Efficacy and safety of tofacitinib in patients with rheumatoid arthritis by previous treatment: post hoc analysis of phase II/III trials.

BACKGROUND: This study sought to evaluate the efficacy and safety of tofacitinib in patients with rheumatoid arthritis with distinct treatment histories. METHODS: Pooled phase II/III trial data from patients who received tofacitinib 5 or 10 mg twice daily or placebo, as monotherapy or with conventional synthetic (cs) disease-modifying antirheumatic drugs (DMARDs), were analyzed post hoc. Separate evaluations were conducted for populations with a prior inadequate response (IR) to: 1) non-methotrexate (MTX) csDMARDs only (non-MTX csDMARD-IR; n = 537); 2) MTX (MTX-IR; n = 3113); and 3) biologic (b)DMARDs (bDMARD-IR; n = 782). Efficacy outcomes included rates of response (American College of Rheumatology 20/50/70% response criteria) and remission (Disease Activity Score in 28 joints derived from 4 measures, erythrocyte sedimentation rate [DAS28-4(ESR)] < 2.6) at month 3, and changes from baseline in DAS28-4(ESR) and Health Assessment Questionnaire-Disability Index scores. Safety was assessed up to month 24. RESULTS: At month 3, efficacy was generally improved with tofacitinib (both doses) vs placebo in each population. Generally, efficacy outcomes with tofacitinib were numerically more favorable in non-MTX csDMARD-IR vs MTX-IR or bDMARD-IR patients. Over 24 months, crude incidence rates for adverse events (AEs), serious AEs, and discontinuations due to AEs were generally numerically lower in non-MTX csDMARD-IR and MTX-IR vs bDMARD-IR populations; rates for AEs of special interest were generally similar across populations. CONCLUSIONS: Tofacitinib provided clinical benefit across patients with rheumatoid arthritis with a range of prior treatment experience but may have greater efficacy and an improved benefit/risk profile in those with fewer prior treatments. TRIAL REGISTRATION: NCT00147498/NCT00413660/NCT00550446/NCT00603512/NCT00687193/NCT00976599/NCT01359150/NCT00847613/NCT00814307/NCT00853385/NCT00960440/NCT01039688/NCT00856544.

A double-blind, placebo-controlled, phase II, randomized study of lovastatin therapy in the treatment of mildly active rheumatoid arthritis.

OBJECTIVES: 3-hydroxy-3-methylglutaryl coenzyme-A (HMG Co-A) reductase inhibitors (statins) are standard treatment for hyperlipidaemia. In addition to lipid-lowering abilities, statins exhibit multiple anti-inflammatory effects. The objectives of this study were to determine whether treatment of patients with RA with lovastatin decreased CRP or reduced disease activity. METHODS: We conducted a randomized double-blind placebo-controlled 12 week trial of lovastatin vs placebo in 64 RA patients with mild clinical disease activity but an elevated CRP. The primary efficacy end point was the reduction in mean log CRP. Secondary end points included disease activity, RF and anti-CCP antibody titres. Mechanistic end points included levels of serum cytokines. Safety was assessed; hepatic and muscle toxicities were of particular interest. RESULTS: Baseline features were similar between groups. No significant difference in mean log CRP reduction between the two groups was observed, and disease activity did not change from baseline in either treatment group. Mechanistic analyses did not reveal significant changes in any biomarkers. A post hoc analysis of subjects not using biologic therapy demonstrated a significantly greater proportion achieving ⩾20% reduction in CRP from baseline in the lovastatin group compared with placebo (P-value = 0.007). No difference was observed in subjects receiving biologics. Lovastatin was well tolerated with no serious safety concerns. CONCLUSION: This study showed no anti-inflammatory or clinical effects on RA disease activity after 12 weeks of treatment with lovastatin. Lovastatin had a modest effect on CRP in subjects not using biologics, suggesting statins may be anti-inflammatory in selected patients. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov, NCT00302952.

Favorable effects of hydroxychloroquine on serum low density lipid in patients with systemic lupus erythematosus: A systematic review and meta-analysis.

AIMS: Hydroxychloroquine (HCQ) has shown to have significant immunomodulatory effects in the treatment of systemic lupus erythematosus (SLE). Current studies show favorable effects of HCQ on traditional cardiac risk factors in patients with SLE. This review examined the effects of HCQ on serum low-density lipoprotein (LDL) level in patients with SLE. METHODS: A systematic search of seven major literature search databases from their inception until 3 April, 2017 identified nine studies. Random-effects pooled mean difference with corresponding 95% confidence intervals (CI) were estimated. Heterogeneity was measured by I2 . Publication bias was assessed by visual inspection of funnel plots. Sensitivity analysis examined whether HCQ effect on serum total cholesterol level was similar to the main analysis. The Grading of Recommendations Assessment, Development, and Evaluation system was used to assess the overall quality of evidence. RESULTS: Pooled study participants were 559 patients from eight observation studies (two before-after studies; six case-control studies) examining the effects of HCQ on serum LDL. Pooled study participants' characteristics were as follows: mean age 45.719, female 95.262%, and prednisone use 58.366%. HCQ reduced mean LDL levels by 24.397 mg/dL (95% CI 8.921-39.872; P = 0.002). The number of studies identifying statin use was too few to perform meta-regression analysis of statin use. Heterogeneity was extensive (I2 = 94.739%). Symmetrical funnel plot visualized no evidence of publication bias. CONCLUSION: HCQ was associated with serum LDL level reduction by mean 24.397 mg/dL in patients with SLE. Future prospective studies are need to fully characterize the treatment effect.

Two-year Efficacy and Safety of Subcutaneous Tocilizumab in Combination with Disease-modifying Antirheumatic Drugs Including Escalation to Weekly Dosing in Rheumatoid Arthritis.

OBJECTIVE: To evaluate the longterm efficacy and safety of subcutaneous tocilizumab (TCZ-SC) every 2 weeks (q2w) over 2 years in patients with rheumatoid arthritis who have an inadequate response to disease-modifying antirheumatic drugs (DMARD). METHODS: Patients (n = 656) were randomized 2:1 to TCZ-SC 162 mg q2w or placebo-SC q2w plus DMARD. After a 24-week double-blind period, patients (n = 457) were rerandomized to open-label TCZ-SC q2w by means of prefilled syringe or autoinjector. Escape therapy with weekly TCZ-SC was available for patients with inadequate efficacy from Week 12. Maintenance of response and safety to 2 years was assessed. Analyses used nonresponder imputation. RESULTS: The American College of Rheumatology (ACR) 20 response after TCZ-SC was maintained beyond Week 24 and was > 70% at each timepoint. ACR50/70, 28-joint Disease Activity Score remission, and ≥ 0.30 decrease from baseline in the Health Assessment Questionnaire-Disability Index response rates were also maintained after Week 24 in the TCZ-SC arm (≥ 50%, > 25%,> 32% and > 56%, respectively). Following escape for inadequate efficacy, many patients achieved ACR20 at the end of the study, 35% after escape from TCZ-SC, and 63% from placebo. The rates of serious adverse events [(11.20/100 patient-years (PY)] including serious infections (3.25/100 PY) were stable through Week 96. No association between anti-TCZ antibody development and loss of efficacy or adverse events was observed. CONCLUSION: Efficacy and safety of TCZ-SC q2w was maintained up to 2 years and remained comparable with previously published data for intravenous TCZ. Dose escalation to weekly TCZ-SC was associated with ACR responses in prior nonresponders and was well tolerated.

Long-Term Safety and Efficacy of Subcutaneously Administered Tocilizumab for Adult Rheumatoid Arthritis: A Multicenter Phase 3b Long-term Extension Study.

INTRODUCTION: To assess the long-term safety and efficacy of subcutaneous tocilizumab (TCZ-SC) in US patients with rheumatoid arthritis (RA) who rolled over from the two global phase 3 studies, SUMMACTA (NCT01194414) and BREVACTA (NCT1232569), into this open-label, single-arm, phase 3b study. METHODS: Patients continued to receive TCZ-SC 162 mg weekly or every other week or switched from intravenous TCZ to TCZ-SC 162 mg qw for up to 84 weeks. The primary endpoint was the proportion of patients with serious adverse events (SAEs). Secondary endpoints included clinical efficacy, laboratory abnormalities, and immunogenicity. RESULTS: Of the 217 patients treated, 76.5% were female, and the mean age was 58.4 years. A total of 23 patients (10.6%) had ≥1 SAE. The most common SAEs were infections (3.7%). Alanine aminotransferase elevations (38.2%) were not associated with hepatic injury. Grade 3/4 neutropenia (3%) was transient and not associated with serious infections. Immunogenicity was low (<1%) and not associated with SAEs. No anaphylaxis or deaths occurred. Thirteen patients (6.0%) withdrew due to safety reasons. Mean Clinical Disease Activity Index and Disease Activity Score in 28 joints remained stable throughout the trial. CONCLUSIONS: The long-term safety of TCZ-SC during the long-term extension period was consistent with the safety profiles from SUMMACTA and BREVACTA, with no new safety signals. Efficacy improvements observed from baseline remained stable over time. These results demonstrated the durability of the safety and efficacy responses, and low immunogenicity, with long-term exposure to TCZ-SC in patients with RA. FUNDING: F. Hoffmann-La Roche, Ltd. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier, NCT01662063.

Biosimilars: Rationale and current regulatory landscape.

OBJECTIVES: To discuss current terminology and the regulatory standards and processes involved in the development of biosimilars. METHODS: An Internet-based literature search through April 2015 was performed for information related to biosimilars in chronic inflammatory disorders. Keywords were as follows: biosimilar, development, manufacturing, characterization, structural, functional, preclinical, clinical, immunogenicity, rheumatoid arthritis, juvenile idiopathic arthritis, psoriasis, psoriatic arthritis, Crohn׳s disease, ulcerative colitis, and ankylosing spondylitis. The European Medicines Agency (EMA) and US Food and Drug Administration (FDA) websites were searched for guidelines and information related to biosimilars. RESULTS: Biosimilars are products that are highly similar to the reference product regarding quality, biological activity, safety, and efficacy. Biosimilars are biological products and not generic drugs and, thus, do not follow the same regulatory pathways as generic molecules. Rigorous early-stage structural, functional, and analytical testing, followed by nonclinical and clinical analyses comparing a biosimilar with its reference product, are required to demonstrate biosimilarity in regulatory markets worldwide. CONCLUSIONS: The addition of biosimilars to the market has the potential to improve access to biologic therapies. Many regulatory agencies have enacted stringent pathways, which must be followed for a biosimilar to be labeled and approved as such; following the pathways will help protect and maintain the integrity, quality, and safety of the biosimilar product.

Development of biosimilars.

OBJECTIVE: To provide an overview of the underlying scientific principles and standards for developing a biosimilar product. METHODS: An Internet-based literature search through June 2015 was performed for information related to biosimilar manufacturing and development, including a review of regulatory guidelines and requirements. RESULTS: Biologics, both biosimilars and their corresponding reference products, are complex molecules produced by biotechnology in living systems. The development of biologics involves multiple levels of intricate, highly controlled manufacturing processes, combined with pre-clinical structural, functional, and biological assessments, as well as clinical efficacy and safety, including immunogenicity, analyses. In addition, to ensure a high degree of similarity, a biosimilar must undergo a comparability exercise at every step of its development, as outlined by regulatory agencies, to demonstrate that potential differences from the reference product are not clinically meaningful with regard to quality, safety, and efficacy [European Medicines Agency (EMA)] or safety, purity, and potency [US Food and Drug Administration (FDA)]. At the foundation of the biosimilar development process lays the establishment of a high degree of structural similarity with its reference product. State-of-the-art technologies must be employed to demonstrate a high degree of structural and functional similarity. Finally, clinical pharmacokinetic and pharmacodynamic as well as clinical efficacy and safety similarity must be confirmed between biosimilar and originator. Regulators, including the FDA and the EMA consider the totality of the evidence from this comprehensive step-wise comparative similarity exercise in its determination of biosimilarity for licensing. CONCLUSIONS: The rigorous and highly regulated processes required to develop a biosimilar have been designed as such to establish a high degree of biosimilarity with a reference product in terms of the structural, functional, biological, and clinical attributes.

Proceedings from The 8th Annual International Society for Musculoskeletal Imaging in Rheumatology (ISEMIR) Conference.

The International Society for Musculoskeletal Imaging in Rheumatology (ISEMIR) was founded in 2005 with the goal of discussing matters related to imaging in rheumatology, particularly, validation, education, and use in both clinical practice and research. The field of musculoskeletal (MSK) imaging is continuously evolving; therefore, education for healthcare providers in this field is of paramount importance. ISEMIR's international faculty and world-renowned experts presented the newest information as it relates to the use of magnetic resonance imaging (MRI) and ultrasound (US) at the 8th annual ISEMIR meeting that took place on April 17-18 in Santa Monica, California. Presentations from the meeting can be viewed at www.isemir.org.

Adrenocorticotropic hormone gel in the treatment of systemic lupus erythematosus: A retrospective study of patients.

OBJECTIVES: Acthar Gel is a long-acting formulation of adrenocorticotropic hormone (ACTH) with anti-inflammatory effects thought to be mediated in part through melanocortin receptor activation. This study was initiated to understand the role of Acthar Gel in SLE treatment in rheumatology practices. METHODS: This is a retrospective case series of nine adult female patients treated with Acthar Gel for at least six months at five academic centers. Treating physicians completed a one-page questionnaire on lupus medications, disease activity, and outcomes. Clinical response was defined using SLEDAI 2K and improvement in the clinical manifestation(s) being treated. RESULTS: The most common clinical SLE manifestations/indications requiring therapy with Acthar Gel were arthritis, rash, and inability to taper corticosteroids. The mean SLEDAI 2K score at baseline was 5.8 ± 5.0 (range 0-16). Six patients were concomitantly treated with corticosteroids (mean dose 18.3mg/day). All patients were on background SLE medications including immunosuppressives. Seven of nine patients had an overall improvement, with a decrease in SLEDAI 2K from 5.8 ± 5.0 at baseline to 3.5 ± 2.7 (range 0-8); four of five patients had improvement or resolution in arthritis, and one of two patients had resolution of inflammatory rash. Four patients discontinued corticosteroids and one patient tapered below 50% of the initial dose by 3 months of treatment with Acthar Gel. No adverse events were reported. CONCLUSIONS: This study suggests a role for Acthar Gel as an alternative to corticosteroids in the treatment of SLE. Acthar Gel appears to be safe and well-tolerated after 6 months of treatment, with a significant reduction in disease activity.

Subcutaneous tocilizumab versus placebo in combination with disease-modifying antirheumatic drugs in patients with rheumatoid arthritis.

OBJECTIVE: The efficacy and safety of subcutaneous tocilizumab (TCZ-SC) versus subcutaneous placebo (PBO-SC) was evaluated in patients with rheumatoid arthritis who had an inadequate response to disease-modifying antirheumatic drugs in the BREVACTA study. METHODS: Patients (n = 656) were randomized 2:1 to receive TCZ-SC 162 mg every other week or PBO-SC every other week for 24 weeks; 20% previously received anti-tumor necrosis factor treatment. Escape therapy with TCZ-SC 162 mg weekly was offered from week 12 for inadequate response. The primary end point was the American College of Rheumatology 20% improvement (ACR20) response at week 24. The key secondary outcomes were radiographic progression and safety. RESULTS: TCZ-SC was superior to PBO-SC for ACR20 response at week 24 (60.9% versus 31.5%; P < 0.0001). All secondary end points showed TCZ-SC to be superior to PBO-SC, including ACR50 and ACR70 response (40% and 20% for TCZ-SC, respectively, and 12% and 5% for PBO-SC, respectively; P < 0.0001 for both) and Disease Activity Score in 28 joints (DAS28) remission (DAS28 <2.6; 32% versus 4% [P < 0.0001]). The mean change in modified Sharp/van der Heijde score was significantly lower in the TCZ-SC group than the PBO-SC group (0.62 versus 1.23; P = 0.0149). Adverse events (AEs) and serious AEs (SAEs) were comparable between the TCZ-SC and PBO-SC groups; 4.6% and 3.7% of patients had at least 1 SAE, respectively, and infection was the most common SAE in 2.1% and 1.8% of patients, respectively. More injection site reactions occurred with TCZ-SC than PBO-SC (7.1% versus 4.1%). No anaphylaxis or serious hypersensitivity reactions occurred. There were 3 deaths in the TCZ-SC group and 0 in the PBO-SC group. CONCLUSION: TCZ-SC every other week had significantly greater efficacy, including ACR end points and inhibition of joint damage, compared with PBO-SC. TCZ-SC was well tolerated and its safety profile was comparable with that of previous intravenous TCZ studies.

The effects of tocilizumab on osteitis, synovitis and erosion progression in rheumatoid arthritis: results from the ACT-RAY MRI substudy.

OBJECTIVE: To examine the imaging-detected mechanism of reduction of structural joint damage progression by tocilizumab (TCZ) in patients with rheumatoid arthritis (RA) using MRI. METHODS: In a substudy of a randomised, double-blind, phase 3b study (ACT-RAY) of biologic-naïve patients with RA who were methotrexate (MTX)-inadequate responders, 63 patients were randomised to continue MTX or receive placebo (PBO), both in combination with TCZ 8 mg/kg every 4 weeks, with optional additional disease-modifying antirheumatic drugs at week 24 if Disease Activity Score of 28 joints < 3.2. The most symptomatic hand was imaged with 0.2 Tesla extremity MRI at weeks 0, 2, 12 and 52. MR images were scored using Outcome Measures in Rheumatology-Rheumatoid Arthritis Magnetic Resonance Imaging Score. Predictors of week 52 erosion progression were determined by logistic regression analysis. RESULTS: TCZ + PBO (n=32) demonstrated mean improvements in synovitis from baseline to weeks 2 (-0.92; p=0.0011), 12 (-1.86; p<0.0001) and 52 (-3.35; p<0.0001), while TCZ + MTX (n=31) had mean improvements in synovitis at week 12 (-0.88; p=0.0074), but not week 52 (-1.00; p=0.0711). TCZ+PBO demonstrated mean reductions in osteitis at weeks 12 (-5.10; p=0.0022) and 52 (-8.56; p=0.0006), while TCZ+MTX had mean reductions at weeks 2 (-0.21; p<0.05) and 12 (-3.63; p=0.0008), but not week 52 (-2.31; p=0.9749). Mean erosion scores did not worsen in either group. MRI erosion scores at weeks 12 and 52 correlated strongly with radiography erosion scores at week 52 (r>0.80). Baseline synovitis and worsening of osteitis predicted erosion progression. CONCLUSIONS: Rapid suppression of synovitis and osteitis with reduction in structural joint damage progression occurred with TCZ, as monotherapy or in combination with MTX, through week 52.

Safety with ocrelizumab in rheumatoid arthritis: results from the ocrelizumab phase III program.

OBJECTIVE: The objective was to determine the safety of ocrelizumab (OCR) in patients with rheumatoid arthritis (RA). METHODS: This was an analysis of the double-blind, placebo-controlled periods and long-term follow-up of 4 OCR phase III trials in RA (SCRIPT, STAGE, FILM and FEATURE). Safety data per study and the results of a meta-analysis of serious infectious events (SIEs) are presented. RESULTS: Overall, 868 patients received placebo, 1064 patients OCR 200 mg×2 (or 400 mg×1) (OCR200), and 827 patients OCR 500 mg×2 (OCR500) plus background methotrexate (MTX) at baseline and 24 weeks. During the double-blind, placebo-controlled periods, the incidence of adverse events and serious adverse events was comparable between the OCR+MTX and placebo +MTX groups. Infusion-related reactions were more common with OCR+MTX and decreased in frequency with subsequent infusions. Serious infusion-related reactions were rare (0.1%). Serious infections occurred more frequently with OCR500+MTX. In the meta-analysis, a statistically significant difference from placebo +MTX in incidence of SIEs per 100 patient-years of 2.4 (95% CI, 0.3-4.5) was observed with OCR500+MTX, but not with OCR200+MTX (0.6; 95% CI, -1.3 to 2.4). Patients recruited in Asia exhibited a higher risk of serious infections (hazard ratio, 1.78; 95% CI, 1.03-3.06). The incidence of human anti-human antibodies was <5%. Long-term follow-up indicated no differences in malignancy rates between the treatment groups. There was no apparent difference in time to B-cell repletion between the OCR dose groups. CONCLUSIONS: In placebo-controlled clinical trials of RA, OCR500+MTX was associated with a higher risk of serious infections compared with placebo +MTX. The safety profile of OCR 200+MTX was comparable with placebo+MTX. TRIAL REGISTRATION: STAGE ClinicalTrials.gov NCT00406419 SCRIPT ClinicalTrials.gov NCT00476996 FILM ClinicalTrials.gov NCT00485589 FEATURE ClinicalTrials.gov NCT00673920.

Emotional modulation of pain and spinal nociception in fibromyalgia.

Fibromyalgia (FM) is characterized by widespread pain, as well as affective disturbance (eg, depression). Given that emotional processes are known to modulate pain, a disruption of emotion and emotional modulation of pain and nociception may contribute to FM. The present study used a well-validated affective picture-viewing paradigm to study emotional processing and emotional modulation of pain and spinal nociception. Participants were 18 individuals with FM, 18 individuals with rheumatoid arthritis (RA), and 19 healthy pain-free controls (HC). Mutilation, neutral, and erotic pictures were presented in 4 blocks; 2 blocks assessed only physiological-emotional reactions (ie, pleasure/arousal ratings, corrugator electromyography, startle modulation, skin conductance) in the absence of pain, and 2 blocks assessed emotional reactivity and emotional modulation of pain and the nociceptive flexion reflex (NFR, a physiological measure of spinal nociception) evoked by suprathreshold electric stimulations over the sural nerve. In general, mutilation pictures elicited displeasure, corrugator activity, subjective arousal, and sympathetic activation, whereas erotic pictures elicited pleasure, subjective arousal, and sympathetic activation. However, FM was associated with deficits in appetitive activation (eg, reduced pleasure/arousal to erotica). Moreover, emotional modulation of pain was observed in HC and RA, but not FM, even though all 3 groups evidenced modulation of NFR. Additionally, NFR thresholds were not lower in the FM group, indicating a lack of spinal sensitization. Together, these results suggest that FM is associated with a disruption of supraspinal processes associated with positive affect and emotional modulation of pain, but not brain-to-spinal cord circuitry that modulates spinal nociceptive processes.

Safety of rituximab in combination with other biologic disease-modifying antirheumatic drugs in rheumatoid arthritis: an open-label study.

OBJECTIVE: To characterize the safety of rituximab (RTX) in combination with biologic disease-modifying antirheumatic drugs (DMARD) in patients with rheumatoid arthritis (RA). METHODS: We did an open-label study of the safety and efficacy of RTX in adult patients with active RA and an inadequate response to ≥ 1 biologic for ≥ 12 weeks (stable dose ≥ 4 weeks). RTX (2 × 500 mg) was added to patients' current biologic and nonbiologic DMARD treatment. After 24 weeks, patients with 28-joint Disease Activity Score ≥ 2.6 were eligible for RTX retreatment. The primary endpoint was the proportion of patients developing a serious adverse event (SAE) within 24 weeks of initiating RTX. RESULTS: Patients (n = 176) received RTX with 18 different biologic/DMARD combinations. Adalimumab alone (n = 46; 26.1%) or etanercept alone (n = 37; 21.0%) plus RTX were the most common combinations. Overall, 90.9% and 76.1% of patients completed 24 and 48 weeks, respectively; 147 patients (83.5%) received a second course of RTX. Over 24 weeks, 9.1% of patients reported SAE (24.3 events/100 patient-yrs, 95% CI 15.5-38.1). The SAE rate was similar over 48 weeks (22.4 events/100 patient-yrs, 95% CI 15.9-31.5). Four serious infections were reported over 48 weeks (2.7 events/100 patient-yrs, 95% CI 1.0-7.2). No SAE occurred within 24 h of any RTX infusion. Efficacy responses improved numerically at Week 48 compared with Week 24. CONCLUSION: The overall safety profile of RTX in combination with 1 other biologic was consistent with that previously reported for RTX plus methotrexate or other nonbiologic DMARD. (Clinicaltrials.gov NCT00443651).

Monitoring cartilage loss in the hands and wrists in rheumatoid arthritis with magnetic resonance imaging in a multi-center clinical trial: IMPRESS (NCT00425932).

INTRODUCTION: Magnetic resonance imaging (MRI) is increasingly being used in clinical trials of rheumatoid arthritis (RA) because of its superiority over x-ray radiography (XR) in detecting and monitoring change in bone erosion, osteitis and synovitis. However, in contrast to XR, the MRI scoring method that was used in most clinical trials did not include cartilage loss. This limitation has been an obstacle to accepting MRI as a potential alternative to XR in clinical trials. Cross-sectional studies have shown MRI to be sensitive for cartilage loss in the hands and wrist; although, longitudinal sensitivity to change has not yet been confirmed. In this study we examined the ability of MRI to monitor change in cartilage loss in patients with RA in a multi-site clinical trial setting. METHODS: Thirty-one active RA patients from a clinical trial (IMPRESS) who were randomized equally into treatment with either rituximab + methotrexate or placebo + methotrexate had MRI of the dominant hand/wrist at baseline, 12 weeks and 24 weeks at 3 clinical sites in the US. Twenty-seven of these patients also had XR of both hands/wrists and both feet at baseline and 24 weeks. One radiologist scored all XR images using the van der Heijde-modified Sharp method blinded to visit order. The same radiologist scored MR images for cartilage loss using a previously validated 9-point scale, and bone erosion using the Outcome Measures in Rheumatology Clinical Trials (OMERACT) RA MRI Score (RAMRIS) blinded to visit order and XR scores. Data from the two treatment arms were pooled for this analysis. RESULTS: Mean MRI cartilage score increased at 12 and 24 weeks, and reached statistical significance at 24 weeks. XR total Sharp score, XR erosion score and XR joint-space narrowing (JSN) score all increased at 24 weeks, but only XR total Sharp score increased significantly. CONCLUSIONS: To our knowledge, this is the first publication of a study demonstrating MRI's ability to monitor cartilage loss in a multi-site clinical trial. Combined with MRI's established performance in monitoring bone erosions in RA, these findings suggest that MRI may offer a superior alternative to XR in multi-site clinical trials of RA.

Proceedings from the 5th Annual International Society for Musculoskeletal Imaging in Rheumatology Annual Conference.

Since its inception, ISEMIR has held an annual education meeting highlighting the changes in the utilization of imaging tools for the management of rheumatic diseases. ISEMIR's international faculty and world-renowned experts have discussed these topics at a very high scientific level. The evolution of the content demonstrates the rapidly changing environment in the field of rheumatology. Advances in treatment have led to the increased use of magnetic resonance imaging (MRI) and ultrasound (US). This publication is based upon the proceedings from the 2012 ISEMIR educational meeting that took place on April 26th in Chicago, Illinois. Presentations from the live proceedings can be viewed at www.isemir.org.

Magnetic resonance imaging applications in early rheumatoid arthritis diagnosis and management.

Early diagnosis and treatment have been recognized as essential for improving clinical outcomes in patients with rheumatoid arthritis (RA). Magnetic resonance imaging (MRI) is a sensitive modality that can assess both inflammatory and structural lesions. MRI can assist in following the disease course in patients treated with traditional disease-modifying antirheumatic drugs and biological therapies both in the clinic and in research trials. Therefore, it is anticipated that MRI becomes the diagnostic imaging modality of choice in RA clinical trials while remaining a useful tool for clinicians evaluating patients with RA.

Evaluating joint-space narrowing and cartilage loss in rheumatoid arthritis by using MRI.

INTRODUCTION: Magnetic resonance imaging (MRI) has been shown to be superior to radiography (XR) for assessing synovitis, osteitis, and bone erosion in rheumatoid arthritis (RA), particularly in clinical trials. However, relatively little has been reported on the ability of MRI to evaluate articular cartilage loss, or joint-space narrowing (JSN), in the hands and wrists. In a previous study, we adapted the nine-point Genant-modified Sharp XR-JSN score for use with MRI (MRI-JSN). In this study, we compare MRI-JSN with XR-JSN by using images from two multicenter clinical trials. METHODS: Baseline XR and 1.5-Tesla MR images of one hand and wrist from each of 47 subjects with RA enrolled in one of two multicenter clinical trials were evaluated by using the XR-JSN and MRI-JSN methods by a single radiologist experienced in the two methods. Radiographs and MR images were read independently on different occasions. RESULTS: In total, 575 of 611 joints were compared (one metacarpophalangeal joint of the thumb and 35 proximal interphalangeal joints were outside the MRI field of view and could not be assessed). The 22 (47%) subjects showed JSN with both XR and MRI, and 25 (53%) subjects showed no JSN with either method. No subject showed JSN with only one or the other method. MRI showed high agreement with XR (intraclass correlation coefficient = 0.83). Sensitivity of MRI for JSN, by using XR as the gold standard, was 0.94; specificity was 0.91; accuracy was 0.91; positive predictive value was 0.64; and negative predictive value was 0.99. CONCLUSIONS: This validation exercise suggests that MRI JSN scoring may offer a viable alternative to XR JSN scoring in multicenter clinical trials of RA. However, the relative longitudinal sensitivity of MRI to change and the ability to discriminate therapeutic effect on JSN were not evaluated in this study.

Safety and efficacy of ocrelizumab in combination with methotrexate in MTX-naive subjects with rheumatoid arthritis: the phase III FILM trial.

OBJECTIVE: To determine the efficacy and safety of ocrelizumab (OCR) with methotrexate (MTX) in MTX-naive rheumatoid arthritis (RA) patients. METHODS: In a randomised, double-blind, controlled trial, patients received placebo+MTX (MTX; n=210), OCR 200 mg×2+MTX (OCR 200; n=200) or OCR 500 mg×2+MTX (OCR 500; n=203). OCR/placebo (two intravenous infusions) was given on days 1 and 15, with fixed re-treatment scheduled at weeks 24/26, 52/54 and 76/78. Due to early termination of OCR dosing, there was no formal primary end point analysis (change from baseline in modified total Sharp score (ΔmTSS) at week 104). Analyses are reported for week 52 outcomes. RESULTS: At week 52, treatment with OCR+MTX compared with MTX alone reduced progression of joint damage (mean (SD) change in ΔmTSS: OCR 200, 0.66 (4.51); OCR 500, 0.27 (2.91); MTX alone, 1.59 (4.82); p=0.001 and p=0.003, respectively vs MTX alone) and improved clinical signs and symptoms (American College of Rheumatology 20 response: OCR 200, 73.0%; OCR 500, 71.0%; MTX alone, 57.5%; p<0.005 for each OCR vs MTX alone). Serious infection rates per 100 patient-years were similar with OCR 200 and MTX alone (2.6 (95% CI 0.9 to 6.1) and 3.0 (1.1 to 6.5), respectively), but higher with OCR 500 (7.1 (3.9 to 11.9)). CONCLUSIONS: OCR 200 mg and 500 mg with MTX in MTX-naive patients with RA were effective in inhibiting joint damage progression and improving RA signs and symptoms. OCR 500 mg with MTX was associated with an increased rate of serious infections.

Magnetic resonance imaging in rheumatoid arthritis clinical trials: emerging patterns based on recent experience.

OBJECTIVE: The current validated magnetic resonance imaging (MRI) scoring method for rheumatoid arthritis (RA) in clinical trials, RA MRI Score (RAMRIS), incorporates all metacarpophalangeal (MCP) and wrist joints except MCP-1. The experience with radiographic scoring, however, was that excluding certain bones in the wrist improved the discriminative power for changes over time. In this study, we pool MRI data from randomized controlled clinical trails (RCT) to determine which combination of MCP and wrist joints are most sensitive and discriminative for structural changes over time. METHODS: MR images from 4 multicenter RCT, including 522 RA patients, were read by 2 radiologists, using the RAMRIS scoring system for erosion, osteitis, and synovitis. In one RCT, joint-space narrowing (JSN) was assessed cross-sectionally by one radiologist using a previously validated method. Baseline frequencies of erosion, JSN, osteitis, and synovitis of different bones and joints in the hand and wrist were compared. Intraclass correlation coefficients between readers were determined for each location. Finally, 7 different combinations of bone/joint locations were compared for their ability to discriminate subjects showing increases or decreases from baseline greater than or equal to smallest detectable changes (SDC) at Weeks 12 or 24. RESULTS: Frequency of involvement and reliability for assessing change varied by location. As in earlier analyses, excluding certain wrist bones increased the percentage of subjects showing changes greater than or equal to SDC. CONCLUSION: These findings suggest that excluding wrist bones that do not frequently or reliably demonstrate structural changes improves the discriminative power of the RAMRIS scoring system.