Post-therapeutic relapse of psoriasis after CD11a blockade is associated with T cells and inflammatory myeloid DCs

Abstract

To understand the development of new psoriasis lesions, we studied a group of moderate-to-severe psoriasis patients who experienced a relapse after ceasing efalizumab (anti-CD11a, Raptiva, Genentech). There were increased CD3(+) T cells, neutrophils, CD11c(+) and CD83(+) myeloid dendritic cells (DCs), but no increase in CD1c(+) resident myeloid DCs. In relapsed lesions, there were many CD11c(+)CD1c(-), inflammatory myeloid DCs identified by TNFSF10/TRAIL, TNF, and iNOS. CD11c(+) cells in relapsed lesions co-expressed CD14 and CD16 in situ. Efalizumab induced an improvement in many psoriasis genes, and during relapse, the majority of these genes reversed back to a lesional state. Gene Set Enrichment Analysis (GSEA) of the transcriptome of relapsed tissue showed that many of the gene sets known to be present in psoriasis were also highly enriched in relapse. Hence, on ceasing efalizumab, T cells and myeloid cells rapidly enter the skin to cause classic psoriasis.

Trial registration: Clinicaltrials.gov NCT00115076.

Conflict of interest statement

Competing Interests: The authors have read the journal's policy and have the following conflicts: JGK has served as a consultant for Genentech, who provided efalizumab for the clinical trial. This does not alter the authors's adherence to all the PLoS ONE policies on sharing data and materials. Other authors declare that they have no competing interests related to this work.

Figures

Figure 1. Enrollment flowchart.

Figure 2. Clinical photographs of two representative patients with disease relapse upon cessation of efalizumab treatment.

(A) Baseline lesions (left), response to efalizumab (center) and a marked erythematous psoriatic reaction 5 weeks after ceasing treatment (right). (B) Baseline photographs showing upper leg psoriatic plaques (left) which responded to efalizumab at week 12 (center) and a relapse in the same location (right). Note the inflammatory nature of the lesions during relapse.

Figure 3. Clinical and histological response to efalizumab and during relapse.

(A) Mean PASI scores, (B) circulating absolute lymphocyte count, (C) epidermal thickness (µm), (all n = 8) and (D) normalized keratin 16 (K16) mRNA expression (n = 4), throughout the trial and at time of relapse. Non-lesional (NL) and lesional skin (LS), error bars represent the standard error of the mean. * p<0.05; ** p<0.01; *** p<0.001. Representative (E) haematoxylin and eosin (H&E), (F) K16 protein, (G) neutrophil elastase, (H) CD3+ T cell immunohistochemistry, and (I) CD3+ T cell counts, showing the psoriasiform nature of the relapse lesion, with characteristic K16 staining, neutrophils and CD3+ T cells. Bar is 100 µm.

Figure 4. Increased inflammatory myeloid DCs in relapsed lesions.

(A) Representative immunohistochemistry and (B) counts of CD11c+ cells per mm in non-lesional skin (NL), lesional skin (LS), and in the index lesional plaque at weeks 2, 6 and 12 and time of disease relapse. (C) The numbers of CD1c+ cells did not change with treatment or relapse. (D) CD83+ mature DCs followed the same pattern as CD11c+ DCs. (E) There were many inflammatory myeloid DCs in the relapsed lesions, shown by immunofluorescence as CD11c+ cells (red) that were not co-expressing CD1c (and thus were not yellow), and (F) quantified as CD11c+ minus CD1c+ cells. (G) Inflammatory CD11c+ DCs were co-expressing TNFSF10/TRAIL. (H) TNF- and iNOS-producing DCs (TIP-DCs) were found in relapsed lesions. CD11c+ cells (red) co-expressing (I) CD14 and (J) CD16 (both green). Cells that co-express the two markers in a similar location are yellow in color. A white line denotes the dermo-epidermal junction. Bar is 100 µm.

Figure 5. Genomic characterization of relapsed psoriasis lesions.

(A) Venn diagram showing DEGs for different comparisons, week 12 versus LS; week 12 versus relapse; relapse versus LS. There were no unique DEGs in relapse compared to LS skin. (B) Scatter plot showing an excellent correlation between the “treatment effect” and “relapse effect”. (C) Number of genes improved by treatment and reversed by relapse. Red blocks were increased DEGs, green blocks were decreased DEGs.