VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) for the dermatologist.

In 2020, Beck et al1 described a novel adult autoinflammatory syndrome entitled VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic), a newly-discovered disorder that connected previously unrelated inflammatory syndromes and a prototype for a new class of hematoinflammatory diseases.2 Eighty-nine percent of published cases have documented skin involvement, but despite the high incidence and diagnostic accessibility of skin manifestations, there has been little focus on the dermatological features of VEXAS syndrome thus far. A PubMed search of all published case reports of VEXAS syndrome to date was performed, with inclusion of all cases confirmed by genetic sequencing, and this review summarizes the reported dermatological signs. There have already been 141 confirmed published cases since original publication, 126 of which had documented cutaneous signs.1-34 A wide range of skin presentations are reported, including Sweet-like urticated and tender erythematous nodules, cartilaginous involvement with chondritis, cutaneous vasculitis, and periorbital angiodema.1-34 Many patients had been diagnosed with Sweet syndrome, relapsing polychondritis, polyarteritis nodosa, or erythema nodosum.1-34 Hallmarks of skin histopathology are a neutrophilic dermatosis with coexisting or exclusive leukocytoclastic vasculitis.1 The new classification therefore helps link previously disparate inflammatory skin conditions into a unifying pathophysiological pathway.

Unusual CD34 positivity in acute myeloid leukaemia with myelodysplasia-related changes with megakaryoblastic differentiation.

Acute megakaryoblastic leukaemia is a rare entity with distinct immunophenotype profile and cytogenetic lesions. Herein, we report a case of acute myeloid leukaemia with myelodysplastic-related changes with megakaryoblastic differentiation in absence of recurrent genomic lesions such as t(1;22), inv(3) and t(3;3). One of the peculiarities of this case is the positivity of CD34+ within the abnormal megakaryoblasts; CD61 immunohistochemistry highlights the heavily infiltration of bone marrow from abnormal megakaryoblasts.

Trimethoprim-induced drug reaction with eosinophilia and systemic symptoms (DRESS) associated with reactivation of human herpes virus-6 (HHV-6) leading to acute liver failure.

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome can have insidious symptoms which may lead to acute liver failure and death. Prompt recognition, stopping offending drug, and initiating corticosteroid are the mainstay of treatment. Early involvement of a specialist liver unit is vital.

The architecture of neoplastic follicles in follicular lymphoma; analysis of the relationship between the tumor and follicular helper T cells.

CD4+ T-follicular helper cells are essential for the survival, proliferation, and differentiation of germinal center B cells and have been implicated in the pathogenesis of follicular lymphoma (FL). To further define the role of these cells in FL, we used multiparameter confocal microscopy to compare the architecture of normal and neoplastic follicles and next generation sequencing to analyze the T-cell receptor repertoire in FL lymph nodes (LN). Multiparameter analysis of LN showed that the proportion of T-follic-ular helper cells (TFH) in normal and neoplastic follicles is the same and that the previously reported increase in TFH numbers in FL is thus due to an increase in the number and not content of follicles. As in normal germinal centers, TFH were shown to have a close spatial correlation with proliferating B cells in neoplastic follicles, where features of immunological synapse formation were observed. The number of TFH in FL correlate with the rate of B-cell proliferation and TFH co-localized to activation induced cytidine deaminase expressing proliferating B cells. T-cell receptor repertoire analysis of FL LN revealed that follicular areas are significantly more clonal when compared to the rest of the LN. These novel findings show that neoplastic follicles and germinal centers share important structural features and provide further evidence that TFH may play a role in driving B-cell proliferation and genomic evolution in TFH Our results also suggest that targeting this interaction would be an attractive therapeutic option.

Chronic relapsing remitting Sweet syndrome--a harbinger of myelodysplastic syndrome.

Sweet syndrome (SS) is an acute febrile neutrophilic dermatosis. It has been associated with malignant disease, especially acute myeloid leukaemia (AML), infections, autoimmune disorders and drugs, particularly granulocyte colony-stimulating factor (GCSF). No cause is found in the rest, which are labelled idiopathic. We describe 15 patients with SS, which we believe represent 'immune dysregulation' secondary to myelodysplastic syndrome (MDS). We initially identified 31 patients with SS in a cohort of 744 patients with MDS and 215 with AML seen over a 6-year period (2004-10). The cause in 16 patients could be attributed either to administration of GCSF or chemotherapy. The eruption was brief and resolved spontaneously or following withdrawal of GCSF. Fifteen patients however, had a chronic debilitating illness dominated by the skin eruptions. Diagnosis of chronic relapsing SS was delayed because the pathology was not always typical of classical neutrophil-rich SS and included lymphocytic and histiocytoid infiltrates and bone marrow was not always performed because the relevance of the eruption to MDS was often not immediately appreciated. All these patients had 'low risk' MDS, diagnosed at a median of 17 months (range 0-157) following the diagnosis of SS. We describe a chronic debilitating episodic clinically distinctive skin eruption with features of SS but not always definitive histopathology often associated with immunological abnormalities affecting other systems related to underlying low risk MDS.

Increased collagen synthesis rate during wound healing in muscle.

Wound healing in muscle involves the deposition of collagen, but it is not known whether this is achieved by changes in the synthesis or the degradation of collagen. We have used a reliable flooding dose method to measure collagen synthesis rate in vivo in rat abdominal muscle following a surgical incision. Collagen synthesis rate was increased by 480% and 860% on days 2 and 7 respectively after surgery in the wounded muscle compared with an undamaged area of the same muscle. Collagen content was increased by approximately 100% at both day 2 and day 7. These results demonstrate that collagen deposition during wound healing in muscle is achieved entirely by an increase in the rate of collagen synthesis.

Diverse gene expression and DNA methylation profiles correlate with differential adaptation of breast cancer cells to the antiestrogens tamoxifen and fulvestrant.

The development of targeted therapies for antiestrogen-resistant breast cancer requires a detailed understanding of its molecular characteristics. To further elucidate the molecular events underlying acquired resistance to the antiestrogens tamoxifen and fulvestrant, we established drug-resistant sublines from a single colony of hormone-dependent breast cancer MCF7 cells. These model systems allowed us to examine the cellular and molecular changes induced by antiestrogens in the context of a uniform clonal background. Global changes in both basal and estrogen-induced gene expression profiles were determined in hormone-sensitive and hormonal-resistant sublines using Affymetrix Human Genome U133 Plus 2.0 Arrays. Changes in DNA methylation were assessed by differential methylation hybridization, a high-throughput promoter CpG island microarray analysis. By comparative studies, we found distinct gene expression and promoter DNA methylation profiles associated with acquired resistance to fulvestrant versus tamoxifen. Fulvestrant resistance was characterized by pronounced up-regulation of multiple growth-stimulatory pathways, resulting in estrogen receptor alpha (ERalpha)-independent, autocrine-regulated proliferation. Conversely, acquired resistance to tamoxifen correlated with maintenance of the ERalpha-positive phenotype, although receptor-mediated gene regulation was altered. Activation of growth-promoting genes, due to promoter hypomethylation, was more frequently observed in antiestrogen-resistant cells compared with gene inactivation by promoter hypermethylation, revealing an unexpected insight into the molecular changes associated with endocrine resistance. In summary, this study provides an in-depth understanding of the molecular changes specific to acquired resistance to clinically important antiestrogens. Such knowledge of resistance-associated mechanisms could allow for identification of therapy targets and strategies for resensitization to these well-established antihormonal agents.

Successful treatment of refractory angioimmunoblastic T-cell lymphoma with thalidomide and dexamethasone.

Angioimmunoblastic T cell lymphoma (AITL) is a peripheral T-cell lymphoma characterized morphologically by lymphadenopathy with a polymorphic infiltrate, marked vascular and follicular dendritic cell proliferation. Patients usually present with advanced disease and the overall prognosis is poor. While intensive chemotherapy has been shown to induce complete remissions in 50-70% of patients, the majority of patients subsequently relapse. Herein we report the case of a 32 year old man with AITL who was refractory to conventional chemotherapy, but achieved a remarkable sustained response to treatment with thalidomide and dexamethasone. Thalidomide may be an effective therapeutic agent against AITL, and given the poor prognosis of AITL, prospective clinical studies with either thalidomide or one of the thalidomide analogues are warranted.

Peripheral blood but not tissue dendritic cells express CD52 and are depleted by treatment with alemtuzumab.

CAMPATH antibodies recognize CD52, a phosphatidylinositol-linked membrane protein expressed by mature lymphocytes and monocytes. Since some antigen-presenting dendritic cells (DCs) differentiate from a monocytic progenitor, we investigated the expression of CD52 on dendritic cell subsets. Four-color staining for lineage markers (CD3, 14, 16, 19, 20, 34, and 56), HLA-DR, CD52, and CD123 or CD11c demonstrated that myeloid peripheral blood (PB) DCs, defined as lineage(-)HLA-DR(+)CD11c(+), express CD52, while expression by CD123(+) lymphoid DCs was variable. Depletion of CD52(+) cells from normal PB strongly inhibited their stimulatory activity in an allogeneic mixed lymphocyte reaction and also reduced the primary autologous response to the potent neoantigen keyhole limpet hemocyanin. CD52 is thus expressed by a myeloid subset of PBDCs that is strongly allostimulatory and capable of initiating a primary immune response to soluble antigen. Administration of alemtuzumab, a humanized monoclonal antibody against CD52, to patients with lymphoproliferative disorders or as conditioning for hematopoietic stem cell transplantation resulted in a marked reduction in circulating lineage(-)HLA-DR(+) DCs (mean 31-fold reduction, P =.043). Analysis of monocyte-derived DCs in vitro revealed a reduction in CD52 expression during culture in granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4, with complete loss following activation-induced maturation with lipopolysaccharide. In contrast to the findings in PB, epidermal and small-intestine DCs did not express CD52, suggesting either that transit from blood to epidermis and gut is associated with loss of CD52 or that DCs in these tissues originate from another population of cells.