Fw: Methotrexate: Vital New Information About a Middle Aged Drug

[Guest guest]

----- Original Message -----

From: " Kathi " <pureheart@...>

Sent: Tuesday, October 01, 2002 6:53 PM

Subject: Methotrexate: Vital New Information About a Middle Aged Drug

> Methotrexate: Vital New Information About a Middle Aged Drug

>

> EDWARD H. GIANNINI, MD, DrPH, MSc, Professor of Pediatrics, University

> of Cincinnati College of Medicine, Cincinnati Children's Hospital

> Medical Center, Division of Rheumatology, Pav 2-129,

> 3333 Burnet Avenue, Cincinnati, OH 45220, USA

>

> Address reprint requests to Dr. Giannini.

>

>

> In this issue of The Journal 3 articles contribute substantially to our

> understanding of methotrexate (MTX) in rheumatoid arthritis (RA), i.e.,

> therapeutic response to MTX1; effect of concomitant hydroxychloroquine

> on the bioavailability of MTX2; and whether serially determined liver

> concentrations of MTX and its chief metabolite affect hepatic damage

> scores, clinical efficacy, or laboratory determined toxicity3.

>

> THERAPEUTIC RESPONSE TO MTX

>

> Ortendahl, et al introduce us to the concept of the " therapeutic

> segment, " 1 defined as the period of time between the start of a therapy

> and its discontinuation, addition of an alternative agent, or initiation

> of a new treatment. Such an approach allows one to study, in a

> relatively pure state, the time to earliest response, to maximum

> response, to loss of response, and disability averted. The model can

> also be used to study other patient centered outcomes, such as pain and

> toxicity-unit years and cumulative dollar costs. Conventional randomized

> clinical trials generally do not permit such estimates of a therapeutic

> response profile because nearly all trials are severely " right

> censored. " That is, the assessment of what happens further out in time

> [to the right in a graph of time (x axis) versus response (y axis)] is

> cut off due to the trial's fixed (relatively short) duration.

>

> One's ability to employ the therapeutic segment approach is contingent

> upon having several resources with which to work. A large, carefully

> monitored cohort of patients to legitimately employ the required

> statistical tools is mandatory. In this regard, the Arthritis,

> Rheumatism and Aging Medical Information System (ARAMIS) parent cohort

> of 4253 patients & mdash; 437 of whom had new MTX starts during the 10

> year period examined & mdash; provides an unparalleled resource.

> Validated response measurement tools must exist for the disease under

> study and these tools must be given at standardized intervals during the

> segment. The Stanford Health Assessment Questionnaire (HAQ) used by

> Ortendahl, et al provides such a tool. It has been serially administered

> to thousands of patients, and, as a measure of disability, found to be

> sensitive to change and highly correlated with a variety of clinical

> outcomes4. In addition, the ARAMIS centers have employed standardized

> patient followup protocols for over 20 years, thus adding to the

> feasibility of doing such a study and increasing the credibility of

> results. Truly remarkable evidence of the rigor with which patients were

> followed is the fact that not one of the 2669 disability indexes (DI)

> required in this study was missing.

>

> Unfortunately, existing cohorts of carefully monitored patients who have

> been assessed at standardized intervals using validated outcome tools

> are lacking to conduct therapeutic segment studies for even the most

> common diseases seen by the rheumatologists, both adult and pediatric.

> Thus, the therapeutic segment approach is likely to be possible for very

> few agents, at least at present. Nevertheless, the concept is sound and

> should be considered a major addition to the methodological tools

> available to the field of evidence based medicine and clinical

> effectiveness research.

>

> Undoubtedly, MTX remains the drug of first choice after failure of

> nonsteroidal antiinflammatory drugs (NSAID), both in adult RA and in

> juvenile idiopathic arthritis1,5. Therefore, the information presented

> for this agent should be viewed in itself as a major advance in our

> understanding of the treatment of RA. As the field awaits biomedical

> research to elucidate the definitive genetic profiles that distinguish

> " complete responders " from " partial responders " from " non-responders " ,

> rheumatologists continue to grapple with the most appropriate sequence

> of therapy, as well as the time a patient should be given in which to

> respond. Importantly, statistical methodologies already well developed

> in theoretical mathematical statistics in the areas of sequential theory

> and sequential estimation may help in addressing these issues.

>

> Compounding the conundrum is the increased use of combination therapy

> and the rapid fire appearance on the market of new, potentially more

> efficacious agents. While Ortendahl, et al make no pretense about

> resolving these questions (e.g., should biologics be added earlier in an

> attempt to " ratchet down " the disease even quicker?), they do spell out

> in exquisite detail the shape, magnitude, and other characteristics of

> the pure MTX response and offer some guidance for its use.

>

> Further discussion and interpretation of the figures presented by

> Ortendahl, et al are necessary. Their Figure 1 shows the rise in MTX use

> and a corresponding fall in HAQ DI scores through the study period

> (1988-1998). The authors are careful to remind the reader that not all

> the patients whose DI appear in the graph received MTX. It is likely

> that the development of more effective treatment regimens, such as

> combination therapy and the appearance of biologics towards the end of

> the study period, account for at least some of the decrease in the DI

> through time.

>

> Their Figure 2 graphs the regression of mean DI on time and introduces

> generalized estimating equations (GEE) (an extension of general linear

> models) now being used in analysis of medical event prediction6. GEE

> take into account the fact that multiple measurements of the DI in the

> same patient through time are correlated with each other, rather than

> being completely independent (i.e., this is a longitudinal dataset). GEE

> may also take into account that patients were followed for differing

> periods of time (segment length differed). Finally, this is a

> " clustered " sample in that the data are from 8 different geographic

> centers and this may also have been taken into account. Yet, the authors

> do not specify exactly which of these facts were considered by GEE. The

> authors do point out the link function, distribution assumptions, and

> covariance structure. However, the reasons for choosing the polynomials

> that they did (cubic, quadratic; also true for their Figures 3 and 4)

> are not given. It is likely that the polynomials chosen fit the data

> better than higher order polynomials or other nonlinear models. The

> authors note that they were surprised to find that improvement in the DI

> continued into the fourth year of the therapeutic segment. Plateau of

> response did not occur until 30 to

> 42 months after therapy began, after which a rise in the DI was

> detected. But how can this be, when the general consensus in the

> literature is that improvement to be appreciated by MTX generally occurs

> up to about 6 months, at which time a plateau is reached7,8? Even the

> accompanying article by Carmichael, et al cites this belief2.

>

> Several explanations are possible including that MTX doses rose

> gradually through the observation period of the study & mdash; a segment

> in real time when rheumatologists were becoming more comfortable giving

> higher doses of the drug. Yet, the authors address this by allowing time

> into a regression model and found MTX dosage not to be a predictor of

> HAQ disability. Other possible explanations for this apparent anomaly

> include continued improvement in range of motion and strength that

> occurs after 6 months due to longterm disease suppression, interstudy

> differences in the patient populations, use of differing measures of

> therapeutic success, differing MTX dosage regimens (perhaps the more

> recent studies got to an ideal dose of MTX faster than was done in

> 1988), and differences in concurrent therapy that may have affected the

> bioavailability of MTX.

>

> Their Figure 4 addresses another important source of bias recognized by

> the investigators. " Right-censoring " (discussed above) can influence

> whether a drug appears more effective, or less effective, depending upon

> whether those who responded better or worse change treatments more

> quickly. In this study, patients could only be right-censored if they

> continued MTX until the end of the 10 year followup. Figure 4 seems to

> quell this concern in that the mean DI of the 2 groups (i.e., those who

> changed therapy vs those who were right-censored) were similar at

> baseline, and the DI over the period of 0 to 6 months was not

> statistically significant. In addition, the therapeutic response curves

> (i.e., the mean DI over time) appear similar.

>

> Their Figure 5 addresses the potential concern that the shape of the

> therapeutic response curve is related to the duration of the therapeutic

> segment. Because the segment may vary for each patient, this question is

> crucial, and Figure 5 seems to suggest one has no effect on the other.

> However, the curves must be interpreted with caution. The curves are not

> mutually exclusive in that each patient contributes to every curve of

> the same length or shorter than that patient's segment. The curves might

> look quite different if groups of patients with similar segment

> durations were plotted separately.

>

> In summary, the data presented by Ortendahl, et al regarding the

> characteristics of the pure MTX treatment segment add considerably to

> our knowledge of this agent. The concept of the therapeutic segment

> approach is a methodological advance of considerable merit, but its

> general usefulness in the study of other agents may be limited due to

> the lack of adequate patient cohorts followed carefully through time

> using standardized measures at predetermined intervals. Despite the

> statistical uncertainties mentioned above, it is likely that the overall

> conclusions and recommendations of the authors are valid.

>

> EFFECT OF HCQ ON MTX BIOAVAILABILITY

>

> The second article, by Carmichael, et al2, addresses the apparent

> increased bioavailability of MTX when prescribed concomitantly with

> hydroxychloroquine. The concurrent use of these 2 agents is common in

> adult rheumatology practices, but uncommon in pediatric rheumatology5,9.

> In brief, the mean area under the time-concentration curve for MTX was

> increased by a significant amount, as was the time to reach the maximum

> concentration (tmax), and a corresponding decrease in the maximum

> concentration (Cmax). Hydroxychloroquine's pharmacokinetic profile

> appeared unaffected. The authors state that these findings may account

> for the apparent increased potency of MTX when given concurrently with

> hydroxychloroquine and the lesser degree of flare of disease after MTX

> discontinuation.

>

> Two safety issues are raised. The decrease in Cmax may account for the

> decreased acute liver toxicity produced by MTX when given with

> hydroxychloroquine. However, since MTX is excreted through the kidneys,

> physicians must be aware of the increased potential for renal

> abnormalities. We live in the age of combination therapies, many times

> introduced early in the disease course10, which in some situations

> institute " off label " approaches (particularly in pediatric

> rheumatology) in which there is little or no pharmacokinetic data about

> the agent/s in the specific disease population. This well done study

> should serve as yet another warning to rheumatologists of the potential

> for toxic drug-drug interactions that may arise unexpectedly even when

> using drugs that have been on the market for years.

>

> LONGITUDINAL MEASUREMENT OF MTX LIVER CONCENTRATIONS

>

> In the third article, Fathi, et al3 present results of a 3.5 year double

> blind study of whether MTX and MTX polyglutamate accumulation in the

> liver correlates with clinical efficacy or laboratory toxicity. In

> addition, a new classification system (the Iowa Score) for grading

> abnormalities is investigated for its construct validity. The first 18

> weeks were by double blind, placebo controlled, dose ranging study.

> After 18 weeks patients who had received placebo were blindly

> re-randomized to either 5 or 10 mg/m2 oral MTX once weekly. Maximum dose

> of MTX was 35 mg per week. Liver biopsies were done at baseline and

> after 1, 2, and 3.5 years after baseline. Histological abnormalities did

> not progress using the Roenigk score. The authors conclude that there is

> no correlation between MTX or MTX polyglutamate accumulation in the

> liver and patient demographics, liver histology, concomitant medications

> (NSAID and prednisone), and disease activity. Thus, MTX serum

> concentrations are likely to be of little value in predicting clinically

> important hepatotoxicity.

>

> The uniqueness and clinical relevance of this study comes from its

> determination of serial liver biopsies (including baseline biopsies)

> assessed with 2 different scoring systems, and its attempt to correlate

> MTX and MTX polyglutamate liver concentrations with a range of

> demographic, disease, and laboratory variables. Although the authors

> make a solid case for their conclusions based upon the data presented,

> use of GEE on this longitudinal dataset may reveal additional

> information and associations not apparent by univariate or multiple

> logistic regression. Nevertheless, it appears that even after years of

> widespread use of MTX, rheumatologists still have few tools to guide

> them in the monitoring of MTX and liver toxicity. Guidelines exist for

> performing liver biopsies based largely on liver function tests11.

> However, it is possible that clinical scenarios exist, such as specific

> clinical and laboratory profiles incorporating variables other than ALT

> and AST, that portend potential hepatic problems. Additionally,

> clinicians have very little guidance for what to do when certain liver

> pathologies appear in terms of adjustment to the therapeutic regimen

> that would still provide some chance of maintaining control of the

> arthritis. Further work on the development of clinical guidelines

> appears to be sorely needed in this area. The Iowa Score, in which

> various abnormalities are weighted for their importance, deserves

> further investigation.

>

> REFERENCES

>

> Search PubMed for:

>

>

>

>

>

> 1. Ortendahl M, Holmes T, Schettler JD, Fries JF. The methotrexate

> therapeutic response in rheumatoid arthritis. J Rheumatol

> 2002;29:2084-91.

>

> 2. Carmichael SJ, Beal J, Day RO, Tett SE. Combination therapy with

> methotrexate and hydroxychloroquine for rheumatoid arthritis increases

> exposure to methotrexate. J Rheumatol 2002;29:2077-83.

>

> 3. Fathi NH, Mitros F, Hoffman J, et al. Longitudinal measurement of

> methotrexate liver concentrations does not correlate with liver damage,

> clinical efficacy or toxicity during a 3.5 year, double-blind study in

> RA. J Rheumatol 2002;29:2092-8.

>

> 4. Hawley DJ, Wolfe F. Sensitivity to change of the health assessment

> questionnaire (HAQ) and other clinical and health status measures in

> rheumatoid arthritis: results of short-term clinical trials and

> observational studies versus long-term observational studies. Arthritis

> Care Res

> 1992;5:130-6. [MEDLINE]

>

> 5. Brunner HI, Kim KN, Ballinger SH, et al. Current medication choices

> in juvenile rheumatoid arthritis II - Update of a survey performed in

> 1993. J Clin Rheumatol 2001;7:295-300.

>

> 6. Wolfe F, Pincus T, O'Dell J. Evaluation and documentation of

> rheumatoid arthritis disease status in the clinic: which variables best

> predict change in therapy. J Rheumatol 2001;28:1712-7. [MEDLINE]

>

> 7. Weinblatt ME, Maier AL, Fraser PA, Coblyn JS. Longterm prospective

> study of methotrexate in rheumatoid arthritis: conclusion after

> 132 months of therapy. J Rheumatol 1998; 25:238-42. [MEDLINE]

>

> 8. O'Dell JR. Methotrexate use in rheumatoid arthritis. Rheum Dis Clin

> North Am 1997;23:779-96. [MEDLINE]

>

> 9. O'Dell JR. Triple therapy with methotrexate, sulfasalazine, and

> hydroxychloroquine in patients with rheumatoid arthritis. Rheum Dis Clin

> North Am 1998;24:465-77. [MEDLINE]

>

> 10. Wolfe F, Rehman Q, Lane NE, Kremer J. Starting a disease modifying

> antirheumatic drug or a biologic agent in rheumatoid arthritis:

> standards of practice for RA treatment. J Rheumatol 2001;28:1704-11.

> [MEDLINE]

>

> 11. Kremer JM, Alarcon GS, Lightfoot RW Jr, et al. Methotrexate for

> rheumatoid arthritis. Suggested guidelines for monitoring liver

> toxicity. American College of Rheumatology. Arthritis Rheum

> 1994;37:316-28. [MEDLINE]

>

>