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Dr. Pincus, et al reply

To the Editor:

We thank Dr. Russell for his thoughtful comments, extending his many contributions to the rheumatology community over the years, including comments concerning glucocorticoids for rheumatoid arthritis (RA)¹. We certainly agree that high doses of glucocorticoids, even at 10 mg per day, which have been reported to be efficacious to retard radiographic progression², are not desirable³. We also agree that "steroids alone" are not adequate for longterm treatment of RA⁴, and are disappointed to learn that Dr. Russell believes such an interpretation is possible. However, let us note several areas of respectful disagreement:

1. Despite improved sensitivity of anti-CCP to identify patients with early arthritis who will develop progressive disease, 30%–40% of patients with RA who need aggressive treatment for RA have negative anti-CCP tests^5-7. Even Dr. Russell's series concerning progression of palindromic rheumatism to RA indicated that 17% (one in 6 patients) who progressed to RA had a negative anti-CCP test⁸. Therefore, it appears preferable to us that some patients might be "overtreated" with a simple n-of-1 trial over 30–90 days with very low dose prednisone and/or MTX than leaving up to 40% of patients who need treatment to control inflammation untreated because of a negative anti-CCP test.

2. The practice advocated is a limited n-of-1 trial 3–5 mg prednisone or prednisolone per day and/or MTX 10 mg weekly for 30–90 days. In our clinical experience, such a trial is adequate to develop a response in patients with suspected early inflammatory arthritis that might be RA but not yet overt disease. It is noteworthy that no significant differences were seen in efficacy over a range of 2.5 to 15 mg daily doses in a metaanalysis of the efficacy of short-term low-dose prednisolone versus placebo⁹.

3. One reason that an n-of-one trial may be preferable to "a simple" anti-CCP test involves costs. The costs of an anti-CCP test are greater than the costs of the visit to a rheumatologist in the United States. Of course, fewer tests for anti-CCP will not resolve spiraling costs for medical services. Nonetheless, physicians have a responsibility to consider costs in their decisions regarding laboratory testing, imaging procedures, and therapies. In view of availability of excellent but expensive therapies for RA at this time, the need for which can be identified clinically in almost all patients (without any laboratory tests), it appears unfortunate to add to the decision process a test that gives a "false-negative" result in one-third of patients.

4. The published results noted by Dr. Russell concerning the absence of significant efficacy of MTX in patients with a negative anti-CCP test¹⁰ were collected over one year, and may not necessarily apply over 5 years. The data presented a subanalysis of a study that included 55 patients who took MTX versus 55 who took placebo. Of the 55 patients treated with MTX, 43 patients who were negative for anti-CCP did not differ in responses to MTX compared to 43 anti-CCP-negative patients treated with placebo. However, in our view, the rate of joint damage in this subgroup was too low to expect differences between the 2 groups. If the patients were followed longer, e.g., 5 years, one may well see differences between the MTX and placebo groups in CCP-negative patients.

One interesting example of differences between one-year and 5-year results can be seen in a metaanalysis published in 1990, in which clinical trial data indicated similar efficacy of injectable gold salts, azathioprine, penicillamine, and MTX over one year¹¹. The proportion of patients who continued each agent over one year for the first DMARD also was similar for all agents over one year in clinical practice, comparable to the metaanalysis. However, MTX courses were continued significantly longer than those of the other agents over 5 years¹², suggesting greater efficacy of MTX, as confirmed in later developments^13,14.

5. We agree that "a few patients getting MTX unnecessarily is not a major issue," as Dr. Russell suggests. However, we prefer to err on the side of treatment that has minimal toxicity^13,14 rather than allow inflammation to potentially progress in patients with possible RA. This approach is consistent with a principle of "tight control" in hypertension and hyperlipidemia^15-17, in which many patients may be treated with relatively safe therapies who may not require these treatments. Ironically, 30–90 days of very low-dose prednisone and/or MTX appears to have lower toxicity than almost any medication for hypertension or hyperlipidemia.

6. We also agree that referral of patients with early arthritis to rheumatologists as soon as possible provides the best possible care. However, this ideal procedure is not present in most locales all over the world. A profound shortage of rheumatologists already exists in many areas, and will likely increase substantially over the coming years^15,18,19.

The case for low-dose prednisone for patients with RA has been made by others^9,20-23, including 2 recently reported clinical trials^24,25 and 2 eloquent more recent editorials in The Journal^26,27, although disagreement remains respectfully recognized^28-30. A randomized trial over 5–10 years with particular attention to adverse events, which would be regarded as ethical in view of the absence of consensus, would appear desirable.

None of these comments reduces the importance of further research concerning anti-CCP to increase understanding of pathogenesis and treatment of RA, such as new information concerning the influence of associations with HLA class II in its severity, although limitations of anti-CCP in clinical care are recognized by others^7,31,32. Rheumatologists might recognize whether some information that is very useful in research settings may not necessarily have value in clinical decisions, and even lead to possibly incorrect conclusions in many patients.

THEODORE PINCUS, MD, Vanderbilt University, Nashville, Tennessee, USA; TOM W.J. HUIZINGA, MD, PhD, Leiden University Medical Center, Leiden, The Netherlands; YUSUF YAZICI, MD, New York University Hospital for Joint Diseases, New York, New York, USA.

REFERENCES

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