Isabelle Templier

Long-Term Remissions of Severe Pemphigus After Rituximab Therapy Are Associated with Prolonged Failure of Desmoglein B Cell Response

Changes in the B cell repertoire mediate long-lasting therapeutic effects of rituximab in pemphigus patients. A Blistering Attack on Autoimmunity The devastating effects of autoimmune diseases like type 1 diabetes and multiple sclerosis are front-page news. However, rare autoimmune diseases may be even more distressing in their relative anonymity. One such condition is pemphigus, which is a severe blistering condition caused by autoantibodies to adhesion proteins in the skin and mucus. The B cell–depleting antibody rituximab has been shown to treat pemphigus short term in early clinical trials. Now, Colliou et al. find that rituximab therapy can help pemphigus patients even after 6 years, in part by reshaping the B cell repertoire during reconstitution. The authors followed pemphigus patients from their early trial out at least 6 years after rituximab therapy. They found that nearly two-thirds of patients achieved a long-term complete response—either completely off of therapy or when treated with low levels of supplementary prednisone. They then compared patients with complete response to those with incomplete response to look at differences in reconstitution of the B cell compartment. Patients with complete response had a greater proportion of naïve and transitional B cells than those with incomplete response, which suggests a barrier to B cell maturation. Indeed, many of these transitional B cells secreted the regulatory cytokine interleukin-10. Moreover, complete responders had a specific loss of anti–desmoglein-specific B cells, which are pathogenic in pemphigus patients, but not B cells that respond to infectious agents. Together, these data suggest that B cell repertoire is reshaped after rituximab therapy, allowing for long-term effects in addition to the short-term loss of pathogenic B cells. If these observations are confirmed in large studies, these data could form the basis for a new frontline therapy for recalcitrant pemphigus. Pemphigus is a severe blistering condition of the skin and mucosa caused by autoantibodies directed against desmogleins, which are a type of keratinocyte adhesion protein. B cell depletion by rituximab has short-term efficacy against pemphigus. We aimed to assess the long-term course of pemphigus patients after B cell depletion and to understand the immunological mechanisms that mediate long-lasting remissions. We evaluated the clinical course of 22 pemphigus patients treated with rituximab after a 79-month median follow-up and compared the anti-desmoglein B cell response and B and T lymphocyte subpopulations and repertoire between patients who achieved complete remission (CR) and those who had incomplete remission (IR). Thirteen patients (59%) experienced CR during the study, including 10 patients off treatment and 3 patients with prednisone doses <10 mg/day; 9 patients had IR. A marked increase was observed in the ratio of CD19+CD27− naïve B cells to CD19+CD27+ memory B cells. Indeed, patients in CR had a fourfold higher number of transitional B cells and interleukin-10–secreting regulatory B cells than those in IR. Furthermore, CR was associated with modification of the initial B cell repertoire and the disappearance of desmoglein-specific circulating immunoglobulin G–positive (IgG+) B lymphocytes, whereas a skewed B cell repertoire was observed in patients in IR. Thus, a blockage of B cell maturation, a prolonged repopulation with naïve B cells, and a delayed reappearance of memory B cells, which resulted in the disappearance of circulating desmoglein-specific IgG+ B lymphocytes, contribute to the long-lasting effectiveness of rituximab for treating pemphigus.

Haploinsufficiency for NR3C1 , the gene encoding the glucocorticoid receptor, in blastic plasmacytoid dendritic cell neoplasms

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and highly aggressive leukemia for which knowledge on disease mechanisms and effective therapies are currently lacking. Only a handful of recurring genetic mutations have been identified and none is specific to BPDCN. In this study, through molecular cloning in an index case that presented a balanced t(3;5)(q21;q31) and molecular cytogenetic analyses in a further 46 cases, we identify monoallelic deletion of NR3C1 (5q31), encoding the glucocorticoid receptor (GCR), in 13 of 47 (28%) BPDCN patients. Targeted deep sequencing in 36 BPDCN cases, including 10 with NR3C1 deletion, did not reveal NR3C1 point mutations or indels. Haploinsufficiency for NR3C1 defined a subset of BPDCN with lowered GCR expression and extremely poor overall survival (P = .0006). Consistent with a role for GCR in tumor suppression, functional analyses coupled with gene expression profiling identified corticoresistance and loss-of-EZH2 function as major downstream consequences of NR3C1 deletion in BPDCN. Subsequently, more detailed analyses of the t(3;5)(q21;q31) revealed fusion of NR3C1 to a long noncoding RNA (lncRNA) gene (lincRNA-3q) that encodes a novel, nuclear, noncoding RNA involved in the regulation of leukemia stem cell programs and G1/S transition, via E2F. Overexpression of lincRNA-3q was a consistent feature of malignant cells and could be abrogated by bromodomain and extraterminal domain (BET) protein inhibition. Taken together, this work points to NR3C1 as a haploinsufficient tumor suppressor in a subset of BPDCN and identifies BET inhibition, acting at least partially via lncRNA blockade, as a novel treatment option in BPDCN.

Identification of a Novel Complex BRAF Mutation Associated With Major Clinical Response to Vemurafenib in a Patient With Metastatic Melanoma

IMPORTANCE There is an increasing interest in BRAF V600 mutations in melanomas and their associated sensitivity to vemurafenib, a BRAF inhibitor. However, physicians cannot find information in the literature about vemurafenib response for rare and/or atypical BRAF mutations. OBSERVATIONS We describe the identification of a novel complex BRAF mutation associated with major clinical response to vemurafenib in a patient with metastatic melanoma. Using a pyrosequencing method, we determined that the tumor positive for mutated BRAF, uncovering a novel c.1799_1803delinsAT; p.V600-K601>D variant. We uncovered this atypical BRAF mutation with 2 different sequencing methods, both in the primary lesion and in 1 metastasis. The patient was immediately treated with vemurafenib as monotherapy and achieved a prolonged (5.5-month) positive response. CONCLUSIONS AND RELEVANCE We analyzed the consequences of the BRAF V600-K601>D mutation in terms of amino acids. We referred to the published data and databases to screen chemical properties of well-known BRAF V600 mutations and other complex BRAF mutations to find common features of activated BRAF mutations. Importantly, we highlighted that both the site of the mutation and the involved amino acids are important to predict vemurafenib response. Our conclusion is that complex BRAF mutation surrounding codon 600 could also be sensitive to BRAF inhibitors.

An "anaplastic" Kaposi's sarcoma mimicking a Stewart-Treves syndrome. A case report and a review of literature.

Cutaneous angiosarcoma (AGS) developing in a lymphedematous arm, after lymphadenectomy in the context of breast cancer, is the definition of the classical Stewart-Treves syndrome. Like AGS, many tumors such as Kaposis sarcoma (KS) could develop in chronic lymphedema. We describe the case of a 50-year-old woman who presented with several nodules on the left lymphedematous arm evocative of a Stewart-Treves syndrome, 2 years after a left mastectomy and a homolateral lymphadenectomy. The histological examination revealed an atypical vascular proliferation suggesting AGS, but endothelial atypical cells nuclei were strongly stained by herpes human virus 8 antibody. The final diagnosis was an “anaplastic” KS mimicking a Stewart-Treves syndrome. The total regression of the lesion was obtained by elastic contention and intradermic liposomal doxorubicin. “Anaplastic” KS is a rare histological form of nodular KS, which mimics a cutaneous AGS but classically expresses herpes human virus 8. It is essential to know about this entity, particularly in a lymphedematous arm, to avoid aggressive treatment such as amputation.

Blue Rubber Bleb Nevus Syndrome Treated with Polidocanol Foam Sclerotherapy

Blue rubber bleb nevus syndrome (BRBNS) is a rare vascular disorder characterized by a vascular malformation at multiple locations on the skin and sometimes in the gastrointestinal tract. Some case reports have described improvements after treatment with polidocanol liquid sclerotherapy. Here we report a new therapeutic approach using polidocanol foam sclerotherapy. Although foam sclerosant agents are superior in efficacy to liquid sclerosants in the treatment of venous insufficiency, the technique has not yet been standardized. Foam sclerosant agents are sometimes proposed as an alternative therapeutic option for the treatment of some types of vascular disorders, such as venous malformations.

Exogenous human herpesvirus 6 reinfection after tumor-infiltrating T-lymphocyte therapy

Exogenous human herpes virus 6 (HHV-6) reinfection has never been reported in patients receiving tumor-infiltrating T lymphocytes therapy. We report an unusual case of HHV-6 infection following infusion of HHV-6 infected autologous T lymphocytes. HHV-6 infection could interfere with the tumor antigen immune recognition and the efficacy of immunotherapy.

Twenty‐two cutaneous primary melanomas in a patient with high genetic predisposition to melanoma receiving levodopa therapy for Parkinson’s disease

Dear Sir,We report the case of a man who developed 22 mel-anomas between 1999 and 2005. He had phototype IIskin by Fitzpatrick’s classification, and had beenexposed to high levels of solar radiation, working out-doors at a ski resort. He had no familial history of mela-noma. He had been diagnosed with Parkinson’s disease(PD) at the age of 50 yr. Levodopa therapy associatedwith a dopa-decarboxylase inhibitor was introducedfrom the age of 55 yr. His first dermatological examina-tion was performed in 1999 at the age of 58 yr,40 months after the introduction of levodopa, andshowed two atypical pigmented lesions, one located inthe upper part of the back and another on the left flank.Multiple nevi without clinical atypia were also found.Histopathological analysis of the two atypical lesionsrevealed superficial spreading melanomas (SSM). Themelanoma on the back had a 0.48 mm Breslow thick-ness, while the lesion on the left flank had a 2.1 mmBreslow thickness. By that time he had received acumulative dose of 638 g of levodopa. An attempt wasmade to discontinue the use of levodopa because acausal link between levodopa and melanoma inductionhas been hypothetized. However, the treatment waseventually resumed because of neurological deteriora-tion. Over the next 4 yr, he developed 20 additionalprimary melanomas with a Breslow thickness C; c.340C>T], [p.Leu113Leu;p.Pro114Ser]. This mutation leads to the synthesis of amutant p16