igg4-related disease ( igg4-rd ) is a newly recognized concept presenting a potentially multiorgan disorder . igg4-rd is a fibroinflammatory condition characterized by a tendency toward the formation of tumefactive lesions , elevated serum igg4 levels , abundant infiltration of igg4-positive plasma cells and lymphocytes with fibrosis , and steroid responsiveness ( 1 , 2 , 3 ) . the pancreas was the first organ in which igg4-rd was identified , but the disease has now been described in virtually every organ system , including the biliary tract , salivary glands , lacrimal glands , kidneys , lungs , lymph nodes , and retroperitoneum . clinical manifestations are identified in single organ in some cases , whereas others show effects on two or more organs simultaneously or metachronously ( 4 , 5 ) . although many reports have described the clinical and pathological characteristics of individual igg4-rds , no investigations appear to have discussed correlations between organs involved in igg4-rd . in this study , clinical and serological features of igg4-rd were retrospectively examined with a focus on correlations between affected organs . participants in this retrospective study were 132 patients diagnosed with and managed for igg4-rd at tokyo metropolitan komagome hospital from 1991 to 2013 . the underlying pathologies were autoimmune pancreatitis ( aip ) in 85 cases , igg4-related sclerosing cholangitis ( igg4-sc ) in 12 , igg4-related sialadenitis ( igg4-sia ) in 56 , igg4-related dacryoadenitis ( igg4-dac ) in 38 , igg4-related lymphadenopathy ( igg4-lym ) in 20 , igg4-related retroperitoneal fibrosis ( igg4-rf ) in 19 , igg4-related kidney disease ( igg4-kd ) in 6 , igg4-related pseudotumor ( igg4-pt ) in 3 ( pleura , n=1 ; breast , n=1 ; and dura , n=1 ) . diagnosis was established by a multidisciplinary approach including imaging , serological , and pathological tests . when the patient was diagnosed as having one igg4-rd , systemic examination by ultrasonography and computed tomography ( ct ) and/or magnetic resonance imaging although whole - body 18f - fluorodeoxyglucose ( fdg)-pet was performed in 10 aip patients , findings from fdg - pet were not included in this study . igg4-related sc was diagnosed using diagnostic criteria for igg4-related sc 2012 ( 7 ) , when the stenosis was located in the hilar and/or intrahepatic bile duct and limited intrapancreatic bile duct stricture associated with aip was excluded . igg4-lym was diagnosed when lymph node swellings occurred at multiple sites , such as the neck , mediastinum , axilla and abdomen . clinical and serological features of each igg4-rd were compared to clarify organ correlations . for statistical analysis , the mann - whitney u test and unpaired t - test were used . this study was approved by the institutional review board of tokyo metropolitan komagome hospital ( irb no . informed consent for invasive modalities and comprehensive informed consent for the study had been obtained . this study was approved by the institutional review board of tokyo metropolitan komagome hospital ( irb no . informed consent for invasive modalities and comprehensive informed consent for the study had been obtained . of the 132 igg4-rd patients , diagnoses in 111 patients were classified as definite , 3 as probable , and 18 as possible ( table 1 ) . sixty - seven patients had only one igg4-rd , while the remaining 65 ( 49% ) showed multiple igg4-rd ( two diseases in 36 patients , three diseases in 19 , four diseases in 8 , five diseases in 1 , and six diseases in 1 ) . serum igg4 levels were significantly higher in patients with multiple lesions ( mean , 783.2 mg / dl ) than in those with a single lesion ( 307.4 mg / dl , p<0.001 ) ( table 2 ) . the proportion of association with other igg4-rds was 42% for aip , the lowest for all igg4-rds . serum igg4 level was lower in aip ( 491 mg / dl ) than in other igg4-rds . steroid therapy was performed mainly for symptomatic igg4-rd patients ( 62% ) ( table 3 ) . frequently associated igg4-rds were : sia ( 25% ) and dac ( 12% ) in aip ; aip ( 75% ) in igg4-sc ; dac ( 57% ) , aip ( 38% ) and lym ( 27% ) in igg4-sia ; sia ( 84% ) , aip ( 26% ) and lym ( 26% ) in igg4-dac ; sia ( 75% ) , dac ( 50% ) and aip ( 45% ) in igg4-lym ; sia ( 58% ) , aip ( 42% ) and lym ( 32% ) in igg4-rf ; aip ( 100% ) and sia ( 67% ) in igg4-kid ; and dac ( 67% ) and sia ( 67% ) in igg4-pt ( fig . 1 , 2 , 3 ) . most associated igg4-rd lesions were diagnosed simultaneously , but igg4-dac and igg4-sia were sometimes identified before other lesions ( table 4 ) . igg4-rd can occur , either synchronously or metachronously , in a variety of organs throughout the body . clinical symptoms of igg4-rd depend on the location of the lesion ( 1 , 2 , 3 , 4 , 5 ) . the proportion of association with another igg4-rd was 42% in aip , but 75% in other igg4-rds . proportions of association with other igg4-rd in aip have been reported as 23% ( 10 ) and 63% ( 11 ) , but the latter study included diabetes and rheumatoid arthritis as other organ involvements . according to the report by hamano et al . ( 12 ) , the proportion of association among aip patients was as high as 91% , but they included hilar lymph node swelling ( 80% ) examined by gallium scintigraphy as extrapancreatic lesions of aip . in our study , the other igg4-rd pathology most commonly associated with aip was igg4-sia ( 25% ) , followed by igg4-dac ( 12% ) , igg4-sc ( 11% ) , igg4-lym ( 10% ) , igg4-rf ( 9% ) , and igg4-kd ( 7% ) . according to a nationwide survey of aip in japan , prevalence of other organ involvements in aip patients was 53% for sc , 14% for sia , 13% for lym , 8% for rf , and 7% for dac , but sc restricted to the lower bile duct was included among extrapancreatic lesions in that survey ( 13 ) . the present study excluded sc restricted to the lower bile duct from igg4-rd associated with aip , as this pathology is sometimes affected by inflammation of the pancreatic head in aip . aip was present in 75% of igg4-sc , and isolated igg4-sc was rare . igg4-dac and aip were associated in 57% and 38% of patients with igg4-sia , respectively , and igg4-sia and aip were present in 84% and 26% of patients with igg4-dac , respectively . symmetrical swelling of the salivary and/or lacrimal glands has been recognized as mikulicz 's disease , and swelling of salivary glands and lacrimal glands is thus known to frequently occur together . in the study by moriyama et al . ( 14 ) into mikulicz 's disease , swelling of the salivary glands was detected in 83% of patients with swelling of the lacrimal glands , and swelling of the lacrimal glands was detected in 28% of patients with swelling of the salivary glands . swelling of both salivary and lacrimal glands was also reportedly detected in 14% and 7% of aip patients ( 13 ) . salivary and lacrimal gland swelling were detected in 33% of patients with systemic igg4-related lymphadenopathy ( 15 ) , and swelling of the lacrimal glands was detected in all 3 patients with systemic igg4-related lymphadenopathy ( 16 ) . although igg4-sia and aip were associated in 58% and 42% of our patients with igg4-related rf , respectively , igg4-sia , igg4-dac and aip were reportedly associated only in 6% of 17 patients with igg4-rf , respectively ( 17 ) . aip and igg4-sia were seen in 100% and 67% of our igg4-kd patients . according to the report by saeki et al . ( 18 ) , igg4-sia , igg4-dac and aip were present in 74% , 26% , and 35% of 43 patients with igg4-kd . although each igg4-rd is frequently associated with other igg4-rd , some patterns of association seem to exist between specific organs ( fig . 1 , 2 , 3 ) . igg4-sc is likely to be present with aip , igg4-sia and igg4-dac are likely to coexist , and igg4-lym is likely to be associated with igg4-dac and igg4-sia . whole - body 18f - fdg pet is useful for detecting igg4-rd lesions ( 19 , 20 ) . according to a study examining the utility of fdg - pet / ct for diagnosing igg4-rd , 97% of 35 patients with igg4-rd had more than one organ and 68% showed the involvement of three or more organs ( 20 ) . in that study , igg4-lym , igg4-sia and aip were involved in 86% , 66% , and 51% of the 35 patients . our study did not include fdg - pet findings , due to the small number of cases examined . the detection rate for igg4-rd lesions appears rather different according to imaging modalities used to screen for other igg4-rd lesions . most associated igg4-rd lesions were diagnosed simultaneously with screening of associated other igg4-rds , but igg4-dac , and igg4-sia were sometimes identified before other lesions . whether the onset periods for each lesion differ between igg4-rds is unclear . however , compared with aip or rf , swelling of the salivary or lacrimal glands when igg4-sia or igg4-dac is diagnosed , other igg4-rds such as aip or rf might be present at a subclinical level . mean serum igg4 level in aip patients was 491 mg / dl , the lowest of all the igg4-rds . mean serum igg4 level in patients with mikulicz 's disease has been reported as 1,110.0 mg / dl ( 21 ) , and aip patients with salivary or lacrimal gland involvement show higher serum igg4 levels than those without ( 12 , 22 ) . however , at this time , it is difficult to determine which organ involvement led to the elevation of serum igg4 because there are cases with many complications . aip patients with other igg4-rd are also reported to have higher serum igg4 levels than those without , reflecting higher disease activity ( 12 ) . there are some limitations of this study that must be considered when interpreting the results . first limitation is that the study was retrospective and we could not include fdg - pet findings . third is that identical screening method was not applied to all the patients due to the long duration of enrolment period . however , this represents the first study to assess organ correlation in igg4-rds . in conclusion , about half of igg4-rd patients displayed multiple igg4-rd lesions , and some patterns of association appear to exist between specific affected organs .
igg4-related disease ( igg4-rd ) is a potentially multiorgan disorder . in this study , 
 clinical and serological features from 132 igg4-rd patients were compared about organ correlations . 
 underlying pathologies comprised autoimmune pancreatitis ( aip ) in 85 cases , igg4-related sclerosing cholangitis ( igg4-sc ) in 12 , igg4-related sialadenitis ( igg4-sia ) in 56 , igg4-related dacryoadenitis ( igg4-dac ) in 38 , igg4-related lymphadenopathy ( igg4-lym ) in 20 , igg4-related retroperitoneal fibrosis ( igg4-rf ) in 19 , igg4-related kidney disease ( igg4-kd ) in 6 , igg4-related pseudotumor ( igg4-pt ) in 3 . 
 sixty - five patients ( 49% ) had multiple igg4-rd ( two affected organs in 36 patients , three in 19 , four in 8 , five in 1 , and six in 1 ) . 
 serum igg4 levels were significantly higher with multiple lesions than with a single lesion ( p<0.001 ) . 
 the proportion of association with other igg4-rd was 42% in aip , the lowest of all igg4-rds . 
 serum igg4 level was lower in aip than in other igg4-rds . 
 frequently associated igg4-rds were sia ( 25% ) and dac ( 12% ) for aip ; aip ( 75% ) for igg4-sc ; dac ( 57% ) , aip ( 38% ) and lym ( 27% ) for igg4-sia ; aip ( 26% ) and lym ( 26% ) for igg4-dac ; sia ( 75% ) , dac ( 50% ) and aip ( 45% ) for igg4-lym ; sia ( 58% ) , aip ( 42% ) and lym ( 32% ) for igg4-rf ; aip ( 100% ) and sia ( 67% ) for igg4-kid ; and dac ( 67% ) and sia ( 67% ) for igg4-pt . 
 most associated igg4-rd lesions were diagnosed simultaneously , but igg4-sia and igg4-dac were sometimes identified before other lesions . 
 about half of igg4-rd patients had multiple igg4-rd lesions , and some associations were seen between specific organs.graphical abstract