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Investigators across the United States and Europe hope to answer questions surrounding the feasibility of preventing rheumatoid arthritis in a series of proof-of-concept clinical trials that are enrolling patients with various risk factors for the disease. At least five trials have begun – with one already completed – to prevent RA with disease-modifying antirheumatic drugs, including a U.S. trial with hydroxychloroquine and European trials involving methotrexate, rituximab, and abatacept. Another trial with atorvastatin is also underway.
All of the trials involve participants with different risk factors for RA and may thereby provide a range of answers about where the most promising areas for disease prevention lie.
Hydroxychloroquine
Perhaps the broadest in scope of all the studies investigating the prevention of RA is the StopRA (Strategy to Prevent the Onset of Clinically Apparent Rheumatoid Arthritis) trial, which is randomizing 200 subjects with an anticyclic citrullinated peptide 3 (anti-CCP3) that’s greater than twice the normal level, with or without arthralgia, to either hydroxychloroquine (HCQ) 200-400 mg/day or placebo for 1 year, followed by 2 years of follow-up. Pilot data indicated that a level of 40 U/mL or higher of anti-CCP3, which is twice the normal level for positivity, gave a 50% chance of developing RA in the next 3 years regardless of symptoms, family history, or other factors.
The trial’s focus on people with an elevated level of anti-CCP3 limits it to just seropositive individuals, specifically those who are anti-citrullinated protein antibody (ACPA)-positive who constitute about 60%-70% of RA patients with established RA.
The investigators chose to use HCQ because it is a safe and well-tolerated medication for RA, and it may have mechanisms of action that may work particularly well in the early development of RA by blocking inflammation and epitope spreading, Dr. Deane said. “While hydroxychloroquine might not be powerful enough to stop active RA, we hypothesize that it’s just the right drug to block key processes early in its development,” Dr. Deane said in an interview, noting that HCQ is also used to block disease flares in palindromic rheumatism and diminish autoantibody responses in systemic lupus erythematosus.
The StopRA trial is being performed by the Autoimmunity Centers of Excellence, a network sponsored by the National Institutes of Health and the National Institute of Allergy and Infectious Diseases. Enrollment began at 18 U.S. sites in April 2016 with screening of first-degree relatives of patients with RA, community-based screening at health fairs, and finding CCP positive individuals without inflammatory arthritis in rheumatology clinics. The investigators estimate that they will need to screen 20,000 individuals to enroll 200 into the study. Dr. Deane said that he and his coinvestigators hope to use the variables that will arise from the diverse population to later determine subgroups who may respond best to the intervention. “We were concerned that if we made everybody too similar we wouldn’t be able to analyze whether symptoms or other factors mattered or not in who responded to the intervention. It may also allow us to catch some people at an early phase of their autoimmunity and others at a later phase and to determine for future studies when is the best time to intervene in preclinical RA with HCQ.”
It’s possible that HCQ will just delay RA rather than prevent it, Dr. Deane said, perhaps indicating that they may find that HCQ needs to be used longer. In any case, by the time the trial is completed in 2020 the investigators hope to gain rich natural history data to determine how to proceed in future trials, whether they use higher doses, longer-term dosing, or try a different target. In addition, the infrastructure of study sites established in StopRA should be incredibly valuable for future prevention studies.
“I envision a future where everybody is screened for RA risk using good blood tests and then given the opportunity for prevention,” first involving high-risk groups such as family members of people with RA, and then ultimately opening up to population-based screening because 90% of RA occurs in individuals without family history of the disease, Dr. Deane said. An analogy for this might be cardiovascular disease, he said, where we screen the cholesterol level of patients before they have had a heart attack, and if it’s above a certain threshold we prescribe a statin, healthy eating, and exercise in an attempt to prevent cardiovascular events. In the same way, it might be possible to screen people for biomarker risk factors and prescribe a drug and/or a lifestyle change to prevent RA or even prevent many of the other rheumatic diseases including lupus and Sjögren’s syndrome.
Methotrexate
The Dutch TREAT EARLIER (Treat Early Arthralgia to Reverse or Limit Impending Exacerbation to Rheumatoid Arthritis) trial is unique among the RA prevention trials for its inclusion of patients with clinically suspect arthralgia and subclinical inflammation on MRI in the hand or foot without any requirement for seropositivity. The trial’s 200 participants are randomized to methotrexate or placebo for 1 year. All subjects receive an initial 120-mg intramuscular injection of methylprednisolone. The primary outcome measured at 2 years is the frequency of clinically detectable arthritis fulfilling the 2010 European League Against Rheumatism/American College of Rheumatology criteria for RA or of unclassified arthritis with a swollen joint count of more than two joints, both persisting for at least 4 weeks. The trial, which is investigator initiated without industry sponsorship, has been enrolling patients for about 1.5 years and will need about that much more time to complete it.
“We do this because we don’t want to confine ourselves to autoantibody-positive patients; we also want to include the autoantibody-negative patients at risk for RA. That’s relevant because in the past, autoantibody-positive patients had more severe disease and more severe joint destruction, but clinically relevant joint destruction doesn’t develop anymore [because of effective treatment], and the problem is more that RA is still a chronic disease. Both ACPA-positive and -negative RA are chronic diseases.”
All the patients included in the trial are considered to be at risk for RA by rheumatologists because of their arthralgia. Because of the clinically relevant population, the results of TREAT EARLIER might be generalized more easily to daily practice, she said in an interview.
Abatacept
The APIPPRA (Arthritis Prevention in the Preclinical Phase of Rheumatoid Arthritis with Abatacept) trial hopes to find out whether RA or clinical synovitis can be prevented with abatacept (Orencia) 125 mg weekly by comparing it against placebo over a 12-month period in 206 British and Dutch patients with arthralgia who are rheumatoid factor (RF) and ACPA-positive. Subjects who are RF negative, but who carry high levels of serum ACPA defined as three times the upper limit of normal may be included. There will be a 1-year follow-up after the intervention period to monitor patients for arthritis.
The ARIAA (Abatacept Reversing Subclinical Inflammation as Measured by MRI in ACPA Positive Arthralgia) trial is randomizing 98 German patients with ACPA-positive arthralgia to 6 months of abatacept 125 mg weekly for 6 months vs. placebo, followed by a 12-month follow-up period. The primary outcome of the double-blind trial is the proportion of patients with an improvement of acute inflammation characterized as improvement of synovitis or osteitis in the MRI of the dominant hand after 6 months of treatment. The proportion of patients who develop RA based on ACR/EULAR 2010 criteria at 6-month intervals is one of a multitude of secondary outcomes that will be measured. Individuals in the study must test positive for ACPA (with or without RF); have joint pain in the hand, feet, knee, shoulder, or elbow for at least 6 weeks prior to inclusion or in past history; and synovitis or osteitis present on MRI of the dominant hand at baseline.
The two abatacept trials, both of which are expected to be completed in 2018, are sponsored by abatacept’s manufacturer, Bristol-Myers Squibb.
Rituximab
Results from the randomized, placebo-controlled PRAIRI (Prevention of RA by Rituximab) trial that were reported at the annual European Congress of Rheumatology in June showed that a single, intravenous infusion of 1,000 mg of rituximab (Rituxan) given to people with arthralgia and a high risk for developing rheumatoid arthritis did not prevent RA, but the treatment did appear to delay the development of RA. During follow-up, 16 of the 40 people in the placebo group (40%) developed RA after a median of 12 months, and 14 of the 41 in the treated arm (34%) developed RA after a median of 17 months. A Kaplan-Meier survival analysis found that the development of RA in 25% of people occurred at about 12 months in the placebo arm, whereas in the intervention arm it did not occur until 24 months.
At three Dutch centers, the PRAIRI trial investigators enrolled people with arthralgia who had never been diagnosed with arthritis, had never used a disease-modifying antirheumatic drug, and had at least one of these two risk factors: a serum level of IgM rheumatoid factor of more than 12.5 IU/mL and a serum level of anticitrullinated peptide antibodies of more than 25 IU/mL. Enrolled participants also needed to have at least one of the following: a serum level of C-reactive protein greater than 3 mg/L, an erythrocyte sedimentation rate of greater than 28 mm/hr, and evidence of subclinical synovitis identified by either ultrasound or MRI.
Atorvastatin
The STAPRA (Statins to Prevent Rheumatoid Arthritis) trial is randomizing 220 people to double-blind treatment with either atorvastatin 40 mg or placebo for 3 years to determine whether the combined lipid-lowering and anti-inflammatory effects of statin therapy may be able to prevent the development of clinical arthritis in people at increased risk for RA. The participants must test positive for RF and ACPA or a high ACPA titer of three times the cut-off value. Arthralgia is not required, and participants must not have current clinically apparent synovitis. The main endpoint is the development of clinical arthritis as confirmed by a rheumatologist in the study. The trial is scheduled to be completed in 2020.
Investigators across the United States and Europe hope to answer questions surrounding the feasibility of preventing rheumatoid arthritis in a series of proof-of-concept clinical trials that are enrolling patients with various risk factors for the disease. At least five trials have begun – with one already completed – to prevent RA with disease-modifying antirheumatic drugs, including a U.S. trial with hydroxychloroquine and European trials involving methotrexate, rituximab, and abatacept. Another trial with atorvastatin is also underway.
All of the trials involve participants with different risk factors for RA and may thereby provide a range of answers about where the most promising areas for disease prevention lie.
Hydroxychloroquine
Perhaps the broadest in scope of all the studies investigating the prevention of RA is the StopRA (Strategy to Prevent the Onset of Clinically Apparent Rheumatoid Arthritis) trial, which is randomizing 200 subjects with an anticyclic citrullinated peptide 3 (anti-CCP3) that’s greater than twice the normal level, with or without arthralgia, to either hydroxychloroquine (HCQ) 200-400 mg/day or placebo for 1 year, followed by 2 years of follow-up. Pilot data indicated that a level of 40 U/mL or higher of anti-CCP3, which is twice the normal level for positivity, gave a 50% chance of developing RA in the next 3 years regardless of symptoms, family history, or other factors.
The trial’s focus on people with an elevated level of anti-CCP3 limits it to just seropositive individuals, specifically those who are anti-citrullinated protein antibody (ACPA)-positive who constitute about 60%-70% of RA patients with established RA.
The investigators chose to use HCQ because it is a safe and well-tolerated medication for RA, and it may have mechanisms of action that may work particularly well in the early development of RA by blocking inflammation and epitope spreading, Dr. Deane said. “While hydroxychloroquine might not be powerful enough to stop active RA, we hypothesize that it’s just the right drug to block key processes early in its development,” Dr. Deane said in an interview, noting that HCQ is also used to block disease flares in palindromic rheumatism and diminish autoantibody responses in systemic lupus erythematosus.
The StopRA trial is being performed by the Autoimmunity Centers of Excellence, a network sponsored by the National Institutes of Health and the National Institute of Allergy and Infectious Diseases. Enrollment began at 18 U.S. sites in April 2016 with screening of first-degree relatives of patients with RA, community-based screening at health fairs, and finding CCP positive individuals without inflammatory arthritis in rheumatology clinics. The investigators estimate that they will need to screen 20,000 individuals to enroll 200 into the study. Dr. Deane said that he and his coinvestigators hope to use the variables that will arise from the diverse population to later determine subgroups who may respond best to the intervention. “We were concerned that if we made everybody too similar we wouldn’t be able to analyze whether symptoms or other factors mattered or not in who responded to the intervention. It may also allow us to catch some people at an early phase of their autoimmunity and others at a later phase and to determine for future studies when is the best time to intervene in preclinical RA with HCQ.”
It’s possible that HCQ will just delay RA rather than prevent it, Dr. Deane said, perhaps indicating that they may find that HCQ needs to be used longer. In any case, by the time the trial is completed in 2020 the investigators hope to gain rich natural history data to determine how to proceed in future trials, whether they use higher doses, longer-term dosing, or try a different target. In addition, the infrastructure of study sites established in StopRA should be incredibly valuable for future prevention studies.
“I envision a future where everybody is screened for RA risk using good blood tests and then given the opportunity for prevention,” first involving high-risk groups such as family members of people with RA, and then ultimately opening up to population-based screening because 90% of RA occurs in individuals without family history of the disease, Dr. Deane said. An analogy for this might be cardiovascular disease, he said, where we screen the cholesterol level of patients before they have had a heart attack, and if it’s above a certain threshold we prescribe a statin, healthy eating, and exercise in an attempt to prevent cardiovascular events. In the same way, it might be possible to screen people for biomarker risk factors and prescribe a drug and/or a lifestyle change to prevent RA or even prevent many of the other rheumatic diseases including lupus and Sjögren’s syndrome.
Methotrexate
The Dutch TREAT EARLIER (Treat Early Arthralgia to Reverse or Limit Impending Exacerbation to Rheumatoid Arthritis) trial is unique among the RA prevention trials for its inclusion of patients with clinically suspect arthralgia and subclinical inflammation on MRI in the hand or foot without any requirement for seropositivity. The trial’s 200 participants are randomized to methotrexate or placebo for 1 year. All subjects receive an initial 120-mg intramuscular injection of methylprednisolone. The primary outcome measured at 2 years is the frequency of clinically detectable arthritis fulfilling the 2010 European League Against Rheumatism/American College of Rheumatology criteria for RA or of unclassified arthritis with a swollen joint count of more than two joints, both persisting for at least 4 weeks. The trial, which is investigator initiated without industry sponsorship, has been enrolling patients for about 1.5 years and will need about that much more time to complete it.
“We do this because we don’t want to confine ourselves to autoantibody-positive patients; we also want to include the autoantibody-negative patients at risk for RA. That’s relevant because in the past, autoantibody-positive patients had more severe disease and more severe joint destruction, but clinically relevant joint destruction doesn’t develop anymore [because of effective treatment], and the problem is more that RA is still a chronic disease. Both ACPA-positive and -negative RA are chronic diseases.”
All the patients included in the trial are considered to be at risk for RA by rheumatologists because of their arthralgia. Because of the clinically relevant population, the results of TREAT EARLIER might be generalized more easily to daily practice, she said in an interview.
Abatacept
The APIPPRA (Arthritis Prevention in the Preclinical Phase of Rheumatoid Arthritis with Abatacept) trial hopes to find out whether RA or clinical synovitis can be prevented with abatacept (Orencia) 125 mg weekly by comparing it against placebo over a 12-month period in 206 British and Dutch patients with arthralgia who are rheumatoid factor (RF) and ACPA-positive. Subjects who are RF negative, but who carry high levels of serum ACPA defined as three times the upper limit of normal may be included. There will be a 1-year follow-up after the intervention period to monitor patients for arthritis.
The ARIAA (Abatacept Reversing Subclinical Inflammation as Measured by MRI in ACPA Positive Arthralgia) trial is randomizing 98 German patients with ACPA-positive arthralgia to 6 months of abatacept 125 mg weekly for 6 months vs. placebo, followed by a 12-month follow-up period. The primary outcome of the double-blind trial is the proportion of patients with an improvement of acute inflammation characterized as improvement of synovitis or osteitis in the MRI of the dominant hand after 6 months of treatment. The proportion of patients who develop RA based on ACR/EULAR 2010 criteria at 6-month intervals is one of a multitude of secondary outcomes that will be measured. Individuals in the study must test positive for ACPA (with or without RF); have joint pain in the hand, feet, knee, shoulder, or elbow for at least 6 weeks prior to inclusion or in past history; and synovitis or osteitis present on MRI of the dominant hand at baseline.
The two abatacept trials, both of which are expected to be completed in 2018, are sponsored by abatacept’s manufacturer, Bristol-Myers Squibb.
Rituximab
Results from the randomized, placebo-controlled PRAIRI (Prevention of RA by Rituximab) trial that were reported at the annual European Congress of Rheumatology in June showed that a single, intravenous infusion of 1,000 mg of rituximab (Rituxan) given to people with arthralgia and a high risk for developing rheumatoid arthritis did not prevent RA, but the treatment did appear to delay the development of RA. During follow-up, 16 of the 40 people in the placebo group (40%) developed RA after a median of 12 months, and 14 of the 41 in the treated arm (34%) developed RA after a median of 17 months. A Kaplan-Meier survival analysis found that the development of RA in 25% of people occurred at about 12 months in the placebo arm, whereas in the intervention arm it did not occur until 24 months.
At three Dutch centers, the PRAIRI trial investigators enrolled people with arthralgia who had never been diagnosed with arthritis, had never used a disease-modifying antirheumatic drug, and had at least one of these two risk factors: a serum level of IgM rheumatoid factor of more than 12.5 IU/mL and a serum level of anticitrullinated peptide antibodies of more than 25 IU/mL. Enrolled participants also needed to have at least one of the following: a serum level of C-reactive protein greater than 3 mg/L, an erythrocyte sedimentation rate of greater than 28 mm/hr, and evidence of subclinical synovitis identified by either ultrasound or MRI.
Atorvastatin
The STAPRA (Statins to Prevent Rheumatoid Arthritis) trial is randomizing 220 people to double-blind treatment with either atorvastatin 40 mg or placebo for 3 years to determine whether the combined lipid-lowering and anti-inflammatory effects of statin therapy may be able to prevent the development of clinical arthritis in people at increased risk for RA. The participants must test positive for RF and ACPA or a high ACPA titer of three times the cut-off value. Arthralgia is not required, and participants must not have current clinically apparent synovitis. The main endpoint is the development of clinical arthritis as confirmed by a rheumatologist in the study. The trial is scheduled to be completed in 2020.
Investigators across the United States and Europe hope to answer questions surrounding the feasibility of preventing rheumatoid arthritis in a series of proof-of-concept clinical trials that are enrolling patients with various risk factors for the disease. At least five trials have begun – with one already completed – to prevent RA with disease-modifying antirheumatic drugs, including a U.S. trial with hydroxychloroquine and European trials involving methotrexate, rituximab, and abatacept. Another trial with atorvastatin is also underway.
All of the trials involve participants with different risk factors for RA and may thereby provide a range of answers about where the most promising areas for disease prevention lie.
Hydroxychloroquine
Perhaps the broadest in scope of all the studies investigating the prevention of RA is the StopRA (Strategy to Prevent the Onset of Clinically Apparent Rheumatoid Arthritis) trial, which is randomizing 200 subjects with an anticyclic citrullinated peptide 3 (anti-CCP3) that’s greater than twice the normal level, with or without arthralgia, to either hydroxychloroquine (HCQ) 200-400 mg/day or placebo for 1 year, followed by 2 years of follow-up. Pilot data indicated that a level of 40 U/mL or higher of anti-CCP3, which is twice the normal level for positivity, gave a 50% chance of developing RA in the next 3 years regardless of symptoms, family history, or other factors.
The trial’s focus on people with an elevated level of anti-CCP3 limits it to just seropositive individuals, specifically those who are anti-citrullinated protein antibody (ACPA)-positive who constitute about 60%-70% of RA patients with established RA.
The investigators chose to use HCQ because it is a safe and well-tolerated medication for RA, and it may have mechanisms of action that may work particularly well in the early development of RA by blocking inflammation and epitope spreading, Dr. Deane said. “While hydroxychloroquine might not be powerful enough to stop active RA, we hypothesize that it’s just the right drug to block key processes early in its development,” Dr. Deane said in an interview, noting that HCQ is also used to block disease flares in palindromic rheumatism and diminish autoantibody responses in systemic lupus erythematosus.
The StopRA trial is being performed by the Autoimmunity Centers of Excellence, a network sponsored by the National Institutes of Health and the National Institute of Allergy and Infectious Diseases. Enrollment began at 18 U.S. sites in April 2016 with screening of first-degree relatives of patients with RA, community-based screening at health fairs, and finding CCP positive individuals without inflammatory arthritis in rheumatology clinics. The investigators estimate that they will need to screen 20,000 individuals to enroll 200 into the study. Dr. Deane said that he and his coinvestigators hope to use the variables that will arise from the diverse population to later determine subgroups who may respond best to the intervention. “We were concerned that if we made everybody too similar we wouldn’t be able to analyze whether symptoms or other factors mattered or not in who responded to the intervention. It may also allow us to catch some people at an early phase of their autoimmunity and others at a later phase and to determine for future studies when is the best time to intervene in preclinical RA with HCQ.”
It’s possible that HCQ will just delay RA rather than prevent it, Dr. Deane said, perhaps indicating that they may find that HCQ needs to be used longer. In any case, by the time the trial is completed in 2020 the investigators hope to gain rich natural history data to determine how to proceed in future trials, whether they use higher doses, longer-term dosing, or try a different target. In addition, the infrastructure of study sites established in StopRA should be incredibly valuable for future prevention studies.
“I envision a future where everybody is screened for RA risk using good blood tests and then given the opportunity for prevention,” first involving high-risk groups such as family members of people with RA, and then ultimately opening up to population-based screening because 90% of RA occurs in individuals without family history of the disease, Dr. Deane said. An analogy for this might be cardiovascular disease, he said, where we screen the cholesterol level of patients before they have had a heart attack, and if it’s above a certain threshold we prescribe a statin, healthy eating, and exercise in an attempt to prevent cardiovascular events. In the same way, it might be possible to screen people for biomarker risk factors and prescribe a drug and/or a lifestyle change to prevent RA or even prevent many of the other rheumatic diseases including lupus and Sjögren’s syndrome.
Methotrexate
The Dutch TREAT EARLIER (Treat Early Arthralgia to Reverse or Limit Impending Exacerbation to Rheumatoid Arthritis) trial is unique among the RA prevention trials for its inclusion of patients with clinically suspect arthralgia and subclinical inflammation on MRI in the hand or foot without any requirement for seropositivity. The trial’s 200 participants are randomized to methotrexate or placebo for 1 year. All subjects receive an initial 120-mg intramuscular injection of methylprednisolone. The primary outcome measured at 2 years is the frequency of clinically detectable arthritis fulfilling the 2010 European League Against Rheumatism/American College of Rheumatology criteria for RA or of unclassified arthritis with a swollen joint count of more than two joints, both persisting for at least 4 weeks. The trial, which is investigator initiated without industry sponsorship, has been enrolling patients for about 1.5 years and will need about that much more time to complete it.
“We do this because we don’t want to confine ourselves to autoantibody-positive patients; we also want to include the autoantibody-negative patients at risk for RA. That’s relevant because in the past, autoantibody-positive patients had more severe disease and more severe joint destruction, but clinically relevant joint destruction doesn’t develop anymore [because of effective treatment], and the problem is more that RA is still a chronic disease. Both ACPA-positive and -negative RA are chronic diseases.”
All the patients included in the trial are considered to be at risk for RA by rheumatologists because of their arthralgia. Because of the clinically relevant population, the results of TREAT EARLIER might be generalized more easily to daily practice, she said in an interview.
Abatacept
The APIPPRA (Arthritis Prevention in the Preclinical Phase of Rheumatoid Arthritis with Abatacept) trial hopes to find out whether RA or clinical synovitis can be prevented with abatacept (Orencia) 125 mg weekly by comparing it against placebo over a 12-month period in 206 British and Dutch patients with arthralgia who are rheumatoid factor (RF) and ACPA-positive. Subjects who are RF negative, but who carry high levels of serum ACPA defined as three times the upper limit of normal may be included. There will be a 1-year follow-up after the intervention period to monitor patients for arthritis.
The ARIAA (Abatacept Reversing Subclinical Inflammation as Measured by MRI in ACPA Positive Arthralgia) trial is randomizing 98 German patients with ACPA-positive arthralgia to 6 months of abatacept 125 mg weekly for 6 months vs. placebo, followed by a 12-month follow-up period. The primary outcome of the double-blind trial is the proportion of patients with an improvement of acute inflammation characterized as improvement of synovitis or osteitis in the MRI of the dominant hand after 6 months of treatment. The proportion of patients who develop RA based on ACR/EULAR 2010 criteria at 6-month intervals is one of a multitude of secondary outcomes that will be measured. Individuals in the study must test positive for ACPA (with or without RF); have joint pain in the hand, feet, knee, shoulder, or elbow for at least 6 weeks prior to inclusion or in past history; and synovitis or osteitis present on MRI of the dominant hand at baseline.
The two abatacept trials, both of which are expected to be completed in 2018, are sponsored by abatacept’s manufacturer, Bristol-Myers Squibb.
Rituximab
Results from the randomized, placebo-controlled PRAIRI (Prevention of RA by Rituximab) trial that were reported at the annual European Congress of Rheumatology in June showed that a single, intravenous infusion of 1,000 mg of rituximab (Rituxan) given to people with arthralgia and a high risk for developing rheumatoid arthritis did not prevent RA, but the treatment did appear to delay the development of RA. During follow-up, 16 of the 40 people in the placebo group (40%) developed RA after a median of 12 months, and 14 of the 41 in the treated arm (34%) developed RA after a median of 17 months. A Kaplan-Meier survival analysis found that the development of RA in 25% of people occurred at about 12 months in the placebo arm, whereas in the intervention arm it did not occur until 24 months.
At three Dutch centers, the PRAIRI trial investigators enrolled people with arthralgia who had never been diagnosed with arthritis, had never used a disease-modifying antirheumatic drug, and had at least one of these two risk factors: a serum level of IgM rheumatoid factor of more than 12.5 IU/mL and a serum level of anticitrullinated peptide antibodies of more than 25 IU/mL. Enrolled participants also needed to have at least one of the following: a serum level of C-reactive protein greater than 3 mg/L, an erythrocyte sedimentation rate of greater than 28 mm/hr, and evidence of subclinical synovitis identified by either ultrasound or MRI.
Atorvastatin
The STAPRA (Statins to Prevent Rheumatoid Arthritis) trial is randomizing 220 people to double-blind treatment with either atorvastatin 40 mg or placebo for 3 years to determine whether the combined lipid-lowering and anti-inflammatory effects of statin therapy may be able to prevent the development of clinical arthritis in people at increased risk for RA. The participants must test positive for RF and ACPA or a high ACPA titer of three times the cut-off value. Arthralgia is not required, and participants must not have current clinically apparent synovitis. The main endpoint is the development of clinical arthritis as confirmed by a rheumatologist in the study. The trial is scheduled to be completed in 2020.