Erdheim-Chester Disease Due to a Novel Internal Duplication of NRAS: Response to Targeted Therapy with Cobimetinib.

Histiocytoses encompass a group of exceptionally rare disorders characterized by the abnormal infiltration of tissues by histocytes. Among these, Erdheim-Chester disease (ECD) stands out as a multisystem histiocytosis that typically affects bones and various other tissues. Historically, the treatment of ECD has been challenging. However, recent breakthroughs in our understanding, particularly the discovery of somatic mutations in the RAS-MAPK pathway, have opened new opportunities for targeted therapy in a significant subset of patients with ECD and other histiocytoses. In this report, we present the case of a patient with ECD harboring a previously unidentified microduplication in the NRAS gene in a small fraction of skin cells. This discovery played a pivotal role in tailoring an effective therapeutic approach involving kinase inhibitors downstream of NRAS. This case underscores the crucial role of deep sequencing of tissue samples in ECD, enabling the delivery of personalized targeted therapy to patients.

Tocilizumab in giant cell arteritis: differences between the GiACTA trial and a multicentre series of patients from the clinical practice.

OBJECTIVES: A potential point of concern among clinicians is whether results derived from the clinical trials can be reasonably applied or generalised to a definable group of patients seen in real world. It can be the case of the GiACTA study that is a phase III randomised controlled trial of tocilizumab (TCZ) in giant cell arteritis (GCA). To address this question, we compared the clinical features and the responses to TCZ from the GiACTA trial patients with those from a series of GCA seen in the daily clinical practice. METHODS: Comparative study of clinical features between patients from the GiACTA trial (overall n=251) and those from a multicentre series of real-world GCA patients undergoing TCZ therapy (n=134). The diagnosis of GCA in the GiACTA trial was established by the ACR modified criteria whereas in the series of real-world patients it was made by using the ACR criteria, a positive biopsy of temporal artery or the presence of imaging techniques consistent with large-vessel vasculitis in individuals who presented cranial symptoms of GCA. GiACTA trial patients received subcutaneous TCZ (162 mg every 1 or 2 weeks) whereas those from the clinical practice series were treated using standard IV dose (8 mg/kg/month) or subcutaneous (162 mg/week). RESULTS: Real-life patients undergoing TCZ were older with longer disease duration and higher values of ESR and had received conventional immunosuppressive therapy (mainly methotrexate) more commonly than those included in the GiACTA trial. Despite clinical differences, TCZ was equally effective in both GiACTA trial and clinical practice patients. However, serious infections were more commonly observed in GCA patients recruited from the clinical practice. CONCLUSIONS: Despite clinical differences with patients recruited in clinical trials, data from real-life patients confirm the efficacy of TCZ in GCA.

COVID-19 patients with psoriasis and psoriatic arthritis on biologic immunosuppressant therapy vs apremilast in North Spain.

Immunosuppressive and immunomodulatory treatments are critical for the management of inflammatory and autoimmune conditions such as psoriasis or psoriatic arthritis. Similar to those illnesses, the lung injury and acute respiratory distress shown in coronavirus disease 2019 (COVID-19) patients are the result of a disruption in the balance of pro- and anti-inflammatory cytokines. This hyperinflammatory response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), associated with the severity of the coronavirus disease, is called the cytokine storm. There is a growing concern regarding how patients on immunosuppressant biologic therapies might be at higher risk of being infected and whether they need to discontinue their treatment preemptively. Clinical data on COVID-19-infected patients with psoriasis or psoriatic arthritis are still scarce. Here, we presented seven cases of these type of patients. The patient infected with COVID-19 on apremilast and the one on apremilast with infected spouse showed the best safety profile and mildest symptoms. One of the secukinumab patients also presented a relatively good outcome. Infliximab patients and the one with serious comorbidities showed the worst outcome. Even though more clinical data are yet needed to draw strong conclusions, apremilast could be a safer alternative for dermatology and rheumatology patients in case of clinically important active infection.

Successful Optimization of Adalimumab Therapy in Refractory Uveitis Due to Behçet's Disease.

PURPOSE: To assess efficacy, safety, and cost-effectiveness of adalimumab (ADA) therapy optimization in a large series of patients with uveitis due to Behçet disease (BD) who achieved remission after the use of this biologic agent. DESIGN: Open-label multicenter study of ADA-treated patients with BD uveitis refractory to conventional immunosuppressants. SUBJECTS: Sixty-five of 74 patients with uveitis due to BD, who achieved remission after a median ADA duration of 6 (range, 3-12) months. ADA was optimized in 23 (35.4%) of them. This biologic agent was maintained at a dose of 40 mg/subcutaneously/2 weeks in the remaining 42 patients. METHODS: After remission, based on a shared decision between the patient and the treating physician, ADA was optimized. When agreement between patient and physician was reached, optimization was performed by prolonging the ADA dosing interval progressively. Comparison between optimized and nonoptimized patients was performed. MAIN OUTCOME MEASURES: Efficacy, safety, and cost-effectiveness in optimized and nonoptimized groups. To determine efficacy, intraocular inflammation (anterior chamber cells, vitritis, and retinal vasculitis), macular thickness, visual acuity, and the sparing effect of glucocorticoids were assessed. RESULTS: No demographic or ocular differences were found at the time of ADA onset between the optimized and the nonoptimized groups. Most ocular outcomes were similar after a mean ± standard deviation follow-up of 34.7±13.3 and 26±21.3 months in the optimized and nonoptimized groups, respectively. However, relevant adverse effects were only seen in the nonoptimized group (lymphoma, pneumonia, severe local reaction at the injection site, and bacteremia by Escherichia coli, 1 each). Moreover, the mean ADA treatment costs were lower in the optimized group than in the nonoptimized group (6101.25 euros/patient/year vs. 12 339.48; P < 0.01). CONCLUSION: ADA optimization in BD uveitis refractory to conventional therapy is effective, safe, and cost-effective.

PLCG1 mutations in cutaneous T-cell lymphomas.

Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of primary cutaneous T-cell lymphoproliferative processes, mainly composed of mycosis fungoides and Sézary syndrome, the aggressive forms of which lack an effective treatment. The molecular pathogenesis of CTCL is largely unknown, although neoplastic cells show increased signaling from T-cell receptors (TCRs). DNAs from 11 patients with CTCL, both normal and tumoral, were target-enriched and sequenced by massive parallel sequencing for a selection of 524 TCR-signaling-related genes. Identified variants were validated by capillary sequencing. Multiple mutations were found that affected several signaling pathways, such as TCRs, nuclear factor κB, or Janus kinase/signal transducer and activator of transcription, but PLCG1 was found to be mutated in 3 samples, 2 of which featured a redundant mutation (c.1034T>C, S345F) in exon 11 that affects the PLCx protein catalytic domain. This mutation was further analyzed by quantitative polymerase chain reaction genotyping in a new cohort of 42 patients with CTCL, where it was found in 19% of samples. Immunohistochemical analysis for nuclear factor of activated T cells (NFAT) showed that PLCG1-mutated cases exhibited strong NFAT nuclear immunostaining. Functional studies demonstrated that PLCG1 mutants elicited increased downstream signaling toward NFAT activation, and inhibition of this pathway resulted in reduced CTCL cell proliferation and cell viability. Thus, increased proliferative and survival mechanisms in CTCL may partially depend on the acquisition of somatic mutations in PLCG1 and other genes that are essential for normal T-cell differentiation.

Histopathologic differences between cutaneous vasculitis associated with severe bacterial infection and cutaneous vasculitis secondary to other causes: study of 52 patients.

OBJECTIVES: To determine if cutaneous vasculitis (CV) associated with severe infection has some histopathologic findings that may help us to differentiate patients with this condition from other patients with CV. METHODS: We reviewed the skin biopsy specimens of patients with leukocytoclastic CV associated with a severe bacterial infection. Histopathologic findings of these patients were compared with those observed in leukocytoclastic CV secondary to other causes. Biopsy-proven leukocytoclastic CV were stratified as follows: group a): CV associated with severe underlying bacterial infection; group b): CV without severe bacterial infection but with systemic involvement; group c): CV without systemic involvement. Slides were reviewed by expert pathologists that were blind to the clinical information. The severity of vascular lesions was measured according to a semiquantitative scale (Hodge index). A comparative study between group a) and the other groups was conducted. RESULTS: group a) included 12 patients (2 women/10 men), mean age± SD 56±15 years; group b) 21 patients (10 women/11 men), 52±18 years; and group c) 19 patients (12 women/7 men), 59±24 years. Presence of neutrophilia was significantly increased in biopsies from group a) when compared with the other two groups. Also, a trend to higher frequency of pustular dermatosis was found in patients from group a). Hodge index, degree of inflammatory infiltrate and deep arterioles involvement were similar in all groups. CONCLUSIONS: Neutrophilia is common in skin biopsies of patients with CV associated with severe bacterial infection. No other histopathological findings help us to establish the presence of a severe underlying infection.

Tocilizumab in patients with Takayasu arteritis: a retrospective study and literature review.

OBJECTIVES: To assess the efficacy of tocilizumab (TCZ) in patients with Takayasu arteritis (TA). METHODS: Multicentre open-label retrospective study. RESULTS: Eight patients (all women) with a mean age of 34±16 years, median 36 years (range: 7-57) were assessed. The main clinical features at TCZ therapy onset were: constitutional symptoms (n=4), fever (n=3), headache (n=2), chest pain (n=1), abdominal pain (n=1), mesenteric ischaemia (n=1), myalgia involving the lower limbs (n=1), cerebral vascular insufficiency (n=1), malaise (n=1), upper limb claudication (n=1) and nodular scleritis (n=1). Besides corticosteroids and before TCZ treatment onset, 7 of 8 patients had also received several conventional immunosuppressive and/or biologic agents. Seven patients experienced marked clinical improvement in the first 3 months after the onset of TCZ therapy. After a median follow-up of 15.5 [interquartile range-IQR: 12-24] months, 7 patients were asymptomatic. The median C-reactive protein decreased from 3.09 [IQR: 0.5-12] to 0.15 [IQR: 0.1-0.5] mg/dL (p=0.018), and median erythrocyte sedimentation rate from 40 [IQ range: 28-72] to 3 [IQR: 2-5] mm/1st hour (p=0.012). The median dose of prednisone was also tapered from 42.5 [IQR: 25-50] to 2.5 [IQR: 0-7.5] mg/day (p=0.011). However, TCZ had to be discontinued in 1 patient because she developed a systemic lupus erythematosus, and in another patient due to inefficiency. TCZ dose was reduced in a patient because of mild thrombocytopenia. CONCLUSIONS: TCZ appears to be effective in the management of patients with TA, in particular in patients refractory to corticosteroids and/or conventional immunosuppressive drugs.

Primary cutaneous anaplastic large cell lymphomas with 6p25.3 rearrangement exhibit particular histological features.

AIMS: CD30-positive primary cutaneous lymphoproliferative disorders include several entities with differing clinical presentation but overlapping histological features, including lymphomatoid papulosis and primary cutaneous anaplastic large cell lymphoma (C-ALCL). DUSP22-IRF4 locus translocation is present in 20-57% of C-ALCLs, and has also been described in a series of 11 lymphomatoid papulosis patients, where it was associated with a particular biphasic histological pattern, including pagetoid reticulosis-type epidermal infiltration. We aimed to study whether the presence of this translocation may define distinctive histological features in C-ALCL. METHODS AND RESULTS: We collected three cases of C-ALCL with histological features similar to those described in the new variant of lymphomatoid papulosis with 6p25.3 rearrangement. We studied their histological features and immunophenotype, using a panel of antibodies against CD30, TCR-ßF1, TCR-γ, CD4, CD8, CD20, Ki-67 and ALK. FISH analyses were performed using an IRF4-DUSP22 break-apart probe for the study of the 6p25.3 rearrangement. FISH results were positive in the three cases, which all showed distinctive histological and immunohistochemical features: a diffuse dermal infiltrate of atypical medium-to-large cells, and marked epidermotrophism with small, atypical intra-epidermal lymphocytes. CONCLUSIONS: Our findings suggest that the presence of 6p25.3 rearrangement might be related to this particular biphasic pattern.

Tocilizumab in refractory aortitis: study on 16 patients and literature review.

OBJECTIVES: Non-infectious aortitis is often refractory to standard immunosuppressive therapy. Since IL-6 has been implicated in the pathogenesis of aortitis, we assessed the efficacy of the anti-IL6 receptor monoconal antibody tocilizumab (TCZ) in a series of patients with refractory non-infectious aortitis. METHODS: Review of 16 patients (14 women/2 men) with refractory aortitis diagnosed by imaging (CT angiography, MR angiography, and/or PET) that were treated with TCZ. RESULTS: The mean age±SD was 51.4±20.1 years. The underlying conditions were: Takayasu arteritis (TakA) (n=7 cases), giant cell arteritis (GCA) (n=7), relapsing polychondritis (RP) (n=1), and aortitis associated with retroperitoneal fibrosis (n=1). TCZ was the first biologic drug used in all patients with GCA and in the patient with aortitis associated with retroperitoneal fibrosis but in only 2 of 7 TakA patients. In the remaining cases anti-TNF inhibitors were prescribed before TCZ (standard dose was 8 mg/kg/iv/4 weeks). After a mean±SD follow-up of 11.8±6.6 months most patients experienced clinical improvement, showing reduction of erythrocyte sedimentation rate from 43±36 mm/1st h to 5±4 mm/1st h at last visit. At TCZ onset, 25% of patients had fever and 19% polymyalgia rheumatica. These manifestations disappeared after 3 months of TCZ therapy. A corticosteroid sparing effect was also achieved (from 27.3±17.6 mg/day of prednisone at TCZ onset to 4.2±3.8 mg/day at last visit). TCZ had to be discontinued in a patient because of severe neutropenia. CONCLUSIONS: TCZ appears to be effective and relatively safe in patients with inflammatory aortitis refractory to corticosteroids or to other biologic immunosuppressive drugs.

Refractory polymyalgia rheumatica as presenting manifestation of large-vessel vasculitis associated to sarcoidosis. Successful response to adalimumab.

Sarcoidosis may present with musculoskeletal features or mimic rheumatic diseases. We report on a patient who had been initially diagnosed as having polymyalgia rheumatica. Because of refractory disease associated to atypical features such as severe inflammatory low back pain, dull and achy pain in the thighs, claudication of the lower limbs and bad response to corticosteroids and methotrexate (MTX), an 18F-fluorodeoxyglucosepositron emission tomography with CT (FDG PET/CT) was performed. This technique disclosed data suggestive of arteritis of large vessels involving the ascending, arch and descending aorta as well as high FDG uptake in the femoral and posterior tibial arteries of both lower extremities. Also, increased FDG uptake was observed in the right paratracheal, retrotracheal, subcarinal, gastrohepatic ligament, coeliac and right renal hilar lymph nodes. Four lymph nodes, taken during mediastinoscopy, confirmed a diagnosis of sarcoidosis. Treatment with adalimumab (40 mg every 2 weeks subcutaneously) along with prednisone and MTX was initiated yielding progressive improvement of symptoms and normalisation of laboratory abnormalities. Five months after the onset of adalimumab a new FDG PET/CT showed complete absence of uptake of lymph nodes as well as decrease of vascular FDG uptake. To our knowledge, this is the first patient treated with adalimumab because of a large-vessel vasculitis in the setting of sarcoidosis refractory to conventional therapy. This case reinforces the claim that sarcoidosis should be considered a diagnostic challenge in the assessment of patients presenting with inflammatory musculoskeletal symptoms.

Polymyalgia rheumatica as presenting manifestation of vasculitis involving the lower extremities in a patient with ulcerative colitis.

Extraintestinal features may be observed in patients with ulcerative colitis (UC). We describe a 69-year-old woman who was initially diagnosed as having polymyalgia rheumatica (PMR). Prednisone was progressively tapered to complete discontinuation a year and a half after PMR diagnosis. However, at that time, she started to complain of asthenia, abdominal cramping and pain on the left side, weight loss and bloody diarrhoea. A colonoscopy confirmed a diagnosis of left-sided UC. She experienced several flares of the disease that required admission and treatment with high-dose corticosteroids and azathioprine. Colectomy was performed as the disease became refractory to these therapies. Four months after surgery, when the patient was not receiving any corticosteroid therapy, she started to feel dull and achy pain in the thighs along with claudication of the lower limbs. An 18F-fluorodeoxyglucosepositron emission tomography with CT (FDG PET/CT) disclosed an inflammatory process with mild-moderate diffuse increased metabolism in the thoracic aorta and markedly increased FDG uptake in the in the femoral and posterior tibial arteries on both sides. Treatment with the anti-TNF-alpha monoclonal antibody-adalimumab (40 mg every 2 weeks subcutaneously) along with prednisone (initial dose 15 mg/day) yielded rapid improvement of symptoms. Also, a new FDG PET/CT performed 4 months later disclosed marked decrease of FDG uptake in the involved arteries.This report emphasises the importance of suspecting the presence of large- and medium-vessel vasculitis in a patient with UC presenting with musculoskeletal features. It also highlights the beneficial effect of TNF-antagonists in vasculitis associated to UC.

Vitiligo-like Depigmentation in a Patient Undergoing Treatment with Nivolumab for Advanced Renal-cell Carcinoma.

Dear Editor, Nivolumab is a fully human monoclonal antibody that targets the programmed cell death 1 (PD-1) immune checkpoint. It has been approved for its use in several types of advanced solid tumors, including melanoma, lung cancer, and renal cell carcinoma (RCC). The inhibition of PD-1 leads to an enhanced adaptive immune response against tumor cells through the activation of T-cells. Vitiligo-like depigmentation (VLD) is a well-known side-effect in patients with melanoma that are being treated with anti PD-1 therapies (1). However, its development in patients undergoing treatment with nivolumab for cancers other than melanomas has been described very rarely. To our knowledge, herein we report the second case of nivolumab-induced VLD in a patient with metastatic RCC (2). The patient was a 63-year-old man who had a medical history of advanced RCC. He had initially undergone nephrectomy, and three months later he presented with local relapse and lung metastases. He had then received different treatment regimes, presenting with progression each time, until he finally started treatment with nivolumab. Five months after its introduction, the patient developed a disseminated hypochromic eruption. No other drugs were started over that period. He had no personal or family history of vitiligo or other autoimmune disorders. Dermatological examination revealed multiple, symmetrical, well-demarcated, depigmented macules involving his face, neck, torso, hands, and forearms. (Figure 1, a). Preservation of pigment in hair follicles could be seen on the dorsal aspect of his hands (Figure 1, b). Two 4-mm punch biopsies were taken, one from one from a depigmented patch and another from normally pigmented skin. In the first one, immunohistochemical analysis with Melan-A immunostaining demonstrated the absence of melanocytes, whereas melanocytes were present in the second one. A CD-8+ positive infiltrate was present in both biopsies, especially in the first one (Figure 2). The patient was diagnosed with VLD associated with nivolumab therapy. Since the patient was asymptomatic, no treatment was prescribed. He was advised to protect the achromic areas from sun exposure. In our patient, a causal association between the onset of VLD and the treatment with nivolumab cannot be completely ruled out. However, the clinical presentation with flecked macules in sun-exposed areas was consistent with what has been described in other patients presenting with VLD after starting treatment with this chemotherapeutic agent. The time to onset in our case was also within the limits which have been previously reported for this side-effect (16-52 weeks) (3). Therefore, we believe that a causal association is very probable. In patients with advanced melanoma who are treated with PD-1 inhibitors, the development of vitiligo-like lesions has been proved to be associated with improved progression-free and overall survival rates (4,5). This mechanism is not fully understood, but it has been suggested that inhibition of PD-1 could cause a loss of tolerance to melanocytic antigens, thus leading to a CD-8 T-cell dependent destruction of melanocytes present in the melanoma as well as in healthy skin (3,5). The presence of CD8 T-lymphocytes in our patient's biopsies supports this theory. However, the development of this condition in patients suffering from non-melanoma cancers suggests that different mechanisms, independent from melanoma, could also be involved. Larger studies are needed in order to determine if VLD also correlates with better survival rates in patients treated with nivolumab for non-melanoma malignancies. In conclusion, new checkpoint inhibitors can cause VLD not only in patients suffering from melanoma but also in those affected by other tumors. We believe dermatologists should play a key role in the management of this side-effect. Therefore, we ought to be familiar with it in order to be able to identify and treat it appropriately without discontinuation of anticancer treatment.

Linear Scleroderma and Primary Sclerosing Cholangitis: An Undescribed Association.

Linear scleroderma (LS) is clinically characterized by the presence of sclerotic areas of skin, which develop in a linear pattern. Primary sclerosing cholangitis is a cholestatic disorder that can lead to end-stage liver disease. We present, for the first time in English literature, the case of a patient suffering from both the diseases. This highlights the fact that, even though LS has conventionally been considered to be a form of localized scleroderma, this does not necessarily imply that it is an exclusively cutaneous disease.

The presence of Merkel cell carcinoma polyomavirus is associated with a distinct phenotype in neoplastic Merkel cell carcinoma cells and their tissue microenvironment.

AIMS: Merkel cell carcinoma (MCC) is an aggressive primary neuroendocrine tumor of the skin, associated with Merkel cell polyomavirus (MCPyV) in 49-89% of cases, depending on the country of origin and the techniques of detection. The presence of MCPyV defines heterogeneity in MCC; MCPyV-negative cases bear a much higher mutational load, with a distinct ultraviolet signature pattern featuring C > T transitions, as a consequence of exposure to ultraviolet light radiation. MCC stroma has not been thoroughly studied, although MCC patients benefit from therapy targeting PD1/PDL1. METHODS AND RESULTS: In this study, using Tissue Microarrays and immunohistochemistry, we have analyzed a series of 219 MCC cases in relation to the presence of MCPyV, and confirmed that the presence of MCPyV is associated with changes not only in the neoplastic cells, but also in the composition of the tumor stroma. Thus, MCPyV, found in 101/176 (57,4%) analyzable cases, exhibits changes in its tumor morphology, the density of the inflammatory infiltrate, the phenotype of the neoplastic cells, and the cell composition of the tumor stroma. MCPyV presence is negatively correlated with a higher level of p53 expression, and associated with a very high frequency (86%) of HLA-I expression loss, a higher apoptotic index, and a stroma richer in T-cells, cytotoxic T-cells, macrophages, PDL1-positive macrophages, and B-cells. CONCLUSIONS: Our findings provide evidence of the basic heterogeneity of MCC, supporting the hypothesis that the presence of MCPyV may induce a rich inflammatory response, which is at least partially avoided through loss of HLA-I antigen expression. On the other hand, MCPyV-negative cases show a much higher frequency of stronger p53 expression and, probably, p53 alterations.

High prevalence of cryofibrinogenemia in patients with chilblains during the COVID-19 outbreak.

BACKGROUND: Many cutaneous manifestations have been described in possible association with the COVID-19 pandemic, including acral lesions resembling chilblains. The underlying pathomechanisms of COVID-19 chilblains are not fully understood. The aim of this study was to describe the clinical, pathological, and laboratory findings of a series of patients who developed chilblains during the COVID-19 outbreak and to investigate the possible factors that could be involved in the pathogenesis of these lesions. METHODS: We conducted a prospective cohort study that included 54 patients who presented with chilblains during the highest peak in the incidence of COVID-19 in Cantabria (northern Spain). Skin biopsies were performed on 10 of these patients who presented with recent lesions. Laboratory investigations, including immunological analysis, serological studies, and the assessment of cryoproteins, were also performed. RESULTS: Most patients presented erythematous plaques located on the toes and/or purpuric macules located on the feet. Histopathological findings were compatible with those of idiopathic chilblains. Immunohistochemical evaluation showed C3d and C4d deposits in the vessel walls in seven cases. The autoimmunity panel was negative in most of our series. Cryoprotein testing showed positive cryofibrinogen in two-thirds (66.7%) of the patients assessed. On follow-up, most patients presented almost complete resolution, although six patients required prednisone and antiaggregant drug treatment. CONCLUSIONS: This study shows, for the first time to our knowledge, a high prevalence of cryofibrinogenemia in patients with chilblains during the COVID-19 pandemic. Cryofibrinogenemia could be implicated in the pathogenesis of chilblains related to COVID-19.