Delving into the literature, this author discusses the current thinking on key markers of early disease activity in patients with rheumatoid arthritis (RA), reviews the impact of anti-TNF medications in early RA and assesses the potential of emerging biologic agents.

Rheumatoid arthritis (RA) affects more than two million adults in the United States.¹ In the past decade, the advent of tumor necrosis factor inhibitors for the treatment of RA has ushered in a new era of targeted biologic modalities. We have seen a shift to more aggressive therapy involving earlier treatment and the use of multiple medications in combination. Although the long-term effects of new treatment approaches are not yet fully known, early results appear favorable.
       A substantial proportion of patients with inflammatory arthritis of short duration have remission and only some patients with persistent disease will go on to develop RA.² Therefore, it is important to determine genetic, clinical, serological or radiographic markers that allow clinicians to identify patients with early disease destined for RA so they can provide appropriately targeted therapy.
       Functional alterations in cytokine regulation can predict and affect destructive disease among patients with early disease. In a genetic analysis to establish prognostic markers, Prots et al., showed that the 150V IL4R single-nucleotide polymorphism may be a candidate marker for early radiographic bone erosions in patients with RA.³ Khanna et al., showed that the TNFA-308 polymorphism is associated with significantly higher radiographic progression in a cohort of early seropositive RA patients.⁴
       Markers of inflammation or osteoclast activation can also provide information on the likelihood of joint destruction among patients with early disease. Aside from an elevated baseline erythrocyte sedimentation rate, researchers have recently shown that the osteoprotegrin/RANKL ratio is inversely related to bone destruction among patients with RA who have not been previously treated with disease modifying antirheumatic drug (DMARD) therapy.^5,6 When it comes to serological findings, antibodies to citrullinated peptides (anti-CCP) serve as specific disease markers whose appearance in the blood can predate the onset of symptoms.⁷
       The presence of anti-CCP2 antibodies during the first three years of RA diagnosis has been associated with more radiographic progression of disease and may also predict damage by bone marrow edema on MRI views of the hands of patients with early RA.^8,9 In regard to radiologic studies, ultrasound can show synovitis as well as cortical bone lesions not visible on plain films while MRI can demonstrate local areas of bone edema, which frequently progress to erosions demonstrated by plain radiographs.
       A small prospective study showed that erosions of the metacarpophalangeal joints on MRI can be helpful in diagnosing RA among patients with mild signs and symptoms, a negative anti-CCP test and no erosions on radiographs.¹⁰ Although MRI may be expensive, using MRI during early disease can clarify the diagnosis and allow one to initiate therapy when plain X-rays may be unrevealing. In a study by Lindegaard et al., bone erosions and/or edema on extremity MRI were predictive of joint damage on radiographs one year later.¹¹
       Radiographic progression occurs early and continues over the lifetime of a patient with RA. Up to 70 percent of patients can show radiographic damage after three years and the rate of progression in the first year is significantly greater than in the following two years.¹² Results of many studies suggest an optimal window of opportunity early in the course of RA in which treatment appears to facilitate favorable long-term clinical outcomes.

Early Treatment With DMARDs: Can It Have An Impact?

Initiating treatment with DMARDs early yields critical functional and clinical benefits that seem to slow radiographic progression. Even a delay of eight to nine months in DMARD initiation could lead to irreversible damage.¹³
       Data from the COBRA trial showed that clinicians can rapidly suppress inflammation in patients with early RA with the benefit often lasting longer than the duration of suppression.¹⁴ An initial six-month cycle of intensive combination therapy (step-down combination therapy with prednisolone, methotrexate and sulfasalazine) led to sustained suppression of radiographic progression in patients with early disease, regardless of subsequent treatment.¹⁵ In a study comparing the effect of early versus delayed treatment in patients with recent onset RA, the prompt initiation (median 15 days) of either chloroquine or salazopyrine versus a median delay of 123 days was correlated with better disease outcomes and significantly lower Sharp scores.¹⁶
       Patients with RA who have experienced inadequate response to DMARD therapy have been shown to benefit from treatment with TNF inhibitors.¹³ Results of a 12-month controlled trial in 20 patients with early, previously untreated RA and poor prognosis showed that induction therapy with infliximab plus methotrexate yielded a significant reduction in joint erosions and synovitis at one year as assessed by MRI.¹⁷ Importantly, patients had sustained functional benefit and quality of life at two years despite infliximab withdrawal after one year of therapy, providing further evidence to support the use of early treatment.
       Another example was the PREMIER study, which involved patients who had RA for less than three years and had symptoms that were not relieved by methotrexate. These patients received adalimumab and methotrexate or either therapy alone. Combination therapy was superior to monotherapy in improving both signs and symptoms. Forty-nine percent had clinical remission with a disease activity score (DAS) <2.6 at two years. In this study, researchers also found that combination therapy was superior to monotherapy when it came to inhibiting radiographic progression of disease.¹⁸
       Data from studies of etanercept (Enbrel, Wyeth), infliximab (Remicade, Centocor) and adalimumab (Humira, Abbott) all indicate that the use of anti-TNF therapy in early disease may reduce disability and radiographic progression more than in late disease.
       For example, during the Early Erosive Rheumatoid Arthritis (ERA) trial, the substantial reduction in Health Assessment Questionnaire (HAQ) scores researchers observed in patients treated with etanercept was greater than that observed in other studies in patients with established disease.¹⁹ A sub-analysis of an adalimumab study at 52 weeks showed that the modality was effective in patients with both early and late RA. However, researchers observed a trend toward higher efficacy in patients with disease of less than two years in duration.²⁰
       The two-year Anti-TNF Trial In Rheumatoid Arthritis With ConComitant Therapy (ATTRACT) evaluated the effect of methotrexate plus infliximab on the progression of structural damage in patients with RA who experienced a suboptimal response to methotrexate. In patients with established disease, the mean change from baseline in modified Sharp scores was 12.6 points in patients receiving methotrexate and 1 point in patients receiving methotrexate plus infliximab. However, in patients with early disease, the mean change in Sharp scores was 25 points in the former group and -0.54 in the latter group. This suggested that early treatment with infliximab plus methotrexate may confer long-term benefit by preserving joint integrity and inhibiting disease progression.²¹
       Researchers have also shown that the extent of clinical or radiographic progression in RA varies by the severity of disease. In efficacy studies of etanercept for example, researchers observed better outcomes among patients with moderate than severe disease. One retrospective analysis assessed four randomized clinical trials in which patients with early RA or later, DMARD-refractory received either methotrexate, etanercept or methotrexate plus etanercept. Researchers found that patients with moderate disease, as measured by DAS28, were more likely to achieve DAS28 remission than patients with severe disease at six months in the combination group (61.9 percent versus 24.2 percent respectively).²²
       Patients with RA suffer not just physical but also serious social and economic consequences due to their disease. The benefits of disease control translate into quality of life and economic benefits as well. Work impairment is common at presentation in patients with RA. After diagnosis, 40 percent of patients suffer job loss within five years.²³ Smolen et al., demonstrated that treatment with methotrexate and infliximab enabled patient to maintain employment with fewer lost workdays.²⁴
       In the Prevention of Work Disability (PROWD) study, methotrexate naïve patients with early RA and related work impairment received either a placebo plus methotrexate (n=73) or adalimumab plus methotrexate (n=75) for 56 weeks. At 56 weeks, all cause imminent job loss was reported by 39.7 percent of patients in the placebo group versus 18.7 percent in the adalimumab group.²³ Similarly, researchers have associated etanercept with higher employment retention rates (55 percent versus 41 percent in non-etanercept users) and a greater number of hours worked (1940 versus 1839 hours/year).²⁵

When Patients Fail Methotrexate Therapy

Abatacept (Orencia, Bristol-Myers Squibb), one of the newer biologic agents introduced for the treatment of RA in 2005, was initially the subject of a 12-month, multicenter, randomized, controlled, double-blind trial involving 339 patients with active RA despite methotrexate therapy.
       At one year, abatacept demonstrated favorable ACR20 response rates (63 percent versus 36 percent), ACR50 response rates (42 percent versus 20 percent) and ACR70 response rates (21 percent versus 8 percent) in comparison to placebo. Researchers found that abatacept therapy was associated with significant reduction in disease activity and improvement in physical function. Over the course of the year, they found the modality to be generally safe and well tolerated.²⁶
       Improvement was even greater in the phase III, one-year Abatacept in Inadequate Responders to Methotrexate (AIM) study, a multicenter trial involving 652 patients with RA who had an inadequate response to methotrexate. At one year, researchers compared response rates between abatacept and placebo. They noted favorable ACR20 response rates (73.1 percent versus 39.7 percent), ACR50 response rates (48.3 percent versus 18.2 percent) and ACR70 response rates (28.8 percent versus 6.1 percent).²⁷ Patients treated with abatacept also demonstrated significant slowing of structural damage progression in comparison to patients treated with placebo. Total mean changes in structural damage progression were 1.21 for abatacept and 2.32 for placebo from a baseline score of 45.

Switching To Another Anti-TNF Agent: What One Study Shows

Clinical experience and studies have shown that many patients have either no response or an inadequate or un-sustained response to TNF inhibitors. Researchers conducted the ReAct trial to investigate the safety and efficacy of adalimumab in patients with RA who had failed treatment with etanercept and/or infliximab.²⁸
       Outcome data at 12 weeks showed that adalimumab was well-tolerated and effective, regardless of previous anti-TNF therapy or reasons for discontinuing such therapy. Researchers achieved ACR20, ACR50, ACR70 responses in 70 percent, 41 percent and 19 percent, respectively, of adalimumab-treated patients with no previous history of etanercept or infliximab use (n=5,713). They also noted ACR20, ACR50 and ACR70 responses of 61 percent, 33 percent and 14 percent, respectively, of adalimumab-treated patients who had previously received therapy with etanercept and/or infliximab (n=819).²⁸
       These data support the use of a different TNF antagonist in patients who have failed initial anti-TNF therapy.

Assessing The Current Literature On Abatacept

The only head-to-head comparison of drugs in different biologic classes with placebo was recently reported as a multicenter, double-blind, randomized trial between abatacept or infliximab versus placebo in patients with an inadequate response to previous methotrexate and no previous exposure to anti-TNF therapy.²⁹
       Patients received approximately 10mg/kg of abatacept every four weeks (n=156), 3mg/kg infliximab every eight weeks (n=165) or placebo every four weeks (n=110) following standard loading doses with a background of methotrexate. The HAQ scores at six months were significantly higher in the abatacept and infliximab groups than the scores for the placebo group. The percentage of patients who achieved remission (DAS28<2.6) was 11.3 percent in the abatacept group, 12.8 percent in the infliximab group and 2.9 percent in the placebo group.²⁹
       At one year, significantly more patients in the abatacept group (35.3 percent) than in the infliximab group (22.4 percent) had a DAS28 of 3.2 or below. Finally, 18.7 percent of the abatacept group and 12.2 percent of the infliximab group achieved remission.²⁹
       Overall, these data suggest that both abatacept and infliximab are promising therapeutic options for patients with RA with an inadequate response to methotrexate, with the study finding better clinical measures at one year for abatacept versus infliximab. However, many patients in our practices receive more than 3mg/kg of infliximab. The use of higher infliximab doses in this study would have been interesting.
       In the six-month Abatacept Trial in Treatment of Anti-TNF Inadequate Responders (ATTAIN) study, researchers found that abatacept facilitated a significant clinical benefit at six months. In the 391-patient study comparing abatacept versus placebo, 50 percent of abatacept-treated patients achieved an ACR 20 in comparison to 20 percent in the placebo group, 20 percent achieved an ACR 50 in comparison to 4 percent in the placebo group, and 10 percent achieved an ACR 70 response in comparison to 2 percent in the placebo group.³⁰
       Schiff et al., recently presented new data from the international, six-month, open-label, phase IIIb Abatacept Researched in Rheumatoid Arthritis Patients with an Inadequate Anti-TNF Response to Validate Effectiveness (ARRIVE) trial. The objective was to assess the clinical safety and tolerability of abatacept in patients typically encountered in clinical practice, specifically to calculate the risk of adverse events when clinicians switched these patients from a TNF inhibitor to abatacept without a washout period.³¹
       Researchers assessed 1285 patients with active RA who had received anti-TNF therapy for at least three months, and divided these patients into prior users and current users. Abatacept was generally safe and well tolerated in both groups, regardless of whether a washout period followed TNF-inhibitor use. The authors concluded that clinicians should not expect any additional risk of adverse events, even if refractory patients have not had a “biologic holiday” before initiating abatacept.³¹

Targeting B Cells: A Closer Look At Rituximab

Although the specific role of B cells in the etiology of rheumatoid arthritis is not fully understood, studies of rituximab, a B-cell depleting therapy, suggest it is significant. In February 2006, the FDA approved rituximab (Rituxan, Genentech) for the treatment of moderate to severe RA when used with methotrexate in patients with an inadequate response to prior use of TNF inhibitors.
       Data from the Randomized Evaluation of Long Term Efficacy of Rituximab in RA (REFLEX) study in patients with active RA and an inadequate response to one or more anti-TNF agents showed favorable responses at 24 weeks for the combination of rituximab and methotrexate. Fifty-one percent of the combination therapy group had an ACR20 response in comparison to 18 percent in the methotrexate monotherapy group. Twenty-seven percent of the combination therapy group had an ACR50 response as opposed to 5 percent in the methotrexate monotherapy group. Twelve percent of the combination therapy group had an ACR70 response as opposed to 1 percent in the methotrexate monotherapy group.³²
       Researchers have shown reduced radiographic progression at one year with rituximab as well.³³ Cohen et al., reported on a specific subgroup of 457 REFLEX patients for whom radiographic data were available at week 56. Rituximab-treated patients experienced inhibition of structural damage progression by at least 50 percent as assessed by the Sharp-Genant total score, only when researchers subgrouped and stratified these patients according to baseline anti-CCP status. The researchers noted that anti-CCP negative patients progressed at the same rate as those in the placebo group.
       Researchers also showed that rituximab-treated patients in the REFLEX study demonstrated clinical improvement and higher remission rates in comparison to those taking the placebo, as measured by simplified disease activity index (SDAI) and clinical disease activity index (CDAI) scores. One may use these scores to analyze treatment efficacy in clinical practice.³⁴
       Recently, van Vollenohoven et al., evaluated the long-term safety of single and multiple rituximab courses in patients with active RA.³⁵ As of September 2006, a total of 1,053 RA patients had been exposed to rituximab in a clinical program (2,438 patient years). Researchers followed 700 patients for more than two years and followed 120 patients for more than three years.
       Patients received up to seven treatment courses. Repeated rituximab dosing was based on recurrence of RA disease activity. A total of 684, 400, and 142 patients received at least two, three or four courses of rituximab respectively. The percentage of patients experiencing adverse events decreased from 88 percent after course one to 81 percent, 72 percent and 65 percent following courses two, three and four respectively. Serious adverse events followed a similar pattern (18 percent, 15 percent, 10 percent and 3 percent respectively).³⁵
       In all, 702 patients (67 percent) experienced at least one infection. The number of serious infections per 100 patient years remained stable despite repeated courses of rituximab. In this series, researchers did not observe opportunistic infections, viral reactivations and tuberculosis. The proportion of patients with immunoglobulin (Ig) G and IgM levels below the lower limit of normal increased with further treatment courses. Patients having IgG concentrations in the lower quartile showed a trend toward more overall infections but not serious infections. Acute infusion reactions decreased with repeated courses of rituximab (23 percent with course one to 11 percent with course four).

Biologic Agents And Potential Side Effects: What You Should Know

Malignancies associated with the use of biologic agents in RA have been the subject of recent investigation. At the 2007 European League Against Rheumatism (EULAR) conference, Simon et al., compared safety data from abatacept clinical trials (4,134 patients) with those from a very large, retrospective, international cohort of 94,000 RA patients treated with a number of non-biologic DMARDs, and found no increase in the standardized incidence ratios of overall malignancies, lung cancer or lympoma.³⁶
       Bongartz et al., calculated a pooled odds ratio for malignancies and serious infections in patients treated with TNF inhibitors as compared with placebo.³⁷ The pooled odds ratio for malignancy was 3.3 and was 2.0 for serious infection. For patients treated with TNF inhibitors in the included clinical trials, the number needed to harm was 154 for one additional malignancy to occur within a treatment period of six to 12 months. For serious infections, the number needed to harm was 59 within a treatment period of three to 12 months. The authors concluded that there is evidence of an increased risk of serious infections and a dose-dependent increased risk of malignancy in patients with RA who receive TNF inhibitors.
       It is not known whether the higher risk one sees with higher doses of these drugs is associated with the disease, its severity or with past or current exposure to other drugs (e.g., methotrexate and azathioprine). A recent report of 10,815 patients who received anti-TNF therapy showed that the incidence of lymphoma did not increase but the odds ratio for patients who received anti-TNF therapy plus methotrexate in comparison to patients who received methotrexate alone was 1.1.³⁸
       The occurrence of active tuberculosis in some RA patients on TNF inhibitor therapy is a serious concern. In the Research in Active Rheumatoid Arthritis (REACT) trial, active tuberculosis occurred at a rate of 0.5 for every 100 patient years.³⁹ Tuberculosis in these patients often presents as extrapulmonary or disseminated disease. Physicians should screen all patients for tuberculosis before initiating RA therapy. Screening strategies employed in the United States have reduced the occurrence of TNF-inhibitor-associated tuberculosis.⁴⁰
       Patients with RA have an increased number of cardiovascular events which cannot be explained by traditional risk factors.⁴¹ Recent evidence that inflammation may play a role in the pathogenesis of atherosclerosis suggests that the inflammatory burden in RA patients contributes to accelerated atherosclerosis. In their study of inflammatory arthritis patients, Goodson et al., observed that C-reactive protein was an independent predictor of cardiovascular mortality.⁴² It is not clearly established whether DMARDs can reduce the excess cardiovascular risk in RA patients. Choi et al., reported that use of methotrexate reduced the risk of cardiovascular mortality in comparison with other nonbiologic DMARDs.⁴³ Another study observed that RA patients without a history of cardiovascular disease who used TNF antagonists had a reduced risk of cardiovascular-related death.⁴⁴

In Conclusion

The progressive understanding of the pathophysiology of RA has lead to the development of targeted therapy and the anticipation of potential alternatives in late development. These therapies reportedly target B cells, B-cell growth factors and IL6 among others. The options for better control or even remission of RA are within reach. It is ultimately up to our profession to advocate the safe, appropriate, expeditious and accessible use of these agents.

       Dr. Dikranian is a rheumatologist at the San Diego Arthritis Medical Clinic. He completed his training at the University of California-San Diego in 2000 and worked for two years in Australia and New Zealand prior to joining his current practice.