Increased risk of PML associated with raptiva in other studies

This study will examine the effect of the drug Raptiva (efalizumab) in patients with Sjögren's syndrome (SS), an autoimmune disease affecting the glands producing saliva & tears. The cause of SS is not known, but inflammation plays an important role. Raptiva is approved by the Food and Drug Administration to treat psoriasis, an inflammatory skin disease. Patients 18 years of age & older with SS may be eligible for this study. Candidates are screened with a history & physical examination, chest x-ray, and oral & eye examinations.

Participants are randomly assigned to receive either Raptiva or placebo (an inactive substance that looks like Raptiva) for the first 3 months of the study. For the next 3 months, all participants receive Raptiva. Both Raptiva & placebo are injected under the skin once a week. Evaluation during treatment & for 2 months after treatment as follows:

Full comprehensive evaluations (beginning of the study, at weeks 13 & 25 and 2 months after treatment ends):

• Physical examination & blood draw.
• Saliva collection done in two ways: 1) suctions cups connected to collection tubes are placed over the salivary gland ducts in the mouth and under the tongue; and 2) a sour-tasting liquid is applied to the top & sides of the tongue at 30-second intervals to stimulate saliva production.
• Eye exam for tear gland function.
• Questionnaires about mouth & eye dryness, energy level and overall well-being.
• Lip biopsy (screening & week 13 visits only). A few minor salivary glands are removed for examination under a microscope. The lower lip is numbed, a small cut is made on the inside of the lip, and several glands are removed. The cut is closed with a few stitches that are removed after 5 to 7 days.
• Magnetic resonance imaging of the parotid glands (salivary glands near the ear) at weeks 1, 13 and 25. The patient lies on a stretcher that is moved into the scanner (a metal cylinder containing a strong magnetic field). The head is held in place during the scan. The study lasts about 90 minutes.
• Short evaluations at weeks 3, 5, 9, 15, 17, 21 and 1 month after treatment ends.
• Medical history & physical examination, blood draw, evaluation for changes in symptoms and side effects, review of current medications at weeks 3, 9, 15 and 21.
• Laboratory tests, evaluation for changes in symptoms and side effects, review of current medications, saliva collection without the sour liquid and short evaluation of tear production at weeks 5 and 17.
• Blood tests at week 29

The LFA-1/ICAM-1 interaction is important in migration of lymphocytes to inflammatory sites, T-lymphocyte activation, antigen presentation, and maintaining the integrity of the immunologic synapse. In both murine and human Sjogren's Syndrome, increased expression of LFA-1 was found on activated lymphocytes, and increased expression of ICAM-1 was present on the activated endothelial cells in the diseased salivary and lacrimal glands. In animal models, blockade of the LFA-1/ICAM-1 interaction resulted in reduction of glandular inflammation.

Raptiva (efalizumab) is a recombinant humanized monoclonal antibody that binds to human CD11a, the alpha-subunit of Leukocyte Function Antigen-1 (LFA-1) and inhibits the LFA-1/ICAM-1 interaction. Raptiva is an FDA-approved medication for treatment of mild-to-moderate psoriasis.

In this pilot, proof of concept, randomized, double-blind, placebo-controlled study, up to 25 patients with Sjogren's syndrome may be enrolled. In the first, double-blind phase of the study, patients will be randomized and treated with weekly subcutaneous (SC) injections of either Raptiva (1mg/kg) or placebo for 12 weeks. In the second open label phase, all patients will be treated with weekly SC injections of Raptiva (1mg/kg) for another 12 weeks and then followed for an additional 8 weeks. Safety will be evaluated using standard clinical and laboratory parameters. To assess the potential effect of Raptiva on Sjogren's syndrome, minor salivary gland biopsy, oral and ocular evaluations, and measurements of surrogate markers of inflammation will be compared between the Raptiva and placebo treated groups before and after the treatment. Patients who either do not tolerate the drug or have worsening in their disease activity will be withdrawn from the protocol.

If Raptiva is well tolerated in this study and the treatment is associated with improvement in clinical parameters of Sjogren's Syndrome, further large studies of efficacy are planned.

• INCLUSION CRITERIA:

Up to 25 patients may be enrolled in this study to obtain at least 20 patients to complete the study and to allow for an estimated up to 20% early attrition rate. Eligible patients will have primary SS diagnosed according to the American-European Consensus Group Sjogren's Syndrome Classification Criteria. Subjects will be chosen based on their potential capacity to reverse the inflammatory process and at least partially recover the exocrine function in the salivary and lacrimal glands, as indicated in the inclusion criteria by requiring a minimal level of salivary flow as a marker of functional gland tissue. Pre-screening, which would include ophthalmologic evaluation, standard laboratory tests, and minor salivary gland biopsy, will be performed under the natural history protocol, and eligible patients will be offered to sign the informed consent for this protocol.

Age at entry at least 18 years

Must give written informed consent prior to entry in the protocol.

Must fulfill at least 4 of the 6 following criteria for Primary SS as defined by the American-European Consensus Group Sjogren's Syndrome Classification Criteria, including either item IV or VI, or fulfill 3 of the 4 objective criteria (III, IV, V, VI) [53] :

Ocular symptoms (at least one):

Dry eyes greater than 3 months

Foreign body sensation in the eyes

Use of artificial tears greater than 3x/day

Oral symptoms (at least one):

Dry mouth greater than 3 months

Swollen salivary glands

Need liquids to swallow dry foods

Ocular signs (at least one):

Schirmer test (without anesthesia) less than or equal to 5 mm/5 min

Positive vital dye staining (van Bijsterveld greater than or equal to 4)

Histopathology: Minor salivary gland biopsy showing focal lymphocyte sialoadenitis (focus score greater than or equal to 1 per 4 mm(2))

Oral signs (at least one):

Unstimulated whole salivary flow (less than or equal to 1.5 ml in 15 min)

Abnormal parotid sialography

Abnormal salivary scintigraphy

Autoantibodies (at least one):

Anti-SSA or Anti-SSB

One or more of the following:

Serum ANA level greater than or equal to 1EU

Serum Anti-SSA level greater than or equal to 20EU

Serum Anti-SSB level greater than or equal to 20EU

Serum RF level greater than or equal to 20 IU/ml

One or more of the following:

ESR greater than 25 mm/hr for men; ESR greater than 42 mm/hr for women

Serum IgG level greater than or equal to 1750 mg/dl

Serum CRP level greater than or equal to 0.8 mg/dl

Stimulated salivary flow of at least 0.1 ml/min.

Minor salivary gland biopsy with a focus score of greater than or equal to 4 within at most 12 months prior to the study enrollment.

Score of 3 or more on Oxford scale in at least one eye at the study entry.

Negative age- and gender- appropriate malignancy screening for breast, cervical, colorectal cancer for women; and prostate and colorectal cancer for men. Specifically:

• All women: pelvic exam with Papanicolaou smear within one year of study entry.
• Women age 40 and older: mammogram within 1 year of study entry,
• Both genders age 50 and older; stool screening for occult blood within one year, or flexible sigmoidoscopy or colonoscopy within five years
• Men age 50 and older: rectal examination or prostate specific antigen testing

EXCLUSION CRITERIA:

Past head and neck irradiation.

Hepatitis B, C, HIV, or HTLV infection.

History of lymphoma or monoclonal gammopathy of unknown significance (MGUS).

Sarcoidosis.

Graft-versus-host disease.

Women of childbearing potential are required to have a negative pregnancy test at screening.

Women of childbearing potential and fertile men who are not practicing or who are unwilling to practice birth control during and for a period of three months after the completion of the study.

Any therapy with human or murine antibodies or any experimental therapy within 3 months.

Therapy with cyclophosphamide, pulse methylprednisolone or IVIg, azathioprine, mycophenolate mofetil, oral cyclosporine or methotrexate within 4 weeks of first study treatment.

History of rituximab therapy.

Prednisone dose greater than or equal to 10 mg/day.

Allergy to murine or human antibodies.

History of anaphylaxis.

Serum creatinine greater than 2.0 mg/dl.

History of any malignancy.

Active infection that requires the use of intravenous antibiotics and does not resolve within 1 week of Day 1.

Any active viral infection that does not resolve within 10 days prior to Day 1.

WBC less than 2000/microL or ANC less than 1500/microL or Hgb less than 9.0 g/dL or platelets less than 150,000/microL or absolute lymphocyte count less than or equal to 500/microL.

ALT and/or AST greater than 1.5x upper limit of normal (ULN) or alkaline phosphatase greater than 1.5x ULN.

Significant concurrent medical condition that, in the opinion of the Principal Investigator, could affect the patient's ability to tolerate or complete the study.

Live vaccines within 12 weeks of first treatment.

2 years and 5 month

Raptiva: AEs occuring in 6 patients receiving Raptiva durig the blinded phase plus the 2 patients who received placebo during the blinded phase but received Raptiva during the open lable phase.

Placebo AEs occuring in the placebo group (n=3) during the blinded phase. One patient withdrew after completing the placebo phase.

Early termination due to serious adverse event described in psoriasis which led to the withdrawal of the drug from market.