Mark C. Genovese

A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis.

BACKGROUND Etanercept, which blocks the action of tumor necrosis factor, reduces disease activity in patients with long-standing rheumatoid arthritis. Its efficacy in reducing disease activity and preventing joint damage in patients with active early rheumatoid arthritis is unknown. METHODS We treated 632 patients with early rheumatoid arthritis with either twice-weekly subcutaneous etanercept (10 or 25 mg) or weekly oral methotrexate (mean, 19 mg per week) for 12 months. Clinical response was defined as the percent improvement in disease activity according to the criteria of the American College of Rheumatology. Bone erosion and joint-space narrowing were measured radiographically and scored with use of the Sharp scale. On this scale, an increase of 1 point represents one new erosion or minimal narrowing. RESULTS As compared with patients who received methotrexate, patients who received the 25-mg dose of etanercept had a more rapid rate of improvement, with significantly more patients having 20 percent, 50 percent, and 70 percent improvement in disease activity during the first six months (P<0.05). The mean increase in the erosion score during the first 6 months was 0.30 in the group assigned to receive 25 mg of etanercept and 0.68 in the methotrexate group (P= 0.001), and the respective increases during the first 12 months were 0.47 and 1.03 (P=0.002). Among patients who received the 25-mg dose of etanercept, 72 percent had no increase in the erosion score, as compared with 60 percent of patients in the methotrexate group (P=0.007). This group of patients also had fewer adverse events (P=0.02) and fewer infections (P= 0.006) than the group that was treated with methotrexate. CONCLUSIONS As compared with oral methotrexate, subcutaneous [corrected] etanercept acted more rapidly to decrease symptoms and slow joint damage in patients with early active rheumatoid arthritis.

Interleukin‐6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease‐modifying antirheumatic drugs: The tocilizumab in combination with traditional disease‐modifying antirheumatic drug therapy study

OBJECTIVE To examine the efficacy and safety of the humanized anti-interleukin-6 receptor antibody tocilizumab combined with conventional disease-modifying antirheumatic drugs (DMARDs) in patients with active rheumatoid arthritis (RA). METHODS A total of 1,220 patients were randomized (2:1 ratio) in the phase III, double-blind, placebo-controlled, multicenter TOWARD (Tocilizumab in Combination With Traditional DMARD Therapy) study. Patients remained on stable doses of DMARDs and received tocilizumab 8 mg/kg or placebo (control group) every 4 weeks for 24 weeks. RESULTS At week 24, the proportion of patients achieving a response according to the American College of Rheumatology criteria for 20% improvement (ACR20) was significantly greater in the tocilizumab plus DMARD group than in the control group (61% versus 25%; P<0.0001). Secondary end points including 50% or 70% improvement (ACR50/70), the Disease Activity Score in 28 joints (DAS28), DAS28 remission responses (DAS28<2.6), European League Against Rheumatism responses, and systemic markers such as the C-reactive protein and hemoglobin levels showed superiority of tocilizumab plus DMARDs over DMARDs alone. Seventy-three percent of patients in the tocilizumab group had >or=1 adverse event (AE), compared with 61% of patients in the control group. AEs leading to withdrawal from the study were infrequent (4% of patients in the tocilizumab group and 2% of those in the control group). Serious AEs occurred in 6.7% and 4.3% of patients in the tocilizumab and control groups, respectively, and serious infections occurred in 2.7% and 1.9%, respectively. Elevations in the alanine aminotransferase level, from normal at baseline to >3-fold the upper limit of normal, occurred in 4% of patients in the tocilizumab group and 1% of those in the control group, and elevated total cholesterol levels were observed in 23% and 6% of patients, respectively. Sixteen patients started lipid-lowering therapy during the study. Grade 3 neutropenia occurred in 3.7% of patients receiving tocilizumab and none of the patients in the control group, and no grade 4 neutropenia was reported. CONCLUSION Tocilizumab combined with any of the DMARDs evaluated was safe and effective in reducing articular and systemic symptoms in patients with an inadequate response to these agents.

Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study

Background: The anti-interleukin (IL) 6 receptor antibody tocilizumab inhibits signalling of IL6, a key cytokine in rheumatoid arthritis (RA) pathogenesis. Objective: To evaluate through the AMBITION study the efficacy and safety of tocilizumab monotherapy versus methotrexate in patients with active RA for whom previous treatment with methotrexate/biological agents had not failed. Methods: This 24-week, double-blind, double-dummy, parallel-group study, randomised 673 patients to either tocilizumab 8 mg/kg every 4 weeks, or methotrexate, starting at 7.5 mg/week and titrated to 20 mg/week within 8 weeks, or placebo for 8 weeks followed by tocilizumab 8 mg/kg. The primary end point was the proportion of patients achieving American College of Rheumatology (ACR) 20 response at week 24. Results: The intention-to-treat analysis demonstrated that tocilizumab was better than methotrexate treatment with a higher ACR20 response (69.9 vs 52.5%; p<0.001), and 28-joint Disease Activity Score (DAS28) <2.6 rate (33.6 vs 12.1%) at week 24. Mean high-sensitivity C-reactive protein was within the normal range from week 12 with tocilizumab, whereas levels remained elevated with methotrexate. The incidence of serious adverse events with tocilizumab was 3.8% versus 2.8% with methotrexate (p = 0.50), and of serious infections, 1.4% versus 0.7%, respectively. There was a higher incidence of reversible grade 3 neutropenia (3.1% vs 0.4%) and increased total cholesterol ⩾240 mg/dl (13.2% vs 0.4%), and a lower incidence of alanine aminotransferase elevations >3×–<5× upper limit of normal (1.0% vs 2.5%), respectively. Conclusion: Tocilizumab monotherapy is better than methotrexate monotherapy, with rapid improvement in RA signs and symptoms, and a favourable benefit–risk, in patients for whom treatment with methotrexate or biological agents has not previously failed. Trial registration number: NCT00109408

Rules of chemokine receptor association with T cell polarization in vivo

Current concepts of chemokine receptor (CKR) association with Th1 and Th2 cell polarization and effector function have largely ignored the diverse nature of effector and memory T cells in vivo. Here, we systematically investigated the association of 11 CKRs, singly or in combination, with CD4 T cell polarization. We show that Th1, Th2, Th0, and nonpolarized T cells in blood and tissue can express any of the CKRs studied but that each CKR defines a characteristic pool of polarized and nonpolarized CD4 T cells. Certain combinations of CKRs define populations that are markedly enriched in major subsets of Th1 versus Th2 cells. For example, although Th0, Th1, and Th2 cells are each found among blood CD4 T cells coordinately expressing CXCR3 and CCR4, Th1 but not Th2 cells can be CXCR3(+)CCR4(-), and Th2 but only rare Th1 cells are CCR4(+)CXCR3(-). Contrary to recent reports, although CCR7(-) cells contain a higher frequency of polarized CD4 T cells, most Th1 and Th2 effector cells are CCR7(+) and thus may be capable of lymphoid organ homing. Interestingly, Th1-associated CKRs show little or no preference for Th1 cells except when they are coexpressed with CXCR3. We conclude that the combinatorial expression of CKRs, which allow tissue- and subset-dependent targeting of effector cells during chemotactic navigation, defines physiologically significant subsets of polarized and nonpolarized T cells.

LY2439821, a humanized anti–interleukin-17 monoclonal antibody, in the treatment of patients with rheumatoid arthritis: A phase I randomized, double-blind, placebo-controlled, proof-of-concept study

OBJECTIVE We undertook this study to evaluate safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of LY2439821, a humanized anti-interleukin-17 (anti-IL-17) monoclonal antibody, in a first in-human trial in rheumatoid arthritis (RA) patients taking oral disease-modifying antirheumatic drugs (DMARDs). METHODS This randomized, double-blind, placebo-controlled study consisted of 2 parts. In part A, 20 patients received 1 intravenous (IV) dose of LY2439821 (0.06, 0.2, 0.6, or 2.0 mg/kg, escalating) or placebo followed by 8 weeks of evaluation. End points included safety, tolerability, and pharmacokinetics. In part B, 77 patients received 1 IV dose of LY2439821 (0.2, 0.6, or 2.0 mg/kg) or placebo every 2 weeks for a total of 5 doses, with a total evaluation period of 16 weeks. End points included safety, tolerability, pharmacokinetics/pharmacodynamics, and efficacy (Disease Activity Score in 28 joints [DAS28] and percentages of patients meeting American College of Rheumatology 20%, 50%, or 70% improvement criteria [achieving an ACR20, ACR50, or ACR70 response]). The primary efficacy end point was the DAS28 at week 10. RESULTS Baseline characteristics were similar across all groups. Changes in the DAS28 were significantly greater in the 0.2 mg/kg, 2.0 mg/kg, and all-LY2439821-combined groups (-2.3, -2.4, and -2.3, respectively) than in the placebo group (-1.7) at week 10 (P < or = 0.05), and these differences were significant as early as week 1. Percentages of ACR20, ACR50, and ACR70 responses as well as improvements in the ACR core set of measures were greater in LY2439821-treated patients than in placebo-treated patients at multiple time points. There was no apparent dose-response relationship in treatment-emergent adverse events. CONCLUSION LY2439821 added to oral DMARDs improved signs and symptoms of RA, with no strong adverse safety signal noted. This first evaluation of LY2439821 supports neutralization of IL-17 as a potential novel goal for the treatment of RA.

Golimumab, a human antibody to tumour necrosis factor α given by monthly subcutaneous injections, in active rheumatoid arthritis despite methotrexate therapy: the GO-FORWARD Study

Objective: The phase III GO-FORWARD study examined the efficacy and safety of golimumab in patients with active rheumatoid arthritis (RA) despite methotrexate therapy. Methods: Patients were randomly assigned in a 3 : 3 : 2 : 2 ratio to receive placebo injections plus methotrexate capsules (group 1, n  =  133), golimumab 100 mg injections plus placebo capsules (group 2, n  =  133), golimumab 50 mg injections plus methotrexate capsules (group 3, n  =  89), or golimumab 100 mg injections plus methotrexate capsules (group 4, n  =  89). Injections were administered subcutaneously every 4 weeks. The co-primary endpoints were the proportion of patients with 20% or greater improvement in the American College of Rheumatology criteria (ACR20) at week 14 and the change from baseline in the health assessment questionnaire-disability index (HAQ-DI) score at week 24. Results: The proportion of patients who achieved an ACR20 response at week 14 was 33.1% in the placebo plus methotrexate group, 44.4% (p = 0.059) in the golimumab 100 mg plus placebo group, 55.1% (p = 0.001) in the golimumab 50 mg plus methotrexate group and 56.2% (p<0.001) in the golimumab 100 mg plus methotrexate group. At week 24, median improvements from baseline in HAQ-DI scores were 0.13, 0.13 (p = 0.240), 0.38 (p<0.001) and 0.50 (p<0.001), respectively. During the placebo-controlled portion of the study (to week 16), serious adverse events occurred in 2.3%, 3.8%, 5.6% and 9.0% of patients and serious infections occurred in 0.8%, 0.8%, 2.2% and 5.6%, respectively. Conclusion: The addition of golimumab to methotrexate in patients with active RA despite methotrexate therapy significantly reduced the signs and symptoms of RA and improved physical function.

Concomitant Leflunomide Therapy in Patients with Active Rheumatoid Arthritis despite Stable Doses of Methotrexate: A Randomized, Double-Blind, Placebo-Controlled Trial

Context Several disease-modifying antirheumatic drugs (DMARDs) slow disease progression in patients with rheumatoid arthritis. Many experts prefer methotrexate, although trials do not uniformly show that it is superior to other DMARDs. It is not known whether combining methotrexate with a second DMARD is better than prescribing methotrexate alone. Contribution This 24-week, randomized, double-blind, placebo-controlled trial shows that leflunomide added to ongoing stable-dose methotrexate therapy in patients with persistently active rheumatoid arthritis improves clinical outcomes compared with methotrexate alone. Cautions Some adverse effects, such as diarrhea, were more common with combination therapy. All patients receiving DMARD therapy need close monitoring for toxicities. The Editors Rheumatoid arthritis has considerable societal costs (1-5). Many patients with rheumatoid arthritis become disabled within a few years of disease onset (4, 5). Methotrexate is the standard treatment for rheumatoid arthritis. During the past several years, investigators have found that some disease-modifying antirheumatic drugs can increase the efficacy of methotrexate monotherapy (6-9). Methotrexate is an antimetabolite and immunomodulator that affects many intracellular metabolic pathways of purine metabolism (10). The precise intracellular biochemical pathway responsible for the observed clinical benefits of methotrexate in the treatment of rheumatoid arthritis is still the subject of some debate (11), but methotrexate is thought to act primarily on purine pathways of cellular metabolism (10). Leflunomide (Arava, Aventis Pharmaceuticals, Bridgewater, New Jersey) also has antimetabolic effects, inhibiting pyrimidine intracellular pathways (12). Leflunomide has been shown to be effective for rheumatoid arthritis in double-blind, placebo-controlled trials (13, 14). Given the diverse intracellular pathways affected by both drugs, the combination of leflunomide and methotrexate has the potential for biochemical synergy. The possibility of increased benefits should be weighed against the possible toxicities of this combination. Abnormal aminotransferase levels have been seen with both methotrexate (15) and leflunomide (14) monotherapy in patients with rheumatoid arthritis. In a small open study, we previously observed that the combination of methotrexate and leflunomide led to considerable clinical improvements and reversible elevations in aminotransferase levels (16). We therefore sought to determine whether similar results could be achieved in a large, double-blind investigation of the combination of these two antimetabolic agents. Methods Patients The study sample consisted of 263 patients who had rheumatoid arthritis as defined by American College of Rheumatology (ACR) criteria (17). Patients were 18 to 75 years of age and were receiving stable dosages of methotrexate (15 to 20 mg/wk, or 10 to 15 mg/wk if this was the maximum tolerated dose). Patients were recruited from active outpatient practice centers, and study participants were approached without a particular schema. Eligible patients had active rheumatoid arthritis despite at least 6 months of methotrexate therapy, including stable dosage for at least 8 weeks. Patients with active rheumatoid arthritis were defined as meeting three of the following criteria on two different evaluations, 7 to 21 days apart: at least nine tender joints, at least six swollen joints, at least 45 minutes of morning stiffness, and an erythrocyte sedimentation rate of at least 28 mm/h. Previous disease-modifying antirheumatic drugs, not including ongoing methotrexate, had failed in 11 patients. Patients receiving corticosteroids were required to have been taking a stable daily dose of 10 mg or less for at least 30 days before study drug administration, and the corticosteroid dose was required to remain constant throughout the study. Complete exclusion criteria are listed in Appendix Table 1. Study Design The 24-week, randomized, double-blind, placebo-controlled study, with evaluations occurring at 4-week intervals (Figure 1), was conducted in 20 centers in the United States and Canada between September 1998 and June 2000. The primary objective was to evaluate the efficacy and safety of adding leflunomide or placebo to stable methotrexate therapy in patients with active rheumatoid arthritis. All participants provided written consent, and the institutional review board at each center approved the protocol. Figure 1. Patient eligibility, randomization, assignment, and discontinuation. Include no wish to continue in study, poor adherence to treatment, protocol violation, and moving away from the study area. A randomization schedule, generated by and stored with Quintiles, Inc., Kansas City, Missouri, was used to assign sequential numbers to randomly allocated treatment codes. Randomization was done by using the Aventis standard random-code generator. Investigators allocated numbers to patients, beginning with the lowest available number. Quintiles, Inc., packaged and labeled the study medication. The randomization code used was concealed from investigators and patients throughout the study. Randomization was stratified by center. A set of 500 random numbers was generated, with treatment groups randomly assigned in a balanced manner (1:1 ratio) within each block of four consecutive random numbers (block size, 4). A set of these blocks was then sent to each investigative center. This method is identical to stratification by center because centers are balanced with respect to treatment assignment. Patients were randomly assigned to receive leflunomide, 100 mg/d, for 2 days followed by 10 mg/d or matching placebo. If substantial adverse events occurred, this dose could be reduced to 10 mg every other day. If 10 mg/d was tolerated but active disease, as defined earlier, was still present at week 8 or thereafter, an increase to 20 mg of leflunomide or matching placebo per day was required. If substantial adverse events occurred while the patient was taking 20 mg of the study drug per day, a one-time dose reduction to 10 mg/d was allowed at the discretion of the investigator. At least 1 mg of folate supplementation per day was mandated by the protocol. Adherence to study medication, assessed at each visit by tablet counts (actual number of tablets returned compared with number expected to be returned), was similar in the two groups. The mean adherence for all patients in the intention-to-treat sample was 98.0% (98.5% for those receiving placebo and 97.4% for those receiving leflunomide). In the placebo group and leflunomide group, respectively, 90.2% (120 of 133 patients) and 87.7% (114 of 130 patients) had adherence rates of 80% to 120%. Measurement of Efficacy The primary efficacy variable was the rate at which the intention-to-treat sample achieved 20% improvement in ACR criteria (ACR20) at the end of the study. To be classified as having achieved ACR20, patients were required to complete 24 weeks of treatment and meet ACR20 response criteria at end of the study (13). The ACR20 criteria were developed to define improvement in rheumatoid arthritis (18). Clinical improvement is indicated by 20% improvement in tender and swollen joint counts and 20% improvement in three of the following five criteria: patient global assessment, physician global assessment, pain intensity, physical function or disability measure, and level of acute-phase reactant (19). All ACR assessments were performed by the investigators, and the same assessor performed all analyses throughout the study whenever possible to increase the reliability of the assessment. Patients who discontinued therapy before the end of week 24 or for whom data were insufficient to assess ACR20 response at week 24 were classified as nonresponders for the primary analysis. Count of tender joints was based on 68 joint assessments, and count of swollen joints was based on 66 joint assessments. Percentage changes in tender joint and swollen joint counts were based on the number of evaluable joints at a visit. Joints that had been replaced or had been injected with corticosteroids within 4 weeks before the assessment were considered nonevaluable. Secondary outcomes included ACR50 and ACR70 responder rates at week 24 (analyses of responders at study end for the nonprimary efficacy measures). The ACR50 and ACR70 were defined as at least 50% and 70% improvement, respectively, in the same criteria used to calculate ACR20 response. Secondary efficacy variables also included change from baseline to end point in each of the individual components of the ACR response criteria and change from baseline to week 24 in levels of rheumatoid factor. Mean changes from baseline in individual efficacy measures are shown in Appendix Table 2. Measurement of Safety Safety was evaluated by adverse event reports; laboratory assays for changes in hematologic characteristics, blood chemistry, urinalysis, and liver function; and physical examination. Potential adverse events were assessed by using open-ended questions at each study visit. The assessor was blinded to reported toxicities and to any additional information obtained at the visit. The study protocol provided recommendations for dosage change and discontinuation of drug therapy, without unblinding, when patients were found to have alanine aminotransferase (ALT) and aspartate aminotransferase (AST) values greater than two times the upper limit of normal. Investigators decreased the dose of the study medication if, on repeated analysis at 72 hours, test values remained greater than two times but less than or equal to five times the upper limit of normal; only one dose adjustment was allowed before discontinuation of therapy with the study drug. Therapy with the study drug was also discontinued in patients with persistent elevations of aminotransferase enzyme levels to more than two times the upper limit of normal on repeated te

An Oral Spleen Tyrosine Kinase (Syk) Inhibitor for Rheumatoid Arthritis

BACKGROUND Spleen tyrosine kinase (Syk) is an important modulator of immune signaling. The objective of this phase 2 study was to evaluate the efficacy and safety of R788, an oral inhibitor of Syk, in patients with active rheumatoid arthritis despite methotrexate therapy. METHODS We enrolled 457 patients who had active rheumatoid arthritis despite long-term methotrexate therapy in a 6-month, double-blind, placebo-controlled trial. The primary outcome was the American College of Rheumatology (ACR) 20 response (which indicates at least a 20% reduction in the number of both tender and swollen joints and improvement in at least three of five other criteria) at month 6. RESULTS R788, at a dose of 100 mg twice daily and at a dose of 150 mg once daily, was significantly superior to placebo at month 6 (ACR 20 response rates of 67% and 57%, respectively, vs. 35%; P<0.001 for the comparison of both doses with placebo). It was also significantly superior with respect to ACR 50, which indicates at least a 50% improvement (43% and 32% vs. 19%; P<0.001 for the comparison of the 100-mg dose with placebo, P=0.007 for the comparison of the 150-mg dose with placebo) and ACR 70 (28% and 14% vs. 10%; P<0.001 for the comparison of the 100-mg dose with placebo, P=0.34 for the comparison of the 150-mg dose with placebo). A clinically significant effect was noted by the end of the first week of treatment. Adverse effects included diarrhea (in 19% of subjects taking the 100-mg dose of R788 vs. 3% of those taking placebo), upper respiratory infections (14% vs. 7%), and neutropenia (6% vs. 1%). R788 was associated with an increase in systolic blood pressure of approximately 3 mm Hg between baseline and month 1, as compared with a decrease of 2 mm Hg with placebo; 23% of the patients taking R788 vs. 7% of the patients receiving placebo required the initiation of or a change in antihypertensive therapy. CONCLUSIONS In this phase 2 study, a Syk inhibitor reduced disease activity in patients with rheumatoid arthritis; adverse events included diarrhea, hypertension, and neutropenia. Additional studies will be needed to further assess the safety and efficacy of Syk-inhibition therapy in patients with rheumatoid arthritis. (Funded by Rigel; ClinicalTrials.gov number, NCT00665925.)

CCR7 Expression and Memory T Cell Diversity in Humans

CCR7, along with L-selectin and LFA-1, mediates homing of T cells to secondary lymphoid organs via high endothelial venules (HEV). CCR7 has also been implicated in microenvironmental positioning of lymphocytes within secondary lymphoid organs and in return of lymphocytes and dendritic cells to the lymph after passage through nonlymphoid tissues. We have generated mAbs to human CCR7, whose specificities correlate with functional migration of lymphocyte subsets to known CCR7 ligands. We find that CCR7 is expressed on the vast majority of peripheral blood T cells, including most cells that express adhesion molecules (cutaneous lymphocyte Ag α4β7 integrin) required for homing to nonlymphoid tissues. A subset of CD27(neg) memory CD4 T cells from human peripheral blood is greatly enriched in the CCR7(neg) population, as well as L-selectin(neg) cells, suggesting that these cells are incapable of homing to secondary lymphoid organs. Accordingly, CD27(neg) T cells are rare within tonsil, a representative secondary lymphoid organ. All resting T cells within secondary lymphoid organs express high levels of CCR7, but many activated cells lack CCR7. CCR7 loss in activated CD4 cells accompanies CXC chemokine receptor (CXCR)5 gain, suggesting that the reciprocal expression of these two receptors may contribute to differential positioning of resting vs activated cells within the organ. Lymphocytes isolated from nonlymphoid tissues (such as skin, lung, or intestine) contain many CD27(neg) cells lacking CCR7. The ratio of CD27(neg)/CCR7(neg) cells to CD27(pos)/CCR7(pos) cells varies from tissue to tissue, and may correlate with the number of cells actively engaged in Ag recognition within a given tissue.

Bonzo/CXCR6 expression defines type 1–polarized T-cell subsets with extralymphoid tissue homing potential

Chemokine receptor expression is finely controlled during T-cell development. We show that newly identified chemokine receptor Bonzo/CXCR6 is expressed by subsets of Th1 or T-cytotoxic 1 (Tc1) cells, but not by Th2 or Tc2 cells, establishing Bonzo as a differential marker of polarized type 1 T cells in vitro and in vivo. Priming of naive T cells by dendritic cells induces expression of Bonzo on T cells. IL-12 enhances this dendritic cell-dependent upregulation, while IL-4 inhibits it. In blood, 35-56% of Bonzo+ CD4 T cells are Th1 cells, and 60-65% of Bonzo+ CD8 T cells are Tc1 cells, while few Bonzo+ cells are type 2 T cells. Almost all Bonzo+ Tc1 cells contain preformed granzyme A and display cytotoxic effector phenotype. Most Bonzo+ T cells lack L-selectin and/or CCR7, homing receptors for lymphoid tissues. Instead, Bonzo+ T cells are dramatically enriched among T cells in tissue sites of inflammation, such as rheumatoid joints and inflamed livers. Bonzo may be important in trafficking of effector T cells that mediate type 1 inflammation, making it a potential target for therapeutic modulation of inflammatory diseases.