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The Dow of Accutane

At home the kids current TV show of choice is How I Met Your Mother, supplanting Scrubs as the veg out show in the evening. Both shows are always on a cable channel somewhere and are often broadcast late at night. Late night commercials can be curious, and as I work on projects, I watch the shows and commercials out of the corner of my eye.

Law firms trolling for business seem common. If you or a family member has had a serious stroke, heart attack or death from Avandia, call now. The non-serious deaths? I suppose do not bother. One ad in particular caught my eye: anyone who developed ulcerative colitis or Crohn’s disease (collectively referred to inflammatory bowel disease, or IBD) after using Accutane, call now. Millions have been awarded.

My eye may have been caught because of my new progressive lenses, but I will admit to an interest in inflammatory bowel disease, having had ulcerative colitis for years until I took the steel cure. It also piqued my interest as these were three conditions among which I could not seen any connections. Accutane, ulcerative colitis, and Crohn’s. One of these is not like the other.

Accutane (its generic name is isotretinoin) is an anti-acne medication, released long after my puberty. The drug is chemically related to retinoic acid, a natural vitamin A derivative, and works in part by decreasing the production of sebum, not an issue with IBD.

Ulcerative colitis (UC) and Crohn’s have the same clinical presentation: lots of bloody diarrhea. Any resemblance stops there. Pathologically they are completely different diseases. Crohn’s can affect the entire GI tract, from the mouth to the rectum, and its hallmark is noncaseating granulomas. While considered an autoimmune disease, I have, for uncertain reasons, been drawn to the data that suggests the disease may be due to atypical mycobacteria. Wherever there are granulomas, some sort of infectious disease is often not far behind.

UC is limited to the colon, has a high risk of leading to colonic cancer, and its etiology is even more uncertain, perhaps also an autoimmune disease. The two illnesses have different rates of extraintestinal manifestations as well.  Besides the bloody diarrhea and abdominal pain, the two diseases have little in common except they can wax and wane for no damn good reason and when active are a compelling reason to know where every public toilet in the city is.

The Wikipedia pages for both diseases have nice ‘compare and contrast’ tables, and it is obvious the illnesses have little in common. UC and Crohn’s are as different as pulmonary tuberculosis and bronchiolitis obliterans with organizing pneumonia, so it would be most curious if an anti-acne medication could be cause either one, much less both.

Ulcerative colitis occurs in 35–100 people for every 100,000 in the United States, and Crohn’s in 6 to 7.1 per 100,000, and there have been over 13 million prescriptions given for Accutane, more if you add in the other brands of isotretinoin. So there are bound to be, by coincidence, some people who will get IBD around the time they get their Accutane. Like Guillain Barré and flu vaccine, the question is whether or not the risk is increased.

As one review pointed out:

Assuming 1) a background incidence of IBD in the US of approximately 45,000 cases per year, 2) the number of persons taking isotretinoin is approximately 400,000 per year, and 3) the total US population is approximately 306 million, the expected number of cases of IBD among isotretinoin users would be 59 cases per year (if there were no association between isotretinoin and IBD), or 0.01% of Accutane users. If more than 59 cases per year were observed in isotretinoin users, this would suggest a positive relationship between isotretinoin use and IBD. However FDA MedWatch reports include an average of only 14 cases per year.

There are a smattering of case reports on the pubmeds of people developing IBD around the time they started isotretinoin. A few cases of IBD waxed on the medication and waned when isotretinoin was stopped. Interesting, but given the variability of the disease, causality is suspect.

Is there a basic mechanism whereby isotretinoin would lead to IBD?

The mechanism by which (endogenous and exogenous) retinoids cause or exacerbate intestinal inflammation is not understood. Retinoic acid affects intestinal epithelial growth and is involved in cell repair and apoptosis. Retinoids also impair neutrophil chemotaxis, a mechanism involved in Crohn’s disease. The production of induced regulatory T cells (iTreg) and T helper 17 (Th17) cells is also controlled by retinoic acid — these also being involved in gut epithelial homeostasis.

But there is also basic science to suggest that retinoic acid has the potential to be protective for IBD.

Retinoic acid, a form of vitamin A, has been shown to enhance barrier function by increasing expression of numerous tight junction proteins such as occludin, claudin-1, claudin-4, and zonula occludens-1. Furthermore, from the standpoint of immune function, retinoic acid has been shown to be capable of inhibiting pro-inflammatory interleukin-17-producing T helper cell (Th17) responses, while augmenting anti-inflammatory regulatory T cell induction. Such responses would be more likely to prevent the development of IBD, as opposed to trigger it.

So maybe there is a supporting mechanism, and maybe there isn’t. The putative mechanisms can go either way, although since there is perhaps less IBD than expected in patients on isotretinoin, the sparse data suggests a protective effect. Whether any of the basic science is clinically applicable is unknown and doesn’t really explain why it could be associated with two such widely divergent illnesses. Still, there may be unknown mechanisms that would be hinted at by epidemiology.

There really is a paucity of data with a grand total of about 49 references on Pubmed. One study found a relationship with UC, but not Crohn’s (which, given the etiology and pathology, perhaps makes more sense):

Isotretinoin use and the risk of inflammatory bowel disease: a case-control study.
OBJECTIVES:
Isotretinoin is commonly prescribed for the treatment of severe acne. Although cases of inflammatory bowel disease (IBD) have been reported in isotretinoin users, a causal association remains unproven.
METHODS:
We performed a case-control study using a large insurance claims database. Incident cases of IBD were identified and matched to three controls on the basis of age, gender, geographical region, health plan, and length of enrollment. Isotretinoin exposure was assessed in a 12-month period before case ascertainment. Conditional logistic regression was used to adjust for matching variables.
RESULTS:
The study population comprised 8,189 cases (3,664 Crohn’s disease (CD), 4,428 ulcerative colitis (UC), and 97 IBD unspecified) and 21,832 controls. A total of 60 subjects (24 cases and 36 controls) were exposed to isotretinoin. UC was strongly associated with previous isotretinoin exposure (odds ratio (OR) 4.36, 95% confidence interval (CI): 1.97, 9.66). However, there was no apparent association between isotretinoin and CD (OR 0.68, 95% CI: 0.28, 1.68). Increasing dose of isotretinoin was associated with elevated risk of UC (OR per 20 mg increase in dose: 1.50, 95% CI: 1.08, 2.09). Compared with non-users, the risk of UC was highest in those exposed to isotretinoin for more than 2 months (OR 5.63, 95% CI: 2.10, 15.03).
CONCLUSIONS:
UC but not CD is associated with previous isotretinoin exposure. Higher dose of isotretinoin seems to augment this risk. Although the absolute risk of developing UC after taking isotretinoin is likely quite small, clinicians prescribing isotretinoin as well as prospective patients should be aware of this possible association.

and another study found no relationship:

Isotretinoin is not associated with inflammatory bowel disease: a population-based case-control study.
OBJECTIVES:
There is anecdotal evidence that isotretinoin use is associated with development of colitis. We aimed at determining whether there is an association between isotretinoin use and development of inflammatory bowel disease (IBD).
METHODS:
The population-based University of Manitoba IBD Epidemiology Database and a control group matched by age, sex, and geographical residence were linked to the provincial prescription drug registry, a registry that was initiated in 1995. The number of users and duration of isotretinoin use were identified in both IBD cases and controls.
RESULTS:
We found that 1.2% of IBD cases used isotretinoin before IBD diagnosis, which was statistically similar to controls (1.1% users). This was also similar to the number of IBD patients who used isotretinoin after a diagnosis of IBD (1.1%). There was no difference between isotretinoin use before Crohn’s disease compared with its use before ulcerative colitis.
CONCLUSIONS:
Patients with IBD were no more likely to have used isotretinoin before diagnosis than were sex-, age-, and geography-matched controls. Although there may be anecdotes of isotretinoin causing acute colitis, our data suggest that isotretinoin is not likely to cause chronic IBD.

One for, one against. Crockett et. al. reviewed all the data, such as it is, and applied the nine Bradford Hill criteria to the data. The conclusions were underwhelming for causality

In conclusion, the only evidence to support a causal association between Accutane and IBD consists of isolated case reports. These reports support a possible temporal association between isotretinoin and the development of IBD, though such observations may have resulted from chance, confounding, bias, and misrepresentation of the natural history of IBD. A causal relationship remains biologically plausible, but beneficial effects of vitamin A derivatives on intestinal injury have been reported as well. None of the other commonly accepted causal criteria are met. The lack of evidence does not necessarily indicate lack of a causal connection.

Doesn’t seem to be the kind of data that warrants millions to plaintiffs. To double check, I asked some drug company shills, er, I mean gastroenterologists, what they thought of the data. They were equally underwhelmed.

Dow Corning was in bankruptcy protection for years stemming from multibillion dollar lawsuits in the 1980’s and 90’s over the assertion that silicone breast implants lead to breast cancer and autoimmune diseases. Subsequently, after billions were spent and the company was bankrupt, it was then determined that silicone breast implants are associated with neither cancer nor autoimmune diseases. Oh. That’s different. Never mind.

Does isotretinoin lead to inflammatory bowel disease? Maybe. Maybe not. The facts to prove or disprove the association lean against, the odds are “Five to one against and rising…Anything you still can’t cope with is therefore your own problem.” It is hard to prove a negative, and money is being spent and awarded, independent of a reasonable set of confirming facts. Hopefully this will not be like the Dow cases, where “a tort system that allowed a few lawyers to extort billions of dollars using a dollop of junk science.” Although as is often the case with corporations, Dow Corning apparently did not act as the model of integrity. No one acts their best when there is money to be made.

As one reference on the topic noted

In most policy matters, scientific evidence is only one among a complex assortment of factors that interact to produce particular decisions.” A careful reading of the events, stakeholders, and outcomes in the silicone breast implant controversy reveals the social, economic, legal, political, and scientific factors involved “the practice of Federal regulation, the relationship between science and courts, the lack of consistently enforced professional standards in law, medicine and journalism.” A major lesson from this case also involves the role of the plaintiffs. The Houston lawyers’ relentless pressure with inconclusive medical facts on Dow Corning, along with their courtroom successes, demonstrates that “facts” alone are insufficient factors in determining truth.

He could have been writing about SCAMs in general: the facts, in quotes, are insufficient factors in determining truth indeed.

Posted in: Legal, Politics and Regulation, Science and Medicine

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