Reduced B lymphocyte and immunoglobulin levels after atacicept treatment in patients with systemic lupus erythematosus: Results of a multicenter,phase ib,double‐blind,placebo‐controlled,dose‐escalating trial

Objective

To assess the safety and tolerability of atacicept in patients with systemic lupus erythematosus (SLE) and the biologic effect of atacicept on B lymphocyte and immunoglobulin levels. Atacicept is a TACI‐Ig fusion protein that inhibits B cell stimulation by binding to B lymphocyte stimulator and a proliferation‐inducing ligand.

Methods

This phase Ib, double‐blind, placebo‐controlled, dose‐escalating trial comprised 6 cohorts of patients treated with atacicept or placebo in a 3:1 ratio of active drug to placebo (n = 8 per group; n = 7 in cohort 5). Cohorts 1–4 received a single subcutaneous dose of placebo or either 0.3 mg/kg, 1 mg/kg, 3 mg/kg, or 9 mg/kg of atacicept. Cohorts 5 and 6 received weekly doses of placebo or either 1 mg/kg or 3 mg/kg of atacicept for 4 weeks. Patients were followed up for 6 weeks (cohorts 1–4) or 9 weeks (cohorts 5 and 6). Patients with mild‐to‐moderate SLE were enrolled.

Results

Biologic activity of atacicept was demonstrated by dose‐dependent reductions in immunoglobulin levels and in mature and total B cell numbers. This effect was most pronounced in the repeated‐dose cohorts and was sustained throughout the followup period. There were no changes in the numbers of T cells, natural killer cells, or monocytes. Mild injection‐site reactions occurred more frequently among the atacicept group than the placebo group. There were no differences in the frequency or type of adverse events and no severe or serious adverse events in patients treated with atacicept.

Conclusion

Atacicept administered subcutaneously was well tolerated and demonstrated biologic activity consistent with the proposed mechanism of action.

     

Atacicept in patients with rheumatoid arthritis and an inadequate response to tumor necrosis factor antagonist therapy: Results of a phase II,randomized, placebo‐controlled,dose‐finding trial

Objective

To assess the efficacy, safety, and biologic activity of atacicept in patients with rheumatoid arthritis (RA) in whom the response to treatment with tumor necrosis factor antagonists was inadequate.

Methods

The Atacicept for Reduction of Signs and Symptoms in Rheumatoid Arthritis Trial (AUGUST I) was a multicenter, phase II, double‐blind, placebo‐controlled dose‐finding study involving 256 patients randomized 1:1:1:1 to receive atacicept (25 mg, 75 mg, or 150 mg) or placebo twice weekly for 4 weeks, then weekly for 21 weeks, with a 13‐week treatment‐free followup period (week 38). The primary end point was a response at week 26 according to the American College of Rheumatology criteria for 20% improvement in disease severity, using the C‐reactive protein level.

Results

No statistically significant differences were observed in the efficacy end points at week 26 (P = 0.410 for overall treatment effect). However, atacicept significantly reduced immunoglobulin and rheumatoid factor (RF) levels, but not anti–citrullinated protein antibody levels, in a dose‐dependent manner, with levels returning toward baseline values during followup. The effects of treatment on IgG‐RF and IgA‐RF were more pronounced than the effects on total IgG and IgA. Adverse events (AEs), including serious AEs, leading to withdrawal were more common among patients treated with atacicept compared with placebo. AEs were variable in nature, and no dose‐dependent trends were observed. The frequency of infection‐related AEs was similar across treatments. No notable effect of treatment on immunization status (protective versus nonprotective titer) was observed after initiation of treatment.

Conclusion

This study did not meet the primary efficacy end point. However, clear biologic activity consistent with the proposed mechanism of action was observed. The results suggest that decreasing the expression of RF may not be sufficient to induce clinical improvement in RA. The safety of atacicept was considered acceptable in this patient population.

     

Atacicept in patients with rheumatoid arthritis and an inadequate response to methotrexate: Results of a phase II,randomized, placebo‐controlled trial

Objective

To assess the efficacy, safety, and biologic activity of atacicept in tumor necrosis factor antagonist–naive patients with rheumatoid arthritis (RA) in whom the response to methotrexate treatment was inadequate.

Methods

In this phase II study, patients with active RA (n = 311) were randomized 1:1:1:1 to receive placebo, atacicept 150 mg weekly with or without a 4‐week loading period (twice‐weekly dosing), or open‐label adalimumab 40 mg every other week, for 25 weeks. The primary end point was 20% improvement in disease severity according to the American College of Rheumatology criteria, assessed using the C‐reactive protein level (ACR20‐CRP), at week 26. Secondary end points included additional assessments of efficacy, biologic activity, and safety.

Results

The proportion of patients meeting the primary end point (ACR20‐CRP response) did not differ significantly in the atacicept groups and the placebo group (46% in the placebo group, 45% in the atacicept loading group, and 58% in the atacicept nonloading group). In contrast, an ACR20‐CRP response was observed in 71% of patients in the adalimumab group (P < 0.001 versus placebo). ACR50‐CRP response rates were significantly higher in all active‐treatment groups compared with placebo, but ACR70‐CRP response rates were superior only in the adalimumab group. Atacicept treatment reduced the levels of serum IgG, IgA, and IgM rheumatoid factor and the levels of circulating mature B cells and plasma cells. The effects of treatment were similar with and without loading. Immunoglobulin levels returned toward baseline values during the treatment‐free followup period (week 38). The most frequent adverse events associated with atacicept represented common illnesses. No serious infections occurred among patients treated with atacicept.

Conclusion

The primary end point (ACR20‐CRP response) was not met despite significant biologic effects of atacicept that were consistent with its proposed mechanism of action. Modest effects of atacicept were seen for some secondary efficacy end points. Treatment with atacicept raised no new safety concerns.

     

Therapeutic efficacy of humanized recombinant anti–interleukin‐6 receptor antibody in children with systemic‐onset juvenile idiopathic arthritis

Objective

To investigate the safety and efficacy of a recombinant human anti–interleukin‐6 (anti–IL‐6) receptor monoclonal antibody (MRA) that indirectly inhibits the effects of IL‐6 in children with systemic‐onset juvenile idiopathic arthritis (JIA) refractory to high‐dose, long‐term corticosteroids.

Methods

An individual escalating‐dose trial was conducted in 11 children with active systemic‐onset JIA who met the inclusion criteria. All were first administered an intravenous dose of 2 mg/kg MRA. Each child without active inflammation was given a second identical dose 2 weeks later and a third identical dose 2 weeks after the second dose. Children with disease flares according to laboratory marker values received a 4‐mg/kg dose. Those without disease flares at this dose received a second 4‐mg/kg dose 2 weeks later and a third 4‐mg/kg dose 2 weeks after the second dose, while those with active inflammation received an additional 3 doses of 8 mg/kg MRA. Efficacy was evaluated every 2 weeks according to responses on the JIA core set of improvement criteria and the results of laboratory tests.

Results

MRA abruptly reduced disease activity in 10 of the 11 children, as assessed by the occurrence of febrile episodes, active arthritis, scores on the Childhood Health Assessment Questionnaire, and levels of acute‐phase reactants. However, levels of inflammatory reactants fluctuated until the proper MRA dose for each child was reached. Two weeks after the third fixed dose of MRA, 90.9% of all patients had a 30% improvement response, 90.9% had a 50% improvement response, and 63.6% had a 70% improvement response.

Conclusion

MRA treatment of children with active systemic disease results in clinical improvement and in normalized levels of acute‐phase reactants. MRA was safe and well tolerated and provided greater clinical benefit than conventional corticosteroids, considering the ill effects of IL‐6 and adverse events.

     

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.

     

Ofatumumab,a human anti‐CD20 monoclonal antibody,for treatment of rheumatoid arthritis with an inadequate response to one or more disease‐modifying antirheumatic drugs: Results of a randomized,double‐blind,placebo‐controlled,phase I/II study

Objective

To investigate the safety and efficacy of ofatumumab, a novel human anti‐CD20 monoclonal antibody (mAb), in patients with active rheumatoid arthritis (RA) whose disease did not respond to ≥1 disease‐modifying antirheumatic drug.

Methods

This combined phase I/II study investigated the safety and efficacy of 3 doses of ofatumumab. In part A (phase I), 39 patients received 2 intravenous (IV) infusions of ofatumumab (300 mg, 700 mg, or 1,000 mg) or placebo in a 4:1 ratio 2 weeks apart, using a specified premedication and infusion regimen. In part B (phase II), 225 patients received study treatment as per phase I in a 1:1:1:1 ratio. Safety was assessed by adverse events (AEs) and laboratory parameters. Efficacy was assessed by the American College of Rheumatology 20% criteria for improvement (ACR20), the Disease Activity Score in 28 joints, and the European League Against Rheumatism (EULAR) response criteria. B cell pharmacodynamics were also investigated.

Results

AEs were predominantly reported at the first infusion and were mostly mild to moderate in intensity. Rapid and sustained peripheral B cell depletion was observed in all dose groups. In phase II, patients in all ofatumumab dose groups had significantly higher ACR20 response rates (40%, 49%, and 44% for the 300 mg, 700 mg, and 1,000 mg doses, respectively) than did patients receiving placebo (11%) at week 24 (P < 0.001). Overall, 70% of patients receiving ofatumumab had a moderate or good response according to the EULAR criteria at week 24.

Conclusion

Our findings indicate that ofatumumab, administered as 2 IV infusions of doses up to 1,000 mg, is clinically effective in patients with active RA.

     

Reduced‐dose rituximab in rheumatoid arthritis: Efficacy depends on degree of B cell depletion

Objective

Studies comparing 500 mg rituximab and 1,000 mg rituximab doses in rheumatoid arthritis have yielded conflicting data on clinical outcomes, but in all of these studies a subgroup of patients has had excellent responses at the lower dose. Historically, it was considered that rituximab uniformly depleted B cells at both doses. Using highly sensitive assays, we have shown that B cell depletion is variable and predictive of clinical response. Using the same techniques, we undertook the present study to test the hypothesis that the level of B cell depletion, rather than the rituximab dose, determines clinical response.

Methods

Nineteen patients were treated with two 500‐mg infusions of rituximab, and 61 patients were treated with two 1,000‐mg infusions of rituximab. Highly sensitive flow cytometry was performed at 0, 2, 6, 14, and 26 weeks. European League Against Rheumatism (EULAR) response rates at 6 months were compared between patients with and those without complete depletion at each dose.

Results

The median B cell count was numerically higher at all time points following therapy in the 500 mg rituximab group. Twenty‐five percent of patients in the 500 mg rituximab group had complete depletion at 2 weeks, compared with 49% of those in the 1,000 mg rituximab group. Complete depletion at 2 weeks after treatment with 500 mg rituximab was associated with lower baseline preplasma cell counts (P = 0.047). Most patients responded after either dose, but response was related to B cell depletion. Notably, in the 500 mg rituximab group all patients with complete depletion had a EULAR good response (P = 0.011).

Conclusion

This pilot study suggests that the degree of B cell depletion, rather than the dose of rituximab, determines clinical response. It may be possible to predict which patients will respond to lower‐dose rituximab, and this may allow more cost‐effective treatment.

     

Early response to immunosuppressive therapy predicts good renal outcome in lupus nephritis: Lessons from long‐term followup of patients in the Euro‐Lupus Nephritis Trial

Objective

In the Euro‐Lupus Nephritis Trial (ELNT), 90 patients with lupus nephritis were randomly assigned to a high‐dose intravenous cyclophosphamide (IV CYC) regimen (6 monthly pulses and 2 quarterly pulses with escalating doses) or a low‐dose IV CYC regimen (6 pulses of 500 mg given at intervals of 2 weeks), each of which was followed by azathioprine (AZA). After a median followup of 41 months, a difference in efficacy between the 2 regimens was not observed. The present analysis was undertaken to extend the followup and to identify prognostic factors.

Methods

Renal function was prospectively assessed quarterly in all 90 patients except 5 who were lost to followup. Survival curves were derived using the Kaplan‐Meier method.

Results

After a median followup of 73 months, there was no significant difference in the cumulative probability of end‐stage renal disease or doubling of the serum creatinine level in patients who received the low‐dose IV CYC regimen versus those who received the high‐dose regimen. At long‐term followup, 18 patients (8 receiving low‐dose and 10 receiving high‐dose treatment) had developed permanent renal impairment and were classified as having poor long‐term renal outcome. We demonstrated by multivariate analysis that early response to therapy at 6 months (defined as a decrease in serum creatinine level and proteinuria <1 gm/24 hours) was the best predictor of good long‐term renal outcome.

Conclusion

Long‐term followup of patients from the ELNT confirms that, in lupus nephritis, a remission‐inducing regimen of low‐dose IV CYC followed by AZA achieves clinical results comparable with those obtained with a high‐dose regimen. Early response to therapy is predictive of good long‐term renal outcome.

     

Efficacy and safety of four doses of lumiracoxib versus diclofenac in patients with knee or hip primary osteoarthritis: A phase II,four‐week,multicenter, randomized,double‐blind,placebo‐controlled trial

Objective

To compare the efficacy and tolerability of the novel cyclooxygenase 2‐selective inhibitor lumiracoxib with placebo and diclofenac in osteoarthritis (OA).

Methods

Adults (n = 583) with knee or hip OA were randomized to receive for 4 weeks lumiracoxib 50, 100, or 200 mg twice daily or 400 mg once daily; placebo; or diclofenac 75 mg twice daily. Efficacy assessments included overall joint pain intensity and Western Ontario and McMaster Universities Osteoarthritis Index subscales; tolerability was evaluated by adverse event and physician reporting.

Results

All lumiracoxib doses were superior to placebo in relieving pain, improving stiffness, and improving physical function after 4 weeks. At study endpoint, pain relief was comparable among all lumiracoxib dosages and similar to diclofenac. Lumiracoxib tolerability was superior to diclofenac and comparable to placebo.

Conclusion

Lumiracoxib provides predictable and sustained relief from pain, stiffness, and impaired physical function in OA. Lumiracoxib shows clinically comparable efficacy and superior tolerability to diclofenac.

     

Safety and pharmacodynamics of rontalizumab in patients with systemic lupus erythematosus: Results of a phase I,placebo‐controlled,double‐blind,dose‐escalation study

Objective

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the presence of autoantibodies and inflammation in multiple organ systems. Elevation of messenger RNA levels of interferon (IFN)–regulated genes (IRGs) has been described in the peripheral blood of SLE patients and has been associated with disease activity. The safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of rontalizumab, a humanized IgG1 monoclonal antibody that neutralizes IFNα, were assessed in a phase I dose‐escalation study of single and repeat doses of rontalizumab in adults with mildly active SLE. The present report describes the safety results and the impact of rontalizumab on expression of IRGs, IFN‐inducible proteins, and autoantibodies.

Methods

Patients were enrolled into dose groups ranging from 0.3 to 10 mg/kg, administered via intravenous (IV) or subcutaneous routes. Expression levels of 7 IRGs and IFN‐inducible serum proteins were monitored as potential biomarkers for the PD activity of rontalizumab.

Results

An acceptable safety profile was demonstrated for rontalizumab in patients with SLE. Prespecified criteria for dose‐limiting toxicity were not met. The incidence of serious adverse events was comparable across cohorts. The PK properties were as expected for an IgG1 monoclonal antibody and were proportional to dose. Following administration of rontalizumab, a rapid decline in the expression of IRGs was observed in the 3 mg/kg and 10 mg/kg IV cohorts, and this effect could be sustained with repeat dosing. There was no apparent decline in the levels of IFN‐inducible proteins or levels of anti–double‐stranded DNA and anti–extractable nuclear antigen autoantibodies following treatment with rontalizumab.

Conclusion

The preliminary safety, PK profile, and observed PD effects of rontalizumab support further evaluation of its safety and efficacy in SLE.

     

Canakinumab for the treatment of acute flares in difficult‐to‐treat gouty arthritis: Results of a multicenter,phase II,dose‐ranging study

Objective

To assess the efficacy and tolerability of canakinumab, a fully human anti–interleukin‐1β monoclonal antibody, for the treatment of acute gouty arthritis.

Methods

In this 8‐week, single‐blind, double‐dummy, dose‐ranging study, patients with acute gouty arthritis whose disease was refractory to or who had contraindications to nonsteroidal antiinflammatory drugs and/or colchicine were randomized to receive a single subcutaneous dose of canakinumab (10, 25, 50, 90, or 150 mg; n = 143) or an intramuscular dose of triamcinolone acetonide (40 mg; n = 57). Patients assessed pain using a 100‐mm visual analog scale.

Results

Seventy‐two hours after treatment, a statistically significant dose response was observed for canakinumab. All canakinumab doses were associated with numerically less pain than triamcinolone acetonide; thus, a dose with equivalent efficacy to triamcinolone acetonide 72 hours after treatment could not be determined. The reduction from baseline in pain intensity with canakinumab 150 mg was greater than with triamcinolone acetonide 24, 48, and 72 hours after treatment (differences of −11.5 mm [P = 0.04], −18.2 mm [P = 0.002], and −19.2 mm [P < 0.001], respectively), and 4, 5, and 7 days after treatment (all P < 0.05). Canakinumab significantly reduced the risk of recurrent flares versus triamcinolone acetonide (P ≤ 0.01 for all doses) (relative risk reduction 94% for canakinumab 150 mg versus triamcinolone acetonide). The overall incidence of adverse events was similar for canakinumab (41%) and triamcinolone acetonide (42%); most were mild or moderate in severity.

Conclusion

Our findings indicate that canakinumab 150 mg provides rapid and sustained pain relief in patients with acute gouty arthritis, and significantly reduces the risk of recurrent flares compared with triamcinolone acetonide.

     

B cell activation biomarkers as predictive factors for the response to rituximab in rheumatoid arthritis: A six‐month,national, multicenter,open‐label study

Objective

To examine whether serum B cell markers can predict response to rituximab, a B cell–depleting monoclonal antibody, in patients with refractory rheumatoid arthritis (RA).

Methods

This rituximab re‐treatment dose study (SMART [eSsai MAbthera sur la dose de Re‐Traitement]) involved 208 patients with refractory RA. Serum markers of B cell activation (anti–cyclic citrullinated peptide [anti‐CCP] antibodies, rheumatoid factor [RF], serum IgG, IgA, and IgM levels, serum κ and λ free light chains, and serum BAFF) were assessed before the first rituximab cycle (1,000 mg on days 1 and 15). Univariate and multivariate analyses were performed to identify factors associated with a European League Against Rheumatism (EULAR) response at 24 weeks.

Results

There were 149 responders (72%). Two baseline factors were associated with a EULAR response at 24 weeks in multivariate analysis: the presence of anti‐CCP antibodies or RF (odds ratio 3.5 [95% confidence interval 1.6–7.6]) and a serum IgG concentration above normal (odds ratio 2.11 [95% confidence interval 1.02–4.33]), with synergy between them (odds ratio 6.0 [95% confidence interval 2.2–16.2]).

Conclusion

The presence of RF or anti‐CCP antibodies and elevated IgG are 2 simple biomarkers that can be used routinely before therapy to predict response to rituximab in patients with refractory RA.

     

Treatment of rheumatoid arthritis with anakinra,a recombinant human interleukin‐1 receptor antagonist,in combination with methotrexate: Results of a twenty‐four–week,multicenter, randomized,double‐blind,placebo‐controlled trial

Objective

To evaluate the efficacy and safety of anakinra in combination with methotrexate (MTX) in patients with active rheumatoid arthritis (RA).

Methods

Patients with moderate‐to‐severe active RA who were receiving MTX for 6 consecutive months, with stable doses for ≥3 months (those with disease duration of >6 months but <12 years) were randomized into 6 groups: placebo or 0.04, 0.1, 0.4, 1.0, or 2.0 mg/kg of anakinra administered in a single, daily, subcutaneous injection. The primary efficacy end point was the proportion of subjects who met the American College of Rheumatology 20% improvement criteria (attained an ACR20 response) at week 12.

Results

A total of 419 patients were randomized in the study. Patient demographics and disease status were similar in the 6 treatment groups. The ACR20 responses at week 12 in the 5 active treatment plus MTX groups demonstrated a statistically significant (P = 0.001) dose‐response relationship compared with the ACR20 response in the placebo plus MTX group. The ACR20 response rate in the anakinra 1.0‐mg/kg (46%; P = 0.001) and 2.0‐mg/kg (38%; P = 0.007) dose groups was significantly greater than that in the placebo group (19%). The ACR20 responses at 24 weeks were consistent with those at 12 weeks. Similar improvements in anakinra‐treated subjects were noted in individual ACR components, erythrocyte sedimentation rate, onset of ACR20 response, sustainability of ACR20 response, and magnitude of ACR response. Anakinra was safe and well tolerated. Injection site reaction was the most frequently noted adverse event, and this led to premature study withdrawal in 7% (1.0‐mg/kg group) to 10% (2.0‐mg/kg group) of patients receiving higher doses.

Conclusion

In patients with persistently active RA, the combination of anakinra and MTX was safe and well tolerated and provided significantly greater clinical benefit than MTX alone.

     

Impact of synthetic and biologic disease‐modifying antirheumatic drugs on antibody responses to the AS03‐adjuvanted pandemic influenza vaccine: A prospective,open‐label,parallel‐cohort,single‐center study

Objective

To identify the determinants of antibody responses to adjuvanted split influenza A (H1N1) vaccines in patients with inflammatory rheumatic diseases.

Methods

One hundred seventy‐three patients (82 with rheumatoid arthritis, 45 with spondylarthritis, and 46 with other inflammatory rheumatic diseases) and 138 control subjects were enrolled in this prospective single‐center study. Controls received 1 dose of adjuvanted influenza A/09/H1N1 vaccine, and patients received 2 doses of the vaccine. Antibody responses were measured by hemagglutination inhibition assay before and 3–4 weeks after each dose. Geometric mean titers (GMTs) and rates of seroprotection (GMT ≥40) were calculated. A comprehensive medical questionnaire was used to identify the determinants of vaccine responses and adverse events.

Results

Baseline influenza A/09/H1N1 antibody levels were low in patients and controls (seroprotection rates 14.8% and 14.2%, respectively). A significant response to dose 1 was observed in both groups. However, the GMT and the seroprotection rate remained significantly lower in patients (GMT 146 versus 340, seroprotection rate 74.6% versus 87%; both P < 0.001). The second dose markedly increased antibody titers in patients, with achievement of a similar GMT and seroprotection rate as elicited with a single dose in healthy controls. By multivariate regression analysis, increasing age, use of disease‐modifying antirheumatic drugs (DMARDs) (except hydroxychloroquine and sulfasalazine), and recent (within 3 months) B cell depletion treatment were identified as the main determinants of vaccine responses; tumor necrosis factor α antagonist treatment was not identified as a major determinant. Immunization was well tolerated, without any adverse effect on disease activity.

Conclusion

DMARDs exert distinct influences on influenza vaccine responses in patients with inflammatory rheumatic diseases. Two doses of adjuvanted vaccine were necessary and sufficient to elicit responses in patients similar to those achieved with 1 dose in healthy controls.

     

Development of the tight‐skin phenotype in immune‐deficient mice

Objective

To determine if cutaneous thickening, a major phenotypic feature of the tight‐skin (Tsk) mutation, could develop in an immune‐deficient mouse.

Methods

Experimental crosses among different strains of mice were conducted to create mice that were genetically Tsk/+, and that were also homozgyous for a mutation at the Prkdc^scid locus and thus lacked mature T and B lymphocytes. Skin samples prepared from experimental and control genotypic groups of mice were evaluated for skin thickness.

Results

The data showed that the Tsk/+ mice developed the Tsk phenotype in the absence of a functional immune system.

Conclusion

Mature T and B cells are not required for the development of the cutaneous thickening in mice carrying the Tsk mutation.

     

Efficacy and tolerability of a selective α2C‐adrenergic receptor blocker in recovery from cold‐induced vasospasm in scleroderma patients: A single‐center,double‐blind,placebo‐controlled,randomized crossover study

Objective

OPC‐28326 is a selective α‐adrenergic antagonist with preferential binding to the α_2C‐adrenergic receptor (α_2C‐AR) subtype. This study observed the effect of OPC‐28326 on skin temperature and digital blood flow following an acute cold challenge in patients with Raynaud's phenomenon secondary to scleroderma.

Methods

The study was designed as a single‐center, double‐blind, placebo‐controlled, randomized, 3‐period crossover study of OPC‐28326 (oral doses of 10 mg or 40 mg) or placebo. The primary outcome measures were the time to recover 50% and 70% of the fall (induced by cold challenge) in baseline digital skin temperature.

Results

Twelve of 13 enrolled patients completed the study. The mean time to achieve 50% and 70% recovery of the change in prechallenge digital skin temperature was shorter after the OPC‐28326 40‐mg dose than after placebo (50% recovery at 5.8 minutes versus 10.0 minutes [P = 0.02]; 70% recovery at 13.8 minutes versus 19.5 minutes [P = 0.01]). These recovery times tended to be shorter in the 10 mg OPC‐28326 group as well, but the difference versus placebo was not significant (50% recovery at 9.0 minutes versus 10.0 minutes [P = 0.65]; 70% recovery at 15.3 minutes versus 19.5 minutes [P = 0.07]). Total digital blood flow tended to be lower prior to the cold challenge and after administration of 40 mg OPC‐28326, as compared with that after placebo, but the difference was not significant. Symptoms that were potentially drug‐related were reported more frequently with 40 mg OPC‐28326 than with 10 mg OPC‐28326 or with placebo, but none were serious or sustained.

Conclusion

OPC‐28326 at doses of 10 mg and 40 mg was well tolerated during this study. The shorter time to skin temperature recovery after 40 mg OPC‐28326 suggests that selective α_2C‐AR blockade improves digital skin perfusion during recovery from cooling in patients with Raynaud's phenomenon secondary to scleroderma.

     

The relationship of serum infliximab concentrations to clinical improvement in rheumatoid arthritis: Results from ATTRACT,a multicenter,randomized, double‐blind,placebo‐controlled trial

Objective

To investigate the relationship between serum concentrations of infliximab, a monoclonal anti–tumor necrosis factor α antibody, and clinical improvement from infliximab therapy for rheumatoid arthritis (RA).

Methods

Multiple blood samples were obtained from each of 428 subjects with active RA who were enrolled in a multicenter, randomized, double‐blind, placebo‐controlled trial (ATTRACT [Anti–Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy]) evaluating the clinical efficacy and safety of infliximab therapy. Serum levels of infliximab were measured by enzyme‐linked immunosorbent assay. Dose‐response trends were analyzed using generalized logistic regression techniques. Pharmacokinetic modeling was used to predict the serum concentrations of infliximab after simulated infusions using doses and dosing intervals not evaluated in the trial.

Results

At week 54, 26% of the subjects receiving 3 mg/kg infliximab every 8 weeks had undetectable trough serum levels of infliximab, a significantly greater proportion than in the other 3 treatment groups (P < 0.001). Increased magnitude of American College of Rheumatology (ACR) response (measured by the ACR‐N, a continuous measure of clinical improvement derived from the ACR 20% response criteria) and greater reduction from baseline in serum C‐reactive protein level were both associated with higher trough serum concentrations of infliximab (P < 0.001), as was less progression of radiographic joint damage (P = 0.004), providing support for a dose‐response relationship. Pharmacokinetic models predicted that decreasing the dosing interval from 8 weeks to 6 weeks would yield higher trough serum levels of infliximab than increasing the dose by 100 mg.

Conclusion

These results suggest that some patients with RA may benefit from infliximab given at higher doses than 3 mg/kg or more frequently than every 8 weeks.

     

Treatment of giant cell arteritis using induction therapy with high‐dose glucocorticoids: A double‐blind,placebo‐controlled,randomized prospective clinical trial

Objective

Glucocorticoid (GC) therapy for giant cell arteritis (GCA) is effective but requires prolonged administration, resulting in adverse side effects. The goal of the current study was to test the hypothesis that induction treatment with high‐dose pulse intravenous (IV) methylprednisolone permits a shorter course of therapy.

Methods

Twenty‐seven patients with biopsy‐proven GCA were enrolled in a randomized, double‐blind, placebo‐controlled study to receive IV methylprednisolone (15 mg/kg of ideal body weight/day) or IV saline for 3 consecutive days. All patients were started on 40 mg/day prednisone and followed the same tapering schedule as long as disease activity was controlled. The numbers of patients with disease in remission after 36, 52, and 78 weeks of treatment and taking ≤5 mg/day prednisone were compared. Cumulative prednisone dose, number of relapses, and development of adverse GC effects were assessed.

Results

Ten of the 14 IV GC–treated patients, but only 2 of 13 control patients, were taking ≤5 mg/day prednisone at 36 weeks (P = 0.003). This difference was maintained; there was a higher number of sustained remissions after discontinuation of treatment in the IV GC–treated group and a lower median daily dose of prednisone at 78 weeks (P = 0.0004). The median cumulative dose of oral prednisone, excluding the IV GC dose, was 5,636 mg in the IV GC–treated group compared with 7,860 mg in the IV saline–treated group (P = 0.001).

Conclusion

Initial treatment of GCA with IV GC pulses allowed for more rapid tapering of oral GCs and had long‐term benefits, with a higher frequency of patients experiencing sustained remission of their disease after discontinuation of treatment.

     

Safety and efficacy of ocrelizumab in patients with rheumatoid arthritis and an inadequate response to methotrexate: Results of a forty‐eight–week randomized,double‐blind,placebo‐controlled,parallel‐group phase III trial

Objective

To evaluate the efficacy and safety of treatment with ocrelizumab plus methotrexate (MTX) in patients with active rheumatoid arthritis (RA) and an inadequate response to MTX.

Methods

STAGE was a phase III randomized, double‐blind, parallel‐group international study to evaluate the safety and efficacy of ocrelizumab compared with placebo in patients with active RA continuing MTX treatment. Patients receiving stable doses of MTX were randomized to receive 2 infusions of placebo (n = 320), ocrelizumab 200 mg (n = 343), or ocrelizumab 500 mg (n = 343) on days 1 and 15 as well as weeks 24 and 26. Coprimary end points were the proportion of patients with an American College of Rheumatology 20% improvement criteria (ACR20) response at weeks 24 and 48. Secondary end points included the change from baseline in the modified Sharp/van der Heijde score (SHS) and the ACR50/70 responses.

Results

The ACR20 response rates were 35.7% in the placebo group, 56.9% in the ocrelizumab 200 mg group, and 54.5% in the ocrelizumab 500 mg group at 24 weeks, and 27.6%, 58.3%, and 62.1%, respectively, at 48 weeks (P < 0.0001 versus placebo for each dose at both time points). At week 48, both of the ocrelizumab doses improved the ACR50 and ACR70 response rates 3‐fold as compared with placebo and showed a statistically significant (P < 0.0001) reduction in joint damage progression relative to placebo (mean change in SHS reduced by 85% and 100% for the 200‐mg and 500‐mg doses, respectively). Rates of serious infection were comparable in the placebo (3.48 per 100 patient‐years) and ocrelizumab 200 mg (3.54 per 100 patient‐years) groups but were elevated in the ocrelizumab 500 mg group (8.66 per 100 patient‐years).

Conclusion

With both ocrelizumab doses, the primary end point was met, and the signs and symptoms of RA were significantly improved at weeks 24 and 48. Ocrelizumab also significantly inhibited the progression of joint damage. A higher rate of serious infections was observed with 500 mg of ocrelizumab as compared with ocrelizumab 200 mg or placebo.