diagnosis of rheumatoid arthritis within 2 years in patients presenting with arthritis?

P:	Patients presenting with arthritis
I:	Index test / diagnostic trajectory: IgM RF anti-CCP2 anti-CarP anti-MCV IgM RF and anti-CCP2 combined
C:	Reference standard: diagnosis of rheumatoid arthritis, based on classification criteria, within 2 years
O:	Outcome measure: Diagnostic valies (sensitivity, specificity, NPV, PPV, LRs, ROC AUC)
T/S:	The tests will be administered after higher pretest probability (for arthritis) in patient with clinically suspected arthralgia, based on history, physical examination

Note: Anti-CCP2 en RF are also part of the classification criteria for RA diagnosis (reference standard. Therefore, results should be interpreted with caution.

Relevant outcome measures

The guideline development group considered the diagnostic value of the test as a critical outcome measure for decision making.

The working group defined the following boundaries for a minimal clinically important difference (MCID) both for mutual comparisons between tests and for tests in themselves:

1. The working group defined a MCID of 10% in sensitivity, specificity, PPV and NPV as a minimal clinically (patient) important difference.

2. The working group defined an area under the ROC of 0.80 (with relevant pretest chance ≈ 10 patients to screen for 1 confirmed diagnosis) as a MCID.

A priori, the working group did not define the outcome measures listed above but used the definitions used in the studies.

Table 1. Overview to elaborate consequences for patient

Outcome	Consequence	Consequence relevant for patient	Importance (1-10)
TP	Confirmation of diagnosis	Start treatment	10
TN	Ruling out diagnosis	Continuing diagnostic proces	7
FP	Wrong diagnosis	Possibly incorrect treatment	8
FN	Missing diagnosis	Delayed start of treatment	8
Inconclusive to interpret results	Diagnosis remains unclear	Possibly incorrect or delayed treatment	8
_{TP= true positives, TN= true negatives, FP= false positives, FN= false negatives}

Search and select (Methods)

The databases Medline (via OVID) and Embase (via Embase.com) were searched with relevant search terms until June 17, 2024. The detailed search strategy is depicted under the tab Methods. A systematic search was conducted for systematic reviews and observational studies on autoantibodies to detect or rule out rheumatoid arthritis in patients presenting with arthralgia/arthritis. The systematic literature search resulted in 3725 hits, of which the systematic reviews were initially selected. A total of 18 systematic reviews were initially selected based on title and abstract screening. After reading the full text, fifteen studies were excluded (see the table with reasons for exclusion under the tab Methods), and three studies were included.

Results

Three studies were included in the analysis of the literature. Important study characteristics and results are summarized in the evidence tables. The assessment of the risk of bias is summarized in the risk of bias tables.

Referenties

Chen D, Li H, Liang L, Xiao Y, Xu T, Qiu Q, Lian F, Zhan Z, Ye Y, Xu H, Yang X. Clinical features and independent predictors in the further development of rheumatoid arthritis in undifferentiated arthritis. Rheumatol Int. 2013 Nov;33(11):2827-32. doi: 10.1007/s00296-013-2799-8. Epub 2013 Jul 9. PMID: 23835879.
Ha YJ, Park YB, Son MK, Jung SY, Lee KH, Lee SK. Predictive factors related to progression toward rheumatoid arthritis in Korean patients with undifferentiated arthritis. Rheumatol Int. 2012 Jun;32(6):1555-61. doi: 10.1007/s00296-011-1806-1. Epub 2011 Feb 16. PMID: 21327433.
Krol A, Garred P, Heegaard NH, Christensen AF, Hetland ML, Stengaard-Pedersen K, Junker P, Madsen HO, Lottenburger T, Ellingsen T, Andersen LS, Hansen I, Pedersen JK, Svendsen AJ, Tarp U, Pødenphant J, Lindegaard H, Østergaard M, Hørslev-Petersen K, Jacobsen S. Interactions between smoking, increased serum levels of anti-CCP antibodies, rheumatoid factors, and erosive joint disease in patients with early, untreated rheumatoid arthritis. Scand J Rheumatol. 2015;44(1):8-12. doi: 10.3109/03009742.2014.918651. Epub 2014 Sep 10. PMID: 25205362.
Kuriya B, Cheng CK, Chen HM, Bykerk VP. Validation of a prediction rule for development of rheumatoid arthritis in patients with early undifferentiated arthritis. Ann Rheum Dis. 2009 Sep;68(9):1482-5. doi: 10.1136/ard.2008.092676. Epub 2008 Nov 17. PMID: 19015211.
Li C, Zhang Y, Song H, Gao J, Zhao DB, Zhu Q, He DY, Wang L, Li XP, Liu XD, Xiao WG, Wu XY, Wu HX, Tu W, Hu SX, Wang X, Li ZJ, Lu ZM, Da ZY, Liang B, Liu XM, Zhao JW, Li L, Han F, Qi WF, Wei W, Ma X, Li ZB, Zheng GM, Zhang FX, Li Y, Wang YL, Ling GH, Chen JW, Hou XQ, Zhang J, Chen QP, Liu CL, Zhang Y, Zeng JS, Zou QH, Fang YF, Su Y, Li ZG. Anti-cyclic citrullinated peptide antibody predicts the development of rheumatoid arthritis in patients with undifferentiated arthritis. Chin Med J (Engl). 2019 Dec 20;132(24):2899-2904. doi: 10.1097/CM9.0000000000000570. PMID: 31855969; PMCID: PMC6964957.
Li X, Wang Z, Yi H, Xie J, Zhu N. Diagnostic Accuracy of Anti-Carbamylated Protein Antibodies in Rheumatoid Arthritis: a Systematic Review and Meta-Analysis. Clin Lab. 2019 Dec 1;65(12). doi: 10.7754/Clin.Lab.2019.190419. PMID: 31850723.
de Rooy DP, van der Linden MP, Knevel R, Huizinga TW, van der Helm-van Mil AH. Predicting arthritis outcomes--what can be learned from the Leiden Early Arthritis Clinic? Rheumatology (Oxford). 2011 Jan;50(1):93-100. doi: 10.1093/rheumatology/keq230. Epub 2010 Jul 16. PMID: 20639266.
Sun J, Zhang Y, Liu L, Liu G. Diagnostic accuracy of combined tests of anti cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis: a meta-analysis. Clin Exp Rheumatol. 2014 Jan-Feb;32(1):11-21. Epub 2013 Sep 18. PMID: 24050751.
van der Helm-van Mil AH, le Cessie S, van Dongen H, Breedveld FC, Toes RE, Huizinga TW. A prediction rule for disease outcome in patients with recent-onset undifferentiated arthritis: how to guide individual treatment decisions. Arthritis Rheum. 2007 Feb;56(2):433-40. doi: 10.1002/art.22380. PMID: 17265478.
Zhu JN, Nie LY, Lu XY, Wu HX. Meta-analysis: compared with anti-CCP and rheumatoid factor, could anti-MCV be the next biomarker in the rheumatoid arthritis classification criteria? Clin Chem Lab Med. 2019 Oct 25;57(11):1668-1679. doi: 10.1515/cclm-2019-0167. PMID: 31141478.

Evidence tabellen

Evidence table for systematic reviews of diagnostic test accuracy studies

Study reference

Study characteristics

Patient characteristics

Index test

(test of interest)

Reference test

Follow-up

Outcome measures and effect size

Comments

Sun, 2014

PS., study characteristics and results are extracted from the SR (unless stated otherwise)

Meta-analysis

Literature search between January 2000 and January 2013.

N=24

A: Schellekens, 2000

B: Bizzaro, 2001

C: Bas, 2002

D: Lee, 2003

E: Vallbracht, 2004

F: Mu, 2005

G: Gao, 2005

H: Greiner, 2005

I: Choi, 2005

J: Ates, 2006

K: Matsoi, 2006
L: Kudo-Tanaka, 2007
M: Silveira, 2007
N: Luis Caro-Oleas, 2007
O: Yamane, 2008
P: Abdel-Nasser, 2008
X: Xie, 2009
R: Aflaky, 2009
S: Heidari, 2009
T: Liu, 2009
U: Hodkinson, 2010
V: Liao, 2011
W: Moghimi, 2012

X: Hou, 2012

.....

Study design: the included studies were either cohorts, cross-sectional studies or case controls.

Setting and Country:

No information on setting and country for each individual study.

Source of funding and conflicts of interest:

No competing interests declared. No information provided on source of funding and conflict of interest for the individual studies.

Inclusion criteria SR: Observational studies without intervention

imposed by researchers; Studies that evaluated the diagnostic accuracy of serum anti-CCP antibody and RF in the same participant group; Studies that provided sufficient data to calculate the diagnostic accuracy

when both anti-CCP antibody and

RF were positive / either anti-CCP

antibody or RF was positive; The 1987 ACR criteria or the 2010 ACR/EULAR criteria as diagnostic reference test.

Exclusion criteria SR: studies that provided data of anti-CCP antibody/RF alone; Reviews, conference abstracts, and lettors to editors.

24 studies included

Important patient characteristics:

No information is provided of the important patient characteristics for each individual study.

Describe index and comparator tests* and

cut-off point(s):

All studies used both anti-CCP and RF antibody tests as their index test. No cut-off points are provided in the SR.

Describe reference test and cut-off point(s):

As a reference test 23 studies used the 1987 ACR classification criteria as its diagnostic criteria for RA. Only one study used the ACR/EULAR 2010 criteria. No cut-off points were provided.

No information was provided of the prevalence or the amount of patients with no complete outcome data.

Not applicable.

Outcome measures and effect size (include 95%CI and p-value if available):

Sensitivity / specificity (95% CI) Anti-CCP and RF

(both anti-CCP and RF are positive)

N=22

See detailed information of the sensitivity and specificity per study in figure 3.

Pooled sensitivity [random effect model]:

Anti-CCP and RF

0.57 [95% CI 0.55 to 0.59]

Pooled specificity [random effect model]:

Anti-CCP and RF

0.96 [95% CI 0.96 to 0.97]

Sensitivity / specificity (95% CI) Anti-CCP or RF

(either anti-CCP or RF is positive)

N=13

See detailed information of the sensitivity and specificity per study in figure 3.

Pooled sensitivity [random effect model]:

Anti-CCP or RF

0.78 [95% CI 0.76 to 0.80]

Pooled specificity [random effect model]:

Anti-CCP or RF

0.82 [95% CI 0.81 to 0.84]

Study quality (ROB): QUADAS criteria was used. No results provided per individual study, only percentage of included studies that fulfilled each QUADAS criterion (figure 2).

Place of the index test in the clinical pathway: add-on

Choice of cut-off point: No cut-off point provided or used.

Facultative:

Brief description of author’s conclusion:

Positivity for anti-CCP and RF combined are useful for establishing the diagnosis of RA, especially in early stage of the disease. The combined positivity maximises the probability of true positivity in classifying RA. Because of the decreased diagnostic accuracy, positivity for anti-CCP antibody or RF should be incorporated with other examinations to make a final diagnosis.

Personal remarks:

This study lacks detailed information of the included studies. E.g., no baseline characteristics of the population or setting.,

Heterogeneity:

A stratified analysis was performed to investigate the heterogeneity of the results. When either anti-CCP or RF was positive, both the estimates of sensitivity and specificity revealed a statistically significant heterogeneity across studies. However, the authors do not provide patient characteristics of the study and do not discuss whether these characteristics have enough similarities.

Zhu, 2019

[individual study characteristics deduced from [Zhu, 2019

]]

PS., study characteristics and results are extracted from the SR (unless stated otherwise)

Meta-analysis

Literature search up to August 2018.

N=33

A: Zahran, 2013

B: Yousefghahari, 2013

C: Damjanovska, 2010

D: Iwaskiewics, 2015

E: Nicaise-Roland, 2008

F: Besada, 2011

G: Liu, 2009

H: Nicaise-Roland, 2013

I: Bizzaro, 2007

J: Kim, 2013

K: Maraina, 2010
L: Kaptanoglu.2010
M: Mutlu, 2009

L: Diaz-Toscano, 2014

N: Zhu and Feng, 2013

O: Svard, 2011

P: Soos, 2007
Q: Dejaco, 2006
R: Wagner, 2009
S: Zehairy, 2012
T: Bang, 2007
U: Barouta, 2017
V: Sizova, 2012
W: Lima, 2013
X: Sghiri, 2008
Y: Sahin, 2011
Z: Reyes-Castillo, 2015
AA: Renger, 2010
BB: Mathsson, 2008
CC: El-Babary, 2011
DD: Bartoloni, 2013
EE: Al-Shukaili, 2012
FF: Meyer, 2018

Study design:

A: Cross-sectional

B: Cross-sectional

C: Prospective

D: Cross-sectional

E: Cross-sectional

F: Cross-sectional

G: Cross-sectional

H: Prospective

I: Cross-sectional

J: Cross-sectional

K: Cross-sectional
L: Cross-sectional
M: Prospective

L: Cross-sectional

N: Cross-sectional

O: Prospective

P: Cross-sectional
Q: Cross-sectional
R: Cross-sectional
S: Cross-sectional
T: Cross-sectional

U: Prospective
V: Cross-sectional
W: Cross-sectional
X: Cross-sectional
Y: Cross-sectional
Z: Cross-sectional

AA: Cross-sectional

BB Cross-sectional

CC: Cross-sectional
DD: Cross-sectional

EE: Cross-sectional

FF: Prospective

Setting and Country:

No information provided on setting

A: Egypt

B: Iran

C: Holland

D: Poland

E: Fance

F: Norway

G: China

H: France

I: Italy

J: Korea

K: Malaysia
L: Turkey
M: Turkey

L: Mexico

N: China

O: Sweden

P: America
Q: Austria
R: Austria
S: Egypt
T: Germany
U: Greece
V: Russian
W: Brazil
X: Tunisia
Y: Turkey
Z: Mexico
AA: Germany
BB: Sweden
CC: Egypt
DD: Italy
EE: Oman
FF: South Africa

Source of funding and conflicts of interest:

For the systematic review: There is no research funding declared and the funding organization(s) played

no role in the study design; in the collection, analysis, and

interpretation of data; in the writing of the report; or in the

decision to submit the report for publication.

Inclusion criteria SR:

studies were prospective or retrospective or cross-sectional

study of the diagnostic value of MCV, with

or without CCP and/or RF in RA study with human

subjects;

studies included a healthy and/or other diseases control

groups for comparison;

RA patients fulfilled either the 1987 ACR classification

criteria or the 2010 ACR/EULAR classification criteria,

as which have been approved by the professional and

scientific authorities;

studies evaluated MCV, with or without CCP and/or

RF levels in serum, and were quantitative tests;

studies provided the necessary data, e.g. the number

of true positive, true negative, false positive, and

false negative, sensitivity, specificity, or likelihood

ratios, to construct 2 × 2 contingency tables of levels

of MCV, with or without CCP and/or RF for the diagnosis

of RA.

Exclusion criteria SR: not available in English or if included duplicate data

33 studies included

Important patient characteristics:

Number of patients; characteristics important to the research question; for example, age, sex, bmi, ...

N, (F/M)

RA: rheumatoid arthritis; NRA: non-rheumatoid arthritis, include health control and disease control (including HC: health control and DC: disease control); FDR, first-degree relatives;

A: RA: 22/8

DC: 30/10

HC: 13/7

B: RA: 116/34

DC: 58/17

C: RA: 376/187

DC: 184/167

HC: 99

D: RA: 32/9

DC: 98/30

E: RA: 157

DC: 158

HC: 50

F: RA: 59/16

DC: 28/41

G: RA: 119/51

DC: 76

HC: 60

H: RA: 452/139

DC: 93

I: RA: 90/10

DC: 202

HC: 70/4

J: RA; 135/0

FDR: 153/49

K: RA: 87/13

DC: 125/28
L: RA: 23/11

DC: 22/8
M: RA: 77/16

DC: 58/25

HC: 15/2

L: RA: 135/7

DC: 86

HC: 56

N: RA: 39/17

DC: 30/12

HC: 15/5

O: RA: 215

DC: 52

P: RA: 100/19

DC: 64/10

HC: 29/13
Q: RA: 140/24

DC: 231/72
R: RA: 156/37

DC: 243/89
S: RA: 30; DC: 55
T: RA: 1151; DC: 257; HC: 232
U: RA: 98/43; DC: 31/22; HC: 20/20
V: RA: 211/39; DC: 6
W: RA: 47/3; DC: 26/24; HC: 8/12
X: RA: 139/31; DC: 250; HC: 59
Y: RA: 23/11; HC: 19/5
Z: RA: 149/21; HC: 103
AA: RA: 87/21; DC: 84/38; HC: 139/61
BB: RA: 193/80; HC: 100
CC: RA: 75/25; HC: 80/20
DD: RA: 285; DC: 136; HC: 91
EE: RA: 71/9; HC: 70/63
FF: RA: 61/14; HC: 19/11; DC: 46

Age, years

A: RA: 25-65; DC: 34-74; HC: 33-48

B: RA: 49.6 ± 11.8; DC: 48.8 ± 12

C: RA: 56.9 ± 15; DC: 45.9 ±16.8

D: RA: 51.7 ± 11.8; DC: 46.1 ±15.2

E: No information

F: RA: 64 ± 15

G: RA: 16- 83

H: RA: 49.06 ± 11.95

I: RA: 64 (40 – 86); HC: 63 (36-74)

J: RA: 53.6 ±10.7; FDR: 26.3 ±11.1

K: RA: 50.0; DC: 49.9
L: RA: 48.91 ±11.64; DC: 57.73 ±11.62
M: RA: 53.8 (26-76); HC: 51 (25-71)

L: RA: 49 ± 10.69

N: RA: 45 (19-71); DC: 47 (26-68); HC: 46 (23-69)

O: Unclear

P: RA: 52.7 ±12.5
Q: RA: 60.4 ±12.0; DC: 58.5 ±15.7
R: RA: 65.30 (36-89); DC: 59 (30-83)
S: Unclear
T: Unclear
U: RA: 60.91 ± 10.87; DC: 53.0 ±15.34; HC: 60.05 ±7.35
V: RA: 46.12 ±11.81
W: RA: 55 ±13; DC: 48 ±17
X: RA: 17-18
Y: RA: 50 (23-76); HC: 45 (28-61)
Z: RA: 47 ±12
AA: RA: 57.9 ±13.8; DC: 57.1 ±14; HC: 47.4 ±19.1
BB: RA: 57.0
CC: RA: 51 (37-65); HC: 48 (36-61)
DD: No information
EE: RA: 41.6 ±14.5
FF: RA: 48 (19); HC: 46

Describe index and comparator tests* and

cut-off point(s):

For all studies, the index test is the Anti-MCV test, the anti-CCP and/or the RF. Most studies used all three index tests.

Cut-off values differed per studie, see for more information table 1. In general;

The cut-off value for anti-MCV ranged from 11.85 U/mL up to 172 U/mL. 25 of the 33 studies used 20 U/mL as cut-off value.

The cut-off value for anti-CCP ranged from 5 U/mL up to 25 U/mL..

The cut-off value for anti-CCP ranged from 6 U/mL up to 50 U/mL..

Describe reference test and cut-off point(s):

As a reference test the 1987 ACR classification criteria was used as its diagnostic criteria for RA. Only one study used the ACR/EULAR 2010 criteria (study D). See table 1 for more information. No cut-off points were provided.

No information provided of the prevalence or the amount of patients with no complete outcome data.

Not applicable.

However, table 1 does provide information on the duration of RA per study which ranges from < 3 months up to > 10 years.

Outcome measures and effect size (include 95%CI and p-value if available):

Diagnostic value of anti-MCV with RA (95% CI) against a disease control group

Studies used for pooled analyses (25/33): A – U, W, and FF)

Sensitivity: 0.71 [0.64 – 0.77)

Specificity: 0.89 [0.85 – 0.92]

Diagnostic value of anti-CCP with RA (95% CI) against a disease control group

Studies used for pooled analyses (24/33): A – S, U, W, DD, and FF)

Sensitivity: 0.71 [0.64 – 0.77]

Specificity: 0.95 [0.94 – 0.97]

Diagnostic value of RF with RA (95% CI) against a disease control group

Studies used for pooled analyses (16/33): A, E, - G, I – M, N, P, Q, S, U, W, and FF)

Sensitivity: 0.77 [0.68 – 0.84]

Specificity: 0.73 [0.63 – 0.82]

Study quality (ROB): method used and results per individual study are present.

Place of the index test in the clinical pathway: add-on.

Choice of cut-off point: The cut-off points of the individual studies were used.

Facultative:

Brief description of author’s conclusion

In summary, anti-MCV demonstrates a comparable

diagnostic value to anti-CCP and RF, therefore is suggested

as an alternative biomarker for RA classification in

clinical practice, and may be written into the next authoritative

criteria.

Personal remarks on study quality, conclusions, and other issues (potentially) relevant to the research question:

Sensitivity analyses

The SR performed sensitivity and specificity analyses in subgroups, e.g., 19 studies that used ELISA as its testing method for MCV with a cutoff set to 20 U/mL. However, the combined sensitivity and specificity showed no difference compared to the original pooled analyses. The subgroup of the prospective study predesign demonstrated the lowest heterogeneity for both sensitivity and specificity and compared with all the other results in the review.

Heterogeneity:

Heterogeneity is examined. This is partly explained in the discussion section.
- different kinds of specific testing methods and reagents, as well as the different

cutoffs set by individual researchers, which varied

in different laboratories or institutions and across time.

In addition, certain baseline clinical characteristics of RA

patients may probably contribute to the heterogeneity,

such as baseline inflammation indicators.

Li, 2019

PS., study characteristics and results are extracted from the SR (unless stated otherwise)

Meta-analysis

Literature search up to December 2019.

N=16

A: Shi, 2011

B: Montes, 2014

C: Shi, 2015

D: Pecani, 2015

E: Alessandri, 2015

F: Brink, 2015

G: Janssen, 2015

H: Verheul, 2015

I: Pecani, 2016

J: Koppejan, 2016
K: Challener, 2016
L: Verheul, 2016
M: Nakabo, 2017
N: Van Delf, 2017
O: Spinelli, 2017
P: Verheul, 2017

Study design: All studies have a case-control design

Setting and Country:

No information provided

Source of funding and conflicts of interest:

The SR was supported by the National Natural Science Foundation of China, Natural Science Foundation of Zhejiang Province3, and Natural Science Foundation of Shang-hai. The authors of the SR have no competing interests to declare.

Inclusion criteria SR:

included if they examined the diagnostic accuracy of anti-CarP, provided sufficient data to calculate the sensitivity and specificity, included patients diagnosed with RA based on the international diagnosis criteria, healthy controls, and patients with other disease who were not going to develop RA, and enrolled at least 50 RA patients and 10 controls.

Exclusion criteria SR:

No exclusion criteria mentioned

16 studies included

Important patient characteristics:

Table 1 and table 2 describes important information on the patient groups (both country and health or other disease), the number of patients, proportion female (%), disease duration and median age (yrs) for both the diseased and control group, for each individual study.

The age of the RA group ranged from 45 – 63, the median age of the healthy controls ranged from 26 – 63.

The disease duration ranged from a median of 7 months up to > 20 years.

Describe index and comparator tests* and

cut-off point(s):

All studies use as method (antigen, type) an ELISA (FCS, IgG). Cut-off can be found in Table 1.

Describe reference test and cut-off point(s):

Reference test; cut-off

A: 1987 ACR; mean + 2 SD

B: 1987 ACR; mean + 2 SD

C: 1987 ACR; mean + 2 SD

D: 2010 ACR; NR

E: 2010 ACR; mean + 3 SD

F: 1987 ACR; a specificity of 97% of ROC curves

G: Established; mean + 2 SD

H: 1987 ACR; a specificity of 97% of ROC curves

I: 2010 ACR; mean + 3 SD

J: 1987 ACR; mean + 2 SD
K: 1987 ACR; mean + 2 SD
L: 1987 ACR; a specificity of 97% of ROC curves
M: Established; mean + 2 SD
N: 1987 ACR; mean + 2 SD
O: 2010 ACR; mean + 3 SD
P: 1987 ACR; mean + 2 SD

No information provided of the prevalence or the amount of patients with no complete outcome data.

Not applicable.

Table 2 describes the TP, FP, FN, TN, sensitivity, and specificity of all 16 individual studies.

Diagnostic value of anti-CarP antibody in detecting RA (% (95% CI)).

All studies are used for this pooled analyses

Sensitivity: 43.1% (95% CI, 41% to 45.2%)

Specificity: 94.4% (95% CI, 91.1% to 96.1%)

Subgroup analyses of studies having healthy individuals as control

16 studies are used for this pooled analyses

Sensitivity: 43% (95% CI, 40.9 % to 45.2%)

Specificity: 96.8% (95% CI, 96% to 97.5%)

Subgroup analyses of studies having a mixture of healthy individuals or other diseases as control.

8 studies are used for this pooled analyses

Sensitivity: 43.4% (95% CI, 41.3 % to 45.5%)

Specificity: 89.8% (95% CI, 83.4% to 93.9%)

Study quality (ROB): Both the QUADAS-1 and QUADAS-2 tools were used. Based on the QUADAS-1 the mean quality score was 11, and 11/16 studies had a score > 10.

Place of the index test in the clinical pathway: add-on

Choice of cut-off point: influences test characteristics (sens, spec); important in relation to the clinical question (e.g. if a disease is to be ruled out, sensitivity is the critical outcome measure and more important than specificity: high sensitivity comes at the expense of low specificity and high rates of false postives, and usually those testing positive are subjected to further diagnostic tests for final diagnosis)

Facultative:

Brief description of author’s conclusion:

Overall, with high specificity but relatively low sensitivity, the anti-CarP antibody is a meaningful serological biomarker for RA. However, due to the low sensitivity (43.1%) and the negative LR (0.603), this suggests that RA can not be excluded if the anti-CarP antibody test is negative.

Personal remarks on study quality, conclusions, and other issues (potentially) relevant to the research question:

none

Sensitivity analyses:

The subgroup analyses were only performed when heterogeneity existed to examine the potential source of theterogeneity, see section heterogeneity below.

Heterogeneity:

The meta-regression analysis showed that the study quality was not the source of heterogeneity. Especially the I² of the specificity was high (≥ 50), which could be partly explained by the higher specificity in the ‘healthy control’ group (16 studies) than in the ‘other diseases’ group (8 studies).

Table of quality assessment for systematic reviews of diagnostic studies

Based on AMSTAR checklist (Shea et al.; 2007, BMC Methodol 7: 10; doi:10.1186/1471-2288-7-10) and PRISMA checklist (Moher et al 2009, PLoS Med 6: e1000097; doi:10.1371/journal.pmed1000097)

Study First author, year	Appropriate and clearly focused question?¹ Yes/no/unclear	Comprehensive and systematic literature search?² Yes/no/unclear	Description of included and excluded studies?³ Yes/no/unclear	Description of relevant characteristics of included studies?⁴ Yes/no/unclear	Assessment of scientific quality of included studies?⁵ Yes/no/unclear	Enough similarities between studies to make combining them reasonable?⁶ Yes/no/unclear	Potential risk of publication bias taken into account?⁷ Yes/no/unclear	Potential conflicts of interest reported?⁸ Yes/no/unclear
Sun, 2014	Yes, although PICO was missing	Yes, the search strategy for MEDLINE (only database used) is provided in the method section.	No, the flow chart of the study selection is provided in figure 1 but no reasons for exclusion are mentioned.	No, there is no information provided. Only a short summary in the result section (section: Characteristics of studies)	Yes, using the QUADAS-2 tool. Information provided in result section, figure 2.	Unclear, characteristics of individual studies are not mentioned.	Yes, publication bias was not statistical significant (data not shown).	Unclear, mentioned for the SR but not for the individual studies.
Zhu, 2019	Yes, although PICO was missing.	No, there is no information provided of the specific search strategy per database.	Yes, summarized in figure 1.	Yes, mentioned in table 1	Yes, using the QUADAS-2 tool. Information provided in result section, figure 2.	Unclkear, many variables differed between the studies ( see table 1, incl age, country, F/M distribution, test cutoff values and duration of RA)[FP1] [MV2] [FP3] [MV4] . The authors did perform sensitivity analyses in subgroups.	Yes, the authors discuss and examined the potential risk of publication bias. A low likelihood of publication bias was observed.	Unclear, mentioned for the SR but not for the individual studies.
Li, 2019	Yes, although PICO is missing.	Yes, detailed search strategy per database (supplementary material 1 – Table 1)	Yes, there is a lists of excluded studies and its reasons (supplementary material 1 – Table 2)	Yes, mentioned in the baseline characteristics table.	Yes, both the QUADAS-1 and the QUADAS-2 tools were used.	Unclear, characteristics of individual studies are not mentioned.	Yes, the Deek’s test revealed little publication bias in the studies.	Unclear, mentioned for the SR but not for the individual studies.

_{^1. Research question (PICO) and inclusion criteria should be appropriate (in relation to the research question to be answered in the clinical guideline) and predefined}

_{^2. Search period and strategy should be described; at least Medline searched}

_{^3. Potentially relevant studies that are excluded at final selection (after reading the full text) should be referenced with reasons}

_{^4. Characteristics of individual studies relevant to the research question (PICO) should be reported}

_{^5. Quality of individual studies should be assessed using a quality scoring tool or checklist (preferably QUADAS-2; COSMIN checklist for measuring instruments) and taken into account in the evidence synthesis}

_{^6. Clinical and statistical heterogeneity should be assessed; clinical: enough similarities in patient characteristics, diagnostic tests (strategy) to allow pooling? For pooled data: at least 5 studies available for pooling; assessment of statistical heterogeneity and, more importantly (see Note), assessment of the reasons for heterogeneity (if present)? Note: sensitivity and specificity depend on the situation in which the test is being used and the thresholds that have been set, and sensitivity and specificity are correlated; therefore, the use of heterogeneity statistics (p-values; I2) is problematic, and rather than testing whether heterogeneity is present, heterogeneity should be assessed by eye-balling (degree of overlap of confidence intervals in Forest plot), and the reasons for heterogeneity should be examined.}

_{^7. There is no clear evidence for publication bias in diagnostic studies, and an ongoing discussion on which statistical method should be used. Tests to identify publication bias are likely to give false-positive results, among available tests, Deeks’ test is most valid. Irrespective of the use of statistical methods, you may score “Yes” if the authors discuss the potential risk of publication bias.}

_{^8. Sources of support (including commercial co-authorship) should be reported in both the systematic review and the included studies. Note: To get a “yes,” source of funding or support must be indicated for the systematic review AND for each of the included studies.}

Table of excluded studies

Reference	Reason for exclusion
Abdelhafiz D, Baker T, Glascow DA, Abdelhafiz A. Biomarkers for the diagnosis and treatment of rheumatoid arthritis - a systematic review. Postgrad Med. 2023 Apr;135(3):214-223. doi: 10.1080/00325481.2022.2052626. Epub 2022 Mar 16. PMID: 35275765.	No meta-analysis performed, only literatuur from past 2 years.
Motta F, Bizzaro N, Giavarina D, Franceschini F, Infantino M, Palterer B, Sebastiani GD, Selmi C. Rheumatoid factor isotypes in rheumatoid arthritis diagnosis and prognosis: a systematic review and meta-analysis. RMD Open. 2023 Aug;9(3):e002817. doi: 10.1136/rmdopen-2022-002817. PMID: 37541740; PMCID: PMC10407415.	Specific on RF isotopes, no according to PICO.
Yang X, Cai Y, Xue B, Zhang B. Diagnostic value of anti-cyclic citrullinated peptide antibody combined with rheumatoid factor in rheumatoid arthritis in Asia: a meta-analysis. J Int Med Res. 2021 Sep;49(9):3000605211047714. doi: 10.1177/03000605211047714. PMID: 34590880; PMCID: PMC8489771.	Specific on Asian population and focus only on combination of RF and anti-CCP. No added value with regard to Zhu (2019).
Verheul MK, Böhringer S, van Delft MAM, Jones JD, Rigby WFC, Gan RW, Holers VM, Edison JD, Deane KD, Janssen KMJ, Westra J, Brink M, Rantapää-Dahlqvist S, Huizinga TWJ, van der Helm-van Mil AHM, van der Woude D, Toes REM, Trouw LA. Triple Positivity for Anti-Citrullinated Protein Autoantibodies, Rheumatoid Factor, and Anti-Carbamylated Protein Antibodies Conferring High Specificity for Rheumatoid Arthritis: Implications for Very Early Identification of At-Risk Individuals. Arthritis Rheumatol. 2018 Nov;70(11):1721-1731. doi: 10.1002/art.40562. Epub 2018 Sep 16. PMID: 29781231.	No added value above other included reviews, no pooled analysis performed.
Mathsson Alm L, Fountain DL, Cadwell KK, Madrigal AM, Gallo G, Poorafshar M. The performance of anti-cyclic citrullinated peptide assays in diagnosing rheumatoid arthritis: a systematic review and meta-analysis. Clin Exp Rheumatol. 2018 Jan-Feb;36(1):144-152. Epub 2017 Nov 28. PMID: 29185968.	Focus on comparison between different available anti-CCP tests. No added value.
Li L, Deng C, Chen S, Zhang S, Wu Z, Hu C, Zhang F, Li Y. Meta-Analysis: Diagnostic Accuracy of Anti-Carbamylated Protein Antibody for Rheumatoid Arthritis. PLoS One. 2016 Jul 20;11(7):e0159000. doi: 10.1371/journal.pone.0159000. PMID: 27437936; PMCID: PMC4954701.	No added value above other included reviews, Li (2019) more recent.
Lee YH, Bae SC, Song GG. Diagnostic accuracy of anti-MCV and anti-CCP antibodies in rheumatoid arthritis: A meta-analysis. Z Rheumatol. 2015 Dec;74(10):911-8. doi: 10.1007/s00393-015-1598-x. PMID: 26111961.	Full tekst not available. Same biomarkers as Zhu (2019).
Zhang WC, Wu H, Chen WX. Meta-analysis: diagnostic accuracy of anti-cyclic citrullinated peptide 2 antibody and anti-cyclic citrullinated peptide 3 antibody in rheumatoid arthritis. Clin Chem Lab Med. 2014 Jun;52(6):779-90. doi: 10.1515/cclm-2013-0798. PMID: 24445240.	Older review, no added value.
Gao F, Ren L, Zhang CQ, Mu FY, You YQ, Liu YH. Diagnostic value of anti-cyclic citrullinated peptide antibody for rheumatoid arthritis in a Chinese population: a meta-analysis. Rheumatol Int. 2012 Oct;32(10):3201-18. doi: 10.1007/s00296-011-2153-y. Epub 2011 Sep 30. PMID: 21960046.	Only studies on Chinese population
Qin X, Deng Y, Xu J, Li TJ, Li S, Zhao JM. Meta-analysis: diagnostic value of serum anti-mutated citrullinated vimentin antibodies in patients with rheumatoid arthritis. Rheumatol Int. 2011 Jun;31(6):785-94. doi: 10.1007/s00296-009-1343-3. Epub 2010 Mar 10. PMID: 20221607.	Older review, no added value.
Schoels M, Bombardier C, Aletaha D. Diagnostic and prognostic value of antibodies and soluble biomarkers in undifferentiated peripheral inflammatory arthritis: a systematic review. J Rheumatol Suppl. 2011 Mar;87:20-5. doi: 10.3899/jrheum.101070. PMID: 21364052.	Older review, no added value.
Taylor P, Gartemann J, Hsieh J, Creeden J. A systematic review of serum biomarkers anti-cyclic citrullinated Peptide and rheumatoid factor as tests for rheumatoid arthritis. Autoimmune Dis. 2011;2011:815038. doi: 10.4061/2011/815038. Epub 2011 Sep 11. Erratum in: Autoimmune Dis. 2012;2012:734069. PMID: 21915375; PMCID: PMC3170888.	Older review, no added value.
Whiting PF, Smidt N, Sterne JA, Harbord R, Burton A, Burke M, Beynon R, Ben-Shlomo Y, Axford J, Dieppe P. Systematic review: accuracy of anti-citrullinated Peptide antibodies for diagnosing rheumatoid arthritis. Ann Intern Med. 2010 Apr 6;152(7):456-64; W155-66. doi: 10.7326/0003-4819-152-7-201004060-00010. PMID: 20368651.	Older review, no added value.
Nishimura K, Sugiyama D, Kogata Y, Tsuji G, Nakazawa T, Kawano S, Saigo K, Morinobu A, Koshiba M, Kuntz KM, Kamae I, Kumagai S. Meta-analysis: diagnostic accuracy of anti-cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis. Ann Intern Med. 2007 Jun 5;146(11):797-808. doi: 10.7326/0003-4819-146-11-200706050-00008. PMID: 17548411.	Older review, no added value.
Avouac J, Gossec L, Dougados M. Diagnostic and predictive value of anti-cyclic citrullinated protein antibodies in rheumatoid arthritis: a systematic literature review. Ann Rheum Dis. 2006 Jul;65(7):845-51. doi: 10.1136/ard.2006.051391. Epub 2006 Apr 10. PMID: 16606649; PMCID: PMC1798205.	Older review, no added value.

Verantwoording

Beoordelingsdatum en geldigheid

Publicatiedatum : 13-04-2026

Beoordeeld op geldigheid : 13-04-2026

Initiatief en autorisatie

Initiatief:

Nederlandse Vereniging voor Reumatologie

Geautoriseerd door:

Nederlandse Vereniging voor Nucleaire geneeskunde
Nederlandse Vereniging voor Pathologie
Nederlandse Vereniging voor Radiologie
Nederlandse Vereniging voor Reumatologie
Verpleegkundigen en Verzorgenden Nederland
Nederlandse Vereniging voor Klinische Chemie en Laboratoriumgeneeskunde
ReumaNederland
Nationale Vereniging ReumaZorg Nederland

Algemene gegevens

De ontwikkeling/herziening van deze richtlijnmodule werd ondersteund door het Kennisinstituut van de Federatie Medisch Specialisten (www.demedischspecialist.nl/kennisinstituut) en werd gefinancierd door de Stichting Kwaliteitsgelden Medisch Specialisten (SKMS). Patiëntenparticipatie bij deze richtlijn werd medegefinancierd uit de Kwaliteitsgelden Patiënten Consumenten (SKPC) binnen het programma Kwaliteit, Inzicht en Doelmatigheid in de medisch specialistische Zorg (KIDZ). De financier heeft geen enkele invloed gehad op de inhoud van de richtlijnmodule.

Samenstelling werkgroep

Voor het ontwikkelen van de richtlijnmodule is in 2023 een multidisciplinaire werkgroep ingesteld, bestaande uit vertegenwoordigers van alle relevante specialismen (zie hiervoor de Samenstelling van de werkgroep) die betrokken zijn bij de zorg voor patiënten met een inflammatoire (reumatische) aandoening.

Werkgroep

Dr. S.M. van der Kooij (voorzitter), reumatoloog, werkzaam in HagaZiekenhuis, NVR.
Dr. A.A. den Broeder, reumatoloog en klinisch epidemioloog, werkzaam in Sint Maartensklinkiek en Radboud Universitair Medische Centrum, NVR.
Prof. Dr. D. van der Woude, reumatoloog, werkzaam in Leids Universitair Medisch Centrum, NVR.
Drs. T. de Mooij, AIOS reumatologie, werkzaam in Erasmus Medisch Centrum, NVR.
Drs. Z. Kerami, reumatoloog, werkzaam in Dijklander Ziekenhuis, NVR (tot december 2024, vanaf mei 2025 werkzaam als reumatoloog bij NHS Lothian).
Dr. M.A. Korteweg, radioloog, Reade, NVvR.
Dr. W. van der Bruggen, nucleair geneeskundige, werkzaam in Slingeland Ziekenhuis en Streekziekenhuis Koningin Beatrix, NVNG.
Dr. M.C.F.J. de Rotte, klinisch chemicus, werkzaam in Amsterdam Universitair Medisch Centrum, NVKC.
MSc. J. Postma, verpleegkundig specialist reumatologie, werkzaam in Martini Ziekenhuis, V&VN.
Drs. H. Koning, patiëntvertegenwoordiger, Nationale Vereniging ReumaZorg Nederland.

Klankbordgroep

P. Borsje, ervaringsdeskundige en beleidsmedewerker Patiëntenparticipatie en Communicatie, Nationale Vereniging ReumaZorg Nederland, Nationale Vereniging ReumaZorg Nederland.

Met ondersteuning van

Dr. L. Küpers , adviseur, Kennisinstituut van de Federatie Medisch Specialisten.
Dr. M.M.A. Verhoeven, adviseur, Kennisinstituut van de Federatie Medisch Specialisten tot april 2025.
Drs. J.M.H. van der Hart MSc, adviseur, Kennisinstituut van de Federatie Medisch Specialisten vanaf april 2025.
Drs. F.A. Pepping MSc, junior adviseur, Kennisinstituut van de Federatie Medisch Specialisten.

Belangenverklaringen

Een overzicht van de belangen van werkgroepleden en het oordeel over het omgaan met eventuele belangen vindt u in onderstaande tabel. De ondertekende belangenverklaringen zijn op te vragen bij het secretariaat van het Kennisinstituut van de Federatie Medisch Specialisten via secretariaat@kennisinstituut.nl.

Tabel Gemelde (neven)functies en belangen werkgroep

Werkgroeplid	Functie	Nevenfuncties	Gemelde belangen	Ondernomen actie
Dr S.M. van der Klooij (voorzitter), NVR	Reumatoloog	-	-	Geen
Dr. A.A. den Broeder, NVR	Reumatoloog en epidemioloog	- Expert advisering ZIN - WAR ReumaNederland - Associate editor Rheumatology	Extern gefinancierd onderzoek door o.a. ZonMw, Abbvie, Galapagos en Novartis. Geen raakvlakken met richtlijnmodules.	Geen
Prof. Dr. D. van der Woude, NVR	Reumatoloog	- Docent Antonius Academy Nieuwegein - Lid Scientific Committee FOREUM - Hoofdredacteur Nederlands Tijdschrift voor Reumatologie - Sectie-redacteur reumatologie Nederlands Tijdschrift voor Geneeskunde - Advisory board Galapagos (gebruik van JAK-remmers, 2019 en 2020)	Onderzoek gefinancierd door ZonMw, NWO en FOREUM. Geen raakvlakken met richtlijnmodules.	Geen
Drs. T. de Mooij, NVR	AIOS reumatologie	-	-	Geen
Drs. Z. Kerami, NVR	Reumatoloog	-	-	Geen
Dr. M.A. Korteweg, NVvR	Radioloog	- Radioloog waarnemer Bovenij ziekenhuis, Acibadem,in Kralendijk Bonaire - Docent Schola medica en Neac - Annotator Quantitas Solutions -PI ESSR uniform grading CT scans of SIjoints -reviewer ECR	-	Geen
Dr. W. van der Bruggen, NVNG	Nucleair geneeskundige	-	-	Geen
Dr. M.C.F.J. de Rotte, NVKC	Klinisch chemicus	Vakspecialist-auditor Raad voor accredatie	Meerdere onderzoeksproejcten in personalized medicine of methotrexaat bij RA (niet extern gefinancierd, geen raakvlakken met richtlijn).	Geen
MSc. J. Postma, V&VN	Verpleegkundig specialist reumatologie	Deelname ontwikkeling ‘ziektekaarten in beeld’ ReumaZorg Nederland	Online sessie ‘patient journey’ reumapatienten Pfizer (eenmalig, geen raakvlakken met richtlijn)	Geen
Drs. H. Koning, ReumaZorg Nederland	Patiëntvertegenwoordiger	- Referent Patientenfederatie Nederland - Projectmanager, Julius Centrum UMCU (tot 1 december 2025)	-	Geen

Inbreng patiëntenperspectief

De werkgroep besteedde aandacht aan het patiëntenperspectief door een afgevaardigde van de patiëntenvereniging Nationale Vereniging ReumaZorg Nederland. De conceptrichtlijn is tevens voor commentaar voorgelegd aan deze patiëntenvereniging en de eventueel aangeleverde commentaren zijn bekeken en verwerkt.

Kwalitatieve raming van mogelijke financiële gevolgen in het kader van de Wkkgz

Bij de richtlijnmodule voerde de werkgroep conform de Wet kwaliteit, klachten en geschillen zorg (Wkkgz) een kwalitatieve raming uit om te beoordelen of de aanbevelingen mogelijk leiden tot substantiële financiële gevolgen. Bij het uitvoeren van deze beoordeling is de richtlijnmodule op verschillende domeinen getoetst (zie het stroomschema bij Werkwijze).

Module	Uitkomst raming	Toelichting
Serologie - Artritis	Geen financiële gevolgen	Uit de toetsing volgt dat de aanbeveling(en) niet breed toepasbaar zijn (<5.000 patiënten per jaar). Daarnaast volgt uit de toetsing dat het overgrote deel van de zorgaanbieders en zorgverleners al aan de norm voldoet. Daarom worden geen substantiële financiële gevolgen verwacht.

Werkwijze

Voor meer details over de gebruikte richtlijnmethodologie verwijzen wij u naar de Werkwijze. Relevante informatie voor de ontwikkeling/herziening van deze richtlijnmodule is hieronder weergegeven.

Zoekverantwoording

Algemene informatie

Cluster/richtlijn: Diagnostiek bij verdenking reumatoïde artritis - UV4 en UV6 lab artralgie of artritis serologie parameters
Uitgangsvraag/modules: Welke autoantilichamen moeten worden bepaald bij patiënten die zich presenteren met artralgie/ artritis om reumatoïde artritis aan te tonen dan wel uit te sluiten?
Database(s): Embase.com, Ovid/Medline	Datum: 17 juni 2024
Periode: vanaf 2000	Talen: geen restrictie
Literatuurspecialist: Esther van der Bijl	Rayyan review: https://rayyan.ai/reviews/1067040
BMI-zoekblokken: voor verschillende opdrachten wordt (deels) gebruik gemaakt van de zoekblokken van BMI-Online https://blocks.bmi-online.nl/ Deduplication: voor het ontdubbelen is gebruik gemaakt van http://dedupendnote.nl:9777/
Toelichting: Voor deze vraag is gezocht op de elementen (artralgie OF reumatoïde artritis) EN autoantilichamen (IgM RF OF anti-CCP2 OF anti-CarP OF anti-MCV OF combinatie IgM RF OF anti-CCP2) EN sensitiviteit/ specificiteit filter. Zoals besproken: zijn de zoekformulieren UV4 en UV6 samengevoegd, omdat in de P van UV4 zowel om artralgie als om artritis wordt gevraagd, hierdoor zijn de P en de I van UV4 en UV6 dezelfde; is er gezocht met ‘reumatoïde artritis’ en niet met ‘artritis’, omdat de zoekopbrengst dan met een factor 3 groter zou worden; worden in eerste instantie alleen de SR’s in Rayyan aangeboden, vanwege de grote opbrengst: 224 SR’s en 3501 Observationele studies; is er gezocht vanaf 2000. De acht sleutelartikelen worden gevonden met deze search.
Te gebruiken voor richtlijntekst: In de databases Embase.com en Ovid/Medline is op 17 juni 2024 systematisch gezocht naar systematische reviews en observationele studies over autoantilichamen om reumatoïde artritis aan te tonen dan wel uit te sluiten bij patiënten die zich presenteren met artralgie/ artritis. De literatuurzoekactie leverde 3725 unieke treffers op.

Zoekopbrengst - 17 junin 2024

	EMBASE	OVID/MEDLINE	Ontdubbeld
SR	212	122	224*
Observationele studies	3238	1777	3501
Totaal	3450	1899	3725

_{*in Rayyan}

Zoekstrategie - 17 juni 2024

Embase.com

No.	Query	Results
#1	'rheumatoid arthritis'/exp OR 'arthralgia'/exp OR (((rheuma* OR reuma* OR revma) NEAR/3 (arthrit OR artrit* OR diseas* OR condition* OR nodule)):ti,ab,kw) OR ((inflammat NEAR/3 (arthrit* OR artrit* OR joint)):ti,ab,kw) OR ((('auto immun' OR autoimmun* OR deform* OR persistent) NEAR/3 (arthrit* OR artrit)):ti,ab,kw) OR ((felty NEAR/2 syndrome):ti,ab,kw) OR ((caplan NEAR/2 syndrome):ti,ab,kw) OR (((ach OR pain) NEAR/3 (joint OR articular)):ti,ab,kw) OR arthralgia:ti,ab,kw OR arthrodynia:ti,ab,kw OR polyarthralgia:ti,ab,kw OR 'acpa positive':ti,ab,kw OR 'positive acpa':ti,ab,kw	441280
#2	'rheumatoid factor'/exp OR 'immunoglobulin m'/exp OR 'cyclic citrullinated peptide antibody'/exp OR 'carbamylated protein antibody'/exp OR (((rheuma* OR reuma* OR revma) NEAR/2 factor):ti,ab,kw) OR ((('anti citrullinated' OR 'anti cyclic citrullinated' OR 'anti-homocitrullinated' OR 'antihomocitrullinated') NEAR/3 (protein* OR peptide)):ti,ab,kw) OR ((('citrullinated protein' OR 'citrullinated peptide') NEAR/3 (antibod OR autoantibod)):ti,ab,kw) OR 'anti-mutated citrullinated vimentin':ti,ab,kw OR 'igm':ti,ab,kw OR 'ig m':ti,ab,kw OR 'immune globulin m':ti,ab,kw OR 'immunoglobulin m':ti,ab,kw OR acpa:ti,ab,kw OR acpas:ti,ab,kw OR 'carbamylated protein* antibod*':ti,ab,kw OR 'anti carp':ti,ab,kw OR ahcpa:ti,ab,kw OR 'anti mcv':ti,ab,kw OR 'ccp2':ti,ab,kw OR 'second generation ccp':ti,ab,kw	187425
#3	'sensitivity and specificity'/de OR sensitivity:ab,ti OR specificity:ab,ti OR predict*:ab,ti OR 'roc curve':ab,ti OR 'receiver operator':ab,ti OR 'receiver operators':ab,ti OR likelihood:ab,ti OR 'diagnostic error'/exp OR 'diagnostic accuracy'/exp OR 'diagnostic test accuracy study'/exp OR 'inter observer':ab,ti OR 'intra observer':ab,ti OR interobserver:ab,ti OR intraobserver:ab,ti OR validity:ab,ti OR kappa:ab,ti OR reliability:ab,ti OR reproducibility:ab,ti OR ((test NEAR/2 're-test'):ab,ti) OR ((test NEAR/2 'retest'):ab,ti) OR 'reproducibility'/exp OR accuracy:ab,ti OR 'differential diagnosis'/exp OR 'validation study'/de OR 'measurement precision'/exp OR 'diagnostic value'/exp OR 'reliability'/exp OR 'predictive value'/exp OR ppv:ti,ab,kw OR npv:ti,ab,kw OR (((false OR true) NEAR/3 (negative OR positive)):ti,ab)	6474160
#4	#1 AND #2 AND #3	9674
#5	#4 NOT (('adolescent'/exp OR 'child'/exp OR adolescent:ti,ab,kw OR child:ti,ab,kw OR schoolchild:ti,ab,kw OR infant:ti,ab,kw OR girl:ti,ab,kw OR boy:ti,ab,kw OR teen:ti,ab,kw OR teens:ti,ab,kw OR teenager:ti,ab,kw OR youth:ti,ab,kw OR pediatr:ti,ab,kw OR paediatr:ti,ab,kw OR puber:ti,ab,kw) NOT ('adult'/exp OR 'aged'/exp OR 'middle aged'/exp OR adult:ti,ab,kw OR man:ti,ab,kw OR men:ti,ab,kw OR woman:ti,ab,kw OR women:ti,ab,kw))	9261
#6	#5 AND [2000-2024]/py NOT ('conference abstract'/it OR 'editorial'/it OR 'letter'/it OR 'note'/it) NOT (('animal'/exp OR 'animal experiment'/exp OR 'animal model'/exp OR 'nonhuman'/exp) NOT 'human'/exp)	4657
#7	'meta analysis'/exp OR 'meta analysis (topic)'/exp OR metaanaly:ti,ab OR 'meta analy':ti,ab OR metanaly:ti,ab OR 'systematic review'/de OR 'cochrane database of systematic reviews'/jt OR prisma:ti,ab OR prospero:ti,ab OR (((systemati OR scoping OR umbrella OR 'structured literature') NEAR/3 (review* OR overview)):ti,ab) OR ((systemic NEAR/1 review):ti,ab) OR (((systemati OR literature OR database* OR 'data base') NEAR/10 search):ti,ab) OR (((structured OR comprehensive* OR systemic) NEAR/3 search):ti,ab) OR (((literature NEAR/3 review):ti,ab) AND (search:ti,ab OR database:ti,ab OR 'data base':ti,ab)) OR (('data extraction':ti,ab OR 'data source':ti,ab) AND 'study selection':ti,ab) OR ('search strategy':ti,ab AND 'selection criteria':ti,ab) OR ('data source':ti,ab AND 'data synthesis':ti,ab) OR medline:ab OR pubmed:ab OR embase:ab OR cochrane:ab OR (((critical OR rapid) NEAR/2 (review* OR overview* OR synthes)):ti) OR ((((critical OR rapid) NEAR/3 (review OR overview* OR synthes)):ab) AND (search:ab OR database:ab OR 'data base':ab)) OR metasynthes:ti,ab OR 'meta synthes':ti,ab	1037188
#8	'major clinical study'/de OR 'clinical study'/de OR 'case control study'/de OR 'family study'/de OR 'longitudinal study'/de OR 'retrospective study'/de OR 'prospective study'/de OR 'comparative study'/de OR 'cohort analysis'/de OR ((cohort NEAR/1 (study OR studies)):ab,ti) OR (('case control' NEAR/1 (study OR studies)):ab,ti) OR (('follow up' NEAR/1 (study OR studies)):ab,ti) OR (observational NEAR/1 (study OR studies)) OR ((epidemiologic NEAR/1 (study OR studies)):ab,ti) OR (('cross sectional' NEAR/1 (study OR studies)):ab,ti)	8275835
#9	'case control study'/de OR 'comparative study'/exp OR 'control group'/de OR 'controlled study'/de OR 'controlled clinical trial'/de OR 'crossover procedure'/de OR 'double blind procedure'/de OR 'phase 2 clinical trial'/de OR 'phase 3 clinical trial'/de OR 'phase 4 clinical trial'/de OR 'pretest posttest design'/de OR 'pretest posttest control group design'/de OR 'quasi experimental study'/de OR 'single blind procedure'/de OR 'triple blind procedure'/de OR (((control OR controlled) NEAR/6 trial):ti,ab,kw) OR (((control OR controlled) NEAR/6 (study OR studies)):ti,ab,kw) OR (((control OR controlled) NEAR/1 active):ti,ab,kw) OR 'open label':ti,ab,kw OR (((double OR two OR three OR multi OR trial) NEAR/1 (arm OR arms)):ti,ab,kw) OR ((allocat NEAR/10 (arm OR arms)):ti,ab,kw) OR placebo:ti,ab,kw OR 'sham-control':ti,ab,kw OR (((single OR double OR triple OR assessor) NEAR/1 (blind* OR masked)):ti,ab,kw) OR nonrandom:ti,ab,kw OR 'non-random':ti,ab,kw OR 'quasi-experiment':ti,ab,kw OR crossover:ti,ab,kw OR 'cross over':ti,ab,kw OR 'parallel group':ti,ab,kw OR 'factorial trial':ti,ab,kw OR ((phase NEAR/5 (study OR trial)):ti,ab,kw) OR ((case* NEAR/6 (matched OR control)):ti,ab,kw) OR ((match NEAR/6 (pair OR pairs OR cohort* OR control* OR group* OR healthy OR age OR sex OR gender OR patient* OR subject* OR participant)):ti,ab,kw) OR ((propensity NEAR/6 (scor OR match)):ti,ab,kw) OR versus:ti OR vs:ti OR compar:ti OR ((compar* NEAR/1 study):ti,ab,kw) OR (('major clinical study'/de OR 'clinical study'/de OR 'cohort analysis'/de OR 'observational study'/de OR 'cross-sectional study'/de OR 'multicenter study'/de OR 'correlational study'/de OR 'follow up'/de OR cohort:ti,ab,kw OR 'follow up':ti,ab,kw OR followup:ti,ab,kw OR longitudinal:ti,ab,kw OR prospective:ti,ab,kw OR retrospective:ti,ab,kw OR observational:ti,ab,kw OR 'cross sectional':ti,ab,kw OR cross?ectional:ti,ab,kw OR multicent:ti,ab,kw OR 'multi-cent':ti,ab,kw OR consecutive:ti,ab,kw) AND (group:ti,ab,kw OR groups:ti,ab,kw OR subgroup:ti,ab,kw OR versus:ti,ab,kw OR vs:ti,ab,kw OR compar:ti,ab,kw OR 'odds ratio':ab OR 'relative odds':ab OR 'risk ratio':ab OR 'relative risk*':ab OR 'rate ratio':ab OR aor:ab OR arr:ab OR rrr:ab OR ((('or' OR 'rr') NEAR/6 ci):ab)))	15167950
#10	#6 AND #7 – SR’s	212
#11	#6 AND (#8 OR #9) NOT #10 – Observationele studies	3238
#12	#10 OR #11	3387

Ovid/Medline

#	Searches	Results
1	exp Arthritis, Rheumatoid/ or exp Arthralgia/ or ((rheuma* or reuma* or revma) adj3 (arthrit or artrit* or diseas* or condition* or nodule)).ti,ab,kf. or (inflammat adj3 (arthrit* or artrit* or joint)).ti,ab,kf. or ((auto immun or autoimmun* or deform* or persistent) adj3 (arthrit* or artrit)).ti,ab,kf. or (felty adj2 syndrome).ti,ab,kf. or (caplan adj2 syndrome).ti,ab,kf. or ((ach or pain) adj3 (joint or articular)).ti,ab,kf. or arthralgia.ti,ab,kf. or arthrodynia.ti,ab,kf. or polyarthralgia.ti,ab,kf. or acpa positive.ti,ab,kf. or positive acpa.ti,ab,kf.	251181
2	exp Rheumatoid Factor/ or exp Immunoglobulin M/ or exp Anti-Citrullinated Protein Antibodies/ or ((rheuma* or reuma* or revma) adj2 factor).ti,ab,kf. or ((anti citrullinated or anti cyclic citrullinated or anti-homocitrullinated or antihomocitrullinated) adj3 (protein* or peptide)).ti,ab,kf. or ((citrullinated protein or citrullinated peptide) adj3 (antibod or autoantibod)).ti,ab,kf. or Anti mutated citrullinated vimentin.ti,ab,kf. or igm.ti,ab,kf. or ig m.ti,ab,kf. or immune globulin m.ti,ab,kf. or immunoglobulin m.ti,ab,kf. or acpa.ti,ab,kf. or acpas.ti,ab,kf. or carbamylated protein* antibod*.ti,ab,kf. or anti carp.ti,ab,kf. or ahcpa.ti,ab,kf. or anti mcv.ti,ab,kf. or ccp2.ti,ab,kf. or second generation ccp.ti,ab,kf.	116431
3	exp "Sensitivity and Specificity"/ or (sensitivity or specificity).ti,ab. or (predict* or ROC-curve or receiver-operator).ti,ab. or (likelihood or LR).ti,ab. or exp Diagnostic Errors/ or (inter-observer or intra-observer or interobserver or intraobserver or validity or kappa or reliability).ti,ab. or reproducibility.ti,ab. or (test adj2 (re-test or retest)).ti,ab. or "Reproducibility of Results"/ or accuracy.ti,ab. or Diagnosis, Differential/ or Validation Study/ or ((false or true) adj3 (negative or positive)).ti,ab.	5113795
4	1 and 2 and 3	4207
5	4 not ((Adolescent/ or Child/ or Infant/ or adolescen.ti,ab,kf. or child.ti,ab,kf. or schoolchild.ti,ab,kf. or infant.ti,ab,kf. or girl.ti,ab,kf. or boy.ti,ab,kf. or teen.ti,ab,kf. or teens.ti,ab,kf. or teenager.ti,ab,kf. or youth.ti,ab,kf. or pediatr.ti,ab,kf. or paediatr.ti,ab,kf. or puber.ti,ab,kf.) not (Adult/ or adult.ti,ab,kf. or man.ti,ab,kf. or men.ti,ab,kf. or woman.ti,ab,kf. or women.ti,ab,kf.))	4096
6	limit 5 to yr="2000 -Current"	3050
7	6 not (comment/ or editorial/ or letter/) not ((exp animals/ or exp models, animal/) not humans/)	2941
8	meta-analysis/ or meta-analysis as topic/ or (metaanaly* or meta-analy* or metanaly).ti,ab,kf. or systematic review/ or cochrane.jw. or (prisma or prospero).ti,ab,kf. or ((systemati or scoping or umbrella or "structured literature") adj3 (review* or overview)).ti,ab,kf. or (systemic adj1 review).ti,ab,kf. or ((systemati or literature or database* or data-base) adj10 search).ti,ab,kf. or ((structured or comprehensive* or systemic) adj3 search).ti,ab,kf. or ((literature adj3 review) and (search or database* or data-base)).ti,ab,kf. or (("data extraction" or "data source") and "study selection").ti,ab,kf. or ("search strategy" and "selection criteria").ti,ab,kf. or ("data source" and "data synthesis").ti,ab,kf. or (medline or pubmed or embase or cochrane).ab. or ((critical or rapid) adj2 (review or overview* or synthes)).ti. or (((critical or rapid) adj3 (review or overview* or synthes)) and (search or database* or data-base)).ab. or (metasynthes or meta-synthes*).ti,ab,kf.	753101
9	Epidemiologic studies/ or case control studies/ or exp cohort studies/ or Controlled Before-After Studies/ or Case control.tw. or cohort.tw. or Cohort analy$.tw. or (Follow up adj (study or studies)).tw. or (observational adj (study or studies)).tw. or Longitudinal.tw. or Retrospective.tw. or prospective.tw. or consecutive*.tw. or Cross sectional.tw. or Cross-sectional studies/ or historically controlled study/ or interrupted time series analysis/ [Onder exp cohort studies vallen ook longitudinale, prospectieve en retrospectieve studies]	4752114
10	Case-control Studies/ or clinical trial, phase ii/ or clinical trial, phase iii/ or clinical trial, phase iv/ or comparative study/ or control groups/ or controlled before-after studies/ or controlled clinical trial/ or double-blind method/ or historically controlled study/ or matched-pair analysis/ or single-blind method/ or (((control or controlled) adj6 (study or studies or trial)) or (compar* adj (study or studies)) or ((control or controlled) adj1 active) or "open label" or ((double or two or three or multi or trial) adj (arm or arms)) or (allocat adj10 (arm or arms)) or placebo* or "sham-control" or ((single or double or triple or assessor) adj1 (blind or masked)) or nonrandom* or "non-random" or "quasi-experiment" or "parallel group" or "factorial trial" or "pretest posttest" or (phase adj5 (study or trial)) or (case adj6 (matched or control)) or (match adj6 (pair or pairs or cohort* or control* or group* or healthy or age or sex or gender or patient* or subject* or participant)) or (propensity adj6 (scor or match))).ti,ab,kf. or (confounding adj6 adjust).ti,ab. or (versus or vs or compar).ti. or ((exp cohort studies/ or epidemiologic studies/ or multicenter study/ or observational study/ or seroepidemiologic studies/ or (cohort or 'follow up' or followup or longitudinal* or prospective* or retrospective* or observational* or multicent* or 'multi-cent' or consecutive).ti,ab,kf.) and ((group or groups or subgroup* or versus or vs or compar).ti,ab,kf. or ('odds ratio' or 'relative odds' or 'risk ratio' or 'relative risk' or aor or arr or rrr).ab. or (("OR" or "RR") adj6 CI).ab.))	5714457
11	7 and 8 – SR’s	122
12	(7 and (9 or 10)) not 11 – Observationele studies	1777
13	11 or 12	1899

Richtlijnendatabase

Reumatoïde Artritis (RA)

Reumatoïde Artritis (RA)

Serologie - Artritis

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