Treatment of IgG4-Related Disease With Revlimid and Rituximab

Immunoglobulin G subclass 4 Related Disease (IgG4-RD) is a recently recognized systemic
fibroinflammatory condition. Various manifestations of IgG4-RD were previously recognized in
individual organ systems, but these entities (including autoimmune pancreatitis, orbital
pseudotumor, Reidel's thyroiditis, retroperitoneal fibrosis, idiopathic sialadenitis and
dacryoadenitis, etc) are now recognized as manifestations of a common disease process that
can affect any organ system. IgG4-RD is characterized by distinctive histologic findings of
tissue infiltration by IgG4-positive plasma cells together with storiform fibrosis and
obliterative phlebitis. Both clinical and pathologic consensus diagnostic criteria have been
defined. Serum IgG4 concentration is a biomarker for IgG4-RD and is elevated in 70% to 90% of
patients with active disease.

Inclusion criteria:

1. Diagnosis of active IgG4-RD based on standard pathologic or clinical criteria (see
below) and requiring medical treatment

2. Patient is:

1. in relapse after prior steroid and/or rituximab (RTX) treatment or while tapering
steroid treatment, OR

2. has disease that is refractory to steroids, OR

3. has contraindications to steroid therapy (including diabetes, mood disorder,
obesity)

3. Absolute neutrophil count >1500 and platelet count >/= 100,000

4. Calculated creatinine clearance (or estimated GFR) greater than or equal to 60ml/min

5. In patients without hepatobiliary involvement by IgG4-RD, total bilirubin less than or
equal to 1.5 x upper limit of normal (ULN), aspartate aminotransferase (AST) (SGOT)
and alanine aminotransferase (ALT) (SGPT) less than or equal to 3 x ULN

6. Not pregnant or nursing

7. All study participants must be registered into the mandatory Revlimid Risk Evaluation
and Mitigation Strategy (REMS™) program, and be willing and able to comply with the
requirements of the REMS™ program

8. Females of reproductive potential must adhere to the scheduled pregnancy testing as
required in the Revlimid REMS™ program

9. Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation (patients
intolerant to acetylsalicylic acid (ASA) may use warfarin or low molecular weight
heparin)

10. Agrees to use acceptable methods of birth control during and for 12 months after
completion of study drug therapy (applies to all men, and women of child bearing
potential)

11. Females must follow pregnancy testing requirements as outlined in the Revlimid REMS™
program

Exclusion criteria:

1. Predominant changes of fibrosis (as opposed to active cellular inflammation) within
the organs affected by IgG4-RD, such that the likelihood of a disease response to
treatment is low

2. Presence of active infection that would interfere with therapy on this study,
including positive serum hepatitis B surface antigen, HIV or active hepatitis C virus
(HCV) infection, untreated syphilis or tuberculosis, clinical history of multiple
herpes virus reactivations

3. Known immunodeficiency state

4. New York Heart Association Classification III or IV heart disease

5. Active malignancy requiring therapy

6. Receipt of a live vaccine within 4 weeks prior to initiating study drug therapy.

7. Allergies: History of severe allergic reactions to human or chimeric monoclonal
antibodies, murine protein, or lenalidomide

8. Substance abuse: Drug or alcohol abuse that could interfere with participation in the
trial according to the protocol

9. Known anti-human anti-chimeric antibody formation

10. Treatment with infliximab, adalimumab, or etanercept within the past 12 months.

11. Currently taking azathioprine, 6-mercaptopurine, methotrexate, mycophenolate mofetil,
or other conventional immunomodulators. Patients receiving these drugs must
discontinue them prior to enrollment

12. Other investigational medication within the previous one month