Tocilizumab-induced psoriatic eruption : a case report and a case-based review.

BACKGROUND: Cases of psoriasis associated with Tocilizumab (TCZ) are scarce. OBJECTIVE: To describe a new case of TCZ-associated psoriasis and to perform a case-based review of similar cases. METHODS: We searched Medline/Pubmed, Embase, Scopus, Web of Science, and Directory of Open Access Journals databases using the terms « Tocilizumab ¼ and « Psoriasis ¼ in the French and English literature. RESULTS: We report a 70-year-old woman with a history of Rheumatoid Arthritis who developed Infliximab-induced plaque psoriatic eruption of the soles and palms, that resolved after Infliximab interruption, then relapsed after TCZ relay, and eventually resolved after TCZ interruption. Including our case, we identified 16 cases of TCZ-induced psoriatic eruption. Three (21%) out of 14 patients had a history of cutaneous psoriasis - data were not available for 2 patients. Eight (50%) patients had previously received TNFα antagonists. TCZ was stopped for 10 patients and continued for 4 patients. For the 2 remaining patients, the interval between two injections of TCZ was shortened. All the patients with available follow-up data had an improvement of the eruption within 4 weeks. CONCLUSION: To conclude, in case of TCZ-induced psoriatic eruption and in light of the published cases, we suggest using topical steroids and reassessing the patient 4 weeks later. If no healing is obtained, we suggest stopping TCZ, and treating the underlying disease with another drug. When no other drug is available, while waiting for more data regarding the value of IL-6 levels, it can be discussed to increase TCZ regimen, as it has been successful for 2 authors. Efficacy assessment of the chosen attitude should not take place before 4 weeks.

In silico calculated affinity of FVIII-derived peptides for HLA class II alleles predicts inhibitor development in haemophilia A patients with missense mutations in the F8 gene.

Forty per cent of haemophilia A (HA) patients have missense mutations in the F8 gene. Yet, all patients with identical mutations are not at the same risk of developing factor VIII (FVIII) inhibitors. In severe HA patients, human leucocyte antigen (HLA) haplotype was identified as a risk factor for onset of FVIII inhibitors. We hypothesized that missense mutations in endogenous FVIII alter the affinity of the mutated peptides for HLA class II, thus skewing FVIII-specific T-cell tolerance and increasing the risk that the corresponding wild-type FVIII-derived peptides induce an anti-FVIII immune response during replacement therapy. Here, we investigated whether affinity for HLA class II of wild-type FVIII-derived peptides that correspond to missense mutations described in the Haemophilia A Mutation, Structure, Test and Resource database is associated with inhibitor development. We predicted the mean affinity for 10 major HLA class II alleles of wild-type FVIII-derived peptides that corresponded to 1456 reported cases of missense mutations. Linear regression analysis confirmed a significant association between the predicted mean peptide affinity and the mutation inhibitory status (P = 0.006). Significance was lost after adjustment on mutation position on FVIII domains. Although analysis of the A1-A2-A3-C1 domains yielded a positive correlation between predicted HLA-binding affinity and inhibitory status (OR = 0.29 [95% CI: 0.14-0.60] for the high affinity tertile, P = 0.002), the C2 domain-restricted analysis indicated an inverse correlation (OR = 3.56 [1.10-11.52], P = 0.03). Our data validate the importance of the affinity of FVIII peptides for HLA alleles to the immunogenicity of therapeutic FVIII in patients with missense mutations.

Predictive immunogenicity of Refacto AF.

The administration of therapeutic factor VIII (FVIII) to treat or prevent haemorrhages in haemophilia A patients results, in up to 30% of the cases, in the development of inhibitory anti-FVIII antibodies. Much debate has taken place on the relevance of the nature of the FVIII product as a risk factor for inhibitor development. Thus, the plasma-derived vs. recombinant origin, the second vs. third generation of the product, or the presence of the B domain have been controversially evoked. A few years ago, Refacto AF, a third-generation recombinant B domain-deleted FVIII was marketed. The aim of this study was to compare the immunogenicity of Refacto AF to that of two recombinant full-length FVIII products: Helixate and Advate. For the three recombinant FVIII products, we compared the binding to the mannose-sensitive endocytic receptor CD206, the dose-dependent endocytosis by immature monocyte-derived dendritic cells (DCs), the activation by FVIII-loaded DCs of a FVIII-specific HLA-DRB1*0101-restricted mouse T-cell hybridoma and the induction of inhibitory anti-FVIII IgG in FVIII-deficient mice. At elevated FVIII concentrations, Refacto AF was less endocytosed than full-length recombinant products. At lower concentrations, however, Refacto AF was endocytosed by DCs and activated T cells as well as Helixate and Advate. The levels of inhibitory anti-FVIII IgG induced by Refacto AF in FVIII-deficient mice were lower or equal to that induced by Helixate and Advate respectively. The predicted immunogenicity of Refacto AF is identical to or lower than that of the two recombinant full-length FVIII products available on the French market.

Anti-PD-1 immunotherapy in combination with sequential involved-site radiotherapy in heavily pretreated refractory Hodgkin lymphoma.

The purpose of this study was to assess efficacy and tolerance of anti-programmed death (PD)-1 immunotherapy in combination with sequential involved-site radiotherapy in heavily pretreated refractory Hodgkin lymphoma. In this case series, we reported the outcome of four heavily pretreated patients with refractory Hodgkin lymphoma treated by anti-PD-1 immunotherapy and involved site radiation therapy. After a median follow-up of 13-month, all patients were alive with complete metabolic response. After radiotherapy, all four patients experienced lung toxicity, which was resolved after antibiotherapy with or without corticosteroid treatment. Anti-PD-1 immunotherapy followed by involved-site radiotherapy is feasible and showed very encouraging results in heavily pretreated patients.

[Human immunodeficiency virus-associated thrombotic microangiopathies]. / Purpura thrombotique thrombocytopénique et autres syndromes de microangiopathie thrombotique au cours de l'infection par le virus de l'immunodéficience humaine.

Human immunodeficiency virus (HIV) infection represents a risk factor for thrombotic microangiopathy. HIV-associated thrombotic microangiopathies encompass two entities with distinct pathophysiology, clinical presentation, treatment and prognosis. Thrombotic thrombocytopenic purpura associated with human immunodeficiency virus is typically characterized by a sudden onset in a patient with a moderate immune deficiency and a few events of opportunistic diseases, and a profound acquired deficiency in the von Willebrand factor cleaving protease ADAMTS13. This diagnosis requires a well-codified management including daily therapeutic plasma exchanges, a highly active antiretroviral therapy and eventually immunomodulatory drugs. The prognosis is good with a response rate and an overall survival comparable to that of HIV-negative thrombotic thrombocytopenic purpura. On the opposite, HIV-associated thrombotic microangiopathy with a progressive onset that occurs in profoundly immunocompromised patients with past history of multiple opportunistic diseases usually have a detectable ADAMTS13 activity and a worse prognosis. Usual treatment is poorly efficient. Forthcoming studies should assess the role of immunomodulatory drugs such as rituximab in the setting of HIV-associated thrombotic microangiopathy, and identify possible risk factors associated with the occurrence of these diseases.