Tocilizumab inhibits structural joint damage in rheumatoid arthritis patients with inadequate responses to methotrexate: Results from the double-blind treatment phase of a randomized placebo-controlled trial of tocilizumab safety and prevention of structural joint damage at one year

Authors

  • Joel M. Kremer,

    Corresponding author
    1. Albany Medical College and the Center for Rheumatology, Albany, New York
    • Center for Rheumatology, Albany Medical College, 367 Washington Avenue, Suite 101, Albany, NY 12206
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    • Dr. Kremer has received consulting fees, speaking fees, and/or honoraria from Roche/Genentech (more than $10,000).

  • Ricardo Blanco,

    1. Hospital Marqués de Valdecilla, Santander, Spain
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    • Dr. Blanco has received consulting fees, speaking fees, and/or honoraria from Roche, Abbott, and Schering-Plough (less than $10,000 each).

  • Marek Brzosko,

    1. Rheumatology and Internal Diseases Clinic and Pomeranian Medical University, Szczecin, Poland
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  • Ruben Burgos-Vargas,

    1. Hospital General de México and Universidad Nacional Autónoma de México, Mexico City, Mexico
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    • Dr. Burgos-Vargas has received speaking fees and/or honoraria for advisory board service from Abbott, Merck Sharp & Dohme, Pfizer, and Roche (less than $10,000 each).

  • Anne-Marie Halland,

    1. Panorama Medical Center, Cape Town, South Africa
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    • Dr. Halland has received honoraria from Roche (less than $10,000).

  • Emma Vernon,

    1. Roche, Welwyn, UK
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  • Petra Ambs,

    1. Roche, Basel, Switzerland
    Current affiliation:
    1. Novartis Pharma, Basel, Switzerland
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    • Dr. Ambs holds stock or stock options in Hoffmann-La Roche.

  • Roy Fleischmann

    1. Metroplex Clinic Research Center, Dallas, Texas
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    • Dr. Fleischmann has received consulting fees, speaking fees, and/or honoraria from Abbott, Amgen, Pfizer, UCB, Bristol-Myers Squibb, Centocor, Schering-Plough, and Roche (less than $10,000 each).


Abstract

Objective

To assess the efficacy and safety of tocilizumab plus methotrexate (MTX) versus MTX alone in preventing structural joint damage and improving physical function and disease activity in patients with moderate-to-severe rheumatoid arthritis and inadequate responses to MTX.

Methods

A total of 1,196 patients were enrolled in a 2-year, randomized, double-blind, placebo-controlled trial. Patients received tocilizumab (8 mg/kg or 4 mg/kg) or placebo every 4 weeks plus MTX. Rescue treatment was available from week 16. Results from year 1 are presented.

Results

Mean change in the total Genant-modified Sharp score was 0.29 and 0.34 with tocilizumab 8 mg/kg plus MTX and 4 mg/kg plus MTX, respectively, versus 1.13 with placebo plus MTX (P < 0.0001 for both comparisons). Analysis of variance of the area under the curve for change from baseline in the disability index of the Health Assessment Questionnaire showed greater decreases with tocilizumab 8 mg/kg and 4 mg/kg (−144.1 and −128.4 units, respectively) than with placebo (−58.1 units; P < 0.0001 for both comparisons). Proportions of patients with American College of Rheumatology 20%, 50%, and 70% improvement and with Disease Activity Score in 28 joints remission were higher in those receiving 8 mg/kg tocilizumab than in those receiving placebo (P < 0.0001 for all comparisons). The safety profile of tocilizumab was consistent with the profiles in previous studies. Infections were the most common adverse and serious adverse events.

Conclusion

The findings of this study show that tocilizumab plus MTX results in greater inhibition of joint damage and improvement in physical function than does MTX alone. Tocilizumab has a well-characterized safety profile.

Rheumatoid arthritis (RA) is characterized by chronic synovitis leading to progressive joint damage, functional impairment, and reduced health-related quality of life (1–3). Only one-third of patients with RA who are treated with conventional disease-modifying antirheumatic drugs (DMARDs) achieve remission according to the Disease Activity Score in 28 joints (DAS28) criteria. Combining DMARDs such as methotrexate (MTX) with biologic agents targeting tumor necrosis factor α (TNFα), interleukin-1 (IL-1), B cells, or T cells significantly limits the progression of joint damage as compared with DMARDs alone (4–14). However, depending on the agent, structural damage continues to progress in 30–40% of patients (7, 10, 15), and some patients discontinue therapy because of lack of sustained efficacy or for safety reasons (16).

IL-6 is a pleiotropic cytokine that has proinflammatory and immune stimulatory actions and plays a major role in RA pathogenesis and disease activity (17). Systemic levels of IL-6 and IL-6 receptor correlate with measures of inflammation, clinical signs and symptoms, and radiographic joint damage (18, 19). As a key regulator of osteoclast differentiation, IL-6 may promote erosive joint changes by activating osteoclast formation and accelerating bone resorption (19). Preclinical and in vitro data suggest that chronic overexpression of IL-6 in the circulation may be associated with decreased osteoblast activity (20).

Tocilizumab is a humanized monoclonal antibody that inhibits IL-6 binding to soluble and membrane-expressed IL-6 receptors, blocking the proinflammatory activities of IL-6/IL-6 receptor signaling (21–23). In a study of patients with RA who had inadequate responses to DMARDs, tocilizumab monotherapy was superior to conventional DMARDs with respect to radiographic progression (24); biochemical markers showed decreased cartilage degradation (25). Similarly, treatment with tocilizumab plus MTX significantly reduced markers of cartilage turnover in a placebo-controlled trial (26).

The Tocilizumab Safety and the Prevention of Structural Joint Damage (LITHE) study is a 2-year trial assessing radiographic progression, physical function, clinical disease activity, and safety in RA patients receiving tocilizumab plus MTX or MTX alone. Efficacy and safety results from a planned 1-year interim analysis are presented herein.

PATIENTS AND METHODS

Study design.

The LITHE study is a phase III, multicenter, randomized, 3-arm, placebo-controlled, parallel-group trial in patients with moderately to severely active RA and inadequate responses to MTX consisting of a 1-year, double-blind, placebo-controlled treatment phase followed by a second year of open-label therapy and an optional 3-year open-label extension phase. Randomization was stratified by site. Each patient received an intravenous infusion of tocilizumab 8 mg/kg or 4 mg/kg or placebo (1:1:1 ratio) every 4 weeks in combination with a stable dosage of MTX (10–25 mg/week). Oral corticosteroids (≤10 mg/day of prednisone or equivalent) and nonsteroidal antiinflammatory drugs (NSAIDs) were permitted if the dosages had been stable for ≥6 weeks before study entry. All patients received ≥5 mg/week of folic acid.

Patients who did not achieve ≥20% improvement from baseline in the swollen joint count and the tender joint count by week 16 were offered rescue therapy. Patients in the control, tocilizumab 4-mg/kg, and tocilizumab 8-mg/kg groups received as rescue therapy tocilizumab 4 mg/kg, tocilizumab 8 mg/kg, and tocilizumab 8 mg/kg, respectively, along with steroids if needed. If <20% improvement from baseline in the swollen joint count and the tender joint count persisted after 3 doses of blinded first-step rescue therapy, patients could advance to second-step rescue with tocilizumab 8 mg/kg through week 52. Patients who did not respond after 3 doses of second-step rescue therapy discontinued treatment. Each investigator used his or her own clinical judgment to determine whether a patient should discontinue the study because of insufficient clinical response.

Efficacy and safety parameters were assessed every 2 weeks until week 8 and then every 4 weeks until week 52. Radiographs of the hands/wrists and feet were obtained at baseline, week 24, and week 52, or at the time of switching to rescue therapy or study discontinuation. Radiographs were assessed with the Genant-modified Sharp scoring system (27) by 2 independent readers (Synarc) who were blinded to treatment assignment, chronological order of radiographs, and patients' clinical responses. Study treatment was interrupted in patients with alanine aminotransferase (ALT) or aspartate transaminase (AST) values ≥3× the upper limit of normal (ULN) and was resumed once levels were <3× the ULN. Treatment was discontinued if a patient experienced a second elevation in the AST or ALT level, missed 2 consecutive doses of tocilizumab because of elevations in liver values, or had ALT/AST levels ≥5× the ULN, bilirubin levels >2× the ULN or >2.5 mg/dl, or an absolute neutrophil count <0.5 × 109/liter. For elevations in the ALT/AST levels that were <3× the ULN, no treatment interruptions or modifications were mandated regardless of whether the elevations were recurrent; interruptions in tocilizumab therapy and reductions in the weekly dose (≥2.5 mg/week) of MTX within 2 weeks of the elevations in liver enzymes could occur at the investigator's discretion. Patients who discontinued therapy underwent followup safety or efficacy assessments, or both, at 4, 8, and 12 weeks after their last dose.

The study was approved by the ethics committee at each participating institution and was conducted according to the Principles of Good Clinical Practice and according to the Declaration of Helsinki. All patients provided written informed consent. No steering committee was used for this study.

Study population.

Eligible patients had RA, as determined according to American College of Rheumatology (ACR) criteria (28), that was moderate to severe in the opinion of the investigator and lasted for ≥6 months; had an inadequate response to MTX therapy, defined as a swollen joint count of ≥6, a tender joint count of ≥8, and either C-reactive protein (CRP) level ≥1 mg/dl or an erythrocyte sedimentation rate (ESR) ≥28 mm/hour; and had ≥1 radiographically confirmed joint erosion despite having received MTX for at least 12 weeks before baseline (stable at a dosage of 10–25 mg/week for ≥8 weeks). All other DMARDs or biologic agents were discontinued before study entry (leflunomide for ≥12 weeks, infliximab or adalimumab for ≥8 weeks, and etanercept for ≥2 weeks).

Patients were excluded if they had serious concomitant diseases, significant systemic involvement of RA, functional class IV RA, other inflammatory joint diseases, or current/recurrent infections. Other exclusion criteria included abnormal ALT or AST (>1.5× the ULN), total bilirubin (above the ULN), hemoglobin (<8.5 gm/dl), or triglyceride (>900 mg/dl) levels or white blood cell (<3 × 109/liter)/platelet (<100 × 109/liter) counts; a history of any chronic lower gastrointestinal (GI) tract condition that could lead to perforation; failure to respond to anti-TNF therapy; and treatment with intraarticular or parenteral corticosteroids ≤6 weeks before baseline.

Study end points.

Co–primary end points at week 52 were change from baseline in the total Genant-modified Sharp score (29) and change in physical function, as measured by the area under the curve (AUC) for change from baseline in the disability index (DI) of the Health Assessment Questionnaire (HAQ) (30). Secondary radiographic end points included change from baseline in erosion and joint space narrowing scores (weeks 24 and 52), total Genant-modified Sharp score at week 24, and proportions of patients with no progression of the total, erosion, or joint space narrowing scores (no progression of the total score was an exploratory analysis). Other secondary end points included response rates according to the ACR criteria for 20% improvement (ACR20), 50% improvement (ACR50), and 70% improvement (ACR70) (31), change in DAS28-ESR (32), and proportions of patients with low levels of disease activity (DAS28 ≤3.2) and DAS remission (DAS28 <2.6). Change in hemoglobin levels from baseline to week 52 in tocilizumab-treated patients was compared with that in the controls (exploratory analysis), and further comparison was made between those with normal and those with low hemoglobin levels at baseline. Safety evaluations included physical examination, laboratory analyses, and assessments of adverse events (AEs).

Statistical methods.

A sample size of 390 patients per treatment group (1,170 patients) was calculated to be required in order to provide 90% power to detect a statistically significant difference between tocilizumab plus MTX and MTX alone, assuming a difference in radiographic score changes of ∼30% of the standard deviation at 52 weeks. The study was not designed to detect differences between the two doses of tocilizumab.

Efficacy analyses were conducted using the intent-to-treat (ITT) population, which included all randomly assigned patients who received ≥1 dose of study medication. Safety analyses were conducted in all patients who received ≥1 dose of study medication and who had ≥1 postrandomization assessment of safety (safety analysis population). For efficacy analyses, only data obtained until the switch to rescue therapy were included. Missing or postrescue radiographic data at week 52 were imputed by linear extrapolation for any patient with 1 baseline assessment and ≥1 postbaseline assessment before rescue therapy. Sensitivity analysis of the change in the total Genant-modified Sharp score at weeks 24 and 52 was performed using “as-observed” data (excluding postwithdrawal and postrescue data). Sensitivity analyses were performed to ensure that the results of radiographic data were robust (i.e., linear extrapolation including postwithdrawal data, escape data, or both; observed cases; median change imputations; 75th/25th percentile imputations; worst-case imputation; best/worst imputation). The AUC of the change in the HAQ DI was calculated using the latest nonmissing values before rescue/missing data and then standardized to 52 weeks. For analyses of continuous variables, data obtained after the switch to rescue therapy were excluded. ACR20, ACR50, and ACR70 and European League Against Rheumatism response rates were analyzed with nonresponder imputation (any missing or postrescue data).

A sequential testing procedure was used for the primary efficacy comparisons. The tocilizumab 8-mg/kg group was first compared with the control group; if this comparison was significant (P ≤ 0.025), the tocilizumab 4-mg/kg group was compared with the control group. For the primary analysis of change from baseline in the total Genant-modified Sharp score at week 52, the nonparametric van Elteren test with region as a stratifying factor was used. Primary analysis of the AUC of the change from baseline in the HAQ DI score at week 52 was performed with an analysis of variance (ANOVA) model adjusted for region.

Secondary end points were hierarchically ordered before unblinding and analyzed according to a predetermined fixed sequence to control the rate of false-positive conclusions. P values less than 0.05 were considered statistically significant. The break in the hierarchically ordered testing sequence of the secondary efficacy end points occurred at the Short Form 36 health survey mental component summary score at week 52 (data not shown), which was not significantly different between the tocilizumab 8-mg/kg group and the control group; all parameters before this break in the hierarchy were considered to be statistically significant. Secondary end point tests that fell after the break in the hierarchical chain of the algorithm included major clinical response (ACR70 response maintained for 6 consecutive months) for the tocilizumab 8-mg/kg and 4-mg/kg group comparisons to the control group and the change in erosion and joint space narrowing, the ACR20/50/70 responses, the change in the ACR core set of disease activity measures (33), and the DAS28 end points for the tocilizumab 4-mg/kg group comparison to the control group. Therefore, no statistical significance was claimed for these tests. The Cochran-Mantel-Haenszel test was used for categorical responses, and ANOVA was used for continuous end points among treatment groups.

RESULTS

Patient disposition and characteristics.

The 52-week data reported herein were collected between December 2004 and February 2008. A total of 1,196 patients were enrolled at 121 centers in 14 countries (see Appendix A). The ITT population comprised 1,190 patients; 86% of these patients completed 52 weeks, including 29% who received rescue therapy (data available upon request from the author). Discontinuations for safety-related reasons occurred more frequently among patients receiving tocilizumab 8 mg/kg (n = 33 [8%]) or tocilizumab 4 mg/kg (n = 28 [7%]) than among controls (n = 11 [3%]). Conversely, more control patients discontinued because of insufficient therapeutic response (n = 12) than did patients receiving tocilizumab (8 mg/kg, n = 2; 4 mg/kg, n = 1). More patients in the control group received rescue therapy (50%) than in the tocilizumab 8-mg/kg (15%) and 4-mg/kg (24%) groups.

Patient demographic features and disease characteristics were similar among the 3 treatment groups at baseline (Table 1). The mean duration of RA was 9 years (range 0.5–48.8 years) across treatment groups, and the mean DAS28 score was ∼6.5.

Table 1. Summary of baseline demographics and disease activity in the intent-to-treat population, by treatment group*
 TocilizumabPlacebo plus MTX (n = 393)
8 mg/kg plus MTX (n = 398)4 mg/kg plus MTX (n = 399)
  • *

    DMARDs = disease-modifying antirheumatic drugs; anti-TNF = anti–tumor necrosis factor; RA = rheumatoid arthritis; DAS28 = Disease Activity Score in 28 joints; HAQ = Health Assessment Questionnaire; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate.

  • Not counting methotrexate (MTX), to which patients had shown an inadequate response at the time of screening.

  • Because erosions were not restricted to the joints that were assessed by the total Genant-modified Sharp score, some patients had an erosion score of 0 at baseline despite the presence of at least 1 erosion.

  • §

    Calculated as the baseline total Genant-modified Sharp score divided by the mean duration of disease at baseline.

% female/male82/1884/1683/17
Age, mean ± SD years53.4 ± 11.751.4 ± 12.651.3 ± 12.4
Medications   
 MTX dose, mean ± SD mg/week15.4 ± 10.615.0 ± 4.315.0 ± 4.2
 No. of previous DMARDs/anti-TNF agents, mean ± SD1.6 ± 1.41.7 ± 1.41.6 ± 1.5
 % with past use of DMARDs75.478.471.2
 % with past use of anti-TNF agents10.812.311.5
 % taking concomitant steroids626970
Duration of RA, mean (range) years9.3 (0.6–48.8)9.4 (0.5–43.2)9.0 (0.5–44.3)
% rheumatoid factor positive838182
DAS28, mean ± SD6.6 ± 1.06.5 ± 0.96.5 ± 1.0
Total Genant-modified Sharp score, mean (range)28.8 (0–178.7)28.7 (0–171.4)28.5 (0–190.5)
Swollen joint count (66 assessed), mean ± SD17.3 ± 9.517.0 ± 9.816.6 ± 9.2
Total joint count (68 assessed), mean ± SD29.3 ± 15.227.9 ± 14.227.9 ± 14.8
HAQ score, mean ± SD1.5 ± 0.61.5 ± 0.61.5 ± 0.6
CRP, mean ± SD mg/dl2.3 ± 2.62.1 ± 2.42.2 ± 2.5
ESR, mean ± SD mm/hour46.4 ± 24.845.9 ± 25.146.5 ± 24.7
Estimated yearly rate of progression in the total Genant-modified Sharp score§3.13.13.2

Clinical efficacy.

Radiographic progression.

At week 52, treatment with tocilizumab plus MTX was associated with significantly less radiographic progression of disease activity as compared with the controls. Progression of structural damage from baseline to week 52 was reduced by 74% and 70% with tocilizumab 8 mg/kg and 4 mg/kg, respectively, as compared with controls (P < 0.0001) (Figure 1A). The cumulative distribution plot of the change from baseline in the total Genant-modified Sharp score at week 52 showed a decreased frequency and severity of disease progression with tocilizumab therapy (Figure 1B).

Figure 1.

Changes in radiologic scores in patients taking tocilizumab (TCZ) 4 mg/kg plus methotrexate (MTX), tocilizumab 8 mg/kg plus MTX, or placebo (PBO) plus MTX. A, Mean change from baseline in the total Genant-modified Sharp score, erosion score, and joint space narrowing score at week 52 in the intent-to-treat (ITT) population. Data collected after withdrawal or while patients were receiving rescue therapy were excluded. Numbers at the top of the bars are the values represented by the bars. B, Cumulative distribution of change from baseline in the total Genant-modified total Sharp score to week 52 in the ITT population. Data collected after withdrawal or while patients were receiving rescue therapy were excluded. C, Change in the total Genant-modified Sharp score over time in the ITT population (as-observed analysis [postwithdrawal, postrescue data excluded]). ∗ = P < 0.0001 versus placebo plus MTX; † = P < 0.05 versus placebo plus MTX (the test fell, however, after the break in hierarchical chain of the algorithm; therefore, statistical significance is not claimed); ‡ = P < 0.01 versus placebo plus MTX.

The as-observed analysis of change in the total Genant-modified Sharp score (postrescue and postwithdrawal data excluded) showed improved radiographic outcomes with tocilizumab therapy as compared with control therapy at week 24 and was consistent with the primary analysis (linear extrapolation of postrescue and postwithdrawal data) at week 52 (Figure 1C). The proportion of patients without radiographic progression (change in total Genant-modified Sharp score ≤0 from baseline to week 52) was significantly higher with tocilizumab therapy (84% for 8 mg/kg; 81% for 4 mg/kg) than with control therapy (67%; P ≤ 0.0001 by linear extrapolation, exploratory analysis).

Results of the sensitivity analyses were consistent with those obtained in the primary analysis. Statistical significance was achieved in favor of tocilizumab 8 mg/kg plus MTX for the change from baseline at week 52 in total Genant-modified Sharp score, regardless of the patient population (ITT or per protocol) or the method of imputation of missing data (except for the best/worst imputation method).

Physical function.

ANOVA of the adjusted mean AUC of the change in the HAQ DI score from baseline to week 52 showed a significantly greater decrease in the 8-mg/kg and 4-mg/kg plus MTX groups (−144.1 and −128.4 units, respectively) than in the control group taking placebo plus MTX (−58.1 units; P < 0.0001 for both comparisons). Significantly more patients treated with tocilizumab 8 mg/kg plus MTX than patients treated with placebo plus MTX showed improvements of ≥0.3 units in the HAQ DI score (Table 2). At week 52, the proportions of patients who maintained an improvement in the HAQ DI score of ≥0.3 from baseline to 24 weeks were higher in the tocilizumab plus MTX groups than in the control group. The mean HAQ DI scores were lower (i.e., improved) in both tocilizumab groups than in the control group and were decreased from baseline to week 52 (data available upon request from the author).

Table 2. Response rates in the intent-to-treat population, by treatment group*
 TocilizumabPlacebo plus MTX (n = 393)
8 mg/kg plus MTX (n = 398)4 mg/kg plus MTX (n = 399)
  • *

    Except where indicated otherwise, response rates are at week 52. MTX = methotrexate; HAQ = Health Assessment Questionnaire; DI = disability index; ACR70 = American College of Rheumatology 70% improvement; ANOVA = analysis of variance; VAS = visual analog scale (0-100 mm); CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; DAS28 = Disease Activity Score in 28 joints.

  • P < 0.05 versus placebo plus MTX.

  • P < 0.05 versus placebo plus MTX. The test fell after the break in the hierarchical chain of the algorithm; therefore, statistical significance is not claimed.

  • §

    P < 0.0001 versus placebo plus MTX.

  • P ≤ 0.0014 versus placebo plus MTX.

HAQ DI, % (no./total)   
 Patients with improvements of ≥0.3 units62.7 (165/263)59.6 (140/235)52.7 (77/146)
 Patients maintaining improvements of ≥0.3 units from baseline to 24 weeks26.6 (106/398)21.1 (84/399)11.2 (44/393)
 Patients with a score of ≤0.533.6 (89/265)34.5 (82/238)22.4 (33/147)
Major clinical response   
 ACR70 response maintained for 6 months, % (no./total)6.5 (26/398)4.0 (16/399)0.5 (2/393)
ACR core set of disease activity measures, adjusted mean change from baseline at week 52 (ANOVA stratified by region)   
 Swollen joint count (66 assessed)−10.5§−8.2−2.7
 Tender joint count (69 assessed)−15.9§−12.5−4.3
 Patient's global assessment, by VAS, mm−29.7−27.1−20.9
 Physician's global assessment, by VAS, mm−45.5§−42.4−34.9
 Patient's assessment of pain, by VAS, mm−26.2§−23.1−15.1
 CRP, mg/dl−2.3§−1.1−0.4
 ESR, mm/hour−38.6§−25.7−11.0
 HAQ DI−0.6−0.5−0.4
DAS28 response, % (no./total)   
 Clinical remission (score of <2.6)47.2 (127/269)§30.2 (70/232)7.9 (12/151)
 Low disease activity (score of ≤3.2)63.6 (171/269)§45.3 (105/232)18.5 (28/151)
High-level clinical benefit, % (no./total)   
 Patients with no radiographic progression and DAS28 remission40.6 (108/266)23.1 (53/229)5.4 (8/147)
 Patients with no radiographic progression and HAQ DI score ≤0.527.3 (71/260)26.3 (62/236)12.6 (18/143)
 Patients with DAS28 remission and HAQ DI score ≤0.522.6 (57/252)15.9 (35/220)3.6 (5/140)
 Patients with no radiographic progression, DAS28 remission, and HAQ DI score ≤0.518.5 (46/249)12.4 (27/218)2.2 (3/136)

Improvement in signs and symptoms.

At week 52, the ACR20, ACR50, and ACR70 response rates were higher in patients treated with tocilizumab plus MTX than in controls; these differences were statistically significant for those taking 8 mg/kg tocilizumab (P < 0.0001 for all response rate comparisons) (Figures 2A–C). More patients achieved major clinical response (ACR70 response maintained for 6 consecutive months) with tocilizumab plus MTX than with placebo plus MTX (Table 2). The mean change from baseline in all of the ACR core set of disease activity measures was higher with either dose of tocilizumab plus MTX than it was for placebo plus MTX and was significantly greater with tocilizumab 8 mg/kg (Table 2). For tocilizumab 4 mg/kg plus MTX, no statistical significance was claimed because of a break in the sequential testing algorithm.

Figure 2.

Percentages of patients achieving a response according to the American College of Rheumatology criteria for 20% improvement (ACR20) (A), 50% improvement (ACR50) (B), and 70% improvement (ACR70) (C) from baseline (BL) to week 52 in those taking tocilizumab (TCZ) 4 mg/kg plus methotrexate (MTX), tocilizumab 8 mg/kg plus MTX, or placebo plus MTX. Analyses were conducted on the intent-to-treat population. Patients who required rescue therapy or withdrew prematurely or those for whom ACR improvement could not be calculated were considered nonresponders. The numbers of patients assessed at each time point in each treatment group are shown across the bottom. ∗ = P < 0.0001 versus placebo plus MTX. The difference between the tocilizumab 4 mg/kg plus MTX versus placebo plus MTX groups was significant at P < 0.05; for this comparison, however, the test fell after the break in hierarchical chain of the algorithm; therefore, statistical significance is not claimed.

The DAS28 decreased over 52 weeks in all treatment groups, with mean improvements of −3.8, −3.0, and −2.0 in the tocilizumab 8-mg/kg and 4-mg/kg plus MTX and control groups, respectively (P < 0.0001 for tocilizumab 8 mg/kg versus placebo). By week 52, a significantly higher proportion of patients treated with tocilizumab 8 mg/kg plus MTX were in remission according to the DAS28 score (<2.6) or had low disease activity (≤3.2) compared with controls (P < 0.0001 for both comparisons) (Table 2). DAS28 remission rates continued to improve between weeks 24 and 52, with the highest proportion of patients in remission in the tocilizumab 8 mg/kg plus MTX group. More patients in the tocilizumab groups achieved 2 of the following 3 criteria: absence of radiographic progression (change ≤0); HAQ DI score ≤0.5; or remission according to the DAS28 (score of <2.6) (Table 2).

Laboratory measures.

The adjusted (for region) mean increase in hemoglobin concentrations from baseline to week 52 was significantly greater in both tocilizumab treatment groups (1.24 gm/dl in the 8-mg/kg group; 0.71 gm/dl in the 4-mg/kg group) than in the control group (0.13 gm/dl; P < 0.0001 versus controls; exploratory analysis). In all groups, patients with low hemoglobin concentrations at baseline had a greater increase in hemoglobin values than did patients with normal values at baseline (data not shown).

Safety.

Adverse events.

Total exposure in the tocilizumab 8-mg/kg and 4-mg/kg groups was 349.2 patient-years and 328.7 patient-years, respectively, compared with 256.1 patient-years in the control group (Table 3). Total exposure in patients requiring rescue therapy was 94.1 patient-years in those initially randomly assigned to placebo plus MTX who received rescue therapy with tocilizumab 4 mg/kg plus MTX; 19.7 patient-years in those initially randomly assigned to placebo plus MTX who received rescue therapy with tocilizumab 4 mg/kg plus MTX and then with tocilizumab 8 mg/kg plus MTX; 55.2 patient-years in patients initially randomly assigned to tocilizumab 4 mg/kg plus MTX who received rescue therapy with tocilizumab 8 mg/kg plus MTX; and 35.3 patient-years in patients initially randomly assigned to tocilizumab 8 mg/kg plus MTX who received rescue therapy with tocilizumab 8 mg/kg plus MTX (Table 3). (Patients randomly assigned to tocilizumab 8 mg/kg plus MTX who had inadequate responses received tocilizumab 8 mg/kg plus MTX as rescue therapy because tocilizumab 8 mg/kg is the highest dose allowed. Although these patients consequently received the same dose for treatment as for rescue, this was necessary to maintain blinding.)

Table 3. Exposure and adverse events in the safety population, by treatment group*
 Initial therapyFirst-step and second-step rescue therapy
TCZ 8 mg/kg plus MTX (n = 399)TCZ 4 mg/kg plus MTX (n = 399)Placebo plus MTX (n = 392)From placebo plus MTX to TCZ 4 mg/kg plus MTX (n = 165)From placebo plus MTX to TCZ 4 mg/kg plus MTX to TCZ 8 mg/kg plus MTX (n = 30)From TCZ 4 mg/kg plus MTX to TCZ 8 mg/kg plus MTX (n = 95)From TCZ 8 mg/kg plus MTX to TCZ 8 mg/kg plus MTX (n = 59)
  • *

    Steroids were included in the rescue therapy, if needed. See Patients and Methods for the rescue therapy protocol. AEs = adverse events; SAEs = serious adverse events.

  • One opportunistic fungal infection (Candida osteomyelitis) occurred during therapy with 8 mg/kg of tocilizumab (TCZ) plus methotrexate (MTX). No cases of tuberculosis or mycobacterial infections were reported.

Total no. of patient-years of exposure349.2328.7256.194.119.755.235.3
No. of AEs per 100 patient-years325.4324.0279.6279.6376.2427.8348.3
SAEs       
 No. of SAEs per 100 patient-years11.512.810.213.8010.914.2
 No. of serious infections per 100 patient-years4.03.72.32.101.82.8
 No. (%) with pneumonia/bronchitis2 (0.5)3 (0.8)2 (0.5)001 (1.1)1 (1.7)
 No. (%) with gastroenteritis02 (0.5)2 (0.5)0000
 No. (%) with cellulitis2 (0.5)001 (0.6)000
 No. (%) with viral gastroenteritis02 (0.5)00000
 No. (%) with infusion/anaphylactic/hypersensitivity reactions02 (0.5)04 (2.4)000

Most AEs were mild or moderate. Exposure-adjusted rates of serious AEs (SAEs) are described in Table 3 and showed no apparent differences between tocilizumab and control groups. Infections were the most common AEs and SAEs observed. Lower respiratory tract and GI infections were the most commonly reported serious infections.

Sixteen neoplasms were reported: 8 solid malignancies, 5 nonmelanoma skin cancers, 1 carcinoma in situ, and 2 unclassified neoplasms. Of the solid malignancies, 1 was seen in the tocilizumab 8-mg/kg group (uterine cancer) with 349.2 patient-years of exposure, 5 in the tocilizumab 4-mg/kg group (1 each breast cancer, cervical carcinoma, lung squamous cell carcinoma, and 2 prostate cancers) with 328.7 patient-years of exposure, 1 in the control group (1 breast cancer) with 256.1 patient-years of exposure, and 1 in a patient receiving first-step rescue therapy with tocilizumab 8 mg/kg (clear cell carcinoma of the kidney) with 55.2 patient-years of exposure. One patient with basal cell carcinoma and 1 with prostate cancer each had a history of the corresponding malignancy. The 2 unclassified neoplasms (1 skin cancer on left forearm and 1 lung neoplasm [tiny nodule in the left lower lobe seen on chest radiograph]) were reported in the tocilizumab 4-mg/kg group.

An infusion reaction, defined as any reaction occurring during or within 24 hours of infusion, resulted in discontinuation of treatment. Six patients receiving tocilizumab 4 mg/kg experienced infusion reactions; among them were 4 serious anaphylactic reaction/shock events. These anaphylactic reactions were generally observed during the second or third infusion of tocilizumab. All reactions resolved without sequelae with the exception of anaphylactic shock in 1 patient receiving rescue therapy with tocilizumab 4 mg/kg plus MTX; that patient had a myocardial infarction with blockage of the right coronary artery and underwent placement of a stent. Serious GI events, which were observed in all groups, were infrequent, and all patients were concurrently receiving NSAIDs or corticosteroids. Six deaths occurred during the study: 2 in the control group (1 patient died of pulmonary embolism while receiving rescue therapy with tocilizumab 4 mg/kg plus MTX; 1 died of Wegener's granulomatosis) and 4 in the tocilizumab 8-mg/kg group (1 patient each died of cerebral hemorrhage, GI infection, bronchopneumonia, and sepsis). Two of the deaths (1 due to pulmonary embolism and 1 due to GI infection) were considered by the investigator to be possibly related to the study treatment.

Laboratory findings.

Changes in laboratory parameters in tocilizumab-treated patients included reduced neutrophil counts, elevated hepatic enzyme levels, and elevated plasma lipid levels (Table 4). The mean neutrophil counts decreased within the normal range; the decreases appeared to be dose dependent. Grade 3 or grade 4 neutropenia occurred more frequently among patients taking tocilizumab than among the controls; the frequency was highest with 8 mg/kg tocilizumab. Treatment was discontinued in the 3 patients who experienced grade 4 neutropenia; their neutrophil counts recovered within 4 weeks. Of the patients who reported serious infections, all except 1, a patient in the 4-mg/kg tocilizumab group who developed a respiratory tract infection, had a normal neutrophil count 1 month before the infection. Neutrophil counts were obtained on the day study medication was administered, and the results were usually not available before study drug administration.

Table 4. Changes in laboratory values during initial randomized therapy in the safety population, by treatment group*
 TocilizumabPlacebo plus MTX (n = 392)
8 mg/kg plus MTX (n = 399)4 mg/kg plus MTX (n = 399)
  • *

    ANC = absolute neutrophil count; TC = total cholesterol; LDL-C = low-density lipoprotein cholesterol; HDL-C = high-density lipoprotein cholesterol.

  • One value was sufficient to qualify; included values were determined by a single elevation to grade 4 neutropenia.

  • Three patients had elevated alanine aminotransferase (ALT) levels: 1 in the tocilizumab (TCZ) 4 mg/kg plus methotrexate (MTX) group with an ALT greater than the upper limit of normal (ULN); 1 in the TCZ 8 mg/kg plus MTX group with an ALT >3 times the ULN; and 1 in the TCZ 8 mg/kg plus MTX group with an ALT >5 times the ULN. All 3 patients were later confirmed to have hepatic steatosis.

  • §

    For ALT patterns of change, n = 274 for the TCZ 8 mg/kg plus MTX group, n = 240 for the TCZ 4 mg/kg plus MTX group, and n = 122 for the placebo plus MTX group. Sustained elevation was defined as >1 consecutive elevation in the ALT level that did not return to normal by study end.

  • For aspartate aminotransferase (AST) patterns of change, n = 226 for the TCZ 8 mg/kg plus MTX group, n = 175 for the TCZ 4 mg/kg plus MTX group, and n = 86 for the placebo plus MTX group. Sustained elevation was defined as >1 consecutive elevation in the AST level that did not return to normal by study end.

Neutrophil counts, no. (%)   
 Grade 3 neutropenia, ANC 0.5 to <1.0 × 109/liter17 (4.3)7 (1.8)0
 Grade 4 neutropenia, ANC <0.5 × 109/liter1 (<1)2 (<1)0
Hepatic enzyme levels, no. (%)   
 ALT   
  Two or more consecutive values above the ULN§28 (10.2)23 (9.6)19 (15.6)
  Sustained elevation§31 (11.3)7 (2.9)6 (4.9)
  Nonconsecutive elevation of ≥2 values§163 (59.5)147 (61.3)49 (40.2)
  Shift from normal to between >1× the ULN and 3× the ULN206 (51.6)184 (46.1)93 (23.7)
  Shift from normal to >3× the ULN36 (9.0)28 (7.0)3 (<1)
 AST   
  Two or more consecutive values above the ULN21 (9.3)13 (7.4)4 (4.7)
  Sustained elevation6 (2.7)3 (1.7)7 (8.1)
  Nonconsecutive elevation of ≥2 values132 (58.4)88 (50.3)36 (41.9)
  Shift from normal to between >1× the ULN and 3× the ULN202 (50.6)158 (39.6)76 (19.4)
  Shift from normal to >3× the ULN11 (2.8)7 (1.8)1 (<1)
 Bilirubin   
  Shift from normal to between >1× the ULN and 3× the ULN40 (10.0)24 (6.0)5 (1.3)
  Shift from normal to >3× the ULN1 (<1)00
Lipid levels, no./total (%)   
 Increase in TC from <240 mg/dl to ≥240 mg/dl102/394 (26)56/396 (14)31/384 (8)
 Increase in LDL-C from <160 mg/dl to ≥160 mg/dl70/381 (18)53/381 (14)15/376 (3.8)
 Increase in HDL-C from <60 mg/dl to ≥60 mg/dl56/386 (15)51/386 (13)39/377 (10)

Increases in the ALT and AST levels to >1× the ULN to 3× the ULN or >3× the ULN occurred more frequently in patients receiving tocilizumab than in controls (Table 4). Most of these elevations were single or nonconsecutive occurrences, and they normalized spontaneously with no clinical sequelae. Three patients with elevated ALT levels (1 in the tocilizumab 4-mg/kg group and 2 in the tocilizumab 8-mg/kg group) were subsequently confirmed by ultrasound or biopsy to have hepatic steatosis. Twelve patients (4.5%), 7 patients (1.8%), and 1 patient (0.3%) in the tocilizumab 8-mg/kg, tocilizumab 4-mg/kg, and control groups, respectively, 2 patients (1.2%) in the control to tocilizumab-4 mg/kg rescue group, and 1 patient (1.1%) in the tocilizumab 4-mg/kg to 8-mg/kg rescue group were withdrawn because of elevated transaminase levels. No clinical symptoms of drug-induced liver injury, including hepatic dysfunction (decreased albumin levels) or hepatitis, were reported, and none of the patients had a concurrent increase in the ALT or AST level >3× the ULN and the total bilirubin level >2× the ULN.

Mean plasma concentrations of total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein, and triglycerides increased over time in all treatment groups. Clinically significant elevations in levels of total cholesterol (≥240 mg/dl) or LDL (≥100 mg/dl) were noted more frequently in the tocilizumab groups than in the control group (Table 4). Thirty-one patients in the tocilizumab groups received a lipid-lowering agent, which resulted in a decrease in the LDL level (data available upon request from the author).

DISCUSSION

This is the first randomized, double-blind, placebo-controlled trial to show that tocilizumab, at either 8 mg/kg or 4 mg/kg, plus MTX administered over 52 weeks significantly reduced the progression of radiographic joint damage and improved physical function as compared with placebo plus MTX in patients with moderate-to-severe RA that was unresponsive to MTX alone. The radiographic, functional, and clinical benefits, including the proportions of patients achieving ACR50 and ACR70 responses and remission according to the DAS28 score, increased from week 24 to week 52 with both doses of tocilizumab plus MTX. In general, therapeutic responses were consistently higher with tocilizumab 8 mg/kg plus MTX, particularly for the parameters defining high-level clinical benefits. Additional benefits, such as achievement of no radiographic progression and DAS28 remission (23–41%) or improvement in HAQ DI score over time, were observed with tocilizumab plus MTX.

These data are consistent with preclinical evidence showing that IL-6 receptor inhibition reduces osteoclast stimulation and corresponding bone resorption and lessens progressive joint damage (34). The inhibition of radiographic progression with tocilizumab plus MTX combination therapy in the current study confirms the finding that tocilizumab monotherapy was superior to conventional DMARDs in preventing joint damage (24). Further studies may elucidate the precise role of IL-6 in osteoclastogenesis and its contribution to progressive joint damage in RA.

Anemia of chronic disease occurs in approximately one-third of RA patients (35). The increase in hemoglobin levels in patients receiving tocilizumab was similar to increases seen in other studies of tocilizumab (36–39). This effect may be related to the ability of IL-6 to induce the production of hepcidin, a blocker of iron transport, as part of the acute-phase response (40). Thus, inhibition of the IL-6 receptor may prevent hepcidin production, which in turn, may result in the release of sequestered iron in macrophages and in the alleviation of anemia.

As is common in placebo-controlled studies in patients with moderate-to-severe RA, the LITHE study incorporated a rescue option, allowing patients who did not respond to therapy to receive rescue treatment with tocilizumab. This added complexity to the study design and analysis of the data. By week 52, half the patients initially assigned to the control group had received rescue therapy with tocilizumab. A potential impact of this switch could be a slower rate of radiographic progression in the control group as compared with the rates reported in similar RA populations in trials of abatacept, adalimumab, and infliximab (8, 12), thereby underestimating the treatment effect. Therefore, the primary method of analysis used linear extrapolation, which allowed estimation of the continued effect of progression by assuming the patient would continue at the rate seen at earlier time points.

Choosing appropriate methodologies for imputing missing data will remain a challenge for future placebo-controlled trials in RA. In this study, several sensitivity analyses were performed in addition to linear extrapolation, and the findings of all of them were consistent with those obtained from the primary analysis, except for the best/worst imputation method. Of note, the use of rescue therapy limits the comparability of these results to other studies. Such comparisons should always be conducted with caution because of differences in study populations and radiographic interpretation methods (41).

It is important to conduct risk–benefit assessments in patients beginning treatment with biologic agents for refractory RA. Potential benefits gained from therapy, such as improved quality of life and, in patients with severe disease, avoidance of disability, must be weighed against potential adverse events.

Safety findings were consistent with those obtained from previous 24-week studies of tocilizumab plus a DMARD in similar patient populations (37, 39), with infections being the most common AEs and SAEs. Analysis of long-term (median treatment duration 3.1 years) safety data pooled from the blinded portions of 5 pivotal tocilizumab studies showed rates of serious infection of 3.4 per 100 patient-years for the comparator group, 3.5 per 100 patient-years for the tocilizumab 4-mg/kg group, and 4.9 per 100 patient-years for the tocilizumab 8-mg/kg group (42). Analysis of pooled long-term data also showed that the overall rate of serious infection was stable over time and that there was no increase in the rate of serious infection with prolonged use (42). In the present study, 3 of the serious infections (GI infection, bronchopneumonia, and sepsis) were fatal.

Although direct comparisons with other trials should be made with caution, the rate of serious infection reported herein is consistent with that reported in studies of other patients with RA, including those treated with anti-TNF agents in combination with MTX (10, 43). As an expected consequence of IL-6 receptor inhibition (44), a decrease in circulating neutrophil counts was observed in patients treated with tocilizumab. Although more patients treated with tocilizumab experienced grade 3 or grade 4 neutropenia, decreases in the absolute neutrophil count were not related to serious infection in this study. As with other biologic agents, every attempt should be made to detect infections early and to aggressively treat any patients receiving tocilizumab who contract these infections.

In the present study, patients who received tocilizumab, either as primary therapy or rescue therapy, had a higher incidence of solid tumors and nonmelanoma skin cancers than did patients who received placebo plus MTX. This observation is in contrast to reports from other tocilizumab clinical trials, in which a higher incidence of neoplasms among tocilizumab-treated patients was not observed (36–39). Analysis of pooled long-term safety data from the blinded portions of 5 pivotal tocilizumab studies showed the overall rates of malignancy were similar between the comparator group (0.7 per 100 patient-years) and the tocilizumab groups (0.7 per 100 patient-years in the tocilizumab 8-mg/kg group; 1.6 per 100 patient-years in the tocilizumab 4-mg/kg group) and were stable over time (42). These rates appear to be within the range observed in other RA patient populations, including those treated with TNF inhibitors (0.61 per 100 patient-years in the abatacept clinical program) and DMARDs (0.67–1.77 per 100 patient-years in observational cohorts) (45).

Six patients receiving tocilizumab 4 mg/kg experienced infusion reactions; among them were 4 serious anaphylactic reaction/shock events. Because the incidence of anaphylactic reactions observed with tocilizumab is low (0.2%) (46), it is unclear at this time whether there is a dose relationship. If an anaphylactic or other serious hypersensitivity reaction occurs, administration of tocilizumab should be stopped immediately, appropriate medical management should be started, and tocilizumab should be permanently discontinued.

As noted in previous clinical studies, tocilizumab treatment was associated with increases in hepatic transaminase levels that, in many cases, were transient and normalized to below the ULN with or without treatment adjustment. Sustained elevations of transaminases above normal levels occurred in 1.7–11.3% of patients receiving tocilizumab. However, only 4.5% and 1.8% of patients in the tocilizumab 8-mg/kg and 4-mg/kg groups, respectively, were withdrawn because of protocol mandates or investigator choice. The elevations were not associated with clinically relevant increases in bilirubin levels or with obvious evidence of clinical symptoms of drug-induced liver injury or hepatitis. IL-6 plays an important role in liver homeostasis (47) and is protective against hepatocyte injury in animal models (48). Therefore, IL-6 receptor inhibition could result in elevated transaminase levels in some patients.

Rheumatologists are skilled in monitoring transaminase levels because of their extensive experience with such treatments as MTX, leflunomide, and NSAIDs. Adjusting the dosage of MTX according to the published guidelines (49) or the dosage of tocilizumab is appropriate in clinical practice in the event of persistent elevations in transaminase levels. Clinicians should follow guidelines provided in the product information for tocilizumab to manage abnormal laboratory findings, such as decreased neutrophil counts or increased lipid or transaminase levels.

There was an increase in mean serum lipid levels in tocilizumab-treated patients. We believe that any elevation of total cholesterol or LDL should be treated according to current guidelines (50). It has been postulated that elevated CRP levels are associated with increased cardiovascular risk (51). The effect on cardiovascular risk of the lipid increases that occur in response to therapy with biologic agents in patients with RA has been proposed to be offset by a concurrent decrease in inflammation (52). The current study was not designed to address this effect; rather, it must be established with observational data.

In summary, these 1-year interim data from a 2-year study show that the combination of tocilizumab plus MTX results in significantly greater inhibition of progression of structural damage, improvement in physical function, and clinical benefits, with improvements over time, as compared with MTX therapy alone in patients with moderate-to-severe RA who previously had inadequate responses to MTX. The safety profile of tocilizumab in this clinical trial has been consistent with that in previously reported studies (36–39).

AUTHOR CONTRIBUTIONS

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Kremer had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. Kremer, Vernon, Ambs, Fleischmann.

Acquisition of data. Kremer, Blanco, Brzosko, Burgos-Vargas, Halland, Vernon, Fleischmann.

Analysis and interpretation of data. Kremer, Blanco, Brzosko, Burgos-Vargas, Halland, Vernon, Ambs, Fleischmann.

ROLE OF THE STUDY SPONSOR

F. Hoffmann-La Roche Ltd. facilitated the study design, collection of the data, and analysis of the results, provided writing assistance for the manuscript, and reviewed and approved the manuscript prior to submission. No steering committee was used for this study. Publication of this article was not contingent upon approval by F. Hoffmann-La Roche Ltd.

APPENDIX A

THE LITHE INVESTIGATORS

The LITHE investigators are as follows: S. Hall (Malvern, Victoria, Australia), G. Major (Newcastle, New South Wales, Australia), A. Taylor (Perth, Western Australia, Australia), L. E. C. Andrade (São Paulo, Brazil), G. Castelar-Pinheiro (Rio de Janeiro, Brazil), R. Souza (São Paulo, Brazil), B. D. B. de Souza (São Paolo, Brazil), J. C. Simon (Porto Alegre, Brazil), S. Chen (Shanghai, China), X. Han (Shanghai, China), Z. Li (Beijing, China), L. Sun (Nanjing, China), Y. Zhao (Beijing, China), P. Junker (Odense, Denmark), T. Moerk Hansen (Herlev, Denmark), M. Kauppi (Heinola, Finland), M. Leirisalo-Repo (Helsinki, Finland), C. L. Benhamou (Orleans, France), P. Bourgeois (Paris, France), A. Cantagrel (Toulouse, France), L. Euller-Ziegler (Nice, France), P. Fardellone (Amiens, France), R. M. Flipo (Lille, France), X. Le Loet (Rouen, France), X. Mariette (Le Kremlin-Bicetre, France), T. Schaeverbeke (Bordeaux, France), J. Sibilia (Strasbourg, France), K. Boki (Athens, Greece), S. Papazoglou (Athens, Greece), F. N. Skopouli (Athens, Greece), S. Adami (Valeggio Sul Mincio, Italy), L. M. Bambara (Verona, Italy), S. Bombardieri (Pisa, Italy), M. Broggini (Varese, Italy), M. Carrabba (Milan, Italy), S. De Vita (Udine, Italy), F. Fantini (Milan, Italy), R. Giacomelli (Coppito, Italy), M. Matucci Cerinic (Florence, Italy), C. M. Montecucco (Pavia, Italy), R. Pellerito (Turin, Italy), L. Punzi (Padua, Italy), C. Salvarani (Reggio Emilia, Italy), B. Seriolo (Genoa, Italy), G. Valentini (Naples, Italy), G. Valesini (Rome, Italy), P. Sarzi-Puttini (Milan, Italy), V. Alvarado (Mexico City, Mexico), S. Carrillo (Mexico City, Mexico), L. J. Elizondo-Alanis (Obregon, Mexico), D. Galarza (Monterrey, Mexico), F. Irazoque (Mexico City, Mexico), C. Pacheco (Chihuahua, Mexico), K. Mikkelsen (Lillehammer, Norway), M. Bartosik (Kalisz, Poland), J. Brzezicki (Elblag, Poland), J. Bucka (Krakow, Poland), H. Chwakinska-Sadowska (Warsaw, Poland), J. Hensel (Dzialdowo, Poland), S. Jeka (Bydgoszcz, Poland), D. Kapolka (Ustron, Poland), M. Korkosc (Krakow, Poland), P. Leszczynski (Poznan, Poland), B. Sarembock (Cape Town, South Africa), M. Tikly (Soweto, South Africa), E. Chamizo Carmona (Merida, Spain), S. Garcia Perez (Cádiz, Spain), M. Larrosa (Sabadell, Spain), F. Navarro (Seville, Spain), R. Sanmarti (Barcelona, Spain), A. Baldassare (St. Louis, MO), A. S. Barron (West Palm Beach, FL), M. Borofsky (West Reading, PA), A. M. Corsi (Missoula, MT), F. Dietz (Rockford, IL), A. H. Dikranian (San Diego, CA), R. K. Dore (Tustin, CA), S. C. English (Billings, MT), K. P. Flint (Columbia, SC), R. Furie (Lake Success, NY), D. E. Furst (Los Angeles, CA), D. Goddard (Brooklyn, NY), W. Gough (Asheville, NC), W. Gruhn (Charlotte, NC), J. Habros (Scottsdale, AZ), J. Harshbarger (Wilmington, NC), R. Hymowitz (Medford, NJ), A. Kivitz (Duncansville, PA), S. A. Lauter (St. Louis, MO), M. Layton (Olympia, WA), R. Leon (Ponce, PR), J. Loveless (Boise, ID), D. Maccarter (Meridan, ID), W. Maier (Eugene, OR), A. Martin (Tulsa, OK), J. Neal (Lexington, KY), N. Neal (Long Beach, CA), K. Nies (Torrance, CA), K. Oelke (Glendale, WI), T. P. Oleginski (Danville, PA), S. M. Reddy (New York, NY), V. Rodriguez (San Juan, PR), R. L. Rosenberg (Wheaton, MD), B. S. Samuels (Dover, NH), C. D. Scoville (Idaho Falls, ID), W. Shergy (Huntsville, AL), Y. Sherrer (Fort Lauderdale, FL), J. Silverfield (Tampa, FL), S. Solomon (Voorhees, NJ), B. A. Vaz (Tucson, AZ), C. Wiesenhutter (Coeur D'Alene, ID), R. A. Yood (Worcester, MA), C. Ludivico (Bethlehem, PA), D. Klashman (Torrance, CA), E. J. Kopp (Raleigh, NC), J. Box (Charlotte, NC), J. Curtis (Birmingham, AL), N. Wei (Frederick, MD), S. Weisman (Boulder, CO), V. Bray (Denver, CO), and K. Kempf (San Antonio, TX).

Ancillary