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The handle http://hdl.handle.net/1887/23638 holds various files of this Leiden University
dissertation.
Author: Koevoets, Rosanne
Title: Measuring and monitoring outcomes in undifferentiated and rheumatoid arthritis
Issue Date: 2014-02-13
Chapter 4
Multinational evidence-based recommendations on “How
to investigate and follow-up undifferentiated peripheral
inflammatory arthritis”: integrating systematic literature
research and expert opinion of a broad international panel of
rheumatologists in the 3E Initiative
P. Machado*
I. Castrejon*
W. Katchamart*
R. Koevoets*
B. Kuriya*
M. Schoels*
L. Silva-Fernández*
K. Thevissen*
W. Vercoutere*
E. Villeneuve*
D. Aletaha
L. Carmona
R. Landewé
D. van der Heijde
J.W.J. Bijlsma
V. Bykerk
H. Canhão
A.I. Catrina
P. Durez
C.J. Edwards
M.D. Mjaavatten
B.F. Leeb
B. Losada
E.M. Martín-Mola
P. Martinez-Osuna
C. Montecucco
U. Müller-Ladner
M. Østergaard
B. Sheane
R.M. Xavier
J. Zochling
C. Bombardier
*all contributed equally
Chapter 4
1. ABSTRACT
2.
3. Objective: To develop evidence-based recommendations on how to investigate and follow4. up undifferentiated peripheral inflammatory arthritis (UPIA).
5.
6. Methods: 697 rheumatologists from 17 countries participated in the 3E (Evidence, Expertise,
7. Exchange) Initiative of 2008-2009 consisting of three separate rounds of discussions and
8. modified Delphi votes. In a first round, 10 clinical questions were selected. A bibliographic
4
9. team systematically searched Medline, Embase, the Cochrane Library and ACR/EULAR
10. 2007-2008 meeting abstracts. Relevant articles were reviewed for quality assessment, data
11. extraction and synthesis. In a second round, each country elaborated a set of national rec12. ommendations. Finally, multinational recommendations were formulated and agreement
13. among the participants and the potential impact on their clinical practice was assessed.
14.
15. Results: A total of 39.756 references were identified, of which 250 were systematically re16. viewed. Ten multinational key recommendations about the investigation and follow-up of
17. UPIA were formulated. One recommendation addressed differential diagnosis and investiga18. tions prior to establishing the operational diagnosis of UPIA, seven recommendations related
19. to the diagnostic and prognostic value of clinical and laboratory assessments in established
20. UPIA (history and physical examination, acute phase reactants, autoantibodies, radiographs,
21. magnetic resonance imaging and ultrasound, genetic markers and synovial biopsy), one
22. recommendation highlighted predictors of persistence (chronicity) and the final recommen23. dation addressed monitoring of clinical disease activity in UPIA.
24.
25. Conclusions: Ten recommendations on how to investigate and follow-up UPIA in the clinical
26. setting were developed. They are evidence-based and supported by a large panel of rheuma27. tologists thus enhancing their validity and practical use.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
58
How to investigate and follow-up UA
1. INTRODUCTION
2.
3. In clinical practice, a large number of patients who present with recent-onset arthritis have
4. undifferentiated peripheral inflammatory arthritis (UPIA). In this context patients’ initial ques5. tions will focus on their likelihood of developing a well-defined rheumatic disease and on
6. what the future holds for disease progression, persistence, functional impairment and quality
7. of life. These are questions about future diagnosis and prognosis. The answers to these ques8. tions are vital for clinical decision making, including the choice of treatment.
9. The 3E Initiative (Evidence, Expertise, Exchange) in rheumatology is a multinational effort,
10. aimed at promoting evidence-based medicine by formulating practical recommendations
11. addressing clinical problems.1,2 The objective of the 3E Initiative of 2008-2009 was to develop
12. practical recommendations on “how to investigate and follow-up undifferentiated peripheral
13. inflammatory arthritis”, by integrating systematically generated evidence and expert opinion
14. of a broad panel of international rheumatologists. Although the term “inflammatory” in UPIA
15. may seem redundant, the reason for its use was to clearly distinguish the target population
16. from patients with degenerative joint disease, often called osteoarthritis or degenerative
17. arthritis in the English medical literature.
18.
19.
20. METHODS
21.
22. A total of 697 rheumatologists from 17 countries participated in the 3E Initiative of 200823. 2009. Each country was represented by a scientific committee, consisting of one principal
24. investigator and 5-13 members. The bibliographic team consisted of ten international fellows
25. (PM, IC, WK, RK, BK, MS, LS-F, KT, WV, EV) and five mentors (DA, LC, RL, DvdH, CB), one of the
26. mentors also being the scientific organizer (CB). The 17 national principal investigators were
27. selected and invited by the 3e scientific organizer (CB) and each national chair was in charge
28. of composing a national steering committee. The experts were all the members of the 17
29. national Steering Committees who attended the multi-national meetings for 3e Initiative.
30. During the first international meeting (n=113 participants), 10 clinically relevant questions
31. on how to investigate and follow-up UPIA were formulated and selected via a modified
32. Delphi vote. The areas addressed were fourfold: 1) the phase prior to establishing the op33. erational diagnosis of UPIA- namely which differential diagnosis should be considered in a
34. patient presenting with (inflammatory) arthritis and the minimal investigations necessary to
35. consider a patient as having UPIA; 2) the diagnostic and prognostic value of clinical assess36. ment and investigations in UPIA (history and physical examination, acute phase reactants,
37. autoantibodies, radiographs, magnetic resonance imaging, ultrasound, genetic markers and
38. synovial biopsy); 3) the predictors of persistence (chronicity) in UPIA; and 4) the measures of
39. clinical disease activity in UPIA.
59
4
Chapter 4
1. The clinical questions were structured using the PIO format (Patients, Participants or Prob2. lem; Intervention or Index test; Outcomes or target conditions).3 The patients included “adults
3. with UPIA”. Duration of symptoms was not an exclusion criterion. The definition of UPIA is
4. controversial and there is no widely accepted classification criterion for this condition. Dur5. ing the 2008-2009 3E Initiative kick-off meeting, experts decided that only patients in whom
6. clinically apparent joint swelling (synovial proliferation or synovial effusion) was observed by
7. the rheumatologist should be included. For our review, we systematically searched for studies
8. of patients who did not fulfil diagnostic/classification criteria for any specific rheumatic disor-
4
9. der after initial assessment. Studies with mixed populations (e.g. UPIA+arthralgia, UPIA+early
10. rheumatoid arthritis [RA]) were also retained, as these could be useful for extrapolating
11. results. The intervention or index test was defined according to each question (e.g. erosions
12. on radiographs, anti-citrullinated protein/peptide antibodies [ACPA] positivity) and the index
13. test should have been assessed at baseline. The outcomes were defined as the development
14. of well-defined rheumatic diseases (e. g. RA, psoriatic arthritis) or relevant disease outcomes
15. (e.g. remission, radiographic progression). As diagnostic/classification criteria we accepted
16. either internationally validated criteria (e.g. American College of Rheumatology criteria for
17. RA4) or the opinion of the treating physician/investigator.
18. A systematic literature search for articles published up to February 2009 was carried out in
19. Medline, Embase and Cochrane Library, using comprehensive search strategies, elaborated in
20. collaboration with experienced librarians. The searches were limited to diagnostic and prog21. nostic studies, using a modification of published sensitive search strategies.5-8 No language
22. restrictions were used. Retrieved citations were screened for titles, abstracts and full text
23. using predefined inclusion and exclusion criteria; full read papers and review articles were
24. hand-searched for additional references. Retained articles were graded for their method25. ological quality according to the Levels of Evidence of the Oxford Centre for Evidence-Based
26. Medicine (http://www.cebm.net/index.aspx?o=1025 [accessed April 2009]).
27. Each question was addressed separately by independent searches. For each question, rel28. evant data were extracted and appropriate statistics were calculated, including odds ratio,
29. sensitivity, specificity, positive/negative predictive values and positive/negative likelihood
30. ratios. Details and results of the literature search for each question will be published sepa31. rately, while the current article describes the merging process between the evidence found
32. for each question and the interpretation of this by the experts, having the ten recommenda33. tions as the result.
34. In the second round, a national meeting was held in each country (total=697 participants)
35. to discuss the generated evidence and propose a set of recommendations. In a third joint
36. meeting, the 17 scientific committees (n=94 participants) merged all propositions into 10
37. final recommendations via discussion and modified Delphi vote. The grade of recommenda38. tion according to the Oxford Levels of Evidence was attributed and the level of agreement
39. was measured on a 10-point numerical rating scale (1=no agreement, 10=full agreement).9
60
How to investigate and follow-up UA
1. Finally, the potential effect of each recommendation in clinical practice was assessed accord2. ing to 3 impact statements voted by the rheumatologists.
3.
4.
5. RESULTS
6.
7. A total of 39756 references were identified, of which 250 were systematically reviewed (table
8. 1). The 10 multinational key recommendations are listed in table 2, with the corresponding
9. level of evidence and grade of recommendation. The mean level of agreement among the
10. rheumatologists was 8.7 (range 7.4 to 9.1). The percentage of rheumatologists who indicated
11. they would change their clinical practice according to each recommendation is shown in
12. table 3. Evidence for repeating investigations was not found for any of the questions, there13. fore all recommendations about this topic were based on expert opinion.
14.
15. Table 1. Results of the systematic literature search for each recommendation topic
16. Recommendation
Retrieved references by systematic
literature search (n)
Articles included in the
systematic reviews (n)
1. Pre-UPIA differential diagnosis and investigations
540
51
2. History and physical examination
2914
37
3. Acute phase reactants
3699
18
4. Autoantibodies
13217
64
5. Radiographs
3585
25
6.1. Magnetic resonance imaging
2595
11
6.2. Ultrasound
2111
2
7. Genetic markers
3109
26
8. Synovial biopsy
6536
4
17.
(number an topic)
18.
19.
20.
21.
22.
23.
24.
25.
26.
9. Predictors of persistence (chronicity)
437
7
27.
10. Measures of clinical disease activity
1013
5
28.
Total
39756
250
29. UPIA: undifferentiated peripheral inflammatory arthritis.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
61
4
Chapter 4
1. Table 2. Multinational recommendations on “How to investigate and follow-up undifferentiated peripheral inflammatory arthritis”
2.
3.
4.
5.
6.
7.
8.
4
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
Recommendation (with level of evidence and grade of recommendation)
Agreement
mean (SD)
1. All possible causes of arthritis (idiopathic, autoimmune, degenerative, infectious,
malignancy, traumatic, metabolic) should be considered in the differential diagnosis.
Complete history and thorough physical examination will determine the ranking order of
possible differential diagnoses [5, D]. Investigations should be based on the differential
diagnosis of the patient [5, D].
9.0 (1.7)
2. To establish a specific diagnosis and prognosis following presentation of UPIA, a careful
systematic history and physical examination should be performed, with particular attention
to age, gender [1a, A], geographic area [5, D], functional status [1a, A], duration of symptoms/
early morning stiffness, number plus pattern of tender/swollen joints [1a, A], axial/entheseal
involvement and extra-articular/systemic features [5, D].
8.8 (1.3)
3. ESR and CRP should be performed at baseline in the work up for diagnosis [2b, B] and
prognosis [2b, B] of UPIA and repeated when clinically relevant [5, D].
9.1 (1.4)
4. Testing of RF and/or ACPA should be performed in the evaluation of patients with UPIA,
as these factors are predictive of RA diagnosis and prognosis; negative tests do not exclude
progression to RA [1a, A]. If a connective tissue disease/systemic inflammatory disorder is
suspected, additional autoantibody tests should be considered [5, D].
9.1 (1.2)
5. Radiographs of affected joints should be performed at baseline [5, D]. Radiographs of
hands, wrists, and feet should be considered in the evaluation of UPIA, as presence of
erosions is predictive for the development of RA and persistence of disease [1a, A]. These
should be repeated within one year [5, D].
7.4 (2.6)
6. There is insufficient evidence to recommend the routine use of MRI and US for diagnosis
or prognosis in UPIA [5, D]; in UPIA and suspicion of RA, MRI of hands and wrists could be
considered for diagnosis [2b, B].
8.2 (2.0)
7. There is no genetic test that can be routinely recommended [3b, D], however HLA-B27
testing may be helpful in specific clinical settings [5, D].
8.8 (1.5)
8. Routine synovial biopsy is not recommended but can give information for differential
diagnosis, especially in patients with persistent monoarthritis [2b, B].
8.8 (1.8)
9. Predictors of persistent inflammatory arthritis should be documented and include disease
duration of ≥6 weeks [1b, A], morning stiffness >30 minutes [4, C], functional impairment [4,
C], involvement of small joints [4, C] and/or knee [4, C], involvement of ≥3 joints [1b, B], ACPA
[4, C] and/or RF positivity [4, C] and presence of radiographic erosion [1b, B].
8.6 (1.7)
10. Disease activity should be monitored [5, D], however no specific tool can be
recommended [3b, C].
9.0 (1.7)
29. Between brackets: [level of evidence, grade of recommendation], according to the Oxford Centre for Evidence-based Medicine Levels of
30. Evidence. Agreement was voted on a scale from 1 to 10 (fully disagree to fully agree) by the 94 rheumatologists attending the 3E Multi31. National Closing Meeting. These attendees were members of the 17 scientific committees involved in the 3E Initiative of 2008-2009. SD:
standard deviation. UPIA: undifferentiated peripheral inflammatory arthritis. ESR: erythrocyte sedimentation rate. CRP: C-reactive protein.
RF: rheumatoid factor. ACPA: Anti-citrullinated protein/peptide antibodies. RA: rheumatoid arthritis. MRI: magnetic resonance imaging. US:
33. ultrasound.
32.
34.
35.
36.
37.
38.
39.
62
How to investigate and follow-up UA
1. Table 3. Percentage of rheumatologists in the 3E Initiative who indicated for each recommendation if it would change their clinical practice
2.
3.
4.
5.
Recommendation
(number an topic)
The recommendation will
change my practice (%)
The recommendation is
already my practice (%)
I don´t want to change
my practice for this
aspect (%)
0
96.5
3.5
1. Pre-UPIA differential diagnosis and
investigations
6.
2. History and physical examination
7.
3. Acute phase reactants
0
98.3
1.8
5.4
91.1
3.6
4. Autoantibodies
1.8
96.4
1.8
5. Radiographs
16.1
48.2
35.7
10.
6. Magnetic resonance imaging and
ultrasound
17.9
64.3
17.9
11.
7. Genetic markers
1.8
92.9
5.4
8.
9.
12.
8. Synovial biopsy
8.9
83.9
7.1
13.
9. Predictors of persistence (chronicity)
24.6
66.7
8.8
14.
10. Measures of clinical disease activity
12.3
84.2
3.5
4
15. UPIA: undifferentiated peripheral inflammatory arthritis.
16.
17.
Table 4. Diagnosis reported as exclusion criteria and baseline investigations undertaken prior to inclusion as UPIA (ordered by the frequency
18. of reporting in the retrieved literature), both in studies including patients exclusively with UPIA as well as in selected mixed populations that
19. included a well-defined subset of patients with UPIA
20.
A) Reported differential diagnosis prior to establishing the operational diagnosis of UPIA
21.
- Rheumatoid arthritis
- Osteoarthritis
- Spondyloarthritis (reactive arthritis, psoriatic arthritis,
ankylosing spondylitis and undifferentiated spondyloarthritis)
- Crystal-related arthritis
- Trauma
- Connective tissue diseases (systemic lupus erythematosus,
Sjögren syndrome and myositis)
- Septic arthritis
22.
23.
24.
25.
26.
27.
28.
- Sarcoidosis
- Soft-tissue disorders
- Polymyalgia rheumaica
- Lyme disease
- Vasculitis
- Juvenile inflammatory arthritis
- Palindromic rheumatism
- Fibromyalgia
- Endocrinologic origin
- Malignancy-related arthritis
- Viral etiology
29.
B) Reported investigations prior to establishing the operational diagnosis of UPIA
30.
- History
- Tender and swollen joint count
- Rheumatoid factor
- C-reactive protein
- Physical examination
- Hands and feet radiographs
- Full blood count
- Anti-nuclear antibodies
- Erythrocyte sedimentation rate
- Biochemistry (liver function tests,
glucose, urate and renal function)
- HLA typing (HLA-B27 and HLA-DR)
31.
32.
33.
34.
35.
36.
37.
38.
39.
- Microbiologic assessment
- Anti-citrullinated protein/peptide antibodies
- Radiography of the chest and/or of other affected joints
- Urinalysis
- Thyroid function tests
- C3, C4
- Immunoglobulins
- Antibodies to extractable nuclear antigens
- Antibodies to double stranded deoxyribonucleic acid
- Specific serologic assessment
UPIA: undifferentiated peripheral inflammatory arthritis.
63
Chapter 4
1. Recommendation 1. All possible causes of arthritis (idiopathic, autoimmune, degenerative,
2. infectious, malignancy, traumatic, metabolic) should be considered in the differential diagnosis.
3. Complete history and thorough physical examination will determine the ranking order of possible
4. differential diagnoses. Investigations should be based on the differential diagnosis of the patient.
5.
6. As UPIA is an operational diagnosis after excluding well-defined rheumatic diseases, the
7. question about pre-UPIA differential diagnosis and investigations was analysed by looking at
8. the diagnosis that were excluded in cohorts of patients with UPIA and by identifying the in-
4
9. clusion and exclusion criteria of these studies as well as the investigations performed before
10. the UPIA cohort was established. RA was the most frequent diagnosis reported as exclusion
11. criterion10-59 and there was no standard baseline investigation undertaken prior to inclusion
12. as UPIA (table 4).41-60
13. Experts agreed that when facing a new patient presenting with arthritis every diagnosis
14. needed to be kept in mind as UPIA is an exclusion diagnosis. Although, the consensus was
15. that it was impossible to name all possible diagnoses, it was felt useful to mention some
16. major disease categories to make sure that these are considered. Experts also advised that
17. UPIA should be constantly rethought, as patients may develop a disease that can be labelled
18. with a specific diagnosis at anytime. Moreover, this recommendation applies only if arthritis
19. persists, and not if it is self-limiting. Again, as the investigations will vary according to context
20. and clinical presentation, experts felt that it would not be useful to make a list of recom21. mended minimal investigations.
22.
23. Recommendation 2. To establish a specific diagnosis and prognosis following presentation of
24. UPIA, a careful systematic history and physical examination should be performed, with particular
25. attention to age, gender, geographic area, functional status, duration of symptoms/early morn26. ing stiffness, number plus pattern of tender/swollen joints, axial/entheseal involvement and
27. extra-articular/systemic features.
28.
29. Although selected observational studies were of good quality, there was large heterogeneity
30. with respect to the type of history and physical exam features that were described.39,40,42-49,61-87.
31. Of the quantified features, advanced age,44,83 female gender44 and greater morning stiffness43,44
32. were predictive of an eventual diagnosis of RA. A higher number of tender44 and swollen
33. joints,43,44,61 involvement of small joints of hands and feet,44,83 involvement of both the upper
34. and lower extremities44 and symmetrical involvement43 were also associated with progres35. sion to RA. Similar features were associated with disease persistence81-87 and development
36. of erosions,48,63,78 while self-reported functional disability (Health Assessment Questionnaire
37. [HAQ] score)67,76 and the presence of extra-articular features76 were uniquely predictive of fu38. ture disability, along with advanced age,67,76 female gender67 and longer symptom duration.67
39.
64
How to investigate and follow-up UA
1. Experts recognized the importance of the above mentioned evidence-based features and
2. based on their clinical experience also highlighted the contribution of the patient’s geo3. graphic area of residence, the presence of axial/entheseal involvement and the presence of
4. extra-articular/systemic features. However, the greater relevance given to features included
5. in the recommendation does not preclude the need to perform a careful systematic history
6. and physical examination in every UPIA patient.
7.
8. Recommendation 3. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) should
9. be performed at baseline in the work-up for diagnosis and prognosis of UPIA and repeated when
10. clinically relevant.
11.
12. Elevated ESR showed some diagnostic value for the development of RA74,85 but no prognostic
13. value for persistence (chronicity) or structural damage.40,45,88 CRP appeared a poor predictor
14. of persistent arthritis, radiological progression and functional disability.80,89 However, there
15. was some evidence for the usefulness of elevated CRP in predicting RA, especially when the
16. CRP levels are higher.48,88 In one study, CRP did not have any diagnostic value with regard
17. to spondylarthropathy.39 For other acute phase reactants, the evidence on diagnostic or
18. prognostic value was scarce, negative, or controversial.32,42,48,79,80,90-95
19. Based on sparse evidence and on personal experience, regarding acute phase reactants,
20. experts recommended that only ESR and CRP should be performed at baseline and repeated
21. according to the clinical setting.
22.
23. Recommendation 4. Testing of rheumatoid factor (RF) and/or ACPA should be performed in the
24. evaluation of patients with UPIA, as these factors are predictive of RA diagnosis and prognosis;
25. negative tests do not exclude progression to RA. If a connective tissue disease/systemic inflamma26. tory disorder is suspected, additional autoantibody tests should be considered.
27.
28. The association of ACPA and RF11,42-44,48,50,73,96-110 with a diagnosis of RA at follow-up was com29. pelling in the retrieved literature. The absence of ACPA or RF was diagnostically less helpful.
30. The presence of ACPA or RF75,106-109,111-115 also increased the probability of developing persis31. tent synovitis or a worse radiographic outcome.73,75,84-86,116 For anti-keratin antibodies (AKA)
32. and anti-perinuclear factor (APF), evidence suggests diagnostic usefulness, AKA also appears
33. to have some prognostic value.11,96-99,107,110,114,117 For all other markers, including a variety of
34. other autoantibodies as well as bone and cartilage biomarkers, the evidence for diagnostic
35. or prognostic value is scarce, negative, or controversial.57,102,118-126 The same applies to disease
36. outcomes different from those already mentioned.59,74,76,81,93,100,116,127,128
37. The value of ACPA and RF in UPIA was recognized, and based on clinical experience, experts
38. also advised consideration of additional autoantibody tests if non-RA systemic inflammatory
39. disorders are suspected. The use of the general term ACPA was preferred, as the literature
65
4
Chapter 4
1. describes several tests for detecting antibodies to citrullinated peptides (such as anti-CCP1
2. and anti-CCP2) and newer-generation tests are also expected to be used in the future.
3. 4. Recommendation 5. Radiographs of affected joints should be performed at baseline. Radio5. graphs of hands, wrists, and feet should be considered in the evaluation of UPIA, as presence
6. of erosions is predictive for the development of RA and persistence of disease. These should be
7. repeated within one year.
8. 4
9. Radiographic erosions43,49 and Larsen grade 1 (in a population without erosions at baseline)20
10. increased the probability of developing RA from UPIA. Moreover, when comparing mild
11. versus progressive disease after 1 year follow-up, Sharp/van der Heijde scores at baseline
12. were significantly higher in the progressive disease group.48 In another study,44 erosions were
13. found to be a predictor of RA in univariate but not in multivariate analysis.
14. Overall, studies in mixed populations also provided some evidence for the usefulness of
15. radiographs in predicting RA.72,88,92,109,122,129-135 In general, prognosis was worse when radio16. graphic abnormalities at baseline were more severe.75,91,109,116,133,136-140
17. Experts recognized the clinical value of hand and feet radiographs in UPIA, and based on
18. clinical experience also recommended that radiographs of affected joints should be per19. formed at baseline; furthermore, experts advised that radiographs should be repeated within
20. one year (in case of disease persistance). Moreover, although not voted to be included in the
21. recommendation, some of the experts expressed their opinion that pelvic/sacroiliac joints
22. radiographs should also be considered, particularly in RF and ACPA negative patients or if
23. spondyloarthritis is suspected.
24. There was a slightly lower agreement about this recommendation (table 2, 7.4 agreement),
25. with a larger proportion of experts stating that they didn’t want to change their practice
26. for this aspect (table 3, 35.7%). This lower concordance was mainly related to the inclusion
27. of “radiographs of affected joints at baseline” and about the advice to repeat radiographs
28. “within one year”.
29.
30. Recommendation 6. There is insufficient evidence to recommend the routine use of magnetic
31. resonance imaging (MRI) and ultrasound (US) for diagnosis or prognosis in UPIA; in UPIA and
32. suspicion of RA, MRI of hands and wrists could be considered for diagnosis.
33.
34. Bone oedema was found to be an independent predictor of the future development of
35. RA from UPIA141 and the presence of a distinct MRI synovitis and erosion pattern with the
36. involvement of several hand joints but not the first carpometacarpal joint also increased the
37. probability of developing RA.20 The absence of the same MRI synovitis pattern decreased the
38. probability of developing RA.20 Overall, MRI studies in mixed populations101,134,142-147 provided
39. some evidence for the usefulness of MRI (bone oedema, synovitis and erosions) in predicting
66
How to investigate and follow-up UA
1. RA. Regarding US, 2 mixed populations revealed US-power Doppler signal and US-gray-scale
2. synovitis as potential candidates for futures studies in UPIA.148,149
3. Experts recognized that MRI of the hands and wrists has already shown to be useful in predict4. ing the development of RA from UPIA, while the value of US in UPIA is still to be determined.
5. However data is still too scarce to recommend the routine use of any of these imaging tools.
6. This recommendation does not dispute the fact that compared to physical examination and
7. radiographs, both MRI and US may offer advantages through more sensitive depiction of
8. inflammatory and destructive disease manifestations. The current recommendation pertains
4
9. only to the diagnostic and prognostic value of these imaging tools in UPIA.
10.
11. Recommendation 7. There is no genetic test that can be routinely recommended, however HLA12. B27 testing may be helpful in specific clinical settings.
13.
14. There was a great heterogeneity among the genetic markers that were test15. ed.39,40,46,50-52,65,84,127,133,150-165 The shared epitope (SE) was the most frequently studied marker.
16. Eight studies40,50,65,133,153-155,158 tested its diagnostic utility showing poor results. Only in one
17. study was the positive likelihood ratio for RA relevant, but this result came from the study
18. with the poorest quality and smallest sample size.40 In isolation, no other genetic marker was
19. informative of a future diagnosis in patients with UPIA. With regard to prognosis, the SE was
20. weakly associated with a poor prognosis of arthritis in terms of development of erosions,
21. mortality, disability and persistent synovitis.65,127,133,163,164 Other genes were not good predic22. tors of erosions or other less studied outcomes.
23. The experts acknowledged the current lack of evidence for the practical utility of genetics
24. in UPIA. However, based on their clinical experience, experts chose to highlight that HLA25. B27 may be helpful in the appropriate clinical setting, namely when spondyloarthritis is
26. suspected.
27.
28. Recommendation 8. Routine synovial biopsy is not recommended but can give information for
29. differential diagnosis, especially in patients with persistent monoarthritis.
30.
31. Studies had significant clinical and statistical heterogeneity.22,23,166,167 Three broad synovial
32. features of interest were identified in the literature: ACPA staining, immunohistochemistry
33. and vascular patterns. In contrast to serologic ACPA testing, ACPA staining was shown not to
34. be highly specific for a diagnosis of RA.167 In one study, synovial histopathology seemed to
35. differentiate between RA and non-RA.166 The vascular pattern in undifferentiated arthritis was
36. not specific enough to differentiate between spondyloarthritis and RA.22,23
37. The exact role of synovial biopsy in UPIA is yet to be determined and experts felt that it
38. could not be recommended as a routine procedure. However, experts also highlighted that
39. synovial biopsy may give important diagnostic clues, especially in some selected cases (e.g.
67
Chapter 4
1. persistent/chronic refractory monoarthritis, suspicion of malignancy or suspicion of chronic
2. infection, such as tuberculosis).
3.
4. Recommendation 9. Predictors of persistent inflammatory arthritis should be documented and
5. include disease duration of ≥6 weeks, morning stiffness >30 minutes, functional impairment,
6. involvement of small joints and/or knee, involvement of ≥3 joints, ACPA and/or RF positivity and
7. presence of radiographic erosion.
8.
4
9. The question about chronicity was investigated by looking at prognostic studies that used
10. multivariate analysis to identify independent predictors of persistence (chronicity). At
11. baseline, the following variables were found to be independent predictors of persistent
12. (inflammatory) arthritis: disease duration,75,82,116 duration of morning stiffness,75,85,86 change of
13. functional status (measured by HAQ) at the first 3 months,82 failure to respond 2 weeks after
14. local treatment with intraarticular corticosteroids,82 small joint involvement,168 knee involve15. ment,85 presence of RF,75,85 presence and level of ACPA,75,86,168 functional status (HAQ),169 arthri16. tis of at least 3 joints,75 proximal interphalageal joint involvement,169 metatarsophalangeal
17. joint involvement75 and radiographic erosion at the hands and feet.75 The magnitude of the
18. association in the same predictor was diverse among the studies depending on the patient
19. characteristics (namely if the population was purely UPIA or not), the study design, and the
20. variables used to adjust for in the models.
21.
22. Recommendation 10. Disease activity should be monitored, however no specific tool can be
23. recommended.
24.
25. Five studies evaluated the validation of different clinical measures in patients with UPIA.
26. Validation aspects of 4 questionnaires - WHO Disability Assessment Schedule (WHODAS),170
27. London Handicap Scale (LHS), Disease Repercussion Profile (DRP) and the HAQ,171 and
28. 3 physical measures - RA Disease Activity Index (RADAI),172 McGill Range of Motion Index
29. (McROMI)173 and NOAR Damage Joint Count (NOAR-DJC),174 were partially assessed in these
30. studies, but none of the instruments of disease activity was fully validated for its use in UPIA.
31. Although no instrument of disease activity has been fully validated for its use in UPIA, experts
32. felt that it was important to recommend that there should be a conscious effort to record
33. disease activity.
34.
35.
36.
37.
38.
39.
68
How to investigate and follow-up UA
1. DISCUSSION
2.
3. Ten multinational recommendations on how to investigate and follow-up UPIA in the clinical
4. setting were developed, which are practical, evidence-based and supported by a large panel
5. of international rheumatologists in the 3E Initiative.
6. We followed an established group decision method. A representative expert panel of 697
7. academic and community rheumatologists from 17 countries selected relevant questions
8. that reflect the challenges of approaching a patient with UPIA. They openly discussed the
9. evidence from the literature followed by a silent voting process. We used the touch pad
10. methodology with pre-specified cut-off levels of agreement to generate the final recom11. mendations. Several rounds of rewording and re-voting were sometimes required to reach
12. the specified cut-off for agreement. This process highlights the International dimension of
13. this collaboration and strengthens the current recommendations.1,2 It ensured that the final
14. recommendations were evidence-driven as well as clinically relevant.
15.
16. Furthermore, the broad participation increases external validity and enhances future dissemi17. nation and implementation into rheumatological practice worldwide. Another main feature
18. of the 3E Initiative was the promotion of epidemiology and systematic literature research, all
19. participants having been updated on how to appraise published evidence.
20. There is widespread interest in predictive medicine. Following a strict methodology, we
21. aimed to find all available evidence regarding each question, which resulted in a large num22. ber of reviewed articles. However, the evidence in truly UPIA populations is scarce, exposing
23. the need to create a research agenda addressing this topic. In particular, future studies
24. should clearly distinguish between individuals with early well-defined rheumatic diseases,
25. individuals with UPIA and individuals with inflammatory joint symptoms but no obvious joint
26. swelling. All these populations can be studied for predictive algorithms and results may be
27. different depending on the study population.
28. The definition of UPIA is controversial and much of the literature is skewed towards early RA.
29. The difficulty in defining UPIA is underlined by the continuous changing face of different
30. categories of patients, which can be well illustrated by the recent new ACR/EULAR criteria for
31. RA,175 as several of the patients we now describe as having UPIA will likely be labelled as RA
32. patients. Nevertheless, despite the influence that this changing may have on research and
33. daily practice, the recommendations presented in this article are based on currently available
34. evidence. They may help the clinician in the effective management of patients with UPIA and
35. can be adjusted if future studies or clinical experience reveal new insights.
36.
37. In summary, multinational recommendations for the investigation and follow-up of patients
38. with undifferentiated arthritis in daily clinical practice were developed, integrating systematic
39.
69
4
Chapter 4
1. literature review and expert opinion, with the aim of promoting evidence-based medicine
2. and ultimately improving patient care.
3.
4.
5. Acknowledgements
6.
7. The authors thank all members of the 3E scientific committees, all participants of the national
8. meetings, the support from Margaux Orange and the librarians who helped in elaborating
4
9. the systematic literature searches. CB holds a Canada Research Chair in Knowledge Transfer
10. for Musculoskeletal Care.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
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