Tight Disease Control in Early RA




The past decade has brought increasing evidence to support aggressive therapeutic intervention in early rheumatoid arthritis (RA). Treat-to-target strategies that focus on frequent monitoring and treatment adjustments to achieve states of low disease activity or clinical remission have shown superior long-term results. Both oral disease-modifying antirheumatic drugs and biologic agents are effective in treating early RA. It remains unclear if initial combination therapy or biologic use is more effective in early active disease as compared with the traditional approach. The authors review various studies on the treatment of early RA with a focus on studies with a treat-to-target approach.








  • Early diagnosis and early treatment of rheumatoid arthritis (RA) leads to improved long-term outcomes.



  • Treatment in early RA should be targeted to achieve low levels of disease activity or remission.



  • Indices that measure disease activity are helpful to guide changes in therapy.



Key Points


Why is treatment of early rheumatoid arthritis important?


The past decade has witnessed a dramatic change in the management of rheumatoid arthritis (RA). In contrast to the textbook description of patients with joint deformities, today patients who receive adequate treatment often bear no stigmata of the disease. The era of biologic disease-modifying antirheumatic drugs (DMARDs) has done more than just place new medications at our disposal; there has been a paradigm shift in the way we view disease management, especially in early disease. We now know that erosive joint disease can occur within months of symptom onset. Loss of function can also occur early in the disease course and may be irreversible thereafter. Recent studies indicate that the high inflammatory burden of early RA may cause the progression of atherosclerotic disease earlier than previously anticipated. The disease process may start earlier than the onset of symptoms suggested by the presence of autoantibodies before disease manifestation.


Early RA is thought to offer a window of opportunity whereby the disease is more sensitive to treatment and during which therapeutic intervention has the potential to alter the disease course. Therefore, the emphasis is on early diagnosis and treatment. Good response early in the disease course is thought to be predictive of better long-term outcomes. Although there is no clear definition of early RA, most clinical trials use disease duration of 3 to 24 months from symptom onset. A survey of rheumatologists indicated that most physicians considered early RA as disease duration of less than 3 months. In 2010, The American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) developed new RA classification criteria to aid the recognition of and facilitate clinical studies in early disease.




Treat to target: but what target?


If we accept the concept of treating to a target, a critical question is: what is the target to which we should treat? Today remission is thought to be an achievable goal of treatment. Remission may be thought of as a state of total absence of articular or extraarticular inflammation, therefore, a complete arrest of disease progression. However, it is impossible to ascertain a complete lack of inflammation and, thus the concept of clinical remission was developed, which would be defined by the absence of activity on measurable parameters and could be widely applicable. It is important to remember that clinical remission does not reflect a true absence of inflammation, and joint damage is known to progress in patients with clinical remission. Also, it may not be possible to attain clinical remission in all patients. If clinical remission cannot be attained in an individual, a state of low disease activity or minimal disease activity is an acceptable alternative. A variety of disease indices have been developed that measure disease activity and define clinical remission; most were developed for randomized control studies. These indices use composite scores reflecting joint counts, inflammatory markers, and physician and patient assessment of disease activity. The international task force on treating RA to target suggests: “The primary target for treatment of rheumatoid arthritis should be a state of clinical remission.” This statement underscores the need of a tool that clearly defines remission, detects minimal levels of disease activity, and is easily applicable to clinical practice.


Of the various indices, the disease activity score (DAS) and the DAS 28 are among the earliest and most widely used in clinical trials. The DAS is a composite score of a 53 tender or 44 swollen joint count, erythrocyte sedimentation rate (ESR), and a patient global assessment on a visual analog scale of 1 to 100. A computational device is required to calculate the score. Possible scores range from 0 to 9. Remission is defined as DAS less than 1.6. The DAS 28 is similar to the DAS except it uses a 28 joint count for tender and swollen joints; the hips, ankles, and feet findings are excluded from the score. The scores can range from 0 to 9, with remission being defined as DAS 28 less than 2.6. This score has been validated to be as effective as the DAS but allows for multiple tender or swollen joints in the lower extremities while achieving scores consistent with remission.


The ACR and EULAR response criterion were both developed to quantify the changes occurring with treatment with an active drug versus placebo. ACR 20, 50, and 70 is defined as a 20%, 50%, and 70% improvement, respectively, in the number of swollen and tender joint counts and a similar improvement in 3 of 5 variables: patient and physician global assessment, health assessment questionnaire (HAQ), ESR, or C-reactive protein (CRP). The EULAR response criterion define good, moderate, and no response based on the current level of disease activity and the decrease in disease activity from a prior time point by a DAS or DAS 28. For example, a reduction in a DAS 28 by more than 1.2 combined with a current DAS 28 less than 2.6 would be a good response. A reduction in a DAS 28 by more than 1.2 combined with a current DAS 28 of 4.0 would qualify as a moderate response. Because both the ACR and EULAR response require the measurement of disease activity at 2 time points, they are difficult to implement in clinical practice. The EULAR criteria are thought to more accurately reflect disease activity as compared with the ACR criteria.


The simplified disease activity index (SDAI) is the numeric value of a 28 swollen and tender joint count, CRP, and a patient and physician global assessment of disease activity on a visual analog scale of 1 to 10. SDAI scores can range from 0 to 86. Remission is defined as a score of less than 3.3. The clinical disease activity index (CDAI) is similar to the SDAI except it does not need the measurement of CRP. Scores range from 0 to 76, and remission is defined as a score of less than 2.8. Both of these indices use a more stringent cutoff, allowing for less swollen and tender joint counts as compared with the DAS 28. The CDAI has the advantage of not requiring a laboratory parameter and can be completed at the time of the office visit, making it more suitable for office practice.


Pincus and colleagues developed an index, the Routine Assessment of Patient Index Data 3 (RAPID 3), that is based purely on patient-reported measures. Patients rate 3 measures: a multidimensional HAQ questionnaire (10 questions), a pain visual analog scale from 1 to 10, and a global status visual analog scale from 1 to 10. The sum of these divided by 3 gives a number from 1 to 10, which constitutes the RAPID 3 score. This score has been validated to correlate significantly with the DAS 28 and the CDAI indices. This index, however, does not take into account any joint assessment for tender or swollen joints.


In 2011, the ACR and EULAR proposed that remission for clinical trials can be defined in one of two ways. A Boolean based definition where patients satisfy all three criteria of tender joint count less than or equal to 1, swollen joint count less than or equal to one and CRP less than or equal to 1. Alternatively an index based definition may be used where remission is defined as SDAI of less than or equal to 3.3. This definition can be modified for clinical practice by substituting CRP with a patient global assessment score.


If remission cannot be attained, minimal disease activity is an alternative goal. Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) has proposed 2 definitions for minimal disease activity (MDA). Five out of 7 criterion had to be met: a patient pain visual analog scale less than or equal to 2 (1–10), swollen joint count less than or equal to 1 (1–28), tender joint count less than or equal to 1 (1–28), HAQ less than or equal to 0.5 (1–3), physician global assessment less than or equal to 1.5 (1–10), patient global assessment less than or equal to 2 (1–10), and an ESR less than or equal to 10. A DAS 28 less than 2.8 was also thought to reflect MDA. The EULAR task force recommendations on treating RA to target emphasize the importance of using a validated composite measure that includes joint assessment in clinical practice.




Treat to target: but what target?


If we accept the concept of treating to a target, a critical question is: what is the target to which we should treat? Today remission is thought to be an achievable goal of treatment. Remission may be thought of as a state of total absence of articular or extraarticular inflammation, therefore, a complete arrest of disease progression. However, it is impossible to ascertain a complete lack of inflammation and, thus the concept of clinical remission was developed, which would be defined by the absence of activity on measurable parameters and could be widely applicable. It is important to remember that clinical remission does not reflect a true absence of inflammation, and joint damage is known to progress in patients with clinical remission. Also, it may not be possible to attain clinical remission in all patients. If clinical remission cannot be attained in an individual, a state of low disease activity or minimal disease activity is an acceptable alternative. A variety of disease indices have been developed that measure disease activity and define clinical remission; most were developed for randomized control studies. These indices use composite scores reflecting joint counts, inflammatory markers, and physician and patient assessment of disease activity. The international task force on treating RA to target suggests: “The primary target for treatment of rheumatoid arthritis should be a state of clinical remission.” This statement underscores the need of a tool that clearly defines remission, detects minimal levels of disease activity, and is easily applicable to clinical practice.


Of the various indices, the disease activity score (DAS) and the DAS 28 are among the earliest and most widely used in clinical trials. The DAS is a composite score of a 53 tender or 44 swollen joint count, erythrocyte sedimentation rate (ESR), and a patient global assessment on a visual analog scale of 1 to 100. A computational device is required to calculate the score. Possible scores range from 0 to 9. Remission is defined as DAS less than 1.6. The DAS 28 is similar to the DAS except it uses a 28 joint count for tender and swollen joints; the hips, ankles, and feet findings are excluded from the score. The scores can range from 0 to 9, with remission being defined as DAS 28 less than 2.6. This score has been validated to be as effective as the DAS but allows for multiple tender or swollen joints in the lower extremities while achieving scores consistent with remission.


The ACR and EULAR response criterion were both developed to quantify the changes occurring with treatment with an active drug versus placebo. ACR 20, 50, and 70 is defined as a 20%, 50%, and 70% improvement, respectively, in the number of swollen and tender joint counts and a similar improvement in 3 of 5 variables: patient and physician global assessment, health assessment questionnaire (HAQ), ESR, or C-reactive protein (CRP). The EULAR response criterion define good, moderate, and no response based on the current level of disease activity and the decrease in disease activity from a prior time point by a DAS or DAS 28. For example, a reduction in a DAS 28 by more than 1.2 combined with a current DAS 28 less than 2.6 would be a good response. A reduction in a DAS 28 by more than 1.2 combined with a current DAS 28 of 4.0 would qualify as a moderate response. Because both the ACR and EULAR response require the measurement of disease activity at 2 time points, they are difficult to implement in clinical practice. The EULAR criteria are thought to more accurately reflect disease activity as compared with the ACR criteria.


The simplified disease activity index (SDAI) is the numeric value of a 28 swollen and tender joint count, CRP, and a patient and physician global assessment of disease activity on a visual analog scale of 1 to 10. SDAI scores can range from 0 to 86. Remission is defined as a score of less than 3.3. The clinical disease activity index (CDAI) is similar to the SDAI except it does not need the measurement of CRP. Scores range from 0 to 76, and remission is defined as a score of less than 2.8. Both of these indices use a more stringent cutoff, allowing for less swollen and tender joint counts as compared with the DAS 28. The CDAI has the advantage of not requiring a laboratory parameter and can be completed at the time of the office visit, making it more suitable for office practice.


Pincus and colleagues developed an index, the Routine Assessment of Patient Index Data 3 (RAPID 3), that is based purely on patient-reported measures. Patients rate 3 measures: a multidimensional HAQ questionnaire (10 questions), a pain visual analog scale from 1 to 10, and a global status visual analog scale from 1 to 10. The sum of these divided by 3 gives a number from 1 to 10, which constitutes the RAPID 3 score. This score has been validated to correlate significantly with the DAS 28 and the CDAI indices. This index, however, does not take into account any joint assessment for tender or swollen joints.


In 2011, the ACR and EULAR proposed that remission for clinical trials can be defined in one of two ways. A Boolean based definition where patients satisfy all three criteria of tender joint count less than or equal to 1, swollen joint count less than or equal to one and CRP less than or equal to 1. Alternatively an index based definition may be used where remission is defined as SDAI of less than or equal to 3.3. This definition can be modified for clinical practice by substituting CRP with a patient global assessment score.


If remission cannot be attained, minimal disease activity is an alternative goal. Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) has proposed 2 definitions for minimal disease activity (MDA). Five out of 7 criterion had to be met: a patient pain visual analog scale less than or equal to 2 (1–10), swollen joint count less than or equal to 1 (1–28), tender joint count less than or equal to 1 (1–28), HAQ less than or equal to 0.5 (1–3), physician global assessment less than or equal to 1.5 (1–10), patient global assessment less than or equal to 2 (1–10), and an ESR less than or equal to 10. A DAS 28 less than 2.8 was also thought to reflect MDA. The EULAR task force recommendations on treating RA to target emphasize the importance of using a validated composite measure that includes joint assessment in clinical practice.




Treatment of early RA: early initiation of DMARD therapy


While treating RA, earlier and more intensive therapy has been shown to be superior to conventional care. If treated within a few months, the disease may be more responsive to DMARD therapy and it may eventually be possible to scale back therapy, signifying a window of opportunity. There is a long history of studies supporting the early administration of DMARDs. One of the first studies to demonstrate this was conducted by Egsmose and colleagues, which showed that the immediate administration of auranoffin was clearly superior to waiting 8 months to begin this agent. There was both functional and radiographic advantage to the former approach that was maintained for an additional 3 years of follow-up. It is noteworthy that this difference was shown with an agent that is not generally considered one of the more effective DMARDs.


Similarly, an open-label study from the Mayo Clinic studied patients with early RA of less than 1-year for response to hydroxychloroquine, if patients did not have an ACR 50 response on hydroxychloroquine alone, methotrexate was added. At 24 months, 59 of 94 patients achieved an ACR 50 response on hydroxychloroquine alone. High pain scores, presence of rheumatoid factor, higher number of swollen joints were factors associated with inability to achieve an ACR 50 response on hydroxychloroquine alone.


The Computer Assisted Management of Early Rheumatoid Arthritis (CAMERA) study looked at 299 patients with a disease duration of less than 1 year who were treated with methotrexate. One group received monthly follow-up with rapid up-titration of methotrexate dose and the addition of cyclosporine. Change of therapy was guided to meet predefined criteria by a computerized decision-making program. The other group had a follow-up every 3 months and received conventional therapy. Fifty percent of the patients in the intensive therapy arm achieved remission compared with 37% in conventional therapy at some point during the 2-year study. The 5-year follow-up results from the CAMERA study found that patients who had a good EULAR response at 6 months had favorable radiographic and disease activity outcomes at 5 years regardless of the therapy used.


A study by Nell and colleagues compared the treatment response of a very-early group (mean disease duration of 3 months) to a late-early group (mean duration of 12 months). Both groups were treated with oral DMARD therapy. At 36 months of follow-up, the very-early RA group had a mean improvement in the DAS 28 of 2.8 ± 1.5 compared with 1.7 ± 1.2 in the late-early RA group ( P <.05). Radiographic progression as measured by the Larsen score increased by 3.6 ± 6.5 in the very-early group versus 14.7 ± 9.9 in the late-early group ( P <.05). This finding suggests that very-early disease may be more responsive to DMARD therapy.


The Finnish Rheumatoid Arthritis Combination Therapy (FIN RaCO) trial was one of the first studies to demonstrate long-term benefits of initial combination therapy. The initial cohort of 195 patients with disease duration less than 2 years was recruited between 1993 and1995 and followed up to 11 years. Ninety-seven of 195 patients received combination therapy with sulfasalazine, methotrexate, hydroxychloroquine, and prednisolone. Ninety-eight patients received single drug therapy with sulfasalazine or methotrexate with or without prednisolone. The aim of therapy was the induction of remission as measured by the ACR criteria. At the end of 2 years, 37% of the patients in combination therapy versus 18% of patients in single drug therapy were in remission. There was also a significantly higher ACR 50 response and less radiographic progression (measured by Larsen scores) in the combination therapy group. At the end of 2 years, more patients in the single drug therapy were on steroids.


After 2 years, therapy was unrestricted and all patients were treated at their rheumatologist’s discretion, with treatment targeted to remission. After 11 years, follow-up was complete with 68 patients from the initial combination group and 70 patients from the single drug therapy group. The modified MDAs were met by 63% in the initial combination therapy group versus 43% in the initial single therapy group. DAS 28 remission was reached in 57% of the patients in the initial combination therapy versus 49% of the patients in the initial single drug therapy group. The ACR remission criteria were met more often at 2, 5, and 11 years in the combination therapy group. Early combination therapy improved the long-term radiographic outcome at 11 years. This finding shows that intensive treatment of early active disease, perhaps with initial combination therapy, can result in improved long-term outcomes both in terms of functional outcomes and radiographic stability.




Treatment of early RA: early initiation of biologic therapy


Since the advent of the biologic DMARDs, there has been much discussion and speculation about whether such agents should be used in the initial treatment regimen of RA. The argument for so doing relies on the consistent observation in numerous studies for Food and Drug Administration approval that radiographic change, in the aggregate, progresses less in the patients treated with biologics as compared with methotrexate in established RA. For example, the Anti TNF Therapy in RA with Concomitant Therapy (ATTRACT) study found that in 428 patients who were randomized to receive methotrexate plus infliximab versus methotrexate plus placebo, median change from baseline at week 102 in Sharp scores was 4.25 in patients who received methotrexate alone versus 0.5 in patients who received infliximab plus methotrexate ( P <.001). Furthermore, when patients with early disease are studied, the difference in radiographic progression between the two treatment groups is even more striking. A subgroup analysis of 82 patients with early disease (<3 years duration) from the ATTRACT study, the median change in Sharp scores at 102 weeks was 12.21 in the methotrexate alone group versus 0.49 in the methotrexate plus infliximab combination group ( P <.001).


Similar results have been observed with other tumor necrosis factor (TNF) inhibitors. The PREMIER study included 799 patients with RA with a mean disease duration of 1 year. Patients were randomized to methotrexate monotherapy, adalimumab monotherapy, or a combination of methotrexate and adalimumab. The primary end point at 2 years was an ACR 20 response and change from baseline in the Sharp score. At 1 year of therapy, 62% in the combination group, 41% in adalimumab group, and 46%in methotrexate group achieved an ACR 50 response. Superior response and significantly less radiographic progression were seen in the combination group at the end of 2 years. A change in Sharp scores at 1 and 2 years were 1.3 and 1.9 in the combination group, 3.0 and 5.5 in the adalimumab monotherapy group, and 5.7 and 10.4 in the methotrexate monotherapy groups, respectively. There was no difference in serious adverse events across groups.


Etanercept versus methotrexate in early rheumatoid arthritis (ERA) trial, 632 patients with a mean disease duration of 1 year were treated with etanercept monotherapy versus methotrexate monotherapy. At 24 months, the patients treated with etanercept 25 mg twice every week had a significantly greater response than the methotrexate monotherapy group ACR 20 response 72% and 59% respectively ( P <.005). A change in the Sharp score and erosion score in the etanercept group was 1.3 and 0.66 units, respectively, compared with 3.2 and 1.86 in the methotrexate group. The study also reported a significant improvement in the HAQ disability index. A subset of 148 patients who received etanercept from this trial was compared with 464 patients with late disease (mean duration of 12 years) who also received etanercept. The mean HAQ score was similar at the onset of therapy in both groups; however, at the end of 3 years of treatment, 26% of the patients with early disease had an HAQ score of 0, whereas only 14% of patients in the late therapy achieved the same result ( P <.0095). This finding signifies that early treatment can have significant benefits at limiting disability.


The Active-Controlled Study of Patients Receiving Infliximab for the treatment of Rheumatoid Arthritis of Early Onset study group studied the effects of elevated levels of ESR and CRP as well as swollen joint count on radiographic progression in patients on methotrexate monotherapy versus a combination of methotrexate and infliximab. They reported that ESR, CRP, and swollen joint counts were associated with joint damage in patients treated with methotrexate but not associated with joint damage in patients treated with a combination therapy of methotrexate and infliximab. The mean changes in the Sharp score among patients with a CRP of more than 3 and an ESR of more than 52 in the methotrexate-only group were 5.62 and 5.89, respectively, compared with 0.73 and 1.12 in the combination group ( P <.001). This finding suggests that very active early disease may benefit from initial TNF therapy. The same group also studied radiographic progression in patients of different disease activity states by an SDAI in methotrexate monotherapy versus a combination therapy of methotrexate and infliximab. A total of 1049 patients with early disease were randomized into 3 groups: methotrexate monotherapy, combination therapy with infliximab 3 mg/kg, or combination therapy with infliximab 6 mg/kg. They found that in patients on methotrexate monotherapy, radiographic progression was halted only in those who achieved SDAI remission. In both combination therapy groups radiographic progression was halted in patients who achieved remission. In patients who achieved low to moderate activity by SDAI radiographic progression was halted or retarded respectively. Results such as these have given rise to the thought that there may be uncoupling of inflammation and bone damage in the setting of anti-TNF therapy.


However, caution is warranted on several grounds. First, the Sharp score differences in the short-term trials are small, and it is unclear what the implications are for damage and function in the long-term. More importantly, probability analysis has consistently demonstrated that the aggregate difference in radiographic change results from only about 20% of the study cohort; in other words, for approximately 80% of patients in such studies, there is no difference between the two treatment groups in radiographic progression. Regrettably, we currently have no way to reliable prospectively identify the patients most likely to enjoy the difference in radiograph progression.

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Oct 1, 2017 | Posted by in RHEUMATOLOGY | Comments Off on Tight Disease Control in Early RA

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