Identifying Hypersensitive Reactions To Rituxan

Sandi, I was doing my normal thing - reading old PDSA posts.
Came across user ' summerrain ' (Carla). What a read. Sounded a lot like what you have described about your Rituxan experience. Thinking about similarities, a few things came to mind.

First the obvious thing. Both of you had strong responses to steroids.
The second thing was the preexisting APS. Was that true with you too?
The third thing was the time line. Carla (like you?) was not suspected, through extensive testing, of Lupus before any ITP treatment. Then in short order, she has Lupus and a major flair from Rituxan. So that makes me wonder. Would it make any sense that the lengthy steroid treatment for ITP, which lowers one's immune system, allowed Lupus to become active during that time? Recall that Carla's doctor wanted her to take Rituxan (or NPlate) because she had been on steroids for so long.

Hal, at the time when I had Rituxan, Lupus wasn't even a consideration. I'd had an antibody test in the late 80's and a doctor that I saw said that one day I might end up with a connective tissue disorder, like Lupus. At the time, I shelved the thought because I wasn't going to worry about something that might never happen. I was a healthy woman in my 20's. Up until the time I had Rituxan, that was the only mention of Lupus that I'd ever had. I didn't have any symptoms and no other labs indicated anything.

When a person has a serum sickness reaction to Rituxan, it is caused by a hypersensitivity to the mouse gene that is used in making the serum. I don't think the steroids had anything to do with it. It's basically a delayed allergic reaction. I also didn't know about the APS antibodies at that time, although I may have had them then. I found out about that after I started seeing a Rheumatologist and those antibodies were part of the criteria for the Lupus diagnosis.

I think that I had a predisposition for Lupus and my reaction to Rituxan was the trigger. Symptoms began immediately after serum sickness occurred and I was never the same again.

Ha, you prompted me to start poking around about this subject. We haven't had anyone with serum sickness lately...there used to be one after the other for a while.
"It is important to recognize RISS clinically, as it may mimic exacerbation of various rheumatologic conditions. Although RISS is typically self-limited, further infusions of rituximab should be avoided, as it may provoke more severe symptoms."
www.semarthritisrheumatism.com/article/S0049-0172(15)00180-8/fulltext

It was unreal how many times I saw doctors misdiagnose serum sickness as a disease flare or a virus, and insist on continuing the rest of the infusions. Serum sickness has classic symptoms and the timing of it is very telling. Further reactions can result in death, but they felt it was SO important to get all four infusions in. It was not. When the risk of death from treatment is greater than the risk of death from the disease itself, you stop the treatment. That is a no-brainer. One woman had serum sickness twice but insisted that she would continue to get the infusions as needed. I couldn't talk her out of it and she disappeared from the Forum.

Ok. So I guess positive ITP steroid response and maybe APS could identify a trigger risk. Probably all there is...

Sounds like I should come across more of these reactions. Blah. I was expecting it to be so rare that I wouldn't find anymore cases.

I actually think the trigger is simply having an allergic reaction to the murine (mouse) cells due to a sensitive immune system. Some people get serum sickness from penicillin. There are quite a few drugs and vaccines that can cause it.

Hi Hal,

I've had serum sickness twice from Rituxan, although like Sandi mentioned, both times it was misdiagnosed as a "lupus flare".

I was diagnosed with Lupus prior to my ITP diagnosis - Lupus at 17 years old and ITP/TTP at 20 years old. Back then, I treated solely with Prednisone for ITP and plasmapheresis for TTP. After a 15 year remission, my platelets crashed again 5 years ago. Prednisone alone did not work, so I had Rituxan. Developed absolutely horrific joint pain and rash post infusion. My doctor thought it was a "lupus flare" from the Rituxan and treated me with a Dex Pulse. I finished the remaining 2 infusions with no issues.

A year later, my platelets again crashed, even lower this time. Started a Dex Pulse, IVIG, and Rituxan. Again, after the 2nd infusion, I developed the same reaction, most specifically, the worst joint pain I've ever had with an inability to move. Started another Dex Pulse which resolved the symptoms and I went for infusion 3. This time, half way through the infusion, I developed hives and my throat began to swell. Ended up needing IV cortisone and Solu-Medrol to stop the reaction. Needless to say, I did not finish the 3rd infusion nor did I have the 4th.

I now list Rituxan as a medication I am allergic to, and under no circumstances will I have that treatment ever again. So far, my platelets have been stable these last 3 years, so I've not needed to treat again. When I do, we will have to try something else. Rituxan is not an option for me.

Interestingly, I had wondered whether the fact that I have Lupus made me more susceptible to serum sickness. However, I discussed recently with my rheumatologist who told me he treats many of his Lupus patients with Rituxan - for Lupus induced nephritis, joint pain, etc. So, that makes me think there is no correlation with patients who have Lupus developing serum sickness post Rituxan.

Thanks,
Lauren

Hey Lauren - nice to see you!
It's odd but I have seen a correlation here between people who have had serum sickness and Lupus. The only people who have ever had serum sickness here have either had Lupus at the time or they developed it shortly thereafter. A few had symptoms and red flag labs prior to serum sickness but no Lupus diagnosis yet. In nearly every case, serum sickness was misdiagnosed which led all of us to have more infusions which resulted in even worse reactions the second time. I've read that it can eventually lead to death due to anaphylaxis which is what you came very close to the third time. Maybe your Rheumatologist keeps misdiagnosing his serum sickness patients with Lupus flares and that's why he doesn't see it? I don't know....it's frustrating that these doctors use these drugs but do not recognize serious side effects. As you know, I fell through the cracks too. I left the ER the first time being told it was a virus and got no medication for relief.

Thanks for adding your comments Lauren. I'm a bit over my head on this subject.

I notice that you, like Sandi, were taking steroids for a long period of time before Rituxan. Just an observation. It is not intuitively causal how steroids could adversely affect the immune system to allow a hypersensitive reaction.

About your Doc reporting no adverse events to Rituxan treatments for SLE induced nephritis, joint pain, etc. I wonder, do those with nephritis or joint pain have a long record of steroid treatments before Rituxan treatments?

Is steroid treatment a cause or just an indicator of Rituxan hypersensitivity?

Actually, the first time I had Rituxan, I had only been taking Prednisone about 3 weeks. I had been on no medications for Lupus or ITP in over 10 years, and then out of nowhere, my platelets crashed. I started Prednisone, but was completely unresponsive on 80 mg., so Rituxan was started just 3 weeks later. So, in my case, I can't say that there is a correlation between prolonged steroid ust contributing to serum sickness.

I am quite intrigued by this discussion because my hematologist has treated hundreds, if not thousands, of patients with Rituxan (both for ITP and Lymphoma, etc.) and none of them have ever had a "reaction" or serum sickness except me. I have to believe the fact that I have SLE has something to do with that. As far as I know, I'm one of his only patients with both SLE and ITP. Throw in the fact that I had TTP previously, and that makes me even more of a rarity, but still. . . .I'm the only patient he's ever had to develop serum sickness. Quite strange. I think, Sandi, you may be right about my rheumatologist. Perhaps he sees these reactions as lupus flares, and not serum sickness. But, it must not be that common in his practice because he has told me has many SLE patients on maintenance Rituxan - 2 infusions every 3 months - so they must be tolerating it without issues.

Thanks,
Lauren

I just think that many doctors are missing it. The first time I had it, my Hemo didn't even know about it. It was just between me and the ER doctor who said it was a virus. Nearly every serum sickness patient I've seen here was told that it was a virus or a flare. My Hemo was aware of it the second time because he happened to be at the hospital and was called in. He diagnosed me, but actually took the diagnosis back a year later. He showed me a list of drugs that caused serum sickness and Rituxan wasn't on it. I told him that he had an incomplete list, because serum sickness was a known side effect. Patients getting maintenance doses are probably not experiencing serum sickness, you're right about that. They would be dead.

Hal, I don't think the steroids have anything to do with it. I had used steroids prior to Rituxan but the prolonged use began only after the second serum sickness event. I've been on them since that day and that was in 2004. We have many people here who use steroids before trying Rituxan and they don't get serum sickness. I was just like anyone else here at that time.

RITUXAN is contraindicated in patients with known anaphylaxis or IgE-mediated hypersensitivity to murine proteins or to any component of this product. (See WARNINGS .)

www.drugs.com/drp/rituxan-i-v.html

Lauren, how about antiphospholipid antibodies and anticardiolipin antibodies? Were you tested positive/negative for those before the bad Rituxan reactions?

' summerrain ' tested positive for those before her Rituxan reaction. The reaction which triggered Lupus symptoms and confirmed by diagnoses and changed blood work.

I have always been negative for anti-phospholipid and anti-cardiolipin antibodies, with one exception. After my son was born in 2009, I tested weekly positive for beta-2 glycoprotein 1. Apparently, you must have 2 sequential elevated test results in order to be considered positive. However, I have tested negative for beta-2 as well as all the others since 2010. First round of Rituxan was in 2013 and second round was in 2014.

I forgot to mention that in addition to the serum sickness, I also developed low grade fever after each infusion and had a big drop in my blood pressure. The low BP lasted for months long after I completed the Rituxan. My pressure was averaging 95/50.

You know your stuff, Lauren!

Oh, talk about throwing a bone to a dog... LOL, don't need any lunch today.

Perhaps there isn't a predicting blood test, but, closely monitoring blood pressure and body temp during the infusion can be. This will be nice idea to explore when someone brings up the topic again.

Hal, monitoring blood pressure and body temp should always be done....usually every 15 to 30 minutes. Mine was fine during the infusions. Abnormailities during the infusion will only help to identify immediate reactions, not a delayed hypersensitivity reaction like serum sickness. After the second or third serum sickness event, if the person keeps using the drug, they will eventually end up with an immediate anaphylactic reaction like Lauren had the third time.

Ack! Normal BP and temp. They didn't measure mine at all. Ok, not an indicator.

Once again I'm out of gas on this subject...

Sorry. I'm telling you, it's a delayed reaction to the murine (mouse) cells. It's that simple. There might be some type of blood test to predict that sensitivity but if there is, they don't do it. People can also get serum sickness from other drugs like penicillin. It's a delayed reaction and they never see it coming.

You didn't have your BP and pulse checked often? Protocol states every 15 to 30 minutes, especially during the first treatment.

I agree with Sandi. I believe I am clearly allergic to, or my body does not tolerate, the murine cells. Perhaps having Lupus contributes to this sensitivity, but I suppose I'll never know. For me, Rituxan clearly works for my platelets, but the reward is not worth any future risk. As Sandi mentioned, should I have Rituxan again, I could very well end up dead from anaphylactic shock.

While undergoing the Rituxan infusions, my blood pressure always was monitored. It was taken every 30 minutes. In some instances, my BP would register so low the automatic BP machine would take it again immediately. And I always left there with petechiae on my arms from the BP cuff. Also, my temperature was taken before and after each infusion, although it was always normal. My low grade temp always developed in the evening some 8 hours post each infusion.

Has anyone looked into non-murine, fully humanized, monoclonal antibodies?
They act like Rituxan but hopefully without triggering serum sickness.
Ofatumumab (Arzerra) is one. Ocrelizumab is another. Of course, their use would be off-label.

Yes, we talked about that before, Rob. Well, as far as me and using one for Lupus (Benlysta). I will never try another monoclonal. Don't you make me dig up that old post with all of my reasons!

Of course you knew I would dig it up for you anyway, Sandi!
www.pdsa.org/forum-sp-534/7-treatment-general/27608-alternative-to-rituximab-ofatumumab.html#35885
That was nearly four years ago, and I was wondering whether anyone had more recent knowledge.

Following a severe reaction to rituximab such as you had, I certainly wouldn't try another monoclonal antibody that had one iota of mouse left in it. But a "fully" humanized mAb (which I understand is fully humanized in name only) might be appropriate for someone else who might have had a previous mild reaction to Rituxan. That is the thinking in some articles I have read, but I have found nothing definitive.

Edit: The January 2017 revision to the Merk Manual section you quoted also contains this statement:

Fully human mAbs are produced using transgenic mice that contain human immunoglobulin genes or using phage display (ie, a bacteriophage-based cloning method) of immunoglobulin genes isolated from human B cells. Fully human mAbs have decreased immunogenicity and therefore may have fewer adverse effects in patients.

I'm cracking up! Yes, I figured you would. I was actually thinking of a more recent conversation that we had with the other Sandy. 5....4....3....2....1....GO!

Sorry for the slow response.
pdsa.org/discussion-group/6-general-itp-discussion/29572-did-i-make-the-correct-choice-after-all.html

LOL! You got it! I didn't want to explain that all over again. Everyone is free to make their own choices....I've made mine. Anyone can tell me it would be safe until they are blue in the face and maybe logically it would be, but I'm not taking the risk unless my life is at stake. Literally.

Pushing a patient to finish the four infusions after a serum sickness reaction is putting their life on the line. They wouldn't die from ITP but could die from the treatment? Makes absolutely no sense and I've seen it happen (not death, the infusions). I know this doesn't have much to do with human monoclonals. I just needed a rant while we're on the subject.

I just came across this, Rob. It was out of the blue, I wasn't looking for it. One last reason why I personally stay away from the monoclonals. This one is a human monoclonal. It might not cause serum sickness, but there are plenty of other problems with it. These drugs are not harmless or without risks. I realize that there are risks with every drug, but when you're using a drug that can cause death for an illness that probably won't result in death, the risk is greater than the benefit, in my opinion.

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