Methotrexate: new info about a middle-aged drug

[Guest guest]

Oct 16, 2002

Methotrexate: new info about a middle-aged drug

Cincinnati, OH This month's issue of the Journal of Rheumatology contains 3

articles that " contribute substantially to our understanding of methotrexate

in rheumatoid arthritis, " says an accompanying editorial [1], authored by

pediatric rheumatologist Dr H Giannini (University of Cincinnati

College of Medicine, OH).

Methotrexate (MTX) may be old, but it is the drug of first choice, and so

this is " vital new information, " he comments. The papers discuss the concept

of a " therapeutic segment " to monitor responses to MTX, whether liver

concentrations of the drug affect hepatic damage scores, and the effect of

concomitant hydroxychloroquine use on MTX bioavailability.

Rheumatologists too conservative in use of methotrexate

In the first paper, Dr Orthendahl (Stanford University School of

Medicine, Palo Alto) and colleagues describe the concept of the " therapeutic

segment " to describe the response to MTX in rheumatoid arthritis (RA) [2].

This segment begins with the start of 1 treatment and ends with

discontinuation of therapy, addition of an alternative agent, or start of a

new treatment. This is a better indicator of therapeutic response profile

than conventional randomized clinical trials, which have a fixed, relatively

short duration, the researchers say.

Using this approach, they found that rheumatologists are too conservative in

their use of MTX. Treatment of RA with this drug in practice differs

substantially from the common perception by being too little, too late and

too long to therapy change, they note.

Orthendahl et al studied the therapeutic response of MTX for up to 10 years

in a large, prospective RA cohort drawn from 8 data systems in the Arthritis

Rheumatism and Aging Medical Information System (ARAMIS). From a cohort of

4253 patents between 1988 and 1996, 437 patients began MTX therapy. Health

Assessment Questionnaire (HAQ) Disability Index Scores were obtained

prospectively each 6 months.

HAQ Disability Index values began at 1.48 at baseline and declined to a

maximal improvement of 1.23 at 30 months. " This long period to maximum

benefit may have been partly driven by a slow titration upward to an optimal

dosage, " they suggest. After 42 months, disability for this population began

to reprogress and reached 1.39 at 84 months, still below the pretreatment

baseline. Reprogression to baseline was about 8 or more years.

" This suggests that physicians take a more cautious approach to raising

methotrexate dosage than we had anticipated, with multiple clinic visits

required between each upward adjustment. "

" On average, our participating centers' physicians took 3 or more years to

reach what seemed to be an optimal dosage, and these data represent the

clinical decisions of 8 centers, scores of physicians, and hundreds of

patients. It seems likely, therefore, that they represent a reasonable

perspective on practice in the real world, " they comment. " This suggests

that physicians take a more cautious approach to raising methotrexate dosage

than we had anticipated, with multiple clinic visits required between each

upward adjustment. "

" Sawtooth " strategy should be reevaluated

Orthendahl et al explain that the " sawtooth strategy " of early, aggressive,

and consistent use of single disease-modifying antirheumatic drugs (DMARDs)

and DMARD combinations sets a strategy for the management of the entire

disease course. Disability and other outcome variables are regularly

monitored, with progression of disability beyond a predetermined value

triggering a decision to change treatment. DMARD therapy is serially changed

to a new regimen by addition, subtraction, or substitution of agents at each

decision point. Although evidence has been presented supporting the

" sawtooth strategy, " estimation of optimal decision points has not been

addressed, the researchers say.

They suggest physicians implement a modification of the " sawtooth strategy, "

in which the disease is " ratcheted down " by change of MTX therapy at 3 years

or when reprogression has proceeded halfway to baseline, rather than wait

for return to baseline. " It may be preferable to begin a new treatment

earlier, before reprogression has occurred. " They also propose that a more

rapid upward dosing titration and longer maintenance of an optimal or

highest-tolerated dose of MTX is needed.

" 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. "

In his editorial, Giannini says these data " add considerably to our

knowledge of this agent [methotrexate] " and these recommendations are

" valid. " " 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, " he observes. But while the concept of the therapeutic segment

" is a methodological advance of considerable merit, " its general usefulness

in the study of other agents may be limited due to the lack of adequate

patient cohorts followed carefully through time, he comments.

No correlation between MTX liver concentrations and liver damage

The second paper describes a 3.5-year prospective double-blind study of

whether methotrexate liver concentrations correlate with liver damage in 40

RA patients [3]. This study is " unique, " Giannini comments, because it

determined serial liver biopsies (including baseline biopsies), assessed

with 2 scoring systems, and it attempted to correlate liver concentrations

of MTX and its metabolite, methotrexate polyglutamate, with a range of

demographic, disease, and laboratory variables.

Dr Nihal H Fathi (Virginia Mason Research Center, Seattle, Washington) and

colleagues found no correlation between MTX concentrations in the liver and

liver histology, patient demographics, and disease and laboratory variables,

" decreasing the likelihood that methotrexate concentrations in serum would

be useful measures to predict significant hepatotoxicity, " they say. The

researchers also used the study to begin a preliminary examination of a new

histologic index of liver toxicity (the Iowa Score) relative to the Roenigk

grading system.

" 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. "

Giannini observes that " even after widespread use of methotrexate,

rheumatologists still have few tools to guide them in the monitoring of

methotrexate and liver toxicity. " Guidelines exist for performing liver

biopsies based largely on liver function tests, but clinical scenarios may

exist where variables other than ALT and AST warn of potential hepatic

problems, he notes. Also, " 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, " he observes. Further work on the development of

clinical guidelines in this area are " sorely needed, " he concludes, adding

that the Iowa Score in which various abnormalities are weighted for their

importance " deserves further investigation. "

Methotrexate in combination with hydroxychloroquine

And finally, Dr Carmichael (School of Pharmacy, University of

Queensland, Australia) and colleagues provide pharmacological evidence for

the apparent increased bioavailability of methotrexate when prescribed with

hydroxychloroquine [4]. They warn that extra vigilance for MTX adverse

effects during combination therapy with hydroxychloroquine is recommended.

For example, there appears to be a reduction in acute liver toxicity

produced by MTX when given with hydroxychloroquine, but doctors need to be

aware of the increased potential for renal abnormalities because MTX is

excreted through the kidneys, they say.

" 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, "

Giannini says.

Nainggolan

[Guest guest]

Thanks a, for the mtx info. It's hard to know what to do, isn't it?

Here I have been on mtx since January - 10 months. As time marches forward,

it gets harder and harder to remember how bad I used to feel. I have to go

back and read my journal to remember. So, I am doing well, still, I worry

about long term effects. Scary...

Suzanne

[ ] Methotrexate: new info about a middle-aged drug

> Oct 16, 2002

>

> Methotrexate: new info about a middle-aged drug

>

> Cincinnati, OH This month's issue of the Journal of Rheumatology contains

3

> articles that " contribute substantially to our understanding of

methotrexate

> in rheumatoid arthritis, " says an accompanying editorial [1], authored by

> pediatric rheumatologist Dr H Giannini (University of Cincinnati

> College of Medicine, OH).

>

> Methotrexate (MTX) may be old, but it is the drug of first choice, and so

> this is " vital new information, " he comments. The papers discuss the

concept

> of a " therapeutic segment " to monitor responses to MTX, whether liver

> concentrations of the drug affect hepatic damage scores, and the effect of

> concomitant hydroxychloroquine use on MTX bioavailability.

> Rheumatologists too conservative in use of methotrexate

>

> In the first paper, Dr Orthendahl (Stanford University School of

> Medicine, Palo Alto) and colleagues describe the concept of the

" therapeutic

> segment " to describe the response to MTX in rheumatoid arthritis (RA) [2].

> This segment begins with the start of 1 treatment and ends with

> discontinuation of therapy, addition of an alternative agent, or start of

a

> new treatment. This is a better indicator of therapeutic response profile

> than conventional randomized clinical trials, which have a fixed,

relatively

> short duration, the researchers say.

>

> Using this approach, they found that rheumatologists are too conservative

in

> their use of MTX. Treatment of RA with this drug in practice differs

> substantially from the common perception by being too little, too late and

> too long to therapy change, they note.

>

> Orthendahl et al studied the therapeutic response of MTX for up to 10

years

> in a large, prospective RA cohort drawn from 8 data systems in the

Arthritis

> Rheumatism and Aging Medical Information System (ARAMIS). From a cohort of

> 4253 patents between 1988 and 1996, 437 patients began MTX therapy. Health

> Assessment Questionnaire (HAQ) Disability Index Scores were obtained

> prospectively each 6 months.

>

> HAQ Disability Index values began at 1.48 at baseline and declined to a

> maximal improvement of 1.23 at 30 months. " This long period to maximum

> benefit may have been partly driven by a slow titration upward to an

optimal

> dosage, " they suggest. After 42 months, disability for this population

began

> to reprogress and reached 1.39 at 84 months, still below the pretreatment

> baseline. Reprogression to baseline was about 8 or more years.

> " This suggests that physicians take a more cautious approach to raising

> methotrexate dosage than we had anticipated, with multiple clinic visits

> required between each upward adjustment. "

>

> " On average, our participating centers' physicians took 3 or more years to

> reach what seemed to be an optimal dosage, and these data represent the

> clinical decisions of 8 centers, scores of physicians, and hundreds of

> patients. It seems likely, therefore, that they represent a reasonable

> perspective on practice in the real world, " they comment. " This suggests

> that physicians take a more cautious approach to raising methotrexate

dosage

> than we had anticipated, with multiple clinic visits required between each

> upward adjustment. "

> " Sawtooth " strategy should be reevaluated

>

> Orthendahl et al explain that the " sawtooth strategy " of early,

aggressive,

> and consistent use of single disease-modifying antirheumatic drugs

(DMARDs)

> and DMARD combinations sets a strategy for the management of the entire

> disease course. Disability and other outcome variables are regularly

> monitored, with progression of disability beyond a predetermined value

> triggering a decision to change treatment. DMARD therapy is serially

changed

> to a new regimen by addition, subtraction, or substitution of agents at

each

> decision point. Although evidence has been presented supporting the

> " sawtooth strategy, " estimation of optimal decision points has not been

> addressed, the researchers say.

>

> They suggest physicians implement a modification of the " sawtooth

strategy, "

> in which the disease is " ratcheted down " by change of MTX therapy at 3

years

> or when reprogression has proceeded halfway to baseline, rather than wait

> for return to baseline. " It may be preferable to begin a new treatment

> earlier, before reprogression has occurred. " They also propose that a more

> rapid upward dosing titration and longer maintenance of an optimal or

> highest-tolerated dose of MTX is needed.

> " 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. "

>

> In his editorial, Giannini says these data " add considerably to our

> knowledge of this agent [methotrexate] " and these recommendations are

> " valid. " " 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, " he observes. But while the concept of the therapeutic segment

> " is a methodological advance of considerable merit, " its general

usefulness

> in the study of other agents may be limited due to the lack of adequate

> patient cohorts followed carefully through time, he comments.

> No correlation between MTX liver concentrations and liver damage

>

> The second paper describes a 3.5-year prospective double-blind study of

> whether methotrexate liver concentrations correlate with liver damage in

40

> RA patients [3]. This study is " unique, " Giannini comments, because it

> determined serial liver biopsies (including baseline biopsies), assessed

> with 2 scoring systems, and it attempted to correlate liver concentrations

> of MTX and its metabolite, methotrexate polyglutamate, with a range of

> demographic, disease, and laboratory variables.

>

> Dr Nihal H Fathi (Virginia Mason Research Center, Seattle, Washington) and

> colleagues found no correlation between MTX concentrations in the liver

and

> liver histology, patient demographics, and disease and laboratory

variables,

> " decreasing the likelihood that methotrexate concentrations in serum would

> be useful measures to predict significant hepatotoxicity, " they say. The

> researchers also used the study to begin a preliminary examination of a

new

> histologic index of liver toxicity (the Iowa Score) relative to the

Roenigk

> grading system.

> " 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. "

>

> Giannini observes that " even after widespread use of methotrexate,

> rheumatologists still have few tools to guide them in the monitoring of

> methotrexate and liver toxicity. " Guidelines exist for performing liver

> biopsies based largely on liver function tests, but clinical scenarios may

> exist where variables other than ALT and AST warn of potential hepatic

> problems, he notes. Also, " 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, " he observes. Further work on the development of

> clinical guidelines in this area are " sorely needed, " he concludes, adding

> that the Iowa Score in which various abnormalities are weighted for their

> importance " deserves further investigation. "

> Methotrexate in combination with hydroxychloroquine

>

> And finally, Dr Carmichael (School of Pharmacy, University of

> Queensland, Australia) and colleagues provide pharmacological evidence for

> the apparent increased bioavailability of methotrexate when prescribed

with

> hydroxychloroquine [4]. They warn that extra vigilance for MTX adverse

> effects during combination therapy with hydroxychloroquine is recommended.

> For example, there appears to be a reduction in acute liver toxicity

> produced by MTX when given with hydroxychloroquine, but doctors need to be

> aware of the increased potential for renal abnormalities because MTX is

> excreted through the kidneys, they say.

>

> " 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, "

> Giannini says.

>

> Nainggolan

>

>

>

>

[Guest guest]

Suzanne,

At least with mtx you can feel more assured than the newer meds. MTX has

such a long track record that the long term side effects are well known.

Having such a great response to it is really wonderful. I hope you never

feel the way you did before mtx.

All the meds we take are scary, but the damage from the disease is more

scary to me.

a

> Thanks a, for the mtx info. It's hard to know what to do, isn't it?

> Here I have been on mtx since January - 10 months. As time marches forward,

> it gets harder and harder to remember how bad I used to feel. I have to go

> back and read my journal to remember. So, I am doing well, still, I worry

> about long term effects. Scary...

>

> Suzanne

>

[Guest guest]

a,

Me too. And I agree.

Suzanne

Re: [ ] Methotrexate: new info about a middle-aged drug

> Suzanne,

> At least with mtx you can feel more assured than the newer meds. MTX has

> such a long track record that the long term side effects are well known.

> Having such a great response to it is really wonderful. I hope you never

> feel the way you did before mtx.

> All the meds we take are scary, but the damage from the disease is more

> scary to me.

> a

>

>

> > Thanks a, for the mtx info. It's hard to know what to do, isn't it?

> > Here I have been on mtx since January - 10 months. As time marches

forward,

> > it gets harder and harder to remember how bad I used to feel. I have to

go

> > back and read my journal to remember. So, I am doing well, still, I

worry

> > about long term effects. Scary...

> >

> > Suzanne

> >

>

>

>

>

[Guest guest]

Recently . . .

> Thanks a, for the mtx info. It's hard to know what to do, isn't it?

> Here I have been on mtx since January - 10 months. As time marches forward,

> it gets harder and harder to remember how bad I used to feel. I have to go

> back and read my journal to remember. So, I am doing well, still, I worry

> about long term effects. Scary... Suzanne

Hi all,

Yes, thank you a. I am taking MTX orally weekly, 8-2.5 mg tabs along

with 1 mg Folic acid daily, with good results. I have been taking this for

something like a year or so now and am basically waiting for the other shoe

to drop. So far I am happy with the results but am wondering how long it

will last. I'm also taking 20 mg of Celebrex, 2x/day.

Oh, as some of you know I had to start taking insulin awhile back when

first diagnosed when they started me on Prednisone for the

pericarditis. I've been off the Pred for almost one year now and as a

result have been able to reduce the amount of insulin I've been taking. GP

started me on Glucovance in a.m. and eliminated insulin injection at that

time a few months ago. He feels I am controlling my blood sugar pretty

well and so after my latest labs, he has now told me to take another

Glucovance in the p.m. and eliminate the insulin shots altogether. I'm

excited about this and we will see how this goes. I will have to watch

what I eat more, I imagine, as I can't take a little bit more insulin to

compensate for a big appetite or in anticipation of eating something I

shouldn't. lol

Wish me luck!

Kossart - RA, Type-2 Diabetes

Peru, IL, USA