Abstract
IgG4-related disease is a rare immune-mediated systemic disease with the capability of involving essentially any organ. Although the presenting clinical features vary substantially according to the speciality to which patients present first, perhaps the most common clinical presentation is that of single or multiple organ enlargement, arousing suspicion of cancer. The disease is frequently diagnosed unexpectedly in pathological specimens or on imaging studies. The diagnostic approach is complex and includes not only IgG4-related tests (serum levels, circulating plasmablasts, and specific immunohistochemical studies), but also clinical, laboratory, and imaging tests as well as the typical histopathological features (lymphocytic infiltration, storiform fibrosis, eosinophilic infiltration, and obliterative phlebitis). IgG4-related tests should not be considered as diagnostic in the absence of an appropriate clinical scenario. Therapeutic approaches reported to date pertain primarily to glucocorticoids, but the use of these medications has not been studied in a controlled or prospective manner. The most current investigational treatment approaches have focused on targeting cells of the B-cell lineage, including B-cell-depleting agents (rituximab) and a non-depleting homodimer monoclonal antibody targeting CD19 and Fc-gamma RIIIb.
Introduction
IgG4-related disease (IgG4-RD) is a chronic, immune-mediated systemic disease first described in Japan . In 2001, Hamano et al. reported unexpectedly high serum levels of IgG4 in patients with type 1 autoimmune pancreatitis (AIP). Two years later, Kamisawa et al. were the first to propose the term ‘IgG4-related autoimmune disease’ after discovering that patients with AIP also had the involvement of organs other than the pancreas. The key pathological feature of the disease is the infiltration of IgG4-bearing plasma cells . IgG4-RD has now been reported in nearly every organ of the human body. However, it is not a new disease, because many diseases previously considered ‘idiopathic’ are now included into the clinical IgG4-RD spectrum (Mikulicz disease, Küttner tumour, Riedel thyroiditis, and Ormond disease, among others) . In 2012, an international multidisciplinary study group proposed the name ‘IgG4-RD’ in preference to other names such as ‘IgG4-related systemic disease’, ‘IgG4-related sclerosing disease’, or ‘IgG4-positive multiorgan lymphoproliferative syndrome’ .
The epidemiology of IgG4-RD has not been characterized thoroughly, due in part to its relatively low prevalence and incidence but also due to continuing under-recognition of the disease by both clinicians and pathologists. Although nearly 75% of reported patients are Japanese , the disease has been described in nearly all racial and ethnic groups. In the last 2 years, the largest reported series of patients are from China ( n = 248, n = 118) , Japan ( n = 158, n = 235) , the USA ( n = 125) , Spain ( n = 55) , and Italy ( n = 41) . A recent review of nearly 3500 reported patients found a mean age at diagnosis of 61 years with a clear male predominance (73% of patients). Although the youngest patient identified was 14 years at presentation, some paediatric cases have recently been reported .
This review addresses current advances in the diagnostic and therapeutic management of patients with IgG4-RD.
Diagnostic approach
Clinical presentation
The key for clinical suspicion of IgG4-RD is a patient presenting with tumefactive lesions in one or more organs (40% of patients have single organ involvement) . The enlarged organs may be visible on the physical examination (salivary or lacrimal gland swelling, lymphadenopathy, and thyroid enlargement) or detected as an incidental finding in imaging diagnostic tests (enlargement of the pancreas, liver, spleen or kidneys) . Some patients also have organ-specific symptoms, including abdominal pain, sicca features, respiratory symptoms, pruritus, and diarrhoea . Lymphadenopathy has been reported in 25% of patients with systemic presentations, while a history of allergy/atopy, manifested primarily by asthma, is reported in 10–20% of patients. Specific IgG4-related skin involvement has been reported in only 1% of patients, but eczema is a frequently reported concurrent condition . The presenting features of IgG4-RD vary substantially according to which speciality the patient present first, but the physicians most frequently involved are gastroenterologists , ophthalmologists , otolaryngologists , nephrologists , urologists , dermatologists , neurologists , and rheumatologists/internists. Rheumatologists tend to receive patients presenting with multiorgan systemic involvement that mimics a systemic autoimmune disease. The prevalence of specific organ involvement varies widely among studies, and is principally influenced by the nature of patient collection (unselected or selected by organ).
The pancreas is the organ most frequently involved (41% of systemic cases). Type 1 AIP is the pancreatic manifestation of IgG4-RD, and the main presenting symptoms include jaundice, pruritus, abdominal pain, steatorrhoea, and new-onset diabetes mellitus. Involvement of the biliary tree is also frequent (20% of systemic cases), especially in patients with concomitant AIP: 83% of patients reported with IgG4-related sclerosing cholangitis had concomitant AIP, while 40% of patients with AIP also had IgG4-related sclerosing cholangitis . Nearly 60 cases of IgG4-related cholecystitis have been reported , mainly diagnosed after an incidental imaging finding (gallbladder thickening) or, more frequently, when the gallbladder is removed due to suspicion of cancer.
The exocrine glands are also frequently affected. The major salivary glands are the second most frequently involved organs in IgG4-RD (40% of systemic cases), including patients with Mikulicz disease (bilateral swelling of at least two major salivary or lacrimal glands) and those with Küttner disease (chronic sclerosing sialadenitis that affects the submandibular glands) . The submandibular glands are affected in nearly 95% of patients with IgG4-related Mikulicz disease. Ophthalmic involvement is centred on the lacrimal glands (dacryoadenitis) and is mainly bilateral, but extra-ocular muscle involvement (orbital myositis) and orbital masses that do not involve the lacrimal glands can also occur .
IgG4-RD affects a large number of other organs and systems, including the lungs, pleura, mediastinum, kidneys (including both interstitial and glomerular disease), retroperitoneum, mesentery, urinary tract, meninges, thyroid, hypophysis, joints and bones, peripheral nerves, prostate, breasts, testes, and the gut . New organ involvements recently reported include the oesophagus , pericardium , cardiac valves , uterus , appendix , and the aorta , as well as other clinical presentations including pulmonary arterial hypertension , coronary arteritis , autoimmune hepatitis , and sensorineural hearing loss .
Imaging studies
Cross-sectional imaging using computed tomography (CT) or magnetic resonance imaging (MRI) plays an important role in supporting the diagnosis of IgG4-RD. The organic lesions caused by IgG4-RD frequently lead to the finding of organ enlargement or pseudotumours on CT, with low signal intensity on T2-weighted MRI. The major organ-by-organ findings reported in the main imaging studies are summarized in Table 1 . Some studies have suggested a potential diagnostic role for 18F-FDG positron emission tomography (PET) , which may detect major extensive diseases in nearly 70% of cases compared with CT evaluation . Characteristic features of PET in IgG4-RD include diffusely elevated 18F-FDG uptake in the pancreas and salivary glands and patchy lesions in the retroperitoneal region. PET is less sensitive for small-sized lesions and for diseases in the organs such as the brain (which normally demonstrates high FDG avidity) and diffuses lesions in the lung. Conversely, PET is more sensitive in detecting involvements of the major salivary glands, lymph nodes, and blood vessels .
| a) Pancreas |
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| b) Biliary tract |
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| c) Salivary glands |
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| d) Ocular involvement |
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| d) Pulmonary involvement |
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| e) Renal involvement |
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| f) Retroperitoneal involvement |
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| g) CNS involvement |
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Laboratory studies
Routine laboratory tests such as complete blood counts and biochemical profiles often provide signs of potential organ involvement. Abnormalities of the liver function test that suggest biliary obstruction should focus diagnostic efforts on the pancreas and biliary tree, while elevated creatinine levels or proteinuria suggest renal involvement. Mild-to-moderate peripheral eosinophilia is found in one-third of the patients, and higher levels of C-reactive protein (CRP) are reported in nearly one quarter of the patients.
Immunological studies
Hypergammaglobulinaemia is found in nearly 60% of patients with a mean serum IgG level of approximately 2600 mg/dL (most studies show a mean range between 1800 and 3600 mg/dL). IgE levels are also elevated in 60% of patients . A recent study reported an illusory monoclonal gammopathy in IgG4-RD patients caused by the relatively restricted migration of polyclonal IgG4, which may form a characteristic focal band bridging the β and γ fractions in serum protein electrophoresis .
Fewer than 30% of patients have positive anti-nuclear antibody (ANA) and/or rheumatoid factor (RF), with low/moderate titres in most patients suggesting that this is a non-specific finding. Identification of more specific autoantibodies such as anti-Ro/SS-A, anti-dsDNA or anti-neutrophil cytoplasmic antibodies (ANCAs) is highly unusual and suggests a concomitant systemic autoimmune disease, for example, Sjögren’s syndrome (SS), systemic lupus erythematosus (SLE) or granulomatosis with polyangiitis (GPA). In contrast, hypocomplementaemia is a frequent immunological abnormality that is reported in 40% of patients with IgG4-RD, and especially in those with IgG4-related renal disease. Immune complexes consisted of other immunoglobulin subclasses that bind complement more effectively, for example, IgG1 and IgG3 may be considered for this finding. However, a recent study by Sugimoto et al. detected high serum levels of C1q-binding IgG4 in patients with hypocomplementaemia, suggesting that IgG4 may participate in complement activation in IgG4-RD in at least some cases.
Histopathological approach
Histopathological analysis of specimens from the affected organ is the diagnostic cornerstone of IgG4-RD . Needle biopsies often provide sufficient proof for the diagnosis of IgG4-RD but, in some cases, a complete histological picture cannot be gleaned from the small portions of tissue obtained by needle biopsy . A recent study suggested the diagnostic usefulness of salivary gland biopsy in patients presenting with systemic IgG4-RD .
The four key morphologic features of IgG-RD are dense lymphoplasmacytic infiltrates (almost 100% of cases; Fig. 1 ) ; fibrosis with a storiform pattern (74%) ; obliterative phlebitis (40%); and eosinophilic infiltration (40%). Some authors have recommended that a positive pathological diagnosis should require at least two of these morphological findings. Other reported histopathological findings include follicular lymphoid formation and germinal centres . Histopathological studies are not pathognomonic and may show significant variations according to the organ biopsied, the time of disease evolution (early vs. advanced disease), or the therapies administered. Subtle variations in the histopathology findings may exist among organs, especially with respect to the storiform pattern of the fibrosis or the obliterative phenomenon observed in cases with phlebitis. The typical storiform fibrosis has infrequently been reported in the lacrimal, parotid, and minor salivary glands and in interstitial lung disease. In contrast, obliterative phlebitis is reported more frequently in the pancreas and submandibular glands than in the parotid/lacrimal glands, lymph nodes, and kidneys .
Some histopathological findings are considered inconsistent with the diagnosis of IgG4-RD . The first is the finding of granulomas that are highly suggestive of mycobacterial infection, sarcoidosis, or GPA. However, Bateman et al. have recently reported two patients presenting with IgG4-related lymphadenopathy together with granulomas, and suggest that the presence of granulomas should not preclude the diagnosis of IgG4-RD in an appropriate clinical context. The second is prominent neutrophilic infiltrates ; in these patients, systemic vasculitis – particularly GPA – should be high on the differential diagnosis .
IgG4-specific studies
- a)
IgG4 serum levels
Elevated serum levels of IgG4 were present in 84% of nearly 2000 patients analysed in a recent systematic review, with a mean serum IgG4 level of approximately 770 mg/dL . The upper limit most commonly used is 135 mg/dL, and of the nearly 40 studies in which the mean level of IgG4 was reported, more than half showed a mean value 4–6 times higher than the upper limit. Some studies also measured the IgG4/IgG ratio (normally <5%) and found a mean ratio of approximately 40% .
Disease activity may correlate with serum IgG4 levels. The serum IgG4 concentration tends to correlate with the number of organs involved: the greater the number of organs affected, the higher is the serum concentration . Matsubayashi et al. reported a higher frequency of jaundice and systemic disease (extrapancreatic lesions), together with larger pancreatic lesions, in AIP patients presenting with higher IgG4 levels. In IgG4-related sialadenitis, serum IgG4 levels were higher and saliva secretion was lower as glandular fibrosis increased . A recent study including 107 patients with active disease showed that although only 51% had elevated serum IgG4 concentrations, these patients had a greater number of organs involved, a higher IgG4-RD Responder Index (RI) score, and a higher frequency of laboratory abnormalities (hypocomplementaemia, hypereosinophilia, and higher IgE levels) in comparison with active patients with normal IgG4 levels .
Recent studies have reported significant limitations of serum IgG4 measurements in the assessment of patients with potential IgG4-RD. Khosroshahi et al. showed that the prozone effect led to falsely low serum IgG4 concentrations in 26% of patients tested. Carruthers et al. found a high sensitivity (90%) and negative predictive value (96%) of elevated serum IgG4 concentrations in the diagnosis of IgG4-RD, but low specificity (60%) and positive predictive value (34%). A recent study by Yu et al. proposed that the optimal cut-off value of serum IgG4 (measured by nephelometry) for the diagnosis of IgG4-RD must be 248 mg/dL (nearly twice as high as that used to date), with a sensitivity of 78% and a specificity of 93%. Cerebrospinal fluid (CSF) IgG4 measurement has been suggested as an adjunct to the diagnosis of IgG4-related hypertrophic pachymeningitis when meningeal biopsy is difficult, but thus far there remain insufficient data about the utility of CSF IgG4 assays for this purpose .
- b)
IgG4+ infiltrating plasma cells
Tissue infiltration by IgG4+ plasma cells is one of the strongest characteristics of IgG4-RD, and immunohistochemical staining for both IgG4 and IgG is a key part of the histopathological diagnosis of the disease ( Fig. 2 ) . Semiquantitative immunostaining analysis of IgG4 measures the total number of IgG4+ cells per high-power field (HPF), with various proposed cut-off values ranging from >10 to >50 IgG4-positive plasma cells. A recent review found that >90% of reported cases had >10 IgG4+ cells per HPF, with a mean number of 120 IgG4+ cells per HPF . Measurement of the IgG4+/IgG+ cell ratio (considered abnormal when the ratio is >30%) may also be useful, with a reported mean ratio of approximately 60%; a practical example of the utility of using this ratio is in IgG4-related involvements in which fibrosis predominates, such as retroperitoneal fibrosis . A recent PRISMA-compliant systematic review evaluated the histopathological diagnostic value of measuring the IgG4+/IgG+ ratio and reported a sensitivity of 59%, a specificity of 90% and positive and negative likelihood ratios of 3.12 and 0.26, respectively .
The demonstration of significant IgG4+ cell infiltration is not a sine qua non for the diagnosis of IgG4-RD. This is because a long list of diseases is characterized by the potential for significant T-cell infiltration by IgG4+ plasma cells (see the Differential diagnosis section) . Conversely, Hart et al. have reported from three cases from the Mayo Clinic database of AIP patients with histologically confirmed type 1 AIP (lymphoplasmacytic sclerosing pancreatitis) who had both normal serum IgG4 without any increase in the number of IgG4-positive plasma cells in multiple sections of pancreatic histology. These investigators, describing ‘IgG4-negative IgG4-RD’, concluded that neither serum nor tissue IgG4 abnormalities are essential for the diagnosis in some cases, assuming that the clinical presentation and histopathological findings (without immunostaining) are highly consistent with that diagnosis . Other recent studies have reported similar findings in patients with sclerosing mesenteritis , interstitial nephritis , and AIP , providing the possibility to the diagnosis of IgG4-RD in the absence of elevated serum IgG4 concentrations and IgG4+ plasma cell infiltration of tissues.
- c)
IgG4+ circulating plasma cells
Approximately two-thirds of the circulating human B-cell pool comprises naive B-lymphocytes. The other one-third comprises memory B cells. Under normal circumstances, very low numbers of circulating plasma cells (2 per μL) are found in the peripheral blood . Steady-state circulating plasma cells lack CD20, may express high CD19 and CD38, and are often called plasmablasts because a sizeable proportion – perhaps 50% – no longer express CD138, a proteoglycan that is a hallmark of plasma cells . Plasmablasts may be identified through flow cytometry of peripheral blood, gating on cells such as CD19 low CD38 + CD20-CD27+ . In patients with IgG4-RD, studies of flow cytometry have reported that circulating plasmablasts are highly elevated even in patients with normal serum IgG4 concentrations.
Wallace et al. recently suggested that plasmablast counts are a useful biomarker for IgG4-RD activity independent of serum IgG4 concentrations. A typical IgG4-RD patient before treatment has a total serum plasmablast count that is approximately 8-fold higher than that of patients with many other types of systemic inflammatory diseases (lupus being a notable exception), and 47 times higher than healthy controls. IgG4-RD patients with elevated serum IgG4 levels had more plasmablasts than patients with normal levels, but the difference was not statistically significant. After receiving rituximab (RTX), blood plasmablast levels decline sharply. Measurement of circulating plasmablasts may be more useful than the measurement of serum IgG4 levels, not only as a better diagnostic biomarker but also to monitor disease activity, to assess the therapeutic response, and to determine the most appropriate time for re-treatment .
Diagnostic criteria
Because the diagnostic approach of IgG4-RD is heterogeneous, the first proposed sets of criteria centred on specific organs rather than IgG4-RD as a systemic multiorgan disease. The best examples of organ-specific criteria were those proposed for AIP , sclerosing cholangitis , major salivary gland disease , pulmonary involvement and renal involvement . In 2012, Umehara et al. proposed a set of criteria for the diagnosis of systemic IgG4-RD designed to be used independently of the predominant organ involvement but exclusively focused on IgG4-related diagnostic tests (higher serum levels, immunohistochemical studies). The sensitivity and specificity of these criteria remain untested. Nevertheless, there remains a wide heterogeneity in the use of the different diagnostic criteria in the main studies, and a significant percentage of reported studies have not specified the criteria used . International multidisciplinary collaboration to promote a new set of classification criteria is needed.
Diagnostic approach
Clinical presentation
The key for clinical suspicion of IgG4-RD is a patient presenting with tumefactive lesions in one or more organs (40% of patients have single organ involvement) . The enlarged organs may be visible on the physical examination (salivary or lacrimal gland swelling, lymphadenopathy, and thyroid enlargement) or detected as an incidental finding in imaging diagnostic tests (enlargement of the pancreas, liver, spleen or kidneys) . Some patients also have organ-specific symptoms, including abdominal pain, sicca features, respiratory symptoms, pruritus, and diarrhoea . Lymphadenopathy has been reported in 25% of patients with systemic presentations, while a history of allergy/atopy, manifested primarily by asthma, is reported in 10–20% of patients. Specific IgG4-related skin involvement has been reported in only 1% of patients, but eczema is a frequently reported concurrent condition . The presenting features of IgG4-RD vary substantially according to which speciality the patient present first, but the physicians most frequently involved are gastroenterologists , ophthalmologists , otolaryngologists , nephrologists , urologists , dermatologists , neurologists , and rheumatologists/internists. Rheumatologists tend to receive patients presenting with multiorgan systemic involvement that mimics a systemic autoimmune disease. The prevalence of specific organ involvement varies widely among studies, and is principally influenced by the nature of patient collection (unselected or selected by organ).
The pancreas is the organ most frequently involved (41% of systemic cases). Type 1 AIP is the pancreatic manifestation of IgG4-RD, and the main presenting symptoms include jaundice, pruritus, abdominal pain, steatorrhoea, and new-onset diabetes mellitus. Involvement of the biliary tree is also frequent (20% of systemic cases), especially in patients with concomitant AIP: 83% of patients reported with IgG4-related sclerosing cholangitis had concomitant AIP, while 40% of patients with AIP also had IgG4-related sclerosing cholangitis . Nearly 60 cases of IgG4-related cholecystitis have been reported , mainly diagnosed after an incidental imaging finding (gallbladder thickening) or, more frequently, when the gallbladder is removed due to suspicion of cancer.
The exocrine glands are also frequently affected. The major salivary glands are the second most frequently involved organs in IgG4-RD (40% of systemic cases), including patients with Mikulicz disease (bilateral swelling of at least two major salivary or lacrimal glands) and those with Küttner disease (chronic sclerosing sialadenitis that affects the submandibular glands) . The submandibular glands are affected in nearly 95% of patients with IgG4-related Mikulicz disease. Ophthalmic involvement is centred on the lacrimal glands (dacryoadenitis) and is mainly bilateral, but extra-ocular muscle involvement (orbital myositis) and orbital masses that do not involve the lacrimal glands can also occur .
IgG4-RD affects a large number of other organs and systems, including the lungs, pleura, mediastinum, kidneys (including both interstitial and glomerular disease), retroperitoneum, mesentery, urinary tract, meninges, thyroid, hypophysis, joints and bones, peripheral nerves, prostate, breasts, testes, and the gut . New organ involvements recently reported include the oesophagus , pericardium , cardiac valves , uterus , appendix , and the aorta , as well as other clinical presentations including pulmonary arterial hypertension , coronary arteritis , autoimmune hepatitis , and sensorineural hearing loss .
Imaging studies
Cross-sectional imaging using computed tomography (CT) or magnetic resonance imaging (MRI) plays an important role in supporting the diagnosis of IgG4-RD. The organic lesions caused by IgG4-RD frequently lead to the finding of organ enlargement or pseudotumours on CT, with low signal intensity on T2-weighted MRI. The major organ-by-organ findings reported in the main imaging studies are summarized in Table 1 . Some studies have suggested a potential diagnostic role for 18F-FDG positron emission tomography (PET) , which may detect major extensive diseases in nearly 70% of cases compared with CT evaluation . Characteristic features of PET in IgG4-RD include diffusely elevated 18F-FDG uptake in the pancreas and salivary glands and patchy lesions in the retroperitoneal region. PET is less sensitive for small-sized lesions and for diseases in the organs such as the brain (which normally demonstrates high FDG avidity) and diffuses lesions in the lung. Conversely, PET is more sensitive in detecting involvements of the major salivary glands, lymph nodes, and blood vessels .
| a) Pancreas |
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| b) Biliary tract |
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| c) Salivary glands |
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| d) Ocular involvement |
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| d) Pulmonary involvement |
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| e) Renal involvement |
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| f) Retroperitoneal involvement |
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| g) CNS involvement |
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Laboratory studies
Routine laboratory tests such as complete blood counts and biochemical profiles often provide signs of potential organ involvement. Abnormalities of the liver function test that suggest biliary obstruction should focus diagnostic efforts on the pancreas and biliary tree, while elevated creatinine levels or proteinuria suggest renal involvement. Mild-to-moderate peripheral eosinophilia is found in one-third of the patients, and higher levels of C-reactive protein (CRP) are reported in nearly one quarter of the patients.
Immunological studies
Hypergammaglobulinaemia is found in nearly 60% of patients with a mean serum IgG level of approximately 2600 mg/dL (most studies show a mean range between 1800 and 3600 mg/dL). IgE levels are also elevated in 60% of patients . A recent study reported an illusory monoclonal gammopathy in IgG4-RD patients caused by the relatively restricted migration of polyclonal IgG4, which may form a characteristic focal band bridging the β and γ fractions in serum protein electrophoresis .
Fewer than 30% of patients have positive anti-nuclear antibody (ANA) and/or rheumatoid factor (RF), with low/moderate titres in most patients suggesting that this is a non-specific finding. Identification of more specific autoantibodies such as anti-Ro/SS-A, anti-dsDNA or anti-neutrophil cytoplasmic antibodies (ANCAs) is highly unusual and suggests a concomitant systemic autoimmune disease, for example, Sjögren’s syndrome (SS), systemic lupus erythematosus (SLE) or granulomatosis with polyangiitis (GPA). In contrast, hypocomplementaemia is a frequent immunological abnormality that is reported in 40% of patients with IgG4-RD, and especially in those with IgG4-related renal disease. Immune complexes consisted of other immunoglobulin subclasses that bind complement more effectively, for example, IgG1 and IgG3 may be considered for this finding. However, a recent study by Sugimoto et al. detected high serum levels of C1q-binding IgG4 in patients with hypocomplementaemia, suggesting that IgG4 may participate in complement activation in IgG4-RD in at least some cases.
Histopathological approach
Histopathological analysis of specimens from the affected organ is the diagnostic cornerstone of IgG4-RD . Needle biopsies often provide sufficient proof for the diagnosis of IgG4-RD but, in some cases, a complete histological picture cannot be gleaned from the small portions of tissue obtained by needle biopsy . A recent study suggested the diagnostic usefulness of salivary gland biopsy in patients presenting with systemic IgG4-RD .
The four key morphologic features of IgG-RD are dense lymphoplasmacytic infiltrates (almost 100% of cases; Fig. 1 ) ; fibrosis with a storiform pattern (74%) ; obliterative phlebitis (40%); and eosinophilic infiltration (40%). Some authors have recommended that a positive pathological diagnosis should require at least two of these morphological findings. Other reported histopathological findings include follicular lymphoid formation and germinal centres . Histopathological studies are not pathognomonic and may show significant variations according to the organ biopsied, the time of disease evolution (early vs. advanced disease), or the therapies administered. Subtle variations in the histopathology findings may exist among organs, especially with respect to the storiform pattern of the fibrosis or the obliterative phenomenon observed in cases with phlebitis. The typical storiform fibrosis has infrequently been reported in the lacrimal, parotid, and minor salivary glands and in interstitial lung disease. In contrast, obliterative phlebitis is reported more frequently in the pancreas and submandibular glands than in the parotid/lacrimal glands, lymph nodes, and kidneys .
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