Eruptive papules during efalizumab (anti-CD11a) therapy of psoriasis vulgaris: a case series
© Lowes et al; licensee BioMed Central Ltd. 2007
Received: 07 November 2006
Accepted: 26 February 2007
Published: 26 February 2007
Newer biological therapies for moderate-to-severe psoriasis are being used more frequently, but unexpected effects may occur.
We present a group of 15 patients who developed inflammatory papules while on efalizumab therapy (Raptiva, Genentech Inc, anti-CD11a). Immunohistochemistry showed that there were increased CD11b+, CD11c+ and iNOS+ cells (myeloid leukocytes) in the papules, with relatively few CD3+ T cells. While efalizumab caused a decreased expression of CD11a on T cells, other circulating leukocytes from patients receiving this therapy often showed increased CD11b and CD11c. In the setting of an additional stimulus such as skin trauma, this may predispose to increased trafficking into the skin using these alternative β2 integrins. In addition, there may be impaired immune synapse formation, limiting the development of these lesions to small papules. There is little evidence for these papular lesions being "allergic" in nature as there are few eosinophils on biopsy, and they respond to minimal or no therapy even if efalizumab is continued.
We hypothesize that these papules may represent a unique type of "mechanistic" inflammatory reaction, seen only in the context of drug-induced CD11a blockade, and not during the natural disease process.
Newer biological agents have dramatically improved therapeutic options for patients with psoriasis vulgaris requiring systemic therapy. Curiously, despite our knowledge of the target antigen of these biologic therapies, there may be unknown or unexpected biological effects. Efalizumab (Raptiva, Genentech Inc) is an FDA-approved treatment for moderate-to-severe psoriasis vulgaris. Recent phase III randomized, double-blind, placebo controlled trials have shown that an excellent clinical result (Psoriasis Activity and Severity Index, PASI 75) is obtained by week 12 in approximately 30% of patients [1–3]. Efalizumab is a humanized monoclonal antibody to CD11a, one of the chains of the β2 integrin lymphocyte function-associated antigen (LFA)-1. LFA-1 binds to intercellular adhesion molecules (ICAMs), allowing leukocyte migration across endothelial membranes during inflammation. Efalizumab appears to block trafficking of leukocytes (particularly memory T cells) into sites of inflammation, leading to a peripheral lymphocytosis . There is also a decrease in dendritic cells with efalizumab treatment . However, efalizumab may have additional effects as the LFA-1/ICAM-1 interaction is also important in antigen presentation to T cells, and trafficking of T cells in the epidermis.
During clinical trials with efalizumab, we observed patients who developed a variable number of small, scattered erythematous papules during the treatment period. The lesions were initially recognized by one of the authors and were called "Papp's papules" by a number of dermatologists. These lesions resolved without additional treatment or with mild-to-moderate topical corticosteroid application, while efalizumab was continued. The relationship of these papular lesions to previously described eruptions that develop while on efalizumab is unclear. An advisory group of dermatologists described a clinical eruption termed "localized mild breakthrough" during the early stages of efalizumab therapy . While these lesions may be papules, they have not been characterized by histology or for cellular composition by immunohistochemistry.
We present a series of patients that developed these papular eruptions during efalizumab therapy, and characterize this reaction histologically. To determine how leukocytes might travel into the skin during efalizumab therapy, we also analyzed integrin levels on circulating leukocytes. We suggest that these lesions represent a unique drug-induced "mechanistic" eruption that occurs during CD11a blockade, where leukocytes enter the skin using alternative integrins, and the number and array of leukocytes in cutaneous lesions may be distinct from those in "normal" inflammatory processes (when CD11a is functioning in its usual manner). In addition, blockade of CD11c and therefore LFA-1/ICAM-1 interaction in the immune synapse may prevent initial and sustained T cell activation and limit the development of these lesions to small papules. Importantly, there is no evidence that this is a conventional drug hypersensitivity or allergic process.
Details of patients with erythematous papules while on efalizumab therapy
PASI at biopsy
CD11c+ and iNOS+ cells mark Tip-DCs, a new type of inflammatory dendritic cell which is present in psoriatic lesions . We quantified the number of CD11c+ and iNOS+ cells in the papular lesions (n = 14), and compared these counts to normal skin (n = 10, n = 14 respectively) and psoriasis (n = 69, n = 10 respectively). The normal skin was obtained under an RU IRB-approved protocol from healthy volunteers, after obtaining informed consent. The CD11c+ psoriatic lesional counts were from a large clinical trial with efalizumab, and this population has been previously described . The iNOS counts in psoriasis lesional skin were also performed on pre-treatment biopsies from IRB-approved clinical trials in our department.
INOS staining showed a similar pattern of intermediate numbers of positive cells in the papules, between normal skin and psoriasis (Fig. 3B). In normal skin, there are no iNOS positive cells in the epidermis, and dermal staining intensity is relatively low. In the papules there were significantly greater numbers of iNOS positive cells in the epidermis (20 cells/mm compared to 0 in the normal skin, P = 0.026). In the dermis, there were similar numbers of iNOS positive cells in papules compared to normal skin (80 and 71 cells/mm respectively, but again lower than psoriasis (126 cells/mm). Overall, there was infiltration of CD11c+ cells into the dermis and epidermis of the papules, and iNOS production was increased, especially in the epidermis.
Integrins are cell-surface heterodimers that mediate cell-cell and cell-matrix interactions . The β2 group of integrins comprise a variable α chain (CD11a, CD11b and CD11c) and constant β2 (CD18) chain. CD11a/CD18, also called LFA-1, binds ICAM-1, -2 and -3, and is present on all leukocytes. As mentioned above, it has important roles in leukocyte trafficking across the endothelium, antigen presentation to T cells and immune synapse formation. These interactions are blocked by efalizumab. CD11b/CD18 (Mac-1) binds ICAM-1 and iC3b. It is present on myeloid cells, and some lymphocyte subsets. Therefore it has some similar functions to LFA-1. CD11c/CD18 (p150/95) binds fibrinogen and iC3b. CD11c is present on myeloid cells, and is a well recognized marker of myeloid dendritic cells and interstitial dendritic cells [9, 10]. The β1 family, also called very late antigens (VLA1-6), comprise a series of molecules with a variable α chain, (CD49a-f) and constant β1 chain (CD29), and with a very wide pattern of expression. The VLA integrins are also involved in leukocyte trafficking.
Leukocyte emigration across the cutaneous vascular endothelium involves a series of steps mediated by various adhesion molecules in response to chemokine gradients: initial tethering of cells to the endothelium, loose rolling along the vascular surface, firm adhesion to the endothelium, and diapedesis between tightly apposing endothelial cells . The cells then traverse the endothelial basal lamina and migrate through the extracellular matrix. Integrins are important for several of these processes, including tethering (VLA-4), adhesion (LFA-1, Mac-1, and VLA-4), and migration through the extracelluar matrix (Mac-1).
It is possible that in the absence of LFA-1 other integrins such as CD11b/CD18 or VLAs may allow leukocyte migration in response to inflammatory signals. For example, a CD11a knockout mouse model demonstrated aggravated Lyme carditis, . Preformed CD11b is stored in leukocytes and rapidly upregulated on activation , and leukocyte CD11b upregulation has been seen in other settings of inflammation [13–15].
However, changes in circulating leukocyte integrins alone do not appear to be sufficient to induce these additional lesions. An external trigger may also be required, such as skin trauma, bacterial colonization, or microbial triggers, and then these activated cells are able to enter the skin using alternative integrins. Both CD11b+ and CD11c+ cells may be playing a role in the development of these papules. Increased numbers of CD11b+ cells have been shown to be pathogenic in disease models such as autoimmune uveitis or lung infection [16, 17]. Recently, we identified a population of CD11c+ myeloid dendritic cells in psoriasis that produce TNF and iNOS, termed "Tip-DCs" . These Tip-DCs were decreased with efalizumab therapy, in parallel with reduction in epidermal thickness. However, if CD11b+ and CD11c+ cells are able to traffic into the skin using alternative means, they may then release inflammatory mediators contributing to these papular lesions.
Recently, we described two psoriasis patients who experienced a flare of their disease while on efalizumab therapy . Treatment was ceased at the time of the systemic flare, but was cautiously reintroduced at a later date, as there was no other therapeutic option. This is in contrast to the 5% of patients who develop a worsening of their psoriasis when therapy is ceased . It is possible that both the small lesions presented here, flare on ceasing therapy, and the occasional systemic flare while on therapy may be part of the same spectrum. However, the smaller scattered lesions are clearly more common, and resolve without treatment, and a more significant additional stimulus may be required to cause a generalized eruption.
Importantly, there is no evidence of an allergic process in the development of these papular lesions: few eosinophils are seen on biopsy of these lesions, and they resolve with minimal treatment even if efalizumab therapy is continued. If this were an allergic reaction, continued therapy would cause worsening of the skin reaction, which is not the case.
The histological differences between these papules and psoriasis are that in the papular lesions there are reduced T cells, neutrophils, CD14+ cells, lack of organized dermal T cell and dendritic cell aggregates, and the epidermal reaction has less acanthosis and psoriasiform rete elongation. We hypothesize that these lesions represent a unique event, a type of "mechanistic" eruption, seen only in the context of drug-induced CD11a blockade, and not during a natural disease process. We hypothesize that these lesions are unable to develop fully into psoriasis because T cell entry across the cutaneous vasculature, and T cell activation, are impaired during LFA-1/ICAM-1 blockade.
lymphocyte function-association antigen
intercellular adhesion molecule
TNF- and iNOS-producing dendritic cell
inducible nitric oxide synthase
very late anitgen
Psoriasis Activity and Severity Index
The authors would like to thank Patricia Gilleadueau and Mary Sullivan-Whalen for clinical care of our patients in clinical trials as well as Toyoko Kikuchi, Inna Novitskaya and Artemis Khatcherian for technical support. JGK is supported by the following National Institutes of Health (NIH) grants; a General Clinical Research Center grant (M01-RR00102) from the National Center for Research Resources at the NIH, NIH grants R01 AI-49572 and AI-49832. MAL is the recipient of NIH/NIAMS grant 1 K23 AR052404-01A1.
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