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Rituximab for the Treatment of IgG4-Related Disease Lessons From 10 Consecutive Patients Arezou Khosroshahi, MD, Mollie N. Carruthers, MD, Vikram Deshpande, MD, Sebastian Unizony, MD, Donald B. Bloch, MD, and John H. Stone, MD, MPH Abstract: Patients with IgG4-related disease (IgG4-RD) typically have elevated serum concentrations of IgG4 and share histopathologic features that are similar across affected organ(s). IgG4-RD patients frequently require prolonged treatment with glucocorticoids and are often unable to taper these medications. Traditional disease-modifying antirheumatic drugs (DMARDs) are generally ineffective. We assessed the clinical and serologic responses to B lymphocyte depletion therapy in 10 consecutive patients with steroid- and DMARD-refractory IgG4-RD. Ten patients with IgG4-RD were treated with rituximab (RTX) (2 in- fusions of 1000 mg, 15 days apart). Clinical improvement was assessed by monitoring the patient’s ability to taper prednisone to discontinuation and to stop DMARDs; by serial measurements of total IgG and IgG subclasses; and by follow-up radiologic assessments guided by the patient’s particular pattern of organ involvement. We also developed and retrospectively ap- plied the IgG4-RD Disease Activity Index and Flare Tool. Organ involvement included the pancreas, biliary tree, aorta, salivary glands (submandibular and parotid), lacrimal glands, lymph nodes, thyroid gland, and retroperitoneum. Nine of 10 patients demonstrated striking clinical improvement within 1 month of starting RTX. One pa- tient with advanced thyroid fibrosis associated with Riedel thyroiditis and a history of disease in multiple other organ systems did not have improvement in the thyroid gland, but the disease did not progress to involve new organs. All 10 patients were able to discontinue prednisone and DMARDs following RTX therapy. Significant decreases in IgG concentrations were observed for the IgG4 subclass only. Four patients were re-treated with RTX after 6 months because of either symptom recurrence and increasing IgG4 concentration at the time of peripheral B cell reconstitution (n = 2) or because of physician discretion (n = 2). Repeated courses of RTX maintained their effectiveness and resulted in further decreases in IgG4 concentrations. In patients who had an increased IgG4 concentration at the time of presentation, the level of serum IgG4 appeared to be a reliable measure of disease activity. IgG4-RD is an idiopathic, multiorgan inflammatory disease in which diverse organ manifestations are linked by characteristic histopathologic and immunohistochemical features. Treatment with RTX led to prompt clinical and serologic improvement in refractory IgG4-RD in all patients with active inflammation. Serial treatments with RTX may lead to pro- gressive declines in serum IgG4 concentrations and better disease con- trol. Serum IgG4 concentrations may remain low, and clinical disease activity may remain quiescent even after B cell reconstitution in a sig- nificant proportion of patients. (Medicine 2012;91: 57Y66) Abbreviations: ANA = antinuclear antibody, CRP = C-reactive protein, CT = computed tomography, DMARD = disease-modifying antirheumatic drugs, ESR = erythrocyte sedimentation rate, FDG = fluorodeoxyglucose, HBcAg = hepatitis B core antigen, HBsAb = hepatitis B surface antibody, HBsAg = hepatitis B surface antigen, HBV = hepatitis B virus, hpf = high-power field, IgG4-RD = IgG4-related disease, PET = positron emission tomography, RTX = rituximab. INTRODUCTION I gG4-related disease (IgG4-RD) is a recently described fibroin- flammatory condition that has distinctive clinical findings, unique histopathologic features, and typically involves multiple organs. 20 Patients often present with tumefactive lesions in 1 or more affected organs, and the majority of cases are associated with elevated serum IgG4 concentrations. Regardless of the organ system involved, patients with IgG4-RD have similar histopathologic findings: a lymphoplasmacytic infiltrate, obliterative phlebitis, fibrosis marked by a ‘‘storiform’’ pattern, and modest tissue eosinophilia. 19 The presence of IgG4-positive plasma cells within an affected organ is the pathologic feature most critical to diagnosis. 29 IgG4-RD is now recognized to affect the pancreas, biliary tree, aorta (with or without retroperitoneal fibrosis), lung, sali- vary and lacrimal glands, thyroid gland, kidneys, pachyme- ninges, pituitary gland, prostate, breast, and other organs. 19,29 The different organs affected by IgG4-RD can be involved si- multaneously, but involvement is often observed to be meta- chronous, evolving over a period of years and making the full recognition of this disorder challenging. 22 The optimal treatment approach to IgG4-RD is not certain. Data on treatment are de- rived primarily from experience with autoimmune pancreatitis. Several reports emphasize that serum IgG4 concentrations de- cline in most patients after treatment with glucocorticoids but remain above the normal range. 5,15 Some patients are refractory to glucocorticoid tapers, 24 and treatment refractoriness appears to be more common in patients with extrapancreatic disease. 25 Autoimmune pancreatitis appears to relapse in up to one-third of patients treated with maintenance glucocorticoids and in more than half of those in whom maintenance glucocorticoids are not used. 26 Reports of the experience with disease-modifying anti- rheumatic drugs (DMARDs) as steroid-sparing agents are lim- ited in both number and detail. 10,31 We recently reported our experience treating 4 IgG4-RD patients with rituximab (RTX). 18 All 4 patients responded swiftly to this intervention, with improvements in clinical symptoms and successful tapering of glucocorticoids to discontinuation. One Medicine & Volume 91, Number 1, January 2012 www.md-journal.com 57 From Rheumatology Unit (AK, MNC, SU, DBB, JHS), Division of Rheu- matology, Allergy, and Immunology, Department of Medicine; and Depart- ment of Pathology (VD); Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. Figures 1 and 3 can be viewed in color online at http://www.md-journal.com. Dr. Deshpande has served as a consultant for Chugai Pharmaceutical. Dr. Stone has served as a consultant and his institution has a grant pending with Genentech. The other authors declare no funding or conflicts of interest. Reprints: John H. Stone, MD, MPH, Rheumatology Unit, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114 (e-mail: jhstone)partners.org). Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal’s Web site (www.md-journal.com). Copyright * 2012 by Lippincott Williams & Wilkins ISSN: 0025-7974 DOI: 10.1097/MD.0b013e3182431ef6 Copyright © 2011 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Rituximab for the Treatment of IgG4-Related Diseasewilliams/igg4_rituximab_2012.pdf · IgG4-related disease, PET = positron emission tomography, RTX = rituximab. INTRODUCTION

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Rituximab for the Treatment of IgG4-Related DiseaseLessons From 10 Consecutive Patients

Arezou Khosroshahi, MD, Mollie N. Carruthers, MD, Vikram Deshpande, MD, Sebastian Unizony, MD,Donald B. Bloch, MD, and John H. Stone, MD, MPH

Abstract: Patients with IgG4-related disease (IgG4-RD) typically haveelevated serum concentrations of IgG4 and share histopathologic featuresthat are similar across affected organ(s). IgG4-RD patients frequentlyrequire prolonged treatment with glucocorticoids and are often unableto taper these medications. Traditional disease-modifying antirheumaticdrugs (DMARDs) are generally ineffective. We assessed the clinical andserologic responses to B lymphocyte depletion therapy in 10 consecutivepatients with steroid- and DMARD-refractory IgG4-RD.

Ten patients with IgG4-RD were treated with rituximab (RTX) (2 in-fusions of 1000 mg, 15 days apart). Clinical improvement was assessed bymonitoring the patient’s ability to taper prednisone to discontinuation andto stop DMARDs; by serial measurements of total IgG and IgG subclasses;and by follow-up radiologic assessments guided by the patient’s particularpattern of organ involvement. We also developed and retrospectively ap-plied the IgG4-RD Disease Activity Index and Flare Tool.

Organ involvement included the pancreas, biliary tree, aorta, salivaryglands (submandibular and parotid), lacrimal glands, lymph nodes,thyroid gland, and retroperitoneum. Nine of 10 patients demonstratedstriking clinical improvement within 1 month of starting RTX. One pa-tient with advanced thyroid fibrosis associated with Riedel thyroiditisand a history of disease in multiple other organ systems did not haveimprovement in the thyroid gland, but the disease did not progress toinvolve new organs. All 10 patients were able to discontinue prednisoneand DMARDs following RTX therapy. Significant decreases in IgGconcentrations were observed for the IgG4 subclass only. Four patientswere re-treated with RTX after 6 months because of either symptomrecurrence and increasing IgG4 concentration at the time of peripheral Bcell reconstitution (n = 2) or because of physician discretion (n = 2).Repeated courses of RTX maintained their effectiveness and resultedin further decreases in IgG4 concentrations. In patients who had anincreased IgG4 concentration at the time of presentation, the level ofserum IgG4 appeared to be a reliable measure of disease activity.

IgG4-RD is an idiopathic, multiorgan inflammatory disease in whichdiverse organ manifestations are linked by characteristic histopathologicand immunohistochemical features. Treatment with RTX led to promptclinical and serologic improvement in refractory IgG4-RD in all patientswith active inflammation. Serial treatments with RTX may lead to pro-

gressive declines in serum IgG4 concentrations and better disease con-trol. Serum IgG4 concentrations may remain low, and clinical diseaseactivity may remain quiescent even after B cell reconstitution in a sig-nificant proportion of patients.

(Medicine 2012;91: 57Y66)

Abbreviations: ANA = antinuclear antibody, CRP = C-reactiveprotein, CT = computed tomography, DMARD = disease-modifyingantirheumatic drugs, ESR = erythrocyte sedimentation rate, FDG =fluorodeoxyglucose, HBcAg = hepatitis B core antigen, HBsAb =hepatitis B surface antibody, HBsAg = hepatitis B surface antigen,HBV = hepatitis B virus, hpf = high-power field, IgG4-RD =IgG4-related disease, PET = positron emission tomography, RTX =rituximab.

INTRODUCTION

IgG4-related disease (IgG4-RD) is a recently described fibroin-flammatory condition that has distinctive clinical findings, unique

histopathologic features, and typically involves multiple organs.20

Patients often present with tumefactive lesions in 1 or more affectedorgans, and the majority of cases are associated with elevated serumIgG4 concentrations. Regardless of the organ system involved,patients with IgG4-RD have similar histopathologic findings: alymphoplasmacytic infiltrate, obliterative phlebitis, fibrosis markedby a ‘‘storiform’’ pattern, and modest tissue eosinophilia.19 Thepresence of IgG4-positive plasma cells within an affected organ isthe pathologic feature most critical to diagnosis.29

IgG4-RD is now recognized to affect the pancreas, biliarytree, aorta (with or without retroperitoneal fibrosis), lung, sali-vary and lacrimal glands, thyroid gland, kidneys, pachyme-ninges, pituitary gland, prostate, breast, and other organs.19,29

The different organs affected by IgG4-RD can be involved si-multaneously, but involvement is often observed to be meta-chronous, evolving over a period of years and making the fullrecognition of this disorder challenging.22 The optimal treatmentapproach to IgG4-RD is not certain. Data on treatment are de-rived primarily from experience with autoimmune pancreatitis.Several reports emphasize that serum IgG4 concentrations de-cline in most patients after treatment with glucocorticoids butremain above the normal range.5,15 Some patients are refractoryto glucocorticoid tapers,24 and treatment refractoriness appearsto be more common in patients with extrapancreatic disease.25

Autoimmune pancreatitis appears to relapse in up to one-third ofpatients treated with maintenance glucocorticoids and in morethan half of those in whom maintenance glucocorticoids are notused.26 Reports of the experience with disease-modifying anti-rheumatic drugs (DMARDs) as steroid-sparing agents are lim-ited in both number and detail.10,31

We recently reported our experience treating 4 IgG4-RDpatients with rituximab (RTX).18 All 4 patients responded swiftlyto this intervention, with improvements in clinical symptoms andsuccessful tapering of glucocorticoids to discontinuation. One

Medicine & Volume 91, Number 1, January 2012 www.md-journal.com 57

From Rheumatology Unit (AK, MNC, SU, DBB, JHS), Division of Rheu-matology, Allergy, and Immunology, Department of Medicine; and Depart-ment of Pathology (VD); Massachusetts General Hospital and HarvardMedical School, Boston, Massachusetts.Figures 1 and 3 can be viewed in color online at http://www.md-journal.com.Dr. Deshpande has served as a consultant for Chugai Pharmaceutical.

Dr. Stone has served as a consultant and his institution has a grantpending with Genentech. The other authors declare no funding orconflicts of interest.

Reprints: John H. Stone, MD, MPH, Rheumatology Unit, MassachusettsGeneral Hospital, 55 Fruit Street, Boston, Massachusetts 02114(e-mail: jhstone)partners.org).

Supplemental digital content is available for this article. Direct URL citationappears in the printed text and is provided in the HTML and PDFversions of this article on the journal’s Web site (www.md-journal.com).

Copyright * 2012 by Lippincott Williams & WilkinsISSN: 0025-7974DOI: 10.1097/MD.0b013e3182431ef6

Copyright © 2011 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

striking finding in this early experience was the targeted effectof B cell depletion on the IgG4 subclass alone. Although IgG4concentrations declined dramatically and correlated with clinicalimprovement, the other IgG subclass concentrations were unaf-fected by this intervention.

The long-term therapeutic response for IgG4-RD patientstreated with RTX is not known. In addition, the effects of serialRTX treatments in this population have not been reported, andthe number of patients with IgG4-RD treated with RTX reportedin the literature to date remains small. The medical literaturecurrently provides no guidance regarding which types of patientswith IgG4-RD are likely to respond to B cell depletion or whichdisease characteristics augur poor treatment responses. We reportour experiencewith 10 consecutive IgG4-RD patients treated withRTX. Follow-up is now available on patients as long as 24 monthsafter initial RTX treatment. Four patients have undergone morethan 1 RTX course. In addition to reporting the responses totreatment in 10 patients, including the results of repeated RTXadministrations, we report our experience with the developmentand retrospective use of a disease activity index and flare tool inthis group of patients. (For more on IgG4-RD, see the article inthis same issue by Ebbo et al7a describing their experience with aFrench national registry.)

PATIENTS AND METHODS

Informed ConsentAll patients were enrolled in the Massachusetts General

Hospital IgG4-RD Registry and gave informed consent for in-clusion in a formal treatment protocol. Both the registry and thelongitudinal treatment protocol were approved by our institu-tional review board. All patients featured in figures gave per-mission for the specific figures to be published.

Inclusion CriteriaPatients were eligible to participate in the study if they had

clinical diagnoses of IgG4-RD and the pathologic features ofIgG4-RD on a tissue biopsy (see below).4,12 Clinical diagnoseswere predicated upon organ involvement in a pattern consis-tent with IgG4-RD, including dysfunction of 1 of the follow-ing organs: pancreas (autoimmune pancreatitis); salivary glands(chronic sclerosing sialadenitis); lacrimal glands (dacryoadenitis);orbital pseudotumor; kidneys; lungs; lymph nodes; meninges;aorta (including periaortitis and/or retroperitoneal fibrosis); andthyroid gland (Riedel thyroiditis).

Histopathologic features considered to be highly suggestiveof IgG4-RD included lymphoplasmacytic infiltrates and fibro-sclerosis within involved organs. Obliterative phlebitis and mildto moderate tissue eosinophilia were observed often but were notrequired for the diagnosis.33 In addition, all patients had eitheran IgG4/IgG plasma cell ratio of 950% within the affectedorgans and/or 930 IgG4-bearing plasma cells per high-powerfield (hpf) (Figure 1). All patients included had disease coursesthat were refractory to prednisone treatment of at least 2 months’duration. The only exception to this was Patient 7, who wastreated with RTX plus daily glucocorticoids from the outsetbecause of the aggressive and destructive nature of his disease(aortitis leading to 2 sequential aneurysms).

IgG4 Plasma Cell QuantitationWe quantified the degree of IgG4+ plasma cell infiltration

within biopsy specimens by the following methods. Immuno-histochemical studies were performed on formalin-fixed, paraffin-embedded tissue sections using antibodies to IgG4 (Zymed,1:200 dilution) and IgG (Dako, 1:3000 dilution). For each case,

the number of plasma cells staining for IgG4 was assessed in3 non-overlapping high-power fields (400�). The 3 fields withthe highest degree of IgG4 reactivity were selected for quantita-tion. The number of IgG4+ plasma cells was then divided by thetotal number of IgG-bearing plasma cells in these fields.

Serum IgG4 AssaySerum IgG4 concentrations were measured by nephelom-

etry (Mayo Medical Laboratories New England; Andover, MA).

RTX Treatment ProtocolPatients received 2 intravenous doses of RTX 1000 mg

separated by 15 days. Methylprednisolone (100 mg) as well asdiphenhydramine (25 mg) and acetaminophen (650 mg) wereadministered with each RTX infusion to decrease the likelihoodof infusion reactions. Patients who experienced disease flaresafter the return of their B cells were treated again with the sameRTX induction protocol.

Glucocorticoid TaperingPatients on prednisone at the time of RTX initiation had the

glucocorticoids tapered at the discretion of the treating physi-cian, with the goal of discontinuing prednisone completely by2 months. The prednisone taper generally took longer in mostpatients who had been on chronic glucocorticoid therapy be-cause of potential adrenal insufficiency. Cumulative glucocor-ticoid doses and the mean time to prednisone discontinuationwere calculated for each patient.

Follow-Up VisitsPatients were evaluated monthly for the first 3 months after

completion of the RTX infusions, and most patients were eval-uated every 3 months thereafter.

Baseline Hematologic and Serologic AssessmentsAll patients underwent complete blood counts with differ-

ential assessments of the white blood cell count, to detect eosin-ophilia. Serial serum samples were tested for total IgG and IgGsubclasses IgG1, IgG2, IgG3, and IgG4; for IgM, IgA, andIgE; and the acute-phase reactants C-reactive protein (CRP) anderythrocyte sedimentation rate (ESR). Patients also underwenttesting for rheumatoid factor by nephelometry, antinuclear anti-body (ANA) testing by immunofluorescence using the HEp-2substrate, and ELISA testing for antibodies against the Ro, La,Sm, and RNP antigens.

Imaging StudiesImaging studies were performed according to the specific

pattern of clinical organ involvement. These studies were re-peated as clinically appropriate every 6 months to assess re-sponse to therapy in most patients.

Clinical AssessmentsDisease activity was assessed by clinical criteria, which

included improvement in patients’ symptoms, resolution or ame-lioration of physical findings, serial testing of serum IgG4 con-centrations, acute-phase reactant measurements, improvement onimaging studies, and ability to taper prednisone successfully.

Disease Activity Index and Flare ToolWe developed the IgG4-RD Activity Index and Flare Tool

for use in clinical trials. (See the Appendix available online asSupplemental Digital Content, http://links.lww.com/MD/A9).We applied this instrument retrospectively to all patients whohad a minimum of 6 months’ follow-up (n = 9; 90%).

Using the IgG4-RD Activity Index and Flare Tool, we de-fined 3 response measures: disease response, complete remission,

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and sustained remission. Disease response at 6 months was de-fined as an improvement of Q2 points over the patient’s baselineIgG4-RD Activity Score, no glucocorticoid or DMARD use be-tween months 4 and 6, and no disease flares, as assessed by theIgG4-RD Flare Tool (see Appendix). Complete remission wasdefined at 6 months as an IgG4-RD Activity Score of 0 and aprednisone dose of 0 mg/d. Sustained remissionwas defined as anIgG4-RD Activity Score of 0 while off prednisone for at least 6months. Patients had to be followed for at least 9 months to beeligible for a sustained remission.

CASE SUMMARYWe provide here a short summary of a patient with an

instructive course who has not been reported elsewhere in themedical literature.

Patient 5A 59-year-old man with severe asthma presented with a

more than 40 year history of recurrent cervical lymphadenopa-

thy. He underwent multiple lymph node biopsies, with pathologyinterpreted as being consistent with ‘‘reactive lymphoid hyper-plasia,’’ and endured many negative evaluations for hemato-logic malignancy. His clinical course had also been characterizedby submandibular gland enlargement. Recurrence of an en-larged right submandibular lymph node 1 year before presenta-tion led to another full evaluation for the purpose of excludingCastleman disease. A computed tomography (CT) scan of thehead, neck, and chest (Figure 2) revealed extensive mediastinal,hilar, and axillary lymphadenopathy. A biopsy of the subman-dibular lymph node revealed a lymphoplasmacytic infiltrate withscattered eosinophils. The plasma cells within the lymph nodestained intensely for IgG4, with a ratio of IgG4-positive cells tototal IgG-positive cells of 90.50. The serum IgG4 concentrationwas 894 mg/dL (5Y140 mg/dL). Because the patient had alreadyundergone numerous courses of prednisone for coexisting asthmawithout significant improvement in lymphadenopathy and suf-fered from obesity, we elected to treat him with RTX.

The patient’s first RTX infusion was complicated by a severeasthma attack that began hours after the infusion was complete

FIGURE 1. Selected pathologic features from 10 patients with IgG4-related disease (IgG4-RD). Images on the left are microphotographsfrom hematoxylin and eosin stained slides. Those on the right are images from the corresponding immunohistochemical slide forIgG4. A & B. Cutaneous IgG4-RD showing a nodular lymphoplasmacytic infiltrate in the superficial and deep dermis with largenumbers of IgG4+ plasma cells. C & D. IgG4-related aortitis showing transmural lymphoplasmacytic infiltrate and IgG4+ plasma cells.E. IgG4-related dacryoadenitis showing a storiform-type fibrosis and a dense lymphoplasmacytic infiltrate. F. Immunoperoxidase stainon tissue corresponding to panel E. The majority of plasma cells are immunoreactive for IgG4. EThis figure can be viewed in color online athttp://www.md-journal.com.^

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and required hospitalization (see Adverse Events, below). Ag-gressive treatment of the asthma during the next 2 weeks per-mitted successful administration of the second dose ofRTX. Within 1 month of the initial RTX treatment, his serumIgG4 concentration had declined from 894 mg/dL to 368 mg/dL(normal: 5Y140 mg/dL). A repeat chest CT scan 6 months afterRTX demonstrated significant interval decrease in the lymph-adenopathy (see Figure 2). Ten months after his RTX treatment,his B-cell pool had undergone reconstitution but his serum IgG4concentration decreased to normal levels (84.5 mg/dL), despitethe absence of any glucocorticoid treatment during that period.Of note, the patient’s asthma has been well controlled sincetreatment with RTX.

RESULTS

Baseline CharacteristicsThe patients’ baseline characteristics are shown in Table 1.

Extent of Organ InvolvementThe patients’ history of organ involvement is summarized

in Table 2. The diagnosis was confirmed by biopsy in all 10patients, and tissue was available from multiple sites in 4. Thepathologic characteristics and immunohistochemical findingsare summarized in Table 3. The patients experienced a broadrange of organ involvement, and multiple organ system in-volvement in individual patients was common (n = 7; 70%). Themost commonly involved organ was the eye (n = 5) (Figure 3).

Orbital disease included dacryoadenitis, orbital myositis, orbitalinflammatory pseudotumor, and extension from the orbit to in-volve the trigeminal nerve. Four patients presented with chronicsclerosing sialadenitis involving the parotid and submandibularglands. Aortitis, sometimes associated with retroperitoneal fi-brosis, was the cardinal manifestation in 3 patients. All 3 patientswith IgG4-related aortitis required surgical repair of the aorta, il-lustrating the potentially tissue-destructive nature of the IgG4-RDlesion. Diffuse lymphadenopathy was detected in 3 patients, lead-ing to multiple sequential lymph node biopsies to exclude lym-phoma and other conditions.

Serologic AbnormalitiesAll 10 patients (100%) had positive ANA assays, 3 with

titers Q1:640 (1:640, 1:1280, and 1:5120, respectively). The pa-tient with the highest ANA titer (Patient 9) had a centromerepattern of immunofluorescence but no clinical features of limitedsystemic sclerosis. None of the other patients had specific auto-antibodies characteristic of particular immune-mediated con-ditions. Patient 3 was rheumatoid factor positive (50 IU/mL;normal: G30 IU/mL). Eight of the 10 patients (80%) had elevatedESRs (range, 35Y111 mm/h).

Glucocorticoid TaperingPrednisone had been a chronic treatment for years in 5 of

the 6 patients who were receiving glucocorticoids at the time ofRTX initiation (Table 4). Four patients were not receiving pred-nisone at the time of entry: Patients 4 and 6 stopped prednisone

FIGURE 2. Patient 5: CT imaging of the chest. A. Remarkable hilar and axillary lymph nodes measuring 3.9 � 1.9 cm in the left axilla(arrow) and 2.5 � 1.8 cm in right axilla (arrow) before RTX treatment. B. Significant interval regression of axillary lymph nodes 6 monthsafter RTX treatment.

TABLE 1. Baseline Characteristics of 10 Patients With IgG4-Related Disease

Patient Age (yr) Sex Race/Ethnicity* Asthma/Allergy Eosinophilia ANA† ESR (mm/h)Serum IgG4Level (mg/dL)

OtherElevated Ig

1 76 M W Y N + 1:40 S 111 92000 IgE2 55 M W Y Y + 1:160 S 13 15603 67 M W Y Y + 1:1280 S 62 688 IgE4 72 F W Y N + 1:320 S 52 1140 IgG35 59 M W Y Y + 1:40 S 7 894 IgE6 56 M W Y Y + 1:640 H 37 670 IgE, IgG27 61 M A-C N N + 1:40 S 108 365 IgG18 40 F W N N + 1:160 S 71 70.89 57 F W N Y + 1:5120 C 55 5810 59 M W N N + 1:40 S 35 22.9

*W = white, A-C = Afro-Caribbean.

†S = speckled, H = homogeneous, C = centromere.

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4 and 2 weeks before the RTX infusions, respectively, and Patients5 and 8 completed trials of prednisone months before RTXtreatment. Following the administration of RTX, all patientstapered their baseline prednisone doses and stopped DMARDs.The prednisone taper was conducted slowly to avoid adrenalinsufficiency in patients on long-standing glucocorticoid thera-py. The mean time to prednisone discontinuation from the firstRTX infusion was 5.3 months (range, 1Y9 mo).

Response to TreatmentNine (90%) of 10 patients demonstrated substantial clini-

cal improvement within 1 month of RTX therapy. Discontin-uation of both prednisone and DMARDs was achieved in all10 patients. Patients 1 and 3 suffered disease recurrences ap-proximately 6 months after RTX treatment and experienced atotal of 4 disease flares between them. Flares were characterizedby symptom recurrence or serum IgG4 elevations. Each diseaseflare occurred in the setting of reconstituted B cells and risingserum IgG4 concentrations. All disease flares responded promptlyto repeat courses of RTX. The only patient who required gluco-corticoid treatment for disease flare was Patient 1; his cholangi-

tis was treated with a 3-week course of prednisone in additionto RTX.

IgG4-RD Activity Index and Flare ToolWe retrospectively applied a Disease Activity Index to the

10 patients in the study (see Table 4). Nine (90%) of 10 patients

TABLE 2. Organ Involvement of 10 Patients With IgG4-RD

Organ Involvement No. (%) (Patient Number) (n = 10)

Orbital involvement 5 (50) (Pt 2, 4, 6, 8, 9)Sialadenitis 4 (40) (Pt 1, 2, 4, 9)Lymphadenopathy 3 (30) (Pt 1, 3, 5)Aortitis 3 (30) (Pt 1, 3, 7)Sclerosing cholangitis 2 (20) (Pt 1, 8)Retroperitoneal fibrosis 2 (20) (Pt 1, 10)Pulmonary involvement 1 (10) (Pt 8)Autoimmune pancreatitis 1 (10) (Pt 1)Riedel thyroiditis 1 (10) (Pt 8)Cutaneous nodule 1 (10) (Pt 4)

FIGURE 3. Clinical pictures of Patients 2, 4, and 6 withIgG4-related orbital involvement and dacryoadenitis.EThis figure can be viewed in color online athttp://www.md-journal.com.^

TABLE 3. Pathologic Characteristics of 10 Patients

PatientOrganAffected

LymphoplasmacyticInfiltrate

StoriformFibrosis

ObliterativePhlebitis

TissueEosinophilia

IgG4/total IgG Ratioin Tissue (%)

IgG4+ in Tissue(Cells/hpf)

1 Liver Y Y Y N 92 37Aorta Y Y N N 82

2 Salivary gland Y N N Y 80 1213 Aorta Y Y Y N 72 30

LN Y N N N 950 NA4 Skin Y N N Y 95 210

Lacrimal gland Y N N Y 90 1265 LN Y N N Y 989 3206 Lacrimal gland Y Y N Y 93 1537 Aorta Y N N N 950 528 Thyroid Y Y N N 80 8

LN Y N N N 83 110Lung Y Y Y Y 87 13Lacrimal gland Y Y Y Y 44 11Ampulla NA 12

9 Parotid gland Y Y N Y 100 36910 Retroperitoneum Y Y N N 50 4

Abbreviations: LN = lymph node, NA = not available.

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achieved ‘‘disease responses,’’ defined as improvement inIgG4-RD Activity Index 92 points after RTX therapy. Four of8 patients who had 6 months’ follow-up (Patients 2, 5, 7, 10)achieved complete remission at 6 months, with IgG4-RD Ac-tivity Index scores of 0 and no prednisone use.

For the 2 patients who experienced disease flares, the FlareTool showed flares of mild to moderate severity in both.

Serologic and Hematologic ResponsesClinical improvements following RTX administration cor-

related with rapid declines in serum IgG4 concentrations. Sevenpatients had elevated serum IgG4 concentrations at baseline, with

a mean concentration of 1045 mg/dL (range, 365Y2000 mg/dL)(normal: 8Y140 mg/dL). Among these patients, the serum IgG4concentrations declined by a mean of 46% within 2 months ofRTX administration (Figure 4). The reduction in IgG levels wasobserved only in the IgG4 subclass (Figure 5). Minor elevations ofthe IgG1, IgG2, or IgG3 subclasses were observed inconsistentlyin 3 patients at baseline (see Table 1), but these concentrationswere not affected significantly by RTX therapy.

Among the patients who did not experience disease recur-rences, serum IgG4 concentrations remained low. Of note, at amean follow-up of 14.3 months (range, 4Y24 mo), all patientshad normal serum IgG4 concentrations except Patients 1 and 3,

FIGURE 4. Serum IgG4 concentrations in 7 of 10 patients with IgG4-RD who had elevated serum IgG4 levels at baseline. Figure shows theserum IgG4 concentrations 2 month before rituximab treatment to 12 months after treatment (time scale is not uniform).

TABLE 4. Response to Treatment

PatientTreatmentBefore RTX

PrednisoneDose at Entry

Disease ActivityScore* Before RTX

Courses ofRTX (no.)

Disease ActivityScore* After RTX

1 Prednisone (3 yr)Azathioprine(2 mo)Mycophenolate mofetil (18 mo)6-mercaptopurine (1 mo)

10 mg 14 4 1

2 Prednisone (4 yr)Methotrexate (4 yr)

10 mg 5 3 0

3 Prednisone (1 yr) 10 mg 6 3 24 Prednisone (1 yr) 0 6 1 15 Prednisone (2 mo) 0 3 1 06 Prednisone (20 yr)

Methotrexate (1 yr)Mycophenolate mofetil (1 mo)

0 3 1 1

7 Prednisone (1 mo) 60 mg 4 1 08 Prednisone (4 mo)

Tamoxifen (2 yr)0 6 1 3

9 Prednisone (18 mo)Methotrexate (1 yr)

10 mg 2 3 0

10 Prednisone (10 yr) 10 mg 1 1 0

*Based on the IgG4-RD Activity Index and Flare Tool described in Methods section.

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both of whom experienced disease flares. Even in Patients 1 and3, however, the serum concentrations of IgG4 were 174 mg/dLand 216 mg/dL, respectively, that is, almost 10 times lower thanbefore treatment with RTX.

Prevalence of Atopy, IgE Concentrations, andEosinophilia and Response to Treatment

Six of 10 patients (60%) had histories of asthma or severeseasonal allergies. Patients 1, 3, 5, and 6 had increased serum IgEconcentrations at baseline (243, 1060, 2680, and 800 IU/mL,respectively; normal: 0Y100 IU/mL). Among the patients in thissubset, the IgE concentrations at 6 months were lower in eachcase: 115, 136, 1060, and 443 IU/mL, respectively.

Patients 2, 3, 5, 6, and 9 had peripheral eosinophilia at base-line, with total eosinophil counts of 0.67, 0.48, 1.31, 0.66, and0.51 � 103/mm3, respectively (normal: G0.1Y0.3). It is possiblethat baseline prednisone therapy suppressed peripheral eosino-philia in some patients, because Patients 1, 2Y4, 6, 9, and 10 wereon prednisone at baseline. Among the patients with peripheraleosinophilia at baseline, the eosinophil counts did not changesignificantly over the 6 months following RTX treatment.

Serial RTX TreatmentPatients 1, 2, 3, and 9 underwent more than 1 course of RTX.

Patients 1 and 3 were treated with serial RTX administrationbecause serum IgG4 concentrations rose steadily following B

FIGURE 5. IgG4 subclass concentrations from the time of diagnosis of IgG4-RD in Patient 1 (A) and Patient 2 (B) (time scales are notuniform or identical). Concentrations of IgG, IgA, and IgM and all IgG subclasses (IgG1, IgG2, IgG3, and IgG4) in both patients show nosignificant decline in any IgG subclass except IgG4.

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cell reconstitution and led to recurrent features of active disease.The disease course of Patient 1 was characterized by involvementof the thoracic and abdominal aorta, liver, pancreas, submandib-ular glands, and lymph nodes.18,22 On 3 separate occasions, heexperienced flares of liver disease within weeks of B cell recon-stitution. The flares were marked by increases in hepatic trans-aminase and alkaline phosphatase levels. Repeat courses of RTXled to progressive normalization in the serum IgG4 concentra-tion but stability of the total IgG and the other IgG subclasses.Following 3 successive cycles of B cell reconstitution, IgG4concentration elevation, and flares of cholangitis manifested byjaundice and abnormal liver function tests, we elected to treathim preemptively with a fourth RTX course. His serum IgG4concentration nadir was lower with each RTX administration (seeFigure 5).

Patient 3, whose disease was associated with lymphade-nopathy, thoracic aortitis, and an aortic dissection,30 was re-treated 3 times over a period of 18 months because of dramaticincreases in the serum IgG4 concentrations following B cell re-constitution, which led to concern about potential recurrentaortitis. In addition to the increase in serum IgG4 concentrationthat accompanied B cell reconstitution, he had a significant in-terval increase in lymphadenopathy at the time of flare.

Patients 2 and 9, both of whom had disease characterized bychronic sialadenitis and orbital pseudotumor, underwent repeatcourses of RTX (3 courses each). The serum IgG4 concentra-tions of Patient 2 declined with each RTX administration suchthat the IgG4 concentration returned to normal over a period of8 months following initial RTX administration. Follow-up imag-ing showed significant improvement in orbital and submandibu-lar gland disease. Patient 9 had sustained clinical improvement.Her serum IgG4 concentration was normal at baseline and re-mained so during follow-up.

Disease Activity Following B Cell ReconstitutionDisease flares following B cell reconstitution were the ex-

ception in the current study. As noted, disease flares occurred in2 patients following B cell reconstitution, and in 2 additionalpatients B cell depletion was maintained by serial RTX therapy.The other 6 patients maintained clinical disease remission fol-lowing B cell reconstitution despite discontinuing prednisone.The duration of follow-up for these 6 patients ranged from 4 to14 months, with a mean of 9.6 months, and the serum IgG4 con-centration in all 6 of these patients remained normal.

Response in Patients With Extensive FibrosisRTX was used in 2 patients (Patients 8, 10) whose dis-

ease was characterized primarily by widespread fibrosis. Thesepatients’ major disease manifestations included Riedel thyroid-itis (Patient 8) and retroperitoneal fibrosis (Patient 10). In bothcases, RTX was administered as an attempt to preserve organfunction. In the patient with Riedel thyroiditis,6 who also had ahistory of IgG4-RD involvement in the lungs, biliary tree, andlacrimal glands, progressive fibrosis of the thyroid gland extend-ing beyond the thyroid capsule threatened vital structures, includ-ing the airway. A positron emission tomography (PET) scanobtained before RTX showedmoderate, diffuse uptake throughoutthe enlarged thyroid gland. However, the patient’s fibrotic thyroiddisease progressed despite RTX, eventually necessitating a deli-cate operation to remove the entire thyroidgland. Therewas no signof IgG4-RD involving other organ systems after RTX.

In contrast, Patient 10 had a 10-year history of retroperi-toneal fibrosis, chronic ureteral stents, and chronic pain forwhich he was dependent on narcotics. An attempt to discontinue

his baseline prednisone dose of 10 mg/d had led to a disease flare2 years earlier, however, suggesting persistence of inflamma-tory disease. A PET scan performed before the administrationof RTX revealed low-level fluorodeoxyglucose (FDG) uptakein the periaortic soft tissue. Although the patient’s retroperito-neal fibrosis did not regress significantly following RTX, a PETscan demonstrated decreased FDG uptake. More importantly,the patient was able to discontinue prednisone and narcotics forthe first time in a decade, underwent successful removal of hisureteral stents, and maintained clinical improvement even afterB cell reconstitution.

Adverse EventsTwo major adverse events, occurring in Patients 5 and 7,

were observed in this series of 10 patients. Patient 5 suffered asignificant flare of asthma within hours of the first RTX infu-sion, requiring hospitalization. His symptoms were consistentwith either a cytokine-release syndrome caused by B cell lysis ora rate-related infusion reaction occurring in the setting of poorlycontrolled asthma. Because the reaction occurred during thefirst RTX administration, the reaction was not thought to be anIgE-mediated immediate hypersensitivity reaction. In general,RTX-associated hypersensitivity reactions occur after initial sen-sitization to the medication.32

Patient 7 suffered a reactivation of HBV. Before initiation ofRTX therapy, this patient was screened for HBV by measuringHBV surface antigen and antibody (HBsAg and HBsAb), neitherof which was detected. Two months after RTX infusion, he de-veloped acute increase in hepatic transaminases and was found tobe HBV core antigen (HBcAg) positive, consistent with HBVreactivation. At this point HBsAg turned positive. The hepatitis Breactivation was controlled successfully with tenofovir. The oc-currence of this adverse event led to the inclusion at our infusioncenter of testing for IgM and IgG antibodies to the HBcAg in allpatients before the administration of RTX.1,8

DISCUSSIONThe medical literature is now burgeoning with papers per-

taining to IgG4-RD, which is a disorder recognized only withinthe past decade and now acknowledged to impact most medi-cal specialties through its protean organ system manifestations.An analogy to sarcoidosis, another multiorgan system disease, isappropriate: regardless of the organ system involved, the histo-pathologic findings have only minor variations from tissue totissue.4,11,12,14 Despite the flourishing of case reports and theestablishment of new associations between clinical entities pre-viously known by names other than IgG4-RD, including Riedelthyroiditis,6 Kuttner tumor,9 and eosinophilic angiocentric fibro-sis,7 there remain relatively few data about treatment interventionsother than glucocorticoid therapy, and no prospective assessmentsof therapies in this condition.

The response to glucocorticoid treatment in IgG4-RD isusually swift and significant. Responsiveness to glucocorticoidsis actually one of the diagnostic criteria for autoimmune pancre-atitis, which is the pancreatic manifestation of IgG4-RD.3,27

Patients with IgG4-RD usually require long-term treatment withglucocorticoids. On the other hand, a substantial percentage ofpatients with IgG4-RD who respond promptly to glucocorticoidsrelapse over time, and many develop other organ system mani-festations of IgG4-RD.13,21 Kamisawa et al13 conducted a large,retrospective, multicenter study at 17 referral centers in Japan andevaluated the efficacy of glucocorticoid treatment in autoimmunepancreatitis. That study showed that approximately 30% of the

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patients treated with prednisone flared each year, such that at theend of a 3-year follow-up period, 92% had experienced diseaserelapse. Thus, steroid-sparing agents are required inmany patientsto manage the frequent disease relapses and avoid the long-termcomplications of prednisone. A variety of immunosuppressiveagents, including azathioprine and mycophenolate mofetil, andbiologic agents have been used to treat patients with refractory orrecurrent IgG4-RD.10,17,18,31 However, data regarding their ef-ficacy are derived from only a few retrospective case series andcase reports that have focused mainly on autoimmune pancrea-titis. These immunosuppressive medications have potentiallysignificant adverse effects. Infusion-related reaction and infec-tion are the most common reported risks associated with B celldepletion (RTX).16

The results of treatment with RTX in the current patientseries strongly suggest that B cell depletion is an effective strategyin many patients with IgG4-RD. Moreover, several specific les-sons related to the use of RTX in this patient population are clear.First, RTX has a strikingly targeted effect on the IgG4 subclass ofIgG. The present series confirms our earlier observation18 in bothpatients treated with RTX for the first time and in patients treatedserially with this medication: the IgG effect of the drug is on theIgG4 subclass alone. This suggests that RTX achieves its effectsin this setting by depleting the subset of CD20-positive B cellsthat differentiate into the short-lived plasma cells producing thedisease-associated IgG4. Whether or not IgG4 itself is patho-genic in this disease or simply an epiphenomenon related to otherprocesses remains to be determined.

Second, the current study confirms the utility of serumconcentrations of IgG4 as a biomarker in a subset of patientswith IgG4-RD. The disease flares observed in this series wereall associated with increases in the serum IgG4 concentrationsthat occurred after B cell reconstitution. This suggests that forpatients who demonstrate a propensity to flare, such as Patients 1and 3 in this study, repeat therapy after B cell reconstitution andIgG4 increase may be appropriate. The long-term effects ofpersistent B cell depletion are not clear and must be determinedthrough long-term follow-up studies in IgG4-RD and otherdiseases. However, data from studies in patients with rheumatoidarthritis indicate that serial treatments with RTX are toleratedwell.32 Although a decline in IgM concentration may be ob-served in rheumatoid arthritis patients treated with multiplecourses of RTX, infection rates did not increase in these patientsover the course of 3 years.30,31 In addition, no increased risk ofmalignancy was reported in 5013 patient-years of RTX expo-sure. Our experience indicates that repeated treatment cycleswith RTX lead to progressive decrease in serum IgG4 concen-trations. It is possible that the discontinuation of RTX in suchpatients might be accompanied by periods of normal serum IgG4concentrations and prolonged clinical quiescence in the absenceof treatment.

Third, treatment with RTXmay be effective even in patientswhose serum IgG4 concentration is not elevated. Patients 9 and10 achieved good treatment responses despite having normalserum IgG4 concentrations at baseline. However, for organ in-volvement characterized by the principal histopathologic find-ing of fibrosis (for example, Patient 8 with Riedel thyroiditis),B cell depletion is not likely to be effective in mediating clinicalimprovement in organ system function.

The availability of several therapies that target B cell func-tion either through depletion or modulation of B-lymphocytestimulator levels23 indicates that a variety of treatment optionsmight be attempted in IgG4-RD. In addition, treatments thattarget plasma cells may be of value in this condition.17 Con-sequently, clinical investigators will require tools to evaluate

treatment responses and to measure disease flares. The IgG4-RDActivity Index and Flare Tool that we employed retrospectivelyin these patients appears to have promise in this regard as acomprehensive, scalable measure of disease activity. Additionalexperience with this instrument in larger numbers of patients isimportant before widespread adoption. We are currently under-taking a formal validation procedure of the IgG4-RD ActivityIndex and Flare Tool.

In conclusion, B cell depletion strategies offer a promisingtreatment approach to IgG4-RD. Additional studies of RTX maylead to novel insights into the pathophysiologic mechanisms ofIgG4-RD and the pathways through which RTX achieves itseffects in other diseases in which IgG4 plays a significant role,such as idiopathic membranous nephropathy and pemphigusvulgaris.2,28 Establishing the most appropriate strategies for em-ploying B cell depletion in IgG4-RD requires further study andcomparison to other interventions focused on the modulation ofB cell and plasma cell function.

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