The anti‐HLA antibody detection has been improved in sensitivity and specificity with solid‐phase antigen bead (SAB) assays based on Luminex. However, false positive results due to denatured HLA ...(dHLA) may arise after single antigen test. The aim of this study was to compare the performance of the two Luminex technology‐based anti‐HLA detection kits available in the market in showing undesired anti‐HLA antibody results. A prospective cohort was assessed for anti‐HLA antibodies with single antigen A manufacturer (AM) kit and a comparison cohort with single antigen B manufacturer (BM) kit. A total of 11 out of 90 patients in a prospective cohort presented monospecific HLA‐I antibodies with AM, and 5 out of 11 confirmed monospecific reaction with BM. Despite the confirmation of monospecific reaction with both manufacturers, 80% were assigned as dHLA reaction by specific crossmatch. Further comparative cohorts detected four out of six monospecific reactions with BM that were confirmed as possible dHLA reactions. A positive SAB test should rule out a reaction against a dHLA molecule, thus avoidance of prolonged waitlist periods or misattribution of anti‐HLA reactions after transplantation.
Blau syndrome (BS) is an autoinflammatory disorder characterized by non-caseating granulomatous dermatitis, arthritis, and uveitis. We present a case of refractory and severe BS that was treated with ...the Janus kinase inhibitors (JAKINIBS), Tofacitinib (TOFA) and then Baricitinib (BARI). Our aim was to describe the clinical and immunological outcomes after treatment with JAKINIBS. Blood tests and serum samples were obtained during follow-up with TOFA and BARI. We assessed their effects on clinical outcomes, acute phase reactants, absolute lymphocyte counts (ALCs), lymphocyte subset counts, immunoglobulins, and cytokine levels. A review of the literature on the use of JAKINIBS for the treatment of uveitis and sarcoidosis was also conducted. TOFA led to a rapid and maintained disease control and a steroid-sparing effect. A decrease from baseline was observed in ALC, CD3+, CD4+, CD8+, and natural killer (NK) cell counts. B-cells were stable. Serum levels of interleukin (IL)-4 and tumor necrosis factor alpha (TNF-α) increased, whereas IL-2, IL-6, IL-10, and IL-17 maintained stable. TOFA was discontinued after 19 months due to significant lymphopenia. The initiation of BARI allowed maintaining adequate control of disease activity with an adequate safety profile. The literature review showed seven patients with uveitis and five with sarcoidosis treated with JAKINIBS. No cases of BS treated with JAKINIBS were found. We report the successful use of JAKINIBS in a patient with refractory and severe BS.
To report a case of fibrinous acute anterior uveitis associated with topical interferon-α2b (IFN-α2b) treatment for ocular surface squamous neoplasia in a patient with HLA-B27 uveitis predisposition.
...Case report.
We present the case of a 57-year-old man who received topical IFN-α2b as adjuvant therapy for a previously surgically removed ocular surface squamous neoplasia with affected surgical margins. Two weeks after topical IFN-α2b initiation, the patient was diagnosed with fibrinous acute anterior uveitis. Complementary tests to rule out other causes of uveitis resulted to be negative, except for HLA-B27, which tested positive. Response to treatment with topical corticosteroids and cyclopentolate was favorable. As IFN-α2b is considered an immune enhancer and has been widely associated with autoimmune side effects, topical therapy with IFN-α2b was temporally ceased until intraocular inflammation resolved. Topical IFN-α2b was resumed, and during follow-up, no signs of uveitis were detected. The main hypothesis is that IFN-α2b acts as a trigger for intraocular inflammation in individuals with uveitis predisposition.
Topical IFN-α2b could trigger intraocular inflammation in patients with uveitis susceptibility. It may be reasonable to use IFN-α2b cautiously in patients with a known history of uveitis or uveitis predisposition.
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.
TPM1 is one of the main hypertrophic cardiomyopathy (HCM) genes. Clinical information on carriers is relatively scarce, limiting the interpretation of genetic findings in individual patients. Our aim ...was to establish genotype-phenotype correlations of the TPM1 p.Arg21Leu variant in a serie of pedigrees.
TPM1 was evaluated by next-generation sequencing in 10 561 unrelated probands with inherited heart diseases. Familial genetic screening was performed by the Sanger method. We analyzed TPM1 p.Arg21Leu pedigrees for cosegregation, clinical characteristics, and outcomes. We also estimated the geographical distribution of the carrier families in Portugal and Spain.
The TPM1 p.Arg21Leu variant was identified in 25/4099 (0.61%) HCM-cases, and was absent in 6462 control individuals with other inherited cardiac phenotypes (P<.0001). In total, 83 carriers (31 probands) were identified. The combined LOD score for familial cosegregation was 3.95. The cumulative probability of diagnosis in carriers was 50% at the age of 50 years for males, and was 25% in female carriers. At the age of 70 years, 17% of males and 46% of female carriers were unaffected. Mean maximal left ventricular wall thickness was 21.4 ±7.65mm. Calculated HCM sudden death risk was low in 34 carriers (77.5%), intermediated in 8 (18%), and high in only 2 (4.5%). Survival free of cardiovascular death or heart transplant was 87.5% at 50 years. Six percent of carriers were homozygous and 18% had an additional variant. Family origin was concentrated in Galicia, Extremadura, and northern Portugal, suggesting a founder effect.
TPM1 p.Arg21Leu is a pathogenic HCM variant associated with late-onset/incomplete penetrance and a generally favorable prognosis.
TPM1 es uno de los principales genes en la miocardiopatía hipertrófica (MCH). La información clínica sobre portadores es relativamente escasa, lo cual limita la interpretación de los estudios genéticos. Nuestro objetivo es establecer la correlación genotipo-fenotipo de la variante p.Arg21Leu de TPM1 en una serie de familias.
Se evaluó el TPM1 mediante secuenciación de nueva generación en 10.561 probandos con cardiopatías hereditarias. Se genotipificó a los familiares mediante Sanger. Se analizaron la cosegregación, las características clínicas y los eventos cardiovasculares. Se estimó la distribuición geográfica de las familias en Portugal y España.
Se identificó la variente p.Arg21Leu de TPM1 en 25/4.099 (0,61%) casos con MCH y estaba ausente en 6.462 controles con otras cardiopatías familiares (p<0,0001). Se identificó a 83 portadores (31 probandos). La LOD score combinada para cosegregación fue 3,95. La probabilidad acumulada de diagnóstico en portadores a los 50 años fue del 50% para los varones y el 25% para las mujeres. El 17 de los varones y el 46% de las mujeres no estaban afectadas a los 70 años. El grosor medio del ventrículo izquierdo fue 21,4 ±7,65mm. El riesgo de muerte súbita-MCH fue bajo en 34 (77,5%), intermedio en 8 (18%) y alto en 2 (4,5%) de los portadores. La supervivencia libre de eventos cardiovasculares fue del 87,5% a los 50 años. El 6% de los portadores eran homocigotos y el 18% tenían una variante adicional. El origen de las familias se concentró en Galicia, Extremadura y norte de Portugal, lo que indica un efecto fundador.
P.Arg21Leu es una variante patogénica de TPM1 asociada con MCH de penetrancia tardía/incompleta y pronóstico generalmente favorable
Background: Cholangiocarcinoma (CCA) encompasses a heterogeneous group of malignant tumors with dismal prognosis and increasing incidence worldwide. Both late diagnosis due to the lack of early ...symptoms and the refractory nature of these tumors seriously compromise patients’ welfare and outcomes. Summary: During the last decade, immunotherapy and, more specifically, modulation of immune checkpoints-mediated signaling pathways have been under the spotlight in the field of oncology, emerging as a potential therapeutic approach for the treatment of several cancers, including CCA. Generally, high expression levels of immune checkpoints in patients with CCA have been associated with worse clinical outcomes, particularly with shorter overall survival and relapse-free survival. Thus, immune checkpoint inhibitors (ICIs), which mainly constitute different monoclonal antibodies, have been developed in order to hamper the immune checkpoint-mediated pathways. Interestingly, chemotherapy may increase the expression of immune checkpoints, while other therapeutic approaches such as ablative and targeted therapies may enhance their antitumor activity. In this sense, several clinical trials evaluated the safety and efficacy of ICIs for CCA, both as a monotherapy and in combination with other ICIs or loco-regional and systemic therapies. Additionally, many other clinical trials are currently ongoing and results are eagerly awaited. Here, we summarize the key aspects of immune checkpoint molecules as prognostic factors and therapeutic targets in CCA, highlighting the most recent advances in the field and future research directions. Key Messages: (1) Effective therapeutic approaches for CCA are urgently needed. (2) Expression levels of immune checkpoints in patients with CCA have been proposed to be related with clinical outcomes. (3) Combination of different ICIs may outperform the efficacy of ICI monotherapy for CCA treatment. (4) Recent studies point toward the combination of ICIs and other common therapies, especially chemotherapy, as a promising strategy for treatment of CCA patients.
Cholangiocarcinoma (CCA) is a heterogeneous group of dysplastic disorders affecting the biliary epithelium. It is the second most common primary liver tumor which accounts for around 3% of all ...gastrointestinal cancers. CCA is very deadly due to its aggressiveness, late diagnosis and high chemoresistance. The incidence is increasing worldwide and the therapeutic options are very limited. Radiotherapy, chemotherapy, surgery and/or liver transplantation may be indicated in patients who meet certain criteria, but chances of success are low. There is therefore increasing interest in understanding the molecular mechanisms involved in the pathogenesis of this cancer type and in identifying new targets for therapy. Current strategies are based on targeting key signaling pathways involved in proliferation, survival, apoptosis and migration. In this review, the most relevant molecular mechanisms involved in the pathogenesis of CCA are discussed and the main preclinical and clinical studies are highlighted. Moreover, future directions in basic and clinical research are indicated.
Non-HLA Abs in Solid Organ Transplantation Gutiérrez-Larrañaga, María; López-Hoyos, Marcos; Renaldo, André ...
Transplantology (Basel, Switzerland),
07/2020, Letnik:
1, Številka:
1
Journal Article
Recenzirano
Odprti dostop
The role of anti-HLA antibodies in solid organ rejection is well established and these antibodies are routinely monitored both in patients in the waiting list and in the post-transplant setting. More ...recently, the presence of other antibodies directed towards non-HLA antigens, or the so-called minor histocompatibility antigens, has drawn the attention of the transplant community; however, their possible involvement in the graft outcome remains uncertain. These antibodies have been described to possibly have a role in rejection and allograft failure. This review focuses on the most studied non-HLA antibodies and their association with different clinical outcomes considered in solid organ transplantation with the aim of clarifying their clinical implication and potential relevance for routine testing.
Non-alcoholic fatty liver disease (NAFLD) is characterized by the excessive and detrimental accumulation of liver fat as a result of high-caloric intake and/or cellular and molecular abnormalities. ...The prevalence of this pathological event is increasing worldwide, and is intimately associated with obesity and type 2 diabetes mellitus, among other comorbidities. To date, only therapeutic strategies based on lifestyle changes have exhibited a beneficial impact on patients with NAFLD, but unfortunately this approach is often difficult to implement, and shows poor long-term adherence. For this reason, great efforts are being made to elucidate and integrate the underlying pathological molecular mechanism, and to identify novel and promising druggable targets for therapy. In this regard, a large number of clinical trials testing different potential compounds have been performed, albeit with no conclusive results yet. Importantly, many other clinical trials are currently underway with results expected in the near future. Here, we summarize the key aspects of NAFLD pathogenesis and therapeutic targets in this frequent disorder, highlighting the most recent advances in the field and future research directions.
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