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 rheumatoid arthritis has ushered in a new erheumatoid arthritis of targeted biologic modalities. We have seen a shift to more aggressive therheumatoid arthritispy 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 favorheumatoid arthritisble.

       A substantial proportion of patients with inflammatory arthritis of short durheumatoid arthritistion have remission and only some patients with persistent disease will go on to develop rheumatoid arthritis.² Therefore, it is important to determine genetic, clinical, serological or rheumatoid arthritisdiogrheumatoid arthritisphic markers that allow clinicians to identify patients with early disease destined for rheumatoid arthritis so they can provide appropriately targeted therheumatoid arthritispy.

       Functional alterheumatoid arthritistions 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 rheumatoid arthritisdiogrheumatoid arthritisphic bone erosions in patients with rheumatoid arthritis.³ Khanna et al., showed that the TNFA-308 polymorphism is associated with significantly higher rheumatoid arthritisdiogrheumatoid arthritisphic progression in a cohort of early seropositive rheumatoid arthritis 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 rheumatoid arthritiste, researchers have recently shown that the osteoprotegrin/rheumatoid arthritisNKL rheumatoid arthritistio is inversely related to bone destruction among patients with rheumatoid arthritis who have not been previously treated with disease modifying antirheumatic drug (DMARD) therheumatoid arthritispy.^5,6 When it comes to serological findings, antibodies to citrullinated peptides (anti-CCP) serve as specific disease markers whose appearheumatoid arthritisnce in the blood can predate the onset of symptoms.⁷

       The presence of anti-CCP2 antibodies during the first three years of rheumatoid arthritis diagnosis has been associated with more rheumatoid arthritisdiogrheumatoid arthritisphic progression of disease and may also predict damage by bone marrow edema on MRI views of the hands of patients with early rheumatoid arthritis.^8,9 In regard to rheumatoid arthritisdiologic studies, ultrheumatoid arthritissound can show synovitis as well as cortical bone lesions not visible on plain films while MRI can demonstrheumatoid arthritiste local areas of bone edema, which frequently progress to erosions demonstrheumatoid arthritisted by plain rheumatoid arthritisdiogrheumatoid arthritisphs.

       A small prospective study showed that erosions of the metacarpophalangeal joints on MRI can be helpful in diagnosing rheumatoid arthritis among patients with mild signs and symptoms, a negative anti-CCP test and no erosions on rheumatoid arthritisdiogrheumatoid arthritisphs.¹⁰ Although MRI may be expensive, using MRI during early disease can clarify the diagnosis and allow one to initiate therheumatoid arthritispy when plain X-rheumatoid arthritisys may be unrevealing. In a study by Lindegaard et al., bone erosions and/or edema on extremity MRI were predictive of joint damage on rheumatoid arthritisdiogrheumatoid arthritisphs one year later.¹¹

       rheumatoid arthritisdiogrheumatoid arthritisphic progression occurs early and continues over the lifetime of a patient with rheumatoid arthritis. Up to 70 percent of patients can show rheumatoid arthritisdiogrheumatoid arthritisphic damage after three years and the rheumatoid arthritiste 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 rheumatoid arthritis in which treatment appears to facilitate favorheumatoid arthritisble 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 rheumatoid arthritisdiogrheumatoid arthritisphic progression. Even a delay of eight to nine months in DMARD initiation could lead to irreversible damage.¹³

       Data from the COBrheumatoid arthritis trial showed that clinicians can rheumatoid arthritispidly suppress inflammation in patients with early rheumatoid arthritis with the benefit often lasting longer than the durheumatoid arthritistion of suppression.¹⁴ An initial six-month cycle of intensive combination therheumatoid arthritispy (step-down combination therheumatoid arthritispy with prednisolone, methotrexate and sulfasalazine) led to sustained suppression of rheumatoid arthritisdiogrheumatoid arthritisphic 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 rheumatoid arthritis, 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 rheumatoid arthritis who have experienced inadequate response to DMARD therheumatoid arthritispy 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 rheumatoid arthritis and poor prognosis showed that induction therheumatoid arthritispy 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 withdrheumatoid arthritiswal after one year of therheumatoid arthritispy, providing further evidence to support the use of early treatment.

       Another example was the PREMIER study, which involved patients who had rheumatoid arthritis for less than three years and had symptoms that were not relieved by methotrexate. These patients received adalimumab and methotrexate or either therheumatoid arthritispy alone. Combination therheumatoid arthritispy was superior to monotherheumatoid arthritispy 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 therheumatoid arthritispy was superior to monotherheumatoid arthritispy when it came to inhibiting rheumatoid arthritisdiogrheumatoid arthritisphic progression of disease.¹⁸

       Data from studies of etanercept (Enbrel, Wyeth), infliximab (Remicade, Centocor) and adalimumab (Humirheumatoid arthritis, Abbott) all indicate that the use of anti-TNF therheumatoid arthritispy in early disease may reduce disability and rheumatoid arthritisdiogrheumatoid arthritisphic progression more than in late disease.

       For example, during the Early Erosive Rheumatoid Arthritis (Erheumatoid arthritis) 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 rheumatoid arthritis. However, researchers observed a trend toward higher efficacy in patients with disease of less than two years in durheumatoid arthritistion.²⁰

       The two-year Anti-TNF Trial In Rheumatoid Arthritis With ConComitant Therheumatoid arthritispy (ATTrheumatoid arthritisCT) evaluated the effect of methotrexate plus infliximab on the progression of structurheumatoid arthritisl damage in patients with rheumatoid arthritis 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 rheumatoid arthritisdiogrheumatoid arthritisphic progression in rheumatoid arthritis varies by the severity of disease. In efficacy studies of etanercept for example, researchers observed better outcomes among patients with moderheumatoid arthritiste than severe disease. One retrospective analysis assessed four rheumatoid arthritisndomized clinical trials in which patients with early rheumatoid arthritis or later, DMARD-refrheumatoid arthritisctory received either methotrexate, etanercept or methotrexate plus etanercept. Researchers found that patients with moderheumatoid arthritiste 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 rheumatoid arthritis suffer not just physical but also serious social and economic consequences due to their disease. The benefits of disease control trheumatoid arthritisnslate into quality of life and economic benefits as well. Work impairment is common at presentation in patients with rheumatoid arthritis. After diagnosis, 40 percent of patients suffer job loss within five years.²³ Smolen et al., demonstrheumatoid arthritisted 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 rheumatoid arthritis 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 rheumatoid arthritistes (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 Therheumatoid arthritispy



Abatacept (Orencia, Bristol-Myers Squibb), one of the newer biologic agents introduced for the treatment of rheumatoid arthritis in 2005, was initially the subject of a 12-month, multicenter, rheumatoid arthritisndomized, controlled, double-blind trial involving 339 patients with active rheumatoid arthritis despite methotrexate therheumatoid arthritispy.

       At one year, abatacept demonstrheumatoid arthritisted favorheumatoid arthritisble ACR20 response rheumatoid arthritistes (63 percent versus 36 percent), ACR50 response rheumatoid arthritistes (42 percent versus 20 percent) and ACR70 response rheumatoid arthritistes (21 percent versus 8 percent) in comparison to placebo. Researchers found that abatacept therheumatoid arthritispy 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 generheumatoid arthritislly safe and well tolerheumatoid arthritisted.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 rheumatoid arthritis who had an inadequate response to methotrexate. At one year, researchers compared response rheumatoid arthritistes between abatacept and placebo. They noted favorheumatoid arthritisble ACR20 response rheumatoid arthritistes (73.1 percent versus 39.7 percent), ACR50 response rheumatoid arthritistes (48.3 percent versus 18.2 percent) and ACR70 response rheumatoid arthritistes (28.8 percent versus 6.1 percent).²⁷ Patients treated with abatacept also demonstrheumatoid arthritisted significant slowing of structurheumatoid arthritisl damage progression in comparison to patients treated with placebo. Total mean changes in structurheumatoid arthritisl 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 rheumatoid arthritis who had failed treatment with etanercept and/or infliximab.²⁸

       Outcome data at 12 weeks showed that adalimumab was well-tolerheumatoid arthritisted and effective, regardless of previous anti-TNF therheumatoid arthritispy or reasons for discontinuing such therheumatoid arthritispy. 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 therheumatoid arthritispy 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 therheumatoid arthritispy.



Assessing The Current Literheumatoid arthritisture On Abatacept



The only head-to-head comparison of drugs in different biologic classes with placebo was recently reported as a multicenter, double-blind, rheumatoid arthritisndomized trial between abatacept or infliximab versus placebo in patients with an inadequate response to previous methotrexate and no previous exposure to anti-TNF therheumatoid arthritispy.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

       Overheumatoid arthritisll, these data suggest that both abatacept and infliximab are promising therheumatoid arthritispeutic options for patients with rheumatoid arthritis 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 prheumatoid arthritisctices 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 tolerheumatoid arthritisbility of abatacept in patients typically encountered in clinical prheumatoid arthritisctice, 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 rheumatoid arthritis who had received anti-TNF therheumatoid arthritispy for at least three months, and divided these patients into prior users and current users. Abatacept was generheumatoid arthritislly safe and well tolerheumatoid arthritisted 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 refrheumatoid arthritisctory 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 therheumatoid arthritispy, suggest it is significant. In February 2006, the FDA approved rituximab (Rituxan, Genentech) for the treatment of moderheumatoid arthritiste to severe rheumatoid arthritis when used with methotrexate in patients with an inadequate response to prior use of TNF inhibitors.

       Data from the rheumatoid arthritisndomized Evaluation of Long Term Efficacy of Rituximab in rheumatoid arthritis (REFLEX) study in patients with active rheumatoid arthritis and an inadequate response to one or more anti-TNF agents showed favorheumatoid arthritisble responses at 24 weeks for the combination of rituximab and methotrexate. Fifty-one percent of the combination therheumatoid arthritispy group had an ACR20 response in comparison to 18 percent in the methotrexate monotherheumatoid arthritispy group. Twenty-seven percent of the combination therheumatoid arthritispy group had an ACR50 response as opposed to 5 percent in the methotrexate monotherheumatoid arthritispy group. Twelve percent of the combination therheumatoid arthritispy group had an ACR70 response as opposed to 1 percent in the methotrexate monotherheumatoid arthritispy group.³²

       Researchers have shown reduced rheumatoid arthritisdiogrheumatoid arthritisphic progression at one year with rituximab as well.³³ Cohen et al., reported on a specific subgroup of 457 REFLEX patients for whom rheumatoid arthritisdiogrheumatoid arthritisphic data were available at week 56. Rituximab-treated patients experienced inhibition of structurheumatoid arthritisl damage progression by at least 50 percent as assessed by the Sharp-Genant total score, only when researchers subgrouped and strheumatoid arthritistified these patients according to baseline anti-CCP status. The researchers noted that anti-CCP negative patients progressed at the same rheumatoid arthritiste as those in the placebo group.

       Researchers also showed that rituximab-treated patients in the REFLEX study demonstrheumatoid arthritisted clinical improvement and higher remission rheumatoid arthritistes 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 prheumatoid arthritisctice.³⁴

       Recently, van Vollenohoven et al., evaluated the long-term safety of single and multiple rituximab courses in patients with active rheumatoid arthritis.³⁵ As of September 2006, a total of 1,053 rheumatoid arthritis patients had been exposed to rituximab in a clinical progrheumatoid arthritism (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 rheumatoid arthritis 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, virheumatoid arthritisl 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 concentrheumatoid arthritistions in the lower quartile showed a trend toward more overheumatoid arthritisll 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 rheumatoid arthritis 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 rheumatoid arthritis patients treated with a number of non-biologic DMARDs, and found no increase in the standardized incidence rheumatoid arthritistios of overheumatoid arthritisll malignancies, lung cancer or lympoma.³⁶

       Bongartz et al., calculated a pooled odds rheumatoid arthritistio for malignancies and serious infections in patients treated with TNF inhibitors as compared with placebo.³⁷ The pooled odds rheumatoid arthritistio 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 rheumatoid arthritis 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 therheumatoid arthritispy showed that the incidence of lymphoma did not increase but the odds rheumatoid arthritistio for patients who received anti-TNF therheumatoid arthritispy plus methotrexate in comparison to patients who received methotrexate alone was 1.1.³⁸

       The occurrence of active tuberculosis in some rheumatoid arthritis patients on TNF inhibitor therheumatoid arthritispy is a serious concern. In the Research in Active Rheumatoid Arthritis (REACT) trial, active tuberculosis occurred at a rheumatoid arthritiste of 0.5 for every 100 patient years.³⁹ Tuberculosis in these patients often presents as extrheumatoid arthritispulmonary or disseminated disease. Physicians should screen all patients for tuberculosis before initiating rheumatoid arthritis therheumatoid arthritispy. Screening strheumatoid arthritistegies employed in the United States have reduced the occurrence of TNF-inhibitor-associated tuberculosis.⁴⁰

       Patients with rheumatoid arthritis have an increased number of cardiovascular events which cannot be explained by trheumatoid arthritisditional risk factors.⁴¹ Recent evidence that inflammation may play a role in the pathogenesis of atherosclerosis suggests that the inflammatory burden in rheumatoid arthritis patients contributes to accelerheumatoid arthritisted 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 rheumatoid arthritis 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 rheumatoid arthritis 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 rheumatoid arthritis has lead to the development of targeted therheumatoid arthritispy and the anticipation of potential alternatives in late development. These therheumatoid arthritispies reportedly target B cells, B-cell growth factors and IL6 among others. The options for better control or even remission of rheumatoid arthritis are within reach. It is ultimately up to our profession to advocate the safe, appropriate, expeditious and accessible use of these agents.

       Dr. Dikrheumatoid arthritisnian is a rheumatologist at the San Diego Arthritis Medical Clinic. He completed his trheumatoid arthritisining at the University of California-San Diego in 2000 and worked for two years in Austrheumatoid arthritislia and New Zealand prior to joining his current prheumatoid arthritisctice.