Materiały źródłowe

• #1 Update on the POEMS syndrome

  https://pmc.ncbi.nlm.nih.gov/articles/PMC9057663/

  POEMS syndrome is an acronym for polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes. It is a rare paraneoplastic disorder related to plasma cell neoplasm. However, its pathophysiology has not yet been clearly elucidated. The production of pro-inflammatory cytokines is thought to play an important role in the pathogenesis of POEMS syndrome. […] The pathophysiology of the POEMS syndrome is not yet fully understood. Pro-inflammatory cytokines, such as VEGF, interleukin (IL)-1, and IL-6, produced by plasma cells could play a critical role in the pathogenesis of the disease. […] Recently, genetic analysis was performed to elucidate the mechanism of POEMS syndrome. The study found 308 somatic mutations in 285 genes using whole-exome sequencing, while target sequencing identified 20 mutations in seven recurrently mutated genes: KLHL6, LTB, EHD1, EML4, HELPHL1, HIPK1, and PCDH10. None of the driver gene mutations found in myeloma driver genes were detected. RNA sequencing showed a transcription profile specific to POEMS syndrome, different from the monoclonal gammopathy of undetermined significance and multiple myeloma. In contrast, Chen et al. revealed 11 genes related to light chain amyloidosis and multiple myeloma (BIRC3, LRP1B, KDM6A, and ATM) using target sequencing. This study suggests possible similarities in mutational profiles between POEMS syndrome and myeloma or amyloidosis, although there is high heterogeneity of the mutational spectrum in POEMS. Currently, no genetic markers can predict survival.

• #2 POEMS Syndrome: Background, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/1097031-overview

  POEMS syndrome is a rare multisystemic disease that occurs in the setting of a plasma cell dyscrasia. The pathophysiologic link between the constellation of symptoms and the underlying disease is not well understood, but the link may be related to changes in the levels of a cytokine or a growth factor. […] The pathophysiology of POEMS syndrome has not been well defined. It is known that in all patients, a plasma cell disorder underlies the development of the syndrome; however, the mechanism by which this occurs is not known. Elevations of cytokines, such as interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-, have been noted. […] Significant elevations in vascular endothelial growth factor (VEGF) levels have been noted. Increased VEGF levels have been postulated to lead to enhanced vascular permeability, resulting in the associated edema, increased endoneural pressure, and deposition of plasma cell-derived material. As myelin is exposed to serum cytokines and complement, demyelination can occur. […] The association of POEMS syndrome with Castleman disease and angioma formation led some to propose a role for human herpesvirus 8 (HHV-8); however, early studies did not confirm this role.

• #3 POEMS SYNDROME: an Update

  https://pmc.ncbi.nlm.nih.gov/articles/PMC5584767/

  POEMS syndrome is a rare, chronic and disabling condition. The causes of this condition remain unknown; however, chronic overproduction of proinflammatory cytokines appears to be a major contributor. […] Up-regulation of various pro-inflammatory cytokines and growth factors (tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL1), interleukin-6 (IL6) and above all vascular endothelial growth factor (VEGF) play a crucial role in the pathogenesis of the POEMS syndrome, contributing to vascular leak and polyneuropathy.35 In particular, VEGF is markedly elevated in POEMS patients and correlates with the activity of the disease. […] It has also been proposed that clonal B/plasma cells with genetic mutations of the V-region of the Ig lambda gene could produce excess cytokines (primarily, VEGF) through an yet undiscovered mechanism, leading to the clinical manifestations of POEMS.8

• #4 Recent Advances in the Treatment and Supportive Care of POEMS Syndrome

  https://www.mdpi.com/2077-0383/11/23/7011

  POEMS is a rare clonal plasma cell disorder characterized by multi-systemic features that include demyelinating peripheral neuropathy, organomegaly, endocrinopathy, presence of monoclonal proteins (M-protein), and skin changes. […] Even though the pathophysiology is poorly understood, recent studies suggest that both clonal and polyclonal plasmacytosis leading to the production of pro-inflammatory cytokines and angiogenic mediators play the central role. These mediators including vascular endothelial growth factor (VEGF) are the driving forces of the syndrome. […] The pathogenesis of POEMS syndrome is complex and not fully understood. It has been suggested that it is caused by two entities: the expansion of clonal and polyclonal plasma cells and the surge of pro-inflammatory and angiogenic cytokines.

• #5 A Review of POEMS Syndrome

  https://www.cancernetwork.com/view/review-poems-syndrome

  POEMS syndrome is a rare paraneoplastic syndrome that is caused by an underlying plasma cell disorder. Its main features include polyradiculoneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes. […] Vascular endothelial growth factor (VEGF) appears to play an important role in the disease and is especially useful for monitoring therapy, but it is not likely the sole factor driving the disease. […] Plasma and serum levels of VEGF are markedly elevated in POEMS and correlate with the activity of the disease. […] The higher level observed in serum is attributable to the release of VEGF from platelets in vitro during serum processing. […] Other proinflammatory markers, such as interleukin 12 (IL-12), tumor necrosis factor (TNF)-alpha, and IL-6, have all been reported to be high in patients with POEMS, but VEGF is the most consistently elevated cytokine and correlates best with disease activity.

• #6 Recent Advances in the Treatment and Supportive Care of POEMS Syndrome

  https://www.mdpi.com/2077-0383/11/23/7011

  The messenger ribonucleic acid (mRNA) levels of vascular endothelial growth factor (VEGF) are higher in CD138 positive plasma cells derived from the bone marrow relative to the CD138 negative plasma cells. […] Interestingly, when Wang et al. immunophenotyped the cells considered to be the major source of serum VEGF, these cells were polyclonal in nature confirming that the polyclonal plasma cells in POEMS play an important role for production of these cytokines leading to the constellation of signs and symptoms. […] However, when Isshiki et al. utilized single-cell RNA-Seq of bone marrow plasma cells from patients with POEMS syndrome, VEGF mRNA was not upregulated in POEMS clones, directly indicating that serum VEGF is not produced by POEMS clones. […] In comparison, monoclonal plasma cells in POEMS, exhibited an increase in the production intracellular interleukin-6 (IL-6) expression, a pro-inflammatory cytokine and inducer of VEGF expression and secretion from the cells.

• #7 POEMS syndrome – Autoimmune Association

  https://autoimmune.org/disease-information/poems-syndrome/

  POEMS syndrome is a rare autoimmune related blood disorder that damages your nerves and affects many other parts of the body. […] The underlying cause of the disorder is not well understood. POEMS syndrome is a paraneoplastic disorder, which means that the signs and symptoms of the syndrome appear as a manifestation of the plasma cell disorder that the patient has (most patients are seen with osteosclerotic myeloma or monoclonal gammopathy of unknown significance); however, the mechanism by which this occurs is unknown. […] It is associated with a chronic overproduction of some substances known as pro-inflammatory cytokines (small molecules that act as messengers between cells to promote inflammation). These include interleukins (IL-1b, IL6) which are cytokines that help regulate immune responses, TNFα (Tumor Necrosis Factor alfa is a cytokine which is involved in the inflammatory process) and vascular endothelial growth factor (VEGF – a powerful vasodilator that may cause leaky blood vessels) which seem to be important in this disorder.

• #8 Recent Advances in the Treatment and Supportive Care of POEMS Syndrome

  https://www.mdpi.com/2077-0383/11/23/7011

  Hence, pathogenesis is an interplay between monoclonal and polyclonal plasma cells in POEMS. […] The serum VEGF level is elevated in most patients with POEMS. This multifunctional cytokine is produced physiologically by cells derived from the bone marrow such as plasma cells, osteoblasts, and platelets. […] Its role is pivotal in the regulation of angiogenesis, microvascular permeability, and migration of hematopoietic stem cells. […] Its high levels are suspected to be the cause of an increase in the intraneural pressure leading to edema and vascular permeability, which may result in nerve damage, instead of direct neuronal invasion. […] However, patients treated with bevacizumab, an anti-VEGF monoclonal antibody, did not show clinical improvement. […] The probability to have POEMS gets higher with greater serum VEFG levels. […] Note that other cytokines such as tumor necrosis factor alpha (TNF-α), Il-6, and Il-12 are also involved in disease progression but the levels of these cytokines are not routinely measured and followed up in clinical practice.

• #9 The unclear role of VEGF in POEMS syndrome: therapeutic implications of neoangiogenesis in a rare plasma cell disorder

  https://www.oaepublish.com/articles/2394-4722.2021.106

  POEMS syndrome is a rare paraneoplastic disorder due to an underlying clone of aberrant plasma cells. […] Little is known about the pathogenic mechanism, although the neoangiogenesis due to overproduction of vascular endothelial growth factor (VEGF) by plasma cells seems to play a key role. […] The pathogenic mechanism of POEMS syndrome is far from being fully understood, but increased production of VEGF by clonal bone marrow plasma cells could be one of the driving forces, as suggested by a Chinese study. […] Even if the role of VEGF in the pathogenesis of POEMS remains unclear, it is still the most important cytokine correlating with disease activity. […] The evidence of high levels of VEGF in serum and plasma of patients with POEMS guided the idea that the syndrome could be successfully treated with drugs directed against this cytokine.

• #10

  https://link.springer.com/article/10.1007/s00415-018-9110-6

  POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes) is a rare paraneoplastic syndrome, caused by a plasma cell proliferative disorder, which is most commonly lambda restricted. […] The discovery of vascular endothelial growth factor (VEGF) in association with POEMS syndrome has been extremely useful in aiding clinical diagnosis, and monitoring response to treatment, as well as helping understand the underlying mechanism of disease. […] Interestingly, however, treatment targeting VEGF has been disappointing, suggesting other disease mechanisms or inflammatory processes are also important. Current understanding of the pathogenesis of POEMS syndrome is outlined in detail in the accompanying article by Cerri et al. […] POEMS syndrome differs from other paraproteinaemic and inflammatory neuropathies by its multi-organ involvement, thought to be caused by elevated pro-inflammatory and angiogenic cytokines.

• #11

  https://link.springer.com/article/10.1007/s00415-018-9068-4

  The search of the origin of VEGF overproduction has led to controversial results. […] These controversial findings suggest that the interplay of several cytokines involved in angiogenesis and microvascular permeability, besides VEGF, might be significant in the pathogenesis of POEMS syndrome, at least by explaining some of its clinical features such as extra-vascular volume overload (ascites, pleural effusion and oedema), skin angioma, papilloedema and presumably peripheral neuropathy. […] Indeed, it is now accepted that VEGF is probably not the pathogenic initiating factor but a downstream mediator of a paraneoplastic syndrome. […] Thus, we propose that the mechanism underlying the peripheral neuropathy in POEMS syndrome is due to endothelial injury, indirectly or directly caused by an abnormal activation of endothelial cells by VEGF, which is overexpressed in the nerves of patients with POEMS syndrome, thereby inducing microvascular changes and impaired vascular permeability.

• #12 Does suppression of VEGF alone lead to clinical recovery in POEMS syndrome? | Journal of Neurology, Neurosurgery & Psychiatry

  https://jnnp.bmj.com/content/84/12/1301

  POEMS syndrome (Crow-Fukase syndrome) is a multisystem disorder characterised by polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes. […] Vascular endothelial growth factor (VEGF) is significantly elevated in serum and used as a good biomarker for diagnosis and disease activity. VEGF is a potent, multifunctional cytokine that induces angiogenesis and microvascular hyperpermeability. In POEMS syndrome, VEGF is mainly produced by plasma cells in bone lesions and lymph nodes. In the circulation, excess VEGF is mainly stored in platelets and released during platelet aggregation leading to markedly increased local VEGF concentration.

• #13

  https://link.springer.com/article/10.1007/s00415-018-9068-4

  These alterations lead to a secondary ischemic microangiopathy and chronic axonal damage of nerve fibers through alteration of the blood-nerve barrier. […] Finally, the disruption of vascular and metabolic dynamics in the nerve leads to a perpetuating hypoxic state, where secondary increases in local VEGF occurs due to induced HIF-1a expression, fueling a positive destructive feedback whereby damage progresses relentlessly.

• #14 POEMS syndrome pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/POEMS_syndrome_pathophysiology

  The overproduction of this cytokine may be related to some of the clinical features seen in POEMS syndrome such as gammopathy, elevated C-Reactive protein (CRP) and thrombocytosis. […] VEGF is a pro-angiogenic cytokine that promotes neovascularization. It is thought to be overproduced in POEMS syndrome and can serve as a marker of disease activity in these patients. […] The neovascularization induced by VEGF leads to increased vascular permeability. […] Unregulated neovascularization also leads to disruption of the blood-nerve barrier in the peripheral nervous system (PNS), which subsequently results in endoneural edema.

• #14 POEMS syndrome pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/POEMS_syndrome_pathophysiology

  POEMS syndrome is a para-neoplastic syndrome characterized by multi-organ system dysfunction, monoclonal plasma cell proliferation and demyelinating inflammatory polyneuropathy. […] The lambda component of immunoglobulin light chains is thought to be overproduced in POEMS syndrome secondary to monoclonal plasma cell proliferation. […] The monoclonal gammopathy or overproduction of lambda light chain stimulates the monocyte/macrophage system to produce various proinflammatory cytokines. […] The monoclonal plasma cell proliferation in POEMS syndrome is thought to play a major role in overproduction of numerous pro-angiogenic and pro-inflammatory cytokines. […] The hypercytokinetic state induced in patients of POEMS syndrome is thought to drive the disease process. […] Interleukin- 6 is overproduced in patients with POEMS syndrome.

• #15

  https://insight.jci.org/articles/view/151482

  POEMS syndrome is a rare monoclonal plasma cell disorder, with unique symptoms distinct from those of other plasma cell neoplasms, including high serum VEGF levels. […] In contrast to the clinical advances in diagnostic and therapeutic strategies, limited information is currently available on the pathogenesis of POEMS syndrome. […] Our recent genome sequencing of BM plasma cells in POEMS syndrome identified 7 recurrently mutated genes: KLHL6, LTB, EHD1, EML4, HEPHL1, HIPK1, and PCDH10. […] Importantly, none of the driver gene mutations frequently found in MM were identified in either of these studies, suggesting that the mutational characteristics of POEMS syndrome are different from those of other plasma cell neoplasms. […] Single-cell transcriptomes revealed unique transcriptional signatures of POEMS clones that were distinct from those of MM or MGUS clones.

• #16 Poems Syndrome, Cryoglobulinemia, and Heavy-Chain Disease | Oncohema Key

  https://oncohemakey.com/poems-syndrome-cryoglobulinemia-and-heavy-chain-disease/

  POEMS syndrome is a rare paraneoplastic syndrome due to an underlying plasma cell disorder. […] The pathogenesis of the syndrome is not understood. […] Distinctive presenting characteristics of the syndrome that differentiate POEMS syndrome from standard multiple myeloma (MM) include the following: (1) dominant symptoms have little or nothing to do with bone pain, extremes of bone marrow infiltration by plasma cells, or renal failure; (2) dominant symptoms are typically neuropathy, endocrine dysfunction, and volume overload; (3) VEGF levels are high; (4) sclerotic bone lesions are present in the majority of cases; (5) overall survival is typically superior; and (6) β clones predominate. […] To date, VEGF is the cytokine that correlates best with disease activity, although it is likely not the driving force of the disease, based on the mixed results seen with anti-VEGF therapy. […] Little is known about the plasma cells in POEMS syndrome except that more than 95% of the time they are β-light chain restricted with restricted immunoglobulin light chain variable gene usage (IGLV1). […] Aneuploidy and deletion of chromosome 13 have been described, but hyperdiploidy is not seen.

• #17 POEMS syndrome associated with Castleman disease: a case report and literature review

  https://www.oaepublish.com/articles/2347-8659.135577

  Polyneuropathy, organomegaly, endocrinopathy, M proteins, and skin changes (POEMS) syndrome is a multisystemic disorder that clinically manifests as paraneoplastic and monoclonal plasma cell dyscrasia. […] The important traits of POEMS syndrome including polyneuropathy, organomegaly, endocrinopathy, M proteins, and skin changes. […] The diagnosis of POEMS syndrome is based on having both polyradiculoneuropathy and monoclonal plasma cell disorder, at least 1 of 3 other major criteria (Castleman disease, sclerotic bone lesions, or elevated VEGF), and at least 1 minor criterion. […] The pathogeny of POEMS syndrome remains unclear. It is assumed that hepatitis B antigen may play a role in the etiology of this lymphatic disorder. […] A previous study confirmed that increased levels of tumor necrosis factor alpha (TNF-), interleukin-6 (IL-6), and VEGF in patients of POEMS syndrome are correlated with disease activity. […] Castleman disease and POEMS syndrome are closely related. An association with MCD was reported in about 50% of patients with POEMS. […] Here, our patient presented with POEMS syndrome in association with Castleman disease.

• #18 Glomeruloid Hemangioma and POEMS Syndrome | Actas Dermo-Sifiliográficas

  https://www.actasdermo.org/en-glomeruloid-hemangioma-poems-syndrome-articulo-S1578219016303468

  As in our patient in Case 1, it has been shown that both kinds of endothelial cells express VEGF and its receptor, Flt-1, supporting the theory that VEGF is a likely etiologic agent of the disease. […] The etiology and pathogenesis of POEMS syndrome do not depend on aberrant immunoglobulin production; instead, several factors are thought to be involved. Elevated production of proinflammatory cytokines (tumor necrosis factor-, IL-6, IL-1) would explain symptoms such as polyneuropathy, hyperpigmentation, and endocrine alterations. […] In patients with POEMS syndrome, there are higher concentrations of VEGF and metalloproteinases than in controls or in patients with multiple myeloma in isolation. These 2 factors act in the endothelium and the smooth muscle cells, playing an important role in angiogenesis and neovascularization. […] Glomeruloid hemangiomas are also sometimes associated with Castleman disease, a rare lymphoproliferative disorder. This disease has a proinflammatory cytokine profile similar to that of POEMS syndrome, justifying this association and the presence of similar symptoms.

• #19 POEMS syndrome | MedLink Neurology

  https://www.medlink.com/articles/poems-syndrome

  POEMS syndrome is a rare multisystemic disease with unknown pathogenesis classified as a plasma cell dyscrasia. […] Although the underlying plasma cell dyscrasia in POEMS syndrome suggests an antibody-mediated etiopathogenesis, the features of the disease are not explained by immune-mediated processes alone. […] Overproduction of proinflammatory cytokines and angiogenic growth factors, mainly vascular endothelial growth factor (VEGF), are believed to play an important pathogenic role. […] However, there is no unifying explanation for all the features of POEMS syndrome, and the pathogenesis remains unknown. […] Regarding vascular endothelial growth factor, significantly elevated serum levels have been found in POEMS syndrome, higher than in other monoclonal gammopathies and other neurologic diseases, and decreased levels in correlation with response to conventional therapy have been described.

• #20 POEMS syndrome | MedLink Neurology

  https://www.medlink.com/articles/poems-syndrome

  This could lead to aggregation of platelets on vascular walls and elevated local VEGF concentration, promoting vascular permeability, angiogenesis, and monocyte and macrophage migration. […] Overexpression of VEGF is thought to affect peripheral nerves by causing endoneurial edema and microangiopathy of endoneurial vessels. […] Glomeruloid hemangiomas, thought to be highly specific for POEMS syndrome, are believed to be a reactive endothelial proliferation in response to angiogenic stimuli.

• #21 POEMS Syndrome: Still an Enigma?

  https://www.cancernetwork.com/view/poems-syndrome-still-enigma

  It is well established that overproduction of vascular endothelial growth factor (VEGF) plays a key role in the symptoms of POEMS syndrome-particularly neuropathy, edema, and hemangioma. Therefore, it is tempting to assume that the monoclonal lambda light chain induces VEGF production by a yet unresolved mechanism. […] The existence of asymptomatic bone lesions in some patients several years before the emergence of clinical symptoms of POEMS syndrome could be explained by the initial absence of monoclonal circulating light chains, with symptoms starting to occur when the light chains begin to circulate, triggering VEGF overproduction. […] The overproduction of VEGF and probably of other interfering cytokines may play a role in the particular behavior of the monoclonal proliferation that presents as osteosclerotic plasmacytoma of low proliferative index, and also in the onset of the frequently associated POEMS syndrome variant, Castleman disease.

• #22 A Review of POEMS Syndrome

  https://www.cancernetwork.com/view/review-poems-syndrome

  In POEMS syndrome, the renal histologic findings are diverse, with membranoproliferative features and evidence of endothelial injury being most common. […] However, there is evidence of endothelial cytoplasmic enlargement, opening of the tight junctions between endothelial cells, and the presence of many pinocytic vesicles adjacent to the cell membranes, which are all consistent with an alteration of the permeability of endoneurial vessels. […] Despite the relationship between disease response and dropping levels of VEGF, most of the successful outcomes in POEMS have been associated with therapy directed at the underlying clonal plasma cell disorder rather than with antibody treatment that solely targets VEGF.

• #23

  https://link.springer.com/article/10.1007/s00415-018-9110-6

  Elevated VEGF is highly specific for POEMS syndrome (though not pathognomonic) and thought to be involved in the pathophysiology of systemic features including organomegaly and volume overload. […] Monitoring VEGF levels may be useful as a disease prognostic marker; Misawa et al. showed that reduction in serum VEGF levels to within the normal range by 6-months post-treatment was associated with longer relapse-free survival and better outcomes.

• #24

  https://haematologica.org/article/view/6589

  POEMS syndrome is a rare clonal plasma cell disease. […] The pathogenesis of this rare clonal plasma cell disorder is not well understood, although a causative role for elevated serum vascular endothelial growth factor (VEGF) in this syndrome has been proposed. […] The pathogenesis of POEMS-related PH is not clear. However, sPAP measured from DE cannot distinguish pulmonary arterial hypertension from pulmonary venous hypertension from severe left ventricular dysfunction. […] Cytokine-mediated proliferation of endothelial cells with resultant pulmonary vasculopathy is thought to be one of the causative mechanisms of PH in POEMS syndrome. […] VEGF, a key proinflammatory cytokine for POEMS syndrome, can cause microvascular hyperpermeability leading to extravascular volume overload, stimulate excess endothelial proliferation, activate vascular smooth cell, and induce vascular endothelial dysfunction.

• #25 Pulmonary manifestations of POEM syndrome: a retrospective analysis of 282 cases | BMC Pulmonary Medicine | Full Text

  https://bmcpulmmed.biomedcentral.com/articles/10.1186/s12890-023-02741-9

  Recently, the monoclonal immunoglobulin light chain was reported to play an important role in disease pathogenesis. […] The pathogenesis of POEMS syndrome is unknown; therefore, no specific factor or gene that can predict survival exists. […] Patients with POEMS syndrome face an elevated risk of pulmonary hypertension, classified as World Health Organization Group 5 pulmonary hypertension, with unclear multifactorial mechanisms. It is hypothesized that elevated VEGF levels stimulate endothelial cell proliferation, leading to endothelial dysfunction and overgrowth of vascular smooth muscle, which in turn causes pulmonary hypertension.

• #26 Pathways Case Record: POEMS Disease – Mass General Advances in Motion

  https://advances.massgeneral.org/research-and-innovation/case-study.aspx?id=1027

  They propose that this permeability enables neurotoxic serum proteins such as complement factors and thrombin to then cross the blood-nerve barrier and cause neuronal injury. […] Another study showed that VEGF is highly expressed in the blood vessels of nerves in POEMS, leading to histopathologic findings of basal lamina thickening and endothelial cell proliferation. […] Given a model where plasma cell-derived cytokines drive POEMS disease features, anti-cytokine therapies should provide symptomatic relief but not cure the underlying disease. […] Though pro-inflammatory cytokines have emerged as likely drivers of POEMS manifestation, basic mechanistic questions remain unanswered. […] If our hypothesis is correct, we may expect that patients with similar cytokine profiles also share key gene expression changes in target tissues.

Zobacz więcej