measurement of disease activity is critical for longitudinal assessments in both observational studies and clinical trials . in the field of rheumatology ,
more than 250 assessment tools have been developed and validated to evaluate pathology , symptoms , function , and health status of patients with rheumatic diseases .
such instruments should be compatible with regulatory requirements of the food and drug administration ( fda ) and generally require prospective studies for completion of the validation process .
igg4-related disease ( igg4-rd ) is an increasingly recognized immune - mediated disease that is characterized by a lymphoplasmacytic infiltrate enriched with igg4-positive plasma cells and a distinctive storiform fibrosis of affected organs .
commonly involved organs include the pancreas , biliary tree , orbits , salivary glands , and retroperitoneum , among many others .
the serum igg4 level is often but not always elevated . because of the novelty of igg4-rd , little effort to date has been devoted to the development of outcome measures for this newly recognized condition .
a disease responder index is a tool designed to detect any changes in disease activity and identify improvement and worsening in the same and/or different organ systems .
a responder index permits objective quantification of the treatment response by providing standardized outcome measures .
assessing clinical response and not simply serologic response is increasingly important to establish endpoints in randomized control trials .
glucocorticoids are the standard first - line treatment for igg4-rd and patients whose disease has not reached an advanced stage of fibrosis generally respond well to this treatment , at least initially .
the first is the complex , multiorgan system nature of this disease , which makes it difficult to summarize the state of disease activity across all organs .
the second is the fact that the stage of disease activity can differ across organs , such that a patient can have active inflammation likely to respond to immunosuppression in one organ and advanced fibrosis ( less likely to respond to treatment ) in another .
we have developed an igg4-rd responder index ( igg4-rd ri ) for use as an outcome measure in an ongoing pilot trial of rituximab in this condition .
we intend that this instrument will measure not only disease activity but will also incorporate features that capture the need for urgent treatment and catalogue disease - related damage .
this paper is designed to provide information on the development and implementation of the igg4-rd ri .
we report the philosophy behind the development of the igg4-rd ri to date , the steps taken to create the instrument through the enlistment of assistance of international experts in this condition , and the plans for completion of the igg4-rd ri validation process .
the igg4-rd ri was designed to assess disease activity from visit to visit using clinician - generated assessments of both objective and subjective measures .
the igg4-rd ri uses a scoring system from 04 for each organ system or site and asks the clinician to rate the extent of disease activity and damage at the time of the clinical encounter .
the igg4-rd ri was revised by the organizing committee of the international igg4-related disease symposium , held in boston in october , 2011 [ http://www2.massgeneral.org/pathology/symposium/igg4_related_systemic_dis.asp ] .
this group was comprised of 39 experts from 9 countries , with subspecialty expertise in rheumatology , gastroenterology , allergy / immunology , nephrology , surgery , pathology , and radiology .
further revisions were made following a simulation exercise involving six paper case descriptions of real patients , completed by igg4-rd symposium participants .
finally , both the igg4-rd ri that emerged from these development steps and a physician global assessment ( pga ) were used to assess the disease retrospectively in terms of disease activity and damage .
the pearson 's correlation coefficient was then calculated to compare the igg4-rd ri and pga responses .
the igg4-rd ri was modeled on the birmingham vasculitis activity score for wegener 's granulomatosis ( bvas / wg ) .
the bvas / wg is a formally validated and widely used instrument for the measurement of disease activity in granulomatosis with polyangiitis ( formerly wegener 's granulomatosis ) and microscopic polyangiitis , a pair of distinct but overlapping conditions often termed antineutrophil cytoplasmic antibody ( anca)-associated vasculitides ( aavs ) .
the bvas / wg is a clinician - scored instrument in which each disease activity in each organ system is graded 
persistent ,   worse ,  or  none  at each clinic visit .
the number of items of  persistent  or  worse  for each organ system is totaled and used to quantify the states of disease flare , persistent disease , or remission .
the bvas / wg was selected because of the experience of one of the authors ( j. h. stone ) as a lead developer of this instrument ; similarities between anca - associated vasculitis and igg4-rd , including the propensities for multi - organ system involvement ; the broad range of disease activity between flare and remission ; the high frequency of disease - related damage ( which must be distinguished from active disease ) ; the absence of reliable biomarkers that necessitates reliance upon clinical indices for longitudinal assessments .
the igg4-rd ri , designed to emphasize ease of use , includes specific reminders to consider activity within all organs involved commonly in igg4-rd ( figure 1 ) .
physicians enter a score from 04 for each organ / site affected , indicating whether the organ / site is normal , improved , new or recurrent , or worse on treatment .
the physician also provides yes / no answers for each organ site to the questions of whether the disease is symptomatic ; whether the disease activity requires treatment urgently ; whether the organ dysfunction observed is related to damage rather than ( or in addition to ) active disease . at the end of this table , the serum igg4 concentration in milligrams per deciliter is entered along with a score of 04 , indicating whether the igg4 concentration has improved , become newly or recurrently elevated , or increased despite treatment since the last visit .
the scoring scheme for serum igg4 concentration , therefore , parallels the schemes for individual organ system activity assessment . the cumulative glucocorticoid dose ( in prednisone equivalents ) since the last visit and total igg4-rd ri score
the numbers for each organ score refer to disease activity , distinguished from organ dysfunction related to damage :  0  signifies the absence of active disease in that organ .
a score of 0 is appropriate when the organ system has never been affected by active igg4-rd , or when previously evident disease within that organ has resolved ;  1  indicates that disease activity within an organ has improved but still persists to some degree ;    2  indicates that the disease within that organ has remained persistent and unchanged since the last visit ;    3  indicates the presence of new or recurrent disease activity ;  4  refers to disease that has worsened despite treatment .
the organ sites were selected for inclusion in the igg4-rd ri based on a review of the existing literature ( table 1 ) .
for ease of conceptualization , the sites of potential organ involvement are listed from head to toe .
this structure is similar to that of the bvas / wg scoring sheet , on which disease activity is scored by organ system , and each disease site is assigned a designation of normal , persistent disease activity , and new / worse disease activity , with numerical scores corresponding to each state .
the igg4-rd ri category of  other  organ / site involvement is important because the protean nature of this disease makes it impossible to capture all potential sites of disease .
in addition , we anticipate that new clinical manifestations of this disease and possible even new sites of organ involvement will be described as the clinical phenotype of this disease is understood more fully .
lists of the most common symptoms and signs within a given organ system are included in the igg4-rd ri instructions ( see the appendix ) , principally as a reminder to the clinician of the possible disease manifestations to consider when scoring disease activity and damage .
the physician simply denotes on the form the presence or absence of symptoms for a given igg4-rd site .
good clinical judgment and a thorough knowledge of the disease manifestations of this condition are essential , as with any clinical responder index .
some disease manifestations of igg4-rd require the immediate institution of treatment to prevent permanent organ damage .
for example , igg4-related sclerosing cholangitis can lead to cirrhosis within several months of diagnosis and requires the prompt initiation of therapy .
in contrast , the lymphadenopathy of igg4-rd remains unchanged for prolonged periods in many patients and may never require treatment .
the  urgent  column in the igg4-rd ri is designed to capture aspects of the disease that require the immediate start of immunosuppression in order to preserve organ function .
the score for an organ site is doubled when the need to initiate treatment for active igg4-rd at a particular or organ / site is considered urgent .
for example , if a patient has new igg4-related sclerosing cholangitis , the total score for that organ / site would be 6 instead of 3 . similarly , if the patient 's biliary status has worsened despite therapy since the time of the last visit and an urgent escalation of therapy is required to treat the igg4-related sclerosing cholangitis , then that organ score would be 8 rather than 4 .
only the score of the individual organ site is doubled in this setting , not the total igg4-rd ri score .
organ damage results from active disease and in some cases both active disease and damage can be present in the same organ system simultaneously . in other cases ,
immunosuppression must be targeted to active igg4-rd , not to damage resulting from previously active therapy .
the most appropriate use of immunosuppression is to control active disease and prevent disease - related damage .
it is particularly ideal to employ immunosuppression at a stage of disease when the histopathology is characterized by a lymphoplasmacytic infiltrate rather than a predominance of acellular fibrosis .
radiographic studies such as computed tomography ( ct ) and positron emission tomography with ct ( pet - ct ) can aid the clinician in determining which organs have been damaged .
for example , even conceding that active disease might be present simultaneously with damage within the pancreas , the finding of atrophic changes by ct scan within that organ would be considered to be the result of damage .
in such a case , both active disease and disease - related damage should be scored .
the serum igg4 level may become elevated in a patient experiencing an active flare [ 6 , 10 ] .
however , not every patient with igg4-rd has an elevated serum igg4 level at baseline , even before treatment .
it is well established that classic igg4-rd can be active in the absence of elevated serum igg4 concentrations .
the igg4-rd serum level in the igg4-rd ri is scored according to normal , improved , persistent , new , recurrent , or worsened despite treatment .
the sum of the disease activity in all of the organ sites plus the serum igg4 concentration score ( also graded on a 04 scale ) yields the total activity score .
an individual active organ site is doubled for urgency and added to the other organ sites .
this number can be compared between visits to assess the disease activity over time as well as being used for a clinical trial endpoint .
the longitudinal recording of damage , though not included in the overall disease activity score , is essential to the formulation of the patient 's overall outcome .
glucocorticoids are the cornerstone of igg4-rd treatment , and most patients respond promptly to this treatment , at least initially .
thus , careful recording of the dose of prednisone ( or prednisone equivalent ) in the interval between the current visit and the preceding one is essential to a full understanding of the degree of disease activity .
the igg4-rd ri went through several development stages and iterations before arriving at its current format .
a simulation exercise using paper case descriptions of six real patients was sent to attendees of the international igg4-rd symposium ( held in boston , ma , usa october 2011 ) .
the participants received written instructions on how to apply the igg4-rd ri but did not attend a training session ( the appendix ) .
twenty - one individuals participated in this exercise , providing valuable feedback from a cross - section of investigators interested in igg4-rd .
the physicians who completed the exercises included a variety of subspecialists , particularly rheumatologists and pathologists ( figure 2 ) .  
the simulation exercises were presented as clinical vignettes , including data from histories , physical examinations , laboratory results , and radiologic findings for each case .
accompanying each clinical vignette was at least one clinical photograph , radiology study , or histologic image to illustrate the case effectively .
the physicians then used all of the information presented in the simulation exercise to complete a separate igg4-rd ri scoring sheet for each case .
the results were scored for each participant against standardized answers prepared by consensus of the four authors .
the purpose of this exercise was to solicit feedback on the igg4-rd ri from physicians who were experts in the evaluation of patients with this disorder from different perspectives .
these included scoring organ involvement in which clinical symptoms and signs had resolved entirely as improved but persistent ( i.e. ,  1  ) rather than resolved ( i.e. ,  0  ) .
another scoring discrepancy resulted from incorrectly scoring patients off treatment who were recurrent (  3  ) as if they were receiving treatment (  4  ) .
a third error was failing to double the organ / site score , when disease requiring treatment urgently was present .
comments from the participants in this exercise contributed substantially to important revisions of the draft instrument .
we reformatted the scoring sheet in order to address the common scoring differences from the simulation case exercises .
the next step in the development of the igg4-rd was the retrospective use of the instrument for fifteen individual clinic and in - patient evaluations among patients in the massachusetts general hospital igg4-rd registry .
two blinded rheumatology experts scored an igg4-rd patient visit using either the igg4-rd ri or the physician 's global assessment scale ( pga ) .
as the field of igg4-rd is poised to move beyond the descriptive phase of the disease , validated outcome measures are required to advance the understanding of this condition and the assessment of new treatment approaches .
the current iteration of the igg4-rd ri marks an important step toward the availability of useful outcome measures in this disease .
we anticipate that additional validation steps for this instrument will be required , but this paper describes accurately the philosophy and goals behind the igg4-rd ri .
the development efforts to date have created a one - page instrument supported by the instruction manual shown in the appendix .
data included on this single page include indications of disease activity across a full spectrum of potential organ involvement ; the serum igg4 concentration ; assessments of the need for treatment on an urgent basis ; the recording of damage in organ systems ; the sum of recent glucocorticoid use .
expertise with the use of the igg4-rd ri may , therefore , become a concise and important tool for clinical trials and other investigations related to this disorder .
although the developers of the igg4-rd ri have relied significantly upon the bvas / wg in creating this instrument , the igg4-rd ri differs in important ways from the bvas / wg .
the  urgent  column in the igg4-rd ri highlights features of the disease that require the prompt institution of treatment and is , therefore , analogous to the  major  designations given to some organ system manifestations in the bvas / wg .
however , the bvas / wg does not record disease damage on the same page .
rather , clinical trials in aav have generally used a separate instrument , the vasculitis damage index , for this purpose .
although it is critical that the concepts of disease activity and damage be kept separate and recorded appropriately during clinical assessments , it may be useful to have an indication of damage on the same one - page case report form even if damage does not contribute to the overall disease activity score .
this model matches more closely the decision - making process that clinicians undertake on a daily basis in encounters with patients : are the signs of organ dysfunction due to active disease , or are they more accurately a reflection of damage rather than a process that requires more intensive immunosuppression ?
the igg4-rd ri will find its greatest use in the research setting , either in the context of clinical trials or in other types of investigations that require the careful longitudinal assessments of patients ' clinical status . because consistency of its application from visit to visit is critical , it will be most useful to ensure whenever possible that the same investigators complete the igg4-rd ri for the same patient across all visits .
significant debate now exists within the community of igg4-rd investigators about the utility of serum igg4 concentration measurements in the diagnosis and management of this disorder .
inclusion of the serum igg4 concentration in the igg4-rd ri at this point permits an analysis of the value of this measurement in the context of other organ disease assessments .
we hypothesize that further analysis of these data will confirm the utility of serial measurements , at least in a subset of patients .
this hypothesis , however , requires confirmation through studies of larger numbers of patients in a variety of states of disease activity .
the simulation case exercises illustrated some shortcomings in early iterations of the igg4-rd ri that led to appropriate revisions of the original index . the experience with the simulation exercise highlighted the importance of adequate training with the instrument prior to its use in the research setting .
the igg4-rd ri is simpler than many clinical assessment tools for multiorgan diseases , but both a thorough understanding of the clinical breadth of igg4-rd itself and a high degree of familiarity with the index are required in order to employ it effectively .
we anticipate that a focused period of instruction for investigators in the context of a formal training course will be required before this tool can be used in the context of a clinical trial . in conclusion ,
progress in igg4-rd will be contingent upon the ability to assess patients rigorously in a longitudinal manner , using validated outcome measures .
the igg4-rd ri described in this paper represents a broad effort at the development of a disease activity and responder index that can be employed in clinical trials and other investigations of patients with this emerging immune - mediated condition .
the next steps in validation will include a multicenter study of patients recruited from a core group of sites with extensive experience in the diagnosis and management of this disease .
 igg4-related disease ( igg4-rd ) is a multiorgan inflammatory disease in which diverse organ manifestations are linked by common histopathological and immunohistochemical features . 
 prospective studies of igg4-rd patients are required to clarify the natural history , long - term prognosis , and treatment approaches in this recently recognized condition . 
 patients with igg4-rd have different organ manifestations and are followed by multiple specialties . 
 divergent approaches to the assessment of patients can complicate the interpretation of studies , emphasizing the critical need for validated outcome measures , particularly assessments of disease activity and response to treatment . 
 we developed a prototype igg4-rd responder index ( igg4-rd ri ) based on the approach used in the development of the birmingham vasculitis activity score for wegener 's granulomatosis ( bvas / wg ) . 
 the igg4-rd ri was refined by members of the international igg4-rd symposium organizing committee in a paper case exercise . 
 the revised instrument was applied retrospectively to fifteen igg4-rd patients at our institution . 
 those scores were compared to physician 's global assessment scale for the same visits . 
 this paper describes the philosophy and goals of the igg4-rd ri , the steps in the development of this instrument to date , and future plans for validation of this instrument as an outcome measure . 
1. Introduction
2. Methods
3. Results
4. Discussion