Dr. Mease has received consulting fees or honoraria from Biogen Idec, Centocor, Genentech, and Wyeth (less than $10,000 per year) and from Abbott and Amgen (more than $10,000 per year) and owns stock in Amgen. Dr. Gladman has received consulting fees or honoraria (less than $10,000 per year) from Abbott, Amgen, Biogen Idec, Centocor, Schering, and Wyeth. Dr. Keystone has received consulting fees or honoraria from Schering (less than $10,000 per year) and from Abbott and Amgen (more than $10,000 per year).
Alefacept in combination with methotrexate for the treatment of psoriatic arthritis: Results of a randomized, double-blind, placebo-controlled study
Version of Record online: 27 APR 2006
Copyright © 2006 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 54, Issue 5, pages 1638–1645, May 2006
How to Cite
Mease, P. J., Gladman, D. D. and Keystone, E. C. (2006), Alefacept in combination with methotrexate for the treatment of psoriatic arthritis: Results of a randomized, double-blind, placebo-controlled study. Arthritis & Rheumatism, 54: 1638–1645. doi: 10.1002/art.21870
- Issue online: 27 APR 2006
- Version of Record online: 27 APR 2006
- Manuscript Accepted: 15 FEB 2006
- Manuscript Received: 18 JUL 2005
To evaluate the efficacy and safety of alefacept in combination with methotrexate (MTX) for the treatment of psoriatic arthritis (PsA).
Patients were eligible for this randomized, double-blind, placebo-controlled trial if they were ages 18–70 years and had active PsA (≥3 swollen joints and ≥3 tender joints) despite treatment with MTX for ≥3 months (a stable dosage for ≥4 weeks prior to enrollment). Patients were stratified according to psoriasis body surface area (BSA) involvement (≥3% or <3%). Alefacept (15 mg) or placebo was administered intramuscularly once weekly for 12 weeks in combination with MTX, followed by 12 weeks of observation during which only MTX treatment was continued. The primary efficacy end point was the proportion of patients achieving a 20% improvement in disease activity according to the American College of Rheumatology criteria (an ACR20 response) at week 24.
One hundred eighty-five patients were randomly assigned to receive alefacept plus MTX (n = 123) or placebo plus MTX (n = 62). At week 24, 54% of patients in the alefacept plus MTX group achieved an ACR20 response, compared with 23% of patients in the placebo plus MTX group (P < 0.001). Mean reductions in tender and swollen joint counts in patients receiving alefacept plus MTX were –8.0 and –6.3, respectively. In patients with psoriasis involving ≥3% BSA (n = 87), a 50% reduction from the baseline Psoriasis Area Severity Index at week 14 was achieved by 53% of patients receiving alefacept plus MTX compared with 17% of those receiving placebo plus MTX (P < 0.001). Most adverse events were mild to moderate in severity. In the alefacept plus MTX group, the incidence of serious adverse events was low (1.6%), and no opportunistic infections or malignancies were reported.
Alefacept in combination with MTX may be an effective and safe treatment for PsA.
Psoriatic arthritis (PsA) is a chronic inflammation of joints and entheses that affects ∼10–30% of patients with psoriasis (1). Joint inflammation in PsA follows a progressive clinical course and, if left untreated, can result in severe damage and deformity that have a considerable negative impact on patients' quality of life (2–4).
The etiology of PsA is multifactorial, with genetic, environmental, and immunologic factors involved in its development (5, 6). Therapeutic strategies have traditionally focused on agents that are used to treat rheumatoid arthritis (RA) (e.g., sulfasalazine, methotrexate [MTX], cyclosporine, leflunomide, and, most recently, anti–tumor necrosis factor [anti-TNF] agents), given the similarity between these 2 diseases (7–9). Variable efficacy and toxicities have been associated with the traditional disease-modifying agents, limiting their long-term use (10).
Research highlighting the immunologic basis of PsA has led to increased interest in the use of biologic agents for the treatment of this disease. Evidence suggests that activated T cells, which are found in the blood and synovium of patients with PsA (11), and inflammatory modulators, such as TNFα, interleukin-1 (IL-1), and IL-2 (12), play a central role in the pathogenesis of PsA. Biologic agents that inhibit TNF activity have been shown to be effective for the treatment of PsA (9, 13–18), and 3 of these agents (etanercept, infliximab, and adalimumab) are approved for this indication. While the efficacy of disease-modifying antirheumatic drugs (DMARDs) that affect the T cell component of PsA pathogenesis has been described (19, 20), the efficacy of biologic agents that affect this component of PsA pathogenesis has yet to be fully determined. A phase II study of efalizumab, a biologic agent that inhibits T cell activation, trafficking, and reactivation in dermal tissues (21), failed to show statistical significance for its primary end point, a 20% improvement in disease activity according to the American College of Rheumatology criteria (an ACR20 response) (22) that was statistically different between the treatment and placebo groups at 12 weeks (23).
Alefacept, a fusion protein of the first extracellular domains of human lymphocyte function–associated antigen 3 (LFA-3) and the Fc portion of IgG1, was the first biologic agent approved for the treatment of chronic plaque psoriasis (24). Alefacept inhibits T cell activation by blocking CD2–LFA-3 costimulation. Alefacept also facilitates granzyme-mediated apoptosis of memory T cells by binding CD2 on these cells and interacting with CD16 (Fcγ receptor III) receptors on natural killer cells and monocytes (25). Memory T cells are selectively targeted by alefacept because these cells express more CD2 than do naive T cells.
Results of an exploratory study (n = 11) suggested that 7.5 mg intravenous (IV) alefacept was safe and well-tolerated in patients with PsA and provided clinical improvement in a substantial proportion of patients (26). Further, in serial synovial tissue biopsy specimens obtained from these patients after treatment with alefacept, significant reductions were seen in cells implicated in the pathogenesis of PsA, including CD4+ and CD8+ T cells and CD68+ macrophages. Given that 7.5 mg IV and 15 mg intramuscular (IM) alefacept have comparable biologic activity (27), and given that 15 mg IM alefacept once weekly is the US Food and Drug Administration–approved dose for patients with psoriasis, 15 mg IM alefacept once weekly was chosen as the dose for this phase II study. The objective of this clinical trial was to further evaluate the efficacy and safety of alefacept in patients with PsA who were also receiving stable doses of MTX.
PATIENTS AND METHODS
Selection of patients.
Eligible patients were ages 18–70 years and had persistently active PsA (defined as ≥3 swollen joints and ≥3 tender joints) despite treatment with MTX for ≥3 months immediately prior to enrollment. The dose of MTX (10–25 mg/week) was required to be stable for ≥4 weeks prior to enrollment. Patients were required to have CD4+ T cell counts at or above the lower limit of normal for Covance Central Laboratory Services, Indianapolis, IN (≥404/mm3). Patients were excluded from the study if they received treatment with infliximab, adalimumab, or systemic retinoids within 3 months, etanercept or cyclosporine within 2 months, or phototherapy or other DMARDs within 4 weeks of enrollment. Patients were also excluded if they had a history of malignancy; unstable erythrodermic, pustular, or guttate psoriasis; serious local or systemic infection within the previous 3 months; human immunodeficiency virus infection; or active tuberculosis.
This was a placebo-controlled, double-blind trial conducted at 27 sites in the US, Canada, and Europe (a list of participating investigators and investigational sites is shown in Appendix A). Eligible patients were randomized in a 2:1 ratio to receive 15 mg alefacept or placebo (0.9% sodium chloride) by IM injection once weekly for 12 weeks. A 12-week observation period followed during which no investigational drug was administered. All patients continued their stable dose of MTX (10–25 mg/week) throughout the 24-week study period. Patients were stratified in the randomization scheme based on psoriasis body surface area (BSA) involvement (≥3% or <3%).
Allowed concomitant therapies included corticosteroids (≤10 mg/day of prednisone or equivalent) and nonsteroidal antiinflammatory drugs (NSAIDs), provided that the patient was receiving a stable dosage of these drugs 2 weeks prior to screening and continued to receive that dosage throughout the trial. Low- and moderate-potency topical steroids, keratolytics, coal tar, and vitamin D analogs were allowed only on the palms, soles, scalp, groin, and anal fold region. A 2-week washout period was required prior to enrollment for higher doses of corticosteroids (>10 mg/day of prednisone or equivalent), high-potency topical steroids, and unstable doses of NSAIDs.
Measures of disease activity for arthritis and psoriasis were assessed at screening and at weeks 1 (prior to the first dose), 7, 14, 18, and 24. For PsA, disease activity measurements included ACR core set (28) measurements of tender joint count (modified criterion: 78 possible tender joints), swollen joint count (modified criterion: 76 possible swollen joints), physician's global assessment of disease activity, patient's global assessment of disease activity, patient's assessment of pain, patient's assessment of disability (the Health Assessment Questionnaire disability index ), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) level (18, 30). Measures of psoriasis disease activity included the Psoriasis Area Severity Index (PASI) (31) and a 7-point physician's global assessment (PGA; ranging from 7 = severe to 1 = clear). PASI evaluations were performed by certified clinicians who had completed training with Biogen Idec (Cambridge, MA). At each time point, the same individual performed the PASI evaluation for a given patient. Lymphocyte subset analysis was conducted at screening, every other week during the 12-week treatment period, and at weeks 14, 18, and 24. Adverse events, new or ongoing infections, and concomitant therapy were monitored throughout the study. Blood chemistry was evaluated at screening and at weeks 1, 5, 9, 14, 18, and 24.
All patients gave informed consent, and the protocol was approved by the Institutional Review Board or Ethics Committee at each investigational site. The trial was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki.
Study end points.
The primary efficacy end point was the proportion of patients who had an ACR20 response at week 24, 12 weeks after alefacept dosing was completed. An ACR20 response is defined as ≥20% reduction in tender and swollen joint counts and ≥20% improvement in ≥3 of the following: physician's global assessment of disease activity, patient's global assessment of disease activity, patient's assessment of pain, patient's assessment of disability, and an acute-phase reactant (ESR or CRP level) (30). Additional efficacy end points were the proportions of patients achieving ACR50 and ACR70 responses at week 24 and ACR20, ACR50, and ACR70 responses at any time during the study. The end points for efficacy in psoriasis were the proportions of patients with psoriasis (BSA involvement ≥3%) who achieved 50% or greater reduction from baseline PASI (PASI50), 75% or greater reduction from baseline PASI (PASI75), and a PGA of “clear” or “almost clear” at week 14 and at any time. The pharmacodynamic end point was the change from baseline in CD4+ T cell counts. Safety end points included the incidence of adverse events, discontinuations because of adverse events, serious adverse events, infections, malignancies, and shifts from baseline to high postbaseline laboratory values for alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin.
Efficacy analyses were conducted on the intent-to-treat population, which included all patients who received ≥1 dose of the study drug. If data for ACR components or PASI assessments were missing for a patient at a visit, the patient was considered a nonresponder for that visit. Safety was assessed in all patients who received ≥1 dose of the study drug and had ≥1 postbaseline assessment of the safety parameter being analyzed.
The primary objective of this study was to evaluate the efficacy of alefacept in combination with MTX in patients with PsA. It was determined that with a sample size of 180 patients randomized 2:1 to receive alefacept plus MTX (n = 120) or placebo plus MTX (n = 60), we would be able to detect a 25% difference in the primary efficacy end point (the proportion of patients achieving an ACR20 response at week 24) with 90% power, using a 2-sided chi-square test with a 5% significance level.
Basic summary statistics were used for presenting demographics and baseline characteristics. A 2-sided chi-square test was used to compare ACR responses between the 2 treatment groups at week 24 and at any time during the study. The likelihood ratio chi-square test was used to compare PASI50, PASI75, and PGA “clear”/“almost clear” responses between treatment groups at week 14.
A total of 185 patients were randomized to receive 15 mg IM alefacept in combination with MTX (alefacept plus MTX group, n = 123) or placebo in combination with MTX (placebo plus MTX group, n = 62) once weekly for 12 weeks (Figure 1). Four patients in the alefacept plus MTX group discontinued treatment (1 of these patients continued in the trial and completed the followup period), and 1 patient in the placebo plus MTX group discontinued treatment.
Patient demographics and baseline disease characteristics were generally similar between the 2 treatment arms (Table 1). Overall, the majority of patients were women (55%) and white (98%). The mean age of patients was 45.6 years, and the median duration of PsA was 5 years. At the time of enrollment, patients were taking an average of 14.0 mg/week of MTX, and the median duration of MTX therapy at study entry was 8 months, with 15% of patients receiving MTX for <4 months.
|Alefacept plus MTX (n = 123)||Placebo plus MTX (n = 62)||Total (n = 185)|
|Age, mean (range) years||45.6 (23–66)||45.5 (21–64)||45.6 (21–66)|
|Weight, mean (range) kg||82.7 (47–159)||81.0 (48–125)||82.1 (47–159)|
|MTX dosage, %|
|MTX dosage, mean mg/week||13.7||14.6||14.0|
|Months of MTX treatment, %|
|Tender joint count, mean||22.2||21.8||22.0|
|Swollen joint count, mean||13.4||10.7||12.5|
|HAQ disability index, mean score†||1.0‡||1.1||1.1§|
|ESR, mean mm/hour||30.2||31.8||30.7|
|CRP, mean mg/dl||13.8||16.7||14.8|
|Concomitant therapy for PsA, %||84||82||83|
|Patients evaluable for psoriasis end points, no. (%)||58 (47)||29 (47)||87 (47)|
|Baseline PASI, mean (range 0–72)||10.2||9.6||10.0|
|Patients with moderate-to-severe psoriasis, %¶||54||41||49|
A total of 87 patients (58 in the alefacept plus MTX group, 29 in the placebo plus MTX group) had psoriasis involving ≥3% BSA and were evaluable for psoriasis efficacy end points. The majority of patients in the alefacept plus MTX group (54%) had moderate-to-severe disease at baseline (defined as having a PGA of “moderate” or worse), with a median baseline PASI of 8.5. Patients in the placebo plus MTX group had a median baseline PASI of 6.4, and 41% had moderate-to-severe psoriasis.
Clinical efficacy in PsA.
The percentage change from baseline to week 24 in individual components of the ACR core set is shown in Table 2. The primary efficacy end point, an ACR20 response at week 24, was achieved by a significantly greater proportion of patients receiving alefacept plus MTX (54%) compared with those receiving placebo plus MTX (23%) (P < 0.001) (Figure 2). Proportions of patients achieving ACR50 and ACR70 responses at week 24 were numerically greater in the alefacept plus MTX group (17% and 7%, respectively) than in the placebo plus MTX group (10% and 2%, respectively) (P not significant) (Figure 2).
|Component, % change from baseline||Alefacept plus MTX (n = 123)||Placebo plus MTX (n = 62)|
|Tender joint count||−30.9||−17.5|
|Swollen joint count||−46.1||−35.1|
|Physician's global assessment of disease activity||−36.5||−22.3|
|Patient's global assessment of disease activity||−22.3||−13.1|
|Patient's assessment of pain||−20.8||−1.7|
|HAQ disability index||−24.3||−7.7|
To determine whether the duration of MTX treatment affected clinical response, ACR responses in both treatment groups were summarized by duration of MTX exposure prior to enrollment (<6 months or ≥6 months). There was no apparent association between the duration of MTX therapy and ACR20, ACR50, or ACR70 response rates (data not shown).
At week 24, patients who had received alefacept plus MTX during the 12-week treatment period experienced a significantly greater mean reduction in tender joint count (–8.0) than patients receiving placebo plus MTX (–4.5) (P = 0.020). At the same time point, a significantly greater reduction was also seen in the swollen joint count of patients receiving alefacept plus MTX (–6.3) than in that of those receiving placebo plus MTX (–3.5) (P = 0.013).
Clinical efficacy in psoriasis.
Patients in the alefacept plus MTX group experienced significantly greater improvements in their psoriasis at week 14 than did patients in the placebo plus MTX group as measured by the PASI50 response (53% versus 17%; P < 0.001) (Figure 3). Response rates at week 24 in the alefacept plus MTX group were similar to those at week 14, with a small decrease in the PASI50 response, a small increase in the PASI75 response, and no change in the PGA “clear”/“almost clear” response (Figure 3).
The administration of alefacept produced a predictable reduction in CD4+ T cell counts that began after the first dose of alefacept was administered and continued throughout the dosing period. The mean baseline CD4+ T cell counts and mean lowest counts during the trial were 773/mm3 and 517/mm3, respectively, in the alefacept plus MTX group and 817/mm3 and 702/mm3, respectively, in the placebo plus MTX group. The mean reduction from baseline CD4+ T cell counts in the alefacept plus MTX group during the 12-week treatment course was 32%. CD4+ T cell counts began to recover toward baseline values after alefacept treatment was concluded; 12 weeks following the completion of the alefacept treatment course, the mean CD4+ T cell count in the alefacept plus MTX group was 645/mm3, indicating a recovery to 83% of baseline values. Eight patients (7%) in the alefacept plus MTX group had CD4+ T cell counts <250/mm3 during the study. Three of these 8 patients had CD4+ T cell counts <250/mm3 during followup, and no doses were held. A total of 7 doses were held in the remaining 5 patients with CD4+ T cell counts <250/mm3 during the dosing period. All 8 patients remained in the trial for its duration.
During the 24-week study period, the incidence and severity of adverse events were similar in the alefacept plus MTX and placebo plus MTX groups. Adverse events occurring in ≥5% of patients in either treatment group are listed in Table 3. Adverse events led to the discontinuation of treatment for 2 patients in the alefacept plus MTX group (1 because of worsening arthritis, 1 because of increased ALT/AST levels). The patient who withdrew due to increased ALT/AST levels had ALT levels 3–5 times the upper limit of normal (ULN) and AST levels 1–3 times the ULN prior to receiving the first dose of alefacept. After discontinuing treatment at week 8, the patient's ALT and AST levels returned to normal. Serious adverse events were reported in 2 patients receiving alefacept plus MTX (metrorrhagia, rectocele, and emphysema) and in 3 patients receiving placebo plus MTX (intervertebral disc protrusion, noninfectious gastroenteritis, and breast cancer). All serious adverse events were judged by the investigators to be unrelated to the study drug.
|Alefacept plus MTX (n = 123)||Placebo plus MTX (n = 62)|
|Increased ALT level||7 (6)||1 (2)|
|Back pain||7 (6)||2 (3)|
|Nasopharyngitis||6 (5)||7 (11)|
|Upper respiratory tract infection||5 (4)||5 (8)|
|Nausea||4 (3)||4 (6)|
Rates of infection were similar in the alefacept plus MTX and placebo plus MTX groups, with nasopharyngitis and upper respiratory tract infections being the most frequently reported. No serious infections were reported in either treatment group, and no malignancies were diagnosed in patients treated with alefacept plus MTX. No association was apparent between the incidence of infection and CD4+ T cell counts.
We summarized the proportions of patients whose ALT, AST, and total bilirubin values were within the normal range at baseline but above the normal range at some time after the initiation of the study drug. For ALT, 1 of 93 patients in the alefacept plus MTX group and 1 of 53 patients in the placebo plus MTX group had postbaseline values from ≥3 to <5 times greater than the ULN. For AST, 1 of 105 patients in the alefacept plus MTX group and 0 of 59 patients in the placebo plus MTX group met the same criterion. In each case, the patient remained in the study and values returned to the normal range without intervention. No patient in either treatment group (120 in the alefacept plus MTX group, 60 in the placebo plus MTX group) had total bilirubin values that increased ≥1.5 times the ULN during the trial.
Patients treated with a 12-week course of alefacept in addition to MTX had significantly greater response rates in composite measures of disease activity in both PsA (ACR20) and psoriasis (PASI50) than did patients who received placebo plus MTX. Response rates did not appear to differ according to the duration of treatment with MTX.
Incremental improvement in ACR20 response was seen during the treatment-free observational phase, indicating that response to alefacept continues after therapy is completed, which is consistent with the response patterns seen in phase III trials evaluating alefacept for the treatment of psoriasis (32, 33). This raises the possibility that an extended treatment period (>12 weeks) may offer additional clinical benefits for patients with PsA, as has been seen in patients with psoriasis (34); this hypothesis may be tested in a future clinical trial. While the safety of extended treatment courses of alefacept plus MTX has not been evaluated, safety data from patients who received multiple courses of alefacept monotherapy have demonstrated that extended exposure to alefacept does not result in cumulative immunosuppression or an increased incidence of adverse events, infections, or malignancies (35).
In order to provide clinical context for the interpretation of the alefacept results, response rates from clinical trials of other agents commonly used for the treatment of PsA are presented briefly below; however, it is important to note that direct comparisons of these results cannot be made owing to differences in study design, allowed concomitant therapies, and patient populations. Results of phase III trials of other biologics assessed in PsA (etanercept, infliximab, and adalimumab) showed ACR20 response rates of 59%, 58%, and 57%, respectively, in the treatment groups and 15%, 11%, and 15%, respectively, in the control groups (all P < 0.001) (14, 15, 17). In these trials, background MTX was allowed, but not required, and was used by approximately half of the patients in each study in both the treatment and control arms. A phase II trial of leflunomide in PsA patients not receiving MTX showed ACR20 response rates of 36% in the treatment group and 20% in the placebo group (P = 0.0138) (19). Head-to-head clinical trials involving each of these agents would be necessary to make definitive statements regarding comparative efficacy and safety.
The PASI and PGA response rates were somewhat greater in the present study than in the phase III trials of alefacept in psoriasis (32, 33), perhaps owing to the use of combination therapy. The placebo response rate in the present study was somewhat higher than that reported in other large trials of biologic agents (9, 14–18), but similar to that reported in a recent trial of leflunomide (19). PASI50 response rates at week 14 in the present study were greater than those seen in clinical trials of leflunomide in patients with PsA (19) and similar to or less than those seen in clinical trials of etanercept, infliximab, and adalimumab in patients with PsA (14–17).
The safety profile of alefacept in this trial is consistent with that seen in the phase III psoriasis studies (32, 33), with no significant concerns noted. Alefacept predictably reduced CD4+ T cell counts; however, no patient discontinued alefacept because of low counts, and no association was apparent between CD4+ T cell counts and the incidence of infection. Reductions in CD4+ T cell counts in patients treated with alefacept plus MTX were consistent with those reported in phase III clinical trials of alefacept monotherapy in patients with psoriasis (32, 33).
Results of this phase II trial indicate that alefacept in combination with MTX may be an effective and well-tolerated therapeutic option for patients with PsA. Additional studies are needed to evaluate the efficacy and safety of this combination in larger populations of patients with PsA, address some of the limitations of the current trial, and provide information on end points such as radiographic evidence of disease progression.
- 1National Psoriasis Foundation. Statistics. Available at: http://www.psoriasis.org/resources/statistics/index.php. Accessed April 7, 2005.
- 15Adalimumab therapy in patients with psoriatic arthritis: 24-week results of a phase III study [poster]. Arthritis Rheum 2004; 50: 4097., , , , , , et al.
- 16Sustained benefits of infliximab therapy for dermatologic and articular manifestations of psoriatic arthritis: results from the infliximab multinational psoriatic arthritis controlled trial (IMPACT). Arthritis Rheum 2005; 52: 1227–36., , , , , , et al.
- 19Treatment of Psoriatic Arthritis Study Group. Efficacy and safety of leflunomide in the treatment of psoriatic arthritis and psoriasis: a multinational, double-blind, randomized, placebo-controlled clinical trial. Arthritis Rheum 2004; 50: 1939–50., , , , , , et al, for the
- 23FaxWatch [press release]. Genentech, Xoma's Raptiva fails to meet endpoint in Phase II psoriatic arthritis trial. March 22, 2004.
- 26Alefacept treatment in psoriatic arthritis: reduction of the effector T cell population in peripheral blood and synovial tissue is associated with improvement of clinical signs of arthritis. Arthritis Rheum 2002; 46: 2776–84., , , , , , et al.
PARTICIPATING INVESTIGATORS AND INVESTIGATIONAL SITES
The following investigators and investigational sites participated in this study: Christopher T. Atkins, MD (Victoria Arthritis Study Group, Victoria, BC, Canada), Herbert Baraf, MD (The Center for Rheumatology and Bone Research, Wheaton, MD), Jan Brzezicki, MD (Oddzial Reumatologii Wojewodzki Szpital Zespolony, Elblag, Poland), Hanna Chwalinska-Sadowska, MD (Klinika Chorób Tkanki La̧cznej Instytut Reumatologiczny, Warsaw, Poland), Anna Filipowicz-Sosnowska, MD (Klinika Reumatologii Instytut Reumatologiczny, Warsaw, Poland), Richard A. Furie, MD (North Shore University Hospital, Division of Rheumatology, Manhasset, NY), Dafna D. Gladman, MD (Toronto Western Hospital, Toronto, ON, Canada), Erika Gromnica-Ihle, MD (Rheumaklinik Berlin-Buch, Berlin, Germany), Boulos Haraoui, MD (Institut de Rhumatologie de Montréal, Montreal, PQ, Canada), Slawomir Jeka, MD (Prakyta Lekarza Rodzinnego “Nasz Lekarz,” Torun, Poland), J. P. Kaltwasser, MD (Bereich Rheumatologie der Med. Klinik III, Klinikum der Johann Wolfgang Goethe Universitat, Frankfurt-am-Main, Germany), Edward C. Keystone, MD (Mt. Sinai Hospital, University of Toronto, Toronto, ON, Canada), Majed Khraishi, MD (St. Clare's Mercy Hospital, St. John's, NF, Canada), Irina Klemenova, MD (Nizhegorodskiy Scientific Institute for Skin and Venereal Diseases MoH, N. Novgorod, Russia), Anna Koubanova, MD (Central Research Institute for Skin and Venereal Diseases, Moscow, Russia), Nadezhda Lomareva, MD (City Hospital #25 City Rheumatology Center, St. Petersburg, Russia), Philip J. Mease, MD (Swedish Medical Center, Seattle, WA), Zbigniew Mencel, MD (Oddział Reumatologiczny Szpital Zespolony im. L. Perzyny, Kalisz, Poland), Larry W. Moreland, MD (University of Alabama at Birmingham), Evgeny Nasonov, MD (Scientific Research Institute of Rheumatology RAMS, Moscow, Russia), Janet E. Pope, MD (St. Joseph Health, London, ON, Canada), Artur Racewicz, MD (Centrum Medyczne Specjalistyczny Gabinet Lekarski, Bialystok, Poland), Christopher T. Ritchlin, MD (University of Rochester, Rochester, NY), Alexy Samtsov, MD (Military Medical Academy, St. Petersburg, Russia), Eugenya Schmidt, MD (City Clinical Hospital #1 named after N. I. Pirogov, Moscow, Russia), Jadwiga Szerla, MD (SPZOZ Krakowski Szpital Reumatologii i Rehabilitacji, Krakow, Poland), Carter Thorne, MD (The Arthritis Program Research Group, Inc., Newmarket, ON, Canada), Vladimir Yakusevich, MD (Municipal Health Organization Soloviev's Clinical Hospital for Urgent Medical Care, Yaroslavl, Russia).