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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Arthritis Rheum. Author manuscript; available in PMC 2014 February 1.
Published in final edited form as:
PMCID: PMC3558563
NIHMSID: NIHMS417935

Rituximab in the Treatment of Refractory Adult and Juvenile Dermatomyositis and Adult Polymyositis: A Randomized, Placebo-phase Trial

Abstract

Objective

To assess the safety and efficacy of rituximab in a randomized, double-blind, placebo-phase, trial of adult and pediatric myositis.

Methods

Adults with refractory polymyositis and adults and children with refractory dermatomyositis were enrolled. Entry criteria included muscle weakness and ≥2 additional abnormal core set measures (CSM) for adults. JDM patients required ≥ 3 abnormal CSM with or without muscle weakness. Patients were randomized to either ‘rituximab early’ or ‘rituximab late’ and glucocorticoid and immunosuppressive therapy were allowed at entry. The primary endpoint compared the time to achieve the preliminary International Myositis Assessment and Clinical Studies Group definition of improvement (DOI) between the 2 groups. The secondary endpoints were time to achieve ≥20% improvement in muscle strength, and the proportion of early and late rituximab patients achieving DOI at week 8.

Results

Among 200 randomized patients (76 PM/76 DM/48 JDM), 195 showed no difference in the time to DOI between the rituximab late (n=102) and rituximab early (n=93) groups (p=0.74, log rank) with a median time to DOI of 20.2 weeks and 20.0 weeks respectively. The secondary endpoints also did not significantly differ between the two treatment groups. However, 161 (83%) of randomized patients met the DOI and individual CSM improved in both groups throughout the 44-week trial.

Conclusion

Although there were no significant differences in the two treatment arms for the primary and secondary endpoints, 83% of refractory adult and juvenile myositis patients met the DOI. The role of B cell depleting therapies in myositis warrants further study with consideration for a different trial design.

The idiopathic inflammatory myopathies (IIM) are a heterogeneous group of acquired disorders characterized by chronic inflammation of striated muscle leading to predominantly proximal muscle weakness. The most common subsets of IIM include adult polymyositis (PM), adult and juvenile dermatomyositis (DM), myositis in overlap with cancer or another connective tissue disease and inclusion body myositis (IBM). The IIM are frequently associated with constitutional symptoms and commonly involve other organ systems including the skin, joints, lungs, gastrointestinal tract and heart. They are rare with an estimated incidence of 4-10 cases/million population per year and a bimodal incidence pattern reflecting childhood onset of juvenile DM (JDM) and a later peak in adulthood [1]. Although the precise pathogenesis is unknown, the IIM likely result from immune-mediated processes initiated by environmental factors in genetically susceptible individuals [2]. Factors strongly supporting their autoimmune basis include: the association of myositis with other autoimmune diseases such as Hashimoto thyroiditis, Grave’s disease and various connective tissue diseases, the high frequency of circulating serum autoantibodies, and their response to immunosuppressive (IS) or immunomodulatory therapy.

The treatment of IIM is challenging, complicated by its rarity and heterogeneity as well as the lack of controlled trials and partially validated outcome measures. Most studies involve single referral centers using cross-sectional and retrospective analyses of small numbers of treatmentrefractory patients observed for relatively short time periods. In addition, widely disparate inclusion criteria have complicated the assessment of treatment response, as disease damage and the inclusion of misdiagnosed patients contribute to suboptimal therapeutic outcomes. Although glucocorticoids have not been formally tested in controlled trials, expert consensus is that they are the primary therapy to be followed by a variety of immunosuppressive or immunomodulatory agents alone or in combination [2]. Rituximab, a B cell depleting agent long recognized as an effective therapy for B cell lymphomas, has gained increased favor in the treatment of many autoimmune diseases and is FDA-approved for use in rheumatoid arthritis [3] as well as granulomatosis with polyangiitis and microscopic polyangiitis [4]. The effectiveness of rituximab in PM and DM has been suggested by case reports and case series in adult and pediatric patients with refractory disease [5-9]. B cells play a critical role in the initiation and propagation of the immune response and are implicated in the pathogenesis of myositis. They localize to the perivascular region of DM muscle and are found in the inflammatory infiltrates of both PM and DM [10]. In addition to functioning as the precursor of autoantibody-producing plasma cells, B cells present antigen to T cells and secrete proinflammatory cytokines [10]. Therefore, based on the autoimmune characteristics of myositis and the aforementioned immunopathogenic role of the B cell, the Rituximab in Myositis (RIM) trial assessed the effectiveness of rituximab in refractory adult PM and adult and juvenile DM using validated measures of myositis disease activity and damage, a consensus-driven definition of improvement [11-13] and a unique randomized placebo-phase trial design [14, 15].

PATIENTS and METHODS

This study was conducted at 31 sites (20 adult/11 pediatric centers), and the protocol was approved by the institutional review board at each location. Written informed consent was obtained from each subject. Eligible patients included adults with a diagnosis of definite or probable DM or PM and patients at least 5 years of age or older with definite or probable JDM by the criteria of Bohan and Peter [16]. In an effort to exclude IBM and other myositis mimics [17], the medical records and muscle biopsy (if available) of adults with PM were reviewed by a 3-member Adjudication Committee before enrollment. Refractory myositis was defined by the intolerance to or an inadequate response to glucocorticoids and at least one other IS or immunomodulatory agent (e.g. azathioprine, methotrexate, mycophenolate mofetil, cyclosporine, tacrolimus, cyclophosphamide, leflunomide or IVIg). An ‘adequate’ glucocorticoid regimen was 60 mg prednisone daily in adults and 1.0mg/kg/day prednisone in pediatric patients – both for at least one month. An adequate IS regimen was three months of the agent at a known effective dose. Adult subjects had demonstrable muscle weakness and manual muscle testing (MMT) was assessed using a validated measure, the MMT-8 [18], a core set measure (CSM) with a maximum score of 150 when tested bilaterally. MMT-8 testing was completed by trained physical therapists. Adult enrollment required a score less than 125/150 in conjunction with 2 other abnormal CSM. JDM patients could enter by the same criteria, but if the MMT-8 was greater than 125/150, a third abnormal CSM was necessary. The other CSM for this trial included [19]: (1) Patient (or parent) global visual analog scale (VAS) with a minimum value of 2.0 cm to qualify for study entry; (2) MD global VAS with a minimum value of 2.0 cm; (3) Health Assessment Questionnaire (HAQ) or Childhood HAQ (CHAQ) disability index with a minimum value of 0.25; (4) Elevation of at least one (locally measured) muscle enzyme [creatine kinase (CK), aldolase, lactate dehydrogenase (LDH), alanine aminotransferase (ALT) or aspartate aminotransferase (AST)] at a minimum level of 1.3 times the upper limit of normal with the most abnormal muscle enzyme selected as the target enzyme to be followed in the trial; and (5) Global extramuscular disease activity score with a minimum value of 1.0 cm (based on the investigator’s composite assessment of disease activity on the constitutional, cutaneous, skeletal, gastrointestinal, pulmonary and cardiac scales of the Myositis Disease Activity Assessment Tool (MDAAT) [13]. All VAS scales were 10 cm, anchored at the ends and midpoint. Patients were on a stable dose of prednisone for 4 weeks prior to screening, preferably <1mg/kg/day, and at least 1 non-glucocorticoid IS agent was required (with stipulated exceptions) at a stable dose for 6 weeks prior to screening. A 4-week washout for methotrexate and an 8-week washout was required for any other IS agent discontinued prior to screening. No live vaccines, creatine dietary supplements, IVIg (in adults), or the initiation of colchicine were permitted during the study.

To minimize confounding, subjects with the following conditions were excluded: drug-induced myositis, juvenile PM, IBM, cancer-associated myositis (myositis diagnosed within 2 years of cancer diagnosis), myositis in overlap with another connective tissue disease, or any concomitant illness that precluded an accurate treatment response in the trial or posed an added risk for participants. Patients were excluded if they had previously received rituximab. Subjects could continue an exercise program initiated before the 4-week screening period, and a stretching program was permitted at any time, but an active muscle strengthening program could not be initiated during the study. JDM patients with baseline IgG or IgM levels below the age-adjusted lower limit of normal and adults with IgM levels >30% below the lower limit of normal were also excluded.

Study Definitions

The definition of improvement (DOI) chosen for this trial was based on the International Myositis Assessment and Clinical Studies Group (IMACS) preliminary validated top ranked response criterion [11] of a ≥ 20% improvement in 3 of any 6 CSM, with no more than 2 worsening by ≥ 25%. Of note, the MMT could not be one of the worsening measures. To meet the DOI, subjects had to satisfy criteria on two consecutive monthly visits, with the time to achieve the DOI designated at the second time-point of these consecutive visits. The definition of worsening (DOW) included (1) MD global VAS worsening ≥ 2 cm and MMT-8 worsening ≥ 20%, or (2) global extramuscular activity worsening ≥ 2 cm on the MDAAT VAS, or (3) any 3 of 6 CSM worsening by ≥ 30% on two consecutive visits.

Design Overview

The RIM Study utilized a ‘Randomized Placebo Phase Design (RPPD)’ [15] in which subjects were randomly assigned, using a computer-generated hidden allocation scheme in double blind fashion, to a ‘rituximab early’ or ‘rituximab late’ arm. An equal number of adult PM, adult DM and JDM patients received drug either at the beginning of the trial or 8 weeks later; this ‘placebo phase’ duration was agreed upon by consensus of the Steering Committee. Figure 1 outlines the trial design. Week 8 represents the time-point where the trial was a ‘randomized placebo controlled trial’ since the ‘rituximab late’ group had not yet received study drug.

Figure 1
Schematic diagram of the design of the Rituximab in Myositis Study demonstrating the Randomized Placebo Phase Design

Rituximab dosing was based on the body surface area (BSA); children with a BSA ≤ 1.5 m2 received 575mg/m2 at each infusion, and adults and children with a BSA > 1.5 m2 received 750 mg/m2 up to 1 gram/infusion. Patients in the ‘rituximab early’ arm received drug at weeks 0 and 1 and placebo infusions were given at weeks 8 and 9. Conversely, subjects in the ‘rituximab late’ arm received placebo infusions at weeks 0 and 1 and rituximab at weeks 8 and 9. The glucocorticoid dose was held constant without reduction until week 16, and intravenous glucocorticoids were not allowed at the time of any study medication infusion; if subjects met the DOI (or experienced complications) a glucocorticoid dose reduction was commenced at no more than 20% of the existing dose every 4 weeks. Other trial features included 14 visits spread over 44 weeks where specimens were obtained and safety and CSM were assessed. It was recommended that the same investigator assess the CSM throughout the trial period except for the MMT-8 that was done by the physical therapist. Patients meeting the DOI who then met defined criteria for worsening (DOW) by week 36 were offered re-treatment with rituximab.

The Data Safety and Monitoring Board (DSMB) monitored overall safety independent of the participating institutions.

Outcomes: Primary and Secondary Endpoints

The primary endpoint was the time to DOI which was compared between the ‘rituximab early’ and ‘rituximab late’ groups. There were two secondary endpoints. The first compared the time to 20% improvement in the MMT-8 on 2 consecutive visits between the 2 groups. This endpoint was chosen since the MMT is quantitative and represents a key CSM in a myositis trial assessing muscle weakness as an important clinical outcome. The other secondary endpoint compared the response rates, or the proportion of patients achieving DOI, at week 8 in the early vs. late treatment groups since this time-point defines the parallel-groups randomized placebo-controlled phase of this trial.

B cell Flow Cytometry

Whole blood samples were collected in cell preparation tubes (BD, Franklin Lakes, NJ) following which peripheral blood mononuclear cells (PBMC) were isolated, aliquoted and stained with a panel of conjugated antibodies recognizing leukocyte cell surface markers CD45 RA/RO as well as B cell-specific surface molecules, CD19 and CD20. This combination permitted calculation of percent B cells among CD45+ leukocytes. An automated, clinical lab complete blood count (CBC) that included a total white blood cell (WBC) count was performed at each study visit. The percentage of lymphocytes and monocytes in the CBC and the fraction of CD19/CD20+ cells among the CD45+ cells in the PBMC preparations were then used to estimate the number of B cells/ul of whole blood.

Statistical Analysis

Randomization was done within disease subsets (adult PM, adult DM, juvenile DM) for each institution. A minimization procedure was used to control overall balance in the two treatments. Assuming a daily hazard of 0.0023 in the 8-week placebo phase of the control group, a daily hazard of 0.017 while on rituximab [6], and an α =0.05 two-sided test, there was statistical power of 0.82 to detect a difference in treatment arms in each of the two adult disease groups (PM and DM). The study was not designed to have sufficient power to detect such a difference in the JDM group. All the analyses were based on the intent-to-treat principle and were performed using two-sided tests. Analysis of the primary outcome and time to ≥20% reduction in baseline MMT score was done using a log rank test and the proportion showing improvement at 8 weeks was analyzed using logistic regression. For the primary outcome, analysis was repeated adjusting for core set measures and potential confounders using a proportional hazards model. As specified a priori in the protocol, comparison of the treatment arms was done within each of the disease subgroups (PM, DM, JDM).

RESULTS

Baseline Characteristics and Core Set Measures

Of the 236 patients that were screened, 200 were randomized (Figure 2). Prior to screening all PM patients were adjudicated for diagnostic accuracy leading to 86 muscle biopsy reviews and 44 subsequent exclusions (14 IBM; 29 undetermined myopathy but not PM or DM; 1 excessive muscle damage). Targeted accrual goals were met for adult PM and DM (76 each), while 48 (of 50 expected) JDM patients were enrolled. The quality of the data was excellent with only 1.2% missing values. There was very low patient dropout, with only five patients having a baseline visit and no subsequent measures. Table 1 summarizes the baseline demographic features for the 2 treatment groups. In general, the demographic characteristics were well-balanced; however, there was a greater percentage of Caucasians in the late rituximab group. This refractory myositis cohort consisted of patients who had failed glucocorticoids and a mean of 3.1 IS agents. At study entry, the prednisone dose averaged 20.8mg/day, and almost 90% of patients were taking additional immunosuppressive agents, alone or in combination. Most patients were Caucasian (70%) and female (73%), with a mean disease duration exceeding 5 years. Their disease was active as evidenced by the entry MD global activity VAS score exceeding 5.0 cm and an average baseline VAS muscle activity score of 4.8 cm on the MDAAT (not shown in Table 1). Autoantibody subsets were well represented, with 80% of the cohort possessing at least one myositis autoantibody by immunoprecipitation [20]. Specifically, 17% had anti-synthetase (primarily anti-Jo-1), 13% had anti-signal recognition particle (SRP), and 37% had DM-associated autoantibodies (either anti-Mi-2 or probable anti-TIF1-gamma [21], or probable anti-MJ [22, 23]).

Figure 2
Participant Flow Diagram: RIM Study
Table 1
Patient Baseline Demographic and Clinical Characteristics and Core Set Measures

The baseline CSM were similar between the early and late rituximab groups except for the baseline muscle enzyme value, which was statistically higher in the early rituximab arm. Patients were weak as evidenced by the low baseline MMT scores; the mean MMT-8 was 105 for adult DM patients, 103 for adult PM and 116 for the JDM subset. Patients generally rated their overall disease activity higher (by VAS) than did the investigators. Extramuscular manifestations appeared mild to moderate, with mean VAS scores of 34.1 and 33.1 for adult DM and JDM, and 21.6 for adult PM – the higher scores reflecting cutaneous involvement in the DM subsets. In 48% of subjects, the same investigator assessed the CSM throughout the trial while 92% of subjects had assessments by 2 or less investigators. If the MMT-8 was not done by trained physical therapists, it was completed by the site PI also trained and certified at the RIM Study investigator meeting.

B Cell Depletion

Peripheral blood B cell depletion (BCD) was complete and appropriate for the timing of rituximab with the lowest B cell counts occurring 4 weeks after rituximab infusion (Figure 3). There were no differences in median nadir B cell counts between the early and late rituximab groups. Seven of 200 patients receiving study drug did not deplete below 5 B cells/ul of blood and were equally distributed among the myositis subsets and between the early and late rituximab groups. There were no differences in median B cell numbers at each time-point following rituximab infusion with a return of median B cells to > 5 B cells/ul approximately 32- 36 weeks after rituximab infusion in both groups (Figure 3).

Figure 3
Peripheral Blood B cell Numbers Prior to and Following Rituximab Treatment of IIM Subjects in the RIM Study

Primary Outcome

Five patients had a baseline visit but no subsequent measurements due to drop out. Of the remaining 195 randomized patients included in the analysis of the primary outcome, 161 (83%) met the predetermined DOI by the week 44 evaluation. The primary outcome in the RIM Study compared time to DOI between the two patient groups (early vs. late) as shown in the Kaplan Meier analysis plotting failure to meet DOI versus time (Figure 4). Unlike most survival plots, the occurrence of the primary event (achieving DOI) represents a favorable outcome; therefore the lower curve of subjects failing to meet DOI signifies superior treatment.

Figures 4A-4D
DOI-free Survival for the Entire Cohort and Individual Myositis Subsets

The early treatment arm had 93 analyzable (assessed through week 8) subjects with a median time from randomization to DOI of 20.0 weeks, while the late rituximab arm had 102 analyzable patients with a median time from randomization to DOI of 20.2 weeks (p=0.74, log rank) – indicating no statistical difference in the time to DOI between the early and late groups. Adjustment for the individual or six combined CSM at baseline did not result in statistical significance for the test of the primary hypothesis. Conducting the analysis requiring only a single time-point of improvement to meet DOI (rather than the predetermined two consecutive time-points) also revealed no statistically significant differences in time to DOI between the two treatment arms. Also included in Figure 4 are separate Kaplan-Meier plots comparing time to DOI in the adult PM and DM as well as JDM subsets – each without evidence of a statistically significant difference in the time to DOI. Although the JDM plot shows an 8-week difference in the median time to DOI and a clear separation in the early and late rituximab arms, this difference was not statistically significant. Since the test for interaction of treatment and disease category is not statistically significant (p = 0.42), there is no justification to conclude that treatment effect differs in the disease subgroups. Only seven subjects treated with rituximab did not deplete B cells below 5 cells/ul, but six of these still met the DOI.

Secondary Outcomes

The time to achieve a 20% improvement in the MMT on two consecutive visits was a secondary endpoint. Comparison of this endpoint for the two treatment arms indicated no statistically significant difference (p>0.90, data not shown). The other secondary endpoint compared the response rates, or the proportion of patients achieving DOI, in the early vs. late treatment groups at week 8. Fifteen percent of patients in the rituximab-treated group met DOI while 20.6% in the placebo-treated group met DOI at this 8-week time-point, with no statistically significant difference between the two groups. Since there was a significant difference in the baseline values for the muscle enzyme CSM (Table 1), we tested the difference in the proportions meeting DOI in the two treatment groups adjusting for these baseline values, but the results remained non-significant. When comparing the proportion showing improvement at either the 4 or 8 week visit, 38% met criteria in the early treatment group compared to 35% in the late treatment group (p=0.73).

Core Set Measures as Outcomes

We also conducted analyses comparing the two treatment arms with regard to ≥ 20% reduction from baseline for individual CSM at two consecutive visits. None of these comparisons revealed statistically significant differences. However, the mean/median CSM values indicated improvement through the entire 44-week trial in both groups (data not shown). Therefore, we also conducted a longitudinal analysis adjusting for baseline level to compare the change over time in the two treatment groups. Again, however, these results did not consistently favor one treatment arm over the other.

Additional Treatment Effect Results

The mean prednisone dose at baseline in the 160 patients taking glucocorticoids was 20.8 mg/day; this dropped to 14.4 mg/day based on the 153 patients taking steroids at their last time point and the seven subjects who were able to completely discontinue prednisone (p<0.001; paired comparison). Four subjects were taking steroids at their last time point, but not at baseline. There was no significant difference in the steroid taper rate between the early and late treatment groups.

Seventeen subjects met criteria for re-treatment with rituximab (by first meeting the DOI and then fulfilling criteria for DOW). Seven were ineligible for re-treatment (low immunoglobulins, did not consent to re-treatment or outside window of eligibility) and 9 of the remaining 10 were re-treated and evaluable (four in the early and five in the late rituximab arms). Their mean time to initial DOI was 12.4 weeks with increased disease activity occurring a mean of 16.5 weeks later. Eight of the nine re-treated patients again met DOI after a mean of 19.9 weeks.

Several potential confounders, if imbalanced at baseline between the two treatment arms, could have affected the results of the trial. When analysis of the primary outcome was repeated, adjusting for global disease damage measured by a validated index [24], disease duration, and myositis autoantibody status, the results remained essentially unchanged. Similarly, 14 patients received add-on therapy during the trial outside of protocol, but adjustment for these also did not affect the overall conclusions.

Safety Analysis

Adverse and serious adverse events (AE/SAE) along with infusion reactions were monitored and reported in a standardized fashion throughout the study period using NCI Common Terminology Criteria, with clinical site investigators determining their relatedness to study drug. During the 44-week trial period, only one patient withdrew early due to an AE (in the late rituximab group). There were 67 SAE in 64 patients, 26 of which were related to study drug. Infections were the most common: pneumonia (n=6), cellulitis (n=6), urosepsis (n=2), herpes zoster (n=2) and one each of septic arthritis, histoplasmosis, urinary tract infection, respiratory failure, heart failure, dysrhythmia, venous thrombosis, syncope, rash, and neurologic symptoms (without evidence of progressive multifocal leukoencephalopathy). There was no difference in adverse events at week 8, the randomized placebo-controlled time-point. Table 2 summarizes the adverse events. There was one death in the trial, involving a 74 year old woman who developed a lung mass suspicious for malignancy followed by a stroke leading to a dense hemiparesis.

Table 2
Common Drug-Related Adverse Events (frequency >2), and all Drug-Related Infectious Adverse Events

Infusion reactions were specifically tracked since no glucocorticoids were administered at the time of study medication infusion. There were significantly more infusion reactions with rituximab (15.4%, 60/389) than placebo (5.3%, 21/393), p<0.01, but no difference was seen between the first and second rituximab infusions. Most reactions (53/60, 88%) were related to drug; four were severe, 24 moderate, and 32 mild. Two events required hospitalization and most subjects (53/60) were able to receive the full dose of rituximab after resolution of the infusion reaction.

DISCUSSION

The RIM Study is the first prospective, double-blind, randomized trial in myositis enrolling both pediatric and adult subjects and is the largest clinical trial ever performed in the inflammatory myopathies. It represents the first collaboration of pediatric and adult rheumatologists and neurologists to study an autoimmune illness affecting children and adults. This trial employed a unique design, the RPPD [15] or delayed-start design [14, 25], and was the first study to implement recently validated myositis disease activity and damage measures [11, 13, 24]. This trial was also the first to test a consensus-driven definition of improvement proposed for juvenile and adult IIM clinical trials [11, 12, 26]. Although the study did not provide sufficient evidence to reject the null hypothesis of no treatment effect in the primary and secondary outcomes, 83% of enrolled subjects met the DOI by the end of the trial. It is important to note that these patients represented a refractory cohort of myositis having failed glucocorticoids and, on average, more than 3 additional immunosuppressive agents in the course of their disease. The addition of rituximab provided a significant steroid-sparing effect between the start and conclusion of this trial, and eight of nine patients meeting DOW after an initial response improved again after re-treatment with rituximab.

Rituximab was generally well tolerated in a trial in which pre-infusion glucocorticoids were not routinely administered. There were significantly more infusion reactions associated with rituximab administration, but 88% of these patients still received the full dose of rituximab. Infectious complications comprised the majority of severe adverse events with a similar frequency to a recently reported trial of rituximab in vasculitis [4].

There were several factors that decreased the probability of detecting an effect of rituximab. First, the power calculations to detect differences in the two treatment groups were based on the premise that rituximab had an earlier effect as a therapeutic agent. Based on the existing literature for rituximab use in IIM at the time of study design [6], the steering committee postulated that >50% of subjects would respond to rituximab by 8 weeks. In fact, one-half of the subjects responded by about 20 weeks, indicating a lower than expected potency for which this study was not adequately powered. Compounding this problem, the anticipated placebo rate was underestimated in the original power calculations – meaning that the response during the two months on placebo was greater than would be expected for the assumed hazard when designing the trial. In essence, there was an overestimate of the rapidity of the rituximab response and an underestimate of DOI in those receiving placebo.

When assessing the results in the individual myositis disease subsets, the JDM cohort response reflected what was originally hypothesized. That is, the early rituximab group in JDM had a median time to DOI nearly 8 weeks sooner than the late rituximab group – mirroring the duration of the placebo phase. However, the trial was not powered for assessing response in individual myositis subsets at the observed potency.

A second factor leading to the statistical failure of the trial relates to the RPPD study design and the selection of the ‘placebo phase’ duration of 8 weeks chosen by the RIM Steering Committee for several reasons: (1) the enrollment of children precluded a traditional parallel-groups randomized controlled trial where only one-half of the patients would receive active drug; (2) international consensus guidelines for the conduct of clinical trials in myositis suggested that the ethical median duration for placebo administration or background therapy in a clinical trial should be 8 weeks for adult and 6 weeks for childhood myositis [26]; and (3) the expected mean of response to rituximab was assumed to be 8 weeks. Ultimately, rituximab’s slower onset of action in our refractory myositis cohort (reflected by the longer than expected time to improvement) coupled with the short 8-week placebo phase made it difficult to distinguish the response in the two treatment arms. Similar delayed-start trial designs have been reported in other chronic diseases with favorable results [25]. Although this design has regulatory support [27], its limitations such as the duration of the placebo phase and the statistical approach to data analysis have been discussed [14]. Nevertheless, the use of the delayed-start design with appropriate attention to stipulated details has been encouraged in chronic rheumatic diseases [14]. It is conceivable that the RPPD or delayed-start design, may still be appropriate for agents with a shorter time to effect.

Finally, although the CSM and the DOI utilized in the RIM Study have been partially validated and agreed upon by myositis experts [11, 13, 18, 24], there were no recent prospective clinical trials that utilized these measures before the RIM Study. Several of the CSM that contributed to the DOI are subjective, including the MD/Patient global activity scores, HAQ and extramuscular disease activity indices. The MMT, although quantitative and fully blinded to patient therapy, may be subject to patient effort [28]. Moreover, muscle enzyme levels may not correlate with either clinical improvement or increased disease activity. Finally, myositis is heterogeneous, as evidenced by the long disease duration (Table 1) and the range of autoantibody subsets in our cohort (28% positivity for an anti-synthetase or anti- SRP autoantibody [9, 29, 30]) that resulted in wide variance around the time to DOI in both treatment groups. Nevertheless, these CSM have been carefully studied and scrutinized by experts from many disciplines caring for both adult and pediatric myositis patients under the auspices of international myositis collaborative groups [11, 18, 19, 31]. In the future, it will be necessary to utilize the prospective data collected from the RIM trial, the largest trial ever performed in adult and juvenile myositis, and other prospective myositis trials, to re-examine the CSM and DOI in order to develop more robust measures of disease activity and improvement for future clinical trials.

While the trial itself showed no statistical difference between treatment groups, the overall response rate in a refractory group of patients, the ability to taper glucocorticoid therapy and the re-treatment responses suggest that the agent had an effect but that certain aspects of the study design made identification of such an effect difficult. The information gleaned from the RIM Study will clearly be enhanced by subsequent immunologic analyses to address the mechanisms of disease response in this cohort of patients with inflammatory myopathy.

Acknowledgements

The authors thank Drs. Mark Gourley and Kathleen Coyle for their critical review of the manuscript. We also acknowledge the efforts of Dr. David Lacomis (University of Pittsburgh) who served on the Adjudication Committee and reviewed the muscle biopsies of patients proposed for enrollment in the RIM Study. The authors wish to acknowledge the superb efforts of all of the physical therapists and research coordinators who participated in this clinical trial. Particularly we wish to thank Christopher Bise (University of Pittsburgh), Joseph Shrader (NIH), and Mina Jain (NIH) who assisted in the training of the physical therapists. The following research coordinators are particularly acknowledged for their efforts in patient recruitment and study coordination at their respective sites: Kelly Reckley and Maureen Laffoon (University of Pittsburgh); Laura Herbelin (University of Kansas Medical Center); Jane Jaquith (Mayo Clinic); Leah Kramer (University of Michigan) and Rita Volochayev (NIH). Further acknowledgments are extended to the members of the DSMB (Robert Wortmann, Chair, Dartmouth Hitchcock Medical Center; Daniel Furst, UCLA; Donna Hummel, Vanderbilt University Medical Center; Lawrence Moye, University of Texas Health Science Center at Houston; Patience White, Arthritis Foundation); NIAMS (Susana Serrate-Sztein and James Witter); the Epidemiology Data Center at the University of Pittsburgh (Steven Belle and Sharon Lawlor) and Lisa Kruse (Genentech).

This study was supported by NIAMS contract number N01-AR-4-2273 and by the Intramural Program of the NIH, National Institute of Environmental Health Sciences; and by GCRC/CTSA MO1 RR023940/UL1RR033179, University of Kansas Medical Center. Study drug was kindly provided by Genentech, Inc.

*Appendix I. RIM Study Group Members (countries, principal investigators and centers)

Canada (Pediatric sites)

Brian Feldman (Hospital for Sick Children, Toronto); Adam Huber (IWK Health Centre, Halifax)

Czech Republic (Adult site)

Jiri Vencovsky and Herman Mann (Institute of Rheumatology)

Sweden (Adult site)

Ingrid E. Lundberg (Karolinska Institutet)

United States (Adult sites)

Richard Barohn, Mazen Dimachkie and Kevin Latinis (University of Kansas Medical Center); Lorinda Chung and David Fiorentino (Stanford University); Leslie Crofford (University of Kentucky); Mary Cronin (Medical College of Wisconsin); Stephen DiMartino (Hospital for Special Surgery); Barri Fessler (University of Alabama at Birmingham); Michael Harris-Love (Washington DC Veterans Affairs Medical Center); Sharon Kolasinski (University of Pennsylvania); Todd Levine (Phoenix Neurological Associates); Galina Marder (North Shore – Long Island Jewish); Richard Martin and Aaron Eggebeen (Michigan State: adult and pediatric site); Frederick Miller (NIEHS, National Institutes of Health); Pushpa Narayanaswami and Seward B. Rutkove (Beth Israel Deaconess Medical Center/Harvard Medical School); Chester Oddis, Dana Ascherman, Rohit Aggarwal, David Lacomis and Christopher Bise (University of Pittsburgh); Nancy Olsen and Andreas Reimold (University of Texas Southwestern); Elena Schiopu, Kristine Phillips and James Seibold (University of Michigan); Khema Sharma (University of Miami); Swamy Venturupalli and Michael Weisman (Cedars-Sinai Medical Center – UCLA); Steven Ytterberg (Mayo Clinic)

United States (Pediatric sites)

Susan Kim (Children’s Hospital of Boston); Tzielan Lee (Stanford University); Daniel Lovell (Cincinnati Children’s Hospital); C. Egla Rabinovich (Duke University Medical Center); Ann Reed (Mayo Clinic); Lisa Rider (NIEHS, National Institutes of Health); Rafael Rivas-Chacon (Miami Children’s Hospital); David Sherry (The Children’s Hospital of Philadelphia)

Footnotes

This trial was registered with ClinicalTrials.gov on March 21, 2005 before any subject was enrolled (Registration Number for the RIM Study is NCT00106184)

Drs. Oddis and Reed have served as advisory board consultants to Genentech, Inc.

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