Palindromic Rheumatism: Part of or Apart From the Spectrum of Rheumatoid Arthritis PIERRE-ANDREGUERNE,M.D., Geneva, Switzerland,
MICHAEL Ii. WEISMAN, M.D.,
San Diego, California
Palindromic rheumatism (PR), or&ally described in 1944,is characterized by recurrent episodeaof mostly 0ligoarticuIar arthritis with peri- and para-articular tissue infkmmation, leavhq no residual clinical and radiographic changea It appears that palindromic syndrome is entity, encompassingother . a heterogeneous mfhnmatory conditions at early stagesof their evolution, and whose relationship with rheumatoid arthritis (RA) is evident but still unclear. Evolution of up to SO%of these cases intO otherwise typical RA, mtuuonly accompaniedby the conversion to rheumatoid factor seropositivity, the frequent occurrence of nodules,the reported responseto RA treatment, and the observation of familial aggregation of the two conditions suggestthatPRispartofthespe&um,ora stagein the evolutkm of RA. However, justification for the distinct exknce of PR corneafrom reports that identity well-defined and recognkable clinical manifestations such as descriptions of the acute attach the frequent peri-articular manifestations, the absenceof bone and cartilage destruction even after extended periods of time, and the generally goodlong-term prognosis. Immunogenetic studies with HLA-DR phenotyping and the absenceof female preponderance tend to add additional support for the separate identity of PR.
From the Department of Medicine, Division of Rheumatology (MHW). University of California at San Diego Medical Center, San Diego, California, and the Division of Rheumatology (PAG). Department of Medicine, HOpital Cantonal Universitaire, Geneva, Switzerland. Requests for reprints should be addressed to Pierre-Andre Guerne, M.D., Division of Rheumatology, Hbpital Cantonal Universitaire. 26 avenue Beau-Sejour. 1211 Geneve-4, Switzerland. Manuscript submitted November 9. 1990. and accepted in revised form June 11,1992.
he term palindromic rheumatism (PR) was T first usedby Hench and Rosenberg[l] in 1944, for their descriptionof 34patients presentingwith a unique set of signs and symptoms. The condition wasmarked by multiple recurring afebrile episodes of acute arthritis, periarthritis, and sometimes para-arthritis, lasting from a few hours to several days before disappearing completely, and apparently producing no residual articular effect. The term palindromic, derived from the Greek “palindromos,” which literally means“to run back,” was chosento expressthis concept of recurrence.The authors separatedthis condition from rheumatoid arthritis (RA) becauseof the totally different pattern of distribution of the arthritis, the frequent attacks of para-arthritis, the generalabsenceof significant constitutional symptoms, and the lack of progression, chronicity, and/or radiographic changes. Fifteen yearsafter the original report, Ansell and Bywaters [2] reexamined the concept of PR by studying 28 patients who fulfilled the criteria defined by Hench and Rosenberg[11.They concluded that PR wasmerely a variant or a modeof presentation of RA, noting that the majority of the patients, if followed long enough,will eventually display residual signsof chronic (rheumatoid) arthritis. Subsequently, a number of series [3-71 followed patients longitudinally and noted that about onehalf of the casesevolveinto RA. Neither clinical, immunologic, nor genetic studies could predict reliably which caseremains PR or evolvesinto chronic RA. The controversyoverwhetherPR deservesa special nosologicplace or servesas a prodroma of RA has not beenresolved. We recently observeda patient whose clinical manifestations consisted mainly of recurrent episodesof severeperi- and para-articular inflammation in addition to arthritis. The special clinical featuresof this inflammation suggestthat at least somecasesof PR truly representan entity different from RA. We therefore believe it would be important to reviewthe literature concerningthis intriguing syndrome, with emphasis on the elements, among its clinical, serologic,etiologic, and genetic features,that can help to retain it in its rightful nosologicplace.
October 1992 The American Journal of Medicine
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PALINDROMIC RHEUMATISM / GUERNE AND WEISMAN
Figure
peri-articular, 1. Articular, the hypothenar and, to a lesser sents a para-articular manifestation. articular swelling and erythema.
and para-articular extent, the thenar Right. Synovitis
manifestations of palindromic rheumatism. eminences, without clear-cut involvement of the second proximal interphalangeal
CASEREPORT A 51-year-old patient, a native of Java, presented to our clinic with a 5-year history of episodic and recurrent pains in the back and the extremities, involving mainly the hands, feet, knees, and ankles. These attacks lasted from 1 to 2 days, sometimes up to a week. They were often, but not always, associated with redness and swelling, both in the joints and in the extra-articular sites (Figure l), including the palms, soles, lateral aspects of the heels, and the forearms. Episodes progressively worsened, both in frequency (one or two per week) and in intensity. The patient had to quit his job in 1986. He saw a variety of doctors, but no diagnosis was established. The different treatments that he received, including analgesics, nonsteroidal anti-inflammatory agents (NSAIDs), and benzodiaxepines, did not improve his condition. A skin biopsy specimen, obtained from the left hypothenar eminence during an 452
October 1992 The American Journal of Medicine
left. Swelling and erythema of of joint structures. This reprejoint in addition to marked peri-
episode of swelling and redness, had shown a positive lupus band, but was otherwise histologically normal. Because of this finding, the diagnosis of systemic lupus erythematosus (SLE) was considered and the patient began to undergo a treatment trial of hydroxychloroquine for 4 months without any benefit. At the first arthritis clinic visit, results of physical examination were entirely unremarkable except for some bilateral tenderness of the trapezius insertion points, pes anserinus insertions, and epicondyles, consistent with the diagnosis of fibromyalgia syndrome. Results of laboratory tests were all normal: erythrocyte sedimentation rate (ESR) 16 mm/h; white blood cell (WBC) count of 14.7 X log/L with 68% neutrophils, 3% bands, 21% lymphocytes, 7% monocytes, and 1% eosinophils; hemoglobin, 13.2 g/dL (mean corpuscular volume, 90 fL); rheumatoid factor (RF), negative times 2; antinuclear antibody (ANA) negative; anti-SSA and anti-SSB nega-
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tive; total hemolytic complement (CH&, 135 U/mL; VDRL negative; muscle enzymes, not elevated; serum protein electrophoresis normal. Radiographic studies including the knees, hands, and the chest were negative. Treatment with amitriptyline only partially relieved the pain. At the second visit, the patient presented with very localized swelling and redness on the medial aspect of the left knee, with a diameter of about 7 cm; synovial fluid aspirated from this knee was mildly inflammatory, containing a WBC count of 2,100/mm3 (56% segmented, 41% monocytes, and 3% lymphocytes). The peri-articular swelling and arthritis disappeared spontaneously. On the third visit, the patient presented with localized swelling, redness, and extreme tenderness of the lateral aspect of the right ankle that was clearly para-articular. Because of the pattern of recurring episodes of arthritis and para-arthritis over a 5-year period, disappearing completely between episodes, and the exclusion of other forms of chronic arthritis, we strongly considered the diagnosis of PR. During the subsequent 3-year period of observation, the patient received complete therapeutic courses of gold, colchicine, sulfasalaxine, methotrexate, dapsone, and systemic steroids. No effect on the patient’s condition was observed; he continued to exhibit even more frequent episodes of peri- and para-arthritis, especially in his pelvis, soles, lateral aspects of his ankles, and heels, and occasional arthritis. On almost all occasions his ESR remained at baseline levels; during one episode, his ESR was elevated to 45 mm/h.
CLINICALFEATURESOF PR The nature of PR arthritis remains its most distinctive feature. Joint involvement is commonly noted to be monoarticular with maximal intensity reached in a matter of hours [1,7], at any time of the day, usually without any obvious inciting event, although, in a few cases, attacks have been noted to relate to another event such as a respiratory tract infection, weather change, childbirth, or overexercise [1,3,7]. The disease can strike almost any joint, although the spine and the hips are rarely affected. When the spine is involved, it is usually at the cervical level. Table I displays the distribution of the joints involved, based on five large series totaling 227 patients [1,3-5,781. The joints involved in initial attacks appear to be mostly knees, fingers, or shoulders. In the vast majority of the patients, the attacks are confined to a single articulation, but in rare cases more than four joints can be affected at a time [l]. The pain is generally described as very severe or excruciating, mimicking gout or septic arthritis in some cases,
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TABLE I Distribution of Joints Involved in AttacksBased Upon a Cumulative ExperienceWith 227 Patients Joint Involvement
Mean% Patients
of
Rangeof % of Patients
MCP & PIP
91
74-100
Wrists
78
54-82
Knees
64
41-94
Shoulders
65
33-75
Ankles
50
lo-67
Feet
43
15-73
Elbows
38
13-60
Hips
17
O-40
Temporo-mandibular
8
O-28
Spine
4
o-11
Sternoclavicular
2
O-6
27
20-29
Para-articular sites
CP = metacarpophalangeal;PIP = proximal interphalangeal
often confining the patient to bed [1,5,7]. A few patients have been described as having only mild pains. In addition, extra-articular tissue inflammation is observed in about 30% of the patients [1,7]. This involvement may be inflammation of a tendon or swelling of undefined para-articular structures, generally close to a joint but often remote enough to allow the patient to clearly distinguish it from joint involvement. The size of these para-articular swellings varies from 2 cm to much larger areas. The PR episodes last less than 2 days in most of the cases, sometimes as short as 2 hours [l]. However, in a few cases, they can extend to more than 2 weeks [1,5]; their frequency is highly variable, from a few to more than 250 a year [1,5,8]. Persons who have frequent attacks (more than one a month) may be more likely to develop frank RA [6]. Only a few patients display constitutional reactions such as fever or weight loss. Of interest is the observation that patients from the Hannonen [7] series (7 of 60) who had such systemic manifestations were all RF-positive and later progressed to erosive RA. A peculiar feature of PR is the occasional occurrence of nodules, usually the size of a pea and overlying the tendons in the hands or fingers or located on the thumb pads. Their appearance parallels the arthritis attacks and generally lasts a week at most [1,3-5,9,10]; however, typical PR may also be associated with more sustained nodules. The presence of nodules has been used to link PR to other forms
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PALINDROMIC RHEUMATISM / GUERNE AND WEISMAN TABLE II Percentagesof Patients RF-Positivein Three Series: RF Determination at Follow-Up in Patients Who Have DevelopedChronic Arthritis (PR-RA)Compared With Patients Who Remained Palindromic (PR-PR) Reference
ii [51
PR(%)
PR-RA(%)
1 l/25 (44) 3116 (19) 2122(9)
29135 (83) 16125 (64) 16/17 (94)
I
I
RF = rheumatoid factor; PR = palindromicrheumatism; RA = rheumatoid arthritis.
of chronic rheumatic diseases. For example, the clinical entity of rheumatoid nodulosis [ll], combining rheumatoid nodules, subchondral bone cysts, and recurrent joint symptoms and considered a variant of RA with a good prognosis, closely resembles PR. A recent review of all of the published cases of rheumatoid nodulosis [12] reveals that 24 of the 26 reported patients were described as having a clinical presentation consistent with PR. Kaye et al [13] place PR with nodules in the group IIa of their proposed classification of conditions associated with rheumatoid nodules. To add further to the confusion, there is a report of a patient with PR and pulmonary nodules [14], and two patients with PR and Felty’s syndrome [7,15]. Finally, in the 60 patients with PR reported by Hannonen et al [7], the criteria for fibromyalgia syndrome were fulfilled by 8 of their 60 patients. In contrast to the female preponderance noted in RA, the incidence of PR is relatively equal in each sex, with a female:male ratio that varies between 1.7:1 and 0.55:1 [1,3-5,7,8]. The mean age of onset of PR is about 45 years, with cases reported from the early 20s to the 80s. The prevalence of this disease is difficult to establish, and certainly may be underestimated. In the most recent studies on PR, the prevalence is estimated to be 1 of 8 [7] to 1 of 20 [8] that of RA.
LABORATORYFEATURESOF PR ESR is frequently increased during or just after the episodes, but rarely between them [1,3,5], and the ESR might be more likely elevated in the patients who subsequently develop RA. There is generally no abnormality of the WBC and red blood cell counts or miscellaneous chemical constituents [l], except for a few patients who were reported to have transient anemia [3]. RF status, associated with the disclosure that a significant number of patients with PR developed chronic arthritis identical to RA, has become an important diagnostic and nosologic issue. A number of reports show that the percentage of seropositive patients among those with PR that has evolved into 454
October 1992 The American Journal of Mediclne
chronic arthritis is not different from the percentage of seropositivity in RA. Among the patients observed in different series [5-71, about one third were found to convert from negative to positive, usually shortly before their evolution to chronic arthritis. The patients who remained palindromic seemed, in one series [7], to be more frequently positive (11 of 25, including 2 followed prospectively for more than 5 years) than the normal population, and in addition, patients with PR and positive RF seemed more susceptible to develop RA [7]. Finally, seropositivity is more frequent in PR patients after they have developed RA than in patients who remained palindromic [5-71 (Table II). Because of the limited follow-up time periods and the dynamic changes in the status of RF and arthritis patterns, the meaning of the seropositivity among patients who remain palindromic is less clear-cut. However, it seems that seroconversion almost always shortly precedes the appearance of chronic arthritis [5]. It is likely, therefore, that there is a true increase in RF positivity in PR patients who remain palindromic in addition to the definite increase in those who convert to RA. ANA studies, on the other hand, are usually negative in PR cases [6,16]. Radiographic studies, as pointed out originally by Hench and Rosenberg [l], are always normal in patients with PR [3,5,6]. Absence of radiographic signs is thus among the six diagnostic criteria proposed by Pasero and Barbieri [8]. In the cases that have evolved into chronic arthritis, erosions not different from the ones seen in classic RA usually develop [3,5,6]. The rare synovial fluid analyses that have been reported [17] show variable leukocyte counts (150 to 12,700/mm3) and differentials (2% to 66% polymorphonuclear cells) that do not correlate with the severity of the symptoms or attacks.
PATHOLOGICFINDINGS Not surprisingly, there are very few pathologic examinations of tissues in this disease. The pathologic studies of tissues obtained by Hench and Rosenberg [l] during an attack showed periarticular edema and gross thickening of the joint capsule. There was infiltration by large numbers of polymorphonuclear leukocytes without the presence of significant numbers of eosinophils. Between episodes, gross and histologic examination of joint tissues revealed no significant evidence of inflammation. Similar changes were described in tendon sheaths. No pannus formation or cartilage destruction was observed in any subject studied. More recently, Schumacher [17] performed a thorough examination, including electron microscopy, of two PR patients before they developed RA. These spec-
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TABLE III Percentageof Patients With HLA-DR4or -5* f201
El
[al
No. of Subjects
DR4
DR5
No. of Subjects
Controls
20
36.6
14
150
PR
20
60+
5
26
20
70’
10
158
DR4
DR5
DR4
DR5
27
9
99
30.3
32.3
38.5
3.8
43
34.9
48.8
:sI
36 31.2
PR-PR PR-RA RA
1221
No. of Subjects
64.6$
No. of Subjects
DR4
44
20.4
34 10
ii
3.2
‘atients with PR are comoared with normal controls and with RA. In the last two series (L6.221). patients with PR are subduded mto ones who remalned palmdromlc (PR-PRI and ones who developf chronic arthritis (Pi-RA). r ‘p co.05. *p t0.005. sp lO% I
‘R = palindromicrheumatism; SF = synovialfluid. Can beabsent at the beginningof the disease.
establishment of a diagnosis of PR. These criteria include the exclusion of other arthritides, as noted in Table VI. A number of clinical conditions can mimic PR, but generally demonstrate distinctive features that usually make them easily recognizable. The etiology of RA is still unknown. It is becoming increasingly clear at the present time, however, that RA is due to the combination of an unknown arthritogenic stimulation and a genetic susceptibility that includes at least an MHC class II antigen association [36]. Conceivably, the links between RA and PR could derive from shared elements, whereas dissimilarities are explained by differences among this combination. The expression of inflammatory diseases is largely determined by the cytokine network activation, whose role is beginning to be well characterized in the regulation of the clinicopathologic manifestations of rheumatic diseases [36,37]. It is likely that some of the features that distinguish PR from RA reflect differences in the expression of these mediators. These differences might involve: interleukin-1 and tumor necrosis factor, and/or their inhibitors, implicated in articular destruction through the induction of proteases [37]; interleukin-6, the main inducer of the acute-phase reaction in RA [38] and a B-cell activator involved in RF production [39,40]; granulocyte-macrophage colony-stimulating factor, which might play a role in
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inflammation maintenance and chronicity [41]; interleukin-4 and tumor growth factor+, which have the potential to downregulate certain immuno-inflammatory mechanisms [42,43]. Although it appears likely that there is a link between RA and PR, it is not possible, at this time, to define it with great precision. In any case, the analysis of the relationship between these two entities and the study of the conversion from one to the other may provide important clues for the pathogenesis of either or both conditions. Examining differences in the expression of cytokines and mediators, together with further study of their immunogenic associations, should be a fruitful area for future investigation. If the diseases differ by external arthritogenic stimuli, examination of the conversion may provide substrate for discovery of the triggering agents. Although its recognition is still very high in some centers [7,8,28], it is probable that PR, dating from its original description, may be diminishing in overall prevalence, likely due to the more accurate diagnosis and proper nosologic placement of other rheumatic diseases in the modern era. Nevertheless, there appears to be a core of evidence, almost 50 years after the original description, that some patients continue to have PR.
ACKNOWLEDGMENT We thank Dr. R. Terkeltaub for helpful discussions, Denise Smith for typing assistance, and Dr. Tuska for kindly providing the photographs.
REFERENCES 1. Hench PS, Rosenberg
EF. Palindromic rheumatism. A “new” oft recurring disease of joints (arthritis, periarthritis, para-arthritis) apparently producing no articular residues. Report of thirty-four cases: its relation to “angio-neural arthrosis.” ” allergic rheumatism” and rheumatoid arthritis. Arch Intern Med
1944; 73: 293-321. 2. Ansell BM, Bywaters
EGL. Palindromic
rheumatism.
Ann Rheum Dis 1959; 18:
331-2. 3. Mattingly S. Palindromic rheumatism. Ann Rheum Dis 1966; 25: 307-17. 4. Wtlliams MH. Sheldon PJ. Torrigiani G, Eisen V. Mattingly S. Palindromic rheumatism. Clinical and immunological studies. Ann Rheum Dis 1971; 30: 37E-BG. 5. Wajad MA. Brown DL. Currey HL. Palindromic rheumatism. Clinical and serum complement study. Ann Rhaum Dis 1977; 36: 56-61. 6. Bregeon C. Dajon JL, Renier L. eta/. Palindromic rheumatism. Rev Rhum Mal Osteoartic 1986; 53: 441-9. 7. Hannonen P, M6tt6nen T, Oka M. Palindromic rheumatism. A clinical survey of sixty patients. Stand J Rheumatol 1987; 16: 413-20. 8. Pasero G, Barbieri P. Palindromic rheumatism: you just have to think about it. Clin Exp Rheumatol 1986; 4: 197-9. 9. Ward LE, Okihiro MM. Palindromic rheumatism: a follow up study. Archives of
Rheumatology 1959; 2: 208-9. 8, Mohammed I, Holborow EJ. Currey HL. Palindromic rheumatism. II. Failure to detect circulating immune complexes during acute episodes. Ann Rheum Dis 1979; 381 329-31. 11. Ginsberg MH, Genant HK, Yu TF, McCarty DJ. Rheumatoid nodulosis: an unusual variant of rheumatoid disease. Arthritis Rheum 1975; 18: 49-58. 12. Couret M, Combe B. Chuong VT, Leroux JL. Blotman F, Sany J. Rheumatoid nodulosis: report of two new cases and discussion of diagnostic criteria. J Rheumatol 1988; 15: 1427-30. 13. Kaye BR, Kaye RL, Bobrove A. Rheumatoid nodules. Review of the spectrum Interamerican
10. Thompson
of associated conditions and proposal of a new classification, with a report of four seronegative cases. Am J Med 1984; 76: 279-92. 14. Franck JL, Durroux R. Condouret J, Arlet J. Seropositive palindromic rheumatism and pulmonary rheumatoid nodule: apropos of a case [letter]. Rev Rhum Mal Osteoartic 1982; 49: 309-10. 15. Davies PG. Thompson PW. Palindromic rheumatism and Felty’s syndrome. Ann Rheum Dis 1985; 44: 640-l. 16. Barbieri P, Benedettini G. Ciompi ML, Campa M. Failure to detect a lymphocyte imbalance during acute attacks of palindromic rheumatism [letter]. Clin Rheumatol 1987: 6: 1023. 17. Schumacher HR. Palindromic onset of rheumatoid arthritis. Clinical, synovial fluid, and biopsy studies. Arthritis Rheum 1982; 25: 361-9. 18. Schreiber S, Schumacher HR, Cherian PV. Palindromic rheumatism with rheumatoid nodules: a case report with ultrastructural studies. Ann Rheum Dis
1986; 45: 78-81. 19. Stastny P. Association of the B-cell alloantigen DRw4 with rheumatoid arthritis. N Engl J Med 1978; 298: 869-71. 20. Fisher LR. Kirk A, Awad J, et a/. HLA antigens in palindromic rheumatism and palindromic onset rheumatoid arthritis. Br J Rheumatol 1986; 25: 345-8. 21. Gran JT. Husby G, Thorsby E. HLA antigens in palindromic rheumatism, nonerosive rheumatoid arthritis and classical rheumatoid arthritis. J Rheumatol
1984; 11: 136-a 22. Barbieri P, Ciompi ML, Menicucci A, Pasero G. HLA antigens in palindromic rheumatism. An Italian study. Clin Rheumatol 1988; 7: 470-3. 23. Hannonen P, Hakola M. Oka M. Palindromic rheumatism in two non-identical brothers with identical HLA including DR4. Ann Rheum Dis 1985; 441 2024. 24. McDermott M, McDevitt H. The immunogenetics of rheumatic diseases. Bull Rheum Dis 1988; 38: l-10. 25. Gregersen P, Shen M, Song QL. eta/. Molecular diversity of HLA DR4 haplotypes. Proc Natl Acad Sci U S A 1986; 83: 2642-6. 26. Grattan CE. Kennedy TD. Yates DB. Prognostic factors in palindromic rheumatism. Bristol Med Chir J 1984; 99: 51-4. 27. Huskisson EC. Treatment of palindromic rheumatism with Dpenicillamine. BMJ 1976; 2: 979. 28. Youssef W, Yan A, Russell AS. Palindromic rheumatism: a response to chloroquine. J Rheumatol 1991; 18: 35-7. 29. Hannonen P. Mbtt6nen T, Oka M. Treatment of palindromic rheumatism with chloroquine [letter]. BMJ 1987; 294: 1289. 30. Golding DN. Sulphasalazine for palindromic rheumatism [letter]. Br J Rheumatol 1988; 27: 79. 31. Meyer 0, Ryckewaert A. Palindromic rheumatism: efficacy of dapsone [letter]. Rev Rhum Mal Osteoartic 1985; 52: 596-7. 32. Schwartzberg M. Prophylactic colchicine therapy in palindromic rheumatism [letter]. J Rheumatol 1982; 9: 3413. 33. Panush RS. Food induced (“allergic”) arthritis: clinical and serologic studies. J Rheumatol 1990; 17: 2914. 34. Shingu M. Yasuda M, Nobunaga M. A case of palindromic rheumatism suggestive of immune complex disease [letter]. J Rheumatol 1982; 9: 480-l. 35. Molnar 2, Metzger AL, McCarty DJ Jr. Tubular structures in endothelium in palindromic rheumatism. Arthritis Rheum 1972; 15: 553-6. 36. Harris ED. Rheumatoid arthritis. Pathophysiology and implications for therapy. N Engl J Med 1990; 322: 1277-89. 37. Arend WP. Dayer J-M. Cytokines and cytokine inhibitors or antagonists in rheumatoid arthritis. Arthritis Rheum 1990: 33: 305-15. 38. Guerne P-A, Zuraw BL, Vaughan JH, Carson DA, Lots M. Synovium as a source of interleukin 6 in vitro. Contribution to local and systemic manifestations of arthritis. J Clin Invest 1989; 83: 585-92. 39. Hirano T. Matsuda T, Turner M. et al. Excessive production of lLb/B cell stimulatory factor-2 in rheumatoid arthritis. Eur J lmmunol 1988; 18:
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PALINDROMIC RHEUMATISM / GUERNE AND WEISMAN 1797-801. 40. Lipsky PE. The control of antibody production by immunomodulatory mole cules. Arthritis Rheum 1989; 32: 1345-55. 41. Alvaro-Gracia J. Firestein GS, Xu WD, Teetle R, Zwaifler NJ. GMCSF is a major macrophage activating factor (MAF) in rheumatoid synovitis [abstract]. Arthritis Rheum 1988; 31: S27. 42. Brandes ME. Allen JB, Ogawa Y, Wahl SM. Transforminggrowth factor beta 1 suppresses acute and chronic arthritis in experimental animals. J Clin Invest
460
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1991; 87: 1108-13. 43. Miossec P. Naviliat M, Dupuy D’Angeac A, Sany J, Banchereau J. Low levels of interleukin-4 and high levels of transforming growth factor beta in rheumatoid synovitis. Arthritis Rheum 1990; 33: 1180-7. 44. Renier JC, Bregeon C, Besson J. Palindromic rheumatism (contribution of 16 cases and general review). Rev Rhum Mal Osteoartic 1969; 36: 583-96. 45. Mattingly S. Jones DW, Robinson WM, Williams RA, Dunn EC. Palindromic rheumatism. J R Coll Physicians Lond 1981; 15: 119-23.
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MICHAEL Ii. WEISMAN, M.D.,
San Diego, California
Palindromic rheumatism (PR), or&ally described in 1944,is characterized by recurrent episodeaof mostly 0ligoarticuIar arthritis with peri- and para-articular tissue infkmmation, leavhq no residual clinical and radiographic changea It appears that palindromic syndrome is entity, encompassingother . a heterogeneous mfhnmatory conditions at early stagesof their evolution, and whose relationship with rheumatoid arthritis (RA) is evident but still unclear. Evolution of up to SO%of these cases intO otherwise typical RA, mtuuonly accompaniedby the conversion to rheumatoid factor seropositivity, the frequent occurrence of nodules,the reported responseto RA treatment, and the observation of familial aggregation of the two conditions suggestthatPRispartofthespe&um,ora stagein the evolutkm of RA. However, justification for the distinct exknce of PR corneafrom reports that identity well-defined and recognkable clinical manifestations such as descriptions of the acute attach the frequent peri-articular manifestations, the absenceof bone and cartilage destruction even after extended periods of time, and the generally goodlong-term prognosis. Immunogenetic studies with HLA-DR phenotyping and the absenceof female preponderance tend to add additional support for the separate identity of PR.
From the Department of Medicine, Division of Rheumatology (MHW). University of California at San Diego Medical Center, San Diego, California, and the Division of Rheumatology (PAG). Department of Medicine, HOpital Cantonal Universitaire, Geneva, Switzerland. Requests for reprints should be addressed to Pierre-Andre Guerne, M.D., Division of Rheumatology, Hbpital Cantonal Universitaire. 26 avenue Beau-Sejour. 1211 Geneve-4, Switzerland. Manuscript submitted November 9. 1990. and accepted in revised form June 11,1992.
he term palindromic rheumatism (PR) was T first usedby Hench and Rosenberg[l] in 1944, for their descriptionof 34patients presentingwith a unique set of signs and symptoms. The condition wasmarked by multiple recurring afebrile episodes of acute arthritis, periarthritis, and sometimes para-arthritis, lasting from a few hours to several days before disappearing completely, and apparently producing no residual articular effect. The term palindromic, derived from the Greek “palindromos,” which literally means“to run back,” was chosento expressthis concept of recurrence.The authors separatedthis condition from rheumatoid arthritis (RA) becauseof the totally different pattern of distribution of the arthritis, the frequent attacks of para-arthritis, the generalabsenceof significant constitutional symptoms, and the lack of progression, chronicity, and/or radiographic changes. Fifteen yearsafter the original report, Ansell and Bywaters [2] reexamined the concept of PR by studying 28 patients who fulfilled the criteria defined by Hench and Rosenberg[11.They concluded that PR wasmerely a variant or a modeof presentation of RA, noting that the majority of the patients, if followed long enough,will eventually display residual signsof chronic (rheumatoid) arthritis. Subsequently, a number of series [3-71 followed patients longitudinally and noted that about onehalf of the casesevolveinto RA. Neither clinical, immunologic, nor genetic studies could predict reliably which caseremains PR or evolvesinto chronic RA. The controversyoverwhetherPR deservesa special nosologicplace or servesas a prodroma of RA has not beenresolved. We recently observeda patient whose clinical manifestations consisted mainly of recurrent episodesof severeperi- and para-articular inflammation in addition to arthritis. The special clinical featuresof this inflammation suggestthat at least somecasesof PR truly representan entity different from RA. We therefore believe it would be important to reviewthe literature concerningthis intriguing syndrome, with emphasis on the elements, among its clinical, serologic,etiologic, and genetic features,that can help to retain it in its rightful nosologicplace.
October 1992 The American Journal of Medicine
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PALINDROMIC RHEUMATISM / GUERNE AND WEISMAN
Figure
peri-articular, 1. Articular, the hypothenar and, to a lesser sents a para-articular manifestation. articular swelling and erythema.
and para-articular extent, the thenar Right. Synovitis
manifestations of palindromic rheumatism. eminences, without clear-cut involvement of the second proximal interphalangeal
CASEREPORT A 51-year-old patient, a native of Java, presented to our clinic with a 5-year history of episodic and recurrent pains in the back and the extremities, involving mainly the hands, feet, knees, and ankles. These attacks lasted from 1 to 2 days, sometimes up to a week. They were often, but not always, associated with redness and swelling, both in the joints and in the extra-articular sites (Figure l), including the palms, soles, lateral aspects of the heels, and the forearms. Episodes progressively worsened, both in frequency (one or two per week) and in intensity. The patient had to quit his job in 1986. He saw a variety of doctors, but no diagnosis was established. The different treatments that he received, including analgesics, nonsteroidal anti-inflammatory agents (NSAIDs), and benzodiaxepines, did not improve his condition. A skin biopsy specimen, obtained from the left hypothenar eminence during an 452
October 1992 The American Journal of Medicine
left. Swelling and erythema of of joint structures. This reprejoint in addition to marked peri-
episode of swelling and redness, had shown a positive lupus band, but was otherwise histologically normal. Because of this finding, the diagnosis of systemic lupus erythematosus (SLE) was considered and the patient began to undergo a treatment trial of hydroxychloroquine for 4 months without any benefit. At the first arthritis clinic visit, results of physical examination were entirely unremarkable except for some bilateral tenderness of the trapezius insertion points, pes anserinus insertions, and epicondyles, consistent with the diagnosis of fibromyalgia syndrome. Results of laboratory tests were all normal: erythrocyte sedimentation rate (ESR) 16 mm/h; white blood cell (WBC) count of 14.7 X log/L with 68% neutrophils, 3% bands, 21% lymphocytes, 7% monocytes, and 1% eosinophils; hemoglobin, 13.2 g/dL (mean corpuscular volume, 90 fL); rheumatoid factor (RF), negative times 2; antinuclear antibody (ANA) negative; anti-SSA and anti-SSB nega-
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tive; total hemolytic complement (CH&, 135 U/mL; VDRL negative; muscle enzymes, not elevated; serum protein electrophoresis normal. Radiographic studies including the knees, hands, and the chest were negative. Treatment with amitriptyline only partially relieved the pain. At the second visit, the patient presented with very localized swelling and redness on the medial aspect of the left knee, with a diameter of about 7 cm; synovial fluid aspirated from this knee was mildly inflammatory, containing a WBC count of 2,100/mm3 (56% segmented, 41% monocytes, and 3% lymphocytes). The peri-articular swelling and arthritis disappeared spontaneously. On the third visit, the patient presented with localized swelling, redness, and extreme tenderness of the lateral aspect of the right ankle that was clearly para-articular. Because of the pattern of recurring episodes of arthritis and para-arthritis over a 5-year period, disappearing completely between episodes, and the exclusion of other forms of chronic arthritis, we strongly considered the diagnosis of PR. During the subsequent 3-year period of observation, the patient received complete therapeutic courses of gold, colchicine, sulfasalaxine, methotrexate, dapsone, and systemic steroids. No effect on the patient’s condition was observed; he continued to exhibit even more frequent episodes of peri- and para-arthritis, especially in his pelvis, soles, lateral aspects of his ankles, and heels, and occasional arthritis. On almost all occasions his ESR remained at baseline levels; during one episode, his ESR was elevated to 45 mm/h.
CLINICALFEATURESOF PR The nature of PR arthritis remains its most distinctive feature. Joint involvement is commonly noted to be monoarticular with maximal intensity reached in a matter of hours [1,7], at any time of the day, usually without any obvious inciting event, although, in a few cases, attacks have been noted to relate to another event such as a respiratory tract infection, weather change, childbirth, or overexercise [1,3,7]. The disease can strike almost any joint, although the spine and the hips are rarely affected. When the spine is involved, it is usually at the cervical level. Table I displays the distribution of the joints involved, based on five large series totaling 227 patients [1,3-5,781. The joints involved in initial attacks appear to be mostly knees, fingers, or shoulders. In the vast majority of the patients, the attacks are confined to a single articulation, but in rare cases more than four joints can be affected at a time [l]. The pain is generally described as very severe or excruciating, mimicking gout or septic arthritis in some cases,
RHEUMATISM
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TABLE I Distribution of Joints Involved in AttacksBased Upon a Cumulative ExperienceWith 227 Patients Joint Involvement
Mean% Patients
of
Rangeof % of Patients
MCP & PIP
91
74-100
Wrists
78
54-82
Knees
64
41-94
Shoulders
65
33-75
Ankles
50
lo-67
Feet
43
15-73
Elbows
38
13-60
Hips
17
O-40
Temporo-mandibular
8
O-28
Spine
4
o-11
Sternoclavicular
2
O-6
27
20-29
Para-articular sites
CP = metacarpophalangeal;PIP = proximal interphalangeal
often confining the patient to bed [1,5,7]. A few patients have been described as having only mild pains. In addition, extra-articular tissue inflammation is observed in about 30% of the patients [1,7]. This involvement may be inflammation of a tendon or swelling of undefined para-articular structures, generally close to a joint but often remote enough to allow the patient to clearly distinguish it from joint involvement. The size of these para-articular swellings varies from 2 cm to much larger areas. The PR episodes last less than 2 days in most of the cases, sometimes as short as 2 hours [l]. However, in a few cases, they can extend to more than 2 weeks [1,5]; their frequency is highly variable, from a few to more than 250 a year [1,5,8]. Persons who have frequent attacks (more than one a month) may be more likely to develop frank RA [6]. Only a few patients display constitutional reactions such as fever or weight loss. Of interest is the observation that patients from the Hannonen [7] series (7 of 60) who had such systemic manifestations were all RF-positive and later progressed to erosive RA. A peculiar feature of PR is the occasional occurrence of nodules, usually the size of a pea and overlying the tendons in the hands or fingers or located on the thumb pads. Their appearance parallels the arthritis attacks and generally lasts a week at most [1,3-5,9,10]; however, typical PR may also be associated with more sustained nodules. The presence of nodules has been used to link PR to other forms
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PALINDROMIC RHEUMATISM / GUERNE AND WEISMAN TABLE II Percentagesof Patients RF-Positivein Three Series: RF Determination at Follow-Up in Patients Who Have DevelopedChronic Arthritis (PR-RA)Compared With Patients Who Remained Palindromic (PR-PR) Reference
ii [51
PR(%)
PR-RA(%)
1 l/25 (44) 3116 (19) 2122(9)
29135 (83) 16125 (64) 16/17 (94)
I
I
RF = rheumatoid factor; PR = palindromicrheumatism; RA = rheumatoid arthritis.
of chronic rheumatic diseases. For example, the clinical entity of rheumatoid nodulosis [ll], combining rheumatoid nodules, subchondral bone cysts, and recurrent joint symptoms and considered a variant of RA with a good prognosis, closely resembles PR. A recent review of all of the published cases of rheumatoid nodulosis [12] reveals that 24 of the 26 reported patients were described as having a clinical presentation consistent with PR. Kaye et al [13] place PR with nodules in the group IIa of their proposed classification of conditions associated with rheumatoid nodules. To add further to the confusion, there is a report of a patient with PR and pulmonary nodules [14], and two patients with PR and Felty’s syndrome [7,15]. Finally, in the 60 patients with PR reported by Hannonen et al [7], the criteria for fibromyalgia syndrome were fulfilled by 8 of their 60 patients. In contrast to the female preponderance noted in RA, the incidence of PR is relatively equal in each sex, with a female:male ratio that varies between 1.7:1 and 0.55:1 [1,3-5,7,8]. The mean age of onset of PR is about 45 years, with cases reported from the early 20s to the 80s. The prevalence of this disease is difficult to establish, and certainly may be underestimated. In the most recent studies on PR, the prevalence is estimated to be 1 of 8 [7] to 1 of 20 [8] that of RA.
LABORATORYFEATURESOF PR ESR is frequently increased during or just after the episodes, but rarely between them [1,3,5], and the ESR might be more likely elevated in the patients who subsequently develop RA. There is generally no abnormality of the WBC and red blood cell counts or miscellaneous chemical constituents [l], except for a few patients who were reported to have transient anemia [3]. RF status, associated with the disclosure that a significant number of patients with PR developed chronic arthritis identical to RA, has become an important diagnostic and nosologic issue. A number of reports show that the percentage of seropositive patients among those with PR that has evolved into 454
October 1992 The American Journal of Mediclne
chronic arthritis is not different from the percentage of seropositivity in RA. Among the patients observed in different series [5-71, about one third were found to convert from negative to positive, usually shortly before their evolution to chronic arthritis. The patients who remained palindromic seemed, in one series [7], to be more frequently positive (11 of 25, including 2 followed prospectively for more than 5 years) than the normal population, and in addition, patients with PR and positive RF seemed more susceptible to develop RA [7]. Finally, seropositivity is more frequent in PR patients after they have developed RA than in patients who remained palindromic [5-71 (Table II). Because of the limited follow-up time periods and the dynamic changes in the status of RF and arthritis patterns, the meaning of the seropositivity among patients who remain palindromic is less clear-cut. However, it seems that seroconversion almost always shortly precedes the appearance of chronic arthritis [5]. It is likely, therefore, that there is a true increase in RF positivity in PR patients who remain palindromic in addition to the definite increase in those who convert to RA. ANA studies, on the other hand, are usually negative in PR cases [6,16]. Radiographic studies, as pointed out originally by Hench and Rosenberg [l], are always normal in patients with PR [3,5,6]. Absence of radiographic signs is thus among the six diagnostic criteria proposed by Pasero and Barbieri [8]. In the cases that have evolved into chronic arthritis, erosions not different from the ones seen in classic RA usually develop [3,5,6]. The rare synovial fluid analyses that have been reported [17] show variable leukocyte counts (150 to 12,700/mm3) and differentials (2% to 66% polymorphonuclear cells) that do not correlate with the severity of the symptoms or attacks.
PATHOLOGICFINDINGS Not surprisingly, there are very few pathologic examinations of tissues in this disease. The pathologic studies of tissues obtained by Hench and Rosenberg [l] during an attack showed periarticular edema and gross thickening of the joint capsule. There was infiltration by large numbers of polymorphonuclear leukocytes without the presence of significant numbers of eosinophils. Between episodes, gross and histologic examination of joint tissues revealed no significant evidence of inflammation. Similar changes were described in tendon sheaths. No pannus formation or cartilage destruction was observed in any subject studied. More recently, Schumacher [17] performed a thorough examination, including electron microscopy, of two PR patients before they developed RA. These spec-
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TABLE III Percentageof Patients With HLA-DR4or -5* f201
El
[al
No. of Subjects
DR4
DR5
No. of Subjects
Controls
20
36.6
14
150
PR
20
60+
5
26
20
70’
10
158
DR4
DR5
DR4
DR5
27
9
99
30.3
32.3
38.5
3.8
43
34.9
48.8
:sI
36 31.2
PR-PR PR-RA RA
1221
No. of Subjects
64.6$
No. of Subjects
DR4
44
20.4
34 10
ii
3.2
‘atients with PR are comoared with normal controls and with RA. In the last two series (L6.221). patients with PR are subduded mto ones who remalned palmdromlc (PR-PRI and ones who developf chronic arthritis (Pi-RA). r ‘p co.05. *p t0.005. sp lO% I
‘R = palindromicrheumatism; SF = synovialfluid. Can beabsent at the beginningof the disease.
establishment of a diagnosis of PR. These criteria include the exclusion of other arthritides, as noted in Table VI. A number of clinical conditions can mimic PR, but generally demonstrate distinctive features that usually make them easily recognizable. The etiology of RA is still unknown. It is becoming increasingly clear at the present time, however, that RA is due to the combination of an unknown arthritogenic stimulation and a genetic susceptibility that includes at least an MHC class II antigen association [36]. Conceivably, the links between RA and PR could derive from shared elements, whereas dissimilarities are explained by differences among this combination. The expression of inflammatory diseases is largely determined by the cytokine network activation, whose role is beginning to be well characterized in the regulation of the clinicopathologic manifestations of rheumatic diseases [36,37]. It is likely that some of the features that distinguish PR from RA reflect differences in the expression of these mediators. These differences might involve: interleukin-1 and tumor necrosis factor, and/or their inhibitors, implicated in articular destruction through the induction of proteases [37]; interleukin-6, the main inducer of the acute-phase reaction in RA [38] and a B-cell activator involved in RF production [39,40]; granulocyte-macrophage colony-stimulating factor, which might play a role in
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inflammation maintenance and chronicity [41]; interleukin-4 and tumor growth factor+, which have the potential to downregulate certain immuno-inflammatory mechanisms [42,43]. Although it appears likely that there is a link between RA and PR, it is not possible, at this time, to define it with great precision. In any case, the analysis of the relationship between these two entities and the study of the conversion from one to the other may provide important clues for the pathogenesis of either or both conditions. Examining differences in the expression of cytokines and mediators, together with further study of their immunogenic associations, should be a fruitful area for future investigation. If the diseases differ by external arthritogenic stimuli, examination of the conversion may provide substrate for discovery of the triggering agents. Although its recognition is still very high in some centers [7,8,28], it is probable that PR, dating from its original description, may be diminishing in overall prevalence, likely due to the more accurate diagnosis and proper nosologic placement of other rheumatic diseases in the modern era. Nevertheless, there appears to be a core of evidence, almost 50 years after the original description, that some patients continue to have PR.
ACKNOWLEDGMENT We thank Dr. R. Terkeltaub for helpful discussions, Denise Smith for typing assistance, and Dr. Tuska for kindly providing the photographs.
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1986; 45: 78-81. 19. Stastny P. Association of the B-cell alloantigen DRw4 with rheumatoid arthritis. N Engl J Med 1978; 298: 869-71. 20. Fisher LR. Kirk A, Awad J, et a/. HLA antigens in palindromic rheumatism and palindromic onset rheumatoid arthritis. Br J Rheumatol 1986; 25: 345-8. 21. Gran JT. Husby G, Thorsby E. HLA antigens in palindromic rheumatism, nonerosive rheumatoid arthritis and classical rheumatoid arthritis. J Rheumatol
1984; 11: 136-a 22. Barbieri P, Ciompi ML, Menicucci A, Pasero G. HLA antigens in palindromic rheumatism. An Italian study. Clin Rheumatol 1988; 7: 470-3. 23. Hannonen P, Hakola M. Oka M. Palindromic rheumatism in two non-identical brothers with identical HLA including DR4. Ann Rheum Dis 1985; 441 2024. 24. McDermott M, McDevitt H. The immunogenetics of rheumatic diseases. Bull Rheum Dis 1988; 38: l-10. 25. Gregersen P, Shen M, Song QL. eta/. Molecular diversity of HLA DR4 haplotypes. Proc Natl Acad Sci U S A 1986; 83: 2642-6. 26. Grattan CE. Kennedy TD. Yates DB. Prognostic factors in palindromic rheumatism. Bristol Med Chir J 1984; 99: 51-4. 27. Huskisson EC. Treatment of palindromic rheumatism with Dpenicillamine. BMJ 1976; 2: 979. 28. Youssef W, Yan A, Russell AS. Palindromic rheumatism: a response to chloroquine. J Rheumatol 1991; 18: 35-7. 29. Hannonen P. Mbtt6nen T, Oka M. Treatment of palindromic rheumatism with chloroquine [letter]. BMJ 1987; 294: 1289. 30. Golding DN. Sulphasalazine for palindromic rheumatism [letter]. Br J Rheumatol 1988; 27: 79. 31. Meyer 0, Ryckewaert A. Palindromic rheumatism: efficacy of dapsone [letter]. Rev Rhum Mal Osteoartic 1985; 52: 596-7. 32. Schwartzberg M. Prophylactic colchicine therapy in palindromic rheumatism [letter]. J Rheumatol 1982; 9: 3413. 33. Panush RS. Food induced (“allergic”) arthritis: clinical and serologic studies. J Rheumatol 1990; 17: 2914. 34. Shingu M. Yasuda M, Nobunaga M. A case of palindromic rheumatism suggestive of immune complex disease [letter]. J Rheumatol 1982; 9: 480-l. 35. Molnar 2, Metzger AL, McCarty DJ Jr. Tubular structures in endothelium in palindromic rheumatism. Arthritis Rheum 1972; 15: 553-6. 36. Harris ED. Rheumatoid arthritis. Pathophysiology and implications for therapy. N Engl J Med 1990; 322: 1277-89. 37. Arend WP. Dayer J-M. Cytokines and cytokine inhibitors or antagonists in rheumatoid arthritis. Arthritis Rheum 1990: 33: 305-15. 38. Guerne P-A, Zuraw BL, Vaughan JH, Carson DA, Lots M. Synovium as a source of interleukin 6 in vitro. Contribution to local and systemic manifestations of arthritis. J Clin Invest 1989; 83: 585-92. 39. Hirano T. Matsuda T, Turner M. et al. Excessive production of lLb/B cell stimulatory factor-2 in rheumatoid arthritis. Eur J lmmunol 1988; 18:
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1991; 87: 1108-13. 43. Miossec P. Naviliat M, Dupuy D’Angeac A, Sany J, Banchereau J. Low levels of interleukin-4 and high levels of transforming growth factor beta in rheumatoid synovitis. Arthritis Rheum 1990; 33: 1180-7. 44. Renier JC, Bregeon C, Besson J. Palindromic rheumatism (contribution of 16 cases and general review). Rev Rhum Mal Osteoartic 1969; 36: 583-96. 45. Mattingly S. Jones DW, Robinson WM, Williams RA, Dunn EC. Palindromic rheumatism. J R Coll Physicians Lond 1981; 15: 119-23.
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