1. Palindromic Rheumatism
三軍總醫院
風濕免疫過敏科
郭三元

2. Introduction
Palindromic– derived form the Greek (palindromos), means to run back
復發性風濕症，陣發性風濕症
First used by Hench and Rosenberg in 1944, they described 34 patients presenting with a unique set of signs and symptoms
Multiple recurring a febrile episodes of acute arthritis, periarthritis, and sometimes para-arthritis, lasting from few hours to several days, then subsided completely, no residual articular effect

3. Cases Presentation

4. Case 1
A 40-year-old female, had migratory arthritis from hands, wrist and knee joints for 6 years, each episode attack one joint and subsided promptly after NSAIDs or spontaneously. PE showed redness and tenderness over right second PIP joint, lab data showed negative RF and ANA, CRP:1.2, uric acid:5.3mg/dl, no family history of rheumatic disease, NSAIDs was given in acute attack and now the clinical symptoms still remained the same presentation

5. Case 2
A 46-year-old female, who complained migratory arthritis from PIP, wrist and knee joints for one year, each episode last for 2-3 days and subsided by spontaneously or by NSAIDs. Lab data showed RF:53, ANA: negative, CRP:0.4, uric acid:4.2, due to the clinical symptoms increased frequency and duration, she received geniquin and salazopyrin treatment, now the clinical condition was well controlled

6. Case 3
A 22-year-old male, who complained migratory arthragia/arthritis from elbow, knee and hip joints for months, no low back pain or morning stiffness, no family history, lab data showed ANA and RF were negative, CRP:0.82, HLA-B27 showed positive and pelvis X-ray was negative findings for sacroillitis, NSAIDs was prescribed

7. Palindromic rheumatism
Age of onset (from 20 to 70)
Female equal to male
No ethnic predisposition
Etiology unknown
Pathogenesis unclear

8. Clinical features
Monoarthritis with maximal intensity in hours, at any time of the day, usually without any obvious inciting event
Strike almost any joint, but the spine and hip joints are rarely affected
Initial attacks at knees, fingers or shoulders, the attacks are confined to a single joint
The pain is very severe or excruciating, like gout or septic arthritis
Para-articular tissues also involved in 30 %

9. Clinical features
The acute episodes last less than 2 days in most of the cases, sometimes 2 hours, rare extend for two weeks
Variable frequency
Rare or no constitutional symptoms
Nodules located at the tendons of hands or finger, or on the thumb pads, but different histology from RA, transient and smaller

12. Joint involvement Mean% of patients Range of % of patients MCP & PIP91
74-100
Wrists 78
54-82
Knees 64
41-94
Shoulders 65
33-75
Ankles 50
10-67
Feet 43
15-73
Elbows 38
13-60
Hips 17
0-40
T-M joints 8
0-28
Spine 4
0-11
S-C joint 2
0-6
Para-articular 27
20-29
Guerne PA Am J Med 1992

13. Lab ESR and CRP are usually elevated during acute episodes
ESR might be more likely elevated in patients who subsequently developed RA ?
Normal CBC
ANA
X-ray
Synovial fluid
Rheumatoid factor
Anti-CCP

14. Rheumatoid factors in PR
In three series studies
Reference
PR(%)
PR → RA
F/U
Hannonen
1987
11/25 (44)
29/35(83)
5 years
Bregeon
1986
3/16(19)
16/25(64)
10 years
Wajed
1977
2/22(9)
16/17(94)

15. Pathology
Periarticular edema and gross thickening of the joint capsule, infiltration with PMN, no pannus formation or cartilage destruction
Between episodes, no significant evidence of inflammation in gross and histologic examination

16. Pathology 5 PR pts before developed to RA were examined, including EM
Minimal superficial reaction and only mild lining cell hyperplasia (1-3 layers) with more neutrophils
Fibrin and cellular thrombi are noted in some small blood vessels along with congestion and some perivascular fibrosis
Synovial fluid analysis showed variable leukocyte couts( )
From pathological findings couldn’t allow to predict the PR progression to RA
Schumacher HR .
Arthitis Rheum 1982

17. Genetic factors HLA-DRB1 shared epitope (SE) in RA, but in PR?
Increased prevalence of the DRB and 0404 in PR patients (65%) versus controls(39%) who progression to RA
HLA-DRB maybe a genetic marker in Korean PR patients , not correlated with RA Ann Rheum Dis 2006
HLA-DR4 ?, no definite conclusion
Cytokine gene polymorphisms – no association
J Rheumatol 2002

18. Triggering factors Single factor Multiple factors None
Physical activity
Foods
Weather change

19. Physical activity Rapid walking Running Hammering Climbing
Limb exercise
Typewriting
Housework

20. Foods Alcohol Fish Eggs Canned vegetables Processed cheese
Nesher, G Clinical & Exp Rheumatol18(3), 2000

21. Proposed diagnostic criteria
A 6-month history of brief sudden-onset and recurrent episodes of monoarthritis or rarely polyarthritis or of soft tissue inflammation
Direct observation of one attack by a physician
Three or more joints involved in different attacks
Absence of erosions on radiographies
Exclusion of other arthritis
Pasero G, Barbieri P , Clin Exp Rheumatol 1986

22. Pregnancy and PR
Over 70% patients with RA experience improvement of symptoms during pregnancy
30-50% PR patients developed to RA, have the same effect ?
Few cases reports support these findings

23. Treatment Avoid triggering factors NSAIDs DMARDs Biologic agents?
Steroids
No large randomized, controlled trials

24. Antimalrials Can decrease progression of PR to RA or other CTD
estimated median time to development of a chronic disease was 162 months in treated and 56 months in untreated patients
Risk reduction for RA –0.36 and for RA or other CTD– 0.41
Gonzalez-Lopez,L Jounrnal of Rheumatology, 27(1), 2000

25. Outcome of PR

26. Prognostic factors for the development to RA or other CTD in PR
LauraG-Lopez J Rheumatol 1999

27. LauraG-Lopez J Rheumatol 1999

28. LauraG-Lopez J Rheumatol 1999

29. Prognostic factors for PR to RA
Positive RF had 3-fold risk
Early involvement of wrist or PIP had 2-fold risk
Female gender+ RF+ hand involvement had 8-fold risk
No major effect on the length or frequency of attacks
LauraG-Lopez J Rheumatol 1999

30. Evolution of PR patients in 9 series
No. of cases Remission persistent PR PR-RA Other Dis
or cure(%) (%) (%) (%)
Guerne PA Am J Med 1992

31. Palindromic rheumatism ∥ Rheumatoid arthritis

32. Anti-cyclic citrullinated peptides (anti-CCP)
A group of antibodies direct to citrullinated antigens, mostly considered as a disease marker for RA
Anti-CCP antibodies are antibodies against antigens containing the unusual amino acid citrulline, including modified fibrin(filaggrin), which is present in RA joint
High specificity for RA (97%) and high sensitivity rate (80-90%)
Powerful diagnostic tool for early detection of RA
Predict the development of RA in healthy subjects
In RF- , clinical suspect RA, the anti-CCP is very helpful
Associated with more aggressive and erosive RA

33. Anti-CCP predict progression to RA in patients with undifferentiated arthritis
318 patients with recent onset arthritis, followed 3 years
Van Gaalen FA, arthritis Rheum 2004

34. Specific autoantibodies precede the symptoms of RA
Can we predict early RA from serum specific antibodies?
IgM-RF
Anti-CCP
IgM-RF + anti-CCP
Markus M.J. Nielen Arthritis & Rheumatism 2004

35. Markus M.J. Nielen Arthritis & Rheumatism 2004

36. Markus M.J. Nielen Arthritis & Rheumatism 2004

37. Results
Near ½ patients with RA have specific serologic abnormalities several years before the onset of symptoms
Elevated serum level of IgM-RF or anti-CCP in a healthy individual implies a high risk for development of RA
IgM-RF and anti-CCP may assist in the early detection of RA in high-risk populations
Markus M.J. Nielen Arthritis & Rheumatism 2004

38. Anti-CCP and PR
In one study with 63 pts,33 pure or persistent PR, 30 as associated PR( past history of PR and developed persistent arthritis---21 with RA),60 early RA and 80 seronegative SpA as control
G. Salvador, Rheumatology 2003

39. G. Salvador, Rheumatology 2003

40. The predictive value of anti-CCP as a marker of PR progression to RA ?
In pure PR patients, anti-CCP was found in 56% and RF in 42%, which were highly correlated
No significant clinical difference between anti-CCP+ and anti-CCP- pure PR pts
The predictive value of anti-CCP as a marker of PR progression to RA ?
PR is a abortive form of RA
G. Salvador, Rheumatology 2003

41. 61 pts with PR within the first year of the presentation
29/61(47%) developed to RA after a mean follow-up of 5.4 years
83% of(29 RA) had anti-CCP in the baseline serum
Anthony S. Russel, J Rheumatol 2006

42. Is palindromic rheumatism a form of rheumatoid arthritis
Is palindromic rheumatism a form of rheumatoid arthritis? Or a distinct entity?

43. Part of RA ? 30-50% PR patients evolved to RA
High prevalence of RF and anti-CCP in PR patients
Cutaneous nodules present in PR patients( different histology)
Common response to DMARDs

44. Distinct entity?
Different inflammatory pattern, frequent remission and symptoms free interval, no apparent accumulation of disease
No bone or joint destruction
Constitutional symptoms are absent or rare
No strong HLA association
Affects male and female equally

45. Conclusion
Palindromic rheumatism is an idiopathic, periodic arthritis, last from few hours to several days, self-limited and no residual effects
Anti-CCP and RF, hands involvement and female were risk factors from PR to RA
Need long-term follow up and large cohort studies

47. Behcet’s syndrome Recurrent oral ulcers Recurrent genital ulcers
Eye involvement
Skin lesions– erythema nodosum
Pathergy test

48. Behcet’s syndrome
Affect young male and female from the Mediterranean region, the Middle East and Far east ( Japan, Turkey)
Blacks are not affected
HLA-B5 (B51) – more expression of clinical manifestations and more severe clinical course
May cause blindness – posterior uveitis

49. Pathergy test