Rituximab for Anti-cytokine Autoantibody-Associated Diseases

Anticytokine autoantibodies are an important and emerging cause of disease. Anticytokine
autoantibody-associated diseases include disseminated nontuberculous mycobacterial infection
caused by anti-interferon- >= autoantibodies, severe mucocutaneous candidiasis caused by
anti-interleukin-17 autoantibodies, and pulmonary alveolar proteinosis caused by
anti-granulocyte macrophage colony stimulating factor autoantibodies. Many subjects
undergoing treatments related to these diseases fail to respond or develop toxicity to long
term therapy. Rituximab, an anti-CD20 monoclonal antibody that targets antibody-producing B
cells, has been used successfully to treat autoimmune diseases (e.g., rheumatoid arthritis),
as well as syndromes caused by pathogenic anticytokine autoantibodies (e.g., myasthenia
gravis and pemphigus vulgaris). This is a phase I, single arm, open-label study evaluating
the safety and clinical response to rituximab treatment in subjects (greater than or equal to
18 years of age; n=20) with anticytokine autoantibody-associated diseases who are intolerant
or refractory to conventional treatment. Rituximab will be administered as intravenous
infusions of 1 gram on days 1 and 15, and subsequently if indicated up to once a month for 5
months (plus or minue 5 days for each visit) starting on approximately day 42. Follow-up
visits will occur within 3, 6, 9, 12, 15, and 18 months (plus or minus 2 weeks for each
visit) after the last infusion. Subjects will be maintained on a background of appropriate
therapy for their respective diseases. The safety and clinical response to rituximab will be
assessed by clinical and laboratory parameters while subjects are receiving rituximab, and
for an additional year and a half after completion of treatment. Patients may be retreated at
the discretion of the Principal Investigator.

- INCLUSION CRITERIA:

Subjects (greater than or equal to 18 years of age) are eligible if they meet the following
criteria:

1. Currently enrolled in one of the following protocols: 95-I-0066, 07-I-0033, 01-I-0202,
or 93-I-0119.

2. Presence of anticytokine autoantibodies in serum or plasma, along with the anticipated
clinical consequences of the identified anticytokine autoantibody including, but not
limited to:

- Anti-IFN- >= autoantibodies and disseminated NTM.

- Anti-IL-17 autoantibodies and CMC.

- Anti-GM-CSF autoantibodies and PAP or cryptococcosis.

3. Progression of anticytokine autoantibody-associated diseases despite conventional
therapy, including, but not limited to:

- Antimycobacterials for disseminated NTM.

- Antifungals for mucocutaneous candidiasis or cryptococcosis.

- Subcutaneous or inhaled GM-CSF and/or whole lung lavage for PAP.

4. For ongoing autoantibody-associated infection, stable, optimized antibiotic regimen
for at least 1 month prior to initiation of rituximab and ability to continue these
antibiotics throughout treatment with rituximab.

5. Willingness to comply with study medication, visits, and procedures, as deemed
necessary by the study investigator.

6. Willingness to have samples stored for future research and genetic testing.

7. Willingness to be hospitalized for the inpatient visits (initial doese on day 1 and
day 15 will occur in the inpatient unit.

8. Negative serum pregnancy test result for women of childbearing potential.

- Women of childbearing potential and men are eligible if they agree to postpone
conception for 18 months following rituximab therapy. They must agree to use 2
adequate methods of contraception, such as:

- Hormonal contraception.

- Male or female condoms with or without a spermicide, diaphragm or cervical cap
with a spermicide, or intrauterine device.

- Sterilization of either partner.

EXCLUSION CRITERIA:

Subjects who meet the following criteria are not eligible to enter the study:

1. HIV seropositivity.

2. Active underlying malignancy, except thymoma and basal and squamous cell carcinoma.

3. Immunomodulatory or immunosuppressive therapy, including:

- Corticosteroids at a dose equivalent to greater than or equal to 15 mg of
prednisone/day at any time during the month immediately prior to enrollment.

- History of using biologic agents or any other systemic immune-suppressive or
immunomodulatory agents within the past year.

4. Use of another investigational study agent within 8 weeks of enrollment.

5. Known anaphylaxis or IgE-mediated hypersensitivity to murine proteins or any component
of the study medication.

6. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal
antibodies.

7. Evidence of significant uncontrolled concomitant diseases, such as cardiovascular
disease, or nervous system, pulmonary, renal, hepatic, endocrine, or gastrointestinal
disorders.

8. Diagnosis of an unrelated underlying immunodeficiency.

9. Hepatitis B (subjects with hepatitis C are eligible to enter the study).

10. Live vaccines within 1 month prior to receiving the study drug.

11. Unsuitable participation as judged by the principal investigator.

12. History of cancer, including solid tumors and hematologic malignancies (except basal
cell or squamous cell carcinoma of the skin that have been excised and cured and
thymoma).

13. History of alcohol, drug, or chemical abuse within 6 months prior to screening.

14. Poor peripheral venous access.

15. Intolerance or contraindications to oral or IV corticosteroids.

16. Screening laboratory values:

- Serum creatinine >1.4 mg/dL for women and >1.6 mg/dL for men.

- Platelet count <100,000/ L.

- Absolute neutrophil count <1500 cells/ L.

- IgG <5.65 times 10(-2) mg/dL or IgM <0.55 times 10(-2) mg/dL.

17. Breastfeeding.