Serologie - Artralgie
Uitgangsvraag
Welke autoantilichamen moeten worden bepaald bij patiënten die zich presenteren met artralgie om een inschatting te kunnen maken van de kans op het ontwikkelen van reumatoïde artritis in de komende jaren?
Aanbeveling
Bepaal bij patienten die zich presenteren met artralgie met verdenking op RA zowel anti-CCP als RF. Een positieve test-uitslag gaat gepaard met een verhoogd risico op toekomstige artritis, waarbij dit risico bij een positieve anti-CCP hoger is dan bij een positieve RF.
Overwegingen
Balans tussen gewenste en ongewenste effecten
In totaal zijn twee prospectieve cohortstudies gevonden die de voorspellende waarde van autoantistoffen hebben onderzocht op het risico op het ontwikkelen van artritis (niet specifiek RA) bij patiënten met artralgie (Ten Brinck, 2017; Khidir, 2023). Hierbij zijn resultaten gevonden voor RF, anti-CCP2, anti-CarP en de combinatie van RF en anti-CarP. Voor anti-MCV zijn geen resultaten gevonden. Meerdere studies zijn geëxcludeerd, vanwege het ontbreken van (correcte) controlegroepen of een onjuiste algehele studiepopulatie.
Beide geïncludeerde studies hebben een etiologisch design en zijn een vorm van prevalentieonderzoek. De GRADE methodiek zoals deze gehanteerd wordt bij medisch-specialistische richtlijnen is echter niet ontwikkeld voor dit type onderzoek. De studies hebben een link onderzocht tussen een auto-antistof en de ontwikkeling naar artritis. Hiermee wordt echter niet direct bewijs gevonden voor hoe zorgverleners dienen te handelen. Voorspelmodellen naar de ontwikkeling van RA bij patiënten met artralgie, waarbij alle mogelijke factoren worden onderzocht (in onderlinge verhouding) zijn niet in de uitgevoerde literatuursearch gevonden. Daarnaast hebben de studies geen progressie naar RA als uitkomst, maar progressie naar klinische artritis (Ten Brinck, 2017) of inflammatoire artritis (Khidir, 2023). Er kunnen dan ook geen sterke conclusies getrokken worden m.b.t. de voorspellende waarde en causale relatie voor het risico op RA, doordat deze van veel andere factoren afhankelijk kunnen zijn. Desondanks laten de studies, die in een Nederlandse populatie zijn uitgevoerd, duidelijk zien dat de aanwezigheid van de gemeten autoantistoffen samenhangt met progressie naar klinische/inflammatoire artritis binnen twee jaar. Bij de combinatie van aanwezigheid van anti-CCP2 en RF is deze relatie het grootst, gevolgd door (in afnemende volgorde van sterkte) anti-CCP2, RF en anti-CarP.
In een tweede studie met hetzelfde cohort van 241 patiënten met artralgie als ten Brinck (2017), werd onderzocht of er een meerwaarde is voor het bepalen van anti-CarP t.o.v. RF en anti-CCP2 wanneer dit al gemeten is (Ten Brinck, 2019). Deze studie is niet uit de literuursearch gekomen, doordat dit een ‘letter to the editor’ betreft. Uitkomsten van de studie betreffen ‘clinical arthritis’ en diagnose van RA na één jaar follow-up. Voor de aanwezigheid van anti-CarP als derde auto-antistof bij patiënten die positief waren zowel ACPA als RF werd een HR gevonden van 1.03 (95%CI: 0.33 tot 3.2), waarmee er geen meerwaarde lijkt te zijn voor bepaling van anti-CarP.
Op basis van de gevonden literatuur kunnen er alleen uitspraken worden gedaan over de waarde van RF, anti-CCP2 en anti-CarP-antilichamen m.b.t. het risico op ontwikkeling van artritis bij artralgie-patiënten. Uit de literatuur blijkt duidelijk dat met name de gezamenlijke aanwezigheid van zowel RF als anti-CCP2 met een duidelijk verhoogd risico op deze uitkomst gepaard gaat. Voor anti-CarP lijkt er (vooralsnog) geen toegevoegde waarde naast de metingen van RF en anti-CCP2.
Waarden en voorkeuren van patiënten (en eventueel hun naasten/verzorgers)
Voor het bepalen van autoantistoffen (in dit geval: anti-CCP en RF) is een bloedafname noodzakelijk. Indien de patiënten en hun naasten/verzorgers graag duidelijkheid willen krijgen over het risico op ontwikkeling van artritis, zal een dergelijke bloedafname over het algemeen acceptabel worden geacht. Anti-CCP en RF kunnen uit dezelfde bloedbuis worden bepaald. Het is belangrijk om patiënten goed te informeren over het te verrichten onderzoek.
Kostenaspecten
Zie submodule Serologie - Artritis
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 lijkt haalbaar. De haalbaarheid van de beschreven diagnostiek hangt af van zorgvuldige patiëntselectie, omdat de waarde van deze tests alleen goed is onderzocht bij patienten met “clincally suspect arthralgia." De waarde van deze testen is alleen in de tweede en derde lijn (dus in de setting van medisch-specialistisch zorg door een reumatoloog) onderzocht en aangetoond voor deze patiëntenpopulatie.
Rationale van de aanbeveling: weging van argumenten voor en tegen de interventies
Bij patiënten die zich met een bepaalde vorm van artralgie (“clinically suspect arthralgia”) presenteren bij een reumatoloog hebben zowel anti-CCP als RF een voorspellende waarde m.b.t. de ontwikkeling van artritis.
Eindoordeel:
Sterke aanbeveling voor doen.
Onderbouwing
Achtergrond
In patients presenting to a rheumatologist with clinically suspect arthralgia, 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 to a rheumatologist. The goal in this setting is to determine whether the patient is at increased risk of developing rheumatoid arthritis (RA).
Conclusies / Summary of Findings
RF
|
No GRADE |
Due to the etiological design of the included study, no GRADE conclusion could be drawn regarding the predictive value of RF for RA diagnosis in patients with (clinically suspected) arthralgia.
Source: (Ten Brinck, 2017) |
Anti-CCP2
|
No GRADE |
Due to the etiological design of the included studies, no GRADE conclusion could be drawn regarding the predictive value of anti-CCP2 for RA diagnosis in patients with (clinically suspected) arthralgia.
Source: (Ten Brinck, 2017; Khidir, 2023) |
Anti-CarP
|
No GRADE |
Due to the etiological design of the included study, no GRADE conclusion could be drawn regarding the predictive value of anti-CarP for RA diagnosis in patients with (clinically suspected) arthralgia.
Source: (Ten Brinck, 2017) |
Anti-MCV
|
No GRADE |
No results were found regarding the predictive value of anti-MCV for RA diagnosis in patients with (clinically suspected) arthralgia.
Source: - |
RF + anti-CCP2
|
No GRADE |
Due to the etiological design of the included study, no GRADE conclusion could be drawn regarding the predictive value of RF and anti-CCP2 combined for RA diagnosis in patients with (clinically suspected) arthralgia.
Source: (Ten Brinck, 2017) |
Samenvatting literatuur
Description of studies
Ten Brinck performed a prospective cohort study to assess the risk for arthritis development of anti-CCP2 (reported as ACPA), RF and anti-CarP in patients with CSA.
A total of 241 patients were included from the Leiden CSA cohort and tested for the presence of the autoantibodies mentioned above (see Table 1). Patients were not allowed treatment with DMARD’s; treatment with NSAIDs was allowed. The follow-up time was two years, with a median of 103 weeks (IQR: 81 to 114 weeks). Of all included patients, 97 patients did not complete follow-up of which 83 patients had no RA diagnosis when lost to follow-up. The study is limited due to the etiological design and the limited number of patients with absence/presence for the antibodies, specifically anti-CarP. Besides, the study reports results regarding progression to clinical arthritis instead of rheumatoid arthritis.
Table 1. Presence of autoantibodies in included patients with CSA (Ten Brinck, 2017)
|
Autoantibody |
Number of patients |
|
Absence of autoantibodies |
176 (73.0%) |
|
Anti-CCP2+ only |
6 (2.5%) |
|
Anti-CCP2+, RF+ |
12 (5.0%) |
|
Anti-CCP2+, RF+, anti-CarP+ |
14 (5.8%) |
|
RF+ only |
24 (10.0%) |
|
RF+, anti-CarP+ |
1 (0.4%) |
|
anti-CarP+ only |
8 (3.3%) |
|
Anti-CCP2+, anti-CarP+ |
0 (0%) |
Khidir (2023) performed a prospective cohort study to assess the ACPA-associated differences for the risk of progression to inflammatory arthritis (IA) in patients with CSA. A total of 845 patients were included, of which 728 patients were included from the Leiden CSA cohort and 117 patients were included from the placebo arm of the TREAT EARLIER trial (Krijbolder, 2022). In the latter trial, patients with CSA and presence of subclinical joint inflammation on MRI were included. No important differences in baseline characteristics were reported between the two study populations. All patients were tested for anti-CCP2 (reported as ACPA) status. A total of 119 patients (14%) were anti-CCP2 positive. Median follow-up time was two years (IQR: 14 to 26 months). The study is limited due to the etiological design. Besides, the study reports results regarding progression to inflammatory arthritis instead of rheumatoid arthritis.
Note: The study populations of Ten Brinck (2017) and Khidir (2023) largely overlap. Ten Brinck (2017) included patients from the Leiden CSA cohort who were included in this cohort between April 2012 and March 2015. Khidir included patients from the same cohort with an inclusion period between April 2012 and June 2022.
Results
For the study of Ten Brinck (2017, all reported hazard ratios below are regarding the risk of progression to clinical arthritis. Khidir reported results for inflammatory arthritis.
RF
Ten Brinck (2017) reported a hazard ratio (HR, 95% CI) of 5.1 (2.8 to 9.3) for presence of RF, independent of other factors. Besides, a HR (95%CI) of 2.6 (1.0 to 6.6) was reported for anti-CCP2-/RF+ with autoantibody negative patients as reference.
Anti-CCP2
Ten Brinck (2017) reported a HR (95% CI) of 8.5 (4.7 to 15.4) for presence of anti-CCP2, independent of other factors. Besides, a HR (95%CI) of 8.0 (2.4 to 27.4) was reported for anti-CCP2+/RF- with autoantibody negative patients as reference.
Khidir (2023) reported that 66/119 anti-CCP2+ patients (55%) developed IA during follow-up, compared to 70/726 anti-CCP2- patients (10%). The corresponding risk ratio (RR, 95%CI) is 5.75 (4.37 to 7.57).
Note: In the study of Khidir (2023), ten patients developed IA in the period after follow-up. Khidir (2023) did not report the anti-CCP2 status of these patients.
Anti-CarP
Ten Brinck (2017) reported a HR (95% CI) of 3.9 (1.9 to 7.7) for presence of anti-CarP, independent of other factors. Besides, separate results were reported for anti-CarP with anti-CCP2-/RF- patients as reference and anti-CCP2+/RF+ patients as reference. Reported HRs (95%CI) were 2.7 (0.62 to 11.9) and 1.0 (0.37 to 2.7) respectively.
Anti-MCV
No results were found regarding the predictive value of anti-MCV for the risk of progression to RA.
RF + anti-CCP2
Ten Brinck (2017) reported a HR (95% CI) of 10.5 (5.4 to 20.6) for presence of both RF and anti-CCP2 with autoantibody negative patients as reference.
Level of evidence from the literature
Due to the etiological design and the fact that only one prognostic factor was evaluated, no GRADE conclusion could be drawn.
Zoeken en selecteren
A systematic review of the literature was performed to answer the following question:
What is the predictive value of the presence of IgM RF, anti-CCP2, anti-CarP, anti-MCV or IgM RF and anti-CCP2 combined for the diagnosis of rheumatoid arthritis (RA) within 2 years in patients with (clinically suspected) arthralgia?
| P: | Patients with (clinically suspected) arthralgia |
| I: | Presence of IgM RF, anti-CCP2, anti-CarP, anti-MCV or IgM RF and anti-CCP2 combined |
| C: | Absence of autoantibodies |
| O: | (risk of) progression to rheumatoid arthritis (RA) |
| T/S: | Diagnosis of RA (or arthritis) within two years after testing for autoantibody status |
Relevant outcome measures
The guideline development group considered risk of progression to RA as a critical outcome measure for decision making. A priori, the working group did not define the outcome measures listed above but used the definitions used in the studies.
The working group defined an absolute difference of 10% (10 patients to monitor for 1 confirmed diagnosis) as a minimal clinically (patient) important difference for the outcome measure.
Search and select (Methods)
The databases Medline (via OVID) and Embase (via Embase.com) were searched with relevant search terms until March 18, 2025. The detailed search strategy is depicted under the tab Methods. A systematic search was conducted for (systematic reviews (SRs) of) observational studies on autoantibodies to detect or rule out rheumatoid arthritis in patients presenting with arthralgia/arthritis. The systematic literature search resulted in 1879 hits. First, SRs were selected. Four studies were initially selected based on title and abstract screening. After reading the full text, three SRs were excluded (see the table with reasons for exclusion under the tab Methods), and one SR was included (Mankia, 2021). As only one relevant individual study was included in the SR, this individual study was described (Ten Brinck, 2017). Observational studies that were published after the search date of the SR by Mankia (2021), were also selected. This resulted in four studies that were selected based on title and abstract screening. After reading the full text, three studies were excluded and one study was included (Khidir, 2023).
Results
Two studies (prospective cohort studies) were included in the analysis of literature (Ten Brinck, 2017; Khidir, 2023). 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
- Khidir SJH, Krijbolder DI, Glas HK, van Mulligen E, van der Helm-van Mil AHM. Patient burden and joint inflammation during development of RA from arthralgia: is it similar in ACPA-positive and ACPA-negative disease? Rheumatology (Oxford). 2024 Sep 1;63(9):2336-2344. doi: 10.1093/rheumatology/keae044. PMID: 38261628; PMCID: PMC11371371.
- Krijbolder DI, Verstappen M, van Dijk BT, Dakkak YJ, Burgers LE, Boer AC, Park YJ, de Witt-Luth ME, Visser K, Kok MR, Molenaar ETH, de Jong PHP, Böhringer S, Huizinga TWJ, Allaart CF, Niemantsverdriet E, van der Helm-van Mil AHM. Intervention with methotrexate in patients with arthralgia at risk of rheumatoid arthritis to reduce the development of persistent arthritis and its disease burden (TREAT EARLIER): a randomised, double-blind, placebo-controlled, proof-of-concept trial. Lancet. 2022 Jul 23;400(10348):283-294. doi: 10.1016/S0140-6736(22)01193-X. PMID: 35871815.
- Mankia K, Siddle H, Di Matteo A, Alpízar-Rodríguez D, Kerry J, Kerschbaumer A, Aletaha D, Emery P. A core set of risk factors in individuals at risk of rheumatoid arthritis: a systematic literature review informing the EULAR points to consider for conducting clinical trials and observational studies in individuals at risk of rheumatoid arthritis. RMD Open. 2021 Sep;7(3):e001768. doi: 10.1136/rmdopen-2021-001768. PMID: 34531306; PMCID: PMC8449955.
- Ten Brinck RM, van Steenbergen HW, van Delft MAM, Verheul MK, Toes REM, Trouw LA, van der Helm-van Mil AHM. The risk of individual autoantibodies, autoantibody combinations and levels for arthritis development in clinically suspect arthralgia. Rheumatology (Oxford). 2017 Dec 1;56(12):2145-2153. doi: 10.1093/rheumatology/kex340. PMID: 28968865; PMCID: PMC6703997.
- Ten Brinck RM, Trouw LA, van der Helm-van Mil AHM. Screening for two or three autoantibodies in persons at risk for RA: implications of current data for clinical practice. Rheumatology (Oxford). 2019 May 1;58(5):914-915. doi: 10.1093/rheumatology/key441. PMID: 30753673.
Evidence tabellen
Evidence table for intervention studies (randomized controlled trials and non-randomized observational studies [cohort studies, case-control studies, case series])1
This table is also suitable for diagnostic studies (screening studies) that compare the effectiveness of two or more tests. This only applies if the test is included as part of a test-and-treat strategy – otherwise the evidence table for studies of diagnostic test accuracy should be used
|
Study reference |
Study characteristics |
Patient characteristics 2 |
Intervention (I) |
Comparison / control (C) 3
|
Follow-up |
Outcome measures and effect size 4 |
Comments |
||||||||||||||||||
|
Ten Brinck, 2017 |
Type of study: Prospective cohort study
Setting and country: The Netherlands
Funding and conflicts of interest: Non-commercial funding and no conflicts of interest reported. |
Inclusion criteria: Patients with clinically suspected arthralgia (CSA)
Exclusion criteria: -
N total at baseline: 241
Important prognostic factors2: Autoantibody presence
Sex: 22% males
Mean age (SD): 44 (13)
No separate baseline characteristics reported for subgroups (by autoantibody presence |
Presence of autoantibodies (anti-CCP2, RF, anti-CarP)
|
Absence of autoantibodies (anti-CCP2, RF, anti-CarP)
|
Length of follow-up: Two years; median 103 weeks (IQR: 81 to 114 weeks)
Loss-to-follow-up: 97 patients (40%) did not complete two year follow-up, of which 83 patients had no RA diagnosis.
Incomplete outcome data: N.a. as test were performed after inclusion for all patients.
|
Outcome measures and effect size (include 95%CI and p-value if available):
Progression to clinical arthritis
RF Independent of other factors HR (95%CI): 5.1 (2.8 to 9.3)
Anti-CCP-/RF+ with autoantibody negative patients as reference HR (95%CI): 2.6 (1.04 to 6.6)
Anti-CCP Independent of other factors HR (95%CI): 8.5 (4.7 to 15.4)
Anti-CCP+/RF- with autoantibody negative patients as reference HR (95%CI): 8.0 (2.4 to 27.4)
Anti-CarP Independent of other factors HR (95%CI): 3.9 (1.9 to 7.7)
Anti-CCP-/RF- as reference HR (95%CI): 2.7 (0.62 to 11.9)
Anti-CCP+/RF+ with autoantibody negative patients as reference HR (95%CI): 1.0 (0.37 to 2.7)
RF + anti-CCP Autoantibody negative patients as reference HR (95%CI): 10.5 (5.4 to 20.6) |
Authors conclude that presence of autoantibodies in CSA patients increases the absolute risk of developing arthritis.
Study with etiological design, therefore limitations on interpretation of results and consequences for daily practice. Besides, outcomes are reported for clinical arthritis and not RA. |
||||||||||||||||||
|
Khidir, 2023 |
Type of study: Prospective cohort study
Setting and country: The Netherlands
Funding and conflicts of interest: Non-commercial funding and no conflicts of interest reported. |
Inclusion criteria: Patients with clinically suspected arthralgia (CSA), arthralgia of the small joints.
Exclusion criteria: Other explanation for arthralgia (osteoarthritis, fibromyalgia) by rheumatologists’ opinion.
N total at baseline: 845, of which 728 were included from the Leiden CSA cohort and 117 were included from the TREAT EARLIER trial.
Important prognostic factors2: Autoantibody presence Anti-CCP2+: 119 Anti-CCP-: 726
Sex: 24% males
Mean age (SD): 44.2 (12.6)
No separate baseline characteristics reported for subgroups (by autoantibody presence |
Presence of autoantibodies (anti-CCP2)
|
Absence of autoantibodies (anti-CCP2)
|
Length of follow-up: Median two years (IQR: 14 to 26 months)
Loss-to-follow-up: Not reported
Incomplete outcome data: Not reported
|
Outcome measures and effect size (include 95%CI and p-value if available):
Progression to inflammatory arthritis
Anti-CCP I: 66/119 (55%) C: 70/716 (10%) RR: 5.75 (4.37 to 7.57)
|
Authors conclude status of anti-CCP2 differs in long-term outcomes, including progression to inflammatory arthritis.
Study with etiological design, therefore limitations on interpretation of results and consequences for daily practice. Besides, outcomes are reported for inflammatory arthritis and not RA. |
Notes:
1. Prognostic balance between treatment groups is usually guaranteed in randomized studies, but non-randomized (observational) studies require matching of patients between treatment groups (case-control studies) or multivariate adjustment for prognostic factors (confounders) (cohort studies); the evidence table should contain sufficient details on these procedures
2. Provide data per treatment group on the most important prognostic factors [(potential) confounders]
3. For case-control studies, provide sufficient detail on the procedure used to match cases and controls
4. For cohort studies, provide sufficient detail on the (multivariate) analyses used to adjust for (potential) confounders
Risk of bias table for interventions studies (cohort studies based on risk of bias tool by the CLARITY Group at McMaster University)
|
Author, year |
Selection of participants
Was selection of exposed and non-exposed cohorts drawn from the same population?
|
Exposure
Can we be confident in the assessment of exposure?
|
Outcome of interest
Can we be confident that the outcome of interest was not present at start of study?
|
Confounding-assessment
Can we be confident in the assessment of confounding factors?
|
Confounding-analysis
Did the study match exposed and unexposed for all variables that are associated with the outcome of interest or did the statistical analysis adjust for these confounding variables?
|
Assessment of outcome
Can we be confident in the assessment of outcome?
|
Follow up
Was the follow up of cohorts adequate? In particular, was outcome data complete or imputed?
|
Co-interventions
Were co-interventions similar between groups?
|
Overall Risk of bias
|
|
Definitely yes, probably yes, probably no, definitely no |
Definitely yes, probably yes, probably no, definitely no |
Definitely yes, probably yes, probably no, definitely no |
Definitely yes, probably yes, probably no, definitely no |
Definitely yes, probably yes, probably no, definitely no |
Definitely yes, probably yes, probably no, definitely no |
Definitely yes, probably yes, probably no, definitely no |
Definitely yes, probably yes, probably no, definitely no |
Low, Some concerns, High |
|
|
Ten Brinck, 2017 |
Definitely yes
Reason: Participants were selected from a registry |
Definitely yes
Reason: Correct test methods used. |
Definitely yes
Reason: Patients were checked prior to inclusion if clinical arthritis was present. |
Definitely no
Reason: Confounding factors not taken into account. |
Definitely no
Reason: Confounding factors not taken into account. |
Definitely no
Reason: Outcome was diagnosis of clinical arthritis, not RA. |
Definitely no
Reason: 40% of patients did not complete 2-year follow-up, of which most patients had no RA diagnosis when lost to follow-up.
|
Probably yes
Reason: Patients were not allowed for treatment with DMARDs or corticosteroids during CSA phase. NSAID’s were allowed, no information on possible difference between study groups. |
High |
|
Khidir, 2023 |
Reason: Participants were partially selected from a registry and partially from a RCT. |
Probably yes
Reason: Test methods not reported, but no signs that thesewere incorrect. |
Definitely yes
Reason: Patients were checked prior to inclusion if inflammatory arthritis was present. |
Definitely no
Reason: Confounding factors not taken into account. |
Definitely no
Reason: Confounding factors not taken into account |
Definitely no
Reason: Outcome was diagnosis of IA, not RA. |
Definitely no
Reason: Ten patients developed IA after follow-up, anti-CCP2 status unknown. Number of patients lost to follow-up not clearly described, although it seems no patients were lost to follow-up. |
Probably yes
Reason: No treatment with DMARDs or corticosteroids allowed during follow-up. |
High |
Table of excluded studies
|
Reference |
Reason for exclusion |
|
Systematic reviews |
|
|
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. |
Comparison between disease and non-disease population. |
|
Rogier C, Frazzei G, Kortekaas MC, Verstappen M, Ohrndorf S, van Mulligen E, van Vollenhoven RF, van Schaardenburg D, de Jong PHP, van der Helm-van Mil AHM. An ultrasound negative for subclinical synovitis in arthralgia patients: is it helpful in identifying those not developing arthritis? Rheumatology (Oxford). 2022 Nov 28;61(12):4892-4897. doi: 10.1093/rheumatology/keac239. PMID: 35416958; PMCID: PMC9707035. |
Focus on ultrasound, cohort of Ten Brinck (2017) also included in the study population. |
|
Dumoulin QA, Boeren AMP, Krijbolder DI, Willemze A, de Jong PHP, van Mulligen E, van Steenbergen HW, van der Helm-van Mil AHM. When does obesity exert its effect in conferring risk of developing RA: a large study in cohorts of symptomatic persons at risk. RMD Open. 2024 Jan 12;10(1):e003785. doi: 10.1136/rmdopen-2023-003785. PMID: 38216289; PMCID: PMC10806477. |
No outcomes of relevance (obesity) |
|
Observational studies |
|
|
Garcia-Montoya L, Nam JL, Duquenne L, Villota-Eraso C, Di Matteo A, Hartley C, Mankia K, Emery P. Prioritising referrals of individuals at-risk of RA: guidance based on results of a 10-year national primary care observational study. Arthritis Res Ther. 2022 Jan 18;24(1):26. doi: 10.1186/s13075-022-02717-w. PMID: 35042555; PMCID: PMC8767684. |
Study population broader that CSA. Diagnosis for anti-CCP negative patients was performed in primary care setting, patients not seen in secondary care setting. |
|
Siddle HJ, Wilson M, Nam JL, Garcia-Montoya L, Duquenne L, Mankia K, Emery P, Hensor EMA. A multivariable prediction model to identify anti-CCP positive people in those with non-specific musculoskeletal symptoms in primary care. Rheumatology (Oxford). 2024 Dec 4:keae653. doi: 10.1093/rheumatology/keae653. Epub ahead of print. PMID: 39656784. |
Prediction modelling study. Same study population as Garcia-Montoya (2022). |
|
Frazzei G, Landewé RBM, Wagenaar C, van de Stadt LA, van Schaardenburg D, Tas SW, van Vollenhoven RF. Predictors of arthritis development in individuals at risk of rheumatoid arthritis: a 5-year follow-up study from a large cohort. Ann Rheum Dis. 2025 Apr;84(4):547-553. doi: 10.1016/j.ard.2025.01.042. Epub 2025 Feb 15. PMID: 39956700. |
Only seropositive patients included. |
Verantwoording
Beoordelingsdatum en geldigheid
Publicatiedatum : 13-04-2026
Beoordeeld op geldigheid : 13-04-2026
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 - 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 - Hoofdredacteur Nederlands Tijdschrift voor Reumatologie - 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 -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 |
- |
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 - Artralgie |
Geen financiële gevolgen |
Hoewel uit de toetsing volgt dat de aanbeveling(en) breed toepasbaar zijn (5.000-40.000 patiënten per jaar), volgt ook uit de toetsing dat het overgrote deel van de zorgaanbieders en zorgverleners al aan de norm voldoet. Er worden daarom 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 lab artralgie serologie parameters |
|
|
Uitgangsvraag/modules: Welke autoantilichamen moeten worden bepaald bij patiënten die zich presenteren met artralgie om reumatoïde artritis aan te tonen dan wel uit te sluiten? |
|
|
Database(s): Embase.com, Ovid/Medline |
Datum: 18 maart 2025 |
|
Periode: vanaf 2000 |
Talen: geen restrictie |
|
Literatuurspecialist: Esther van der Bijl |
Rayyan review: https://new.rayyan.ai/reviews/1370022/overview |
|
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 EN autoantilichamen (IgM RF OF anti-CCP2 OF anti-CarP OF anti-MCV OF combinatie IgM RF OF anti-CCP2).
Zoals besproken:
Drie sleutelartikelen worden gevonden met deze search:
De volgende sleutelartikele vallen uit op de P:
|
|
|
Te gebruiken voor richtlijntekst: In de databases Embase.com en Ovid/Medline is op 18 maart 2025 systematisch gezocht naar systematische reviews en observationele studies over autoantilichamen om artralgie aan te tonen dan wel uit te sluiten bij patiënten die zich presenteren met artralgie/ artritis. De literatuurzoekactie leverde 1879 unieke treffers op. |
|
Zoekopbrengst - 18 maart 2025
|
|
EMBASE |
OVID/MEDLINE |
Ontdubbeld |
|
SR |
144 |
33 |
147 |
|
Observationele studies |
1644 |
501 |
1732 |
|
Totaal |
1788 |
534 |
1879* |
*in Rayyan
Zoekstrategie - 18 maart 2025
Embase.com
|
No. |
Query |
Results |
|
#1 |
'arthralgia'/exp 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 |
113857 |
|
#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 |
193728 |
|
#3 |
#1 AND #2 |
7417 |
|
#4 |
#3 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)) |
6806 |
|
#5 |
#4 AND [2000-2025]/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) |
3828 |
|
#6 |
'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 |
1115068 |
|
#7 |
'major clinical study'/de OR 'clinical study'/de OR 'family study'/de OR 'longitudinal study'/de OR 'retrospective study'/de OR 'prospective study'/de OR 'cohort analysis'/de OR '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 ((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) 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 (('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))) |
17898335 |
|
#8 |
#5 AND #6 - SR |
144 |
|
#9 |
#5 AND #7 NOT #8 - Observationeel |
1644 |
|
#10 |
#8 OR #9 - Totaal |
1788 |
Ovid/Medline
|
# |
Searches |
Results |
|
1 |
exp Arthralgia/ 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. |
46503 |
|
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. |
118953 |
|
3 |
1 and 2 |
1657 |
|
4 |
3 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.)) |
1543 |
|
5 |
limit 4 to yr="2000 -Current" |
1224 |
|
6 |
5 not (comment/ or editorial/ or letter/) not ((exp animals/ or exp models, animal/) not humans/) |
1188 |
|
7 |
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. |
821762 |
|
8 |
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.)) 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/ |
7979708 |
|
9 |
6 and 7 - SR |
33 |
|
10 |
(6 and 8) not 9 - Observationeel |
501 |
|
11 |
9 or 10 - Totaal |
534 |