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H. RALPH SCHUMACHER, Jr., MD
Professor of Medicine,
University of Pennsylvania,
Chief of Rheumatology,
VA Medical Center, 151 K,
University and Woodland Avenue,
Philadelphia, PA 19104, USA.
E-mail: schumacr@mail.med.upenn.edu
Address reprint requests to Dr. Schumacher.

It has seemed intuitive that evaluating patients during the very earliest phases of arthritis should help us identify factors important for disease initiation and after followup allow identification of prognostic features. The report in this issue by Machold, et al¹ is another in a series of potentially useful studies coming from early arthritis clinics that have been functioning mostly in Europe over the last 20 years. Also, in a supplement published in The Journal early arthritis clinics are reviewed².

Features of early arthritis clinics have varied as to the duration of arthritis that qualifies as "early" and the clinical criteria for entry. The Austrian study by Machold, et al¹ insisted on less than 3 months of symptoms in an attempt to get "very recent onset arthritis." This is to be commended, as other studies have occasionally considered up to 2–3 years as "early." The cut off at 3 months should be able to provide a group in which guidelines for practical management decisions may be useful. Three months is almost certainly not enough to define key initiating steps in pathogenesis, but that was not their intended focus. Some studies have centered only on people felt to have early RA, while this investigation is fortunately more inclusive. Actual entry criteria may however influence findings. For entry in this study, patients had to have either swelling or pain in at least one joint "not related to trauma," plus any laboratory sign of inflammation, which interestingly included elevated erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) and peripheral blood leukocytosis or rheumatoid factor (RF). Arthrocenteses were not mentioned, although later diagnoses were to consider exclusions among which crystal diseases might be important.

One of the striking aspects of the study is the apparent effort to classify as many people as possible as "rheumatoid arthritis" (RA) by including individuals with "polyarthritis" without evidence of other inflammatory rheumatic diseases based on laboratory investigation, or people who met American College of Rheumatology (ACR) criteria cumulatively although not all at one time. How useful is this approach? It was striking how well much of this "RA" did. Might it not be more interesting to see if those for whom inclusion criteria were stretched may really have something somewhat different with a better prognosis? Patients with RF who may have more typical RA did have more erosions at one year; this was despite usual treatment by rheumatologists. Maybe early diagnosis did not improve outcomes but included people with "something else" than RA.

I am interested that 16 patients still had undifferentiated arthritis at one year, despite the liberal criteria for RA. Seventeen patients were initially considered undifferentiated but were called RA at one year. It could be important to know what changed the diagnosis and whether these people's course was reflected more by that initial impression or the later diagnosis.

Whatever the answer, I would like to focus discussion on these many unclassified cases. Several series have emphasized the frequency of unclassified arthritis in early arthritis populations, with Hulseman and Zeidler leading thoughts on this^3,4. Of 217 patients with inflammatory arthritis of less than one year's duration, 117 were considered undifferentiated. These patients in general did well, with 54% of those followed in remission and 7% having evolved into RA. Wolfe, et al⁵ and Morel, et al⁶ also noted unclassified cases in their early cohorts. The latter group noted that about 50% later evolved into RA. In the US National Institutes of Health (NIH) early arthritis studies in which I participated, undifferentiated arthritis was a more frequent diagnosis in patients with disease of less than one year's duration than either RA or reactive arthritis⁷. In the study reported here, 219 were entered, but it is noted that at least 59 were lost to followup before one year. What had been their presenting impressions? Maybe this group could be expected to include even more patients who were hard to classify and had better prognoses.

Some have found RF to be an early important predictor of diagnosis and course⁸, but Gerber, et al⁹ studying our NIH early patients (during the first year) found that polyarticular disease was actually a better predictor of poor functional outcome⁹. Antibodies to citrullinated antigens, although not widely available, need to be considered for help with diagnosis and prognosis¹⁰. We and other groups also believe that features of synovial tissue merit consideration as prognostic, but biopsies are usually not available early^11,12. The role of the shared epitope is still complex¹³. A variety of other studies appropriate to an approach in clinical practice have been reviewed¹⁴.

I like the idea suggested by Machold, et al to use the term "early inflammatory arthritis" for some period during early observations of many patients. I do that in our clinics to be sure that we keep thinking about other diagnoses that may have more specific treatments or other systemic implications. Such a term need not delay treatment that can be based more on signs and symptoms than on a name. Perhaps some unclassified cases or others that we believe may have better prognoses still could be treated aggressively with DMARD as these could be the people who will get remissions not "just" 40–50% ACR 50 improvement. This needs to be studied.

As one can probably gather from the preceding comments, I am concerned about the unsatisfactory state of our current classification criteria in general and that of early RA in particular. I have addressed this previously^15-17 and remain concerned that many factors must be considered as influencing the unique course of each person's encounter with an inflammatory process. The factors certainly include a wide variety of genetically determined responses and traits, education, personality, support systems, previous infections and immune responses, how they handle drugs, hormones, etc.¹⁵. Although many would emphasize that classification criteria should not be used for diagnosis, the concepts in the criteria certainly are used in diagnosis.

The report by Machold, et al supports other previous studies that early diagnosis is especially difficult¹⁸, and perhaps we should be looking for different terms for many early patients. In only about 70% of cases in this study were diagnoses "correct" one year later. Earlier work from our group at the University of Pennsylvania with the late John Eisenberg showed that in patients with new knee effusions, diagnoses made by rheumatologists (and even more importantly treatments given) were changed in about 20% by simple synovial fluid analyses¹⁹. It could be fascinating to see in the study reported here¹ how often arthrocentesis changed impressions. Some early arthritis studies such as our projects at the NIH specifically required exclusion of crystal disease. Our work assessing the ACR criteria in RA²⁰ would suggest that crystal disease is present in some cases that would meet criteria for RA. Such missed diagnoses certainly might influence outcomes.

Berthelot, et al²¹ have presented 10 scenarios of early arthritis patients to 25 international experts. Understanding and interpretation of ACR criteria for RA and European Spondylarthropathy Study Group criteria for spondyloarthropathy varied widely. In only one case did all experts agree on classification.

Some points made by Machold, et al deserve reemphasis. Patients felt to have RA tended to have more indolent early courses and were referred later than patients with more acute problems. Some patients with RA may not have been referred during the 3 month window even in the well tuned Austrian referral pattern. Referral to specialists may be even slower in North America. These patients did relatively well with standard disease modifying antirheumatic drug approaches, but whether this reflects the treatment or features of patients seen so early is not yet clear. RF, although not unique to RA, did tend to predict more erosions during the first year. Other potential predictors, such as ESR, CRP, and tender and swollen joint counts did not identify those with erosions at one year.

Finally, patients who are difficult to diagnose are often frustrated by the lack of a name to go with their symptoms. Studies to date all suggest that such patients do better. I like to reassure patients that we will keep looking for new clues, but as long as they do not meet criteria for RA or other specific diseases they actually have a better prognosis.

REFERENCES

Search PubMed for:

1. Machold KP, Stamm TA, Eberl GJM, et al. Very recent onset arthritis -- clinical, laboratory and radiological findings during the first year of disease. J Rheumatol 2002;29:2278.

2. Bresnihan B. Rheumatoid arthritis. Principles of early treatment. J Rheumatol 2002;29 Suppl 66:9.

3. Hulseman JL, Zeidler H. Undifferentiated arthritis in an early synovitis out-patient clinic. Clin Exp Rheumatol 1995:13:37-43. [MEDLINE]

4. Zeidler H, Hülseman JL. Benign polyarthritis and undifferentiated arthritis. An epidemiological terra incognita. Scand J Rheumatol 1989;Suppl 79:13-20.

5. Wolfe F, Ross K, Hawley DJ, Roberts FK, Cathey MA. The prognosis of rheumatoid arthritis and undifferentiated polyarthritis syndrome in the clinic: a study of 1141 patients. J Rheumatol 1993;20:2005-9. [MEDLINE]

6. Morel J, Legouffe MC, Bozonat MC, et al. Outcomes in patients with incipient undifferentiated arthritis. Joint Bone Spine 2000;67:49-53. [MEDLINE]

7. Kotake S, Schumacher HR, Yarboro CH, et al. In vivo gene expression of type 1 and type 2 cytokines in synovial tissues from patients in early stages of rheumatoid, reactive and undifferentiated arthritis. Proc Assoc Am Phys 1997;109:286-302. [MEDLINE]

8. Saraux A, Berthelot JM, Chalès G, et al. Value of laboratory tests in early prediction of rheumatoid arthritis. Arthritis Rheum 2002;47:155-65. [MEDLINE]

9. Gerber L, El-Gabalawy H, Arayssi T, Furst DG, Yarboro C, Schumacher HR. Polyarticular arthritis, independent of rheumatoid factor, is associated with poor functional outcome in recent onset synovitis. J Back Musculo Rehab 2000;14:105-9.

10. Aho K, Palosuo T. Can outcome of early synovitis be predicted by serological tests? Clin Rheumatol 2002;21:97-102. [MEDLINE]

11. Klimiuk OA, Goronzy JJ, Bjornsson J, Beckenbaugh RD, Weyand CM. Tissue cytokine patterns distinguish variants of rheumatoid synovitis. Am J Pathol 1997;151:1311-9. [MEDLINE]

12. Goldbach-Mansky R, Hudson A, Gerard H, et al. Does the presence of C. trachomatis in synovial tissue correlate with immune serology and outcome in recent onset synovitis? [abstract]. Arthritis Rheum 1998;41 Suppl:S148.

13. El-Gabalawy HS, Goldbach-Mansky R, Smith D 2nd, et al. Association of HLA alleles and clinical features in patients with synovitis of recent onset. Arthritis Rheum 1999;42:1696-705. [MEDLINE]

14. Van Riel PLCM, Schumacher HR. How does one assess early rheumatoid arthritis in daily clinical practice? Best Pract Res Clin Rheumatol 2001;15:67-76. [MEDLINE]

15. Schumacher HR. The end of 'disease' as a simple concept [editorial]. Curr Rheumatol Rep 2000;2:271-2. [MEDLINE]

16. Schumacher HR, Bardin T. The spondylarthropathies: classification and diagnosis. Do we need new terminologies? Ballieres Clin Rheumatol 1998;12:551-64. [MEDLINE]

17. Schumacher HR. Classification of rheumatic diseases. In: Klippel JH, Dieppe PA, editors. Rheumatology. St. Louis; Mosby; 1994:7.1-7.4.

18. Harrison BJ, Symmons DPM, Barret EM, Silman AJ. The performance of the 1987 ARA classification criteria for rheumatoid arthritis in a population based cohort of patients with early inflammatory polyarthritis. J Rheumatol 1998;28:2324-30. [MEDLINE]

19. Eisenberg JM, Schumacher HR, Davidson PK, Kauffman L. Usefulness of synovial fluid analysis in the evaluation of joint effusions. Use of threshold analysis and likelihood ratios to assess a diagnostic test. Arch Intern Med 1984;144:715-9. [MEDLINE]

20. Levin RW, Park RJ, Ostrov B, et al. Clinical assessment of the 1987 ACR criteria for rheumatoid arthritis. Scand J Rheumatol 1996;25:277-81. [MEDLINE]

21. Berthelot JM, Bernelot-Moens HJ, Klarlund M, et al. Differences in understanding and application of 1987 ACR criteria for rheumatoid arthritis and 1991 ESSG criteria for spondyloarthropathy. A pilot survey. Clin Exp Rheumatol 2002;20:145-50. [MEDLINE]