Q:

7/14/2013
Stelara (anti-IL-12 and anti-IL-23), approved for psoriasis, lists "allergen immunotherapy" as a Caution. Are there any specific concerns with Stelara and allergen immunotherapy? SCIT stimulates IL-12 and maybe Stelara will interfere with benefits of SCIT or SCIT, by stimulating IL-12, may interfere with efficacy of Stelara. I cannot find any specific literature. Should I stop SCIT in patient starting Stelara? Thank you.

A:

Thank you for your inquiry.

For our reader’s sake, I am copying below the direct quote from the package insert of ustekinumab so that when this response is read, the readers will have access to the warning you cited.

Quote:
"Allergen Immunotherapy Stelara has not been evaluated in patients who have undergone allergy immunotherapy. STELAR may decrease the protective effect of allergen immunotherapy (decrease tolerance) which may increase the risk of an allergic reaction to a dose of allergen immunotherapy. Therefore, caution should be exercised in patients."

From my perspective, there are a couple of key features of this warning regarding immunotherapy. These are:

1. First of all, it states that Stelara has not been evaluated in patients who have undergone allergen immunotherapy; thus implying that the possible risk is theoretical at this point in time.

2.There is no reference supporting this warning.

Having mentioned this it is important to look at this question from the standpoint of both activities of Stelara, it’s effect on IL12 as well as it’s anti-IL 23 activity. I think the effect on IL-12, as alluded to in your response, is the most obvious to consider and the easiest to analyze. It probably underlies the intent of the warning as well.

In my opinion, the warning is based on the observation that immunotherapy skews the immune response to the allergen in question to a Th-1 (from a Th-2) response, which then in turn theoretically increases the tolerance (both by inhalation as well as ingestion or injection) to the allergen in question .One would therefore be cautious in employing any drug that might diminish this Th-1 response which, as you know, is in part dependent on IL-12.Thus the anti-IL-12 activity of Stelara theoretically could, according to the warning in the package insert“decrease the protective effect of allergen immunotherapy” and “increase the risk of an allergic reaction to a dose of allergen immunotherapy” that was previously tolerated. It is curious however that no such admonition, to my knowledge, exists for any of the anti-TNF preparations although TNF can co-stimulate Interferon-gamma (1) and therefore anti-TNF might theoretically diminish the TH2 skew induced by immunotherapy as well (but probably to a lesser extent).

On the other hand, however, the Th-1 response induced by allergen immunotherapy is, at least for the most part, allergen specific, so I don’t think there would be a worry about immunotherapy reducing the efficacy of Stelara.

But in addition to its anti-IL12 activity Stelara inhibits the activity of IL23. This introduces subtle twists to this issue which need to be taken into consideration. And unfortunately there are less data to assist in making a judgement as to the effect of blocking the activity of this cytokine. But there is one article that gives some insight in this regard (2).

In brief, IL-23 is critical for the development and maintenance of Th-17 cells, inducing IL-17 expression in humans while exerting an inhibitory effect on IL-12-induced interferon gamma responses.Therefore, at least theoretically, IL-23 expression would be expected to diminish the effectiveness of allergen immunotherapy while simultaneously producing an inflammatory response .And in the article mentioned above(2), it was shown that immunotherapy reduced the expression of IL-23, and this was accompanied by a lower level of IL-17. One would postulate that this effect would actually enhance the switch to a Th-1 profile induced by immunotherapy. It was also of note in this article that IL-17 responses correlated with poor therapeutic outcomes and increased symptoms.Thus, reducing the synthesis of IL-17 by blocking the effect of IL-23 would be, as noted, at least a theoretical advantage and, in this article, it seemed to be a clinically significant phenomenon.

To quote the authors, “Taken together, these data suggest that SLIT with optimal therapeutic allergen concentrations may be effective in preventing the development of poor inflammatory Th-17 promoting immune responses (e.g., induced by IL-23).”

Thus, Stelara, on at least a theoretical basis, could have a bimodal and opposing effect on allergen immunotherapy.I would not, however, be concerned about the effect of allergen immunotherapy on the Stelara for the reasons noted above.

In sum, there are sparse data to confirm or contradict the rather nonspecific warning given in the Stelara package insert regarding its simultaneous administration with allergen immunotherapy. And no definitive decision can be made about the potential risk involved with the simultaneous administration of both therapies.But the interpretation of the only available data I could find gives some reassurance that the two treatments are compatible. And, based on this information, if immunotherapy was considered an important aspect of therapy in a given patient, I would not feel it necessary to discontinue it.

(1) Immunoregulatory activity of recombinant human tumor necrosis factor (TNF)-alpha: induction of TNF receptors on human T cells and TNF-alpha-mediated enhancement of T cell responses. The Journal of Immunology March 15, 1987vol. 138no. 61786-1790

(2) Clinical outcome and IL-17, IL-23, IL-27 and FOXP3 expression in peripheral blood mononuclear cells of pollen-allergic children during sublingual immunotherapy. Pediatr Allergy Immunol. 2010 Feb;21(1 Pt 2):e174-84. doi: 10.1111/j.1399-3038.2009.00920.x. Epub 2009 Jun 29.

Thank you again for your inquiry and hope this helps

Warm Regards,
Phil Lieberman MD

AAAAI - American Academy of Allergy Asthma & Immunology