igg4-related disease ( igg4-rd ) , a new disease classification first established in japan in the 21st century , is characterized by hyper - igg4-gammaglobulinemia and massive infiltration of igg4-positive plasma cells into various swollen organs [ 110 ] . in general , a serum igg4 concentration > 135  mg / dl has been established as the cutoff value for the diagnosis of patients with igg4-rd and is used in the joint consensus criteria of the okazaki and umehara groups investigating igg4-rd for the ministry of health , labor , and welfare of japan . some patients with early or limited stage igg4-rd , however , may show the sufficient pathological characteristics and clinical features of this disease , such as good response to glucocorticoids , despite having serum igg4 concentrations < 135  mg / dl . in addition , an igg4+/igg+ ratio > 40% in tissue and > 10 cells / high - power field ( hpf ) have been used in the histopathologic diagnosis of igg4-rd in japan . thus , a proper diagnosis of these patients may require the use of other criteria , including igg4+/igg plasma cell ratio . since lower cutoff values may increase sensitivity while decreasing specificity , it is necessary to establish accurate cut off values for this ratio . to better establish the diagnostic criteria for igg4-rd , we , the members of the igg4+molps / mikulicz 's disease research group in japan , sought to determine the cutoff values for serum igg4 and igg4/igg and for igg4+/igg+ plasma cells in tissue diagnostic of igg4-rd using retrospectively collected data . serum igg4 concentrations and igg4/igg ratio and the ratio of igg4+/igg+ plasma cells in tissue were determined in 132 patients with igg4-rd and 48 patients with other disorders registered retrospectively in the igg4+molps / mikulicz 's disease research group ( table 1 ) . the 48 patients with other disorders included 33 with sjgren 's syndrome , 3 with multicentric castleman 's disease ( mcd ) , 3 with b - cell lymphoma , 2 with sarcoidosis , and 1 each with kimura 's disease , ulcerative colitis , autoimmune hepatitis , igg - type monoclonal gammopathy of undetermined significance , progressive transformation of the germinal center , scleritis , and severe keratoconjunctivitis sicca . the study was approved by the review boards of kanazawa medical university and all other collaborating institutions , and all patients provided written informed consent for the use of their data and samples . the sensitivities , specificities , and roc curves of serum igg4 > 135  mg / dl and various serum igg4/igg ratios were statistically analyzed using spss v.11 ( spss inc . , patients with borderline igg4-rd were defined carefully as those with ( 1 ) > 40% igg4+/igg+ plasma cells in tissue , ( 2 ) strict pathological differential , and ( 3 ) a typical clinical course ( spontaneous regression or no change without treatment , or good response to an initial daily dose of < 0.6  mg / kg prednisolone ) . the numbers of igg4 + and igg+ cells in tissue samples from 36 patients with igg4-rd and from 21 with other disorders were determined by counting cells counts in 5 high - power fields ( hpf ) under light microscopy . we also recounted cell areas of 17 samples from patients with igg4-rd that contained both fibrotic and nonfibrotic parts . we also assessed the sensitivity and specificity of igg4+/igg+ cell ratios > 10% , > 20% , > 30% , > 40% , and > 50% , and of > 10 , > 20 , > 30 , > 40 and > 50 igg4+cells / hpf , as well as the presence of obliterative phlebitis , storiform fibrosis , eosinophilia , fibrosis , and lymphocyte infiltration as determined by hematoxylin and eosin staining in the diagnosis of igg4-rd . tissue samples with borderline igg4-rd were defined as those with ( 1 ) serum igg4 > 135  mg / dl , ( 2 ) strict pathological differential , and ( 3 ) typical clinical course . clinical course including response to steroid is not included in the comprehensive diagnostic criteria for igg4-rd , to avoid the needless treatment with steroid of patients suspected of having igg4-rd . as this was a retrospective analysis , however , we analyzed the clinical course of these borderline patients , including their response to steroid treatment . a serum igg4 cutoff value > 135  mg / dl had a sensitivity of 97.0% and a specificity of 79.6% for the diagnosis of igg4-rd . in 4 patients with relatively small and restricted lesions , however , this criterion was not adequate to diagnose igg4-rd , although all had a histopathology and clinical course compatible with igg4-rd ( table 2 ) . all 4 patients were diagnosed with igg4-rd based on a serum igg4/igg ratio > 8% . in contrast , neither a serum igg4 cutoff of > 135  mg / dl nor a serum igg4/igg ratio > 8% was adequate for the diagnosis of four patients with mcd and one each with b - cell lymphoma , scleritis , and sjgren 's syndrome , because all of these patients had hyper - igg4-globulinemia associated with polyclonal gammopathy . we therefore estimated the sensitivity and specificity of various igg4/igg ratios ( table 3 ) . we found that the roc curves for absolute serum igg4 concentration and serum igg4/igg ratio were almost identical ( figure 1 ) . we also assessed the ability of the ratio of igg4+/igg+ plasma cell ratios in 5 hpfs of tissue samples to diagnose igg4-rd . we found that a ratio > 40% had a sensitivity of 94.4% and a specificity of 85.7% ( table 4 ) . although > 10 igg4 + cells per hpf had a sensitivity of 100% , they had specificities of only 38.1% . in tissues containing both fibrotic and nonfibrotic areas , we counting the number cells in each part showed that fibrotic areas contained fewer igg4 + cells ( table 5 ) . although both had specificities of 100% , their sensitivities were not very high ( table 4 ) . serum igg4 > 135  mg / dl has been widely accepted as a cutoff value for diagnosis of igg4-rd . although this concentration was determined by comparing patients with igg4-related sclerosing pancreatitis and those with pancreatic cancer , it has also been used to diagnose igg4-rd involving other organs . for example , we have utilized this cutoff value as a diagnostic criterion for igg4-related mikulicz 's disease   and igg4-related kidney disease , and , in 2011 , it was adopted in the comprehensive clinical diagnostic criteria of igg4-related diseases . most patients with igg4-rd show multiple organ involvement at diagnosis , with both high absolute serum igg4 concentrations and serum igg4/igg ratios . however , some patients with early and/or limited stage igg4-rd do not present with high igg4-globulinemia ( figure 2 ) , with some not having igg4 concentrations > 135  mg / dl . we have therefore tested the ability of alternative criteria to diagnose for igg4-rd . although we found that a serum igg4/igg ratio > 5% had the highest sensitivity , the normal ratio is about 5 - 6% , making this cut off value misleading . an igg4/igg ratio > 8% had a sensitivity similar to that of absolute igg4 > 135  mg / dl , but a greater specificity , enabling us to diagnose 4 patients with lower absolute igg4 concentrations as having igg4-rd ( table 2 ) . since the standard cut off of absolute igg4 > 135  mg / dl demonstrated excellent sensitivity and specificity , it should be utilized , except for patients with early and/or limited igg4-rd , for whom we propose using an igg4/igg ratio > 8% . careful diagnosis is required in patients with lower igg4 concentrations , since those patients may have other distinct disorders with different clinical features than igg4-rd . igg4+/igg+ plasma cell ratios in tissue > 40% and > 50% , and > 10 igg4 + cells per hpf have been used for the diagnosis of igg4-rd . we found that an igg4+/igg+ cell ratio > 40% in tissue had a sensitivity of 94.4% and a specificity of 85.7% in the diagnosis of igg4-rd . we also found that igg4 + plasma cell concentrations in tissue were diminished in fibrotic tissue areas , suggesting that a ratio > 40% is a better histopathologic cutoff value . the presence of obliterative phlebitis and storiform fibrosis demonstrated specificities of 100% , but their sensitivities were much lower , indicating that these findings would be useful when added to , but not in place of , other results . since patients with disorders such as mcd and lymphoma may demonstrate hyper - igg4-gammaglobulinemia and massive igg4 + plasma cell infiltration in tissue , serum igg4 concentration and igg4 + cells in tissue are not specific indicators of igg4-rd . rather , a diagnosis of igg4-rd should be based on the overall balance of clinical features , such as disease distribution throughout the body , clinical course , serum concentrations , and histopathology . the pathologic consensus statement of the first international symposium on igg4-rd in boston did not adopt igg4+/igg+ cell ratio in tissue as diagnostic , although it did suggest cutoffs for numbers of igg4 + cells in hpfs of various organs . although pathologic findings are very important in the diagnosis for igg4-rd , clinical features and serological findings should be included . recently , some patients with igg4-rd were found to have lymphoma [ 13 , 14 ] and other types of cancer [ 15 , 16 ] . many patients referred to our centers with glucocorticoid refractory igg4-rd were diagnosed incorrectly , suggesting the need for more accurate diagnostic criteria for these diseases .
igg4-related disease is a new disease classification established in japan in the 21st century . 
 patients with igg4-related disease display hyper - igg4-gammaglobulinemia , massive infiltration of igg4 + plasma cells into tissue , and good response to glucocorticoids . since igg4 overexpression 
 is also observed in other disorders , it is necessary to diagnose igg4-related disease carefully and correctly . 
 we therefore sought to determine cutoff values for serum igg4 and igg4/igg and for igg4+/igg+ plasma cells in tissue diagnostic of igg4-related disease . 
 patients and methods . 
 we retrospectively analyzed serum igg4 concentrations and igg4/igg ratio and igg4+/igg+ plasma cell ratio in tissues of 132 patients with igg4-related disease and 48 patients with other disorders . 
 result . 
 serum igg4 > 135  mg / dl demonstrated a sensitivity of 97.0% and a specificity of 79.6% in diagnosing igg4-related disease , and serum igg4/igg ratios > 8% had a sensitivity and specificity of 95.5% and 87.5% , respectively . 
 igg4+cell / igg+ cell ratio in tissues 
 > 40% had a sensitivity and specificity of 94.4% and 85.7% , respectively . 
 however , the number of igg4 + cells was reduced in severely fibrotic parts of tissues . 
 conclusion . 
 although a recent unanimous consensus of all relevant researchers in japan recently established the diagnostic criteria for igg4-related disease , findings such as ours indicate that further discussion is needed .