Hypogammaglobulinaemia after rituximab treatment—incidence and outcomes

[Firestormm]

Oxford Journals Medicine
28 April 2014

Hypogammaglobulinaemia after rituximab treatment—incidence and outcomes

Background:

Rituximab, a chimeric monoclonal antibody against CD20, is increasingly used in the treatment of B-cell lymphomas and autoimmune conditions.

Transient peripheral B-cell depletion is expected following rituximab therapy.

Although initial clinical trials did not show significant hypogammaglobulinaemia, reports of this are now appearing in the literature.

Results:

We identified 19 post-rituximab patients with persistent, symptomatic panhypogammaglobulinaemia. Mean IgG level was 3.42 ± 0.4 g/l (normal range 5.8–16.3 g/l).

All patients had reduced or absent B-cells. Haemophilus Influenzae B, tetanus and Pneumococcal serotype-specific antibody levels were all reduced and patients failed to mount an immune response post-vaccination.

Nearly all of them ultimately required IVIG. The mean interval from the last rituximab dose and need for IVIG was 36 months (range 7 months–7 years). Of note, 23.7% of 114 patients included in the audit had hypogammaglobulinaemia.

Conclusion:

With the increasing use of rituximab, it is important for clinicians treating these patients to be aware of hypogammaglobulinaemia and serious infections occurring even years after completion of treatment and should be actively looked for during follow-up. Referral to clinical immunology services and, if indicated, initiation of IVIG should be considered.

Read more: http://qjmed.oxfordjournals.org/content/early/2014/05/30/qjmed.hcu094

Medscape:
Hypogammaglobulinemia
...The common clinical feature of hypogammaglobulinemia relates to a predisposition toward infections that normally are defended against by antibody responses (including Streptococcus pneumoniae and Haemophilus influenzae infections)...

Wikipedia:
Intravenous immunoglobulin (IVIG) is a blood product administered intravenously. It contains the pooled, polyvalent, IgG antibodies extracted from the plasma of over one thousand blood donors. IVIG's effects last between 2 weeks and 3 months. It is mainly used as treatment in three major disease categories:

• Immune deficiencies such as X-linked agammaglobulinemia, hypogammaglobulinemia (primary immune deficiencies), and acquired compromised immunity conditions (secondary immune deficiencies) featuring low antibody levels.
• Autoimmune diseases, e.g. immune thrombocytopenia, and inflammatory diseases, e.g. Kawasaki disease.
• Acute infections.

 

[daisybell]

How do they know that this is a result of the Rituximab treatment rather than the primary medical condition given that this will have been something affecting the immune system?

 

[N.A.Wright]

How do they know that this is a result of the Rituximab treatment rather than the primary medical condition given that this will have been something affecting the immune system?

Hypogammaglobulinaemia is a rare condition, highest prevalence estimates are around 1:20,000 - http://ccjm.org/content/73/2/133.full.pdf . If one considers Rituximab to be used only in cases of RA - where the the highest prevalence rates are put at 1.5% then one can see that only a small percentage of RA patients could be expected to have pretreatment hypogammaglobulinaemia, this is borne out by research http://www.abstracts2view.com/eular/view.php?nu=EULAR11L_FRI0324 .

In dealing with serious illness, there's rarely such a thing as a free lunch (pharmacetical industry promos excepted) and treatments such as Rituximab should be expected to have downsides, a least for some patients. At this stage we really need be looking at what Rituximab tells us about ME, not whether Rituximab is a cureall for ME. In cases where Rituximab treatment is not a major alleviation of symptoms, an inheritance of hypogammaglobulinaemia could be a pretty grim prospect.

 

[daisybell]

Thanks for that link @N.A.Wright
Looking at the abstract for the article Firestormm posted, I see this was patients referred to Immunology. I don't know if the authors have any way of knowing what percentage of people with RA treated with Rituximab this represents...

Given that the incidence of such immunological problems in people with RA is around 5%, it would be interesting to know by how much Rituximab actually increases the incidence, if it does do so. Presumably if this was a serious risk, the approval of the drug would have been withdrawn?

 

[N.A.Wright]

Thanks for that link @N.A.Wright
Looking at the abstract for the article Firestormm posted, I see this was patients referred to Immunology. I don't know if the authors have any way of knowing what percentage of people with RA treated with Rituximab this represents...

Given that the incidence of such immunological problems in people with RA is around 5%, it would be interesting to know by how much Rituximab actually increases the incidence, if it does do so. Presumably if this was a serious risk, the approval of the drug would have been withdrawn?

Re: the Oxford Journals article - what I read they are saying is that hypogammaglobulinaemia is an emerging problem - and from that I would assume it would be unlikely that there's data on the scale of the problem because no one has been looking for it as a long term issue. It would not have been a question that regulators addressed because it wasn't envisioned as problematic, in any case the consequences of hypogammaglobulinaemia are probably managable in otherwise reasonably healthy people, so it's a side effect to be dealt with rather than a fatal flaw in the treatment.

But ME/CFS isn't RA; of course the incidence of Rituximab promoted hypogammaglobulinaemia may turn out to be low in both RA and ME/CFS but the spectrum of aetiologies covered by the ME/CFS label is likely to mean that the ME/CFS population is far more diverse than the RA population. That could in turn mean that a much smaller proportion of ME/CFS patients could benefit from Rituximab while the consequences of long term hypogammaglobulinaemia in ME/CFS could be less easily managed, in some cases it could be devastating. Rituximab promoted hypogammaglobulinaemia isn't a reason not to explore Rituximab's potential benefits but we should not be blind to potential risks and at the very least be prepared for how to deal with them.

 

[Jonathan Edwards]

Re: the Oxford Journals article - what I read they are saying is that hypogammaglobulinaemia is an emerging problem - and from that I would assume it would be unlikely that there's data on the scale of the problem because no one has been looking for it as a long term issue. It would not have been a question that regulators addressed because it wasn't envisioned as problematic, in any case the consequences of hypogammaglobulinaemia are probably managable in otherwise reasonably healthy people, so it's a side effect to be dealt with rather than a fatal flaw in the treatment.

This is actually a rather oddly written article, especially as I know some of the co-authors. Hypogammaglobulinaemia after rituximab is not 'an emerging problem' really. We have been looking at it in RA for 16 years and know how big a problem it is and have a reasonably good idea how to minimise the risk. Falling gammaglobulin levels were reported by our group even before the major trial in RA. In lymphoma I think the problem has been known about since about 1994. I think the problem is that this article is written from the viewpoint of an immunology service receiving referrals rather than primarily from people giving rituximab on a regular basis. There is no harm in raising awareness of the problem but it is not new.

The great majority of patients treated with rituximab fro RA do not get panhypogammaglobulinaemia. Some get low levels that need monitoring and may require switch to other treatments. A very few get sudden drops in levels even with the first treatment - I think the figure is 1 out of the first 200 patients I am aware of treating. One or two more developed low enough levels to need replacement after repeated treatments which were given in full knowledge that levels were dropping. There is no doubt that it is a real problem that has to be taken seriously, if infrequent. What I think is misleading is to suggest that it is only just now becoming apparent and might be underappreciated.

 

[Marky90]

I want to try IVIG for my ME, is there anything one should check before starting such treatment @Jonathan Edwards? I got one subclass deficiency and borderline IGM levels.

 

[Jonathan Edwards]

I want to try IVIG for my ME, is there anything one should check before starting such treatment @Jonathan Edwards? I got one subclass deficiency and borderline IGM levels.

I cannot think of any specific contraindication to using IVIG at the moment. IVIG is not generally used to top up Igs but for some other reason that we do not understand - it seems that other people's IgG may counteract bad effects of your own or something like that. IVIG does not have IgM in it if I remember rightly, although it may depend on the preparation.

 

[Marky90]

I cannot think of any specific contraindication to using IVIG at the moment. IVIG is not generally used to top up Igs but for some other reason that we do not understand - it seems that other people's IgG may counteract bad effects of your own or something like that. IVIG does not have IgM in it if I remember rightly, although it may depend on the preparation.

Right! Yeah the last thing youre pointing out is why i wanna try it, i dont really care about the low values of IGM or subclass IgG to be honest. There are some cases in Norway who have experienced a "rituximab-effect" from IVIG, but theres also many with no effect. Just goes to show the heterogenous nature of autoimmune disorders i guess..

 

[Marky90]

One case was completely bedbound, and is now actively studying. (albeit still experiencing relapses)

 

[Jonathan Edwards]

Right! Yeah the last thing youre pointing out is why i wanna try it, i dont really care about the low values of IGM or subclass IgG to be honest. There are some cases in Norway who have experienced a "rituximab-effect" from IVIG, but theres also many with no effect. Just goes to show the heterogenous nature of autoimmune disorders i guess..

IVIG has been found to help in trials over quite a long period, it is just that the trials are a bit small. I would be in favour of further IVIG trials. The trouble is that it is fiendishly expensive at the traditional dosage. And nobody knows whether it is safer than rituximab. You can get reactions and there is always the worry of prions or unknown viruses although to be honest the screening procedures these days are pretty tight and I think the Ig purification technique is likely to exclude most things.

We just need a little bit more weight behind the antibody/B cell/autoimmunity angle (probably for a subset) and then there would be some leverage on funding bodies and industry to get their fingers out. It is a slow process but the Norwegians are putting in the work and getting some funding. Other people are trying to contribute, but these things take time.

 

[Marky90]

IVIG has been found to help in trials over quite a long period, it is just that the trials are a bit small. I would be in favour of further IVIG trials. The trouble is that it is fiendishly expensive at the traditional dosage. And nobody knows whether it is safer than rituximab. You can get reactions and there is always the worry of prions or unknown viruses although to be honest the screening procedures these days are pretty tight and I think the Ig purification technique is likely to exclude most things.

We just need a little bit more weight behind the antibody/B cell/autoimmunity angle (probably for a subset) and then there would be some leverage on funding bodies and industry to get their fingers out. It is a slow process but the Norwegians are putting in the work and getting some funding. Other people are trying to contribute, but these things take time.

I agree! I saw a couple studies on pubmed.. Im expecting a lot of activity and more funding, as u say, if the big one in Norway goes the right way. And the new cytokine findings is probably an important spark as well. Personally i cant imagine anything else than the immune system as the main problem maker in this disease. But thats just a gut feeling of course Things are definitely heading the right way, compared to before!

 

[Joolz]

Right! Yeah the last thing youre pointing out is why i wanna try it, i dont really care about the low values of IGM or subclass IgG to be honest. There are some cases in Norway who have experienced a "rituximab-effect" from IVIG, but theres also many with no effect. Just goes to show the heterogenous nature of autoimmune disorders i guess..

I'm equally thrilled about immunoglobulins as you are and really hope there will be a big trial soon, but from what I heard (talked to the Norwegian doctor who treated around 50 of her patients with Gammanorm) no one had an improvement that can be compared to improvement from RTX treatment. Around 50% of those treated with Gammanorm got an effect, for some it was a significant change, which of course should give us hope. For some patients, Gammanorm seemed to work for recurrent infections (not really a surprise I guess), while for others, it worked as an immunomodulant agent. Most of all, it worked for immunological symptoms and pain, but less for fatigue. I have heard one single recovery story which involved treatment with Gammanorm only, but I am not sure how long that recovery lasted.

BTW I'm not aware of any CFS patients in Norway who got IVIG. Most patients got their immunoglobulines through intramuscular injections. Some few got subcutaneous infusions as well ("SCIG").

SCIG is also used by Prof Scheibenbogen, as far as I know (although I'm not sure if she actually prescribes it or only recommends it). The patient who got considerably worse from RTX (Olaf Bodden) got better from immunoglobulines (I think IVIG) some years earlier, if I remember correctly.

There was also one story in the newspaper about a girl who recovered (completely?) from RTX, Valcyte (both from OMI) and later on immunoglobulins.

Those trials from the 1990s are pretty inconclusive. It's time for a big trial, but unfortunately this is not going to happen in Norway. As far as I know, one very dedicated physician really tried to set up a trial, but it was never approved (for reasons I don't know).

 

[Marky90]

I'm equally thrilled about immunoglobulins as you are and really hope there will be a big trial soon, but from what I heard (talked to the Norwegian doctor who treated around 50 of her patients with Gammanorm) no one had an improvement that can be compared to improvement from RTX treatment. Around 50% of those treated with Gammanorm got an effect, for some it was a significant change, which of course should give us hope. For some patients, Gammanorm seemed to work for recurrent infections (not really a surprise I guess), while for others, it worked as an immunomodulant agent. Most of all, it worked for immunological symptoms and pain, but less for fatigue. I have heard one single recovery story which involved treatment with Gammanorm only, but I am not sure how long that recovery lasted.

BTW I'm not aware of any CFS patients in Norway who got IVIG. Most patients got their immunoglobulines through intramuscular injections. Some few got subcutaneous infusions as well ("SCIG").

SCIG is also used by Prof Scheibenbogen, as far as I know (although I'm not sure if she actually prescribes it or only recommends it). The patient who got considerably worse from RTX (Olaf Bodden) got better from immunoglobulines (I think IVIG) some years earlier, if I remember correctly.

There was also one story in the newspaper about a girl who recovered (completely?) from RTX, Valcyte (both from OMI) and later on immunoglobulins.

Those trials from the 1990s are pretty inconclusive. It's time for a big trial, but unfortunately this is not going to happen in Norway. As far as I know, one very dedicated physician really tried to set up a trial, but it was never approved (for reasons I don't know).

Thanks for the info! I was a bit quick on the keyboard triggers. The case i was referring to is the girl from the "sykt mørkt-documentary, who i think went from bedridden in a dark room to quite functional just from Gammanorm. Im not sure in what way she received it. I agree that it probably wont be significant in the majority of cases. but its probably great for the immune system taken together with Rituximab..

 

[Joolz]

Yes, that's the one I was referring to when I wrote "I have heard one single recovery story which involved treatment with Gammanorm only, but I am not sure how long that recovery lasted". She was supposed to give an interview some months ago and unfortunately had to be filmed while lying in bed, that's why I am a bit unsure about her lasting recovery. But I really don't know. Let's hope she just had a bad stomach bug

If I understood correctly, Rituximab might lower your IgG so there wouldn't be any point in giving RTX and Gammanorm simultaneously, right @Jonathan Edwards ?

What would be the difference between s.c. and i.m., if we're talking about the same drug, same concentration, same dosage? Sorry, this is a bit OT.

 

[ElinLunde]

I cannot think of any specific contraindication to using IVIG at the moment. IVIG is not generally used to top up Igs but for some other reason that we do not understand - it seems that other people's IgG may counteract bad effects of your own or something like that. IVIG does not have IgM in it if I remember rightly, although it may depend on the preparation.

What is the status on the role of the neonatal Fc receptor in this? Ten years ago, when I worked in the field (immunology), the FcRn was thought to play a role. Normally it prolongs the half life of antibodies, but if saturated with IVIG antibodies, our own antibodies will get a shorter t1/2. Is the FcRn still thought to contribute to the effect of IVIG in autoimmune patients?

 

[Jonathan Edwards]

If I understood correctly, Rituximab might lower your IgG so there wouldn't be any point in giving RTX and Gammanorm simultaneously, right @Jonathan Edwards ?

What would be the difference between s.c. and i.m., if we're talking about the same drug, same concentration, same dosage? Sorry, this is a bit OT.

The point of using IVIG is not to raise Ig levels but to give you other people's IgG instead of your own. This is a pretty weird concept since we do not know in what way other people's IgG might be any different. In autoimmunity some of your IgG is doing harm but there is no particular reason to think the rest is or that other people's IgG could somehow counteract a problem. But if your own IgG is generally bad for some reason then giving IVIG with rituximab makes perfect sense because you would be reducing your own IgG and have more of other people's. The only problem is that both are very expensive so using the two together is likely to break the bank.

There is no reason for a difference in giving Ig IV or IM in terms of effect that I can think of but IM is pretty hard on the poor old muscle after a while and SC can produce local tissue reactions. I would prefer to have it IV I think.

 

[Jonathan Edwards]

What is the status on the role of the neonatal Fc receptor in this? Ten years ago, when I worked in the field (immunology), the FcRn was thought to play a role. Normally it prolongs the half life of antibodies, but if saturated with IVIG antibodies, our own antibodies will get a shorter t1/2. Is the FcRn still thought to contribute to the effect of IVIG in autoimmune patients?

I am not sure whether FcRn has any special role to play. I was not aware that FcRn inhibited IgG degradation, I thought it was more involved in cross-endothelial transport, but it is not something I have studied in detail. If your own IgG is bad then maybe if IVIG increases the rate of destruction that would help further?

 

[SaraEngland]

Does IgG decline after every RTX infusion? Or does it not reduce IgG for everyone? Do we have any numbers on this? I am considering treatment at OMI, in S.F. Could 6 RTX infusions could lead to a decline IgG? Not sure if one should worry about a slight decrease though. Probably not.

 

[Jonathan Edwards]

Does IgG decline after every RTX infusion? Or does it not reduce IgG for everyone? Do we have any numbers on this? I am considering treatment at OMI, in S.F. Could 6 RTX infusions could lead to a decline IgG? Not sure if one should worry about a slight decrease though. Probably not.

We have very detailed information about this. IgG levels tend to go down only a small amount after a dose of rituximab. If B cells are allowed to come back then IgG comes back to normal. If further doses of rituximab are given the IgG goes down about the same amount each time (not usually to make any difference) but it may go down a bit more as time goes by. If rituximab doses are repeated without allowing B cells to return - which is one way of using it and what the Norwegians have done over a 18 month to 2 year period then IgG will tend to go down more each dose. Even so, for most people it remains within the normal range but maybe 10-20% of people may have to give their B cells a rest after three or more doses.

You say that you are due to get six doses of rituxmab and that puzzles me because I cannot see any particular reason why anyone should recommend six doses - unless this is a pair of induction infusions and maintenance doses at 3-4 month intervals after that to prevent B cell return. More often than that is probably a waste of time since there are no B cells to target.