Re: Rituximab in RA: we should aim for permanent remission

[Guest guest]

Onward, research!

Jefersea

[ ] Rituximab in RA: " we should aim for permanent remission "

Rituximab in RA: " we should aim for permanent remission "

June 16, 2004 17:00 Zosia Chustecka

Rheumawire

Berlin, Germany - Reviewing the clinical data on rituximab in rheumatoid

arthritis (RA) during an oral presentation at last week's EULAR 2004

meeting, Prof (University College, London, UK), who

pioneered this approach, emphasized the successes of treatment so far.

" B-cell depletion has altered our perception of RA, and rituximab can

produce dramatic benefits, " commented, although he cautioned

that " nothing is perfect, and this approach has problems, but the

problems are manageable. "

The drug, already marketed for use in lymphoma (as MabThera® and

Rituxan®, by Genentech/Roche), is currently in phase 3 trials in RA and

is also being studied in lupus. A monoclonal antibody directed against

the CD20 antigen on the surface of B cells, it is administered by

infusion and results in a depletion of B cells. The fact that it works

in RA was at first rather surprising, as historically RA has been

regarded as largely a T-cell-mediated disease.

One of the most striking aspects of this new approach is the

long-lasting response to therapy with a single, short course of

treatment. In his clinical experience with rituximab, says, " The

average duration of benefit has been about 15 months, and the longest

period of improvement so far is 42 months. "

" But if we can get the recipe right, maybe we can get to 3 or 5 years,

maybe even 10 years of benefit, " he said, adding that it may even be

possible to achieve permanent remission. " This was our original aim, to

achieve permanent remission, and this should continue to be our aim, " he

said.

Another striking observation is that rituximab works only in RA patients

who are rheumatoid factor positive (RF+), which leads to suggest

that B cells are involved only in RF+ RA and that RF- RA is a

T-cell-mediated disease like psoriasis.

first reported positive results with rituximab in RA in 2000 and

has since headed a large randomized clinical trial, which is published

this week in the June 17, 2004 issue of the New England Journal of

Medicine [1]. The first results were greeted with much skepticism,

especially as they came from an open-label trial, but the positive

results from this randomized trialwhich have already been presented at

several large meetings, as previously reported by rheumawirehave

transmuted the initial skepticism into a growing but cautious

excitement.

" Rheumatoid arthritis is a seriously debilitating disease. This study

shows that rituximab can alleviate key symptoms of RA such as pain and

can also improve the patients' ability to carry out normal day-to-day

activities that may otherwise prove difficult. These results offer a

promising future for patients with RA, " says Prof Emery (University

of Leeds, UK) in a press release issued by Roche. Emery was 1 of several

UK researchers involved in the trial, which was carried out in

collaboration with 3 centers in Poland.

The trial involved 161 patients with active RA despite methotrexate

treatment, randomized to receive:

Methotrexate alone (>10 mg per week, orally) the control

group.

Rituximab alone (1000 mg by infusion on days 1 and 15).

Rituximab with methotrexate.

Rituximab with cyclophosphamide (750 mg on days 3 and 17).

All of the patients also received a short course of corticosteroids, the

researchers note. This consisted of an intravenous infusion of

methylprednisolone 100 mg before infusions of rituximab or

cyclophosphamide or their placebos, plus oral prednisone on day 2 and

days 4 through 7 and 30 mg on days 8 though 14.

A single short course of rituximab, either alone or in a combination,

resulted in a significant improvement in disease symptoms. In all the

groups treated with rituximab, a significantly higher proportion of

patients had a 20% improvement in disease symptoms according to ACR

criteria (65%-76% vs 38%, p<0.025) or EULAR responses (83%-85%vs 50%,

p<0.004). In the group receiving rituximab with methotrexate, all ACR

responses were maintained at week 48.

The groups receiving rituximab had a profound and prolonged depletion of

peripheral blood B cells, which raises the question of whether these

patients may be more susceptible to infection, the researchers comment.

However, at weeks 24 and 48, the overall incidence of infection was

similar in the control group and the rituximab groups, with no obvious

pattern in types of causative organisms. At 24 weeks, serious infections

occurred in 1 patient (2.5%) in the control group and in 4 patients

(3.3%) in the rituximab groups, and a further 2 serious infections

occurred in the extended observation period to 48 weeks. One patient in

the rituximab monotherapy group, who had a concomitant cardiac

condition, died from fatal bronchopneumonia. " This incidence of

infection will require careful monitoring in future studies, as will

long-term effects on acquired immunity, " the researchers comment.

This was a formal phase 2 study, sponsored by Roche, intended to be used

for the licensing of a new indication for the drug, explained to

rheumawire in an interview. He was the initiator of this trial but " had

a relatively hands-off involvement because the study was designed to

confirm my own preliminary findings. " He is concerned that the results

may be misinterpreted as suggesting that rituximab should be used

together with methotrexate, but he says: " To me, it's completely

illogical, because the 2 treatments are unrelated, they're not doing the

same thing. " Also, most of the patients like rituximab because there

aren't regular medications, whereas if methotrexate is given as well,

" you spoil that benefit . . . and the patients get perfectly adequate

benefit from rituximab without methotrexate. "

is continuing with his own clinical studies and so far has

treated 40 patients over the past 5 years. " Some of these data have been

published in review articles, and we're intending to publish another

bank of data soon, " he says. (There are details on the experience with

38 patients in 's abstracts for the EULAR meeting [2, 3]. He

reports that overall about 80% of seropositive patients may experience

continuing control of the disease, but seronegative RA appears to be

unresponsive.)

uses rituximab alone, with some steroid cover for the infusion

only. " For the time being, it's a sensible way of using it, " he says,

and the patients are happy that they have only a short course of

treatment and then have a year or more free from any medication. " But

the real issue is, after 3 or 4 years, when the patients have had 3

courses of treatment, the immunoglobulin levels (IgM) levels fall, and

they can fall very low. Also, the levels of immunoglobulins and B cells

as well don't return to baseline. We haven't got any clear evidence that

it's caused any problems, but, logically, if these levels fell any

lower, there could be problems in the long term; the patients could

become immunodeficient and at risk of infections. "

" I think the difficulty is that, although we can use rituximab for those

3 to 4 years, we may not be able to use it for much longer, so I think

we may have to change how we're doing it. . . . Either we need to give

them 1 shot and do it right, or we may need to change the strategy and

give a course of treatment that may be rather longer but that would

cause the disease to disappear rather more gradually, " he says. It may

also be useful to explore other agentsthere are several new drugs now

approaching clinical trials, and while some are also B-cell depleters,

others are targeting the B cells in other ways.

So far, there are no data on the effect of rituximab on radiographic

progression of RAthe number of patients so far have been too smallbut

this data should come out of phase 3, says. " I would expect it

to. . . . If you get rid of the disease, you get rid of the x-ray

progression, it's as simple as that. " But is it important? " Well, it's

important for the regulatory authorities and also for rather obsessive

academic rheumatologists who go around giving lectures at meetings, but

for general rheumatologists who want to help their patients get out of

bed in the morning, it doesn't make any difference at al. . . . If you

have patients who can't get out of bed in the morning, and you give them

rituximab and they can go to work, you're not really interested in

whether or not their x-rays have changed. "

Disability comes from damage to the soft tissue, and x-rays are very

poor predictor of disability, he maintains. " There's a lot of rubbish

talked about x-ray progression and in another 2 or 3 years, people will

realize this, but at the moment the regulatory authorities have got a

bee in their bonnet about it, " he says, adding that he considers it to

be " of secondary importance. "

As rituximab is already marketed, it can already be used off label for

rheumatoid arthritis. " To any rheumatologists who want to use it off

label, I would say first of all make sure they understand why they are

considering using it, and if they do that, then they will know whether

they should use it or not, " says. " Because the biological

mechanism is so completely different from anything else, the way you use

it is completely different from anything else, and a doctor who starts

using it without understanding this can get into deep trouble. "

" You have to understand what rituximab is doing to the B cells, and what

the significance of that is, and sadly, 99% of rheumatologists don't

understand that and some may be using it in an inappropriate way, " he

says. Even experts who have written editorials and reviews about this

therapeutic approach " still haven't understood what we did in the first

place, and so they are promoting the wrong explanationthey seem to think

that you take away the B cells to quiet down the T cells, and that's

nonsenseyou take way the B cells because the B cells cause the disease,

it's very simple, " he says.

" We published that 5 to 6 years ago in Immunology [4], and most people

haven't got around to reading that, " he adds. " That's the key to why we

did it and why it worksthat's the thing to go back to, " insists.

" Most of the editorials and reviews that have been written about our

work have missed the point completely. "

Sources

JCW, Szczepanski L, Szechinski J, et al.

Efficacy of B-cell-targeted therapy with rituximab in patients with

rheumatoid arthritis. N Engl J Med 2004; 350:2572-2581.

Nahir A, J, Pavelka K. Selective depletion of

cd20+ b cells with a single course of rituximab: pronounced and

sustained benefits for up to 48 weeks in patients with rheumatoid

arthritis. Presented at: EULAR 2004; Berlin, Germany; June 9-12, 2004.

Abstract FRI0131

Nahir A, J, Pavelka K. Selective depletion of

cd20+ b cells with a single course of rituximab: pronounced and

sustained benefits for up to 48 weeks in patients with rheumatoid

arthritis. Presented at: EULAR 2004; Berlin, Germany; June 9-12, 2004.

Abstract FRI0131.

JC, Cambridge G, Abrahams VM. Do

self-perpetuating B-lymphocytes drive human autoimmune disease?

Immunology 1999; 97:188-196.

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]

Hi ,

I was really happy to read this, because it's pretty discouraging when all that

is experienced is pain and uncertainty, to say the least. As with all

experiments, there will be trials and errors, but I think they're perhaps on the

right track.

, thank you for sharing this info with us.

Jefersea

[ ] Rituximab in RA: " we should aim for permanent

remission "

Rituximab in RA: " we should aim for permanent remission "

June 16, 2004 17:00 Zosia Chustecka

Rheumawire

Berlin, Germany - Reviewing the clinical data on rituximab in rheumatoid

arthritis (RA) during an oral presentation at last week's EULAR 2004

meeting, Prof (University College, London, UK), who

pioneered this approach, emphasized the successes of treatment so far.

" B-cell depletion has altered our perception of RA, and rituximab can

produce dramatic benefits, " commented, although he cautioned

that " nothing is perfect, and this approach has problems, but the

problems are manageable. "

The drug, already marketed for use in lymphoma (as MabThera® and

Rituxan®, by Genentech/Roche), is currently in phase 3 trials in RA and

is also being studied in lupus. A monoclonal antibody directed against

the CD20 antigen on the surface of B cells, it is administered by

infusion and results in a depletion of B cells. The fact that it works

in RA was at first rather surprising, as historically RA has been

regarded as largely a T-cell-mediated disease.

One of the most striking aspects of this new approach is the

long-lasting response to therapy with a single, short course of

treatment. In his clinical experience with rituximab, says, " The

average duration of benefit has been about 15 months, and the longest

period of improvement so far is 42 months. "

" But if we can get the recipe right, maybe we can get to 3 or 5 years,

maybe even 10 years of benefit, " he said, adding that it may even be

possible to achieve permanent remission. " This was our original aim, to

achieve permanent remission, and this should continue to be our aim, " he

said.

Another striking observation is that rituximab works only in RA patients

who are rheumatoid factor positive (RF+), which leads to suggest

that B cells are involved only in RF+ RA and that RF- RA is a

T-cell-mediated disease like psoriasis.

first reported positive results with rituximab in RA in 2000 and

has since headed a large randomized clinical trial, which is published

this week in the June 17, 2004 issue of the New England Journal of

Medicine [1]. The first results were greeted with much skepticism,

especially as they came from an open-label trial, but the positive

results from this randomized trialwhich have already been presented at

several large meetings, as previously reported by rheumawirehave

transmuted the initial skepticism into a growing but cautious

excitement.

" Rheumatoid arthritis is a seriously debilitating disease. This study

shows that rituximab can alleviate key symptoms of RA such as pain and

can also improve the patients' ability to carry out normal day-to-day

activities that may otherwise prove difficult. These results offer a

promising future for patients with RA, " says Prof Emery (University

of Leeds, UK) in a press release issued by Roche. Emery was 1 of several

UK researchers involved in the trial, which was carried out in

collaboration with 3 centers in Poland.

The trial involved 161 patients with active RA despite methotrexate

treatment, randomized to receive:

Methotrexate alone (>10 mg per week, orally) the control

group.

Rituximab alone (1000 mg by infusion on days 1 and 15).

Rituximab with methotrexate.

Rituximab with cyclophosphamide (750 mg on days 3 and 17).

All of the patients also received a short course of corticosteroids, the

researchers note. This consisted of an intravenous infusion of

methylprednisolone 100 mg before infusions of rituximab or

cyclophosphamide or their placebos, plus oral prednisone on day 2 and

days 4 through 7 and 30 mg on days 8 though 14.

A single short course of rituximab, either alone or in a combination,

resulted in a significant improvement in disease symptoms. In all the

groups treated with rituximab, a significantly higher proportion of

patients had a 20% improvement in disease symptoms according to ACR

criteria (65%-76% vs 38%, p<0.025) or EULAR responses (83%-85%vs 50%,

p<0.004). In the group receiving rituximab with methotrexate, all ACR

responses were maintained at week 48.

The groups receiving rituximab had a profound and prolonged depletion of

peripheral blood B cells, which raises the question of whether these

patients may be more susceptible to infection, the researchers comment.

However, at weeks 24 and 48, the overall incidence of infection was

similar in the control group and the rituximab groups, with no obvious

pattern in types of causative organisms. At 24 weeks, serious infections

occurred in 1 patient (2.5%) in the control group and in 4 patients

(3.3%) in the rituximab groups, and a further 2 serious infections

occurred in the extended observation period to 48 weeks. One patient in

the rituximab monotherapy group, who had a concomitant cardiac

condition, died from fatal bronchopneumonia. " This incidence of

infection will require careful monitoring in future studies, as will

long-term effects on acquired immunity, " the researchers comment.

This was a formal phase 2 study, sponsored by Roche, intended to be used

for the licensing of a new indication for the drug, explained to

rheumawire in an interview. He was the initiator of this trial but " had

a relatively hands-off involvement because the study was designed to

confirm my own preliminary findings. " He is concerned that the results

may be misinterpreted as suggesting that rituximab should be used

together with methotrexate, but he says: " To me, it's completely

illogical, because the 2 treatments are unrelated, they're not doing the

same thing. " Also, most of the patients like rituximab because there

aren't regular medications, whereas if methotrexate is given as well,

" you spoil that benefit . . . and the patients get perfectly adequate

benefit from rituximab without methotrexate. "

is continuing with his own clinical studies and so far has

treated 40 patients over the past 5 years. " Some of these data have been

published in review articles, and we're intending to publish another

bank of data soon, " he says. (There are details on the experience with

38 patients in 's abstracts for the EULAR meeting [2, 3]. He

reports that overall about 80% of seropositive patients may experience

continuing control of the disease, but seronegative RA appears to be

unresponsive.)

uses rituximab alone, with some steroid cover for the infusion

only. " For the time being, it's a sensible way of using it, " he says,

and the patients are happy that they have only a short course of

treatment and then have a year or more free from any medication. " But

the real issue is, after 3 or 4 years, when the patients have had 3

courses of treatment, the immunoglobulin levels (IgM) levels fall, and

they can fall very low. Also, the levels of immunoglobulins and B cells

as well don't return to baseline. We haven't got any clear evidence that

it's caused any problems, but, logically, if these levels fell any

lower, there could be problems in the long term; the patients could

become immunodeficient and at risk of infections. "

" I think the difficulty is that, although we can use rituximab for those

3 to 4 years, we may not be able to use it for much longer, so I think

we may have to change how we're doing it. . . . Either we need to give

them 1 shot and do it right, or we may need to change the strategy and

give a course of treatment that may be rather longer but that would

cause the disease to disappear rather more gradually, " he says. It may

also be useful to explore other agentsthere are several new drugs now

approaching clinical trials, and while some are also B-cell depleters,

others are targeting the B cells in other ways.

So far, there are no data on the effect of rituximab on radiographic

progression of RAthe number of patients so far have been too smallbut

this data should come out of phase 3, says. " I would expect it

to. . . . If you get rid of the disease, you get rid of the x-ray

progression, it's as simple as that. " But is it important? " Well, it's

important for the regulatory authorities and also for rather obsessive

academic rheumatologists who go around giving lectures at meetings, but

for general rheumatologists who want to help their patients get out of

bed in the morning, it doesn't make any difference at al. . . . If you

have patients who can't get out of bed in the morning, and you give them

rituximab and they can go to work, you're not really interested in

whether or not their x-rays have changed. "

Disability comes from damage to the soft tissue, and x-rays are very

poor predictor of disability, he maintains. " There's a lot of rubbish

talked about x-ray progression and in another 2 or 3 years, people will

realize this, but at the moment the regulatory authorities have got a

bee in their bonnet about it, " he says, adding that he considers it to

be " of secondary importance. "

As rituximab is already marketed, it can already be used off label for

rheumatoid arthritis. " To any rheumatologists who want to use it off

label, I would say first of all make sure they understand why they are

considering using it, and if they do that, then they will know whether

they should use it or not, " says. " Because the biological

mechanism is so completely different from anything else, the way you use

it is completely different from anything else, and a doctor who starts

using it without understanding this can get into deep trouble. "

" You have to understand what rituximab is doing to the B cells, and what

the significance of that is, and sadly, 99% of rheumatologists don't

understand that and some may be using it in an inappropriate way, " he

says. Even experts who have written editorials and reviews about this

therapeutic approach " still haven't understood what we did in the first

place, and so they are promoting the wrong explanationthey seem to think

that you take away the B cells to quiet down the T cells, and that's

nonsenseyou take way the B cells because the B cells cause the disease,

it's very simple, " he says.

" We published that 5 to 6 years ago in Immunology [4], and most people

haven't got around to reading that, " he adds. " That's the key to why we

did it and why it worksthat's the thing to go back to, " insists.

" Most of the editorials and reviews that have been written about our

work have missed the point completely. "

Sources

JCW, Szczepanski L, Szechinski J, et al.

Efficacy of B-cell-targeted therapy with rituximab in patients with

rheumatoid arthritis. N Engl J Med 2004; 350:2572-2581.

Nahir A, J, Pavelka K. Selective depletion of

cd20+ b cells with a single course of rituximab: pronounced and

sustained benefits for up to 48 weeks in patients with rheumatoid

arthritis. Presented at: EULAR 2004; Berlin, Germany; June 9-12, 2004.

Abstract FRI0131

Nahir A, J, Pavelka K. Selective depletion of

cd20+ b cells with a single course of rituximab: pronounced and

sustained benefits for up to 48 weeks in patients with rheumatoid

arthritis. Presented at: EULAR 2004; Berlin, Germany; June 9-12, 2004.

Abstract FRI0131.

JC, Cambridge G, Abrahams VM. Do

self-perpetuating B-lymphocytes drive human autoimmune disease?

Immunology 1999; 97:188-196.

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]

You're very welcome, Jefersea. This is an era full of promise for better

RA therapies.

Research and trials of rituximab have been going on for several years;

it's already approved for use in lymphoma. Even if it isn't the perfect

therapy for RA, it has shown remarkable results for some. Perhaps more

importantly, through the study of rituximab, much has been learned about

the nature of RA itself.

I'll tell you where to go!

Mayo Clinic in Rochester

http://www.mayoclinic.org/rochester

s Hopkins Medicine

http://www.hopkinsmedicine.org

[ ] Rituximab in RA: " we should aim for permanent

remission "

Rituximab in RA: " we should aim for permanent remission "

June 16, 2004 17:00 Zosia Chustecka

Rheumawire

Berlin, Germany - Reviewing the clinical data on rituximab in

rheumatoid

arthritis (RA) during an oral presentation at last week's EULAR 2004

meeting, Prof (University College, London, UK), who

pioneered this approach, emphasized the successes of treatment so

far.

" B-cell depletion has altered our perception of RA, and rituximab

can

produce dramatic benefits, " commented, although he cautioned

that " nothing is perfect, and this approach has problems, but the

problems are manageable. "

The drug, already marketed for use in lymphoma (as MabThera® and

Rituxan®, by Genentech/Roche), is currently in phase 3 trials in RA

and

is also being studied in lupus. A monoclonal antibody directed

against

the CD20 antigen on the surface of B cells, it is administered by

infusion and results in a depletion of B cells. The fact that it

works

in RA was at first rather surprising, as historically RA has been

regarded as largely a T-cell-mediated disease.

One of the most striking aspects of this new approach is the

long-lasting response to therapy with a single, short course of

treatment. In his clinical experience with rituximab, says,

" The

average duration of benefit has been about 15 months, and the

longest

period of improvement so far is 42 months. "

" But if we can get the recipe right, maybe we can get to 3 or 5

years,

maybe even 10 years of benefit, " he said, adding that it may even be

possible to achieve permanent remission. " This was our original aim,

to

achieve permanent remission, and this should continue to be our

aim, " he

said.

Another striking observation is that rituximab works only in RA

patients

who are rheumatoid factor positive (RF+), which leads to

suggest

that B cells are involved only in RF+ RA and that RF- RA is a

T-cell-mediated disease like psoriasis.

first reported positive results with rituximab in RA in 2000

and

has since headed a large randomized clinical trial, which is

published

this week in the June 17, 2004 issue of the New England Journal of

Medicine [1]. The first results were greeted with much skepticism,

especially as they came from an open-label trial, but the positive

results from this randomized trialwhich have already been presented

at

several large meetings, as previously reported by rheumawirehave

transmuted the initial skepticism into a growing but cautious

excitement.

" Rheumatoid arthritis is a seriously debilitating disease. This

study

shows that rituximab can alleviate key symptoms of RA such as pain

and

can also improve the patients' ability to carry out normal

day-to-day

activities that may otherwise prove difficult. These results offer a

promising future for patients with RA, " says Prof Emery

(University

of Leeds, UK) in a press release issued by Roche. Emery was 1 of

several

UK researchers involved in the trial, which was carried out in

collaboration with 3 centers in Poland.

The trial involved 161 patients with active RA despite methotrexate

treatment, randomized to receive:

Methotrexate alone (>10 mg per week, orally) the control

group.

Rituximab alone (1000 mg by infusion on days 1 and 15).

Rituximab with methotrexate.

Rituximab with cyclophosphamide (750 mg on days 3 and

17).

All of the patients also received a short course of corticosteroids,

the

researchers note. This consisted of an intravenous infusion of

methylprednisolone 100 mg before infusions of rituximab or

cyclophosphamide or their placebos, plus oral prednisone on day 2

and

days 4 through 7 and 30 mg on days 8 though 14.

A single short course of rituximab, either alone or in a

combination,

resulted in a significant improvement in disease symptoms. In all

the

groups treated with rituximab, a significantly higher proportion of

patients had a 20% improvement in disease symptoms according to ACR

criteria (65%-76% vs 38%, p<0.025) or EULAR responses (83%-85%vs

50%,

p<0.004). In the group receiving rituximab with methotrexate, all

ACR

responses were maintained at week 48.

The groups receiving rituximab had a profound and prolonged

depletion of

peripheral blood B cells, which raises the question of whether these

patients may be more susceptible to infection, the researchers

comment.

However, at weeks 24 and 48, the overall incidence of infection was

similar in the control group and the rituximab groups, with no

obvious

pattern in types of causative organisms. At 24 weeks, serious

infections

occurred in 1 patient (2.5%) in the control group and in 4 patients

(3.3%) in the rituximab groups, and a further 2 serious infections

occurred in the extended observation period to 48 weeks. One patient

in

the rituximab monotherapy group, who had a concomitant cardiac

condition, died from fatal bronchopneumonia. " This incidence of

infection will require careful monitoring in future studies, as will

long-term effects on acquired immunity, " the researchers comment.

This was a formal phase 2 study, sponsored by Roche, intended to be

used

for the licensing of a new indication for the drug,

explained to

rheumawire in an interview. He was the initiator of this trial but

" had

a relatively hands-off involvement because the study was designed to

confirm my own preliminary findings. " He is concerned that the

results

may be misinterpreted as suggesting that rituximab should be used

together with methotrexate, but he says: " To me, it's completely

illogical, because the 2 treatments are unrelated, they're not doing

the

same thing. " Also, most of the patients like rituximab because there

aren't regular medications, whereas if methotrexate is given as

well,

" you spoil that benefit . . . and the patients get perfectly

adequate

benefit from rituximab without methotrexate. "

is continuing with his own clinical studies and so far has

treated 40 patients over the past 5 years. " Some of these data have

been

published in review articles, and we're intending to publish another

bank of data soon, " he says. (There are details on the experience

with

38 patients in 's abstracts for the EULAR meeting [2, 3]. He

reports that overall about 80% of seropositive patients may

experience

continuing control of the disease, but seronegative RA appears to be

unresponsive.)

uses rituximab alone, with some steroid cover for the

infusion

only. " For the time being, it's a sensible way of using it, " he

says,

and the patients are happy that they have only a short course of

treatment and then have a year or more free from any medication.

" But

the real issue is, after 3 or 4 years, when the patients have had 3

courses of treatment, the immunoglobulin levels (IgM) levels fall,

and

they can fall very low. Also, the levels of immunoglobulins and B

cells

as well don't return to baseline. We haven't got any clear evidence

that

it's caused any problems, but, logically, if these levels fell any

lower, there could be problems in the long term; the patients could

become immunodeficient and at risk of infections. "

" I think the difficulty is that, although we can use rituximab for

those

3 to 4 years, we may not be able to use it for much longer, so I

think

we may have to change how we're doing it. . . . Either we need to

give

them 1 shot and do it right, or we may need to change the strategy

and

give a course of treatment that may be rather longer but that would

cause the disease to disappear rather more gradually, " he says. It

may

also be useful to explore other agentsthere are several new drugs

now

approaching clinical trials, and while some are also B-cell

depleters,

others are targeting the B cells in other ways.

So far, there are no data on the effect of rituximab on radiographic

progression of RAthe number of patients so far have been too

smallbut

this data should come out of phase 3, says. " I would expect

it

to. . . . If you get rid of the disease, you get rid of the x-ray

progression, it's as simple as that. " But is it important? " Well,

it's

important for the regulatory authorities and also for rather

obsessive

academic rheumatologists who go around giving lectures at meetings,

but

for general rheumatologists who want to help their patients get out

of

bed in the morning, it doesn't make any difference at al. . . . If

you

have patients who can't get out of bed in the morning, and you give

them

rituximab and they can go to work, you're not really interested in

whether or not their x-rays have changed. "

Disability comes from damage to the soft tissue, and x-rays are very

poor predictor of disability, he maintains. " There's a lot of

rubbish

talked about x-ray progression and in another 2 or 3 years, people

will

realize this, but at the moment the regulatory authorities have got

a

bee in their bonnet about it, " he says, adding that he considers it

to

be " of secondary importance. "

As rituximab is already marketed, it can already be used off label

for

rheumatoid arthritis. " To any rheumatologists who want to use it off

label, I would say first of all make sure they understand why they

are

considering using it, and if they do that, then they will know

whether

they should use it or not, " says. " Because the biological

mechanism is so completely different from anything else, the way you

use

it is completely different from anything else, and a doctor who

starts

using it without understanding this can get into deep trouble. "

" You have to understand what rituximab is doing to the B cells, and

what

the significance of that is, and sadly, 99% of rheumatologists don't

understand that and some may be using it in an inappropriate way, "

he

says. Even experts who have written editorials and reviews about

this

therapeutic approach " still haven't understood what we did in the

first

place, and so they are promoting the wrong explanationthey seem to

think

that you take away the B cells to quiet down the T cells, and that's

nonsenseyou take way the B cells because the B cells cause the

disease,

it's very simple, " he says.

" We published that 5 to 6 years ago in Immunology [4], and most

people

haven't got around to reading that, " he adds. " That's the key to why

we

did it and why it worksthat's the thing to go back to, "

insists.

" Most of the editorials and reviews that have been written about our

work have missed the point completely. "

Sources

JCW, Szczepanski L, Szechinski J, et al.

Efficacy of B-cell-targeted therapy with rituximab in patients with

rheumatoid arthritis. N Engl J Med 2004; 350:2572-2581.

Nahir A, J, Pavelka K. Selective depletion of

cd20+ b cells with a single course of rituximab: pronounced and

sustained benefits for up to 48 weeks in patients with rheumatoid

arthritis. Presented at: EULAR 2004; Berlin, Germany; June 9-12,

2004.

Abstract FRI0131

Nahir A, J, Pavelka K. Selective depletion of

cd20+ b cells with a single course of rituximab: pronounced and

sustained benefits for up to 48 weeks in patients with rheumatoid

arthritis. Presented at: EULAR 2004; Berlin, Germany; June 9-12,

2004.

Abstract FRI0131.

JC, Cambridge G, Abrahams VM. Do

self-perpetuating B-lymphocytes drive human autoimmune disease?

Immunology 1999; 97:188-196.