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Rituximab for Treatment of Systemic Sclerosis-Associated Pulmonary Arterial Hypertension (SSc-PAH)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT01086540
Recruitment Status : Active, not recruiting
First Posted : March 15, 2010
Last Update Posted : June 24, 2019
Sponsor:
Collaborator:
Autoimmunity Centers of Excellence
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

Brief Summary:
Systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH) is a serious, life-threatening manifestation of systemic sclerosis (SSc), an autoimmune disease of the connective tissue characterized by scarring (fibrosis) and atrophy of the skin, joints and tendons, skeletal muscles, and internal organs, and immunological disturbances. One-year survival for patients with SSc-PAH ranges from 50-81%. There is currently no cure for SSc-PAH and treatment is limited to vasodilator therapy used in all forms of PAH. In recent studies, immunotherapy was shown to be effective in treating SSc-interstitial lung disease, another serious, life-threatening manifestation of SSc. In addition, there are compelling pre-clinical data and anecdotal clinical reports that suggest modulation of the immune system may be an effective strategy for treating SSc-PAH. To test this approach, this trial will determine if rituximab, an immunotherapy, has a marked beneficial effect on clinical disease progression, with minimal toxicity, in patients with SSc-PAH when compared to placebo.

Condition or disease Intervention/treatment Phase
Systemic Sclerosis-Associated PAH Biological: Rituximab Other: Placebo Diagnostic Test: CMRI Drug: Pre-medications for receipt of infusions Phase 2

Detailed Description:

This prospective, double-blind, placebo-controlled, multi-center, randomized trial will evaluate the effect of rituximab on disease progression in subjects with SSc-PAH receiving concurrent stable-dose standard medical therapy with a prostanoid, endothelin receptor antagonist, and/or phosphodiesterase 5 (PDE-5) inhibitor. The study will focus on assessment of clinical response and safety measures longitudinally. In addition, the effects of treatment with rituximab on the underlying immune mechanisms associated with B-cell dysregulation and pathogenic autoantibody response in this disease will be investigated. 1000 mg of rituximab or placebo will be administered as two IV infusions given two weeks apart. Clinical assessments and sample collection will occur at monthly visits through Week 48. If a participant has not recovered B cells by Week 48, B cell studies will be conducted quarterly until reconstitution is documented or for 2 years after initial treatment.

This trial will include a sub-study, entitled "Right Ventricular Response to Rituximab in Systemic Sclerosis-Associated Pulmonary Arterial Hypertension - A Magnetic Resonance Imaging Sub-study" (RESTORE Sub-study). The objective of the RESTORE sub-study is to evaluate the therapeutic effect of rituximab on the right ventricle of patients with SSc-PAH. Changes in right ventricular end diastolic volume index (RVEDVI) and stroke volume (SV) determined by cardiac MRI will be used as surrogates of right ventricle function and prognosis. Enrollment for the RESTORE sub-study will parallel that of main trial. Twenty patients from each treatment arm, distributed among all participating sites, will be recruited for this sub-study. Each patient will be studied at baseline (i.e. prior to initiation of study drug) and after 24 weeks or at time of discontinuation. In addition to the data collection and testing specified in the main trial, participants in RESTORE will undergo comprehensive cardiac MRI evaluation. All main trial study inclusion and exclusion criteria apply, as well as additional exclusion criteria that pertain only to the RESTORE sub-study: 1) known hypersensitivity to Gadolinium; 2) inability to tolerate or cooperate with MRI; 3) morbid obesity; and 4) presence of metallic objects or pacemakers.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 58 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized, Double-Blind, Placebo-Controlled, Phase II Multicenter Trial of a Monoclonal Antibody to CD20 (Rituximab) for the Treatment of Systemic Sclerosis-Associated Pulmonary Arterial Hypertension (SSc-PAH)
Actual Study Start Date : June 24, 2011
Actual Primary Completion Date : June 5, 2018
Estimated Study Completion Date : December 2019


Arm Intervention/treatment
Experimental: Rituximab+PAH SOC

Rituximab (1000 mg) will be administered as 2 intravenous infusions given 2 weeks apart.

Concurrent stable-dose Pulmonary Arterial Hypertension (PAH) medical therapy will be continued/managed as per standard of care (PAH SOC).

Biological: Rituximab

Participants receive rituximab intravenous (IV) infusions, 1000 mg each, 14 days apart (Day 0 and Week 2).

Rituximab is supplied as a sterile, clear, colorless, preservative-free liquid concentrate for intravenous (IV) administration in either 100 mg (10 mL) or 500 mg (50 mL) single-use vials, which must be diluted before administration

Standard rituximab pre-medications will be provided in preparation for the rituximab infusions.

Other Name: Rituxan®

Diagnostic Test: CMRI
Up to 20 participants from each treatment arm will be assessed by CMRI at Baseline and at Week 24.
Other Names:
  • cardiac MRI
  • cardiac Magnetic Resonance Imaging

Drug: Pre-medications for receipt of infusions

All participants will receive the following pre-medication prior to each infusion to prevent hypersensitivity reactions and to reduce the frequency of infusion-related reactions:

  • Night before and morning of each study drug infusion:

    --Prednisone 40mg PO (or equivalent)

  • Approximately thirty minutes prior to each study drug infusion:

    --Methylprednisolone 100 mg IV (or equivalent).

  • Approximately thirty to sixty minutes prior to each study drug infusion:

    • Diphenhydramine 50 mg PO (or equivalent). Dose may be repeated every four hours, as needed.

      ---Note: Subjects should be advised that this pre-medication given for the prevention and treatment of infusion-related reactions may cause drowsiness and impairment of driving ability prior to discharge.

    • Acetaminophen 650 mg PO (or equivalent). Dose may be repeated every four hours, as needed.
Other Names:
  • Rituximab pre-medications
  • Prednisone
  • Methylprednisolone
  • Diphenhydramine
  • Acetaminophen

Placebo Comparator: Placebo + PAH SOC

Placebo will be administered as 2 intravenous infusions given 2 weeks apart.

Concurrent stable-dose Pulmonary Arterial Hypertension (PAH) medical therapy will be continued/managed as per standard of care (PAH SOC).

Other: Placebo

Participants receive placebo intravenous (IV) infusions 14 days apart (Day 0 and Week 2).

Standard pre-medications will be provided in preparation for the infusions.

Other Name: Placebo for rituximab

Diagnostic Test: CMRI
Up to 20 participants from each treatment arm will be assessed by CMRI at Baseline and at Week 24.
Other Names:
  • cardiac MRI
  • cardiac Magnetic Resonance Imaging

Drug: Pre-medications for receipt of infusions

All participants will receive the following pre-medication prior to each infusion to prevent hypersensitivity reactions and to reduce the frequency of infusion-related reactions:

  • Night before and morning of each study drug infusion:

    --Prednisone 40mg PO (or equivalent)

  • Approximately thirty minutes prior to each study drug infusion:

    --Methylprednisolone 100 mg IV (or equivalent).

  • Approximately thirty to sixty minutes prior to each study drug infusion:

    • Diphenhydramine 50 mg PO (or equivalent). Dose may be repeated every four hours, as needed.

      ---Note: Subjects should be advised that this pre-medication given for the prevention and treatment of infusion-related reactions may cause drowsiness and impairment of driving ability prior to discharge.

    • Acetaminophen 650 mg PO (or equivalent). Dose may be repeated every four hours, as needed.
Other Names:
  • Rituximab pre-medications
  • Prednisone
  • Methylprednisolone
  • Diphenhydramine
  • Acetaminophen




Primary Outcome Measures :
  1. Change from Baseline in Six Minute Walk Distance (6MWD) at Week 24 [ Time Frame: Baseline, Week 24 ]
    The 6MWD is a 6 minute walk test. This test, a measure of exercise capacity, assesses the distance that a subject can walk in a period of 6 minutes.


Secondary Outcome Measures :
  1. Change from Baseline in Pulmonary Vascular Resistance (PVR) at Week 24 [ Time Frame: Baseline, Week 24 ]
    Change in PVR measured by right heart catheterization.

  2. Change from Baseline in 6-minute walk distance (6MWD) Through Week 48 [ Time Frame: Baseline, Week 4, Week 12, Week 24, Week 36, Week 48 ]
    The 6MWD is a 6 minute walk test. This test, a measure of exercise capacity, assesses the distance that a subject can walk in a period of 6 minutes.

  3. Time to Clinical Worsening [ Time Frame: Baseline through Week 48 ]

    Any outcome measure that indicates the participant is clinically worse, defined as first occurrence of:

    • death,
    • hospitalization for Systemic Sclerosis-Associated Pulmonary Arterial Hypertension (SSc-PAH),
    • lung transplantation,
    • atrial septostomy,
    • addition of other Pulmonary Arterial Hypertension (PAH) therapeutic agents, OR
    • worsening of 6MWD by > 20% and a decrease in functional class.

  4. Percent of Participants Who Either Changed or Added Pulmonary Arterial Hypertension (PAH) Therapeutic Agents [ Time Frame: Week 24, Week 48 ]
    Percent of participants who changed or added PAH therapeutic agents at Weeks 24 and Week 48 status post treatment initiation.

  5. Change from Baseline in Participant Quality of Life Using the SF-36 [ Time Frame: Baseline, Week 24, Week 48 ]
    The SF-36 is a quality of life assessment that that will be performed at Baseline, Week 24 and Week 48. Eight scale scores are derived from responses to the 36 items of the SF-36 questionnaire which are combined to produce the Physical Component Score and the Mental Component Score. The Physical Component Score is based on the Physical Functioning Scale (10 items), the Role-Physical Scale (4 items), the Bodily Pain Scale (2 items), and the General Health Scale (5 items). The Mental Component Score is based upon the Vitality Scale (4 items), the Social Functioning Scale (2 items), the Role-Emotional Scale (3 items) and the Mental Health Scale (5 items). Each component score is transformed into a 0-100 scale, with higher numbers indicating greater quality of life.

  6. Change from Baseline in Participant Quality of Life Using the Scleroderma Health Assessment Questionnaire-Disability Index [ Time Frame: Baseline, Week 24, Week 48 ]
    This is a patient self-administered health assessment questionnaire. The SHAQ-DI assesses five scleroderma-specific visual analogue scale (VAS) items to explore the impact of participant's disease. These items were developed to measure the effect of scleroderma on five elements of disease that could have a great impact on a participant's daily activities. Each VAS item is rated separately (0−100 millimeters [mm]), with higher scores indicating more severe disease. The five items are: 1) intestinal disease, 2) breathing problem, 3) Raynaud syndrome, 4) finger ulcers, and 5) overall disease. The measure produces a discrete value that can change through time and in response to medication.

  7. Change in Number of New Digital Ulcers (DUs) Up to Week 48 [ Time Frame: Baseline,Week 24, Week 48 ]
    Number of new digital ulcers assessed longitudinally, from Baseline to Week 24 and Week 48.

  8. Change in Severity of Raynaud Phenomenon Using the Self-Administered Health Assessment Questionnaire (SHAQ) [ Time Frame: Baseline, Week 4, Week 12, Week 24, Week 36, Week 48 ]
    Severity of Raynaud phenomenon, as measured by the Visual Analog Scale (VAS) scale of the SHAQ.

  9. Change From Baseline in Diffusion in Liters of Carbon Monoxide (DLCO) [ Time Frame: Baseline,Week 24, Week 48 ]
    Diffusion in liters of carbon monoxide (DLCO) is a measure of lung function.

  10. Percentage Change From Baseline in Pulmonary Vascular Resistance (PVR) [ Time Frame: Baseline, Week 24 ]
    Pulmonary vascular resistance (PVR) is the general pressure which the right ventricle must counteract to pump blood through the lungs. PVR is measured by right heart catheterization performed at Baseline and Week 24. Percentage change in PVR from Baseline at Week 24 is calculated as [(Baseline-Week 24)/Baseline]. Standard deviation is reported as a percentage.

  11. Change From Baseline in Oxygen Saturation [ Time Frame: Baseline, Week 4, Week 12, Week 24, Week 36, Week 48 ]
    Oxygen saturation at rest with room air, as a measure of lung function.

  12. Number of Participants With Regimen-Related Toxicities [ Time Frame: Randomization through end of study follow-up (up to Week 48 Post-Randomization) ]

    Regimen-related toxicities are defined as Grade 3 or higher adverse events reported by site physicians as possibly, probably, or definitely related to study therapy.

    The study will grade the severity of adverse events experienced by study participants according to the criteria set forth in the National Cancer Institute's Common Terminology Criteria for Adverse Events Version (CTCAE) 4.0.


  13. Number of NCI-CTCAE Grade 3 to 5 Adverse Events [ Time Frame: Randomization through end of study follow-up (up to Week 48 Post-Randomization) ]
    The study will grade the severity of adverse events experienced by study participants according to the criteria set forth in the National Cancer Institute's Common Terminology Criteria for Adverse Events Version (CTCAE) 4.0.

  14. Number of Infection Related Events [ Time Frame: Randomization through end of study follow-up (up to Week 48 Post-Randomization) ]
    Infectious complications include any events that code to the Medical Dictionary for Regulatory Activities (MedDRA) system organ class of "Infections and infestations" or events that a site has classified as an infectious event. These can include bacteremia, septicemia, fungemia, fever associated with infection, infectious pneumonia, idiopathic pneumonia syndrome, clinical infection (i.e. infection diagnosed with clinical features without identification of an organism) and other local/organ site-specific infections.

  15. Treatment-Related Mortality [ Time Frame: Randomization through end of study follow-up (up to Week 48 Post-Randomization) ]
    Death, occurring at any time between randomization and Week 48 post-randomization, which is possibly, probably, or definitely resulting from treatment given in the study.

  16. Mean Count of CD19 Positive B Cells [ Time Frame: Baseline, Week 2, Week 4, Week 12, Week 24, Week 36, Week 48 ]
    Assessment of the number of peripheral blood CD19+ B cells by flow cytometry.

  17. Evaluation of Biomarkers as Indicators of Change in Disease Status [ Time Frame: Baseline, Week 4, Week 12, Week 24, Week 36, Week 48 ]
    To assess pre-specified laboratory assessment for change over time with treatment (i.e., CD19 assessments, autoantibodies, immunoglobulins, cytokines).

  18. Change from Baseline in Right Ventricular End Diastolic Volume Index (RVEDVI) at Week 24 [ Time Frame: Baseline, Week 24 ]

    A measure of right ventricle (RV) function, RVEDVI is a measure of the volume of blood in the right ventricle at the end of diastole, normalized over body surface area, measured using Cardiac Magnetic Resonance imaging (CMRI). RVEDVI is calculated as the right ventricular end diastolic volume (RDEDV) divided by the body surface area (BSA).

    This outcome will include the ≤20 participants per arm (i.e., 20 in the rituximab intervention arm and 20 in the placebo intervention) who undergo cardiac Magnetic Resonance Imaging (CMRI) evaluations at Baseline and Week 24.


  19. Change From Baseline in Right Ventricular (RV) Stroke Volume Index at Week 24 [ Time Frame: Baseline, Week 24 ]
    A measure of right ventricle (RV) function. This outcome will include the ≤20 participants per arm (i.e., 20 in the rituximab intervention arm and 20 in the placebo intervention) who undergo cardiac Magnetic Resonance Imaging (CMRI) evaluations at Baseline and Week 24.



Information from the National Library of Medicine

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Layout table for eligibility information
Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Subject has provided written informed consent.
  • Clinical diagnosis of systemic sclerosis (either limited or diffuse cutaneous disease).
  • Diagnosis of SSc-PAH within the past 5 years, with a mean pulmonary arterial pressure of ≥ 25 mmHg at entry.
  • Mean Pulmonary Vascular Resistance (PVR) of > 3 Wood units.
  • Screening 6-minute Walking Distance (6MWD) of at least 100 meters.
  • New York Heart Association (NYHA) Functional Class II, III, or IV.
  • Subject must be able to maintain O2 saturation ≥ 90% at rest (with or without oxygen);

    --Oxygen use is permitted.

  • Subject must be vaccinated with the pneumococcal vaccine at least one month prior to initiation of therapy, unless subject was vaccinated within 5 years of study entry.
  • Subject must have been treated with background medical therapy for PAH (prostanoid, endothelin receptor antagonist, PDE-5 inhibitor, and/or guanylate cyclase stimulators) for a minimum of 8 weeks and have been on stable dose medical therapy for at least 4 weeks prior to randomization with no expectation of change for 24 weeks after randomization.

Exclusion Criteria:

  • Documented PAH for greater than 5 years at the time of randomization defined as:

    • Measurement of a mean Pulmonary Artery Pressure (PAP) > 25 mmHg by right heart catheterization at least 5 years previously, OR
    • Treatment with targeted background PAH therapy for > 5 years.
  • Pulmonary Capillary Wedge Pressure > 15 mmHg or Left Ventricular End Diastolic Pressure > 15 mmHg.
  • Persistent hypotension with Systolic Blood Pressure (SBP) < 90 mmHg.
  • Treatment with cyclophosphamide within 4 weeks of randomization.
  • Treatment with immunocompromising biologic agents within 4 weeks prior to treatment initiation or treatment with infliximab within 8 weeks prior to treatment initiation.
  • If being treated with a non-biologic immunosuppressive or immunomodulating drug, changes in dosage within 4 weeks prior to randomization. Subjects taking prednisone or equivalent corticosteroid > 10mg daily are excluded.
  • Previous exposure to any lymphocyte or B cell depleting agent.
  • PAH for any reason other than SSc.
  • History of coronary artery disease, significant ventricular tachy-arrhythmia, stent placement, coronary artery bypass surgery, and/or myocardial infarction.
  • Moderate or severe interstitial lung disease.
  • Chronic infections.
  • Positive serology for infection with hepatitis B or C.
  • A deep space infection within the past 2 years.
  • Evidence of active infection within 2 weeks of randomization
  • Presence of a positive tuberculosis (TB) skin test (e.g., PPD test) or positive QuantiFERON®-TB blood test, an indeterminate QuantiFERON®-TB blood test, or latent tuberculosis (TB).
  • Significant renal insufficiency.
  • Active, untreated SSc renal crisis at the time of enrollment.
  • Recent administration of a live vaccine (< 8 weeks) or any other immunization within 4 weeks of treatment.
  • History of anaphylaxis or Immunoglobulin E (IgE) -mediated hypersensitivity to murine proteins or any component of rituximab.
  • Pregnancy.
  • Lactation.
  • History of malignancy within the last 5 years, except for resected basal or squamous cell carcinoma, treated cervical dysplasia, or treated in situ cervical cancer Grade I.
  • A woman of childbearing potential who is unwilling to use a medically acceptable form of birth control
  • History of non-compliance with other medical therapies.
  • History of alcohol or drug abuse within 1 year of randomization.
  • Receipt of any investigational drug or device within 4 weeks before the Screening Visit, with the exception of investigational prostanoids, endothelin receptor antagonists, and PDE-5 inhibitors, and guanylate cyclase stimulators.
  • Recipient of lung transplant.
  • Laboratory parameters at the screening visit showing any of the following abnormal results: Transaminases > 2x the upper limit of normal (ULN) and/or bilirubin > 2x ULN; Absolute neutrophil count < 1,500/mm3; Platelet count < 100,000/mm3; Hemoglobin < 9 g/dL.
  • Concurrent treatment in a clinical research study using a non-FDA approved agent with the exception of an open-label study/study extension of investigational prostanoids, endothelin receptor antagonists, and PDE-5 inhibitors, and guanylate cyclase stimulators, provided the open-label investigational drug will be available and dose will remain stable through the trial's primary outcome time point of 24 weeks after randomization in this study, ASC01 (NCT01086540).
  • Any condition or treatment, which in the opinion of the investigator, places the subject at unacceptable risk as a participant in the trial.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01086540


Locations
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United States, California
Stanford University
Palo Alto, California, United States, 94304
United States, Colorado
University of Colorado Health Sciences Center
Aurora, Colorado, United States, 80045
United States, Iowa
University of Iowa
Iowa City, Iowa, United States, 52242
United States, Maryland
Johns Hopkins University
Baltimore, Maryland, United States, 21205
United States, Massachusetts
Boston University Medical Center
Boston, Massachusetts, United States, 02118
United States, Michigan
University of Michigan
Ann Arbor, Michigan, United States, 48109
United States, Minnesota
University of Minnesota Medical Center
Minneapolis, Minnesota, United States, 55455
United States, New York
Hospital for Special Surgery
New York, New York, United States, 10021
Columbia University
New York, New York, United States, 10032
University of Rochester Medical Center
Rochester, New York, United States, 14642
United States, North Carolina
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, United States, 27599
United States, Ohio
Ohio State University
Columbus, Ohio, United States, 43210
United States, Pennsylvania
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania, United States, 15261
United States, South Carolina
Medical University of South Carolina
Charleston, South Carolina, United States, 29425
United States, Texas
University of Texas Southwestern
Dallas, Texas, United States, 75390
University of Texas Houston
Houston, Texas, United States, 77030
United States, Utah
University of Utah
Salt Lake City, Utah, United States, 84132
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
Autoimmunity Centers of Excellence
Investigators
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Study Chair: Mark Nicolls, M.D. Stanford University Medical Service/VA Palo Alto Health Care System
Study Chair: David B. Badesch, M.D. University of Colorado, Denver
Study Chair: Thomas A. Medsger, Jr., M.D. University of Pittsburgh
Study Chair: Lorinda Chung, MD Stanford University
Study Chair: Robyn Domsic, MD University of Pittsburgh
Study Chair: Aryeh Fischer, MD National Jewish Health/University of Colorado School of Medicine
Study Chair: Roham Zamanian, MD Stanford University

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT01086540     History of Changes
Other Study ID Numbers: DAIT ASC01
First Posted: March 15, 2010    Key Record Dates
Last Update Posted: June 24, 2019
Last Verified: June 2019

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
Pulmonary Arterial Hypertension (PAH)
Autoimmune Disease
Systemic Scleroderma

Additional relevant MeSH terms:
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Hypertension
Sclerosis
Familial Primary Pulmonary Hypertension
Scleroderma, Systemic
Scleroderma, Diffuse
Vascular Diseases
Cardiovascular Diseases
Pathologic Processes
Hypertension, Pulmonary
Lung Diseases
Respiratory Tract Diseases
Connective Tissue Diseases
Skin Diseases
Rituximab
Prednisone
Methylprednisolone Hemisuccinate
Prednisolone
Methylprednisolone
Methylprednisolone Acetate
Prednisolone acetate
Prednisolone hemisuccinate
Prednisolone phosphate
Acetaminophen
Diphenhydramine
Promethazine
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents