IgG4 producing POEMS syndrome: A rarely recognized subtype.

Serum IgG4 is typically measured for Immunoglobulin G4-related Disease (IgG4-RD), a fibroinflammatory condition associated with polyclonal increase in serum IgG4. Yet, increased IgG4 may still be monoclonal, and little is known about IgG4 POEMS syndrome. We present a case of 40-year-old male with a mass lesion in the left sacral ala. The mass was composed of non-neoplastic fibrous tissue and dense infiltrate of mature plasmacytes with dense eosinophilic cytoplasm and eccentrically placed nuclei that express monoclonal Lambda free light chains and show diffuse positivity for IgG and IgG4. We discuss clinical manifestations and challenges encountered in the diagnosis and treatment of this rare coexistence.

Clonal immunoglobulin λ light-chain gene rearrangements detected by next generation sequencing in POEMS syndrome.

Polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome is a rare plasma cell dyscrasia characterized by polyneuropathy, organomegaly, endocrinopathy, extravascular fluid overload, M protein, and a myriad of skin changes. The pathogenesis is poorly understood, but monoclonal plasma cells are λ-restricted and these immunoglobulin λ light chain variable (IGLV) region genes are derived from only two germlines, either IGLV1-44 or 1-40. Here we analyzed the clonal IGLV gene rearrangements of genomic DNA samples of bone marrow mononuclear cells using next-generation sequencing (NGS) to understand the clonal composition of IGLV genes in patients with POEMS syndrome (n = 30). The dominant IGLV gene rearrangement of POEMS syndrome-specific germline sequences were significantly increased in 11 POEMS patients (36.7%; IGLV1-44: n = 9, IGLV1-40: n = 2). In some cases, IGLV gene rearrangement clone was not detected as significant increase but was detected using cDNA samples by heteroduplex (HD) analysis and Sanger sequencing, suggesting that the quite small number of monoclonal plasma cells may produce large quantity of mRNA of monoclonal proteins. However, significant increase of dominant clone sizes was not directly linked to the initial disease status. On the other hand, in cases with significantly increased dominant clones, they decreased and increased accompanying with disease remission and relapse. These data demonstrate that monoclonal plasma cells are related to the pathogenesis of POEMS syndrome.

[Sarcoidosis flare after autologous stem cell transplantation: An immune paradox?] / Aggravation d'une sarcoïdose après autogreffe de cellules souches hématopoïétiques : un effet paradoxal ?

INTRODUCTION: Sarcoidosis is a systemic granulomatous disorder of unknown cause. Apparition or flare of previously diagnosed sarcoidosis following hematopoietic stem cell transplantation (HSCT) has rarely been reported. OBSERVATION: We report a 62-year-old woman who presented a radiological flare of sarcoidosis post-autologous stem cell transplantation for a POEMS syndrome. Imaging findings and lymph node histology, which revealed non-caseating granuloma, were consistent with the sarcoidosis diagnosis. The patient was asymptomatic and was kept free of treatment. CONCLUSION: Sarcoidosis must be considered ahead of compatible clinicoradiological presentation occurring after HSCT. Sarcoidosis can mimic metastatic cancer or lymphatic relapse. Tissue biopsies and exclusion of differential diagnosis of granuloma diseases are warranted to confirm sarcoidosis diagnosis.

Free light chains and heavy/light chains in monitoring POEMS patients.

BACKGROUND: POEMS syndrome is defined by Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy and Skin changes. The vascular endothelial growth factor (VEGF) appears to play a key role in the pathogenesis of the syndrome, and its concentrations are deemed to correlate to disease activity. The aim of the present study was to verify whether other biochemical markers including serum free light chains (FLC) and heavy/light chains (HLC) would be of value in monitoring POEMS patients. METHODS: Fifty-three serum samples were collected from seven POEMS patients at diagnosis and during a follow-up period (range 14-56 months). VEGF was measured using an ELISA method, while FLC and HLC concentrations were measured using Binding Site reagents on a BNII (Siemens) nephelometer. RESULTS: At diagnosis all patients presented high VEGF concentrations, while the κ/λFLC ratio (FLCr) was within the reference range. Four patients had abnormal HLC, HLCκ/HLCλ (HLCr) and FLC values. The relationship between the trend of VEGF and both HLC and FLC during the follow-up was analysed by means of Cohen's κ coefficient. VEGF and HLC values displayed a significant κ-Cohen (0.537, p=0.002) in all chemotherapy-responder patients while in non-responders it did not. Conversely, in both responders and non-responders, VEGF and FLC values did not attain a significance on κ-Cohen analysis. In three out of four responders HLCr values increased, thus reflecting an improved clinical condition. CONCLUSIONS: The findings made in the present study indicate that HLC, either as intact immunoglobulin or as HLCr, may provide useful information, particularly in identifying responders and confirm that the role of FLC is unreliable in monitoring patients with POEMS syndrome.

POEMS Syndrome with IgG-λ/IgA-κ Biclonal Gammopathy and Abnormal Serum Free Light Chain Ratio: a Case Report.

BACKGROUND: POEMS syndrome is a rare paraneoplastic disorder with atypical plasma cell proliferation. Cases of POEMS syndrome presented with either biclonal gammopathy or an abnormal serum free light chain ratio are considered uncommon. The present authors encountered a case of POEMS syndrome with IgG-λ/IgA-κ biclonal gammopathy with dominant κ free light chain and abnormal serum free light chain ratio. CASE: A 56-year-old man with a history of Castleman disease was suspected with POEMS syndrome and admitted for further evaluation for B-cell proliferative disease to rule out multiple myeloma. He also had a sustained tingling sensation on both feet and gait disturbance, which were compatible with diffuse peripheral sensorimotor polyneuropathy with demyelinating features. His laboratory findings revealed hyperlipidemia and hypothyroidism, and he had hypertrichosis. The results of the serum and urine protein electrophoresis seemed normal, except a very weak band at the end of the serum gamma region. Serum immunofixation electrophoresis confirmed IgG-λ and IgA-κ biclonal gammopathy, with an increased serum IgA concentration and normal levels of IgG, IgM, and IgD. Both serum free light chain κ and λ values were increased, and the κ/λ ratio was higher than normal. CONCLUSIONS: The finding of IgG-λ/IgA-κ biclonal gammopathy and abnormal serum free light chain ratio with dominant κ clonality in our case was definitely rare. However, a primary pathogenic role of the different paraproteinemia in POEMS syndrome remains unclear. Further studies to identify better management modalities for POEMS syndrome is needed.

Engraftment Syndrome after Autologous Stem Cell Transplantation: An Update Unifying the Definition and Management Approach.

Engraftment syndrome (ES) encompasses a continuum of periengraftment complications after autologous hematopoietic stem cell transplantation. ES may include noninfectious fever, skin rash, diarrhea, hepatic dysfunction, renal dysfunction, transient encephalopathy, and capillary leak features, such as noncardiogenic pulmonary infiltrates, hypoxia, and weight gain with no alternative etiologic basis other than engraftment. Given its pleiotropic clinical presentation, the transplant field has struggled to clearly define ES and related syndromes. Here, we present a comprehensive review of ES in all documented disease settings. Furthermore, we discuss the proposed risk factors, etiology, and clinical relevance of ES. Finally, our current approach to ES is included along with a proposed treatment algorithm for the management of this complication.

Serum immunoglobulin free light chain and heavy/light chain measurements in POEMS syndrome.

POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome is a rare plasma cell dyscrasia. Nearly all patients present with a λ-restricted monoclonal gammopathy. Most patients with POEMS syndrome have been reported to have a normal serum free light chain ratio (sFLC-R), but the underlying mechanism is still unclear. We assessed the serum free light chains in 83 patients with newly diagnosed POEMS syndrome. The clinical and laboratory data associated with this disorder were collected to identify factors affecting sFLC-R. Fifty-six patients (67 %) showed elevated serum free λ light chains, but only 11 patients (13 %) had an abnormal sFLC-R. A comparison of patients with and without abnormal sFLC-Rs indicated that the latter group had more common splenomegaly and worse renal function. However, the introduction of an extended renal range for sFLC-R did not dramatically improve the diagnostic value of sFLC-R in these patients. Further analyses identified a correlation between the serum free κ light chain and the uninvolved immunoglobulin in patients with an IgAλ clone, implying that the activation of polyclonal immunoglobulin production could mask the presumed skewing of the sFLC-R induced by the underlying monoclonal gammopathy. Therefore, a serum heavy/light chain (sHLC) assay was performed in a subset of patients with stored serum samples available, and the prevalence of abnormal sHLC ratios was high in these patients. In summary, the overproduction of polyclonal immunoglobulin accounts for the high frequency of normal sFLC-R in patients with POEMS syndrome. The sHLC assay may provide unique information about this disorder.

[Skin manifestations of monoclonal gammopathies]. / Manifestations cutanées associées aux gammapathies monoclonales.

Whatever their aetiology, monoclonal gammopathies can be associated to several clinical features. Mechanisms are various and sometimes unknown. Skin is frequently involved and may represent a challenging diagnosis. Indeed, skin manifestations are either the presenting features and isolated, or at the background of a systemic syndrome. Our objective was to review the various skin manifestations that have been associated with monoclonal gammopathies.

Low levels of interleukin-1 receptor antagonist (IL-1RA) predict engraftment syndrome after autologous stem cell transplantation in POEMS syndrome and other plasma cell neoplasms.

A rare, multisystem, plasma cell neoplasm, POEMS (polyradiculoneuropathy, organomegaly, endocrinopathy, M-spike, skin changes) syndrome is characterized by an abundance of proinflammatory and angiogenic cytokines. Patients with POEMS are known to have a high incidence of engraftment syndrome after autologous stem cell transplantation. We conducted a pilot study assessing levels of 30 different pro- and anti-inflammatory cytokines before and serially after transplantation in 18 patients with plasma cell neoplasms: POEMS syndrome (n = 9), multiple myeloma (n = 4), and amyloidosis (n = 5). We show that POEMS patients have higher pretransplantation levels of IL-4, IL-10, IL-13, IFN-α, and EGF as compared with those with non-POEMS plasma cell neoplasms. Higher pre- and posttransplantation IL-13 levels correlated with delayed neutrophil engraftment in POEMS patients. Low posttransplantation IL-1RA levels correlated with engraftment syndrome in both POEMS and non-POEMS patients. We conclude that differences in the peri-transplantation cytokine milieu may explain the higher transplantation morbidity in patients with POEMS syndrome. Our results need validation in a larger cohort.

Thyroid autoimmunity and polyglandular endocrine syndromes.

Even though autoimmune thyroiditis is considered as the most emblematic type of organ-specific autoimmune disorder of autoimmunity, autoimmune thyroid diseases can be associated with other autoimmune endocrine failures or non-endocrine diseases (namely vitiligo, pernicious anemia, myasthenia gravis, autoimmune gastritis, celiac disease, hepatitis). Thyroid disorders, which are the most frequent expression of adult polyendocrine syndrome type 2, occur concomitantly with or secondarily to insulinodependent diabetes, premature ovarian failure, Addison's disease (Schmidt syndrome, or Carpenter syndrome if associated with diabetes). Testicular failure and hypoparathyroidism are unusual. The disease is polygenic and multifactorial. Disorders of thyroid autoimmunity are, surprisingly, very rare in polyendocrine syndrome type 1 (or APECED) beginning during childhood. They are related to mutations of the AIRE gene that encodes for a transcriptional factor implicated in central and peripheral immune tolerance. Hypothyroidism can also be observed in the very rare IPEX and POEMS syndromes.

Characterization of immunoglobulin λ light chain variable region (IGLV) gene and its relationship with clinical features in patients with POEMS syndrome.

The M protein of POEMS syndrome is essentially λ light chain restricted. Several studies have demonstrated the restrict usage of immunoglobulin λ light chain variable region (IGLV) genes in patients with POEMS syndrome. However, these studies only included a limited number of cases, and it is not clear whether the clinical features are influenced by the IGLV gene in POEMS syndrome. Here we demonstrated that the clonal IGLV genes were strictly derived from IGLV 1-40 (11 patients, 36.7 %) and IGLV 1-44 (19, 63.3 %) gene in 30 patients with POEMS syndrome. We further evaluated the relationship between clinical features and IGLV genes. Our study showed that patients with IGLV 1-44 were older than those with IGLV 1-40, and patients with IGLV 1-40 had more severe neuropathy, hypertrichosis, and papilledema. It was suggested that the IGLV gene influenced clinical characteristics in POEMS syndrome.

Successful treatment with bortezomib and thalidomide for POEMS syndrome associated with multicentric mixed-type Castleman's disease.

Polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes syndrome is a rare multi-systematic disorder of uncertain etiology, if associated with multicentric Castleman's disease, it can lead to a more serious condition. We here presented a case of polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes syndrome in a 37-year-old male patient who initially presented with progressive lower limb weakness accompanied by pain, low skin temperature, and hyperpigmentation. He was admitted with increasingly serious dyspnea and lower leg edema. Fluid of serous cavities in the patient were also indicated in ultrasonic inspection and X-ray. Furthermore, biopsy of a left axillary lymph node showed mixed hyaline-vascular and plasma cell type of multicentric Castleman's disease. Administration of bortezomib (Velcade) (1.3 mg/m(2) on days 1, 4, 8 and 11 of a 21-day cycle) combined with thalidomide (100 mg/day and 21-day cycle) dramatically improved the condition of this disease. Of note, in our study, combination therapy of bortezomib and thalidomide successfully improved the condition of the patient with polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes syndrome associated with multicentric Castleman's disease, suggesting that the combination therapy may be an effective therapeutic strategy for the intractable polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes syndrome associated with multicentric Castleman's disease.

[Diagnosis of immune-mediated neuropathies]. / Az immunmediált neuropathiák diagnosztikája.

Separate discussion of immune-mediated neuropathies from other neuropathies is justified by the serious consequences of the natural course of these diseases, like disability and sometimes even life threatening conditions. On the other hand nowadays effective treatments already exist, and with timely and correct diagnosis an appropriately chosen treatment may result in significant improvement of quality of life, occasionally even complete recovery. These are rare diseases, and the increasing number of different variants makes it more difficult to recognize them. Their diagnosis is based on the precise knowledge of clinical signs and symptoms, and it is verified by the help of neurophysiologic and laboratory, first of all CSF examinations. Description of clinical features of the classic acute immune-mediated neuropathy, characterized by ascending paresis and demyelination is followed by a summary of characteristics of newly recognized axonal, regional and functional variants. Chronic immune-mediated demyelinating polyneuropathies are not diagnosed in due number even today. This paper does not only present the classic form but it also introduces the ever increasing special variants, like distal acquired demyelinating sensory neuropathy, Lewis-Sumner syndrome, multifocal motor neuropathy and paraproteinemic neuropathies. Vasculitic neuropathies can be divided into two groups: systemic and non-systemic ones. The first sign of a vasculitic neuropathy is a progressive, painful mononeuropathy; the classic clinical presentation is the mononeuritis multiplex. It is characterized by general signs like fever, loss of weight, fatigue. In systemic vasculitis organ specific symptoms are also present. From the paraneoplastic diseases the subacute sensory neuropathy and the sensory neuronopathy are members of the immune-mediated neuropathies, being most frequently associated with small cell lung cancer.

Serum immunoglobulin free light chain measurements and heavy chain isotype usage provide insight into disease biology in patients with POEMS syndrome.

POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes) syndrome is a rare paraneoplastic syndrome in which nearly all patients have a monoclonal lambda restricted plasma cell disorder. We investigated whether patients with POEMS have abnormal serum immunoglobulin free light chain (FLC) ratios. Fifty patients with newly diagnosed POEMS syndrome were assessed. Cystatin C levels were measured to discern whether subclinical renal insufficiency could account for FLC elevations in the presence of a normal FLC ratio. Forty-five patients (90%) had elevated lambda FLC; however, only nine (18%) had abnormal FLC ratios. The rise in serum FLC of POEMS patients appeared to be multifactorial-both a function of subclinical renal insufficiency and polyclonal activation of medullary and extramedullary plasma cells. Those patients expressing a clonal IgA were more likely to have clonal plasmacytosis observed on iliac crest biopsy than those with IgG. In summary, serum immunoglobulin profiles are unique in POEMS syndrome as compared with other plasma cell disorders.

[Advances and perspectives in treatment for refractory neuropathies with special reference to immune-mediated neuropathies and Crow-Fukase syndrome].

There are significant advances in immune-modulating treatments for Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP) in the past 20 years. GBS, however, is still a serious disease with a mortality rate of 8% and 20% of the patients being unable to walk independently a year after onset For CIDP and related disorders such as multifocal motor neuropathy, and demyeinating neuropathy with anti-myelin-associated-glycoprotein (MAG) antibody, treatments should be based on individual pathophysiology. Rituximab could be a promising agent for the subtypes of CIDP refractory to conventional immune treatments. Crow-Fukase syndrome is a rare cause of demyelinating neuropathy with multiorgan involvement Overproduction of vascular endothelial growth factor (VEGF), probably mediated by monoclonal proliferation of plasma cells, is likely to be responsible for most of the characteristic symptoms. There is no established treatment regimen for Crow-Fukase syndrome. In appropriate candidates, high-dose chemotherapies with autologous peripheral blood stem cell transplantation is highly recommended, because this treatment could result in obvious improvement in neuropathy as well as other symptoms. Indication of this treatment has not yet been established, and long-term prognosis is unclear at present. Treatments that should be considered as future therapy against Crow-Fukase syndrome include thalidomide, and anti-VEGF monoclonal antibody (bevacizumab).