A total of 39 756 references were identified, of which 250 were systematically reviewed (). The 10 multinational key recommendations are listed in with the corresponding level of evidence and grade of recommendation. The mean level of agreement among the rheumatologists was 8.7 (range 7.4–9.1). The percentage of rheumatologists who indicated they would change their clinical practice according to each recommendation is shown in . Evidence for repeating investigations was not found for any of the questions, therefore all recommendations about this topic were based on expert opinion.
Results of the systematic literature search for each recommendation topic
Multinational recommendations on how to investigate and follow-up undifferentiated peripheral inflammatory arthritis
Percentage of rheumatologists in the 3E Initiative who indicated for each recommendation if it would change their clinical practice
Recommendation 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. Investigations should be based on the differential diagnosis of the patient.
As UPIA is an operational diagnosis after excluding well-defined rheumatic diseases, the question about pre-UPIA differential diagnosis and investigations was analysed by looking at the diagnosis that was excluded in cohorts of patients with UPIA and by identifying the inclusion and exclusion criteria of these studies as well as the investigations performed before the UPIA cohort was established. RA was the most frequent diagnosis reported as exclusion criterion10–59
and there was no standard baseline investigation undertaken prior to inclusion as UPIA ().41–60
Table 4 Diagnosis reported as exclusion criteria and baseline investigations undertaken prior to inclusion as UPIA (ordered by the frequency of reporting in the retrieved literature), both in studies including patients exclusively with UPIA as well as in selected (more ...)
Experts agreed that, when facing a new patient presenting with arthritis, every diagnosis needed to be kept in mind as UPIA is an exclusion diagnosis. Although the consensus was that it was impossible to name all possible diagnoses, it was felt useful to mention some major disease categories to make sure that these are considered. Experts also advised that UPIA should be constantly rethought, as patients may develop a disease that can be labelled with a specific diagnosis at any time. Moreover, this recommendation applies only if arthritis persists and not if it is self-limiting. Again, as the investigations will vary according to context and clinical presentation, experts felt that it would not be useful to make a list of recommended minimal investigations.
Recommendation 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, geographical area, functional status, duration of symptoms/early morning stiffness, number plus pattern of tender/swollen joints, axial/entheseal involvement and extra-articular/systemic features.
Although selected observational studies were of good quality, there was large heterogeneity with respect to the type of history and physical examination features described.39 40 42–49 61–87
Of the quantified features, advanced age,44 83
and greater morning stiffness43 44
were predictive of an eventual diagnosis of RA. A higher number of tender44
and swollen joints,43 44 61
involvement of small joints of hands and feet,44 83
involvement of both the upper and lower extremities44
and symmetrical involvement43
were also associated with progression to RA. Similar features were associated with disease persistence81–87
and development of erosions,48 63 78
while self-reported functional disability (Health Assessment Questionnaire (HAQ) score)67 76
and the presence of extra-articular features76
were uniquely predictive of future disability, along with advanced age,67 76
and longer symptom duration.67
Experts recognised the importance of the abovementioned evidence-based features and, based on their clinical experience, also highlighted the contribution of the patient's geographical area of residence, the presence of axial/entheseal involvement and the presence of extra-articular/systemic features. However, the greater relevance given to features included in the recommendation does not preclude the need to perform a careful systematic history and physical examination in every patient with UPIA.
Recommendation 3. Erythrocyte sedimentation rate (ESR) and C reactive protein (CRP) should be performed at baseline in the investigation for diagnosis and prognosis of UPIA and repeated when clinically relevant.
Elevated erythrocyte sedimentation rate (ESR) showed some diagnostic value for the development of RA74 85
but no prognostic value for persistence (chronicity) or structural damage.40 45 88
C reactive protein (CRP) appeared to be a poor predictor of persistent arthritis, radiological progression and functional disability.80 89
However, there was some evidence for the usefulness of elevated CRP in predicting RA, especially when the CRP levels are higher.48 88
In one study, CRP did not have any diagnostic value with regard to spondylarthropathy.39
For other acute phase reactants, the evidence on diagnostic or prognostic value was scarce, negative or controversial.32 42 48 79 80 90–95
Based on sparse evidence and on personal experience regarding acute phase reactants, experts recommended that only ESR and CRP should be performed at baseline and repeated according to the clinical setting.
Recommendation 4. Testing of rheumatoid factor (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. If a connective tissue disease/systemic inflammatory disorder is suspected, additional autoantibody tests should be considered.
The association of ACPA and rheumatoid factor (RF)11 42–44 48 50 73 96–110
with a diagnosis of RA at follow-up was compelling in the retrieved literature. The absence of ACPA or RF was diagnostically less helpful. The presence of ACPA or RF75 106–109 111–115
also increased the probability of developing persistent synovitis or a worse radiographic outcome.73 75 84–86 116
For anti-keratin antibodies (AKA) and anti-perinuclear factor, the evidence suggests diagnostic usefulness; AKA also appears to have some prognostic value.11 96–99 107 110 114 117
For all other markers including a variety of other autoantibodies as well as bone and cartilage biomarkers, the evidence for diagnostic or prognostic value is scarce, negative or controversial.57 102 118–126
The same applies to disease outcomes different from those already mentioned.59 74 76 81 93 100 116 127 128
The value of ACPA and RF in UPIA was recognised and, based on clinical experience, experts also advised consideration of additional autoantibody tests if non-RA systemic inflammatory disorders are suspected. The use of the general term ACPA was preferred as the literature describes several tests for detecting antibodies to citrullinated peptides (such as anti-CCP1 and anti-CCP2) and newer generation tests are also expected to be used in the future.
Recommendation 5. X-rays of affected joints should be performed at baseline. X-rays of hands, wrists and feet should be considered in the evaluation of UPIA as the presence of erosions is predictive for the development of RA and persistence of disease. These should be repeated within 1 year.
Radiographic erosions43 49
and Larsen grade 1 (in a population without erosions at baseline)20
increased the probability of developing RA from UPIA. Moreover, when comparing mild versus progressive disease after 1 year follow-up, Sharp/van der Heijde scores at baseline were significantly higher in the progressive disease group.48
In another study,44
erosions were found to be a predictor of RA in univariate but not in multivariate analysis.
Overall, studies in mixed populations also provided some evidence for the usefulness of x-rays in predicting RA.72 88 92 109 122 129–135
In general, prognosis was worse when radiographic abnormalities at baseline were more severe.75 91 109 116 133 136–140
Experts recognised the clinical value of hand and feet x-rays in UPIA and, based on clinical experience, also recommended that x-rays of affected joints should be performed at baseline; furthermore, experts advised that x-rays should be repeated within 1 year (in case of disease persistence). Moreover, although not voted to be included in the recommendation, some of the experts expressed their opinion that pelvic/sacroiliac joint x-rays should also be considered, particularly in RF- and ACPA-negative patients or if spondyloarthritis is suspected.
There was a slightly lower agreement about this recommendation (, 7.4 agreement), with a larger proportion of experts stating that they did not want to change their practice for this aspect (, 35.7%). This lower concordance was mainly related to the inclusion of ‘x-rays of affected joints at baseline’ and about the advice to repeat x-rays ‘within 1 year’.
Recommendation 6. There is insufficient evidence to recommend the routine use of magnetic resonance imaging (MRI) and ultrasound (US) for diagnosis or prognosis in UPIA; in UPIA and suspicion of RA, MRI of hands and wrists could be considered for diagnosis.
Bone oedema was found to be an independent predictor of the future development of RA from UPIA,141
and the presence of a distinct MRI synovitis and erosion pattern with the involvement of several hand joints but not the first carpometacarpal joint also increased the probability of developing RA.20
The absence of the same MRI synovitis pattern decreased the probability of developing RA.20
Overall, MRI studies in mixed populations101 134 142–147
provided some evidence for the usefulness of MRI (bone oedema, synovitis and erosions) in predicting RA. Regarding US, two mixed populations revealed US-power Doppler signal and US-gray scale synovitis as potential candidates for future studies in UPIA.148 149
Experts recognised that MRI of the hands and wrists has already been shown to be useful in predicting the development of RA from UPIA, while the value of US in UPIA is still to be determined. However, data are still too scarce to recommend the routine use of any of these imaging tools. This recommendation does not dispute the fact that, compared with physical examination and x-rays, both MRI and US may offer advantages through more sensitive depiction of inflammatory and destructive disease manifestations. The current recommendation pertains only to the diagnostic and prognostic value of these imaging tools in UPIA.
Recommendation 7. There is no genetic test that can be routinely recommended, however HLA-B27 testing may be helpful in specific clinical settings.
There was a great heterogeneity among the genetic markers tested.39 40 46 50–52 65 84 127 133 150–165
The shared epitope (SE) was the most frequently studied marker. Eight studies40 50 65 133 153–155 158
tested its diagnostic utility and showed poor results. Only in one study was the positive likelihood ratio for RA relevant, but this result came from the study with the poorest quality and smallest sample size.40
In isolation, no other genetic marker was informative of a future diagnosis in patients with UPIA. With regard to prognosis, the SE was weakly associated with a poor prognosis of arthritis in terms of development of erosions, mortality, disability and persistent synovitis.65 127 133 163 164
Other genes were not good predictors of erosions or other less studied outcomes.
The experts acknowledged the current lack of evidence for the practical utility of genetics in UPIA. However, based on their clinical experience, experts chose to highlight that HLA-B27 may be helpful in the appropriate clinical setting—namely, when spondyloarthritis is suspected.
Recommendation 8. Routine synovial biopsy is not recommended but can give information for differential diagnosis, especially in patients with persistent monoarthritis.
Studies had significant clinical and statistical hetero-geneity.22 23 166 167
Three broad synovial features of interest were identified in the literature: ACPA staining, immunohistochemistry and vascular patterns. In contrast to serological ACPA testing, ACPA staining was shown not to be highly specific for a diagnosis of RA.167
In one study, synovial histopathology seemed to differentiate between RA and non-RA.166
The vascular pattern in undifferentiated arthritis was not specific enough to differentiate between spondyloarthritis and RA.22 23
The exact role of synovial biopsy in UPIA is yet to be determined and experts felt that it could not be recommended as a routine procedure. However, experts also highlighted the fact that synovial biopsy may give important diagnostic clues, especially in some selected cases (eg, persistent/chronic refractory monarthritis, suspicion of malignancy or suspicion of chronic infection such as tuberculosis).
Recommendation 9. Predictors of persistent inflammatory arthritis should be documented and include disease duration of ≥6 weeks, morning stiffness >30 min, functional impairment, involvement of small joints and/or knee, involvement of ≥3 joints, ACPA and/or RF positivity and presence of radiographic erosion.
The question about chronicity was investigated by looking at prognostic studies that used multivariate analysis to identify independent predictors of persistence (chronicity). At baseline the following variables were found to be independent predictors of persistent (inflammatory) arthritis: disease duration,75 82 116
duration of morning stiffness,75 85 86
change of functional status (measured by HAQ) in the first 3 months,82
failure to respond 2 weeks after local treatment with intra-articular corticosteroids,82
small joint involvement,168
presence of RF,75 85
presence and level of ACPA,75 86 168
functional status (HAQ),169
arthritis of at least three joints,75
proximal interphalangeal joint involvement,169
metatarsophalangeal joint involvement75
and radiographic erosion at the hands and feet.75
The magnitude of the association in the same predictor was diverse among the studies depending on the patient characteristics (namely, if the population was purely UPIA or not), the study design and the variables used to adjust for in the models.
Recommendation 10. Disease activity should be monitored, however no specific tool can be recommended.
Five studies evaluated the validation of different clinical measures in patients with UPIA. Validation aspects of four questionnaires (WHO Disability Assessment Schedule,170
London Handicap Scale, Disease Repercussion Profile and the HAQ171
) and three physical measures (RA Disease Activity Index,172
McGill Range of Motion Index173
and NOAR Damage Joint Count174
) were partially assessed in these studies but none of the instruments of disease activity was fully validated for its use in UPIA.
Although no instrument of disease activity has been fully validated for its use in UPIA, experts felt that it was important to recommend that there should be a conscious effort to record disease activity.