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 infusions 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 applied 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 patient 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 proFrom Rheumatology Unit (AK, MNC, SU, DBB, JHS), Division of Rheumatology, Allergy, and Immunology, Department of Medicine; and Department 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

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gressive declines in serum IgG4 concentrations and better disease control. Serum IgG4 concentrations may remain low, and clinical disease activity may remain quiescent even after B cell reconstitution in a significant 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 fibroinflammatory 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, salivary and lacrimal glands, thyroid gland, kidneys, pachymeninges, pituitary gland, prostate, breast, and other organs.19,29 The different organs affected by IgG4-RD can be involved simultaneously, but involvement is often observed to be metachronous, 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 derived primarily from experience with autoimmune pancreatitis. Several reports emphasize that serum IgG4 concentrations decline 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 antirheumatic drugs (DMARDs) as steroid-sparing agents are limited 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 www.md-journal.com

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striking finding in this early experience was the targeted effect of B cell depletion on the IgG4 subclass alone. Although IgG4 concentrations declined dramatically and correlated with clinical improvement, the other IgG subclass concentrations were unaffected by this intervention. The long-term therapeutic response for IgG4-RD patients treated with RTX is not known. In addition, the effects of serial RTX treatments in this population have not been reported, and the number of patients with IgG4-RD treated with RTX reported in the literature to date remains small. The medical literature currently provides no guidance regarding which types of patients with IgG4-RD are likely to respond to B cell depletion or which disease characteristics augur poor treatment responses. We report our experience with 10 consecutive IgG4-RD patients treated with RTX. Follow-up is now available on patients as long as 24 months after initial RTX treatment. Four patients have undergone more than 1 RTX course. In addition to reporting the responses to treatment in 10 patients, including the results of repeated RTX administrations, we report our experience with the development and retrospective use of a disease activity index and flare tool in this group of patients. (For more on IgG4-RD, see the article in this same issue by Ebbo et al7a describing their experience with a French national registry.)

PATIENTS AND METHODS Informed Consent All patients were enrolled in the Massachusetts General Hospital IgG4-RD Registry and gave informed consent for inclusion in a formal treatment protocol. Both the registry and the longitudinal treatment protocol were approved by our institutional review board. All patients featured in figures gave permission for the specific figures to be published.

Inclusion Criteria Patients were eligible to participate in the study if they had clinical diagnoses of IgG4-RD and the pathologic features of IgG4-RD on a tissue biopsy (see below).4,12 Clinical diagnoses were predicated upon organ involvement in a pattern consistent with IgG4-RD, including dysfunction of 1 of the following 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); and thyroid gland (Riedel thyroiditis). Histopathologic features considered to be highly suggestive of IgG4-RD included lymphoplasmacytic infiltrates and fibrosclerosis within involved organs. Obliterative phlebitis and mild to moderate tissue eosinophilia were observed often but were not required for the diagnosis.33 In addition, all patients had either an IgG4/IgG plasma cell ratio of 950% within the affected organs and/or 930 IgG4-bearing plasma cells per high-power field (hpf) (Figure 1). All patients included had disease courses that were refractory to prednisone treatment of at least 2 months’ duration. The only exception to this was Patient 7, who was treated with RTX plus daily glucocorticoids from the outset because of the aggressive and destructive nature of his disease (aortitis leading to 2 sequential aneurysms).

IgG4 Plasma Cell Quantitation We quantified the degree of IgG4+ plasma cell infiltration within biopsy specimens by the following methods. Immunohistochemical studies were performed on formalin-fixed, paraffinembedded tissue sections using antibodies to IgG4 (Zymed, 1:200 dilution) and IgG (Dako, 1:3000 dilution). For each case,

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the number of plasma cells staining for IgG4 was assessed in 3 non-overlapping high-power fields (400). The 3 fields with the highest degree of IgG4 reactivity were selected for quantitation. The number of IgG4+ plasma cells was then divided by the total number of IgG-bearing plasma cells in these fields.

Serum IgG4 Assay Serum IgG4 concentrations were measured by nephelometry (Mayo Medical Laboratories New England; Andover, MA).

RTX Treatment Protocol Patients received 2 intravenous doses of RTX 1000 mg separated by 15 days. Methylprednisolone (100 mg) as well as diphenhydramine (25 mg) and acetaminophen (650 mg) were administered with each RTX infusion to decrease the likelihood of infusion reactions. Patients who experienced disease flares after the return of their B cells were treated again with the same RTX induction protocol.

Glucocorticoid Tapering Patients on prednisone at the time of RTX initiation had the glucocorticoids tapered at the discretion of the treating physician, with the goal of discontinuing prednisone completely by 2 months. The prednisone taper generally took longer in most patients who had been on chronic glucocorticoid therapy because of potential adrenal insufficiency. Cumulative glucocorticoid doses and the mean time to prednisone discontinuation were calculated for each patient.

Follow-Up Visits Patients were evaluated monthly for the first 3 months after completion of the RTX infusions, and most patients were evaluated every 3 months thereafter.

Baseline Hematologic and Serologic Assessments All patients underwent complete blood counts with differential assessments of the white blood cell count, to detect eosinophilia. Serial serum samples were tested for total IgG and IgG subclasses IgG1, IgG2, IgG3, and IgG4; for IgM, IgA, and IgE; and the acute-phase reactants C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Patients also underwent testing for rheumatoid factor by nephelometry, antinuclear antibody (ANA) testing by immunofluorescence using the HEp-2 substrate, and ELISA testing for antibodies against the Ro, La, Sm, and RNP antigens.

Imaging Studies Imaging studies were performed according to the specific pattern of clinical organ involvement. These studies were repeated as clinically appropriate every 6 months to assess response to therapy in most patients.

Clinical Assessments Disease activity was assessed by clinical criteria, which included improvement in patients’ symptoms, resolution or amelioration of physical findings, serial testing of serum IgG4 concentrations, acute-phase reactant measurements, improvement on imaging studies, and ability to taper prednisone successfully.

Disease Activity Index and Flare Tool We developed the IgG4-RD Activity Index and Flare Tool for use in clinical trials. (See the Appendix available online as Supplemental Digital Content, http://links.lww.com/MD/A9). We applied this instrument retrospectively to all patients who had a minimum of 6 months’ follow-up (n = 9; 90%). Using the IgG4-RD Activity Index and Flare Tool, we defined 3 response measures: disease response, complete remission, * 2012 Lippincott Williams & Wilkins

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FIGURE 1. Selected pathologic features from 10 patients with IgG4-related disease (IgG4-RD). Images on the left are microphotographs from hematoxylin and eosin stained slides. Those on the right are images from the corresponding immunohistochemical slide for IgG4. A & B. Cutaneous IgG4-RD showing a nodular lymphoplasmacytic infiltrate in the superficial and deep dermis with large numbers 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 stain on tissue corresponding to panel E. The majority of plasma cells are immunoreactive for IgG4. EThis figure can be viewed in color online at http://www.md-journal.com.^

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

CASE SUMMARY We provide here a short summary of a patient with an instructive course who has not been reported elsewhere in the medical literature.

Patient 5 A 59-year-old man with severe asthma presented with a more than 40 year history of recurrent cervical lymphadenopa* 2012 Lippincott Williams & Wilkins

thy. He underwent multiple lymph node biopsies, with pathology interpreted as being consistent with ‘‘reactive lymphoid hyperplasia,’’ and endured many negative evaluations for hematologic malignancy. His clinical course had also been characterized by submandibular gland enlargement. Recurrence of an enlarged right submandibular lymph node 1 year before presentation led to another full evaluation for the purpose of excluding Castleman disease. A computed tomography (CT) scan of the head, neck, and chest (Figure 2) revealed extensive mediastinal, hilar, and axillary lymphadenopathy. A biopsy of the submandibular lymph node revealed a lymphoplasmacytic infiltrate with scattered eosinophils. The plasma cells within the lymph node stained intensely for IgG4, with a ratio of IgG4-positive cells to total IgG-positive cells of 90.50. The serum IgG4 concentration was 894 mg/dL (5Y140 mg/dL). Because the patient had already undergone numerous courses of prednisone for coexisting asthma without significant improvement in lymphadenopathy and suffered from obesity, we elected to treat him with RTX. The patient’s first RTX infusion was complicated by a severe asthma attack that began hours after the infusion was complete www.md-journal.com

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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 months after RTX treatment.

and required hospitalization (see Adverse Events, below). Aggressive treatment of the asthma during the next 2 weeks permitted successful administration of the second dose of RTX. Within 1 month of the initial RTX treatment, his serum IgG4 concentration had declined from 894 mg/dL to 368 mg/dL (normal: 5Y140 mg/dL). A repeat chest CT scan 6 months after RTX demonstrated significant interval decrease in the lymphadenopathy (see Figure 2). Ten months after his RTX treatment, his B-cell pool had undergone reconstitution but his serum IgG4 concentration decreased to normal levels (84.5 mg/dL), despite the absence of any glucocorticoid treatment during that period. Of note, the patient’s asthma has been well controlled since treatment with RTX.

RESULTS Baseline Characteristics The patients’ baseline characteristics are shown in Table 1.

Extent of Organ Involvement The patients’ history of organ involvement is summarized in Table 2. The diagnosis was confirmed by biopsy in all 10 patients, and tissue was available from multiple sites in 4. The pathologic characteristics and immunohistochemical findings are summarized in Table 3. The patients experienced a broad range of organ involvement, and multiple organ system involvement in individual patients was common (n = 7; 70%). The most commonly involved organ was the eye (n = 5) (Figure 3).

Orbital disease included dacryoadenitis, orbital myositis, orbital inflammatory pseudotumor, and extension from the orbit to involve the trigeminal nerve. Four patients presented with chronic sclerosing sialadenitis involving the parotid and submandibular glands. Aortitis, sometimes associated with retroperitoneal fibrosis, was the cardinal manifestation in 3 patients. All 3 patients with IgG4-related aortitis required surgical repair of the aorta, illustrating the potentially tissue-destructive nature of the IgG4-RD lesion. Diffuse lymphadenopathy was detected in 3 patients, leading to multiple sequential lymph node biopsies to exclude lymphoma and other conditions.

Serologic Abnormalities All 10 patients (100%) had positive ANA assays, 3 with titers Q1:640 (1:640, 1:1280, and 1:5120, respectively). The patient with the highest ANA titer (Patient 9) had a centromere pattern of immunofluorescence but no clinical features of limited systemic sclerosis. None of the other patients had specific autoantibodies characteristic of particular immune-mediated conditions. Patient 3 was rheumatoid factor positive (50 IU/mL; normal: G30 IU/mL). Eight of the 10 patients (80%) had elevated ESRs (range, 35Y111 mm/h).

Glucocorticoid Tapering Prednisone had been a chronic treatment for years in 5 of the 6 patients who were receiving glucocorticoids at the time of RTX initiation (Table 4). Four patients were not receiving prednisone at the time of entry: Patients 4 and 6 stopped prednisone

TABLE 1. Baseline Characteristics of 10 Patients With IgG4-Related Disease Patient Age (yr) Sex Race/Ethnicity* Asthma/Allergy Eosinophilia 1 2 3 4 5 6 7 8 9 10

76 55 67 72 59 56 61 40 57 59

M M M F M M M F F M

W W W W W W A-C W W W

Y Y Y Y Y Y N N N N

N Y Y N Y Y N N Y N

ANA† + 1:40 S + 1:160 S + 1:1280 S + 1:320 S + 1:40 S + 1:640 H + 1:40 S + 1:160 S + 1:5120 C + 1:40 S

Serum IgG4 Other ESR (mm/h) Level (mg/dL) Elevated Ig 111 13 62 52 7 37 108 71 55 35

92000 1560 688 1140 894 670 365 70.8 58 22.9

IgE IgE IgG3 IgE IgE, IgG2 IgG1

*W = white, A-C = Afro-Caribbean. †S = speckled, H = homogeneous, C = centromere.

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

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

Orbital involvement Sialadenitis Lymphadenopathy Aortitis Sclerosing cholangitis Retroperitoneal fibrosis Pulmonary involvement Autoimmune pancreatitis Riedel thyroiditis Cutaneous nodule

5 (50) (Pt 2, 4, 6, 8, 9) 4 (40) (Pt 1, 2, 4, 9) 3 (30) (Pt 1, 3, 5) 3 (30) (Pt 1, 3, 7) 2 (20) (Pt 1, 8) 2 (20) (Pt 1, 10) 1 (10) (Pt 8) 1 (10) (Pt 1) 1 (10) (Pt 8) 1 (10) (Pt 4)

4 and 2 weeks before the RTX infusions, respectively, and Patients 5 and 8 completed trials of prednisone months before RTX treatment. Following the administration of RTX, all patients tapered their baseline prednisone doses and stopped DMARDs. The prednisone taper was conducted slowly to avoid adrenal insufficiency in patients on long-standing glucocorticoid therapy. The mean time to prednisone discontinuation from the first RTX infusion was 5.3 months (range, 1Y9 mo).

Response to Treatment Nine (90%) of 10 patients demonstrated substantial clinical improvement within 1 month of RTX therapy. Discontinuation of both prednisone and DMARDs was achieved in all 10 patients. Patients 1 and 3 suffered disease recurrences approximately 6 months after RTX treatment and experienced a total of 4 disease flares between them. Flares were characterized by symptom recurrence or serum IgG4 elevations. Each disease flare occurred in the setting of reconstituted B cells and rising serum IgG4 concentrations. All disease flares responded promptly to repeat courses of RTX. The only patient who required glucocorticoid treatment for disease flare was Patient 1; his cholangi-

FIGURE 3. Clinical pictures of Patients 2, 4, and 6 with IgG4-related orbital involvement and dacryoadenitis. EThis figure can be viewed in color online at http://www.md-journal.com.^

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

IgG4-RD Activity Index and Flare Tool We retrospectively applied a Disease Activity Index to the 10 patients in the study (see Table 4). Nine (90%) of 10 patients

TABLE 3. Pathologic Characteristics of 10 Patients Patient 1 2 3 4 5 6 7 8

9 10

Organ Affected

Lymphoplasmacytic Infiltrate

Storiform Fibrosis

Obliterative Phlebitis

Tissue Eosinophilia

IgG4/total IgG Ratio in Tissue (%)

IgG4+ in Tissue (Cells/hpf)

Liver Aorta Salivary gland Aorta LN Skin Lacrimal gland LN Lacrimal gland Aorta Thyroid LN Lung Lacrimal gland Ampulla Parotid gland Retroperitoneum

Y Y Y Y Y Y Y Y Y Y Y Y Y Y

Y Y N Y N N N N Y N Y N Y Y

Y N N Y N N N N N N N N Y Y

N N Y N N Y Y Y Y N N N Y Y

37

Y Y

Y Y

N N

Y N

92 82 80 72 950 95 90 989 93 950 80 83 87 44 NA 100 50

121 30 NA 210 126 320 153 52 8 110 13 11 12 369 4

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

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TABLE 4. Response to Treatment Patient 1

Treatment Before RTX Prednisone (3 yr) Azathioprine(2 mo) Mycophenolate mofetil (18 mo) 6-mercaptopurine (1 mo) Prednisone (4 yr) Methotrexate (4 yr) Prednisone (1 yr) Prednisone (1 yr) Prednisone (2 mo) Prednisone (20 yr) Methotrexate (1 yr) Mycophenolate mofetil (1 mo) Prednisone (1 mo) Prednisone (4 mo) Tamoxifen (2 yr) Prednisone (18 mo) Methotrexate (1 yr) Prednisone (10 yr)

2 3 4 5 6

7 8 9 10

Prednisone Dose at Entry

Disease Activity Score* Before RTX

Courses of RTX (no.)

Disease Activity Score* After RTX

10 mg

14

4

1

10 mg

5

3

0

10 mg 0 0 0

6 6 3 3

3 1 1 1

2 1 0 1

60 mg 0

4 6

1 1

0 3

10 mg

2

3

0

10 mg

1

1

0

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

achieved ‘‘disease responses,’’ defined as improvement in IgG4-RD Activity Index 92 points after RTX therapy. Four of 8 patients who had 6 months’ follow-up (Patients 2, 5, 7, 10) achieved complete remission at 6 months, with IgG4-RD Activity Index scores of 0 and no prednisone use. For the 2 patients who experienced disease flares, the Flare Tool showed flares of mild to moderate severity in both.

Serologic and Hematologic Responses Clinical improvements following RTX administration correlated with rapid declines in serum IgG4 concentrations. Seven patients 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 IgG4 concentrations declined by a mean of 46% within 2 months of RTX administration (Figure 4). The reduction in IgG levels was observed only in the IgG4 subclass (Figure 5). Minor elevations of the IgG1, IgG2, or IgG3 subclasses were observed inconsistently in 3 patients at baseline (see Table 1), but these concentrations were not affected significantly by RTX therapy. Among the patients who did not experience disease recurrences, serum IgG4 concentrations remained low. Of note, at a mean follow-up of 14.3 months (range, 4Y24 mo), all patients had 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 the serum IgG4 concentrations 2 month before rituximab treatment to 12 months after treatment (time scale is not uniform).

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FIGURE 5. IgG4 subclass concentrations from the time of diagnosis of IgG4-RD in Patient 1 (A) and Patient 2 (B) (time scales are not uniform or identical). Concentrations of IgG, IgA, and IgM and all IgG subclasses (IgG1, IgG2, IgG3, and IgG4) in both patients show no significant decline in any IgG subclass except IgG4.

both of whom experienced disease flares. Even in Patients 1 and 3, however, the serum concentrations of IgG4 were 174 mg/dL and 216 mg/dL, respectively, that is, almost 10 times lower than before treatment with RTX.

Prevalence of Atopy, IgE Concentrations, and Eosinophilia and Response to Treatment Six of 10 patients (60%) had histories of asthma or severe seasonal allergies. Patients 1, 3, 5, and 6 had increased serum IgE concentrations at baseline (243, 1060, 2680, and 800 IU/mL, respectively; normal: 0Y100 IU/mL). Among the patients in this subset, the IgE concentrations at 6 months were lower in each case: 115, 136, 1060, and 443 IU/mL, respectively. * 2012 Lippincott Williams & Wilkins

Patients 2, 3, 5, 6, and 9 had peripheral eosinophilia at baseline, with total eosinophil counts of 0.67, 0.48, 1.31, 0.66, and 0.51  103/mm3, respectively (normal: G0.1Y0.3). It is possible that baseline prednisone therapy suppressed peripheral eosinophilia in some patients, because Patients 1, 2Y4, 6, 9, and 10 were on prednisone at baseline. Among the patients with peripheral eosinophilia at baseline, the eosinophil counts did not change significantly over the 6 months following RTX treatment.

Serial RTX Treatment Patients 1, 2, 3, and 9 underwent more than 1 course of RTX. Patients 1 and 3 were treated with serial RTX administration because serum IgG4 concentrations rose steadily following B www.md-journal.com

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cell reconstitution and led to recurrent features of active disease. The disease course of Patient 1 was characterized by involvement of the thoracic and abdominal aorta, liver, pancreas, submandibular glands, and lymph nodes.18,22 On 3 separate occasions, he experienced flares of liver disease within weeks of B cell reconstitution. The flares were marked by increases in hepatic transaminase and alkaline phosphatase levels. Repeat courses of RTX led to progressive normalization in the serum IgG4 concentration but stability of the total IgG and the other IgG subclasses. Following 3 successive cycles of B cell reconstitution, IgG4 concentration elevation, and flares of cholangitis manifested by jaundice and abnormal liver function tests, we elected to treat him preemptively with a fourth RTX course. His serum IgG4 concentration nadir was lower with each RTX administration (see Figure 5). Patient 3, whose disease was associated with lymphadenopathy, thoracic aortitis, and an aortic dissection,30 was retreated 3 times over a period of 18 months because of dramatic increases in the serum IgG4 concentrations following B cell reconstitution, which led to concern about potential recurrent aortitis. In addition to the increase in serum IgG4 concentration that accompanied B cell reconstitution, he had a significant interval increase in lymphadenopathy at the time of flare. Patients 2 and 9, both of whom had disease characterized by chronic sialadenitis and orbital pseudotumor, underwent repeat courses of RTX (3 courses each). The serum IgG4 concentrations of Patient 2 declined with each RTX administration such that the IgG4 concentration returned to normal over a period of 8 months following initial RTX administration. Follow-up imaging showed significant improvement in orbital and submandibular gland disease. Patient 9 had sustained clinical improvement. Her serum IgG4 concentration was normal at baseline and remained so during follow-up.

Disease Activity Following B Cell Reconstitution Disease flares following B cell reconstitution were the exception in the current study. As noted, disease flares occurred in 2 patients following B cell reconstitution, and in 2 additional patients B cell depletion was maintained by serial RTX therapy. The other 6 patients maintained clinical disease remission following B cell reconstitution despite discontinuing prednisone. The duration of follow-up for these 6 patients ranged from 4 to 14 months, with a mean of 9.6 months, and the serum IgG4 concentration in all 6 of these patients remained normal.

Response in Patients With Extensive Fibrosis RTX was used in 2 patients (Patients 8, 10) whose disease was characterized primarily by widespread fibrosis. These patients’ major disease manifestations included Riedel thyroiditis (Patient 8) and retroperitoneal fibrosis (Patient 10). In both cases, RTX was administered as an attempt to preserve organ function. In the patient with Riedel thyroiditis,6 who also had a history of IgG4-RD involvement in the lungs, biliary tree, and lacrimal glands, progressive fibrosis of the thyroid gland extending beyond the thyroid capsule threatened vital structures, including the airway. A positron emission tomography (PET) scan obtained before RTX showed moderate, diffuse uptake throughout the enlarged thyroid gland. However, the patient’s fibrotic thyroid disease progressed despite RTX, eventually necessitating a delicate operation to remove the entire thyroid gland. There was no sign of IgG4-RD involving other organ systems after RTX. In contrast, Patient 10 had a 10-year history of retroperitoneal fibrosis, chronic ureteral stents, and chronic pain for which he was dependent on narcotics. An attempt to discontinue

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his baseline prednisone dose of 10 mg/d had led to a disease flare 2 years earlier, however, suggesting persistence of inflammatory disease. A PET scan performed before the administration of RTX revealed low-level fluorodeoxyglucose (FDG) uptake in the periaortic soft tissue. Although the patient’s retroperitoneal fibrosis did not regress significantly following RTX, a PET scan demonstrated decreased FDG uptake. More importantly, the patient was able to discontinue prednisone and narcotics for the first time in a decade, underwent successful removal of his ureteral stents, and maintained clinical improvement even after B cell reconstitution.

Adverse Events Two major adverse events, occurring in Patients 5 and 7, were observed in this series of 10 patients. Patient 5 suffered a significant flare of asthma within hours of the first RTX infusion, requiring hospitalization. His symptoms were consistent with either a cytokine-release syndrome caused by B cell lysis or a rate-related infusion reaction occurring in the setting of poorly controlled asthma. Because the reaction occurred during the first RTX administration, the reaction was not thought to be an IgE-mediated immediate hypersensitivity reaction. In general, RTX-associated hypersensitivity reactions occur after initial sensitization to the medication.32 Patient 7 suffered a reactivation of HBV. Before initiation of RTX therapy, this patient was screened for HBV by measuring HBV surface antigen and antibody (HBsAg and HBsAb), neither of which was detected. Two months after RTX infusion, he developed acute increase in hepatic transaminases and was found to be HBV core antigen (HBcAg) positive, consistent with HBV reactivation. At this point HBsAg turned positive. The hepatitis B reactivation was controlled successfully with tenofovir. The occurrence of this adverse event led to the inclusion at our infusion center of testing for IgM and IgG antibodies to the HBcAg in all patients before the administration of RTX.1,8

DISCUSSION The medical literature is now burgeoning with papers pertaining to IgG4-RD, which is a disorder recognized only within the past decade and now acknowledged to impact most medical specialties through its protean organ system manifestations. An analogy to sarcoidosis, another multiorgan system disease, is appropriate: regardless of the organ system involved, the histopathologic findings have only minor variations from tissue to tissue.4,11,12,14 Despite the flourishing of case reports and the establishment of new associations between clinical entities previously known by names other than IgG4-RD, including Riedel thyroiditis,6 Ku¨ttner tumor,9 and eosinophilic angiocentric fibrosis,7 there remain relatively few data about treatment interventions other than glucocorticoid therapy, and no prospective assessments of therapies in this condition. The response to glucocorticoid treatment in IgG4-RD is usually swift and significant. Responsiveness to glucocorticoids is actually one of the diagnostic criteria for autoimmune pancreatitis, which is the pancreatic manifestation of IgG4-RD.3,27 Patients with IgG4-RD usually require long-term treatment with glucocorticoids. On the other hand, a substantial percentage of patients with IgG4-RD who respond promptly to glucocorticoids relapse over time, and many develop other organ system manifestations of IgG4-RD.13,21 Kamisawa et al13 conducted a large, retrospective, multicenter study at 17 referral centers in Japan and evaluated the efficacy of glucocorticoid treatment in autoimmune pancreatitis. That study showed that approximately 30% of the * 2012 Lippincott Williams & Wilkins

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patients treated with prednisone flared each year, such that at the end of a 3-year follow-up period, 92% had experienced disease relapse. Thus, steroid-sparing agents are required in many patients to manage the frequent disease relapses and avoid the long-term complications of prednisone. A variety of immunosuppressive agents, including azathioprine and mycophenolate mofetil, and biologic agents have been used to treat patients with refractory or recurrent IgG4-RD.10,17,18,31 However, data regarding their efficacy are derived from only a few retrospective case series and case reports that have focused mainly on autoimmune pancreatitis. These immunosuppressive medications have potentially significant adverse effects. Infusion-related reaction and infection are the most common reported risks associated with B cell depletion (RTX).16 The results of treatment with RTX in the current patient series strongly suggest that B cell depletion is an effective strategy in many patients with IgG4-RD. Moreover, several specific lessons related to the use of RTX in this patient population are clear. First, RTX has a strikingly targeted effect on the IgG4 subclass of IgG. The present series confirms our earlier observation18 in both patients treated with RTX for the first time and in patients treated serially with this medication: the IgG effect of the drug is on the IgG4 subclass alone. This suggests that RTX achieves its effects in this setting by depleting the subset of CD20-positive B cells that differentiate into the short-lived plasma cells producing the disease-associated IgG4. Whether or not IgG4 itself is pathogenic in this disease or simply an epiphenomenon related to other processes remains to be determined. Second, the current study confirms the utility of serum concentrations of IgG4 as a biomarker in a subset of patients with IgG4-RD. The disease flares observed in this series were all associated with increases in the serum IgG4 concentrations that occurred after B cell reconstitution. This suggests that for patients who demonstrate a propensity to flare, such as Patients 1 and 3 in this study, repeat therapy after B cell reconstitution and IgG4 increase may be appropriate. The long-term effects of persistent B cell depletion are not clear and must be determined through long-term follow-up studies in IgG4-RD and other diseases. However, data from studies in patients with rheumatoid arthritis indicate that serial treatments with RTX are tolerated well.32 Although a decline in IgM concentration may be observed in rheumatoid arthritis patients treated with multiple courses of RTX, infection rates did not increase in these patients over the course of 3 years.30,31 In addition, no increased risk of malignancy was reported in 5013 patient-years of RTX exposure. Our experience indicates that repeated treatment cycles with RTX lead to progressive decrease in serum IgG4 concentrations. It is possible that the discontinuation of RTX in such patients might be accompanied by periods of normal serum IgG4 concentrations and prolonged clinical quiescence in the absence of treatment. Third, treatment with RTX may be effective even in patients whose serum IgG4 concentration is not elevated. Patients 9 and 10 achieved good treatment responses despite having normal serum IgG4 concentrations at baseline. However, for organ involvement characterized by the principal histopathologic finding of fibrosis (for example, Patient 8 with Riedel thyroiditis), B cell depletion is not likely to be effective in mediating clinical improvement in organ system function. The availability of several therapies that target B cell function either through depletion or modulation of B-lymphocyte stimulator levels23 indicates that a variety of treatment options might be attempted in IgG4-RD. In addition, treatments that target plasma cells may be of value in this condition.17 Consequently, clinical investigators will require tools to evaluate * 2012 Lippincott Williams & Wilkins

Rituximab for Treatment of IgG4-Related Disease

treatment responses and to measure disease flares. The IgG4-RD Activity Index and Flare Tool that we employed retrospectively in these patients appears to have promise in this regard as a comprehensive, scalable measure of disease activity. Additional experience with this instrument in larger numbers of patients is important before widespread adoption. We are currently undertaking a formal validation procedure of the IgG4-RD Activity Index and Flare Tool. In conclusion, B cell depletion strategies offer a promising treatment approach to IgG4-RD. Additional studies of RTX may lead to novel insights into the pathophysiologic mechanisms of IgG4-RD and the pathways through which RTX achieves its effects in other diseases in which IgG4 plays a significant role, such as idiopathic membranous nephropathy and pemphigus vulgaris.2,28 Establishing the most appropriate strategies for employing B cell depletion in IgG4-RD requires further study and comparison to other interventions focused on the modulation of B cell and plasma cell function. REFERENCES 1. Artz AS, Somerfield MR, Feld JJ, Giusti AF, Kramer BS, Sabichi AL, et al. American Society of Clinical Oncology provisional clinical opinion: chronic hepatitis B virus infection screening in patients receiving cytotoxic chemotherapy for treatment of malignant diseases. J Clin Oncol. 2010;28:3199Y3202. 2. Beck LH Jr, Bonegio RG, Lambeau G, Beck DM, Powell DW, Cummins TD, et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med. 2009;361:11Y21. 3. Chari ST, Smyrk TC, Levy MJ, Topazian MD, Takahashi N, Zhang L, et al. Diagnosis of autoimmune pancreatitis: the Mayo Clinic experience. Clin Gastroenterol Hepatol. 2006;4: 1010Y1016. 4. Cheuk W, Chan JK. IgG4-related sclerosing disease: a critical appraisal of an evolving clinicopathologic entity. Adv Anat Pathol. 2010;17:303Y332. 5. Church NI, Pereira SP, Deheragoda MG, Sandanayake N, Amin Z, Lees WR, et al. Autoimmune pancreatitis: clinical and radiological features and objective response to steroid therapy in a UK series. Am J Gastroenterol. 2007;102:2417Y2425. 6. Dahlgren M, Khosroshahi A, Nielsen GP, Deshpande V, Stone JH. Riedel’s thyroiditis and multifocal fibrosclerosis are part of the IgG4-related systemic disease spectrum. Arthritis Care Res (Hoboken). 2010;62:1312Y1318. 7. Deshpande V, Khosroshahi A, Nielsen GP, Hamilos DL, Stone JH. Eosinophilic angiocentric fibrosis is a form of IgG4-related systemic disease. Am J Surg Pathol. 2011;35:701Y706. 7a. Ebbo M, Daniel L, Pavic M, Seve P, Hamidou M, Andres E, Burtey S, Chiche L, Serratrice J, Longy-Boursier M, Ruivard M, Haroche J, Godeau B, Beucher AB, Berthelot JM, Papo T, Pennaforte JL, Benyamine A, Jourde N, Landron C, Roblot P, Moranne M, Silvain C, Granel B, Bernard F, Veit V, Mazodier K, Bernit E, Rousset H, Boucraut J, Boffa JJ, Weiller PJ, Kaplanski G, Aucouturier P, Harle JR, Schleinitz N. IgG4-related systemic disease: features and treatment response in a French cohort: results of a multicenter registry. Medicine (Baltimore). 2012;91:49Y56. 8. Ferri C, Govoni M, Calabrese L. The A, B, Cs of viral hepatitis in the biologic era. Curr Opin Rheumatol. 2010;22:443Y450. 9. Geyer JT, Ferry JA, Harris NL, Stone JH, Zukerberg LR, Lauwers GY, et al. Chronic sclerosing sialadenitis (Kuttner tumor) is an IgG4-associated disease. Am J Surg Pathol. 2010;34:202Y210. 10. Ghazale A, Chari ST. Optimising corticosteroid treatment for autoimmune pancreatitis. Gut. 2007;56:1650Y1652.

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11. Kamisawa T, Funata N, Hayashi Y, Eishi Y, Koike M, Tsuruta K, et al. A new clinicopathological entity of IgG4-related autoimmune disease. J Gastroenterol. 2003;38:982Y984. 12. Kamisawa T, Okamoto A. Autoimmune pancreatitis: proposal of IgG4-related sclerosing disease. J Gastroenterol. 2006;41:613Y625. 13. Kamisawa T, Shimosegawa T, Okazaki K, Nishino T, Watanabe H, Kanno A, et al. Standard steroid treatment for autoimmune pancreatitis. Gut. 2009;58:1504Y1507. 14. Kamisawa T, Takuma K, Egawa N, Tsuruta K, Sasaki T. Autoimmune pancreatitis and IgG4-related sclerosing disease. Nat Rev Gastroenterol Hepatol. 2010;7:401Y409. 15. Kamisawa T, Yoshiike M, Egawa N, Nakajima H, Tsuruta K, Okamoto A. Treating patients with autoimmune pancreatitis: results from a long-term follow-up study. Pancreatology. 2005;5:234Y238; discussion 238-240. 16. Keystone E, Fleischmann R, Emery P, Furst DE, van Vollenhoven R, Bathon J, et al. Safety and efficacy of additional courses of rituximab in patients with active rheumatoid arthritis: an open-label extension analysis. Arthritis Rheum. 2007;56:3896Y3908. 17. Khan ML, Colby TV, Viggiano RW, Fonseca R. Treatment with bortezomib of a patient having hyper IgG4 disease. Clin Lymphoma Myeloma Leuk. 2010;10:217Y219. 18. Khosroshahi A, Bloch DB, Deshpande V, Stone JH. Rituximab therapy leads to rapid decline of serum IgG4 levels and prompt clinical improvement in IgG4-related systemic disease. Arthritis Rheum. 2010;62:1755Y1762. 19. Khosroshahi A, Stone JH. A clinical overview of IgG4-related systemic disease. Curr Opin Rheumatol. 2011;23:57Y66. 20. Khosroshahi A, Stone JH. IgG4-related systemic disease: the age of discovery. Curr Opin Rheumatol. 2011;23:72Y73. 21. Khosroshahi A, Stone JH. Treatment approaches to IgG4-related systemic disease. Curr Opin Rheumatol. 2011;23:67Y71. 22. Khosroshahi A, Stone JR, Pratt DS, Deshpande V, Stone JH. Painless jaundice with serial multi-organ dysfunction. Lancet. 2009;373:1494.

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23. Liu Z, Davidson A. BAFF inhibition: A new class of drugs for the treatment of autoimmunity. Exp Cell Res. 2011;317:1270Y1277. 24. Matsushita M, Ikeura T, Fukui T, Uchida K, Okazaki K. Refractory autoimmune pancreatitis: azathioprine or steroid pulse therapy? Am J Gastroenterol. 2008;103:1834; author reply 1834Y1835. 25. Naitoh I, Nakazawa T, Ohara H, Sano H, Ando T, Hayashi K, et al. Autoimmune pancreatitis associated with various extrapancreatic lesions during a long-term clinical course successfully treated with azathioprine and corticosteroid maintenance therapy. Intern Med. 2009;48:2003Y2007. 26. Okazaki K, Kawa S, Kamisawa T, Ito T, Inui K, Irie H, et al. Japanese clinical guidelines for autoimmune pancreatitis. Pancreas. 2009;38:849Y866. 27. Otsuki M, Chung JB, Okazaki K, Kim MH, Kamisawa T, Kawa S, et al. Asian diagnostic criteria for autoimmune pancreatitis: consensus of the Japan-Korea Symposium on Autoimmune Pancreatitis. J Gastroenterol. 2008;43:403Y408. 28. Rock B, Martins CR, Theofilopoulos AN, Balderas RS, Anhalt GJ, Labib RS, et al. The pathogenic effect of IgG4 autoantibodies in endemic pemphigus foliaceus (fogo selvagem). N Engl J Med. 1989;320:1463Y1469. 29. Smyrk TC. Pathological features of IgG4-related sclerosing disease. Curr Opin Rheumatol. 2011;23:74Y79. 30. Stone JH, Khosroshahi A, Hilgenberg A, Spooner A, Isselbacher EM, Stone JR. IgG4-related systemic disease and lymphoplasmacytic aortitis. Arthritis Rheum. 2009;60:3139Y3145. 31. Topazian M, Witzig TE, Smyrk TC, Pulido JS, Levy MJ, Kamath PS, et al. Rituximab therapy for refractory biliary strictures in immunoglobulin G4-associated cholangitis. Clin Gastroenterol Hepatol. 2008;6:364Y366. 32. van Vollenhoven RF, Emery P, Bingham CO III, Keystone EC, Fleischmann R, Furst DE, et al. Longterm safety of patients receiving rituximab in rheumatoid arthritis clinical trials. J Rheumatol. 2010;37:558Y567. 33. Zen Y, Nakanuma Y. IgG4-related disease: a cross-sectional study of 114 cases. Am J Surg Pathol. 2010;34:1812Y1819.

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