1. 3e Initiative 2009 How to investigate and follow-up Undifferentiated Peripheral Inflammatory Arthritis? Case 1

2. 2 Elisa, an art teacher and active smoker comes to your consultation because of a swelling of the left knee and the right 4 th proximal (ring finger) interphalangeal joint Symptoms began 2 months ago with tenderness of both hands She has no family history Her Hashimoto’s disease is treated by L-thyroxine and at present is well controlled Case 1

3. 3 Question 1 In your opinion, which features on history may help to predict diagnosis of rheumatoid arthritis? 1.Her age 2.Her reproductive history 3.A recent infection history 4.The duration of morning stiffness 5.Self report of pain

4. 4 Answer Question 1 In your opinion, which features on history may help to predict diagnosis of rheumatoid arthritis? 1.Her age 2.Her reproductive history 3.A recent infection history 4.The duration of morning stiffness 5.Self report of pain

5. 5 Question 2 In your opinion, which features on physical exam may help to predict a diagnosis of rheumatoid arthritis? 1.Tender Joint Count 2.Swollen Joint Count 3.Joint distribution 4.Stress Pain 5.Joint symmetry 6.Body Mass Index

6. 6 Answer Question 2 In your opinion, which features on physical exam may help to predict diagnosis of rheumatoid arthritis? 1.Tender Joint Count 2.Swollen Joint Count 3.Joint distribution 4.Stress Pain 5.Joint symmetry 6.Body Mass Index

7. 7 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 [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 Extra-articular / systemic features [5, D]

8. 8 Historical Feature No. Studies Author, Year Point Estimate (95% CI) Interpretation Age2van der Helm-van Mil, 2007OR= 1.02 (1.01-1.04)Age reported as continuous Small magnitude of effect in both Mjaavatten, 2008OR = 1.05 (1.02-1.08) Gender2van der Helm-van Mil, 2007OR= 2.1 (1.30-3.60)Female sex may predict RA diagnosis Mjaavatten, 2008OR= 1.67 (0.71-3.92)Female sex does not predict RA diagnosis AM Stiffness2van Galen, 2004OR= 2.9 (1.20-6.50)Severity AMS >90 mm on VAS scale diagnostic of RA van der Helm-van Mil, 2007OR= 9.3 (3.0-28.7)Duration of AMS >1 hour diagnostic of RA Painful Joints1Quinn, 2003OR= 1.06 (1.00-1.12)Self-report of pain not associated with RA progression Reproductive History 1Hernandez-Avila, 1990RR= 1.0 (0.7-1.3)Previous OCP/HRT use not predictive of RA diagnosis Historical features with diagnostic utility for the development of RA *Estimates did not cross null value of no association *

9. 9 Physical Exam Feature No. Studies Author, Year Point Estimate (95% CI) Interpretation # Tender Joints 2Alarcon, 1996OR = 0.61 (0.27-1.46)Low # not associated with RA diagnosis van der Helm-van Mil, 2007OR = 3.3 (1.50-7.00)>10 joints diagnostic of RA progression # Swollen Joints 3Alarcon, 1996OR = 2.93 (1.06- 8.10)>6 joints may predict progression to RA van der Helm-van Mil, 2007OR = 2.8 (1.1-7.6)>10 may predict progression to RA van Galen, 2004OR = 5.8 (2.4-13.6)>3 associated with RA diagnosis Joint Distribution 3Mjaavatten, 2008OR = 5.64 (2.06-15.5)Small joint involvement diagnostic for RA van der Helm-van Mil, 2007OR = 3.5 (1.7-7.5) OR = 1.8 (1.1-3.1) Upper/lower involvement associated with RA Small joints in hands/feet may be associated with RA van Galen, 2004OR = 1.8 (0.7-4.5)MCP/PIP/wrist involvement not predictive of RA Symmetry2 van der Helm-van Mil, 2007OR = 1.6 (1.0-2.8)Symmetrical involvement not predictive of RA van Galen, 2004OR = 2.6 (1.1-6.0) Symmetrical involvement may be associated with RA progression Physical exam features found to have diagnostic utility for the development of RA *Estimates did not cross null value of no association *

10. 10 Question 3 She is 51 years old and has the following disease activity parameters: –Morning stiffness >1 hour –Tender joints: 4 –Swollen joints: 2 You are planning to perform laboratory tests to help classify this arthritis In your opinion, which acute phase reactants have some diagnostic value for defining RA? 1.ESR 2.CRP 3.Ferritin 4.Matrix MetalloProteinase 3 (MMP) 5.Complete Blood Count

11. 11 Answer Question 3 She is 51 years old and has the following disease activity parameters: –Morning stiffness >1 hour –Tender joints: 4 –Swollen joints: 2 You are planning to perform laboratory tests to help classify this arthritis In your opinion, which acute phase reactants have some diagnostic value for defining RA? 1.ESR 2.CRP 3.Ferritin 4.Matrix MetalloProteinase 3 (MMP) 5.Complete Blood Count

12. 12 Recommendation 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]

13. 13 Diagnostic value of ESR and CRP Author, YearOutcomeSeSpLR+LR- ESR Morel, 2002RA vs non-RA72% (49-87) 76% (57-88) 3.01 (1.42-6.4) 0.37 (0.17-0.8) Zeidler, 1987RA, ReA, UA, def RA, probable RA, SpA, OA In 59% of UA ESR elevated CRP Kvien, 1996Reactive arthritis, sarcoid arthropathy, non-inflammatory, other 69%94%1.060.33 Van der Helm, 2007RA vs non-RARegression coefficient and OR: CRP 5-50: 0.6 and 1.6 (0.9-3.0) CRP> 50 : 1.6 and 5.0 (2.0-12.1) Kudo, 2007RA vs non-RA arthropathy 83% (61-94) 74% (65-81) --

14. 14 Question 4 Which antibodies will help predict the development of RA? 1.Rheumatoid factor 2.ANA 3.ACPA (anti-CCP) 4.ANCA 5.Anti-MCV 6.Anti-RA33

15. 15 Answer Question 4 Which antibodies will help predict the development of RA? 1.Rheumatoid factor 2.ANA 3.ACPA (anti-CCP) 4.ANCA 5.Anti-MCV 6.Anti-RA33

16. 16 Recommendation 4 Testing of RF and/or ACPA should be performed in the evaluation of patients with UIPA, 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]

17. 17 Marker N of studies that show association N of studies that disprove association RA at [yrs] ACPA1401 ACPA402-3 RF1601 ANA041-2 AKA331-3 APF521-3 aMCV/aSa131 RA33231-2 Antibodies: diagnostic value for prediction of RA at 1 to 3 years RF is consistently associated with the diagnosis of RA (LR+ 1.1 to 13.5) The absence of RF is diagnostically less helpful (LR- 0.3 to 0.8) Anti-CCP is consistently associated with the diagnosis of RA (LR+ 1.2 to 20.5) The absence of anti-CCP is diagnostically less helpful (LR- 0.4 to 0.9)

18. 18 Question 5 You want to order radiographs. Which one(s) should you request? 1.Right hand radiograph 2.Both hands and wrists radiographs 3.Feet radiographs 4.Left knee radiograph 5.Pelvic/sacroiliac joints radiographs

19. 19 Answer Question 5 You want to order radiographs. Which one(s) should you request? 1.Right hand radiograph 2.Both hands and wrists radiographs 3.Feet radiographs 4.Left knee radiograph 5.Pelvic/sacroiliac joints radiographs

20. 20 Question 6 She comes back with her X-ray. Which pathological features will help you to predict the development of RA? 1.Bony decalcification 2.Radiographic erosion 3.Joint space narrowing 4.Calcifications 5.Enthesophytes

21. 21 Answer Question 6 She comes back with her X-ray. Which pathological features will help you to predict the development of RA? 1.Bony decalcification 2.Radiographic erosion 3.Joint space narrowing 4.Calcifications 5.Enthesophytes

22. 22 Recommendation 5 (beginning) 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] […]

23. 23 Studies Q/ levels of evidence (GR) Outcome Prognostic factor Sens % Spec % PPV % NPV % LR+ (95%CI) LR- (95%CI) Van Aken 2005 Good/ 2b(B)RA acc. ACR criteria at 1 year Erosive disease acc. to SvdH 309257783.5 (2.1-6.0) 0.8 (0.7-0.9) Van der Helm 2007 Good/ 2b(B)RA acc. ACR criteria at 1 year Erosive disease acc. to SvdH Univariate analysis: baseline SvdH significantly different between UA-RA and UA-non RA group Multivariate logistic regression analysis: Not independent predictor Van Gaalen 2004 Moderate/ 2b(B)RA acc. ACR criteria at 1 year ErosionsOR 7.6 (2.4-24.4) p=0.001; model without anti-CCP: OR 8.7 (2.4-31.2) p=0.001; model with anti-CCP: Duer 2008 Moderate/ 2b(B)RA acc. ACR criteria at 2 years Larsen grade 13697808110.9 (1.4-87.3) 0.7 (0.4-1.0) Diagnostic value of X-ray: UA cohorts

24. 24 StudiesPrognostic factorOutcome Sens % Spec % PPV % NPV % LR+ (95%CI) LR- (95%CI) Devauchelle 2001 Erosions hand X-rayRA acc to panel17%96%70%67%4,1 (1.7-9.5)0,9 (0.8-1.0) Bony decalcifications5%92%26%63%0,6 (0.2-1.7)1,0 (1.0-1.1) Both23%87%50%67%1,8 (1.0-3.1)0,9 (0.8-1.0) Sharp erosions17%96%70%67%4,1 (1.7-9.5)0,9 (0.8-1.0) Devauchelle 2004 Erosions foot X-rayRA acc to panel18%98%83%67%8,6 (1.9-37.6)0,8 (0.7-0.9) Bony decalcifications4%96%33%63%0,9 (0.2-4.5)1 (1.0-1.1) Both22%94%67% 3,4 (1.4-8.6)0,8 (0.7-1.0) Erosions hands18%97%77%67%5,7 (1.6-19.8)0,8 (0.7-1.0) Erosions hands and/or feet33%95%78%71%6,2 (2.4-15.6)0,7 (0.6-0.9) Devauchelle 2006 Erosions and/or bonydecalcification on hand X-ray RA acc to panel23%87%50%67%1.8 (1.0-3.1)0.9 (0.8-1.0) Saraux 2001 Erosions and/or bonydecalcification Hand and/or foot X-ray RA acc to panel22%98%85%69%9.7 (3.4-27.2)0.8 (0.7-0.9) Diagnostic value of X-ray: mixed population

25. 25 Study Prognostic factor OutcomeResults Jensen 2004 Knudsen 2008 Klarlund 2000 Erosions Larsen score>0 RA (ACR) at 1 yearBoth different in RA, UA and UA>RA group at 1y Cunnane 2001ErosionsRA (ACR) at 1,5 yearsNumber of erosions lower in UA group compared to RA Nielen 2005SvdH scoreRA according to rheumatologist at 1y Univariate analysis SvdH score associated with diagnosis, multivariate not Daragon 2001Modified sharp scoreRA (ACR) at 1 yearModified sharp score not significantly different Kuriya 2008Erosive diseaseRA (ACR) at 6 monthsErosive disease not independently predictive Diagnostic value of X-ray: mixed population

26. 26 Question 7 The results of the lab tests and radiographs are the following: –ESR: 25 mm at 1 st hour –CRP: 30 mg/L –RF negative –Anti-CCP negative –Normal X-ray How do you interpret these results so far in making a diagnosis? 1.Reconsider diagnosis of RA 2.Reconsider diagnosis of UPIA 3.Match progression to RA 4.Match diagnosis of UPIA

27. 27 Answer Question 7 The results of the lab tests and radiographs are the following: –ESR: 25 mm at 1 st hour –CRP: 30 mg/L –RF negative –Anti-CCP negative –Normal X-ray Do these results ESR 1.Reconsider diagnosis of RA 2.Reconsider diagnosis of UPIA 3.Match progression to RA 4.Match diagnosis of UPIA

28. 28 Question 8 The results of the lab tests and radiographs are the following: –ESR: 25 mm at 1 st hour –CRP: 30 mg/L –RF negative –Anti-CCP negative –Normal X-ray How often will you repeat these exams? 1.Never 2.Acute phase reactants once a month 3.Auto-antibodies every three months 4.According to the clinical setting 5.Radiographs not before 2 years

29. 29 Answer Question 8 The results of the lab tests and radiographs are the following: –ESR: 25 mm at 1 st hour –CRP: 30 mg/L –RF negative –Anti-CCP negative –Normal X-ray How often will you repeat these exams? 1.Never 2.Acute phase reactants once a month 3.Auto-antibodies every three months 4.According to the clinical setting 5.Radiographs not before 2 years

30. 30 Recommendations 3, 4 and 5 ESR and CRP should be [...] repeated when clinically relevant [5, D] No data available concerning the fact whether acute phase reactants should be repeated at certain time-intervals […] RF and/or anti-citrullinated negative tests ACPA do not exclude progression to RA [1a, A] The current evidence does not allow to make conclusions on the optimal frequency of serological assessments in the evaluation of patients with UPIA. Radiographs [...] should be repeated within one year [5, D] No data was found about the value of repeating X-rays in UA patients or mixed populations

31. 31 Question 9 Elisa comes back to your consultation 2 months later. In spite of analgesic and NSAIDs you gave her, she has a a pain and stiffness of her right wrist and a persistent swelling of the right 4 th proximal interphalangeal joint. Considering results of her first exams, which imaging investigations can you propose to her to confirm a potential diagnosis of RA? 1.New hands and wrists radiographs 2.Right hand and wrist Magnetic resonance imaging (MRI) 3.Hands and Wrists ultra-sound (US)

32. 32 Answer Question 9 Elisa comes back to your consultation 2 months later. In spite of analgesic and NSAIDs you gave her, she has a a pain and stiffness of her right wrist and a persistent swelling of the right 4 th proximal interphalangeal joint. Considering results of her first exams, which imaging investigations can you propose to her to confirm a potential diagnosis of RA? 1.New hands and wrists radiographs 2.Right hand and wrist Magnetic resonance imaging (MRI) 3.Hands and Wrists ultra-sound (US)

33. 33 Recommendation 6 and 5 There is insufficient evidence to recommend the routine use of magnetic resonance imaging (MRI) and ultra-sound (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] […] Radiographs should be repeated within one year [5, D]

34. 34 Study Popula- tion, nº (type) Final Dx, nº (%) Index test SE (%) SP (%) PPV (%) NPV (%) LR+ (95% CI) LR- (95% CI) Duer 08-41 UA -♀ = 85.4% -Mean disease duration = 18 months (6-180) -RF+ = 34.1% -X-ray erosion = 0% -Mean follow-up = 24 months RA = 11 (26.8) 1) MRI synovitis and erosion pattern of RA* 648764874.8 (1.7-13)0.4 (0.2-0.9) 2) MRI synovitis pattern of RA*10060481002.5 (1.6-3.9)0 (NA) 3) MRI erosion pattern of RA*647750852.7 (1.2-6.0)0.5 (0.2-1.1) 4) MRI synovitis or erosion pattern of RA* 10050421002.0 (1.4-2.9)0 (NA) 5) MRI synovitis and erosion and scintigraphy patterns of RA* 45100 83Inf0.5 (0.3-0.9) 6) RF+366729741.1 (0.4-2.8)1 (0.6-1.6) 7) CRP >1mg/dl646339831.7 (0-9-3.3)0.6 (0.3-1.3) 8) Larsen grade 13697808110.9 (1.4-87)0.7 (0.4-1) 9) Scintigrahy pattern of RA*647450832.5 (1.1-5.3)0.5 (0.2-1.1) Tamai EULAR 07 -118 UA -Follow-up 3 years Progression to RA = 66 (55.9%) - MRI BME - MRI erosion - anti-CCP - IgM RF - MMP-3 Progression to RA (n= 66, 55.9%): - anti-CCP antibodies - MRI BME Diagnostic value of MRI: UA population

35. 35 Study Population, nº (type) Final Dx, nº (%) Index test SE (%) SP (%) PPV (%) NPV (%) LR+ (95% CI) LR- (95% CI) Freeston 09 -49 (UA? + Arthralgia) -♀ = 76% -Mean disease duration = <3 months (NR) -RF+ = 24% -Anti-CCP = 35% -X-ray erosion = NR -Mean follow-up = 12 months Persistent Inflammatory Arthritis (IA) = 38 (77.6) (23 RA, 12 UA, 1 reactive IA and 2 connective tissue disease-associated IA) US GS≥1†921880401.1 (0.8-1.5)0.4 (0.1-2.3) US GS≥2†766488442.1 (0.9-4.7)0.4 (0.2-0.8) US GS=3†479195335.2 (0.8-35)0.6 (0.4-0.8) US PD≥1†718293453.9 (1.1-14)0.4 (0.2-0.6) US PD≥2†50100 35Inf0.5 (0.4-0.7) US FT in any finger476482261.3 (0.6-3.0)0.8 (0.5-1.4) Erosive on US‡537387311.9 (0.7-5.3)0.7 (0.4-1.1) RF+32100 30Inf0.7 (0.6-0.8) CCP+45100 34Inf0.6 (0.4-0.7) Diagnostic value of US: mixed population NB:In patients seronegative for RF and CCP BUT positive for CRP, swollen joints and X-ray erosion, the presence of US GS=3, US PD≥1 and at least 1 erosion increased the probability of IA from 30% to 94%. If only 1 US feature was positive, the probability of IA was 0-39% If 2 US features were positive it was 8-85% If all US features were negative, the probability of IA was only 0-5%.

36. 36 Question 10 MRI shows bone edema on her right wrist. She asks you how long she will suffer from this arthritis. Which elements in this observation are predictors of persistent inflammatory arthritis? 1.Disease duration (4 months) 2.Morning stiffness (>1 hour) 3.Swelling of 2 joints 4.Involvement of the knee 5.ESR: 25 mm at 1 st hour and CRP: 30 mg/L 6.Bone edema on IRM

37. 37 Answer Question 10 MRI shows bone edema on her right wrist. She asks you how long she will suffer from this arthritis. Which elements in this observation are predictors of persistent inflammatory arthritis? 1.Disease duration (4 months) 2.Morning stiffness (>1 hour) 3.Swelling of 2 joints 4.Involvement of the knee 5.ESR: 25 mm at 1 st hour and CRP: 30 mg/L 6.Bone edema on IRM

38. 38 Recommendation 9 Predictors of persistent inflammatory arthritis should be documented and include disease duration of ≥6 weeks [1b, A], morning stiffness >30 min [4, C], functional impairment [4, C], involvement of small joints [4, C] and/or knee [4, C], ≥ 3 joints [1b, B], ACPA [4, C] and/or RF positivity [4, C] and presence of radiographic erosion [1b, B].

39. 39 Study Sample size Study Quality Inclusion criteriaExclusion criteria Tunn, et al 1993 65Fair Symmetrical inflammatory polyarthritis Symptom duration ≤6 mo Diagnoses other than symmetrical polyarthritis Green, et al 2001 51Good Synovitis ≤5 joints* Symptom duration ≤12 mo No previous steroid or DMARDS Not stated El Miedany, et al 2008 173Fair Synovitis >2 joints* Symptom duration ≤6 mo Morning stiffness >30 min MCP/MTP squeeze test + RA or SpA Predictors of persistent (chronic) UPIA: Study Characteristics * Synovitis = 2 of following 3 criteria :- swelling, tenderness, and decreased range of motion

40. 40 StudyPredictorTrial durationβ or OR (95%CI)Comments Tunn, et al 1993 Morning stiffness 1 y β 0.17 DIP involvemet had negative association (β-0.6) Knee involvementβ 0.71 RFβ 1.11 Green, et al 2001Synovitis at 2 wk 12 wkOR 15.75 (3.62-68.04) adjusted for HLA-DRB1*04 or*01, RF, HLAB27, CRP, swollen joint count 26 wkOR 9.36 (2.46-37.68) 52 wkOR 18 (3.68-87.99) Disease duration 26 wkOR 1.06 (1.01-1.12) 52 wkOR 1.11 (1.03-1.21) El Miedany, et al 2008 Morning stiffness 1 y OR 1.16 (1.09-1.22) Anti-CCPOR 11.22 (1.68-75.16) Change in HAQ at 3 moOR 1.04 (1.01-1.06) Predictors of persistent (chronic) UPIA: Results

41. 41 UAMixed population HistoryDisease durationDisease duration ≥ 4 mo Symptom duration > 6 wk Morning stiffness Change of HAQ at 3 moHAQ at baseline Physical examSynovitis at 2 wkArthritis ≥ 3 joints Swollen PIP joint, Small joint arthritis Knee involvementMTP squeeze test + LabRheumatoid factorIgM- Rheumatoid factor Anti-CCPAnti-CCP (presence and level) ImagingErosion (hand or feet) Oxford level of evidence :- 1b Predictors of persistent disease: Summary

42. 42 Question 11 You would like to evaluate the disease activity to better manage the follow-up. Which are the most suitable clinical measures (any activity index, measure or scales) to evaluate the diagnosis and the follow-up of UPIA? 1.DAS (Disease Activity Score) 2.CDAI (Clinical Disease Activity Index) 3.SDAI (Simplified Disease Activity Index) 4.WHODAS II (WHO Disability Assessment Schedule) 5.HAQ (Health Assessment Questionnaire) 6.McROMI (McGill Range of Motion Index) 7.RADAI (RA Disease Activity Index) 8.No specific tool can be recommended

43. 43 Answer Question 11 You would like to evaluate the disease activity to better manage the follow-up. Which are the most suitable clinical measures (any activity index, measure or scales) to evaluate the diagnosis and the follow-up of UPIA? 1.DAS (Disease Activity Score) 2.CDAI (Clinical Disease Activity Index) 3.SDAI (Simplified Disease Activity Index) 4.WHODAS II (WHO Disability Assessment Schedule) 5.HAQ (Health Assessment Questionnaire) 6.McROMI (McGill Range of Motion Index) 7.RADAI (RA Disease Activity Index) 8.No specific tool can be recommended

44. 44 Recommendation 10 Disease activity should be monitored [no evidence, D], however no specific tool can be recommended [3b, C] No instrument of disease activity has been fully validated for its use in UPIA Specifically the more frequent indexes, such as DAS28, SDAI, SDAI... Literature search has not found any direct evidence on neither what is the most useful index to follow up patients with UPIA, nor, obviously, at which interval we should repeat it

45. 45 Indexes QuestionnaireDescriptionScore F (0-3) WHODAS II (WHO Disability Assessment Schedule) 36 Likert questions in 6 domains. 0 – 100 best to worst 2 DRP (Disease Repercussion Profile) 6 VAS on the importance to the patients for 6 domains 0 – 10 None to extremely important 3 LHS (London Handicap Scale) 6 domains covering handicap dimensions 100 – 0 None to extreme disadvantage 2 HAQ 20 items on the ability for daily activities 0 – 3 None to complete disability 3 Activity measures in UPIA: Questionnaires

46. 46 Activity measures in UPIA: Indexes IndexDescriptionScoring and range F (0-3) McROMI (McGill Range of Motion Index) Measure of the movements of 9 areas 37 scores Each one 0-3 Max. 111 1 NOAR-DJC (NOAR Damage Joint Count) Presence or absence of deformity 51 joints/score 0-51 1 RADAI (RA Disease Activity Index) Self-administer disease activity index 0-103

47. 47 Feasibility Internal consistency Test- retest Responsiveness Construct validity WHODAS2 +++ ++ DRP3 ++- LHS2 ++- HAQ3 ++- McROMI1 ++ NOAR-DJC1 ++ RADAI3 +++ Activity measures in UPIA: Summary of the results Indexes Questionnaires