Toward an understanding of drug resistance in RA?

[Guest guest]

Rheumawire

Feb 17, 2004

Toward an understanding of drug resistance in RA?

Los Angeles, CA - Rheumatoid arthritis (RA) patients may develop

resistance to disease-modifying antirheumatic drugs (DMARDs) partly as a

result of the induction of " drug efflux pumps " within cells, 2 new

research papers suggest [1,2].

Reporting their findings in the February 2004 issue of ls of the

Rheumatic Diseases, Dr Joost van de Heijden (Vrije Universiteit Medical

Centre, Amsterdam, the Netherlands) and colleagues say: " This is the

first report to show that long-term exposure of human T cells to the

DMARD sulfasalazine can lead to development of resistance by induction

of a drug efflux pump. "

Development of drug resistance is a common cause of treatment failure

for anticancer drugs or antimalarials, say van de Heijden et al, but

" drug resistance to DMARDs has received little attention in

rheumatology, even though loss of efficacy for several DMARDs, including

sulfasalazine, is well established upon long-term treatment. "

In an accompanying editorial [3], Dr Furst (University of

California, Los Angeles Medical School) says the work is " fascinating "

but that caution is warranted for several reasons, including the fact

that the work was not done in rheumatoid arthritis cells.

Senior author on the 2 Dutch papers, Dr Gerrit Jansen (Vrije

Universiteit Medical Centre)who coauthored a recent review on this

subject in the Scandinavian Journal of Rheumatology [4]told rheumawire:

" Multidrug resistance research in RA is still in its infancy . . . but

we are currently doing experiments in blood cells and synovial cells of

RA patients. "

The Dutch researchers used an immortalized human cancer T lymphocyte in

their studies and showed that sulfasalazine resistance occurred as a

result of induction of a drug efflux pump, ABCG2. The work indicates

that some, but not all, of the effects of sulfasalazine resistance are

due to this efflux pump, they say. The research also provides insight

into strategies that may successfully circumvent sulfasalazine

resistance, including the use of blockers of ABCG2, they note.

And interestingly, when cells became resistant to sulfasalazine, they

also had some increase in resistance to leflunomide and

methotrexateso-called collateral resistance. On the other hand, there

was increased sensitivity to chloroquine and cyclosporin and signs of

hypersensitivity to the glucocorticoid dexamethasone, so these drugs

could perhaps be used instead.

Furst says these findings are intriguing because they may explain the

resistance to DMARDs that occurs and " even supply a rational approach to

the use of some of these drugs together. "

But prudence is necessary, he adds, because the cell type that was being

tested was not a rheumatoid arthritis cell, something the authors

comment on, he notes, " but the problem remains. " For example, it has

been shown that different cell types have different sensitivities;

" thus, one needs to be cautious about applying the results using . . . T

cells directly to rheumatoid arthritis. "

Furst also notes that the active component of sulfasalazine in RA,

sulfapyridine, was not active in this cell system and conferred no

resistance to T cells. " It is hard to understand how the sulfasalazine

resistance can apply in RA without an effect by sulfapyridine. "

Nevertheless, despite these issues, the concept of drug resistance in RA

as a consequence of the induction of drug efflux pumps is " attractive

and is an important direction to follow, " Furst stresses. " Understanding

the appearance of drug resistance and applying the multidrug resistance

gene concept to rheumatology may eventually improve our ability to treat

patients effectively and rationally, " he concludes.

Jansen told rheumawire: " We started off . . . following strategies that

are quite common in cancer research to gain insight in mechanisms of

drug resistance. We have observed similar results with

monocytic/macrophage cell lines as a model system for an immunological

cell type relevant in RA. The advantage of these in vitro systems is

that you can continuously culture them in the presence of an

antirheumatic drug, thereby mimicking prolonged exposure of RA patients

to therapeutic drugs. "

His team is now doing experiments using cells from RA patients, he says,

" and we are in the process of writing and submitting these data. At this

moment I cannot disclose too many details, but we have obtained evidence

for expression of multidrug resistant proteins in blood cells of RA

patients. "

Nainggolan

Sources

1. van der Heijden J, de Jong MC, Dijkmans BA, et al. Acquired

resistance of human T cells to sulfasalazine: stability of the resistant

phenotype and sensitivity to non-related DMARDs. Ann Rheum Dis 2004 Feb;

63(2):131-7.

2. van der Heijden J, de Jong MC, Dijkmans BA, et al. Development of

sulfasalazine resistance in human T cells induces expression of the

multidrug resistance transporter ABCG2 (BCRP) and augmented production

of TNFalpha. Ann Rheum Dis 2004 Feb; 63(2):138-43.

3. Furst DE. Acquired resistance of human T cells to sulfasalazine. Ann

Rheum Dis 2004 Feb; 63(2):115-6.

4. Jansen G, Scheper RJ, Dijkmans BA. Review. Multidrug resistance

proteins in rheumatoid arthritis, role in disease-modifying

anti-rheumatic drug efficacy and inflammatory processes: an overview.

Scand J Rheumatol 2003; 32:325-339.

I'll tell you where to go!

Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org

[Guest guest]

Is this drug resistance only in non-biological DMARDs? I don't see

reference to biologicals. Has anyone had drug resistence with one of

the biologicals? My mom has had RA for over 20 years and always ran

into drug resistance problems. She has been on Enbrel since it was

in the study phase and it isn't working for her as good as it used

to. That could partly be because her joint destruction is so

advanced, but maybe not. Anyone?

Jennie

> Rheumawire

> Feb 17, 2004

>

> Toward an understanding of drug resistance in RA?

>

> Los Angeles, CA - Rheumatoid arthritis (RA) patients may develop

> resistance to disease-modifying antirheumatic drugs (DMARDs) partly

as a

> result of the induction of " drug efflux pumps " within cells, 2 new

> research papers suggest [1,2].

>

> Reporting their findings in the February 2004 issue of ls of the

> Rheumatic Diseases, Dr Joost van de Heijden (Vrije Universiteit

Medical

> Centre, Amsterdam, the Netherlands) and colleagues say: " This is the

> first report to show that long-term exposure of human T cells to the

> DMARD sulfasalazine can lead to development of resistance by

induction

> of a drug efflux pump. "

>

> Development of drug resistance is a common cause of treatment

failure

> for anticancer drugs or antimalarials, say van de Heijden et al, but

> " drug resistance to DMARDs has received little attention in

> rheumatology, even though loss of efficacy for several DMARDs,

including

> sulfasalazine, is well established upon long-term treatment. "

>

> In an accompanying editorial [3], Dr Furst (University of

> California, Los Angeles Medical School) says the work

is " fascinating "

> but that caution is warranted for several reasons, including the

fact

> that the work was not done in rheumatoid arthritis cells.

>

> Senior author on the 2 Dutch papers, Dr Gerrit Jansen (Vrije

> Universiteit Medical Centre)who coauthored a recent review on this

> subject in the Scandinavian Journal of Rheumatology [4]told

rheumawire:

> " Multidrug resistance research in RA is still in its infancy . . .

but

> we are currently doing experiments in blood cells and synovial

cells of

> RA patients. "

>

> The Dutch researchers used an immortalized human cancer T

lymphocyte in

> their studies and showed that sulfasalazine resistance occurred as a

> result of induction of a drug efflux pump, ABCG2. The work indicates

> that some, but not all, of the effects of sulfasalazine resistance

are

> due to this efflux pump, they say. The research also provides

insight

> into strategies that may successfully circumvent sulfasalazine

> resistance, including the use of blockers of ABCG2, they note.

>

> And interestingly, when cells became resistant to sulfasalazine,

they

> also had some increase in resistance to leflunomide and

> methotrexateso-called collateral resistance. On the other hand,

there

> was increased sensitivity to chloroquine and cyclosporin and signs

of

> hypersensitivity to the glucocorticoid dexamethasone, so these drugs

> could perhaps be used instead.

>

> Furst says these findings are intriguing because they may explain

the

> resistance to DMARDs that occurs and " even supply a rational

approach to

> the use of some of these drugs together. "

>

> But prudence is necessary, he adds, because the cell type that was

being

> tested was not a rheumatoid arthritis cell, something the authors

> comment on, he notes, " but the problem remains. " For example, it has

> been shown that different cell types have different sensitivities;

> " thus, one needs to be cautious about applying the results

using . . . T

> cells directly to rheumatoid arthritis. "

>

> Furst also notes that the active component of sulfasalazine in RA,

> sulfapyridine, was not active in this cell system and conferred no

> resistance to T cells. " It is hard to understand how the

sulfasalazine

> resistance can apply in RA without an effect by sulfapyridine. "

>

> Nevertheless, despite these issues, the concept of drug resistance

in RA

> as a consequence of the induction of drug efflux pumps

is " attractive

> and is an important direction to follow, " Furst

stresses. " Understanding

> the appearance of drug resistance and applying the multidrug

resistance

> gene concept to rheumatology may eventually improve our ability to

treat

> patients effectively and rationally, " he concludes.

>

> Jansen told rheumawire: " We started off . . . following strategies

that

> are quite common in cancer research to gain insight in mechanisms of

> drug resistance. We have observed similar results with

> monocytic/macrophage cell lines as a model system for an

immunological

> cell type relevant in RA. The advantage of these in vitro systems is

> that you can continuously culture them in the presence of an

> antirheumatic drug, thereby mimicking prolonged exposure of RA

patients

> to therapeutic drugs. "

>

> His team is now doing experiments using cells from RA patients, he

says,

> " and we are in the process of writing and submitting these data. At

this

> moment I cannot disclose too many details, but we have obtained

evidence

> for expression of multidrug resistant proteins in blood cells of RA

> patients. "

>

> Nainggolan

>

> Sources

>

> 1. van der Heijden J, de Jong MC, Dijkmans BA, et al. Acquired

> resistance of human T cells to sulfasalazine: stability of the

resistant

> phenotype and sensitivity to non-related DMARDs. Ann Rheum Dis 2004

Feb;

> 63(2):131-7.

>

> 2. van der Heijden J, de Jong MC, Dijkmans BA, et al. Development of

> sulfasalazine resistance in human T cells induces expression of the

> multidrug resistance transporter ABCG2 (BCRP) and augmented

production

> of TNFalpha. Ann Rheum Dis 2004 Feb; 63(2):138-43.

>

> 3. Furst DE. Acquired resistance of human T cells to sulfasalazine.

Ann

> Rheum Dis 2004 Feb; 63(2):115-6.

>

> 4. Jansen G, Scheper RJ, Dijkmans BA. Review. Multidrug resistance

> proteins in rheumatoid arthritis, role in disease-modifying

> anti-rheumatic drug efficacy and inflammatory processes: an

overview.

> Scand J Rheumatol 2003; 32:325-339.

>

>

>

>

> I'll tell you where to go!

>

> Mayo Clinic in Rochester

> http://www.mayoclinic.org/rochester

>

> s Hopkins Medicine

> http://www.hopkinsmedicine.org