Insights on Dupilumab: AD and Lymphoid Infiltrates

Olayemi Sokumbi, MD, is a dermatologist and dermatopathologist at Mayo Clinic in Jacksonville, FL. As a researcher, her expertise covers quality improvement in dermatopathology, effective dermatopathology resident education, and the diagnosis and management of dysplastic nevi and cutaneous lymphoproliferative disorders. Dr Sokumbi has special interests in hidradenitis suppurativa, connective tissue disorders, cutaneous manifestation of systemic diseases, cutaneous lymphoma, immunobullous diseases, and more. In this exclusive interview, Dr Sokumbi joined The Dermatologist to discuss her recent study, “Evolution of Dupilumab-Associated Cutaneous Atypical Lymphoid Infiltrates.”

Your study found that “notable histopathologic features across pre-dupilumab and post-dupilumab biopsies included progressive increase in the densities of the atypical lymphoid infiltrates, presence of atypical epidermotropic lymphocytes, and papillary dermal fibrosis.” What is the significance of these findings?
We had the opportunity to review the slides of the seven patients prior to being on dupilumab. We saw that their biopsies demonstrated spongiotic dermatitis, a finding that we come to recognize in atopic dermatitis (AD).

However, when we followed these patients after being on dupilumab, those were the three main findings that we found to differentiate the pre-dupilumab and the post-dupilumab biopsies. We saw that all patients had progressive increase in the density of lymphocytes that was not present at the original onset biopsy before dupilumab. We also found that six of the seven patients had epidermotropic lymphocytes, meaning atypical lymphocytes were present within the epidermis, and finally, that they had papillary dermal fibrosis.

The importance of these findings is that these are some of the histologic findings seen in cases of mycosis fungoides (MF). In fact, we used the definition as provided by the International Society of Cutaneous Lymphoma Task Force.

When we saw those three findings in addition to the immunohistochemical stains, we were able to demonstrate that patients who had originally had a spongiotic dermatitis pattern on their biopsy before dupilumab met diagnostic criteria on histopathology for MF.

What should clinicians keep in mind when conducting clinical and histopathologic evaluations before and during treatment with dupilumab for treating AD?
It would be important for clinicians, particularly when taking care of patients who have treatment-refractory AD, that they perform biopsies before the initiation of dupilumab. The importance of the biopsy will be to confirm the diagnosis of AD. Biopsies should also be considered during the treatment course of dupilumab. As we saw in our studies, we did have pre-biopsies, which were still consistent with spongiotic dermatitis. Performing biopsies during the course of treatment with dupilumab would be important to pick up the early clues that might suggest the evolution of lymphoid infiltrates into MF.

Finally, I would say that when clinicians are taking care of patients with AD and they are not responding as expected to dupilumab, it is important to rebiopsy.  For instance, if you have a patient with presumed diagnosis of AD on dupilumab who is progressively getting worse, that is a very important clue not to ignore. It might represent that there has been evolution into the development of an atypical lymphoid infiltrate that would meet diagnostic criteria for cutaneous T-cell lymphoma (CTCL), MF type.

Can you share what area(s) of future research are needed to better understand the relationship between CTCL after treating with dupilumab for AD?
The understanding of the mechanism by which this occurs is critical to making recommendations as we go forward. We know that AD and advanced stages of MF tend to have a helper T (T_H) 2 cytokine profile with IL-4, IL-5, IL-10, and IL-13, which eventually leads to increased eosinophils and increased immunoglobulin E levels. We also know that early-stage MF tends to be the T_H1 profile. The important areas of research to focus on is to distinctively understand the role IL-4 and IL-13 inhibition play in the microenvironment of MF. We know that this probably leads to an imbalance in that T_H1/T_H2 profile. A better understanding of the effect of that alteration on microenvironment and MF evolution will be an important next step.

What clinical implications and considerations should dermatologists take from your study?
If you have a patient with AD, do not forget the importance of performing a biopsy. Biopsy confirmation is critical.

If you are going to initiate a patient with AD on dupilumab, be particularly sensitive to the understanding that if they progress or worsen on dupilumab, you should consider that they perhaps have unmasked an undiagnosed CTCL.

It is important to also perform routine biopsies during the treatment of dupilumab, particularly if the patient is not responding as you would expect. Understand that there are limitations to the biopsy. If you look at the literature in terms of inflammatory dermatosis and early-stage MF, it is very easy to miss the diagnosis of early MF. I don't call it a miss—I call it a challenge of early-disease evolution, because in the early stages of MF, the reactive T lymphocytes are usually greater than the neoplastic T lymphocytes. Therefore, it is very easy to diagnose those patients as having an inflammatory dermatosis. Usually, it will evolve over time, but recognition and an understanding are important so that we can pick up these progressions earlier if MF does occur.

Any insights or advice you’d like to offer dermatologists regarding MF and melanoma?
Dermatologists should be aware—and most are aware—that MF is the most common type of CTCL, and that it is indolent. It is important that dermatologists understand the history of MF and that patients usually present with patches over time, then they develop plaques, and then perhaps, eventually, tumors.

The patch stage of MF can mimic a lot of our very common inflammatory dermatoses that we see, such as with AD, psoriasis, psoriasiform dermatitis, or even drug-induced eruptions. Dermatologists should be particularly in tuned to the understanding that there is a lag time to diagnose MF, and that repeated evaluations and biopsies over time is important to eventually making that diagnosis, so that patients could receive appropriate treatment for their condition.

Reference
Sokumbi O, Shamim H, Davis M, Wetter D, Newman C, Comfere N. Evolution of dupilumab-associated cutaneous atypical lymphoid infiltrates. Am J Dermatopathol. Published online June 15, 2021. doi:10.1097/DAD.0000000000001875