Comparison of long‐term clinical outcome with etanercept treatment and adalimumab treatment of rheumatoid arthritis with respect to immunogenicity

Objective

To compare rates of sustained low and minimal disease activity and remission according to the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria during 3‐year followup in rheumatoid arthritis (RA) patients treated with etanercept and adalimumab in routine care.

Methods

Four hundred seven RA patients previously unexposed to tumor necrosis factor antagonists were treated with etanercept (n = 203) or adalimumab (n = 204) and assessed at 3‐ and later 6‐month intervals. Treatment allocation was at the discretion of the treating rheumatologist. Clinical parameters were measured at each time point, as were anti‐adalimumab antibodies in adalimumab‐treated patients. Achievement of clinical outcome was defined as the occurrence of sustained (at least 12 consecutive months) low disease activity (28‐joint Disease Activity Score [DAS28] <3.2), minimal disease activity (DAS28 <2.6), or ACR/EULAR remission based on the Simplified Disease Activity Index (SDAI). Non‐overlapping response rates were calculated.

Results

Among the adalimumab group, 13% reached sustained low disease activity but not sustained minimal disease activity, 15% reached sustained minimal disease activity but not sustained remission according to the SDAI, and 16% reached sustained ACR/EULAR remission. In the etanercept group the corresponding rates were 16%, 11%, and 12%, respectively (P = 0.42, overall test for linear trend). Adalimumab‐treated patients without anti‐adalimumab antibodies (n = 150 [74%]) had the best outcomes, and adalimumab‐treated patients with anti‐adalimumab antibodies the worst, with outcomes in etanercept‐treated patients in between (P < 0.0001). Differences were most apparent in the sustained SDAI remission and sustained minimal disease activity categories. For example, 40% of anti‐adalimumab antibody–negative patients, 23% of etanercept‐treated patients, and 4% of anti‐adalimumab antibody–positive patients achieved at least sustained minimal disease activity.

Conclusion

Overall, etanercept and adalimumab treatment appear similar in inducing a good long‐term clinical outcome. However, in the case of adalimumab this is strongly dependent on the presence or absence of anti‐adalimumab antibodies.

     

Implementation of a treat‐to‐target strategy in very early rheumatoid arthritis: Results of the Dutch Rheumatoid Arthritis Monitoring remission induction cohort study

Objective

Clinical remission is the ultimate therapeutic goal in rheumatoid arthritis (RA). Although clinical trials have proven this to be a realistic goal, the concept of targeting at remission has not yet been implemented. The objective of this study was to develop, implement, and evaluate a treat‐to‐target strategy aimed at achieving remission in very early RA in daily clinical practice.

Methods

Five hundred thirty‐four patients with a clinical diagnosis of very early RA were included in the Dutch Rheumatoid Arthritis Monitoring remission induction cohort study. Treatment adjustments were based on the Disease Activity Score in 28 joints (DAS28), aiming at a DAS28 of <2.6 (methotrexate, followed by the addition of sulfasalazine, and exchange of sulfasalazine with biologic agents in case of persistent disease activity). The primary outcome was disease activity after 6 months and 12 months of followup, according to the DAS28, the European League Against Rheumatism (EULAR) response criteria, and the modified American College of Rheumatology (ACR) remission criteria. Secondary outcomes were time to first DAS28 remission and outcome of radiography.

Results

Six‐month and 12‐month followup data were available for 491 and 389 patients, respectively. At 6 months, 47.0% of patients achieved DAS28 remission, 57.6% had a good EULAR response, and 32.0% satisfied the ACR remission criteria. At 12 months, 58.1% of patients achieved DAS28 remission, 67.9% had a good EULAR response, and 46.4% achieved ACR remission. The median time to first remission was 25.3 weeks (interquartile range 13.0–52.0). The majority of patients did not have clinically relevant radiographic progression after 1 year.

Conclusion

The successful implementation of this treat‐to‐target strategy aiming at remission demonstrated that achieving remission in daily clinical practice is a realistic goal.

     

Thresholds in disease activity for switching biologics in rheumatoid arthritis patients: experience from a large U.S. cohort

Objective

To examine the threshold in disease activity associated with switching biologic treatment regimens in rheumatoid arthritis (RA) patients in real‐world clinical practice.

Methods

Using data from a prospective observational North American cohort of RA patients through December 30, 2009, patients who initiated a new anti–tumor necrosis factor α (anti‐TNFα) agent with ≥6 months of followup were identified. Patients were classified as switchers or maintainers depending on whether they continued their anti‐TNF treatment or switched (including discontinuation) within 12 months. Level of disease activity measured by the Clinical Disease Activity Index (CDAI) and Disease Activity Score in 28 joints (DAS28) at the time of the switch (corresponding followup visit for maintainers) was examined and random‐effect multivariable logistic regression was used to adjust for covariates.

Results

Mean age and RA duration among 1,549 eligible patients were 56.1 and 9.6 years, respectively, 80% were women, 62% were initiating their first biologic, and 30% were initiating their second biologic. At the time of the switch, the median DAS28 and CDAI score were 3.1 and 8.4 among maintainers and 4.0 and 15.2 among switchers, respectively. Maintainers also experienced a greater amount of reduction in disease activity compared with switchers (CDAI: ?7.7 versus ?2.3, DAS28: ?1.1 versus ?0.3). The threshold to switch decreased over calendar time, with the greatest amount of reduction observed among patients with moderate disease activity.

Conclusion

On average, physicians and patients were willing to continue biologic treatment for patients who were at or near low disease activity. The threshold to switch decreased over time, especially among partial responders.

     

Reexamination of the assessment criteria for rheumatoid arthritis disease activity based on comparison of the Disease Activity Score 28 with other simpler assessment methods

Objective

To explore simpler and possibly more appropriate tools than the conventional Disease Activity Score 28 (DAS28) for assessing rheumatoid arthritis (RA) and to derive more reliable DAS28-based criteria.

Methods

The capabilities of assessing disease activities in 250 RA patients were compared between DAS28 and other methods, including the Simplified DA Index (SDAI), Clinical DA Index (CDAI), and Routine Assessment of Patient Index Data-3 (RAPID-3).

Results

SDAI and CDAI showed a good correlation and consistency with DAS28, whereas RAPID-3 yielded inferior results. In terms of remission criteria, DAS28 was less stringent than SDAI or CDAI; when RA remission was reexamined based on more stringent SDAI or CDAI criteria, cut-off values for DAS28-C-reactive protein of <1.72 were considered to be appropriate. The conventional DAS28 was considered to be appropriate for assessing low, middle and high disease activities because it provides criteria similar to or more stringent than those of other methods, while SDAI and CDAI were considered to be simpler and more appropriate criteria for assessing remission.

Conclusion

For assessing remission, DAS28-CRP provides the most appropriate criterion of the methods compared when the currently used cut-off value of 2.3 is lowered to a new value of 1.72.     

A home‐based two‐year strength training period in early rheumatoid arthritis led to good long‐term compliance: A five‐year followup

Objective

To evaluate the impact of a 2‐year home‐based strength‐training program on physical function in patients with early rheumatoid arthritis (RA) after a subsequent 3‐year followup.

Methods

Seventy patients with early RA were randomized to perform either strength training (experimental group [EG]) or range‐of‐motion exercises (control group [CG]). Maximal strength values were recorded by dynamometers. The Modified Disease Activity Score (DAS28), pain, Health Assessment Questionnaire (HAQ), walking speed, and stair‐climbing speed were also measured.

Results

The maximum strength of assessed muscle groups increased by 19–59% in the EG during the training period and remained at the reached level throughout the subsequent 3 years. Muscle strength improved in the CG by 1–31%, but less compared with the EG. During the 2‐year training period, DAS28 decreased by 50% and 45% and pain by 67% and 39% in the EG and CG, respectively. The differences in muscle strength, DAS28, and HAQ were significantly in favor of the EG both at the 2‐year and 5‐year followup assessments.

Conclusions

The improvements achieved during the 2‐year strength‐training period were sustained for 3 years in patients with early RA.

     

Responsiveness of the self‐assessed rheumatoid arthritis disease activity index to a flare of disease activity

Objective

To assess the responsiveness of the Rheumatoid Arthritis Disease Activity Index (RADAI) to increases in disease activity, using the occurrence of a flare of disease activity as an external standard.

Methods

A post hoc analysis was performed on data from a randomized, double‐blind, controlled trial of methotrexate versus type II collagen in 92 patients with rheumatoid arthritis (RA). Responsiveness was analyzed by 1) correlating change in the RADAI score with change in the Disease Activity Score (DAS28), 2) determining the RADAI's ability to detect a disease flare by plotting a receiver operating characteristic (ROC) curve, and 3) using a responsiveness statistic, the standardized effect size (SES). The contribution of the single RADAI items to the change in total RADAI score was analyzed by the item score change in absolute value, the item responsiveness by the standardized response mean, and the correlation of item score change with total RADAI score change by Cronbach's alpha.

Results

Changes in the RADAI score correlated strongly with changes in the DAS28 (R² = 0.70, P < 0.0001). The area under the ROC curve for the RADAI was 0.88 (95% confidence interval 0.78–0.95), which was similar to that for the DAS28. The SES for the RADAI was 1.56, which was also similar to that for the DAS28. The RADAI items of past global disease activity and morning stiffness contributed least to the total score change.

Conclusion

This study provides evidence that the RADAI is sensitive to relevant increases in disease activity in RA patients. The RADAI may complement clinical measures in clinical studies, or may be used as a proxy for disease activity in epidemiologic studies.

     

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

Objective

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

Methods

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

Results

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

Conclusion

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

     

Disease remission state in patients treated with the combination of tumor necrosis factor blockade and methotrexate or with disease‐modifying antirheumatic drugs: A clinical and imaging comparative study

Objective

For patients with rheumatoid arthritis (RA) in remission who are receiving disease‐modifying antirheumatic drugs (DMARDs), radiographic progression correlates with imaging‐detected synovitis as measured by power Doppler activity. In contrast, patients with disease in remission who are receiving the combination of tumor necrosis factor (TNF) blockade with methotrexate (MTX) (combination treatment) have reduced radiographic damage for the equivalent clinical state. We undertook this study to determine whether the difference in radiographic outcome is a result of more complete suppression of imaging‐detected synovitis.

Methods

One hundred patients with RA in remission (Disease Activity Score in 28 joints [DAS28] <2.6) for at least 6 months while receiving either combination treatment (n = 50) or DMARDs (n = 50) were matched for clinical variables. Ultrasound of metacarpophalangeal joints 1–5 and the wrist joints was performed. Remission according to imaging results was defined as a score of 0 for both grey scale synovitis and power Doppler activity.

Results

In patients receiving combination treatment or DMARDs (median DAS28 1.65 versus 1.78, median disease duration 120 months versus 90 months, and median duration of remission 13 months versus 18 months), the proportion with remission according to imaging results was not significantly different (10% versus 16%, respectively). The combination treatment group had more grey scale synovitis (P < 0.001) but similar power Doppler activity (48% versus 60%, respectively; P = 0.229) in any joint as compared with the DMARD group. Results were not affected by stratification for duration of disease or remission.

Conclusion

In RA patients with disease in remission, imaging‐detected synovitis persists, with power Doppler activity seen in ≥48% of the patients regardless of therapy. These results suggest that superior radiographic outcomes in patients treated with the combination of TNF blockade and MTX may not be due to complete suppression of imaging‐detected synovitis.

     

Direct comparison of treatment responses,remission rates,and drug adherence in patients with rheumatoid arthritis treated with adalimumab,etanercept, or infliximab: Results from eight years of surveillance of clinical practice in the nationwide Danish DANBIO registry

Objective

To compare tumor necrosis factor α inhibitors directly regarding the rates of treatment response, remission, and the drug survival rate in patients with rheumatoid arthritis (RA), and to identify clinical prognostic factors for response.

Methods

The nationwide DANBIO registry collects data on rheumatology patients receiving routine care. For the present study, we included patients from DANBIO who had RA (n = 2,326) in whom the first biologic treatment was initiated (29% received adalimumab, 22% received etanercept, and 49% received infliximab). Baseline predictors of treatment response were identified. The odds ratios (ORs) for clinical responses and remission and hazard ratios (HRs) for drug withdrawal were calculated, corrected for age, disease duration, the Disease Activity Score in 28 joints (DAS28), seropositivity, concomitant methotrexate and prednisolone, number of previous disease‐modifying drugs, center, and functional status (Health Assessment Questionnaire score).

Results

Seventy percent improvement according to the American College of Rheumatology criteria (an ACR70 response) was achieved in 19% of patients after 6 months. Older age, concomitant prednisolone treatment, and low functional status at baseline were negative predictors. The ORs (95% confidence intervals [95% CIs]) for an ACR70 response were 2.05 (95% CI 1.52–2.76) for adalimumab versus infliximab, 1.78 (95% CI 1.28–2.50) for etanercept versus infliximab, and 1.15 (95% CI 0.82–1.60) for adalimumab versus etanercept. Similar predictors and ORs were observed for a good response according to the European League Against Rheumatism criteria, DAS28 remission, and Clinical Disease Activity Index remission. At 48 months, the HRs for drug withdrawal were 1.98 for infliximab versus etanercept (95% 1.63–2.40), 1.35 for infliximab versus adalimumab (95% CI 1.15–1.58), and 1.47 for adalimumab versus etanercept (95% CI 1.20–1.80).

Conclusion

Older age, low functional status, and concomitant prednisolone treatment were negative predictors of a clinical response and remission. Infliximab had the lowest rates of treatment response, disease remission, and drug adherence, adalimumab had the highest rates of treatment response and disease remission, and etanercept had the longest drug survival rates. These findings were consistent after correction for confounders and sensitivity analyses and across outcome measures and followup times.

     

Comment on the use of self‐reporting instruments to assess patients with rheumatoid arthritis: The longitudinal association between the DAS28 and the VAS general health

Objective

Recently, the use of patient self‐reporting instruments instead of clinical, objective measurements to assess rheumatoid arthritis (RA) patients was proposed. This assumes a constant association between disease activity and the self‐reporting instruments. The objective was to explore the association (in time) between disease activity and patient perception of general health, disease activity, pain, and functional disability in patients with RA.

Methods

Data of 624 newly diagnosed RA patients who completed 3 years of followup were analyzed. Cross‐sectional linear regression models and longitudinal regression models were estimated, with a visual analog scale (VAS) measuring general health (VAS‐GH; 0 = best, 100 = worst) as a dependent variable and the Disease Activity Score (DAS28) without the VAS‐GH as an independent variable. Other dependent variables were VAS disease activity, pain, and the Health Assessment Questionnaire.

Results

The DAS28 and VAS‐GH were significantly associated in RA patients (P < 0.001). However, the explained variance was low (6.7%). From diagnosis to 3 years after the diagnosis, the intercept decreased given the same regression coefficient. The longitudinal regression model showed that the VAS‐GH improved during disease course independent of a change in DAS28. Analyses on the other outcome parameters showed similar results.

Conclusion

Patients' perception of health can be different with equal disease activity, depending on the moment in the disease course. Furthermore, our results indicate that self‐reported measures on functionality, disease activity, and general health cannot substitute for objective measures of disease activity in RA in longitudinal studies; subsequently, both need to be measured.

     

Polymorphism at position −308 of the tumor necrosis factor α gene influences outcome of infliximab therapy in rheumatoid arthritis

Objective

To test whether the G‐to‐A polymorphism at position −308 in the promoter of the tumor necrosis factor α (TNFα) gene influences response to infliximab therapy in patients with rheumatoid arthritis (RA).

Methods

We genotyped 59 RA patients by polymerase chain reaction and subdivided them into two groups: those with the A/A or A/G genotype and those with the G/G genotype. We compared the groups' clinical responses to infliximab treatment after 22 weeks, using the Disease Activity Score in 28 joints (DAS28).

Results

We found that 42% of patients in the A/A and A/G group and 81% of patients in the G/G group had improvement of at least 1.2 in the DAS28 score (P = 0.0086). The average improvement in the DAS28 score was 1.24 in the A/A and A/G patients and 2.29 in the G/G patients (P = 0.029).

Conclusion

These data suggest that patients with a TNFα −308G/G genotype are better infliximab responders than are patients with A/A or A/G genotypes. TNFα −308 genotyping may be a useful tool for predicting response to infliximab treatment.

     

Tocilizumab in systemic lupus erythematosus: Data on safety,preliminary efficacy,and impact on circulating plasma cells from an open‐label phase I dosage‐escalation study

Objective

To assess the safety of interleukin‐6 receptor inhibition and to collect preliminary data on the clinical and immunologic efficacy of tocilizumab in patients with systemic lupus erythematosus (SLE).

Methods

In an open‐label phase I dosage‐escalation study, 16 patients with mild‐to‐moderate disease activity were assigned to receive 1 of 3 doses of tocilizumab given intravenously every other week for 12 weeks (total of 7 infusions): 2 mg/kg in 4 patients, 4 mg/kg in 6 patients, or 8 mg/kg in 6 patients. Patients were then monitored for an additional 8 weeks.

Results

The infusions were well tolerated. Tocilizumab treatment led to dosage‐related decreases in the absolute neutrophil count, with a median decrease of 38% in the 4 mg/kg dosage group and 56% in the 8 mg/kg dosage group. Neutrophil counts returned to normal after cessation of treatment. One patient was withdrawn from the study because of neutropenia. Infections occurred in 11 patients; none was associated with neutropenia. Disease activity showed significant improvement, with a decrease of ≥4 points in the modified Safety of Estrogens in Lupus Erythematosus National Assessment version of the Systemic Lupus Erythematosus Disease Activity Index score in 8 of the 15 evaluable patients. Arthritis improved in all 7 patients who had arthritis at baseline and resolved in 4 of them. Levels of anti–double‐stranded DNA antibodies decreased by a median of 47% in patients in the 4 mg/kg and 8 mg/kg dosage groups, with a 7.8% decrease in their IgG levels. These changes, together with a significant decrease in the frequency of circulating plasma cells, suggest a specific effect of tocilizumab on autoantibody‐producing cells.

Conclusion

Although neutropenia may limit the maximum dosage of tocilizumab in patients with SLE, the observed clinical and serologic responses are promising and warrant further studies to establish the optimal dosing regimen and efficacy.

     

Complement activation in patients with rheumatoid arthritis mediated in part by C‐reactive protein

Objective

Complement activation in patients with rheumatoid arthritis (RA) is considered to be triggered by immune complexes. Recently, it was shown that C‐reactive protein (CRP) can activate the complement system in vivo. We therefore hypothesized that part of the complement activation in RA is due to CRP. The aim of this study was to investigate CRP‐mediated complement activation in RA, and to assess its correlation with disease activity.

Methods

Complexes between CRP and the activated complement components C3d (C3d–CRP) and C4d (C4d–CRP), which reflect CRP‐mediated complement activation, as well as the overall levels of activated C3 and C4 were measured in the plasma of 107 patients with active RA and 177 patients with inactive RA. Inactive RA was defined according to the American College of Rheumatology criteria for clinical remission. Disease activity was assessed by the modified Disease Activity Score (DAS28).

Results

Plasma levels of C3d–CRP and C4d–CRP were increased in the majority of the patients, and were significantly higher in patients with active disease versus those with inactive RA (P < 0.001). In patients with active RA, the plasma concentrations of C3d–CRP and C4d–CRP correlated significantly with the DAS28 (Spearman's rho 0.61 and 0.55, respectively; P < 0.001), whereas these correlations were less pronounced in patients with inactive RA (Spearman's rho 0.28 [P < 0.001] and 0.25 [P = 0.001], respectively). Levels of activated C3 and C4 were also increased in the majority of the patients, particularly in patients with active RA.

Conclusion

Part of the activation of complement in RA is mediated by CRP and is correlated with disease activity. We suggest that this activation is involved in the pathogenesis of RA.

     

Brief Report: Inhibition of interleukin‐6 function corrects Th17/Treg cell imbalance in patients with rheumatoid arthritis

Objective

From an immunologic standpoint, the mechanisms by which treatment with tocilizumab (TCZ), a humanized anti–interleukin‐6 (anti–IL‐6) receptor antibody, results in improvement in rheumatoid arthritis (RA) patients are still not fully understood. In vitro studies and studies in mouse models have demonstrated the critical role of IL‐6 in Th17 cell differentiation. Th17 lymphocytes have been shown to be strongly involved in RA pathogenesis, and the purpose of this study was to investigate the effect of IL‐6 blockade on the balance between Th17 cells and Treg cells in patients with active RA.

Methods

Patients with active RA for whom TCZ had been prescribed by a rheumatologist were enrolled in this study. Phenotypic analyses of T cell populations were performed, and the Disease Activity Score in 28 joints (DAS28) was assessed. Serum cytokine levels and other parameters of inflammation were measured before the first infusion and after the third infusion of TCZ (8 mg/kg).

Results

Compared to controls, levels of Th17 cells (CD4+IL‐17+) were increased and Treg cells (CD4+CD25^highFoxP3+) were decreased in the peripheral blood of patients with active RA. The suppressive function of circulating Treg cells was not impaired in patients with active RA. TCZ treatment induced a significant decrease in the DAS28 associated with a significant decrease in the percentage of Th17 cells (from a median of 0.9% to 0.45%; P = 0.009) and an increase in the percentage of Treg cells (from a median of 3.05% to 3.94%; P = 0.0039) in all patients.

Conclusion

This study demonstrates for the first time that inhibition of IL‐6 function by TCZ corrects the imbalance between Th17 cells and Treg cells in patients with RA.

     

Reliability of patient self‐evaluation of swollen and tender joints in rheumatoid arthritis: A comparison study with ultrasonography,physician, and nurse assessments

Objective

Swollen and tender joints, important in assessing rheumatoid arthritis (RA) activity, have traditionally been evaluated by health professionals. Whether patients can accurately evaluate joints is uncertain. This study evaluated 1) the reliability of patient‐assessed swollen joint counts (SJCs) and tender joint counts (TJCs) versus those assessed by a physician, nurse, and B‐mode ultrasonography (US) and 2) patient‐derived Disease Activity Score in 28 joints (DAS28) compared with physician‐, nurse‐, and US‐derived DAS28.

Methods

Fifty RA patients self‐assessed 28 joints (shoulders, elbows, wrists, metacarpophalangeal, proximal interphalangeal, and knees) for swelling and tenderness. They were then assessed separately by a physician, a nurse, and an ultrasonographer. Nine patients were tested twice (intraobserver reliability), and reliability was assessed at the patient level (28 joints) by intraclass correlation coefficients (ICCs) and at the joint level by prevalence‐adjusted bias‐adjusted kappa.

Results

TJC reliability was good for patient versus physician (ICC 0.85 [95% confidence interval (95% CI) 0.65, 0.94]) and patient versus nurse (ICC 0.76 [95% CI 0.47, 0.90]). However, SJC reliability was poor for patient versus physician (ICC 0.41 [95% CI ?0.05, 0.72]) and patient versus nurse (ICC 0.44 [95% CI ?0.005, 0.74]). SJC reliability was poor in all assessors compared with B‐mode US, particularly patient‐assessed SJC (ICC 0.22 [95% CI ?0.25, 0.61]). However, patient‐derived DAS28 correlated well with US‐derived DAS28 (ICC 0.95 [95% CI 0.87, 0.98]). Intraobserver reliability was good for all assessors for TJC, but was lower for SJC.

Conclusion

Patient‐derived DAS28 is at least as reliable as physician‐, nurse‐, or US‐derived DAS28, despite poor reliability in patient‐assessed SJC.

     

Double‐blind randomized controlled clinical trial of the interleukin‐6 receptor antagonist,tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate

Objective

To establish the safety and efficacy of repeat infusions of tocilizumab (previously known as MRA), a humanized anti–interleukin‐6 (IL‐6) receptor antibody, alone and in combination with methotrexate (MTX), for the treatment of rheumatoid arthritis (RA).

Methods

The study group comprised 359 patients with active RA in whom the response to MTX was inadequate. During a stabilization period, these patients received their current dose of MTX for at least 4 weeks. Following stabilization, they were randomized to 1 of 7 treatment arms, as follows: tocilizumab at doses of 2 mg/kg, 4 mg/kg, or 8 mg/kg either as monotherapy or in combination with MTX, or MTX plus placebo.

Results

A 20% response (improvement) according to the American College of Rheumatology criteria (ACR20 response) was achieved by 61% and 63% of patients receiving 4 mg/kg and 8 mg/kg of tocilizumab as monotherapy, respectively, and by 63% and 74% of patients receiving those doses of tocilizumab plus MTX, respectively, compared with 41% of patients receiving placebo plus MTX. Statistically significant ACR50 and ACR70 responses were observed in patients receiving combination therapy with either 4 mg/kg or 8 mg/kg of tocilizumab plus MTX (P < 0.05). A dose‐related reduction in the Disease Activity Score in 28 joints was observed from week 4 onward, in all patients except those receiving monotherapy with 2 mg/kg of tocilizumab. In the majority of patients who received 8 mg/kg of tocilizumab, the C‐reactive protein level/erythrocyte sedimentation rate normalized, while placebo plus MTX had little effect on these laboratory parameters. Tocilizumab was mostly well tolerated, with a safety profile similar to that of other biologic and immunosuppressive therapies. Alanine transaminase and aspartate transaminase levels followed a sawtooth pattern (rising and falling between infusions). There were moderate but reversible increases in the nonfasting total cholesterol and triglyceride levels and reversible reductions in the high‐density lipoprotein cholesterol and neutrophil levels. There were 2 cases of sepsis, both of which occurred in patients who were receiving combination therapy with 8 mg/kg of tocilizumab plus MTX.

Conclusion

These results indicate that targeted blockade of IL‐6 signaling is a highly efficacious and promising means of decreasing disease activity in RA.

     

Serum levels of matrix metalloproteinase 3 and macrophage colony‐stimulating factor 1 correlate with disease activity in ankylosing spondylitis

Objective

To assess the usefulness of measuring serum matrix metalloproteinase 3 (MMP‐3) and macrophage colony‐stimulating factor (M‐CSF) in patients with ankylosing spondylitis (AS).

Methods

Serum levels of MMP‐3 and M‐CSF were measured in AS patients who did and did not receive infliximab treatment. These were compared with those of 28 healthy subjects.

Results

In the group of AS patients not treated with biologics, both M‐CSF and MMP‐3 correlated with the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) values, but not with each other. Logistic regression analysis showed that MMP‐3 values were high in those with severely active disease. Infusions of infliximab in AS patients led to a significant decrease in the values of the BASDAI as well as the serum MMP‐3, but no change in the serum M‐CSF values.

Conclusion

MMP‐3 and M‐CSF are potentially useful markers of AS disease activity.

     

Tyr323‐dependent p38 activation is associated with rheumatoid arthritis and correlates with disease activity

Objective

The p38 MAPK is important in the pathogenic immune response in rheumatoid arthritis (RA). The p38 molecule can be activated through phosphorylation on Thr¹⁸⁰–Tyr¹⁸² by upstream MAPK kinases and via an alternative pathway through phosphorylation on Tyr³²³. We undertook this study to quantify the phosphorylation of Tyr³²³ p38 and of Thr¹⁸⁰–Tyr¹⁸² p38 on T cells from healthy controls and patients with RA or ankylosing spondylitis (AS) to identify variables associated with p38 phosphorylation and disease activity.

Methods

We measured p38 phosphorylation on Tyr³²³ and Thr¹⁸⁰–Tyr¹⁸² by flow cytometry and Western blotting on T cells from 30 control subjects, 33 AS patients, 30 patients with RA in remission, and 79 patients with active RA. We collected the clinical characteristics and analyzed correlations between clinical variables, the Disease Activity Score in 28 joints (DAS28), and p38 phosphorylation levels. Multivariate regression analysis was performed to identify variables associated with p38 phosphorylation on Tyr³²³ and Thr¹⁸⁰–Tyr¹⁸².

Results

Phosphorylation of p38 on Tyr³²³ was higher in T cells from patients with active RA (P = 0.008 versus healthy controls) than in patients with RA in remission or in patients with AS. Tyr³²³ p38 phosphorylation was associated with disease activity determined by the DAS28 (P = 0.017). Enhanced p38 phosphorylation was linked to Lck‐mediated activation of the Tyr³²³‐dependent pathway in the absence of upstream MAPKK activation.

Conclusion

Our results indicate that phosphorylation status on Tyr³²³ p38 correlates with RA disease activity and suggest that the Tyr³²³‐dependent pathway is an attractive target for down‐regulation of p38 activity in RA patients.

     

Methotrexate polyglutamate concentrations are not associated with disease control in rheumatoid arthritis patients receiving long‐term methotrexate therapy

Objective

There are limited data suggesting that methotrexate polyglutamate (MTXGlu) concentrations can guide MTX dosing in patients with rheumatoid arthritis (RA). The aim of this study was to define a therapeutic range of red blood cell (RBC) MTXGlu_n concentrations (where n refers to the number of glutamate groups), including threshold values for efficacy and adverse effects in patients receiving long‐term oral MTX treatment.

Methods

A cross‐sectional study of 192 patients receiving oral MTX was undertaken. Disease activity was assessed by the swollen and tender joint counts, the C‐reactive protein level, and the Disease Activity Score in 28 joints (DAS28). High disease activity was defined as a DAS28 of >3.2. A standardized questionnaire regarding common MTX adverse effects was completed.

Results

The MTX dosage was significantly higher in patients in whom the swollen joint count and DAS28 were higher. The MTXGlu₄, MTXGlu₅, MTXGlu_3–5, and MTXGlu_1–5 concentrations were significantly higher in patients with high disease activity. After correction for age, the estimated glomerular filtration rate, and the MTX dosage, the association remained significant for MTXGlu₅. RBC folate concentrations were significantly higher in the group with high disease activity. There was no association between any MTXGlu_n concentration and adverse effects.

Conclusion

In contrast to other studies, the results of the present study did not show a relationship between the MTXGlu_n concentration and reduced disease activity in patients with RA who were receiving long‐term MTX therapy. However, disease activity was influenced by the RBC folate level, which may be a more important factor than MTXGlu_n concentrations for disease control. In accordance with the findings of previous studies, we were unable to show a relationship between MTXGlu_n concentrations and adverse effects. Prospective studies will be important to determine whether there is a role for measuring MTXGlu_n concentrations in patients receiving long‐term treatment with MTX.

     

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

Objective

We undertook this study to evaluate safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of LY2439821, a humanized anti–interleukin‐17 (anti–IL‐17) monoclonal antibody, in a first in‐human trial in rheumatoid arthritis (RA) patients taking oral disease‐modifying antirheumatic drugs (DMARDs).

Methods

This randomized, double‐blind, placebo‐controlled study consisted of 2 parts. In part A, 20 patients received 1 intravenous (IV) dose of LY2439821 (0.06, 0.2, 0.6, or 2.0 mg/kg, escalating) or placebo followed by 8 weeks of evaluation. End points included safety, tolerability, and pharmacokinetics. In part B, 77 patients received 1 IV dose of LY2439821 (0.2, 0.6, or 2.0 mg/kg) or placebo every 2 weeks for a total of 5 doses, with a total evaluation period of 16 weeks. End points included safety, tolerability, pharmacokinetics/pharmacodynamics, and efficacy (Disease Activity Score in 28 joints [DAS28] and percentages of patients meeting American College of Rheumatology 20%, 50%, or 70% improvement criteria [achieving an ACR20, ACR50, or ACR70 response]). The primary efficacy end point was the DAS28 at week 10.

Results

Baseline characteristics were similar across all groups. Changes in the DAS28 were significantly greater in the 0.2 mg/kg, 2.0 mg/kg, and all‐LY2439821–combined groups (−2.3, −2.4, and −2.3, respectively) than in the placebo group (−1.7) at week 10 (P ≤ 0.05), and these differences were significant as early as week 1. Percentages of ACR20, ACR50, and ACR70 responses as well as improvements in the ACR core set of measures were greater in LY2439821‐treated patients than in placebo‐treated patients at multiple time points. There was no apparent dose‐response relationship in treatment‐emergent adverse events.

Conclusion

LY2439821 added to oral DMARDs improved signs and symptoms of RA, with no strong adverse safety signal noted. This first evaluation of LY2439821 supports neutralization of IL‐17 as a potential novel goal for the treatment of RA.