Extramedullary and extranodal manifestations in chronic lymphocytic leukemia - an update.

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is a common leukemia characterized by clonal expansion of mature CD5+/CD23 + B cells in the blood, bone marrow (BM) and lymphoid tissues. CLL can undergo extramedullary and extranodal infiltration, with one study noting an incidence of only 0.3 per 100,000 people, and in 17.6% of CLL patients in another report. The most common extranodal sites of leukemic involvement are the skin and central nervous system; however, other organs, including liver, lungs, kidney, gastrointestinal tract, bone, prostate and heart, are occasionally involved. The prognostic significance of extra-medullary CLL is still under debate, but the prognosis in such patients seems to be better in the era of novel targeted drugs. Following a diagnosis of extranodal CLL, survival appears to depend on the site of infiltration. This review presents an overview of CLL in patients with extramedullary and extranodal leukemic lesions, focusing on its epidemiology, pathogenesis, prognosis, clinical characteristics and treatment results.

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.

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.

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.

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.

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.

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.

[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.

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.

[Connective tissue diseases during pregnancy - therapeutic aspect. Part 1: SLE, antiphosholipid syndrome]. / Ukladowe choroby tkanki lacznej w ciazy - postepowanie terapeutyczne. Czesc 1: SLE, zespól antyfosfolipidowy.

Connective tissue diseases, defined as chronic, multi-system autoimmune dysfunctions, occur predominantly in women of childbearing age. Pregnancy, as a specific state of hormonal and immunological diversity, may involve adverse influence on maternal disease activity, causing remission or exacerbation necessitating appropriate therapy. In the first part of the article the influence of female hormones on the immunological cells is presented, as well as their role in the autoimmunological process. The special emphasis is put on most frequent connective tissue diseases among young women- systemic lupus erythematosus and antiphospholipid syndrome. The article also highlights the risk of potential obstetric complications, the gravity of careful planning, restrictive monitoring and necessary treatment to minimalize the risk of intricacy.

[Connective tissue diseases during pregnancy - therapeutic aspect. Part 2: the other connective tissue diseases]. / Ukladowe choroby tkanki lacznej w ciazy - postepowanie terapeutyczne. Czesc 2: inne ukladowe choroby tkanki lqcznej.

Pregnancy in women with connective tissue diseases is classified as a high risk pregnancy. Therefore, a proper treatment which is safe both for mother and child, arouses a problem. The second part of the article presents main pregnancy complications among women with systemic sclerosis, rheumatoid arthritis, ankylosing spondylitis and dermatomyositis. General groups of medications are discussed, which are most frequently used in treatment of pregnant women with connective tissue diseases. Furthermore, the article presents treatment schedule which obtained the United States Food and Drug Administration (FDA) recommendation. Nowadays, advancing technology and treatment improved outcomes in connective tissue diseases pregnancies.

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.

Psychiatric disorders in patients with systemic lupus erythematosus: association of anxiety disorder with shorter disease duration.

Physicians' awareness about neuropsychiatric syndromes in systemic lupus erythematosus (SLE) is not rarely limited to seizures and psychoses included in the American College of Rheumatology (ACR) classification. Involvement of the central nervous system (CNS) with its rich symptomatology still belongs to the faintly recognised and understood aspects of lupus. The objective was to investigate prevalence and clinical correlations of psychiatric disorders in SLE patients. Fifty-two SLE patients were included. Disease duration and current and cumulative corticosteroid doses were calculated. Disease activity was assessed with the Systemic Lupus Activity Measure (SLAM). All subjects were examined by a psychiatrist. Psychiatric disorders were classified according to ACR criteria for neuropsychiatric systemic lupus erythematosus (NPSLE). Mini-Mental State Examination (MMSE) and Clock Drawing Test (CDT) were used to screen for cognitive impairments. Mental disorders were diagnosed in 16 (30.77%), depressive disorder in 6 (11.54%), cognitive dysfunction in 5 (9.62%), anxiety disorder in 4 (7.69%) and psychosis in one patient (1.92%). SLE duration was shorter in patients diagnosed with anxiety disorder (P < 0.05), and cumulative dose of corticosteroids was lower in patients with anxiety disorder (P < 0.01). There was high positive correlation between SLE duration and cumulative dose of corticosteroids (r = 0.684, P < 0.001). Shorter SLE duration in patients with anxiety disorder seems to reflect its adaptative nature.

[Current views on etiopathogenesis of systemic lupus erythematosus]. / Wspólczesne poglady na etiopatogeneze ukladowego tocznia rumieniowatego.

The article is a review of information concerning etiopathogenesis of systemic lupus erythematosus (SLE). Due to the risk of serious complications, including death, the clarification of etiology could result in substantial improvement or even complete cure of the disease. Progress in scientific research of observed disorder mechanisms together with implementation of appropriate therapies contributed to a higher detection rate, improved course and decreased mortality in SLE. However, there are still many doubts, which legitimate the need of further research. A significant role in development of the disease and further exacerbations is played by environmental factors. Therefore, decreased exposure to UV light, female sex hormone and microbial antigens is associated with improved course and decreased frequency of exacerbations. Less is known about the genetic basis of SLE, which results from a multigene disease background and complex hereditary mechanisms. It is estimated that the disease may be conditioned by around 100 genes, that only in part are functionally determined. Only part of them is already functionally characterized. The role played by most of them is still unknown. Research currently being conducted is aimed at detecting genetic polymorphism in large and genetically diverse populations. It will allow evaluation of the role of a particular gene in protein biosynthesis, which is responsible for development of regulatory process disturbances, commonly observed in the course of SLE. The article presents current directions of research and the latest advances in epidemiology as well as environmental and genetic risk factors of SLE.

[Rosacea]. / Tradzik rózowaty--wspólczesne poglady na patomechanizm i terapie.

Rosacea is a chronic, inflammatory disease of the skin, usually localized on the face. The disease predominantly affects inhabitants of Northern and Western Europe and North America and is rarely found among other ethnic groups. The disease usually starts at the age of 20-30, with visible progression in the next decade of life and full clinical presentation at the age of 40-50. The pathogenesis of rosacea is heterogenic and not fully elucidated. The disease is associated with many different factors. The pathomechanism of the disease is complex and depends on: natural immunity, vascular disturbances, action of reactive oxygen species and proteolytic enzymes, UV radiation and infectious factors. The influence of environmental factors on natural, innate immunity can be responsible for different symptoms of the disease and can determine a type of treatment. At present rosacea is divided into 4 subtypes based on a type of clinical manifestations: erythematotelangiectatic, papulopustular, phymatous and ocular rosacea. The course of the disease is characterized by remissions and progressions. In most cases it is sufficient to use a topical, but sometimes even a systemic treatment. Every relapse to the disease is connected with progression of skin damage and aggravation of symptoms. Different topical and systemic ways of treatment are used but some of them are not accepted by FDA as a standard therapy of the disease. Except of the treatment also a proper care and life style are also important to control the disease. In the review the contemporary opinions on pathogenesis, clinical manifestations and therapeutic strategies were presented.

[Role of Toll-like receptors in etiology of selected diseases of the skin]. / Udzial receptorów Toll-like w patogenezie wybranych chorób skóry.

Toll-like receptors (TLR) play an important role in anti-infectious defense of organisms. So far in humans 10 receptors have been identified. They were classified into five different subfamilies according to their affinity to characteristic ligands. Every receptor has a similar structure (extracellular part, intramembrane part and cytoplasmic part), irrespective of a type of the ligands with which it reacts. Ligands are present on many cell types, including on those which make up the skin. That is why Toll-like receptors are an important part of the cutaneous, non-specific immunologic response. In the review problems associated with the structure and functions of Toll-like receptors are presented. Moreover, the latest information about the role of TLR in the etiology of some dermatoses (psoriasis, atopic dermatitis, acne vulgaris, rosacea, infections, systemic lupus erythematosus, mycosis fungoides) is discussed. In addition, therapeutic implications are described.