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Infliximab for Crohn's disease: the first 500 patients followed up through 2009

http://link.springer.com/article/10.1007%2Fs10620-012-2405-z"

Infliximab for Crohn's disease: the first 500 patients followed up through 2009.

Seminerio JL, Loftus EV Jr, Colombel JF, Thapa P, Sandborn WJ.

March 2013

Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street, S.W., Rochester, MN 55905, USA.

BACKGROUND:

The aim of this study was to assess the long-term usage patterns and safety of infliximab in patients with Crohn's disease in clinical practice.

METHODS:

The medical records of 492 unselected patients treated with infliximab at Mayo Clinic were reviewed and abstracted for demographic features, usage patterns, and adverse events.

RESULTS:

The patients received a median of seven infusions and had a median follow-up of 6.3 years. Twenty-eight patients (6 %) were lost to follow-up, 63 patients (13 %) had no clinical benefit, and 401 patients (80 %) had partial or complete response. Of the responding patients, 114 (28 %) received induction treatment only, 167 (42 %) received initial episodic treatment (62 switched to scheduled maintenance treatment of whom 32 [42 %] were still on infliximab at last follow-up), and 120 (30 %) received scheduled maintenance treatment (56 patients [32 %] still on infliximab at last follow-up).

Three patients (0.6 %) developed septic shock and six patients (1.5 %) developed septicemia.

One patient (0.2 %) developed Mycobacterium avium complex.

Histoplasmosis occurred in three patients (0.6 %).

The cumulative 10-year probability for developing cancer after infliximab was 9 %.

Among the 31 patients developing malignancies (6 %), 15 (3 %) had solid tumors, 11 (2 %) had melanoma and non-melanoma skin cancers, three (0.6 %) had lymphomas (0.6 %), and two (0.4 %) had leukemia.

Overall 10-year survival after the final course of infliximab was 94 %.

Among the 28 deaths (6 %), nine occurred within 12 weeks of an infliximab infusion-two of these deaths were due to infections.

CONCLUSIONS:

Long-term follow-up of patients with Crohn's disease who were treated with infliximab initially between 1998 and 2002 showed persistence of therapy (due to clinical benefit) and an acceptable safety profile, despite the fact that less than one-third initially received three-dose induction followed by scheduled maintenance therapy. Infections and malignancy occurred at rates similar to those previously reported.
 

afidz

Super Moderator
So, really long term use is not proven to be deadly or dangerous as previously mentioned. 94% survival rate sounds pretty good to me. The way I see it, your in a bad predicament either way, so why not choose the path that is most likely to give you positive results?
 
I'm very interested to know what amount of those people would die if they weren't treated. How often do people die from Crohn's? I've looked around the internet before for a rate of Crohn's deaths but I don't feel like I found good information. Does anyone know a good reference?

Also what exactly does it mean "induction therapy only"?

I took Remicade for the first time in July 2001 and it slowly lost it's efficacy until 2006 when it was doing nothing for me. Then I had surgery. Now I'm good. Wish I would've just had surgery in the beginning and skipped the Remicade.

And BTW thanks so much for posting this!
 
I second what kss said, I would also be interested what the average survival rate for the same group of people (same age, same country of origin, same gender etc.) would be. Same for cancer rates.

As far as I know the stats don't say much about a reduced life expectancy for Crohn's patients. The negative effects of Crohn's are partially compensated for by the increased awareness of illnesses that affect Crohn's patients and their constant supervision by doctors.

Still, thanks for posting it. Remicade definitely is a drug with long term side effects and increased risk of cancer, no doubt.
 
I just read through the summary again and I noticed the study ended in 2009 but it wasn't published until March 2013. Why would it be withheld that long?

And also it looks like 56+32 were still on Remicade in 2009, that's only 18%.

If you add up the deaths and cancer it's 31+28 which is 12%.
If you add up deaths cancer and serious side effects it's 31+28+13 which is 15%.

(btw I'm using 492 as the total and not 492-63(had no benefit).)

I'd also like to point out that their reports of medians (number of infusions and years of follow up) are completely meaningless without reporting the associated standard deviations. Perhaps it's in the full paper. Does anyone have a copy? I'd really like to read the whole thing.
 
The numbers in this study is somewhat concerning. I am curious to know if the numbers would be the same with the knowledge researchers have today. I was under the impression that lymphoma risk is about 4 or 6 in 10,000. This article says the risk is 0.6% for lymphoma, 0.4% for leukemia, and overall 6% risk of developing malignancies. To me, 6% risk is very high. Is there anything I am missing in interpreting these numbers? I appreciate any insight.
 

my little penguin

Moderator
Staff member
6 in 10000 is the risk of T cell lymphoma when a biologic is combined with 6-mp/aza
T cell lymphoma is mostly fatal

Lymphoma Risk Higher with IBD Combo Therapy
Monotherapy for inflammatory bowel disease should be tried first, reserving combination therapy for patients who really need it

  • by Diana Swift
    Contributing Writer
  • This Reading Room is a collaboration between MedPage Today® and:
    Medpage Today
Expert Critique
FROM THE AGA READING ROOM
Bradley W. Anderson, MD

Bradley W. Anderson, MDGastroenterology and Hepatology FellowMayo ClinicRochester, MN
The following article discusses several studies that frame our current understanding of the relationship between immunosuppressant medications used for the treatment of inflammatory bowel disease (IBD) and lymphoma. While uncommon, the incidence of lymphoproliferative disease including non-Hodgkin lymphoma has previously been shown to be higher amongst patients receiving certain IBD-directed medications, such as thiopurines, compared with non-exposed patients. What has been less clear to date is the lymphoma risk posed by combination therapy (patients receiving both thiopurines and biologic agents) -- a relationship that is difficult to define given several confounding factors. In a recent large cohort study highlighted by this article, hazard ratios reflecting lymphoma risk were defined for several patient groups including unexposed patients, both thiopurine and anti-TNF monotherapy groups, as well as patients on combination therapy. While this study and interpretation of these findings are not without limitations, they do serve to further emphasize the importance of a careful discussion between patient and provider regarding potential medication-associated benefits and risks before selecting a particular IBD treatment option.


Full Critique

The connection between lymphoma, inflammatory bowel disease (IBD), and immunosuppressives has been controversial at least as far back as 1978, when Hecker and colleagues documented Hodgkin's disease as a complication of azathioprine treatment for Crohn's disease (CD). Today the precise connection between lymphoma and immunomodulators remains unclear, with different studies showing varying risk levels.
A 2013 study by Nabeel Khan et al reported that ulcerative colitis (UC) patients in a nationwide Veterans Administration cohort of 4,734 patients showed a fourfold increase in lymphoma risk during thiopurine treatment compared with patients not receiving thiopurines. Lymphoma risk increased gradually for successive years of treatment and, fortunately, diminished with discontinuation of the drug.

The incidence rates of lymphoma were 0.60 per 1,000 person-years among patients who had not been treated with thiopurines, 2.31 among those treated with thiopurines, and 0.28 among patients who had discontinued treatment with thiopurines.
In a 2015 meta-analysis of 18 IBD studies, David Kotlyar et al reported that relative to studies from referral centers, population-based studies showed a lower but still significantly increased risk of lymphoma among thiopurine-treated patients. The overall standardized incidence rate was 4.92, ranging from 2.80 in eight population studies to 9.24 in 10 referral studies.
"Population-based data are the most relevant for community-based care because referral-center studies inherently have more severely ill patients," one of the co-authors, Gary R. Lichtenstein, MD, director of the Inflammatory Bowel Disease Center at the University of Pennsylvania in Philadelphia, told MedPage Today.
Especially at risk from thiopurines were men, patients younger than 30, and patients older than 50. "Males were twice as likely to get lymphoma when exposed to azathioprine, and patients under age 30 had the highest relative risk, with a standardized incidence rate of 6.99, rising to about nine-fold in males under age 30," Lichtenstein noted. The highest absolute risk emerged in the 50-and-older age category. "Lymphoma is an age-dependent disease. Over age 50 the relative risk was 4.78, but the absolute risk was highest at one in 354 cases per patient-year."
As for biologics, in a 2014 national Danish study of approximately 56,000 IBD patients, Nyboe Andersen and colleagues found that exposure to anti-tumor necrosis factor (anti-TNF) therapy was not associated with an increased risk of cancer over a median follow-up of 3.7 years. An increased risk did emerge, however, with longer-term accumulated doses, suggesting that longer follow-up might have found a different outcome.

Most recently, a 2017 study by Magali Lemaitre and co-authors looked at the risk impact of three treatments -- thiopurines alone, TNF antagonists alone, or both classes of drugs combined -- in a cohort drawn from French national health insurance databases.
Almost 250,000 IBD patients age 18 or older treated from 2009 to 2013 were identified, and of these, 189,289 eligible participants with a median age of 43 (54% women) were followed to the end of 2015.
In that sample, 123,069 were never exposed to either drug class during follow-up, while 50,405 were exposed to thiopurine monotherapy, 30,294 to anti-TNF monotherapy, and 14,229 to combination therapy. By treatment category, the exposure durations were 27, 17, and 8 months, respectively.
Overall, there were 336 lymphoma cases, and 281 of non-Hodgkin's disease:
  • 220 cases in unexposed patients, for an incidence rate (IR) per 1,000 person-years of 0.26 (95% CI 0.23-0.29)
  • 70 in patients exposed to thiopurine monotherapy, for an IR of 0.54 (95% CI 0.41-0.67)
  • 32 in patients exposed to anti-TNF monotherapy, for an IR of 0.41 (95% CI 0.27-0.55), and
  • 14 in patients exposed to combination therapy, for an IR of 0.95 (95% CI 0.45-1.45)

Compared with in unexposed patients, the risk of lymphoma was higher among those exposed to either therapy or both therapies in combination. Thiopurine monotherapy had an adjusted hazard ratio (aHR) of 2.60 (95% CI 1.96-3.44, P<0.001), while anti-TNF monotherapy had an aHR of 2.41 (95% CI 1.60-3.64, P<0.001). Combination therapy had the highest aHR – 6.11 (95% CI 3.46-10.8, P<0.001).


The risk was also higher in patients exposed to combination therapy relative to those exposed to thiopurine monotherapy (aHR 2.35, 95% CI 1.31-4.22, P<0.001) or anti-TNF monotherapy (aHR 2.53, 95%CI1.35-4.77, P<0.001).
Lymphoma risk did not differ between adalimumab (Humira) and infliximab (Remicade) -- the absolute risk difference was just 0.04 per 1,000 person-years (aHR 0.95, 95% CI 0.47-1.90, P=0.97).
The researchers cautioned that because combination therapy is often used in severe forms of IBD, the association with elevated lymphoma risk may also reflect the impact of the burden of inflammation rather than treatment alone. The team concluded that the findings could help inform doctor-patient decisions about the benefits and risks of treatment.
Studies such as SONIC (Study of Biologic and Immunomodulator Naïve Patients in Crohn's Disease) have shown benefits from combination therapy with azathioprine plus anti-TNF. "Combination therapy means higher blood levels of anti-TNF that predict a benefit of therapy," Lichtenstein said, adding that individuals on combination therapy are less likely to develop antibodies against biologics because the immune system is suppressed. "These drugs are foreign proteins, and antibodies to them are a common reason people lose the benefit."
Lichtenstein noted that methotrexate has also recently been shown not to cause lymphoma in IBD patients. In looking at the safety of newer treatments, he said, "patients need to understand that individuals with untreated UC or CD have twice the mortality of the general population, and double the death rate and the severe infectious complication rate when treated with steroids. So you want to limit exposure to steroids yet effectively treat active disease."
For patients at the vulnerable extreme ends of the age scale, it's preferable to try a single agent and avoid combination therapy unless really needed. "Look at disease severity and future prognosis and determine if patients can be treated with a biologic alone rather than combination therapy -- particularly for patients over age 50 and under age 30, especially males," Lichtenstein said. In a recent reanalysis of the SONIC study, CD patients on combination therapy or those achieving high drug levels on monotherapy did about equally well, he noted.
The risk of lymphoma must be kept in perspective, however, Lichtenstein stressed. Lymphoma remains an uncommon cancer compared with colon and lung, and the risk of lymphoma with azathioprine rises only after a full year of exposure and goes down after cessation. "If you use it for 6 to 9 months, the risk does not go up. Furthermore, IBD does not predispose to cancer, and using biologics does not raise the risk of solid-organ cancers."
From
 
Thanks so much my little penguin for the reply. I still think there is a big difference in the study you posted and the 500 follow up study. Although the lymphoma risk study does not specifically state that the incident rates for treatment categories are per 1000 person-years, I imply they should be per 1000, so to be comparable to the unexposed category.
  • 220 cases in unexposed patients, for an incidence rate (IR) per 1,000 person-years of 0.26 (95% CI 0.23-0.29)
  • 70 in patients exposed to thiopurine monotherapy, for an IR of 0.54 (95% CI 0.41-0.67)
  • 32 in patients exposed to anti-TNF monotherapy, for an IR of 0.41 (95% CI 0.27-0.55), and
  • 14 in patients exposed to combination therapy, for an IR of 0.95 (95% CI 0.45-1.45)

    This still translate into 5, 4 and 9 cases of lymphoma per 10,000, which is much lower than the 0.6% that is listed in the “500 patient follow-up” study. Any thought?
 

my little penguin

Moderator
Staff member
So I try not to get too caught up in the “risk” anymore I did the first year or two maybe three

Since I don’t have crohns - my kiddo does
He was dx at age 7 and now is almost 17
Odds are he will have 80- 90 years of this disease
We plan to keep his intestine as healthy as possible for as long as possible since uncontrolled or under controlled disease has a much higher rate of colon cancer .
Add in he has juvenile arthritis-double whammy for inflammation and risk all around

however when you compare them to risks we take everyday with our kids just to enjoy life
These drugs have a very low risk profile
Risk of death in kids under 14 (few years ago )
By car 1 in 250
By drowning 1 in 1000
And the list goes on and on
Other simple drugs we don’t think about also have big risks
Infant Tylenol /antibiotics causes liver failure , Steven Johnson syndrome and death but my kids used it when it was needed for fever /infection
Benefits out weighed the risks

So in my kiddos case
Nice healthy pink intestine
Fecal caloprotectin below
And no joint damage /active arthritis
While taking biologics (Stelara) and methotrexate

That’s is what I focus on for now
His docs are conservative - they do the homework and won’t let him take the drugs where the risks are too high (6-mp or aza for example )
 
I hear you, my little penguin. I am a mom to a teenage boy in the undiagnosed club. I am driving myself crazy. I guess we all are going through the worrying phase. I appreciate all you parents here.
 

my little penguin

Moderator
Staff member
I can addd Ds has been on biologics including remicade since age 8 and has not had any issues in almost 9 years .
Hope you get answers soon undx is harder .
 
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