This study will examine the safety and effects of the monoclonal antibody MRA in patients
with systemic lupus erythematosus (SLE). Antibodies normally fight invading organisms. In
autoimmune diseases, such as lupus, however, antibodies attack the body s own tissues. MRA is
an antibody manufactured in the laboratory that blocks the action of interleukin-6 (IL-6), a
substance that increases antibody production and is involved in inflammation that may cause
organ damage in SLE.
Patients 18 years of age and older with moderately active systemic lupus erythematosus may be
eligible for this 6-month study. Candidates will be screened with blood and urine tests,
chest X-ray, electrocardiogram (EKG), and screening tests for certain cancers.
Participants will receive a total of up to seven infusions of MRA given every 2 weeks in the
clinic. The MRA is infused over a period of about 1 hour through a catheter (thin plastic
tube) inserted into an arm vein. Patients will be observed for 1 to 2 hours after each
infusion for drug side effects. For the first and last infusions, patients will return to the
clinic for blood tests 24 to 48 hours after the infusion. Additional tests may be done if
Three different doses of MRA will be used in three groups of patients. The first group (4
patients) will receive the lowest dose. If this dose is well tolerated, a second group (6
patients) will receive a higher dose. If this dose is also well tolerated, a third group (6
patients) will receive the highest study dose.
Patients will be evaluated at various intervals for up to 3 months after the last dose of
MRA. The follow-up visits will include a review of the patient s medical history, a physical
examination, blood and urine tests, and an EKG.
Interleukin-6 (IL-6) levels are elevated in both human and murine systemic lupus
erythematosus (SLE). Blocking the action of IL-6 ameliorates disease activity in murine
models of SLE. MRA is a humanized monoclonal antibody against the human IL-6 receptor. Data
from clinical trials in patients with rheumatoid arthritis suggest that MRA may be a safe
agent to block the effect of IL-6 and therefore may be used to evaluate the effects of IL-6
blockade in patients with SLE. In this open label, dose-escalating, Phase I study, up to 27
subjects with moderately active SLE may be enrolled. Subjects will be treated with bi-weekly
infusions of one of three doses (2mg/kg, 4 mg/kg or 8 mg/kg) of MRA for 12 weeks and followed
for 8 weeks after the last dose. Patients with or without lupus nephritis may be enrolled if
they do not require immediate immunosuppressive therapy other than prednisone at doses of
less than or equal to 0.3 mg/kg/day. Safety will be evaluated using standard clinical and
laboratory parameters. To assess the potential effect of MRA on SLE, clinical and laboratory
evaluations and surrogate markers of inflammation and disease activity, such as autoantibody
production and lymphocyte subsets, will be compared before and after the treatment. Patients
who either do not tolerate the drug or those who have a clinically significant increase in
their disease activity that does not respond to moderate doses of corticosteroids will be
withdrawn from the protocol.
If this regimen is shown to be well tolerated, studies of efficacy will be planned. This
agent is expected to be devoid of the most common toxicities of therapies commonly used in
the treatment of SLE, such as myelosuppression, amenorrhea and osteoporosis.
This study will provide important preliminary information about the safety and possible
effect of IL-6 blockade in SLE patients, an intervention that has been successful in animal
models but has not yet been studied in humans.
- IINCLUSION CRITERIA:
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 following criteria for SLE as defined by the American
College of Rheumatology:
- Malar rash. Fixed Erythema, flat or raised, over the malar eminences.
- Discoid rash. Erythematous raised patches with adherent keratotic scaling and
follicular plugging; atrophic scarring may occur.
- Photosensitivity. Exposure to UV light causes rash.
- Oral Ulcers. Includes oral and nasopharyngeal, observed by physician.
- Arthritis. Nonerosive arthritis involving two or more peripheral joints, characterized
by tenderness, swelling or effusion.
- Serositis. Pleuritis or pericarditis documented by ECG or rub or evidence of
- Renal disorder. Proteinuria greater than 0.5 g/d or greater than 3+, or cellular
- Neurologic disorder. Seizures without other cause or psychosis without other cause.
- Hematologic disorder. Hemolytic anemia or leukopenia (less than 4000/microL) or
lymphopenia (less than 1500/microL) or thrombocytopenia (less than 100,000/microL) in
the absence of offending drugs.
- Immunologic disorder. Anti-dsDNA, anti-Sm, and/or anti-phospholipid.
- Antinuclear antibodies. An abnormal titer of ANAs by immunofluorescence or an
equivalent assay at any point in time in the absence of drugs known to induce ANAs.
Moderately active lupus not requiring immediate immunosuppressive therapy other than oral
prednisone less than or equal to 0.3 mg/kg/day (or its equivalent). Moderately active lupus
is defined by either of these two (a and b) sets of criteria:
a. Chronic glomerulonephritis with inadequate response to at least 6 months of adequate
immunosuppressive therapy (with pulse methylprednisolone, cyclophosphamide, azathioprine,
cyclosporine, mycophenolate mofetil or high dose daily corticosteroids, MTX or IV Ig), and
i. less than 30% increase in creatinine compared to lowest level during treatment,
ii. proteinuria less than or equal to 1.5 times the baseline before treatment,
iii. less than or equal to 2+ cellular casts in the urinary sediment (on a scale of 0-4),
iv. Extra-renal disease activity does not exceed 10 on the non-renal components of the
b. Patients with moderately active extra-renal lupus defined as an extra-renal
SELENA-SLEDAI score in the range of 3 to 10, inclusive. The SELENA-SLEDAI score should have
been stable for at least two weeks prior to screening.
One or more of the following:
i) Serum dsDNA level greater than or equal to 30 IU
ii) IgG anticardiolipin antibody levels greater than or equal to 20 GPL
iii) CRP greater than 0.8 mg/dL
iv) ESR greater than 25 mm/hr for men; ESR greater than 42 mm/hr for women.
Stable doses of prednisone less than or equal to 0.3 mg/kg/day (or its equivalent) for at
least 2 weeks before the first treatment.
Pregnant or lactating women. 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
Any therapy with human or murine antibodies or any experimental therapy within 3 months
Therapy with cyclophosphamide; pulse methylprednisolone or IV Ig within 4 weeks; or
azathioprine, mycophenolate mofetil, cyclosporine or methotrexate within 2 weeks of first
Initiation or a change in the dose of an ACE-inhibitor within 2 weeks of first study
Allergy to murine or human antibodies
History of anaphylaxis
Serum creatinine greater than 3.0 mg/dL
Active severe CNS lupus (encephalopathy, cerebrovascular accident, transverse myelitis,
severe depression, psychosis)
Previous history of ischemic heart disease or evidence of ischemic heart disease on ECG
Congestive heart failure or cardiomyopathy
History of thrombosis or recurrent 2nd trimester abortions (3 or more) and elevated levels
of anti-cardiolipin antibodies or lupus anticoagulant unless the patient is on
History of malignancy with the exception of basal cell or squamous cell carcinoma of the
skin or in situ carcinoma of the cervix within the last 3 years
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
History of reactivation on EB viral infection or greater than 1,000 EBV genome
equivalent/10(6) cells in PBMC preparations
Active hepatitis B, hepatitis C or HIV infection
WBC less than 3500/microL or ANC less than 3000/microL or Hgb less than 8.0 g/dL or
platelets less than 50,000/microL or absolute lymphocyte count less than or equal to
ALT and/or AST greater than 2 times the upper limit of normal (ULN) or alkaline phosphatase
greater than 1.5 times the 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 4 weeks of first infusion