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Correspondence

This Letter to the Editor from Dr. D'Arcy and Dr. Willkens and the reply by Dr. Listing and Dr. Rau were intended to be published in July 2001, but have been delayed until now due to an oversight by the publisher. We regret the error.

Use of Prognostic Markers to Guide Biologic Therapies for Rheumatoid Arthritis

To the Editor:

The ATTRACT trial, a landmark study of the combination of infliximab with methotrexate (MTX), provides dramatic evidence of the potential ability of modern pharmacotherapy to arrest the progression of erosive disease in patients with rheumatoid arthritis (RA). At 54 weeks, the mean radiographic score actually improved by 0.7 (SD ± 3.8) in the group treated with 10 mg/kg infliximab every 4 weeks and an average dose of 17 mg MTX per week, compared with the score worsening by 7.0 (SD ± 10.3) in the MTX group¹.

This data lends support to the rationale that tumor necrosis factor-a (TNF-a) inhibitors be used as first-line therapy in RA, and etanercept has been FDA approved and is being marketed for use in "DMARD-naive" patients with moderately to severely active disease. In an editorial on biologic therapies for RA, Dr. John Klippel assessed the case for using TNF-a inhibitors early in the course of all patients with documented RA, citing 3 barriers to adopting this approach: high cost, unavailability of longterm efficacy and safety data, and lack of studies comparing them with other drugs that also slow the rate of erosive disease². We would like to draw attention to a fourth barrier, which has received little attention in the midst of the excitement over the benefits of biologic therapies: a significant percentage of patients diagnosed with RA do not go on to develop joint destruction.

In a study of radiographic progression in 256 patients from a referral based population with early RA who were followed on average 8.7 years, 15-20% never developed erosions³. Followup studies from the 1960's of RA diagnosed in community based populations suggest that the number with benign disease is even higher^4,5. RA is clearly a heterogeneous clinical entity, and a combination of markers, such as C-reactive protein (CRP), DRB1*04/*01 HLA alleles, and rheumatoid factor, could prove useful in identifying those patients most likely to develop significant erosive disease. The study by Listing, et al of 139 patients with early RA demonstrated that only 5% of those who were both negative for DRB1*04*01 HLA class II alleles and had a CRP < 1.5 mg/dl at presentation went on to develop erosions in 5 or more joints at 4 year followup⁶.

If rheumatologists were able to risk-stratify patients with RA early in the course of their disease, they could tailor a therapeutic strategy accordingly. It is critical that reliable prognostic markers of erosive disease now be identified as the biologic agents, which show promise of halting the destructive effects of RA, move from bench to bedside.

CHRISTOPHER A. D'ARCY, MD; ROBERT F. WILLKENS, MD, Division of Rheumatology, University of Washington, Seattle, Washington, USA.

REFERENCES

1. Lipsky PE, van der heijde DMFM, St. Clair EW, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. N Engl J Med 2000;343:1594-602.

2. Klippel JH. Biologic therapy for rheumatoid arthritis. N Engl J Med 2000;343:1640-1.

3. Wolfe F, Sharp JT. Radiographic outcome of recent-onset rheumatoid arthritis: a 19[year study of radiographic progression. Arthritis Rheum 1998;41:1571-82.

4. Mikkelsen WM, Dodge H. A four-year follow-up of suspected rheumatoid arthritis: the Tecumseh, Michigan, community health study. Arthritis Rheum 1969;12:89-91.

5. O'Sullivan JB, Cathcart ES. The prevalence of rheumatoid arthritis. Follow-up evaluation of the effect of criteria on rates in Sudbury, Massachusetts. Ann Intern Med 1971;76:573-7.

6. Listing J, Rau R, Müller B, et al. HLA-DRB1 genes, rheumatoid factor, and elevated C-reactive protein: independent risk factors of radiographic progression in early rheumatoid arthritis. J Rheumatol 2000;27:2100-9.

Dr. Listing and Dr. Rau reply

To the Editor:

Several predictors of progressive disease have been described including severe disease activity as measured in swollen joint count and CRP levels, high titer of serum rheumatoid factor (RF), erosive disease, and the presence of HLA-DRB1 04/01 alleles. As Drs. D'Arcy and Willkens point out, our study¹ confirmed the important role of CRP, RF, and HLA-DRB1 04/01. Indeed, 73% of patients with a double dose of disease related alleles developed erosive disease. In contrast, patients with no disease related alleles, patients with no RF, and patients without erosions at baseline had a good chance that their disease remained non-erosive, especially if their CRP was normal¹. However, we have to consider that still nearly 40% of patients with 2 alleles had a benign disease with a Ratingen score of less than 5 (~ 2.55 of the maximum score) after 4 years. The situation is different when looking at patients with existing erosive disease: in this case, HLA alleles had no influence on radiographic progression, whereas a persistently elevated CRP strongly indicated progressive disease¹. This is confirmed in another study with early erosive RA followed over 6 years: there was no difference regarding disease progression between seropositive patients with and without disease related alleles². In that study the mean CRP could be reduced from 3.5 mg/dl to < 1 mg/dl after 6-18 months, leading to a significant decrease of the slope of progression over time. Forty-six of 109 patients had a radiographic score of < 5% of the maximum possible score after 6 years. This and another study³ may indicate that early aggressive treatment with conventional DMARD (here, im gold or im MTX) may overcome the predictive value of genetic markers. The importance of effective treatment is underscored by the fact that the time-integrated CRP is a better indicator of progression than baseline CRP^1,4,5. The best predictor of progressive disease in individual patients may be high disease activity reflected in elevated CRP, because disease activity after a certain time gap translates into destruction⁵

Without any doubt the availability of TNF inhibitors is a great step forward, not only because they have improved our ability to treat many patients unresponsive to conventional DMARD effectively, but even more so because they confirm the theory about the role of cytokines in inflammatory rheumatic disease. On the other hand we must admit that the study comparing MTX with MTX + infliximab consisted of patients who were partial nonresponders to MTX⁶. It is also true that a median progression rate of 0 does not mean an arrest of progression in all patients. In a head to head comparison of etanercept with MTX in early active seropositive or erosive disease⁷, MTX performed surprisingly well: although the progression rate in the group of patients treated with 2 ´ 25 mg etanercept/week was lower during the first 6 months, there was no significant difference regarding progression between both treatment regimens in the second 6 months; the progression during the second half-year had significantly decreased with MTX treatment compared to the first half-year. The earlier onset of clinical effect with etanercept translated into earlier inhibition of progression. A similar result could be achieved with prednisolone doses as low as 7.5 or 5.0 mg/day in addition to conventional DMARD^8,9.

Many patients with active RA can be treated sufficiently with conventional DMARD, including patients with "bad" prognostic markers, and the superiority of TNF blockade is not proven for all patients. Therefore, it seems unnecessary to treat all patients with documented RA with TNF inhibitors, as discussed by Dr. Klippel¹⁰. Instead, we recommend following the consensus statement of an international expert panel¹¹ to restrict treatment with TNF inhibitors to patients fulfilling certain disease activity criteria in spite of sufficiently dosed treatment with 2 conventional DMARD (one of them MTX) for at least 6 months.

JOACHIM LISTING, PhD, German Rheumatism Research Center, Berlin; ROLF RAU, MD, PhD, Department of Rheumatology, Evangelisches Fachkrankenhaus Ratingen, Ratingen, Germany.

REFERENCES

1. Listing J, Rau R, Müller B, et al. HLA-DRB1 genes, rheumatoid factor, and elevated C-reactive protein: independent risk factors of radiographic progression in early rheumatoid arthritis. J Rheumatol 2000;27:2100-9.

2. Rau R, Herborn G, Zueger S, Fenner H. The effect of HLA-DRB1 genes, rheumatoid factor, and treatment on radiographic disease progression in rheumatoid arthritis over 6 years. J Rheumatol 2000;27:2566-75.

3. Eberhardt K, Fex E, Johnson U, Wollheim FA. Associations of HLA-DRB and -DQB genes with two or five year outcome in rheumatoid arthritis. Ann Rheum Dis 1996;55:34-9.

4. van Leeuwen MA, van Rijswijjk MH, van der Heijde DMFM, et al. The acute-phase response in relation to radiographic progression in early rheumatoid arthritis: a prospective study during the first three years of the disease. Br J Rheumatol 1993;32:9-13.

5. Rau R, Herborn G, Menninger H, Sangha O. Radiographic outcome after 36 months in rheumatoid arthritis patients treated with methotrexate and gold sodium thiomalate. Rheumatology — in press.

6. Lipsky PE, van der Heijde DMFM, St. Clair EW, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. N Engl J Med 2000;343:1594-602.

7. Bathon JM, Martin RW, Fleischmann RM, et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med 2000;343:1586-93.

8. Kirwan JR. The effect of glucocorticoids on joint destruction in rheumatoid arthritis. N Engl J Med 1995;333:142-6.

9. Rau R, Wassenberg S. Zeidler H, for the LDPT Study Group. Low dose prednisolone therapy (LDPT) retards radiographically detectable destruction in early rheumatoid arthritis. Z Rheumatol 2000 (Suppl 2); 59:90-6.

10. Klippel JH. Biologic therapy for rheumatoid arthritis [editorial]. N Engl J Med 2000;343:1640-1.

11. Consensus statement. Access to disease modifying treatments for rheumatoid arthritis patients. Ann rheum Dis 1999;58 Suppl 1:129-30.

Removal of Hyaline Articular Cartilage Reduces Lymphocyte Infiltration and Activation in Rheumatoid Synovial Membrane

To the Editor:

I read with interest the recent article on synovial membrane pathology in chronic arthritis after removal of hyaline articular cartilage¹. Based on immunochemical staining methods and morphometry, it was shown that revision rheumatoid arthritis (RA) or ankylosing spondylitis synovial membranes, in contrast to primary RA samples, did not manifest lymphocyte infiltration and/or activation, "as there would be no antigen there to be processed and presented by the antigen presenting cells to T lymphocytes." As concluded by the authors, autoantigens that perpetuate the autoimmune synovitis might originate from avascular hyaline articular cartilage; this was proved in the article; however, no potential autoantigen was mentioned¹.

Further, the hypothesis that an autoimmune reaction in the articular cartilage initiates the immunopathological events leading to synovial inflammation is not new, and has been already stated in the literature². Clinical as well as experimental (collagen induced arthritis mouse) data² strongly suggest involvement of the type II collagen degradation peptides in the autoimmune response that occurs in the articular cartilage, primary to pathological changes in synovium. I wonder why Konttinen, et al did not discuss these data in their report.

KATSUYUKI FUJII, MD, Department of Orthopaedic Surgery, The Jikei University School of Medicine, Tokyo, Japan.

REFERENCES

1. Konttinen YT, Li TF, Lassus J, Waris V, Santavirta S, Virtanen I. Removal of hyaline articular cartilage reduces lymphocyte infiltration and activation in rheumatoid synovial membrane. J Rheumatol 2001;28:2184-9.

2. Fujii K, Tsuji M, Tajima M. Rheumatoid arthritis: A synovial disease? Ann Rheum Dis 1999;58:727-30.

Dr. Konttinen replies

To the Editor:

Thank you for letting us share the comments from Dr. Fujii. The idea about the hyaline articular cartilage being the perpetuating stimulus, containing potential sequestrated antigens, is not new. Our observation provides new evidence¹ for this old hypothesis.

Dr. Fujii and his team refer in their hypothesis article² to previous work on the early appearance of anti-type II collagen IgG antibody in rheumatoid arthritis (RA). The major antigenic determinants recognized by RA sera have been found to reside in the region represented by cyanogen bromide (CNBr) peptides 11 and 8 (CB-11, CB-8) of human type II collagen molecule. Anti-type II collagen antibody was negative in gout and osteoarthritis (OA). In their work they also describe that although the superficial zone of the hyaline articular cartilage in RA looked healthy, the deep zone contained less intact type II collagen and intense staining for CNBr derived peptides of type II collagen. Such a reciprocal staining pattern was not seen in OA. Further, islands invading from the subchondral bone into the deep zone of articular cartilage were described and thought to be of relevance for the immune response against type II collagen in RA.

It makes sense to consider sequestrated autoantigens as potential targets for the immune system after some type of injury has damaged the cartilage. This requires suprathreshold concentrations of the autoantigen and a proimmune context. But it is difficult to prove this hypothesis. One should probably be able to (1) identify the autoantigens involved, (2) demonstrate that these cartilaginous autoantigens are necessary for the development of the disease, (3) demonstrate that specific antigen reactive T lymphocytes and antigen presenting cells are involved in the pathogenesis, and (4) demonstrate that the disease can be transferred by T lymphocytes. Therefore, it is too early to identify any particular candidate antigen by name, and this was not the focus of our work. We discussed this topic when we reported our results on induction of peroral tolerance against (Gly-X-Y)_n sequences in RA, which is an interesting way to test the collagen autoantigen hypothesis³. However, the evidence presented thus far by, for example, Dr. Fujii or by us, although compelling, is far from convincing.

In contrast to the speculations presented by Dr. Fujii and his team, it might well be that the immune response against autologous type II collagen is a late event in disease pathogenesis. Further, degradation of the hyaline articular cartilage and type II collagen are by no means specific for inflammatory arthritides^4,5. It is possible that cartilaginous autoantigens are perpetuating factors contributing to the chronicity of the disease rather than initiating early triggers. For example, it has been described that many immunoreactive epitopes in the hyaline articular cartilage need to be revealed by chondroitinase or hyaluronidase pretreatment^4,5 before they can be confirmed using specific antibodies.

YRJÖ T. KONTTINEN, MD, Department of Medicine/Invärtes medicin, HUS and ORTON Research Institute and the Orthopaedic Hospital of the Invalid Foundation, Helsinki, Finland.

REFERENCES

1. Konttinen YT, Li TF, Lassus J, Waris V, Santavirta S, Virtanen I. Removal of hyaline articular cartilage reduces lymphocyte infiltration and activation in rheumatoid synovial membrane. J Rheumatol 2001;28:2184-9.

2. Fujii K, Tsuji M, Tajima M. Rheumatoid arthritis: A synovial disease? Ann Rheum Dis 1999;58:727-30.

3. Arborelius M Jr, Konttinen YT, Nordström DC, Solovieva S. Gly-X-Y repeat sequences in the treatment of active rheumatoid arthritis. Rheumatol Int 1999;18:129-35.

4. Hollander AP, Pidoux I, Reiner A, Rorabeck C, Bourne R, Poole AR. Damage to type II collagen in aging and osteoarthritis starts at the articular surface, originates around chondrocytes, and extends into the cartilage with progressive degeneration. J Clin Invest 1995;96:2859-69.

5. Konttinen YT, Mandelin J, Li TF, et al. Acidic cysteine endoproteinase cathepsin K in the degeneration of the superficial articular hyaline cartilage in osteoarthritis. Arthritis Rheum 2002;46:953-60.

Should We Be Reading This Journal?

To the Editor:

I read with great interest the editorial by M. Stanbrook¹. Medical doctors need to read such articles.

Almost all efficient doctors read medical journals. In the same way, rheumatologists read not one, but 3, 4, or even 5 rheumatology journals, plus one or more internal medicine journals, for the necessary contact with other specialties. They are trying to maintain old knowledge and be informed of all the new data. They wish to miss nothing. The problem in our times is the limited availability of time. We all are tremendously busy with our specialties, research work, patients, and family. As a result, we select the articles we read and in some cases we read only the abstract and the introduction of the article. Many articles seem to be very important and sometimes very impressive.

However, very few original articles, e.g., the initial work about anti-TNF treatment, survive and create a new era in medicine. The problem is that even when you read an article that appears exciting and covers your specific or general interests, you cannot be sure it will prove to be important, that it will survive, or that it is worth reading. And we are talking about thousands of such articles.

In my opinion, the 20,000 medical journals, with few exceptions, do not solve problems, they rather create problems. I don't believe it is a question of which journal we should be reading. Everybody selects a few, depending on many factors including specific interest(s), general knowledge, clinical and/or laboratory practice and/or investigational interest, and country of medical studies. The aim must always be improvement of knowledge and of patient care.

I agree most doctors begin reading journals as a normal educational activity from the time medical training commences. Most of them are influenced by their trainers in choosing journals. Very often doctors choose journals because of coincidence, and so on. In my opinion, the only solution to the cascade of information of our time is the dramatic reduction of the number of medical journals, perhaps through merging. Additionally, the articles should be fewer but of higher quality, which means there must be stricter review before publication, which ultimately will allow acceptance of only very high standard papers. I believe that "publish or perish" or other similar practices concerning career advancement do not favor high quality of articles.

Probably several drug companies and journals will not agree. University hospital clinics receiving grants will not agree either (but they may still be able to publish in internal hospital journals). Still, international medical journals should be very few; only works of the highest level should be accepted for publication.

GEORGE M. PAPADIMITRIOU, MD, Professor, University of Athens, Athens, Greece.

REFERENCE

1. Stanbrook MB. Should you be reading this journal? J Rheumatol 2001;28:2571-2.

Dr. Stanbrook replies

To the Editor:

I thank Dr. Papadimitriou for his kind words and thoughtful remarks. His comments, like mine, acknowledge that the conflict between the expanding body of medical knowledge and the limited time available to acquire and process it represents a fundamental dilemma faced by all physician readers. As a solution, he suggests that we should have fewer journals, publishing higher quality articles that have been subjected to a stricter peer review process.

It would certainly make our task easier if all the genuinely important articles could be concentrated into a few journals. However, given the minimal scientific information that exists at present about journals and what they publish, this would raise several difficulties. First, as Papadimitriou admits, it is hard to know what articles will ultimately prove to be important in future, even among those that seem promising now. If it were possible to identify the most important articles easily, readers could just ignore the less important ones, and the volume of material being published might then pose no dilemma. Second, quality and importance are relative, and in practice, their evaluation remains largely subjective. I suspect that many, if not most, journal editors would claim that their own publications already put articles through a strict review process and select only those that are of the highest quality available. Third, some novel and ultimately very important discoveries have been initially ignored and rejected by major peer reviewed journals (for example, the discovery of the relationship between Helicobacter pylori and peptic ulcer disease). If publication opportunities were limited to a few journals with strict, standardized acceptance criteria, suppression of innovation might be the consequence, which would defeat the purpose of having such journals. Finally, it must be recognized that the pace of research and discovery drives the quantity of what is published, not the other way around. Creating fewer places to publish would not decrease the amount of important new knowledge uncovered, any more than decreasing the number of hospital beds will reduce the burden of illness in the community.

I am pessimistic, therefore, about the likelihood of decreasing the number of journals or journal articles. Finding rational solutions to the physician reader's dilemma will require well designed scientific studies to improve our understanding of the nature and effectiveness of knowledge transfer between medical journals and practicing physicians.

MATTHEW B. STANBROOK, MD, FRCPC, University of Toronto, Toronto, Ontario, Canada.