Polyclonal hypergammaglobulinaemia assessment, clinical interpretation, and management

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<p>www.thelancet.com/haematology Vol 8 May 2021 e365</p><p>Review</p><p>Lancet Haematol 2021;</p><p>8: e365–75</p><p>Division of Hematology</p><p>(E J Zhao MD, L Y C Chen MD),</p><p>Department of Pathology and</p><p>Laboratory Medicine</p><p>(C V Cheng MD,</p><p>Prof A Mattman MD), and</p><p>Centre for Health Education</p><p>Scholarship (L Y C Chen),</p><p>University of British Columbia,</p><p>Vancouver, BC, Canada;</p><p>Department of Medicine,</p><p>Vancouver General Hospital,</p><p>Vancouver, BC, Canada</p><p>(E J Zhao, C V Cheng MD,</p><p>Prof A Mattman, L Y C Chen);</p><p>Department of Pathology and</p><p>Laboratory Medicine, St Paul’s</p><p>Hospital, Vancouver, BC,</p><p>Canada (Prof A Mattman)</p><p>Correspondence to:</p><p>Dr Luke Y C Chen, Vancouver</p><p>General Hospital,</p><p>Vancouver, BC V5Z 1M9, Canada</p><p>lchen2@bccancer.bc.ca</p><p>Polyclonal hypergammaglobulinaemia: assessment, clinical</p><p>interpretation, and management</p><p>Eric J Zhao, Catherine V Cheng, Andre Mattman, Luke Y C Chen</p><p>This Review outlines a practical approach to assessing and managing polyclonal hypergammaglobulinaemia in adults.</p><p>Polyclonal hypergammaglobulinaemia is most commonly caused by liver disease, immune dysregulation, or</p><p>inflammation, but can also provide an important diagnostic clue of rare diseases such as histiocyte disorders,</p><p>autoimmune lymphoproliferative syndrome, Castleman disease, and IgG4-related disease. Causes of polyclonal</p><p>hypergammaglobulinaemia can be divided into eight categories: liver disease, autoimmune disease and vasculitis,</p><p>infection and inflammation, non-haematological malignancy, haematological disorders, IgG4-related disease,</p><p>immunodeficiency syndromes, and iatrogenic (from immunoglobulin therapy). Measuring serum concentrations of</p><p>C-reactive protein and IgG subclasses are helpful in diagnosis. IL-6-mediated inflammation, associated with persistently</p><p>elevated C-reactive protein concentrations (≥30 mg/L), is an important driver of polyclonal hypergammaglobulinaemia</p><p>in some cases. Although the presence of markedly elevated serum IgG4 concentrations (>5 g/L) is around 90% specific</p><p>for diagnosing IgG4-related disease, mildly elevated serum IgG4 concentrations are seen in many conditions. In most</p><p>cases, managing polyclonal hypergammaglobulinaemia simply involves treating the underlying condition. Rarely,</p><p>however, polyclonal hypergammaglobulinaemia can lead to hyperviscosity, requiring plasmapheresis.</p><p>Introduction</p><p>Serum protein electrophoresis is commonly used to</p><p>investigate cytopenias or suspected autoimmune</p><p>disease, immunodeficiency, inflammatory conditions, or</p><p>lympho proliferative or plasma cell disorders. Patients</p><p>with abnormal results are often referred to haema­</p><p>tologists.1 Expert guidelines exist for common and rare</p><p>monoclonal paraprotein conditions,2,3 yet there is very</p><p>little literature on the investigation and management of</p><p>polyclonal hypergammaglobulinaemia. In many cases,</p><p>polyclonal hypergammaglobulinaemia is a physiological</p><p>reaction to liver disease, auto immunity, or inflammation.</p><p>However, polyclonal hyper gammaglobulinaemia can</p><p>also provide an important clue for diseases that are</p><p>difficult to diagnose and have variable manifestations,</p><p>such as eosinophilic granulomatosis with polyangiitis,</p><p>IgG4­related disease, and Rosai–Dorfman disease.4,5</p><p>Moreover, polyclonal hypergammaglobulinaemia is part</p><p>of the diagnostic criteria for rare diseases such as</p><p>idiopathic multi centric Castleman disease6 and auto­</p><p>immune lympho proliferative syndrome.7</p><p>In this Review, we present a systematic approach to</p><p>assessing and managing polyclonal hyper gamma­</p><p>globulinaemia. Causes of increases in all five</p><p>immunoglobulin heavy chain isotypes are listed in</p><p>table 1. Polyclonal increases in IgM concentration are</p><p>typically associated with impaired B­cell immuno­</p><p>globulin class switching.8,9 Polyclonal increases in IgA</p><p>concentration are most commonly due to liver cirrhosis</p><p>but are also seen with IgA nephropathy, IgA vasculitis</p><p>(Henoch–Schönlein purpura), AIDS, and autoimmune</p><p>diseases (eg, celiac disease, rheumatoid arthritis, and</p><p>systemic lupus erythematosus). More recently, elevated</p><p>IgA concen trations have been reported in patients with</p><p>severe COVID­19.10 Elevated IgD is seen in hyper­IgD</p><p>syndrome, which also presents with elevated IgA in</p><p>most cases.11 Increased serum IgE concentrations occur</p><p>in various allergic and atopic diseases, lymphoma, and</p><p>hyper­IgE syndrome.12 Importantly, normal serum</p><p>concentrations of IgD and IgE are much lower than</p><p>normal serum concentrations of IgG, IgM, and IgA</p><p>(table 1). Thus, although polyclonal increases in IgE</p><p>concentration reaching a value of more than 10 000 μg/L,</p><p>as seen in atopy and other conditions, seem considerable</p><p>at first, these concentrations are typically still less than</p><p>1 g/L and thus would not appear on serum protein</p><p>electrophoresis. Physicians unfamiliar with plasma cell</p><p>myeloma are sometimes concerned that polyclonal IgE</p><p>Reference range* Causes of polyclonal elevation</p><p>IgG 7·0–16·0 g/L Liver disease; autoimmune and autoinflammatory disease and vasculitis; infection; haematological disorders;</p><p>non-haematological malignancy; immunodeficiency; IgG4-related disease; and iatrogenic (from intravenous</p><p>immunoglobulin administration)</p><p>IgM 0·4–2·3 g/L Impaired B-cell immunoglobulin class switching; acute infection; and hyper-IgM syndrome</p><p>IgA 0·7–4·0 g/L Liver disease; alcohol excess; IgA vasculitis (eg, Henoch–Schönlein purpura); HIV infection; autoimmune disease (eg, celiac</p><p>disease, rheumatoid arthritis, and systemic lupus erythematosus); and IgA nephropathy</p><p>IgD <153 mg/L Hyper-IgD syndrome (commonly caused by MVK mutations; also presents with elevated IgA concentrations)</p><p>IgE <430 μg/L Allergy, atopy, and asthma; lymphoma; and hyper-IgE syndrome (commonly caused by STAT3 mutations)</p><p>*Reference ranges for Vancouver General Hospital, Vancouver, BC, Canada.</p><p>Table 1: Causes of elevated immunoglobulin concentrations</p><p>http://crossmark.crossref.org/dialog/?doi=10.1016/S2352-3026(21)00056-9&domain=pdf</p><p>e366 www.thelancet.com/haematology Vol 8 May 2021</p><p>Review</p><p>concentrations of more than 10 000 μg/L in IgG4­related</p><p>disease and other conditions might represent IgE</p><p>myeloma. However, in the rare reports of true</p><p>monoclonal IgE myeloma, which represents less</p><p>than 1% of all myeloma cases, the median paraprotein</p><p>concentrations are closer to 10 g/L.13 The remainder of</p><p>this Review will focus on polyclonal increases of IgG</p><p>concentration in adults.</p><p>Causes of polyclonal elevation in IgG</p><p>concentrations</p><p>We divide the causes of polyclonal elevation in IgG</p><p>concentrations into eight major categories (table 1;</p><p>figure 1). Historically, five categories were recognised:</p><p>liver disease, autoimmune disease and vasculitis,</p><p>infection and inflammation, haematological disorders,</p><p>and non­haematological malignancies.14 To these five,</p><p>we add three more: immunodeficiency syndromes,</p><p>iatrogenic hypergammaglobulinaemia from intravenous</p><p>immunoglobulin therapy, and IgG4­related disease.</p><p>Many primary immunodeficiencies, such as dysgamma­</p><p>globulinaemia (dysfunctional immunoglobulins) and</p><p>autoimmune lymphoproliferative syndrome, present</p><p>with elevated IgG concentrations.9 Although patients</p><p>with common variable immunodeficiency and baseline</p><p>hypogammaglobulinaemia might have normal IgG</p><p>concentrations after immunoglobulin replacement,</p><p>patients with conditions such as immune thrombo­</p><p>cytopenia or myasthenia gravis who have normal or</p><p>elevated IgG at baseline might have polyclonal</p><p>hypergammaglobulinaemia after intravenous immuno­</p><p>globulin therapy.</p><p>Liver disease</p><p>Liver disease is the single most common cause of</p><p>polyclonal hypergammaglobulinaemia in the primary</p><p>care setting. Liver disease­related polyclonal hyper gamma­</p><p>globulinaemia is typically mild, but autoimmune and viral</p><p>hepatitis can be associated with more profound increases</p><p>in IgG concentrations. Patient history is crucial in</p><p>directing confirmatory investigations, and should include</p><p>alcohol use, history of inflammatory bowel disease,</p><p>cystic fibrosis, Wilson’s disease, haemo chromatosis,</p><p>α1­antitrypsin</p><p>deficiency, and use of hepatotoxic medi­</p><p>cations. Autoimmune hepatitis commonly presents with</p><p>polyclonal hyper gamma globu linaemia, and a subset of</p><p>these patients have IgG4­associated autoimmune</p><p>hepatitis.15 In addition to the tests in figure 1, serologies</p><p>for autoimmune hepatitis (eg, antinuclear antibodies,</p><p>anti­smooth muscle antibodies, and anti­liver­kidney</p><p>microsomal antibodies), along with abdominal imaging</p><p>(ultrasonography or CT), might be helpful in diagnosis.16</p><p>Ultrasound elastography (eg, FibroScan) can provide a</p><p>non­invasive assessment of the degree of fibrosis. A</p><p>pattern of beta–gamma bridging on serum protein</p><p>electrophoresis often reflects polyclonal increases in IgA</p><p>concentration and is commonly seen in liver disease.17,18</p><p>Autoimmune disease and vasculitis</p><p>Autoimmune disorders that are associated with</p><p>considerable polyclonal hypergammaglobulinaemia</p><p>include Sjögren’s syndrome, rheumatoid arthritis,</p><p>and eosinophilic granulomatosis with polyangiitis. For</p><p>connective tissue disorders, the antinuclear antibody test,</p><p>followed by more specific anti­extractable nuclear antigen</p><p>testing, is recommended. Lupus nephritis can cause both</p><p>polyclonal hypergamma globulinaemia and hypogamma­</p><p>globu linaemia.19 Anti­neutrophil cytoplasmic antibodies</p><p>are associated with vasculitides, including eosinophilic</p><p>granulomatosis with polyangiitis, granulomatosis with</p><p>polyangiitis, and microscopic polyangiitis. Importantly,</p><p>up to 70% of patients with eosinophilic granulomatosis</p><p>with polyangiitis are negative for anti­neutrophil cyto­</p><p>plasmic antibodies, and these patients often present to</p><p>haema tologists with both eosinophilia and polyclonal</p><p>hyper gammaglobulinaemia.20 Persistently elevated con­</p><p>cen trations of C­reactive protein (CRP) in the absence of</p><p>infection or malignancy might indicate an atypical</p><p>presentation of vasculitis, such as eosinophilic granu­</p><p>lomatosis with polyangiitis or giant cell arteritis.</p><p>Infection and inflammation</p><p>Polyclonal hypergammaglobulinaemia occurs in up to</p><p>half of patients with HIV before they initiate antiretroviral</p><p>treatment.21 HIV infection has been shown to reduce</p><p>populations of memory B cells and hyperactivate naive</p><p>B cells.22 Other chronic infections, such as tuberculosis,</p><p>can also cause polyclonal hypergammaglobulinaemia,</p><p>and elevated IgM and IgG concentrations can be seen in</p><p>patients with acute infections.23</p><p>IgG4-related disease</p><p>IgG4­related disease is a fibroinflammatory disorder</p><p>that can present with tumefactive lesions in virtually</p><p>any organ, retroperitoneal fibrosis, and mediastinal</p><p>fibrosis. Common reasons for referral to haematologists</p><p>include lymphadenopathy, eosinophilia, and polyclonal</p><p>hypergammaglobulinaemia. Some patients with a label</p><p>of hypereosinophilic syndrome and polyclonal hyper­</p><p>gammaglobulinaemia might in fact have undiagnosed</p><p>IgG4­related disease.24,25 Although most patients with</p><p>IgG4­related disease do not manifest atopy, a subset of</p><p>these non­atopic patients still have elevated IgE</p><p>concentrations and peripheral eosinophilia.26 T follicular</p><p>helper cells secrete IL­4 and IL­10 and are responsible for</p><p>B­cell class switching to IgG4 expression. Because IL­4</p><p>alone promotes B­cell class switching to both IgG4 and</p><p>IgE expression, the relative abundance of IL­4­secreting</p><p>T cells and IL­10­secreting T cells might cause B cells to</p><p>class switch to IgE expression, contributing to the</p><p>markedly elevated IgE concentrations in some patients.27</p><p>The reliability of serum IgG4 concentration as a</p><p>screening test for IgG4­related disease is variable. In</p><p>general, IgG and IgG4 production is higher in</p><p>Asian people than in White people with the disease,</p><p>www.thelancet.com/haematology Vol 8 May 2021 e367</p><p>Review</p><p>Figure 1: Investigations and initial approach in the evaluation of undifferentiated polyclonal hypergammaglobulinaemia</p><p>+/– means additional tests to be considered. ALP=alkaline phosphatase. ALT=alanine transaminase. ANA=antinuclear antibodies. ANCA=anti neutrophil cytoplasmic</p><p>antibodies. AST=aspartate transaminase. DAT=direct antiglobulin test. EGPA=eosinophilic granulomatosis with polyangiitis. GGT=γ-glutamyl transferase.</p><p>GPA=granulomatosis with polyangiitis. MPA=microscopic polyangiitis. SPEP=serum protein electrophoresis. UPEP=urine protein electrophoresis.</p><p>Initial laboratory investigations</p><p>• Complete blood count, blood differential test, and blood film</p><p>• SPEP, UPEP, and quantitative immunoglobulin</p><p>• Liver enzymes (ie, AST, ALT, ALP, and GGT)</p><p>• ANA, ANCA, complement C3, complement C4, and DAT</p><p>• Hepatitis B virus, hepatitis C virus, and HIV serologies, +/– Epstein–Barr virus and human herpesvirus-8 serologies</p><p>• IgG subclasses</p><p>• C-reactive protein</p><p>• +/– Cytokine profile (IL-5, IL-6, and soluble IL-2 receptor)</p><p>• +/– Imaging for liver disease, lymphadenopathy, and malignancy</p><p>• +/– Bone marrow biopsy if lymphoma or haematological disorder suspected</p><p>• +/– Genetic testing for immunodeficiency syndromes</p><p>History and physical examination</p><p>• Lymphadenopathy</p><p>• Arthritis</p><p>• Skin lesions</p><p>• Fever and infection; travel and exposures</p><p>• Signs and symptoms of hyperviscosity</p><p>• Intravenous immunoglobulin therapy</p><p>• Family history of immunodeficiency</p><p>• Swelling of lacrimal, salivary, and parotid glands</p><p>• Hepatosplenomegaly</p><p>• Signs of chronic liver disease</p><p>Persistently high C-reactive protein</p><p>concentrations (≥30 mg/L)</p><p>Variable C-reactive protein concentrations</p><p>Patient with undifferentiated polyclonal hypergammaglobulinaemia</p><p>Low or modestly elevated C-reactive protein</p><p>concentrations (<30 mg/L)</p><p>Chronic infection</p><p>• Viral (eg, HIV, Epstein–Barr virus, and varicella</p><p>zoster)</p><p>• Mycobacterial (eg, Mycobacterium</p><p>tuberculosis and Mycobacterium leprae)</p><p>• Bacterial (eg, bacterial endocarditis and</p><p>Whipple disease)</p><p>• Protozoan (eg, Leishmania and</p><p>Trypanosoma cruzi)</p><p>Malignancy</p><p>• Non-haematological malignancy associated</p><p>with inflammation</p><p>Haematological disorders</p><p>• Multicentric Castleman disease</p><p>• Rosai–Dorfman disease</p><p>Autoimmune and autoinflammatory diseases</p><p>• Vasculitis:</p><p>- ANCA vasculitis (eg, EGPA, GPA, and MPA)</p><p>- Giant cell arteritis</p><p>• Dermatomyositis and polymyositis</p><p>• Inflammatory bowel disease</p><p>• Ankylosing spondylitis</p><p>• Familial Mediterranean fever</p><p>• Sarcoidosis</p><p>Immunodeficiency syndromes</p><p>• Activated PI3Kdelta syndrome</p><p>Haematological disorders</p><p>• Lymphoma and lymphoproliferative disorders</p><p>Autoimmune and autoinflammatory diseases</p><p>• Sjögren’s syndrome</p><p>• Systemic lupus erythematous and</p><p>inflammatory arthritis</p><p>• Sarcoidosis</p><p>Iatrogenic</p><p>• Intravenous immunoglobulin therapy in</p><p>patients with diseases with normal or elevated</p><p>IgG concentrations at baseline (eg, immune</p><p>thrombocytopenia and neurological disease)</p><p>Liver disease</p><p>• Autoimmune hepatitis</p><p>• α1-Antitrypsin deficiency</p><p>• Alcoholic and non-alcoholic steatohepatitis</p><p>• Haemochromatosis</p><p>• Primary biliary cirrhosis</p><p>• Primary sclerosing cholangitis</p><p>• Viral hepatitis</p><p>Haematological disorders</p><p>• Angioimmunoblastic T-cell lymphoma</p><p>• Fanconi anaemia</p><p>• Hypereosinophilic syndromes</p><p>• Autoimmune cytopenias</p><p>• Myelodysplastic syndromes</p><p>• Haemophilia A (inherited and acquired)</p><p>• Haemoglobinopathies (eg, sickle cell anaemia</p><p>and thalassaemia major)</p><p>Autoimmune and inflammatory disorders</p><p>• Graves’ disease</p><p>• Scleroderma</p><p>Immunodeficiency syndromes</p><p>• Autoimmune lymphoproliferative disorder</p><p>• Dysgammaglobulinaemias</p><p>• Severe combined immunodeficiency</p><p>• Ataxia-telangiectasia</p><p>• Wiskott–Aldrich syndrome</p><p>• Autoimmune polyendocrinopathy with</p><p>candidiasis and ectodermal dysplasia</p><p>IgG4-related disease</p><p>• Polyclonal hypergammaglobulinaemia in more</p><p>than 95% of Asian patients and in around 60% of</p><p>White patients</p><p>e368 www.thelancet.com/haematology Vol 8 May 2021</p><p>Review</p><p>and therefore test sensitivity is higher in Asian</p><p>patients.5,28 Given the propensity of IgG4­related disease</p><p>to mimic other conditions, definitive diagnosis relies on</p><p>close clinical–pathological correlation. In most cases,</p><p>histological confirmation is ideal. The American College</p><p>of Rheumatology and the European</p><p>League Against</p><p>Rheumatism have released classification criteria to aid</p><p>in diagnosis and eliminate the need for histological</p><p>confirmation in some cases.29 Investigations have</p><p>implicated the self­antigens annexin A11, laminin­511,</p><p>prohibitin, and galectin­3 in the pathogenesis of IgG4­</p><p>related disease, suggesting that this disease is</p><p>fundamentally an autoimmune disorder. However, there</p><p>is still controversy as to the mechanism of the antigen­</p><p>driven immune response and the role these auto­</p><p>antibodies play. There is evidence that having IgG4</p><p>autoantibodies against more than two of these self­</p><p>antigens correlates with more severe disease, suggesting</p><p>a more severe defect in immune tolerance.30</p><p>Haematological disorders</p><p>Many rare haematological diseases present with polyclonal</p><p>hypergammaglobulinaemia, which represents a diag­</p><p>nostic challenge. Key features of some of these conditions</p><p>are summarised in the appendix (pp 1–3). Polyclonal</p><p>hypergammaglobulinaemia is included in the diagnostic</p><p>criteria of idiopathic multicentric Castleman disease and</p><p>autoimmune lymphoproliferative syndrome. There is</p><p>considerable overlap in the presentation of IgG4­related</p><p>disease and idiopathic multicentric Castleman disease in</p><p>that both often present with multiorgan involvement,</p><p>lymphadenopathy, and polyclonal hyper gamma glo buli­</p><p>naemia with elevated serum IgG4 concentrations,</p><p>although Castleman disease tends to have a much more</p><p>acute presentation than does IgG4­related disease. The</p><p>2017 international consensus diagnostic criteria for</p><p>human herpesvirus­8­negative, idiopathic multicentric</p><p>Castleman disease indicates that a diagnosis of Castleman</p><p>disease should supersede a diagnosis of IgG4­related</p><p>disease, even if patients have very high serum IgG4</p><p>concentrations and a high number of IgG4­positive</p><p>plasma cells in tissue.6 Idiopathic multicentric Castleman</p><p>disease is a hyper­IL­6 syndrome and typically presents</p><p>with an elevated concentration of CRP (≥30 mg/L;</p><p>figure 1). Although tissues in Castleman disease, such as</p><p>lymph nodes, can be enriched with IgG4­positive plasma</p><p>cells, the IgG4­positive to IgG­positive plasma cell ratio is</p><p>typically less than the 40% required for a diagnosis of</p><p>IgG4­related disease, and other features of IgG4­related</p><p>disease, such as storiform fibrosis and obliterative</p><p>phlebitis, are generally not seen in patients with idiopathic</p><p>multicentric Castleman disease.31 Autoimmune lympho­</p><p>proliferative syndrome can also mimic IgG4­related</p><p>disease.32 Autoimmune lymphoproliferative syndrome</p><p>can be caused by germline or somatic mutations in the</p><p>FAS gene. Uncontrolled lymphocyte proliferation results</p><p>in lymphadenopathy, splenomegaly, and hepatomegaly.</p><p>Other features of autoimmune lymphoproliferative</p><p>syndrome include autoimmune cytopenias, glomerulo­</p><p>nephritis, autoimmune hepatitis, and constitutional</p><p>symptoms.7</p><p>The causes of polyclonal increases in IgG concentration</p><p>provided in this Review form a representative, rather than</p><p>exhaustive, list. Any condition that causes inflammation</p><p>leading to elevated IL­6 concentrations can cause</p><p>polyclonal hypergamma globulinaemia. Furthermore,</p><p>novel mechanisms, such as serine/threonine­protein</p><p>kinase mTOR dysregulation and as­yet undiscovered</p><p>genetically mediated and acquired pathways, might also</p><p>lead to excessive IgG production.</p><p>Pathophysiology of polyclonal</p><p>hypergammaglobulinaemia</p><p>Mechanisms of polyclonal hypergammaglobulinaemia</p><p>in patients with elevated CRP</p><p>The inflammatory cytokine IL­6 has long been known</p><p>to play an integral role in the pathogenesis of many</p><p>diseases that have polyclonal hypergammaglobulinaemia</p><p>as a core feature (figure 2).33,34 IL­6 stimulates</p><p>hepatocytes to produce the acute phase reactant CRP.35</p><p>Because most clinical laboratories do not measure IL­6,</p><p>a CRP concentration of 30 mg/L or more can be used as</p><p>an approximate surrogate measure for hyper­IL­6</p><p>states. Studies have shown correlation between CRP</p><p>and IL­6 in diverse states of inflammation, including</p><p>ankylosing spondylitis, post­myocardial infarction, and</p><p>obesity.36,37 IL­6 was discovered in the 1970s and was</p><p>initially known as B­cell stimulatory factor 2.38 This</p><p>pleiotropic cytokine has numerous roles in inflam­</p><p>mation, haematopoiesis, and the immune response,</p><p>such as the induction of B­cell maturation into</p><p>antibody­secreting cells, aiding the maintenance and</p><p>survival of plasma cells, and the synthesis of acute</p><p>phase proteins in hepatocytes.39</p><p>Multicentric Castleman disease is considered a</p><p>prototypical hyper­IL­6 syndrome; constitutively</p><p>activating the IL6 gene in mouse haematopoietic cells</p><p>produces a syndrome resembling multicentric Castleman</p><p>disease, which includes polyclonal hyper gamma­</p><p>globulinaemia.40 The lymph nodes of patients with</p><p>Castleman disease express large amounts of IL­6, and</p><p>most patients can be effectively treated with IL­6</p><p>inhibitors such as tocilizumab or siltuximab.40 Cutaneous</p><p>and systemic plasmacytosis is a rare hyper­IL­6 syndrome</p><p>characterised by plasmacytic infiltrate in various organ</p><p>systems, including the skin, lymph nodes, and bone</p><p>marrow, and polyclonal hypergamma globulinaemia,</p><p>sometimes to the point of hyperviscosity syndrome.41,42</p><p>IL­6 is also implicated in the pathogenesis of Rosai–</p><p>Dorfman disease,43 and nucleoside analogues that impair</p><p>monocyte function through IL­6 inhibition are effective</p><p>in the treatment of this disease.44 In autoimmune</p><p>hepatitis, a triggering environmental event (eg, infection)</p><p>is thought to damage hepatocytes, which results in the</p><p>See Online for appendix</p><p>www.thelancet.com/haematology Vol 8 May 2021 e369</p><p>Review</p><p>presentation of liver autoantigens to T cells and B cells.</p><p>IL­6 and transforming growth factor β (TGF­β) induce</p><p>the differentiation of naive CD4+ T­helper (Th) cells to</p><p>Th17 cells. Th17 cells then release IL­17 and IL­23, which</p><p>induce the production of IL­6 by hepatocytes, setting up a</p><p>positive feedback loop.</p><p>IL­6 signalling occurs when the cytokine engages IL­6</p><p>receptors on cells expressing IL­6 receptor subunit</p><p>beta (IL­6RB). The classical signalling pathway via</p><p>membrane­bound IL­6RB is limited to immune cells</p><p>(eg, lymphocytes and monocytes), hepatocytes, and gut</p><p>epithelial cells. Most other tissues rely on the trans­</p><p>signalling pathway involving soluble IL­6 receptor and</p><p>the soluble IL­6RB buffering system. Trans­signalling</p><p>has also been implicated in polyclonal hypergamma­</p><p>globulinaemia. In the presence of immune stimulation,</p><p>classical dendritic cells secrete enough soluble IL­6</p><p>receptor to overcome soluble IL­6RB inhibition, which</p><p>in turn facilitates plasmablast maturation into plasma</p><p>cells.45</p><p>Mechanisms of polyclonal hypergammaglobulinaemia</p><p>in patients with low or modestly elevated CRP</p><p>Although IL­6 has a key role in the polyclonal</p><p>hypergammaglobulinaemia seen in inflammatory</p><p>conditions, polyclonal hypergammaglobulinaemia can</p><p>also occur in the absence of severe systemic inflam­</p><p>mation. Moreover, polyclonal hypergamma glo buli­</p><p>naemia is not a common feature in some hyper­IL­6</p><p>syndromes, such as COVID­19 cytokine storm.46</p><p>IgG4­related disease does have similarities in its clinical</p><p>presentation to Rosai–Dorfman disease and Castleman</p><p>disease (eg, lymphadenopathy, and polyclonal hyper­</p><p>gamma globu linaemia), but is associated with consid­</p><p>erably less systemic inflammation, typically presenting</p><p>with a CRP concen tration less than 30 mg/L. The</p><p>polyclonal hypergamma globulinaemia of IgG4­related</p><p>disease occurs in a complex background of immune</p><p>dysregulation involving CD4+ effector memory cells, B</p><p>cells, plasmablasts, and a mixture of cytokines and</p><p>growth factors, including IL­4, IL­10, and TGF­β.47</p><p>In cirrhosis, the loss of hepatic filtering capacity</p><p>allows enteric antigens and endotoxins access to the</p><p>immune system, leading to increased IgA and IgG</p><p>production.48 This loss in filtering capacity might be due</p><p>to a cellular defect in Kupffer cells or might simply be a</p><p>manifestation of haemodynamic shunting</p><p>of antigens</p><p>from the portal circulation into the systemic circulation.</p><p>Evidence for haemodynamic shunting has been found</p><p>in rat studies with surgically created portosystemic</p><p>shunts.17 In pulmonary sarcoidosis, activated T lympho­</p><p>cytes are thought to mediate local production of</p><p>immunoglobulins in lung tissue.49 Elevated IgG and</p><p>decreased IgM concentrations are common features of</p><p>autoimmune lymphoproliferative syndrome, and these</p><p>serological abnormalities are caused by a defective</p><p>polysaccharide response, splenic marginal zone</p><p>disorganisation, and increased plasma cells in the</p><p>lymph nodes and spleen.50</p><p>Mice infected with lymphocytic choriomeningitis</p><p>virus develop hypergammaglobulinaemia when CD4+ T</p><p>cells recognise viral peptides that have been processed</p><p>by B cells, irrespective of B­cell receptor specificity,</p><p>perhaps through a pinocytosis process.51 The B cells</p><p>then receive help from virus­specific T cells, interacting</p><p>via the T­cell receptor, MHC class II molecules, and</p><p>CD40–CD40­L binding. These activated B cells then</p><p>produce the non­specific immunoglobulins of poly­</p><p>clonal hypergamma globulinaemia, which could also</p><p>lead to the generation of potentially harmful</p><p>autoantibodies or immune complexes, as can be seen in</p><p>hepatitis B virus­associated glomerulonephritis and</p><p>hepatitis C virus��associated cryoglobulinaemia. Aberrant</p><p>B­cell and T­cell activation in HIV infection has been</p><p>studied extensively, although a precise mechanistic</p><p>understanding of this cause of polyclonal hypergamma­</p><p>globulinaemia remains elusive. Most studies suggest</p><p>that B­cell activation in this context is antigen­</p><p>independent,22 with interactions between B cells and</p><p>T cells occurring in the non­specific manner already</p><p>described. Naive B cells are activated, express CD70,</p><p>class switch to IgG expression, and produce polyclonal</p><p>IgG antibodies.52 B cells could be activated by Toll­like</p><p>receptor 9 recognising CpG sites in DNA,53 directly by</p><p>Figure 2: Mechanisms of polyclonal hypergammaglobulinaemia</p><p>Macrophages and monocytes recognise PAMPs from the infection and DAMPs from cellular damage via Toll-like</p><p>receptors. This recognition induces the release of IL-6, which mediates hepatic production of acute phase reactants.</p><p>IL-6 stimulates naive CD4+ T cells to become Tfh cells, which in turn support the maturation of B cells into plasma</p><p>cells, B-cell proliferation, and B-cell class switching. IL-6 increases the Th17 cell to regulatory T cell ratio, which</p><p>supports autoimmunity and chronic inflammation. In autoimmune hepatitis, a positive feedback loop is set up</p><p>whereby IL-6 induces the differentiation of naive CD4+ T cells to Th17 cells, and Th17 cells stimulate hepatocytes to</p><p>produce more IL-6 via IL-17 and IL-23. In human herpesvirus-8-associated multicentric Castleman disease, the virus</p><p>produces viral IL-6 and endothelial cells produce endogenous IL-6. DAMPs=danger-associated molecular patterns.</p><p>HHV-8=human herpesvirus-8. PAMPs=pathogen-associated molecular patterns. Tfh=T follicular helper.</p><p>TGF-β=transforming growth factor β. Th17=T-helper-17.</p><p>Monocytes and macrophages</p><p>Toll-like receptor PAMPs</p><p>DAMPs</p><p>IL-6</p><p>IL-6</p><p>IL-6</p><p>IL-17</p><p>IL-23</p><p>Viral IL-6CD4+ T Cell</p><p>CD4+ T cell</p><p>T� cell</p><p>Th17 cell</p><p>B cell</p><p>Plasma cell</p><p>Hepatocyte</p><p>↑Th17</p><p>↓Regulatory T cell</p><p>↑Autoimmunity</p><p>↑Chronic inflammation</p><p>Hepatocyte</p><p>↑C-reactive protein</p><p>↑Serum amyloid A</p><p>↑Fibrinogen</p><p>↑Hepcidin</p><p>↑Haptoglobin</p><p>↓Albumin</p><p>↓Transferrin</p><p>↑ Proliferation</p><p>↑ Class switching</p><p>Immunoglobulin</p><p>production</p><p>Endothelial cell</p><p>TGF-β</p><p>HHV-8</p><p>e370 www.thelancet.com/haematology Vol 8 May 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A</p><p>N</p><p>A=</p><p>an</p><p>tin</p><p>uc</p><p>le</p><p>ar</p><p>a</p><p>nt</p><p>ib</p><p>od</p><p>y.</p><p>AN</p><p>CA</p><p>=a</p><p>nt</p><p>i-n</p><p>eu</p><p>tr</p><p>op</p><p>hi</p><p>l c</p><p>yt</p><p>op</p><p>la</p><p>sm</p><p>ic</p><p>an</p><p>tib</p><p>od</p><p>ie</p><p>s.</p><p>CR</p><p>P=</p><p>C-</p><p>re</p><p>ac</p><p>tiv</p><p>e</p><p>pr</p><p>ot</p><p>ei</p><p>n.</p><p>H</p><p>BV</p><p>=h</p><p>ep</p><p>at</p><p>iti</p><p>s B</p><p>v</p><p>iru</p><p>s.</p><p>H</p><p>CV</p><p>=h</p><p>ep</p><p>at</p><p>iti</p><p>s C</p><p>v</p><p>iru</p><p>s.</p><p>H</p><p>H</p><p>V-</p><p>8=</p><p>hu</p><p>m</p><p>an</p><p>h</p><p>er</p><p>pe</p><p>sv</p><p>iru</p><p>s-</p><p>8.</p><p>M</p><p>CV</p><p>=m</p><p>ea</p><p>n</p><p>co</p><p>rp</p><p>us</p><p>cu</p><p>la</p><p>r v</p><p>ol</p><p>um</p><p>e.</p><p>R</p><p>F=</p><p>rh</p><p>eu</p><p>m</p><p>at</p><p>oi</p><p>d</p><p>fa</p><p>ct</p><p>or</p><p>. S</p><p>PE</p><p>P=</p><p>se</p><p>ru</p><p>m</p><p>p</p><p>ro</p><p>te</p><p>in</p><p>e</p><p>le</p><p>ct</p><p>ro</p><p>ph</p><p>or</p><p>es</p><p>is.</p><p>S</p><p>SA</p><p>=S</p><p>jö</p><p>gr</p><p>en</p><p>’s</p><p>sy</p><p>nd</p><p>ro</p><p>m</p><p>e-</p><p>re</p><p>la</p><p>te</p><p>d</p><p>an</p><p>tig</p><p>en</p><p>A</p><p>. S</p><p>SB</p><p>=S</p><p>jö</p><p>gr</p><p>en</p><p>’s</p><p>sy</p><p>nd</p><p>ro</p><p>m</p><p>e t</p><p>yp</p><p>e</p><p>B</p><p>an</p><p>tig</p><p>en</p><p>.</p><p>Ta</p><p>bl</p><p>e 2</p><p>: F</p><p>ou</p><p>r c</p><p>as</p><p>e</p><p>vi</p><p>gn</p><p>et</p><p>te</p><p>s</p><p>www.thelancet.com/haematology Vol 8 May 2021 e371</p><p>Review</p><p>the HIV accessory protein Tat,54 indirectly via HIV­</p><p>infected macrophages and HIV viral proteins,55 and by</p><p>stimulation from T cells specific to latent or coinfecting</p><p>viruses such as cytomegalovirus and Epstein–Barr</p><p>virus.22</p><p>Investigating polyclonal</p><p>hypergammaglobulinaemia</p><p>Patient histories should focus on the eight causes</p><p>of polyclonal hypergammaglobulinaemia, noting symp­</p><p>toms of liver disease and histories of autoimmune disease</p><p>and vasculitis, chronic inflammatory conditions or</p><p>infections, malignancy, and immunoglobulin replacement</p><p>therapy (figure 1). Physical examinations should be done</p><p>for lymphadenopathy, swelling of the lacrimal, salivary,</p><p>and parotid glands, hepato splenomegaly, arthritis and</p><p>synovitis, signs of chronic liver disease, and cutaneous</p><p>lesions. In patients with extremely elevated IgG</p><p>concentrations (ie, a total IgG concentration >60 g/L),</p><p>symptoms and signs of hyper viscosity, including an altered</p><p>level of consciousness, visual disturbances, high­output</p><p>heart failure, mucosal bleeding, retinal haemorrhages, and</p><p>papilloedema, should be assessed. Serum protein</p><p>electrophoresis, alongside tests for liver enzymes, viral</p><p>serology, antinuclear antibodies, CRP, quantitative</p><p>immuno globulins (ie, IgG, IgA, and IgM), and IgG</p><p>subclasses, should be ordered in most patients in whom</p><p>the cause is not immediately evident on clinical</p><p>examination. A pattern of beta–gamma bridging on serum</p><p>protein electrophoresis might reflect polyclonal increases</p><p>in IgA concentration, which is most commonly seen in</p><p>liver disease, or elevated serum IgG4 concentration.17,18,48</p><p>Some patients might require imaging to examine for liver</p><p>disease (eg, hepatic steatosis, which is a common cause of</p><p>mild polyclonal hyper gamma globulinaemia in the primary</p><p>care setting) and malignancy.</p><p>On the basis of this initial evaluation, we broadly</p><p>divide the causes of polyclonal hypergamma globu­</p><p>linaemia into hyperinflammatory conditions associated</p><p>with persistently high CRP concentrations (≥30 mg/L)</p><p>and those with low or modestly elevated CRP</p><p>concentrations (<30 mg/L; figure 1). Of note, the use of</p><p>CRP concentration and a cutoff of 30 mg/L is a rough</p><p>guideline. Some inflammatory conditions, such as</p><p>eosinophilic granulomatosis with polyangiitis and</p><p>chronic infections, will reliably present with markedly</p><p>elevated CRP concentrations, whereas others, such as</p><p>Sjögren’s syndrome and systemic lupus erythematous,</p><p>might sometimes present with low CRP concentrations.</p><p>Likewise, some conditions, such as IgG4­related</p><p>disease and alcoholic liver cirrhosis, typically present</p><p>with low CRP concentrations, but might initially present</p><p>with a concomitant infection or other transient</p><p>acute inflammatory processes. We summarise four</p><p>case vignettes in table 2 and figure 3 to illustrate the</p><p>range of conditions in which polyclonal hypergamma­</p><p>globulinaemia can occur and the pitfalls in the</p><p>interpretation of polyclonal hypergammaglobulinaemia.</p><p>Figure 3: Serum protein electrophoresis densitometry tracings of the four case vignettes described in table 2</p><p>(A) Case 1: SjÖgren’s syndrome. Tracing for a healthy control is overlaid in blue. (B) Case 2: inflammation from hidradenitis suppurativa. (C) Case 3: idiopathic</p><p>multicentric Castleman disease. (D) Case 4: IgG4-related disease; the dense polyclonal IgG4 band, causing beta–gamma bridging, was mistaken for a monoclonal</p><p>band. (E) Electrophoretic distribution of the major immunoglobulins and IgG subclasses in relation to the classical electrophoretic fractions. Reproduced and adapted</p><p>from Jacobs and colleagues,56 by permission of Oxford University Press.</p><p>Albumin</p><p>Beta1</p><p>Beta2</p><p>Alpha2</p><p>Alpha1</p><p>Gamma</p><p>Albumin</p><p>Beta1</p><p>Beta2</p><p>Beta</p><p>Alpha2</p><p>Alpha1</p><p>Gamma</p><p>Albumin</p><p>Albumin</p><p>Beta1</p><p>Alpha2</p><p>Alpha2</p><p>Alpha1</p><p>Alpha1</p><p>Gamma</p><p>Gamma</p><p>Albumin</p><p>Beta1</p><p>Beta2</p><p>Alpha2</p><p>Alpha1</p><p>Gamma</p><p>Beta2</p><p>IgA</p><p>IgM</p><p>IgG</p><p>IgG1</p><p>IgG2</p><p>IgG3</p><p>IgG4</p><p>A Case 1 B Case 2</p><p>C Case 3 D Case 4 E</p><p>Case</p><p>Control</p><p>e372 www.thelancet.com/haematology Vol 8 May 2021</p><p>Review</p><p>Methods of measuring serum immunoglobulins</p><p>Serum protein electrophoresis, quantitative immuno­</p><p>nephelometry, and IgG subclass testing all have important</p><p>complementary roles in the investigation of polyclonal</p><p>hypergammaglobulinaemia. Although increased IgG1,</p><p>IgG2, and IgG3 concentrations typically appear in</p><p>the gamma region on serum protein electrophoresis,</p><p>polyclonal increases in IgA and IgG4 concentration</p><p>typically run in the fast gamma region (figure 3D) and</p><p>might obscure the normal depression between the</p><p>beta and gamma regions, a pattern known as beta–</p><p>gamma bridging. The typical electrophoretic migration</p><p>pattern of the major immunoglobulins and subclasses</p><p>is illustrated in figure 3E.56 Traditionally, polyclonal</p><p>hypergammaglobulinaemia with beta–gamma bridging</p><p>on serum protein electrophoresis is attributed to</p><p>polyclonal increases in IgA concentration due to liver</p><p>cirrhosis, but if quantitative immunonephelometry</p><p>for IgG, IgA, and IgM is also done, the elevated</p><p>immunoglobulin isotype is readily apparent. The</p><p>immunoglobulin concentrations obtained from immuno­</p><p>nephelometry are often considerably higher than those</p><p>obtained from serum protein electrophoresis. Unlike in</p><p>monoclonal gammopathies, urine protein electrophoresis</p><p>and serum free light chain assays provide little additional</p><p>information in polyclonal hypergamma globulinaemia.</p><p>Conditions, such as idiopathic multicentric Castleman</p><p>disease and chronic HIV infection, can result in serum</p><p>protein electrophoresis results that resemble a</p><p>monoclonal gammopathy, but immunofixation can</p><p>distinguish between the presence of a monoclonal</p><p>immunoglobulin band and an unusual distribution of</p><p>polyclonal γ­globulins.</p><p>Clinicians interpreting results from serum protein</p><p>electrophoresis should be aware that polyclonal hyper­</p><p>gammaglobulinaemia caused by an increase of serum</p><p>IgG4 concentration could resemble a monoclonal</p><p>gammopathy, and thus serum protein electrophoresis</p><p>and immunofixation should be done along with IgG</p><p>subclass testing.57 Although the typical clinical features of</p><p>IgG4­related disease (eg, autoimmune pancreatitis,</p><p>swelling of the lacrimal, salivary, and parotic glands,</p><p>orbital pseudotumour, and retroperitoneal fibrosis) and</p><p>plasma cell myeloma (eg, anaemia, hypercalcaemia, and</p><p>lytic bony lesions) are usually distinct, there are some</p><p>areas of overlap (eg, renal failure, increased plasma cell</p><p>number in the bone marrow and affected tissue, and</p><p>cytopenias), and there are rare case reports of IgG4­</p><p>related disease mimicking myeloma58,59 and vice versa.60</p><p>Roughly, IgG4 myeloma comprises 1–5% of all IgG</p><p>myleomas, a prevalence matching the proportion of total</p><p>IgG made up by IgG4 in healthy individuals.61</p><p>Although recent interest in measuring IgG subclasses</p><p>has been driven by the advent of IgG4­related disease,</p><p>the four subclasses of IgG were discovered in studies of</p><p>IgG myeloma in the 1960s. The subclasses were named</p><p>in order of abundance, and thus IgG4 has the lowest</p><p>serum concentration, with an upper limit of normal of</p><p>1·25–1·50 g/L in most laboratories. Most causes of</p><p>polyclonal hypergammaglobulinaemia are driven</p><p>primarily by increases in IgG1 concentration. Mild</p><p>elevation of serum IgG4 concentrations (ie, 1·5–5·0 g/L)</p><p>is non­specific and can be seen in various diseases, but</p><p>a concentration of more than 5·0 g/L is around</p><p>90% specific for the diagnosis of IgG4­related disease.62</p><p>Marked elevations of IgG4 concentrations can be seen</p><p>in eosinophilic granulomatosis with polyangiitis,</p><p>idiopathic multicentric Castleman disease, and other</p><p>conditions (table 2).62,63 In IgG4­related disease, the</p><p>serum IgG4:IgG ratio is often well in excess of 10%</p><p>(table 2). Importantly, serum protein electrophoresis</p><p>and IgG subclass testing should be done in conjunction</p><p>to confirm whether elevated immunoglobulins are</p><p>monoclonal or polyclonal. In most laboratories, IgG</p><p>subclasses are measured by immunonephelometry. In</p><p>British Columbia, Canada, a cost­effective liquid</p><p>chromatography with tandem mass spectrometry assay</p><p>is the method of choice.64 This assay avoids the Hook</p><p>effect (whereby the effectiveness of an antibody­based</p><p>assay to form immune complexes is impaired by very</p><p>high concentrations of an analyte) and other errors</p><p>such as spuriously elevated IgG2 concentrations. Mass</p><p>spectrometry is rapidly gaining prominence as a</p><p>method of identifying and monitoring serum</p><p>immunoglobulins. The exquisite specificity of mass</p><p>spectrometry methods allows assessment of minimal</p><p>residual disease in plasma cell myeloma and provides</p><p>high reliability in quantifying low concentration</p><p>monoclonal bands by eliminating the subjectivity of</p><p>densitometry interrogation.65</p><p>IgG subclass analysis might have value in other</p><p>diseases as well. A retrospective study of 552 patients</p><p>with isolated increases in one of the IgG subclasses</p><p>revealed statistically significant associations with several</p><p>specific diseases.66 Hepatitis C virus infection and</p><p>monoclonal gammopathy were significantly associated</p><p>with isolated increases in IgG1 concentrations. Patterns</p><p>of IgG subclass changes are associated with specific</p><p>causes of liver disease; increased IgG1:IgG ratios are</p><p>seen in viral hepatitis, autoimmune hepatitis is</p><p>associated with increased IgG1 concentrations, and</p><p>primary biliary cholangitis is associated with increased</p><p>IgG3 and decreased IgG4 concentrations.67 Systemic</p><p>lupus erythematosus, chronic infections, and HIV</p><p>infection typically cause increases in IgG1 concen­</p><p>trations. Rheumatoid arthritis can be associated with an</p><p>isolated elevation in IgG1 concentration or IgG3</p><p>concentration.66 Hypothyroidism and irritable bowel</p><p>syndrome can be associated with isolated elevations in</p><p>IgG2 concentration.66 Eosinophilic granulomatosis with</p><p>polyangiitis, Sjögren’s syndrome, idiopathic multicentric</p><p>Castleman disease, and lymphocytic­variant hyper­</p><p>eosinophilic syndromes can be associated with markedly</p><p>elevated IgG4 concentrations.68</p><p>www.thelancet.com/haematology Vol 8 May 2021 e373</p><p>Review</p><p>Management of polyclonal</p><p>hypergammaglobulinaemia</p><p>In most cases, treatment of the underlying condition</p><p>typically leads to resolution of the immune dysregulation</p><p>and inflammation driving the polyclonal hypergamma­</p><p>globulinaemia. Some treatment options for rare</p><p>haematological conditions associated with polyclonal</p><p>hypergammaglobulinaemia are listed in table 2</p><p>and the appendix (pp 1–3). Patients with immune</p><p>cytopenias, such as autoimmune haemolytic anaemia</p><p>and immune thrombocytopenia, should have serum</p><p>protein electrophoresis and quantitative immunoglobulin</p><p>testing at baseline to rule out conditions such as</p><p>autoimmune lymphoproliferative syndrome (which</p><p>presents with polyclonal hyper gammaglobulinaemia)</p><p>and common variable immune deficiency (which</p><p>presents with hypogamma globulinaemia). For IgG4­</p><p>related disease, first­line therapies are corticosteroids and</p><p>rituximab.69 Approxi mately 80% of patients will have a</p><p>satisfactory response to corticosteroids; prednisone</p><p>administered at 0·5–1·0 mg per kg of bodyweight for</p><p>3–4 weeks before tapering is effective, with the main</p><p>toxicity being new or worsening diabetes.5 B­cell depletion</p><p>with rituximab appears to disrupt the immune milieu</p><p>necessary for disease activity in IgG4­related disease and</p><p>more than 95% of patients will have a satisfactory clinical</p><p>and biochemical response.5,70 Our preferred approach to</p><p>the management of patients with IgG4­related disease</p><p>is to induce remission with 1 g of intravenous</p><p>rituximab given twice 2 weeks apart. Patients with a</p><p>reduction in baseline serum IgG4 concentrations of more</p><p>than 90% and improvements in symptoms and end organ</p><p>damage can be followed up with monthly bloodwork,</p><p>including serum protein electro phoresis, total IgG, and</p><p>IgG subclasses (along with key markers of organ</p><p>damage—eg, liver enzymes, lipase, creatinine, and urine</p><p>albumin:creatinine ratio). Many patients will either need</p><p>retreatment with rituximab within 1 year or maintenance</p><p>therapy with low­dose prednisone or a steroid­sparing</p><p>agent such as azathioprine or mycophenolate mofetil. For</p><p>steroid­resistant and rituximab­resistant disease, there is</p><p>no standard therapy, although bendamustine and</p><p>rituximab have been used in cases of life­threatening,</p><p>treatment­refractory disease.71</p><p>Hyperviscosity syndrome is a rare complication of</p><p>monoclonal and polyclonal increases in immunoglobulin</p><p>concentrations, and symptomatic patients require</p><p>urgent plasmapheresis followed by treatment of the</p><p>underlying cause.72 Classic symptoms include mucosal</p><p>bleeding, visual abnormalities, and neurological changes.</p><p>Hyperviscosity syndrome is typically associated with</p><p>monoclonal IgM concentrations of more than 50 g/L by</p><p>serum protein electrophoresis in lymphoplasmacytic</p><p>lymphoma, or elevated IgG (typically >60–70 g/L)</p><p>or IgA (>50 g/L) concentrations in plasma cell myeloma.</p><p>Polyclonal hypergammaglobulinaemia causing hyper­</p><p>viscosity syndrome is typically associated with IgG</p><p>concentrations well in excess of 60 g/L and has</p><p>been reported in Sjögren’s syndrome, HIV infection,</p><p>rheumatoid arthritis, autoimmune lymphoproliferative</p><p>syndrome, and IgG4­related disease.68,72–75 One report</p><p>describes a young man with a markedly elevated IgG</p><p>concentration of 77 g/L, which was initially interpreted</p><p>on serum protein electrophoresis as a biclonal IgG kappa</p><p>and IgG lambda band, but was subsequently found to be</p><p>polyclonal IgG by mass spectrometry, caused by biopsy­</p><p>proven IgG4­related disease.76</p><p>Conclusion</p><p>Just as monoclonal proteins require investigation to</p><p>determine whether they represent monoclonal</p><p>gammopathy of undetermined significance or other</p><p>discrete plasma cell neoplasms and lymphoproliferative</p><p>disorders, polyclonal hypergamma globulinaemia also</p><p>warrants investigation to determine which of the eight</p><p>categories is the underlying cause. The approach we</p><p>have outlined allows clinicians and laboratory physicians</p><p>to take a rational approach in the accurate diagnosis of</p><p>polyclonal hypergamma globulinaemia. In most cases,</p><p>careful clinical examination and basic laboratory</p><p>investigations, including IgG subclass testing and</p><p>measurement of CRP concentration, will provide a</p><p>discrete cause. In rare cases, polyclonal hypergamma­</p><p>globulinaemia might be an important diagnostic clue</p><p>for rare conditions such as idiopathic multicentric</p><p>Castleman disease, autoimmune lympho proliferative</p><p>syndrome, IgG4­related disease, or Rosai–Dorfman</p><p>disease. Manage ment of polyclonal hyper gamma glo­</p><p>bulinaemia typically involves treatment of the underlying</p><p>condition, but, rarely, extreme polyclonal hypergamma­</p><p>globulinaemia can cause hyperviscosity syndrome,</p><p>requiring plasmapheresis.</p><p>Contributors</p><p>EJZ, CVC, AM, and LYCC contributed to the design of the Review, the</p><p>development of figures, the literature review, and the writing of the</p><p>manuscript. EJZ and LYCC reviewed the manuscript for clinical</p><p>accuracy.</p><p>Declaration of interests</p><p>LYCC received advisory board contributions from GlaxoSmithKline,</p><p>outside the submitted work. EJZ, CVC, and AM declare no competing</p><p>interests.</p><p>Search strategy and selection criteria</p><p>We searched PubMed for articles on the causes of polyclonal</p><p>hypergammaglobulinaemia published in English between</p><p>database inception and Jan 10, 2021, using the search terms</p><p>“((polyclonal) AND ((gammopathy) OR</p><p>(hypergammaglobulinemia))) NOT (monoclonal)”.</p><p>We reviewed the abstracts and retrieved the full texts of</p><p>articles that were deemed relevant. 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All rights reserved.</p><p>Polyclonal hypergammaglobulinaemia: assessment, clinical interpretation, and management</p><p>Introduction</p><p>Causes of polyclonal elevation in IgG concentrations</p><p>Liver disease</p><p>Autoimmune disease and vasculitis</p><p>Infection and inflammation</p><p>IgG4-related disease</p><p>Haematological disorders</p><p>Pathophysiology of polyclonal hypergammaglobulinaemia</p><p>Mechanisms of polyclonal hypergammaglobulinaemia in patients with elevated CRP</p><p>Mechanisms of polyclonal hypergammaglobulinaemia in patients with low or modestly elevated CRP</p><p>Investigating polyclonal hypergammaglobulinaemia</p><p>Methods of measuring serum immunoglobulins</p><p>Management of polyclonal hypergammaglobulinaemia</p><p>Conclusion</p><p>References</p>