Cutaneous granulomas associated with rubella virus: A clinical review.

Since the initial identification of vaccine-derived rubella virus (RuV) in the cutaneous granulomas of pediatric patients with inborn errors of immunity in 2014, more than 80 cases of RuV granulomas have been reported implicating both vaccine-derived and wild type RuV. Previously thought to arise exclusively in patients with significant immunocompromise, the identification of RuV granulomas in clinically immunocompetent patients adds nuance to our understanding of the interplay between host environment, immune dysregulation, and RuV granuloma formation. This review summarizes the literature on RuV granulomas including clinical and histopathologic features, proposed pathomechanisms supporting granuloma development, and potential therapeutic options. There is no standardized algorithm to guide the workup and diagnosis of suspected RuV granulomas. We highlight the importance of contributing RuV granuloma cases to ongoing Centers for Disease Control and Prevention surveillance efforts to monitor wild type and vaccine-derived RuV transmission. Studies advancing our understanding of RuV granulomas may provide insights into the role of viral infectious agents in granulomatous disease pathogenesis and guide the development of improved therapeutic options.

Pilot Study of a Novel Therapeutic Approach for Refractory Advanced Stage Folliculotropic Mycosis Fungoides.

Folliculotropic mycosis fungoides is a variant of cutaneous T-cell lymphoma characterized as having a folliculocentric infiltrate of malignant T cells along with a worse prognosis in comparison to the epidermotropic variants. Patients with advanced forms of folliculotropic mycosis fungoides are often poorly responsive to both skin-directed as well as to systemic therapies. We report here a high response rate using a novel therapeutic regimen combining interferon gamma, isotretinoin in low dose and topical carmustine, and in some cases concomitant skin-directed therapies, among 6 consecutive patients with refractory folliculotropic mycosis fungoides with stages IB through IIIB who had previously failed both topical and systemic therapies. The potential mechanisms of this multimodality approach are discussed.

Persistent Agminated CD30+ Lymphoproliferative Disorder.

Lymphomatoid papulosis (LyP) is a chronic skin condition, characterized by recurrent eruptions of papules and nodules with or without central necrosis that spontaneously resolve. This condition was originally described by Macaulay in 1968 as a self-healing rhythmical paradoxical eruption that was clinically benign yet histologically malignant.1 Clinically, it is defined by papules that wax and wane, are generally less than 1cm in diameter, and heal spontaneously after 6­8 weeks with subsequent scarring.2

Immune checkpoint inhibitors and the development of granulomatous reactions.

Immune checkpoint inhibitors (ICPIs) have emerged as a frontline treatment for a growing list of malignancies. Disruption of the negative regulatory immune checkpoints by ICPIs has been associated with many immune-related adverse events. Granulomatous reactions, such as sarcoidosis-like reactions, granulomatous panniculitis, granuloma annulare, and granulomatous dermatitis, are uncommon but increasingly recognized immune-related adverse events seen in patients treated with ICPIs. The frequency and significance of these eruptions, including whether they portend responsiveness to treatment, remain unclear. Additionally, understanding the role of immune checkpoint blockade in these reactions may provide mechanistic insight into the relevant signaling pathways involved in sarcoidosis and other granulomatous disorders.

Cutaneous mantle cell lymphoma presenting as a diffuse morbilliform rash: A case report.

This case describes a patient with known mantle cell lymphoma without cutaneous involvement presenting with a diffuse morbilliform rash during an inpatient admission for bacterial pneumonia. The patient was thought to have a hypersensitivity to antibiotics but failed to improve after the offending agents were stopped. A skin biopsy revealed metastatic cutaneous mantle cell lymphoma. Treatment with high-dose corticosteroids and chemotherapy was initiated resulting in the resolution of the rash.

Identifying highly active anti-CCR4 CAR T cells for the treatment of T-cell lymphoma.

A challenge when targeting T-cell lymphoma with chimeric antigen receptor (CAR) T-cell therapy is that target antigens are often shared between T cells and tumor cells, resulting in fratricide between CAR T cells and on-target cytotoxicity on normal T cells. CC chemokine receptor 4 (CCR4) is highly expressed in many mature T-cell malignancies, such as adult T-cell leukemia/lymphoma (ATLL) and cutaneous T-cell lymphoma (CTCL), and has a unique expression profile in normal T cells. CCR4 is predominantly expressed by type-2 and type-17 helper T cells (Th2 and Th17) and regulatory T cells (Treg), but it is rarely expressed by other T helper (Th) subsets and CD8+ cells. Although fratricide in CAR T cells is generally thought to be detrimental to anticancer functions, in this study, we demonstrated that anti-CCR4 CAR T cells specifically depleted Th2 and Tregs, while sparing CD8+ and Th1 T cells. Moreover, fratricide increased the percentage of CAR+ T cells in the final product. CCR4-CAR T cells were characterized by high transduction efficiency, robust T-cell expansion, and rapid fratricidal depletion of CCR4-positive T cells during CAR transduction and expansion. Furthermore, mogamulizumab-based CCR4-CAR T cells induced superior antitumor efficacy and long-term remission in mice engrafted with human T-cell lymphoma cells. In summary, CCR4-depleted anti-CCR4 CAR T cells are enriched in Th1 and CD8+ T cells and exhibit high antitumor efficacy against CCR4-expressing T-cell malignancies.

Association of Persistent Rubella Virus With Idiopathic Skin Granulomas in Clinically Immunocompetent Adults.

Importance: Vaccine-derived and wild-type rubella virus (RuV) has been identified within granulomas in patients with inborn errors of immunity, but has not been described in granulomas of healthy adults. Objective: To determine the association between RuV and atypical granulomatous inflammation in immune-competent adults. Design, Setting, and Participants: This case series, conducted in US academic dermatology clinics from January 2019 to January 2021, investigated the presence of RuV in skin specimens using RuV immunofluorescent staining of paraffin-embedded tissue sections, real-time reverse-transcription polymerase chain reaction, whole-genome sequencing with phylogenetic analyses, and cell culture by the US Centers for Disease Control and Prevention. Rubella immunoglobulin G, immunoglobulin M enzyme-linked immunoassay, and viral neutralization assays were performed for the sera of immunocompetent individuals with treatment refractory cutaneous granulomas and histopathology demonstrating atypical palisaded and necrotizing granulomas. Clinical immune evaluation was performed. Main Outcomes and Measures: Identification, genotyping, and culture of vaccine-derived and wild-type RuV within granulomatous dermatitis of otherwise clinically immune competent adults. Results: Of the 4 total immunocompetent participants, 3 (75%) were women, and the mean (range) age was 61.5 (49.0-73.0) years. The RuV capsid protein was detected by immunohistochemistry in cutaneous granulomas. The presence of RuV RNA was confirmed by real-time reverse-transcription polymerase chain reaction in fresh-frozen skin biopsies and whole-genome sequencing. Phylogenetic analysis of the RuV sequences showed vaccine-derived RuV in 3 cases and wild-type RuV in 1. Live RuV was recovered from the affected skin in 2 participants. Immunology workup results demonstrated no primary immune deficiencies. Conclusions and Relevance: The case series study results suggest that RuV (vaccine derived and wild type) can persist for years in cutaneous granulomas in clinically immunocompetent adults and is associated with atypical (palisaded and necrotizing type) chronic cutaneous granulomas. These findings represent a potential paradigm shift in the evaluation, workup, and management of atypical granulomatous dermatitis and raises questions regarding the potential transmissibility of persistent live RuV.

Dermatologic Events Associated with the Anti-CCR4 Antibody Mogamulizumab: Characterization and Management.

The CCR4-directed monoclonal antibody mogamulizumab has been shown to significantly improve progression-free survival and overall response rate compared with vorinostat in adults with relapsed/refractory mycosis fungoides (MF) and Sézary syndrome (SS). One of the most common adverse events seen with mogamulizumab in MF/SS patients is rash. Because of the protean nature of MF/SS and the variable clinical and histopathological features of mogamulizumab-associated rash, healthcare providers may have difficulty distinguishing rash from disease, and may not be aware of appropriate treatment strategies for this generally manageable adverse event. The objective of this report was to combine results from published literature with experiences and recommendations from multiple investigators and institutions into clinical best practice recommendations to assist healthcare providers in identifying and managing mogamulizumab-associated rash. Optimal management, which includes biopsy confirmation and steroid treatment, requires a multidisciplinary approach among oncology, dermatology, and pathology practitioners. INFOGRAPHIC.

Brentuximab Vedotin for Relapsed or Refractory Sézary Syndrome.

Importance: Treatment options for Sézary syndrome (SS) are limited and associated with low response rates. Brentuximab vedotin is a CD30-directed antibody-drug conjugate approved for refractory CD30-positive cutaneous T-cell lymphoma. However, limited data exist on its efficacy in SS, including in the pivotal phase 3 ALCANZA (A Phase 3 Trial of Brentuximab Vedotin (SGN-35) Versus Physician's Choice [Methotrexate or Bexarotene] in Participants With CD30-Positive Cutaneous T-Cell Lymphoma) trial. Objective: To assess the preliminary efficacy and tolerability of brentuximab vedotin for SS. Design, Setting, and Participants: From January 1, 2017, to July 31, 2020, a total of 13 patients with SS received brentuximab vedotin and were analyzed as part of a retrospective case series. Median follow-up was 10.4 months (range, 1.4-34.6 months). All patients were 18 years or older with a diagnosis of SS and with B2 blood involvement at the time brentuximab vedotin therapy was initiated. This single-center study was conducted at a major academic referral center. Interventions: Intravenous brentuximab vedotin administration approximately every 3 weeks. Main Outcomes and Measures: The primary end point was the global response rate. Outcomes were assessed in the skin and lymph nodes per the 2011 European Organization for Research and Treatment of Cancer-International Society of Cutaneous Lymphoma response criteria and in the blood per the 2018 Prospective Cutaneous Lymphoma International Prognostic Index revised blood response criteria. Results: The study included 13 patients (8 [62%] male; mean [SD] age, 68.2 [8.6] years). Of these 13 patients, 5 (38%) achieved a global response after a median of 6 cycles, including 1 complete response. Response rates by disease compartment were 38% in the skin, 63% in the blood, and 50% in the lymph nodes. Three of 11 patients (27%) with pruritus reported improvement. Skin CD30 positivity (>10%) was detected in 9 patients but was not associated with responses. Among responders, the median time to response was 6 weeks (range, 6-9 weeks), and the median duration of response was 5.5 months (range, 2.5-28.9 months). The median time to next treatment was 3.2 months (range, 1.5-36.7 months). Peripheral neuropathy occurred in 4 patients but resolved in 2 patients. Grade 2 adverse events were neuropathy (n = 2), constipation (n = 1), and hand-foot syndrome (n = 1). Conclusions and Relevance: In this case series, brentuximab vedotin use was associated with some efficacy in SS across multiple disease compartments and in the setting of refractory disease or low CD30 skin expression. Brentuximab vedotin may offer a manageable treatment schedule and low incidence of significant toxic effects.

Granulomatous Dermatitis Associated With Rubella Virus Infection in an Adult With Immunodeficiency.

IMPORTANCE: Immunodeficiency-related, vaccine-derived rubella virus (RuV) as an antigenic trigger of cutaneous and visceral granulomas is a rare, recently described phenomenon in children and young adults treated with immunosuppressant agents. OBJECTIVE: To perform a comprehensive clinical, histologic, immunologic, molecular, and genomic evaluation to elucidate the potential cause of an adult patient's atypical cutaneous granulomas. DESIGN, SETTING, AND PARTICIPANTS: A prospective evaluation of skin biopsies, nasopharyngeal swabs, and serum samples submitted to the Centers for Disease Control and Prevention was conducted to assess for RuV using real-time reverse-transcriptase polymerase chain reaction (RT-PCR) and viral genomic sequencing. The samples were obtained from a man in his 70s with extensive cutaneous granulomas mimicking both cutaneous sarcoidosis (clinically) and CD8+ granulomatous cutaneous T-cell lymphoma (histopathologically). The study was conducted from September 2019 to February 2021. MAIN OUTCOMES AND MEASURES: Identification and genotyping of a novel immunodeficiency-related RuV-associated granulomatous dermatitis. RESULTS: Immunohistochemistry for RuV capsid protein and RT-PCR testing for RuV RNA revealed RuV in 4 discrete skin biopsies from different body sites. In addition, RuV RNA was detected in the patient's nasopharyngeal swabs by RT-PCR. The full viral genome was sequenced from the patient's skin biopsy (RVs/Philadelphia.PA.USA/46.19/GR, GenBank Accession #MT249313). The patient was ultimately diagnosed with a novel RuV-associated granulomatous dermatitis. CONCLUSIONS AND RELEVANCE: The findings of this study suggest that clinicians and pathologists may consider RuV-associated granulomatous dermatitis during evaluation of a patient because it might have implications for the diagnosis of cutaneous sarcoidosis, with RuV serving as a potential antigenic trigger, and for the diagnosis of granulomatous cutaneous T-cell lymphoma, with histopathologic features that may prompt an evaluation for immunodeficiency and/or RuV.

Low-Dose Total Skin Electron Beam Therapy as Part of a Multimodality Regimen for Treatment of Sézary Syndrome: Clinical, Immunologic, and Molecular Analysis.

Importance: Sézary syndrome (SS) is an advanced form of cutaneous T-cell lymphoma with few long-term remissions observed. Objective: To profile 3 patients with SS who have experienced long-term remission following the addition of low-dose total skin electron beam therapy (TSEBT) to systemic regimens of extracorporeal photopheresis, bexarotene, and interferon-γ. Design, Setting, and Participants: This is a retrospective case series with additional investigations of patient-donated samples to assess therapeutic response. The study was conducted at the University of Pennsylvania Cutaneous Lymphoma Clinic and follows 3 patients with stage IVA1 CD4+ SS who presented to the clinic between November 1, 2009, and November 1, 2017, and who had a history of SS that was refractory to multimodality systemic therapy prior to receiving low-dose TSEBT. Interventions: Patients were treated in a multimodality fashion with combined extracorporeal photopheresis, bexarotene, interferon-γ, and low-dose TSEBT. Main Outcomes and Measures: To characterize treatment responses in these patients, the extent of skin disease was measured with the modified severity weighted assessment tool. Blood disease was measured with flow cytometric assessments of Sézary cell count, CD4:CD8 ratio, and high throughput sequencing of the T-cell receptors. To assess for restoration of immune function, we measured markers of immune exhaustion, including PD-1 (programmed cell death 1), TIGIT (T-cell immunoreceptor with immunoglobulin and ITIM domains), CTLA4 (cytotoxic T-lymphocyte-associated protein 4), TOX (thymocyte selection-associated high mobility group box protein), and Foxp3 (forkhead box P3) on circulating CD4 and CD8 T cells, along with production capacity of interferon-γ by lymphocytes following activation stimuli. Results: Following administration of low-dose TSEBT and maintenance of the other therapies, remissions ranged from 24 to 30 months, with complete responses in 2 patients ongoing. Markers of immune exhaustion including PD-1, TIGIT, CTLA4, TOX, and Foxp3 were significantly reduced from baseline following TSEBT, along with enhanced production capacity of interferon-γ by lymphocytes following activation stimuli. High throughput sequencing demonstrated near-complete eradication of the circulating clone among 2 of 3 patients with stable levels in 1. Conclusions and Relevance: We describe 3 patients who achieved long-term clinical and molecular remissions following low-dose TSEBT as part of a multimodality regimen for treatment of SS. As long-term remissions in SS are uncommon, this approach demonstrates promise, and clinical trials should be considered.

Activating transcription factor 3 (ATF3) expression is increased in erythema multiforme and is regulated by IFN-gamma in human keratinocytes.

Activating transcription factor 3 (ATF3) expression is increased in erythema multiforme and is regulated by IFN-gamma in human keratinocytes. Experimental Dermatology 2010; 19: e310-e313. Abstract: Activating transcription factor 3 (ATF3) is a member of the ATF/cyclic AMP responsive element-binding protein (CREB) family of transcription factors and is involved in the regulation of immune responses, apoptosis, DNA repair and oncogenesis. The epidermal expression of ATF3 in the setting of cutaneous inflammation has not been well characterized. To examine the expression of ATF3 in the setting of inflammatory skin disease, ATF3 protein expression was analysed by immunohistochemistry (IHC). We found diffuse epidermal ATF3 protein expression in skin biopsies of erythema multiforme (EM). Given the role of interferon (IFN)-gamma in erythema multiforme, we sought to examine the impact of IFN-gamma on ATF3 expression in human keratinocytes. IFN-gamma induced ATF3 mRNA and protein in primary human keratinocytes and HaCaT cells. Thus, epidermal ATF3 expression can be increased in the setting of inflammatory skin diseases and is regulated by IFN-gamma in human keratinocytes.