Primary Cutaneous CD30-Positive Lymphoproliferative Disorders-Current Therapeutic Approaches with a Focus on Brentuximab Vedotin.

One of the most common subgroups of cutaneous T-cell lymphomas is that of primary cutaneous CD30-positive lymphoproliferative disorders. The group includes lymphomatoid papulosis (LyP) and primary cutaneous anaplastic large cell lymphoma (pcALCL), as well as some borderline cases. Recently, significant progress has been made in understanding the genetics and treatment of these disorders. This review article summarises the clinical evidence supporting the current treatment options for these diseases. Recent years have seen the introduction of novel agents into clinical practice; most of these target CD30, such as anti-CD30 monoclonal antibodies and conjugated antibodies (brentuximab vedotin), bispecific antibodies and cellular therapies, particularly anti-CD30 CAR-T cells. This paper briefly reviews the biology of CD30 that makes it a good therapeutic target and describes the anti-CD30 therapies that have emerged to date.

Leukemia Cutis-The Current View on Pathogenesis, Diagnosis, and Treatment.

Leukemia cutis (LC) is defined as the leukemic infiltration of the epidermis, the dermis, and the subcutaneous tissue. Leukemia cutis may follow or occur simultaneously with the diagnosis of systemic leukemia. However, cutaneous lesions are occasionally diagnosed as the primary manifestation of leukemia. Leukemic skin infiltrations demonstrate considerable variation regarding a number of changes, distribution, and morphology. The highest incidence of LC is observed in chronic lymphocytic leukemia, monocytic and myelomonocytic acute myeloid leukemia, and T-cell lineage leukemia. Although the pathogenic mechanism of the invasion of leukemic cells into the skin is not well understood, chemokine receptors and adhesion molecules as well as the genetic characteristics of leukemia are thought to play a role. Leukemic skin lesions may be localized or disseminated and may occur alone or in combination on any site of the skin, most frequently in the trunk and extremities. The most common clinical presentations of leukemia cutis are papules, nodules, macules, plaques, and ulcers. In most patients, the complete or partial resolution of cutaneous infiltrations occurs simultaneously with hematologic remission. However, in patients with resistant disease or recurrent skin infiltration, local radiotherapy can be used. This review presents recent data on the pathogenesis, diagnosis, and treatment of leukemic skin involvement in different types of leukemia.

Psoriatic Arthritis: Development, Detection and Prevention: A Scoping Review.

Psoriatic arthritis is a heterogenous chronic inflammatory disease that develops over time in some patients with psoriasis. The course of the disease is variable, with a broad clinical spectrum. The management of PsA has changed tremendously over the last decade, thanks to earlier diagnosis, a multidisciplinary approach and progress in pharmacological therapies. Therefore, screening for risk factors and the early signs of arthritis is highly important and recommended. Currently, research is focused on finding soluble biomarkers and developing imaging techniques that can improve the prediction of psoriatic arthritis. Among imaging modalities, ultrasonography seems to be the most accurate in detecting subclinical inflammation. Early intervention is based on the assumption that it is possible to prevent or delay psoriatic arthritis if systemic treatment for psoriasis can be administered early enough. This review article provides an overview of the current perspectives and evidence regarding the diagnosis, management and prevention of psoriatic arthritis.

Bruton's Kinase Inhibitors for the Treatment of Immunological Diseases: Current Status and Perspectives.

The use of Bruton's tyrosine kinase (BTK) inhibitors has changed the management of patients with B-cell lymphoid malignancies. BTK is an important molecule that interconnects B-cell antigen receptor (BCR) signaling. BTK inhibitors (BTKis) are classified into three categories, namely covalent irreversible inhibitors, covalent reversible inhibitors, and non-covalent reversible inhibitors. Ibrutinib is the first covalent, irreversible BTK inhibitor approved in 2013 as a breakthrough therapy for chronic lymphocytic leukemia patients. Subsequently, two other covalent, irreversible, second-generation BTKis, acalabrutinib and zanubrutinib, have been developed for lymphoid malignancies to reduce the ibrutinib-mediated adverse effects. More recently, irreversible and reversible BTKis have been under development for immune-mediated diseases, including autoimmune hemolytic anemia, immune thrombocytopenia, multiple sclerosis, pemphigus vulgaris, atopic dermatitis, rheumatoid arthritis, systemic lupus erythematosus, Sjögren's disease, and chronic spontaneous urticaria, among others. This review article summarizes the preclinical and clinical evidence supporting the role of BTKis in various autoimmune, allergic, and inflammatory conditions.

Variability of the rs333 in Polish patients with lupus erythematosus.

INTRODUCTION: Lupus erythematosus (LE) is an autoimmune disease with a strong influence of genetic and environmental factors. C-C motif chemokine receptor 5 (CCR5) gene expression may affect the development and intensity of LE. AIM: To evaluate the possible association between the 32bp deletion in rs333 locus located within the CCR5 gene and the development of LE or the occurrence of various clinical symptoms in the course of the disease. MATERIAL AND METHODS: One hundred and twenty patients with LE (77 with systemic lupus erythematosus (SLE) and 43 with discoid lupus erythematosus (DLE)) and 100 healthy controls from the Polish population were genotyped for deletion in rs333. RESULTS: 32 bp deletion in the rs333 was significantly more frequent among healthy individuals than DLE patients. Moreover, heterozygotes and homozygotes with deletion in rs333 were significantly more frequent within the control group than the group of patients with discoid lupus erythematosus. In contrast, any statistically significant differences in allele or genotype frequencies between healthy persons and SLE patients were observed. Furthermore, nucleotide sequence variability of rs333 was not associated with certain clinical symptoms of LE patients. CONCLUSIONS: Deletion in the rs333 might be a protective factor for DLE, but not SLE in the Polish population. Nevertheless further studies performed on larger populations are needed to confirm these observations.

Skin changes in hairy cell leukemia.

Skin lesions have been reported in about 10-12% of hairy cell leukemia (HCL) patients. Most are etiologically related to autoimmune or infectious processes, although secondary cutaneous neoplasms and drug-induced lesions are also reported. However, leukemia cutis with the direct infiltration of the skin by leukemic cells is extremely rare in HCL patients. This paper reviews the epidemiology, pathogenesis, clinical symptoms, diagnosis, and approach to treating skin lesions in HCL. A literature review of the MEDLINE database for articles in English concerning hairy cell leukemia, skin lesions, leukemia cutis, adverse events, infectious, cutaneous, drug reactions, neutrophilic dermatoses, secondary neoplasms, and vasculitis was conducted via PubMed. Publications from January 1980 to September 2020 were scrutinized. Additional relevant publications were obtained by reviewing the references from the chosen articles.

Methotrexate use and NAD+/NADH metabolism in psoriatic keratinocytes.

Methotrexate inhibits tetrahydrofolic acid production and influences mitochondrial oxygen uptake and activity of several enzymes in the respiratory chain reactions, which utilize nicotinamide adenine dinucleotide-linked (NAD-linked) substrates. Hyperproliferation of keratinocytes in psoriasis requires oxidative phosphorylation, in which the reduced form of nicotinamide adenine dinucleotide (NADH) is an electron donor. One hypothesis links increased cellular metabolism to the increased NADH/NAD+ ratio; as expected, the topical application of NAD+ (oxidized form of nicotinamide-adenine dinucleotide) resulted in a clinical improvement of psoriatic lesions in one study. Nevertheless, another report revealed reduced fluorescence of NADH in psoriatic plaques. The biological activity of NADH is not limited only to serving as the electron donor. It was also found to regulate gene transcription.

The role of endocan and selected pro-inflammatory cytokines in systemic lupus erythematosus.

INTRODUCTION: Systemic lupus erythematosus (SLE) is a multisystem inflammatory autoimmune disease with a wide spectrum of clinical manifestations. Cytokines such as interleukin-1 (IL-1) and tumour necrosis factor α (TNF-α) are involved in its pathogenesis. Endocan is a novel marker of endothelial dysfunction and is likely to be engaged in proinflammatory processes in SLE. AIM: To determine whether endocan serum concentration in SLE patients vary from healthy controls. MATERIAL AND METHODS: The study included 36 patients with SLE. SLEDAI-2K score was used to assess disease activity. The control group comprised 23 healthy volunteers. ELISA kits were used to assess serum concentrations of endocan, IL-1ß, TNF-α, vascular endothelial growth factor (VEGF) and high-sensitivity C reactive protein (hs-CRP). RESULTS: The serum concentration of endocan was significantly higher (p < 0.001) in the SLE group than in healthy individuals. A positive correlation was found between serum levels of endocan and IL-1ß (r = 0.47, p < 0.05). Active SLE patients (SLEDAI-2K score above 6 points) with an elevated total cholesterol level (above 5.17 mmol/l) were found to have VEGF concentration higher than those with a normal cholesterol level (p < 0.03). No other relevant relationships were found between the serum concentration of endocan, other laboratory parameters, anthropometric features, activity and duration of SLE. CONCLUSIONS: A higher serum level of endocan in SLE patients indicates its possible role in the pathogenesis of the disease and reflects endothelial dysfunction. Our findings indicate that endocan could serve as a potential marker of endothelial dysfunction in SLE.

Serum concentrations of IL-17A, IL-17B, IL-17E and IL-17F in patients with systemic sclerosis.

INTRODUCTION: Immune system activation, microvascular abnormalities and extracellular matrix deposition in tissues play roles in systemic sclerosis (SSc). Th17 cells producing interleukin (IL)-17 are involved in the pathogenesis of many autoimmune-mediated inflammatory diseases; however, the role of IL-17 in SSc remains unclear. MATERIAL AND METHODS: The concentrations of IL-17A, IL-17B, IL-17E, and IL-17F in the serum of patients with SSc and in the healthy control group were assessed with regard to type of the disease - whether limited (lSSc) or diffuse (dSSc) - and symptoms. RESULTS: No difference was found between patients with SSc and the control group as regards the serum concentration of IL-17A. However, IL-17B and IL-17E levels in patients with SSc, and its types diffuse and limited were higher (p < 0.001) compared to the control. The serum level of IL-17F was higher in SSc (p < 0.005) and lSSc (p < 0.05) compared to the control. Serum concentration of IL-17B was elevated in SSc patients with renal abnormalities (p < 0.05) compared to those without. Serum levels of IL-17B correlated with the levels of IL-17E in patients with SSc (r = 0.54, p < 0.05). CONCLUSIONS: Increased synthesis of IL-17B, IL-17E and IL-17F appears to play a role in the pathogenesis of SSc, in contrast to IL-17A. Higher levels of IL-17B and IL-17E are associated with the development of both lSSc and dSSc, whereas IL-17F is associated with lSSc only. Further studies are needed to elucidate their role in the pathogenesis of the disease.

Primary cutaneous CD4+ small-/medium-sized T-cell lymphoproliferative disorder: A case report.

Primary cutaneous CD4+ small-/medium-sized T-cell lymphoproliferative disorder is usually characterized by nodules and plaques affecting the upper part of the body. The present case presented with a large, single tumor located on a lower extremity. The patient did not respond to surgical therapy but responded to cyclophosphamide, methotrexate, and radiotherapy.

X-linked TLR7 gene polymorphisms are associated with diverse immunological conditions but not with discoid lupus erythematosus in Polish patients.

INTRODUCTION: Toll-like receptor 7 (TLR7) is an important molecule involved in the development of autoimmunity and the response to different pathogens. Several polymorphisms within the TLR7 gene were previously found to be associated with systemic lupus erythematosus (SLE). However, none of those studies investigated the TLR7 promoter flanking variants rs1634318 and rs1616583. TLR7 gene diversity has not been analyzed with respect to discoid lupus erythematosus (DLE) development, while its role in the human immunological response to fungal infection is not fully known. AIM: To clarify the potential involvement of two novel single-nucleotide polymorphisms (SNPs) located in the TLR7 gene (rs1634318 and rs1616583) in a variety of immune-related conditions, we studied the variability of these loci in patients from a Polish population with SLE and DLE, as well as in immunocompromised patients who were affected by invasive aspergillosis (IA) and those who were not affected. MATERIAL AND METHODS: Real-time polymerase chain reaction was used to genotype SNPs. Statistically significant differences between case and control groups for both allele and genotype frequencies were assessed using the χ2 test with Yates' correction or two-tailed Fisher's exact test. The results were Bonferroni-corrected for multiple comparisons and odds ratios were calculated. RESULTS: Two polymorphisms located in TLR7 might be associated with the development of SLE but not DLE within the Polish population. Moreover, variation of the two investigated SNPs was found to be associated with IA in immunocompromised Polish patients. CONCLUSIONS: In Polish patients, TLR7 promoter flanking gene polymorphisms might be associated with IA and SLE but not DLE.

The impact of agonists and antagonists of TLR3 and TLR9 on concentrations of IL-6, IL10 and sIL-2R in culture supernatants of peripheral blood mononuclear cells derived from patients with systemic lupus erythematosus.

Toll-like receptors (TLR), especially TLR3, 7 and 9, play an important role in the pathogenesis of systemic lupus erythematosus (SLE). In our study blood was collected from 16 patients with SLE and from 8 healthy volunteers. Concentrations of IL-6, IL-10 and sIL-2R were measured by ELISA in mononuclear cell culture supernatant after 24 hours of stimulation by agonists and antagonists of TLR3 and 9 (for TLR3-poli I/C, resveratrol and for TLR9-ODN2006, IRS 945). Stimulation of TLR9 by ODN2006 led to an increase of IL-6 concentration in cell culture supernatants from the cells of healthy volunteers compared with unstimulated cells from controls. Inhibition of TLR3 activation by resveratrol caused a significantly lower concentration of IL-10 in cell culture supernatants derived from both patients and healthy donors. Moreover, resveratrol significantly decreased the level of IL-10 and sIL-2R in culture supernatants of cells derived from patients with active disease compared to the inactive stage. A positive correlation was also found between IL-6 concentration following ODN2006 administration and disease activity. In conclusions, our results indicate that TLRs play a role in the modulation of the inflammatory response in SLE patients. This suppressive action on IL-10 synthesis demonstrated by resveratrol suggests that it may be useful in SLE therapy.

The Role of CXC Chemokines in Pulmonary Fibrosis of Systemic Lupus Erythematosus Patients.

The inflammatory process in systemic lupus erythematosus (SLE) affects many organs including the lungs. CXC chemokines are suggested to play an important role in the pathogenesis of SLE and pulmonary fibrosis. To estimate the concentrations of CXCL9, CXCL10, CXCL11 in bronchoalveolar lavage fluid (BALF) of patients with and without pulmonary involvements of SLE to evaluate CXC chemokines role in the pathogenesis of pulmonary fibrosis in SLE. Twenty-six SLE patients and 31 healthy controls were evaluated using high-resolution computed tomography (HRCT), pulmonary function tests, the SLE Disease Activity Index (SLEDAI), assessing CXCL9, CXCL11, CXCL10 level in BALF (an enzyme-immunosorbent assay kit). The mean CXCL9 and CXCL11 concentrations in BALF were higher in SLE patients compared to healthy controls (34.09 ± 102.34 vs 10.98 ± 14.65 pg/mL, p < 0.001; 72.65 ± 112.89 vs 16.12 ± 83.75 pg/mL, p = 0.012, respectively). The disease activity scored by SLEDAI and the concentration of CXCL10 in BALF were significantly higher in the SLE patients with pulmonary fibrosis when compared with patients with normal HRCT (8.23 ± 3.19 vs 5.01 ± 2.41; 73.45 ± 34.12 vs 40.76 ± 41.65, respectively, in both p < 0.05). In SLE patients positive correlations were found between SLEDAI and the percentage of lymphocytes in BALF (r = 0.51, p < 0.05); CXCL9 and CXCL10 concentrations in BALF (r = 0.65, p < 0.001); CXCL9 and CXCL11 concentrations in BALF (r = 0.69, p < 0.001). In lupus patients with pulmonary manifestations positive correlations were found between CXCL11 concentration in BALF and SLEDAI (r = 0.55, p < 0.05), CXCL11 concentration and the percentage of neutrophils in BALF (r = 0.69, p < 0.05), CXCL10 concentration and the percentage of neutrophils in BALF (r = 0.57, p < 0.05). Our observations indicate that CXCL9 and CXCL11 play an important role in the pathogenesis of SLE but it needs further studies. These results suggest that CXCL10 and CXCL11 are associated with neutrophils accumulation in the alveolar space of SLE patients with pulmonary fibrosis and should be considered as potential factor of interstitial fibrosis.

[Pro-angiogenic cytokines in systemic sclerosis]. / Wybrane cytokiny proangiogennnew twardzinie ukladowej.

Systemic sclerosis (SSc) is a multifactorial connective tissue disease characterized by excessive and progressive fibrosis along with microvasculopathy due to poor vascular formation and repair. Despite a general increase in many potent angiogenic factors, the vasculopathy compensatory angiogenesis and vasculogenesis are impaired. In this review, we discuss the role of proangiogenic factors--VEGF, PlGF, endoglin, PDGF, endothelin-1, angiopoietins, SDF-1, uPAR--and the paradoxical paucity of an inadequate angiogenic response in SSc.

Current Phase II antibody-drug conjugates for the treatment of lymphoid malignancies.

INTRODUCTION: Antibody-drug conjugates (ADCs) are mAb attached to biologically active drugs through specialized chemical linkers with labile bonds. They deliver the cytotoxic agent and release it at the tumor with limited systemic exposure. AREAS COVERED: In this review, the authors summarize and discuss antibody conjugates in Phase II clinical trials in lymphoid malignancies. Furthermore, the article gives a critical overview of Phase II clinical trials of these therapies. EXPERT OPINION: ADCs have increased selectivity and a longer half-life in comparison to systemic chemotherapy. These agents improve the potency of chemotherapy by increasing the accumulation of the cytotoxic drug within neoplastic cells with reduced systemic effects. Improvements in cytotoxin selection and the use of partial antibodies have further improved the clinical value of ADCs. Newer ADCs currently in Phase II clinical trials show promise as treatments for several lymphoid malignancies, especially lymphoma, multiple myeloma and lymphoid leukemia. In the near future, the addition of ADCs to the armamentarium of anticancer drugs should offer novel and more targeted treatment strategies.

Expression of toll-like receptors 3, 7, and 9 in peripheral blood mononuclear cells from patients with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown aetiology. The results of experimental studies point to the involvement of innate immunity receptors-toll-like receptors (TLR)-in the pathogenesis of the disease. The aim of the study was to assess the expression of TLR3, 7, and 9 in the population of peripheral blood mononuclear cells (PBMC) and in B lymphocytes (CD19(+)), T lymphocytes (CD4(+) and CD8(+)) using flow cytometry. The study group included 35 patients with SLE and 15 healthy controls. The patient group presented a significantly higher percentage of TLR3- and TLR9-positive cells among all PBMCs and their subpopulations (CD3(+), CD4(+), CD8(+), and CD19(+) lymphocytes) as well as TLR7 in CD19(+) B-lymphocytes, compared to the control group. There was no correlation between the expression of all studied TLRs and the disease activity according to the SLAM scale, and the degree of organ damage according to the SLICC/ACR Damage Index. However, a correlation was observed between the percentage of various TLR-positive cells and some clinical (joint lesions) and laboratory (lymphopenia, hypogammaglobulinemia, anaemia, and higher ESR) features and menopause in women. The results of the study suggest that TLR3, 7, and 9 play a role in the pathogenesis of SLE and have an impact on organ involvement in SLE.

Exhaled IL-8 in systemic lupus erythematosus with and without pulmonary fibrosis.

The purpose of this study is to evaluate the relationship between the concentration of interleukin-8 (IL-8) in exhaled breath condensate (EBC) and bronchoalveolar lavage fluid (BALF) with the disease activity score and pulmonary function of systemic lupus erythematosus (SLE) patients with and without pulmonary fibrosis. Thirty-four SLE patients and 31 healthy controls were enrolled and evaluated using high-resolution computed tomography (HRCT), pulmonary function tests, systemic lupus activity measure (SLAM), assessing BALF and EBC. IL-8 levels in BALF and EBC samples were measured with an enzyme-immunosorbent assay kit. The mean (±SEM) IL-8 concentrations in BALF and EBC were higher in SLE patients compared to healthy controls (34.84 ± 95.0 vs. 7.65 ± 21.22 pg/ml, p < 0.001; 3.82 ± 0.52 pg/m vs. 1.7 ± 1.7 pg/ml, p < 0.001, respectively). SLE patients had increased percentage of neutrophils in BALF when compared with control group (1.00 ± 5.99 vs. 0.00 ± 0.56 %, p = 0.0003). Pulmonary fibrosis in HRCT was found in 50 % of SLE patients. The disease activity scored by SLAM was significantly higher and total lung capacity was significantly lower in SLE patients with pulmonary fibrosis (8.00 ± 3.17 vs. 6.00 ± 2.31, p = 0.01; 88.00 ± 28.29 vs. 112.00 ± 21.08 % predicted, p = 0.01, respectively). In SLE patients with pulmonary fibrosis, correlations were found between SLAM and IL-8 concentration in BALF, forced expiratory volume in 1 s and forced vital capacity (r = 0.65, p = 0.006; r = -0.53, p = 0.035; r = -0.67, p = 0.006, respectively). Our results indicate that IL-8 plays an important role in the pathogenesis of SLE. An increased concentration of IL-8 according to BALF could be considered as a useful biomarker of SLE activity and pulmonary fibrosis in SLE.

Vitamin D Receptor Gene BsmI Polymorphism in Polish Patients with Systemic Lupus Erythematosus.

The hormonally active form of vitamin D3, 1,25(OH)2D3 (calcitriol), exerts actions through VDR receptor, which acts as a transcriptional factor. Calcitriol is an immunomodulator that affects various immune cells, and several studies link it to many autoimmune diseases. BsmI polymorphism affects the level of VDR gene transcription, transcript stability, and posttranscriptional modifications. It seems to be related to the systemic lupus erythematosus (SLE). Our study examined the characteristics of VDR gene BsmI polymorphism in Polish SLE patients and their relationship with clinical manifestations of the disease. We genotyped 62 patients with SLE and 100 healthy controls using the real-time PCR. There were no differences observed in the frequency of BsmI genotypes in SLE patients and in the control group. There was no significant correlation between BsmI genotypes and clinical symptoms of SLE, but the AA genotype correlates with higher levels of antinuclear antibodies (ANA) in this group (r = 0.438; P = 0.002). A larger study examining BsmI and other VDR gene polymorphisms is needed. It may allow explaining differences in the clinical picture of the disease and choosing a personalized therapy.