Humoral responses after influenza vaccination are severely reduced in patients with rheumatoid arthritis treated with rituximab

Objective

For patients with rheumatoid arthritis (RA), yearly influenza vaccination is recommended. However, its efficacy in patients treated with rituximab is unknown. The objectives of this study were to investigate the efficacy of influenza vaccination in RA patients treated with rituximab and to investigate the duration of the possible suppression of the humoral immune response following rituximab treatment. We also undertook to assess the safety of influenza vaccination and the effects of previous influenza vaccination.

Methods

Trivalent influenza subunit vaccine was administered to 23 RA patients who had received rituximab (4–8 weeks after rituximab for 11 patients [the early rituximab subgroup] and 6–10 months after rituximab for 12 patients [the late rituximab subgroup]), 20 RA patients receiving methotrexate (MTX), and 29 healthy controls. Levels of antibodies against the 3 vaccine strains were measured before and 28 days after vaccination using hemagglutination inhibition assay. The Disease Activity Score in 28 joints (DAS28) was used to assess RA activity.

Results

Following vaccination, geometric mean titers (GMTs) of antiinfluenza antibodies significantly increased for all influenza strains in the MTX‐treated group and in healthy controls, but for no strains in the rituximab‐treated group. However, in the late rituximab subgroup, a rise in GMT for the A/H3N2 and A/H1N1 strains was demonstrated, in the absence of a repopulation of CD19+ cells at the time of vaccination. Seroconversion and seroprotection occurred less often in the rituximab‐treated group than in the MTX‐treated group for the A/H3N2 and A/H1N1 strains, while seroprotection occurred less often in the rituximab‐treated group than in the healthy controls for the A/H1N1 strain. Compared with unvaccinated patients in the rituximab‐treated group, previously vaccinated patients in the rituximab‐treated group had higher pre‐ and postvaccination GMTs for the A/H1N1 strain. The DAS28 did not change after vaccination.

Conclusion

Rituximab reduces humoral responses following influenza vaccination in RA patients, with a modestly restored response 6–10 months after rituximab administration. Previous influenza vaccination in rituximab‐treated patients increases pre‐ and postvaccination titers. RA activity was not influenced.

     

Studies of cell‐mediated immune responses to influenza vaccination in systemic lupus erythematosus

Objective

Both antibody and cell‐mediated responses are involved in the defense against influenza. In patients with systemic lupus erythematosus (SLE), a decreased antibody response to subunit influenza vaccine has been demonstrated, but cell‐mediated responses have not yet been assessed. This study was therefore undertaken to assess cell‐mediated responses to influenza vaccination in patients with SLE.

Methods

Fifty‐four patients with SLE and 54 healthy control subjects received subunit influenza vaccine. Peripheral blood mononuclear cells and sera were obtained before and 1 month after vaccination. Cell‐mediated responses to A/H1N1 and A/H3N2 vaccines were evaluated using an interferon‐γ (IFNγ) enzyme‐linked immunospot assay and flow cytometry. Antibody responses were measured using a hemagglutination inhibition test.

Results

Prior to vaccination, patients with SLE had fewer IFNγ spot‐forming cells against A/H1N1 compared with control subjects and a lower frequency of IFNγ‐positive CD8+ T cells. After vaccination, the number of IFNγ spot‐forming cells increased in both patients and control subjects, although the number remained lower in patients. In addition, the frequencies of CD4+ T cells producing tumor necrosis factor and interleukin‐2 were lower in patients after vaccination compared with healthy control subjects. As expected for a subunit vaccine, vaccination did not induce a CD8+ T cell response. For A/H3N2‐specific responses, results were comparable. Diminished cell‐mediated responses to influenza vaccination were associated with the use of prednisone and/or azathioprine. The increase in A/H1N1‐specific and A/H3N2‐specific antibody titers after vaccination was lower in patients compared with control subjects.

Conclusion

In addition to a decreased antibody response, cell‐mediated responses to influenza vaccination are diminished in patients with SLE, which may reflect the effects of the concomitant use of immunosuppressive drugs. This may render these patients more susceptible to (complicated) influenza infections.

     

Validity of self‐administered quality of well‐being scale in musculoskeletal disease

Objective

To evaluate the self‐administered Quality of Well‐Being (QWB‐SA) Scale for patients with rheumatic diseases.

Methods

Family medicine patients (n = 562) and rheumatology patients (n = 334) were assessed using the following tools: QWB‐SA, Health Assessment Questionnaire (HAQ), Arthritis Impact Measurement Scales (AIMS), and Rapid Assessment of Disease Activity in Rheumatology (RADAR).

Results

Patients with arthritis had significantly lower QWB‐SA scores and significantly higher HAQ scores than family medicine patients with and without adjustment for covariates. The QWB‐SA was significantly associated with quartiles from the RADAR, AIMS, and HAQ, providing evidence for the validity of the generic measure in patients with arthritis. Discriminant function analysis was used to create an arthritis‐specific scoring system for the QWB‐SA. Analyses demonstrated systematic relationships between the Quality of Well‐Being arthritis composite and the disease‐specific RADAR, AIMS, and HAQ.

Conclusions

Evidence supports the validity of the QWB‐SA for patients with rheumatic diseases. QWB‐SA items can be used to calculate an arthritis‐specific score. The QWB‐SA can be used to gain generic information for cost‐utility analysis and disease‐specific outcomes information for patients with arthritis.

     

Epistatic effect of plasminogen activator inhibitor 1 and β‐Fibrinogen genes on risk of glomerular microthrombosis in lupus nephritis: Interaction with environmental/clinical factors

Objective

Glomerular microthrombosis (GMT) is not uncommon in lupus nephritis and has been associated with active renal injury and progressive kidney destruction. We undertook this study to determine whether genetic variations of hemostasis factors, such as plasminogen activator inhibitor 1 (PAI‐1) and fibrinogen, affect the risk of GMT.

Methods

A cross‐sectional cohort of 101 lupus nephritis patients with or without GMT was genotyped for PAI‐1 –675 4G/5G and β‐fibrinogen (FGB) –455 G/A gene polymorphisms and analyzed.

Results

PAI‐1 4G/4G homozygotes and FGB A allele carriers were both at increased risk for GMT. When the data were stratified for both gene polymorphisms, an epistatic effect was detected. The PAI‐1 4G/4G genotype was found to predispose to GMT not equally in all lupus nephritis patients, but only in FGB A allele carriers. Likewise, the association between the FGB A allele and GMT was restricted to lupus nephritis patients homozygous for the PAI‐1 4G allele. This epistatic effect was revalidated by the multifactor dimensionality reduction (MDR) analysis and further assessed by incorporating a variety of environmental and clinical factors into the MDR analysis. The most parsimonious model that had a cross‐validation consistency of 100% included joint effects of PAI‐1 and FGB gene polymorphisms and anticardiolipin antibody (aCL) status and yielded the best prediction of GMT, with 66.6% accuracy.

Conclusion

Our findings suggest that risk of GMT in lupus nephritis is attributable, at least in part, to an epistatic effect of PAI‐1 and FGB genes, likely via an interaction with environmental/clinical factors, such as aCL.

     

Magnitude and characteristics of arthritis and other rheumatic conditions on ambulatory medical care visits,United States, 1997

Objective

To describe ambulatory medical care utilization, defined to exclude injury‐related visits, for persons with arthritis and other rheumatic conditions.

Methods

National estimates, rates, and other characteristics of ambulatory care visits were calculated from a national sample of patient visits to physician offices and acute care hospital outpatient and emergency departments.

Results

An estimated 36.5 million ambulatory care visits were related to arthritis and other rheumatic conditions. Visit rates increased with age and, overall, were twice as high among women as men. Rates of visits by race varied by ambulatory care setting. Soft tissue disorders (9.3 million), osteoarthritis (7.1 million), nonspecific joint pain/effusion (7.0 million), and rheumatoid arthritis (3.9 million) were the most common diagnoses.

Conclusions

Arthritis and other rheumatic conditions account for about as many ambulatory care visits as cardiovascular disease or essential hypertension. These visits serve as excellent opportunities to counsel patients regarding prevention messages for arthritis.

     

Pre‐appointment management of new patient referrals in rheumatology: a key strategy for improving health care delivery

Objective

To analyze the impact of a rheumatologist reviewing each newly referred patient's medical records prior to scheduling an appointment (pre‐appointment management).

Methods

All 279 new patients who were referred in the 6 months after initiating pre‐appointment management were studied. The authors reviewed systemwide patient records, appointment intake information, visit schedules, physician comments, and patient complaint data.

Results

Only 59% of referred patients required a rheumatology consultation for appropriate care. Some problems were rapidly resolved without consultation. In some cases, other specialty consultation or continuing prior care was considered to be more appropriate. The latter alternative did not compromise these patients' outcomes. Practice access and efficiency were improved. Profitability was maintained. Referring physicians and patients were generally accepting and cooperative.

Conclusion

New patient pre‐appointment management should be a key strategy for reducing health care costs, addressing personnel shortage, and improving access to and coordination of rheumatic disease care.

     

Epstein‐Barr virus load in the peripheral blood of patients with rheumatoid arthritis: Accurate quantification using real‐time polymerase chain reaction

Objective

To determine whether patients with rheumatoid arthritis (RA) have elevated Epstein‐Barr virus (EBV) load in their peripheral blood mononuclear cells (PBMCs) and whether it is correlated with the HLA–DR genes they express, we developed an accurate EBV DNA quantitative assay using real‐time polymerase chain reaction (PCR) with fluorescent probes.

Methods

We studied the EBV DNA load in the PBMCs of 84 patients with RA, 69 normal controls, and 22 patients with rheumatic conditions other than RA. A 214‐bp segment from the long internal repeat of EBV was amplified from 500 ng of PBMC DNA (150,000 cells) and quantified by real‐time PCR with fluorescent probes.

Results

We demonstrated that in patients with RA, the EBV DNA load in PBMCs is increased almost 10‐fold compared with that in normal controls. The EBV load is stable over time and is not obviously influenced by disease‐modifying antirheumatic drugs or HLA–DR.

Conclusion

Patients with RA have elevated EBV load in their peripheral blood.

     

The lifetime risk of adult‐onset rheumatoid arthritis and other inflammatory autoimmune rheumatic diseases

Objective

Understanding of the personal risks for rheumatoid arthritis (RA) and other rheumatic diseases remains poor, despite advances in knowledge with regard to their pathogenesis, therapeutics, and clinical impact, in part because the personal lifetime risk of developing these diseases is unknown. This study was undertaken to estimate the lifetime risk of RA, as well as other inflammatory autoimmune rheumatic diseases, including systemic lupus erythematosus, psoriatic arthritis, polymyalgia rheumatica (PMR), giant cell arteritis, ankylosing spondylitis, and Sjögren's syndrome, and to provide an overall estimate of the risk of developing inflammatory autoimmune rheumatic disease over a lifetime.

Methods

Using the incidence rates obtained from our population‐based studies of rheumatic diseases among residents of Olmsted County, Minnesota, and mortality rates from life tables for the general population, we estimated the sex‐specific lifetime risk of rheumatic disease.

Results

The lifetime risk of RA developing in US adults was 3.6% for women and 1.7% for men, and the lifetime risk of rheumatoid factor–positive RA was 2.4% for women and 1.1% for men. The second most common inflammatory autoimmune rheumatic disease was PMR, with a lifetime risk of 2.4% for women and 1.7% for men. The overall lifetime risk of inflammatory autoimmune rheumatic disease was 8.4% for women and 5.1% for men.

Conclusion

One in 12 women and 1 in 20 men will develop an inflammatory autoimmune rheumatic disease during their lifetime. These results can serve as useful guides in counseling patients regarding their lifetime risk of these conditions and have important implications regarding disease awareness campaigns.

     

Rheumatology patients' use of complementary therapies: Results from a one‐year longitudinal study

Objective

To examine the natural history of complementary and alternative medicine (CAM) use and its impact on outcomes within a cohort of rheumatology patients.

Methods

Consecutive patients were recruited from 3 university and 3 private rheumatology practices. Baseline chart reviews provided demographic information and rheumatic diagnoses. Patients answered questions on CAM use and health status during 1 year. We identified correlates of 4 CAM usage patterns (started, maintained, stopped, nonuse) and compared outcomes among these groups.

Results

Of 232 baseline participants, 203 (87%) and 177 (76%) responded to the 6‐ and 12‐month surveys. In each survey, approximately 34% reported currently using CAM. During the year, 44% of patients remained nonusers whereas 12% started, 22% maintained, and 22% stopped use. The most frequent reasons for stopping CAM were lack of effectiveness and expense. CAM users and nonusers had no difference in outcomes.

Conclusions

Arthritis patients' usage behavior varied substantially, but CAM use was not associated with a difference in outcomes.

     

Randomized comparison of a multidisciplinary job‐retention vocational rehabilitation program with usual outpatient care in patients with chronic arthritis at risk for job loss

Objective

Work disability is a major consequence of inflammatory rheumatic conditions. Evidence regarding the effectiveness of interventions aimed at the prevention or reduction of work disability in rheumatic diseases is limited. We conducted a randomized controlled trial to investigate the effectiveness of a multidisciplinary job‐retention vocational rehabilitation (VR) program in patients with a rheumatic condition who were at risk for job loss.

Methods

A total of 140 patients with a chronic rheumatic condition were randomly assigned to either a multidisciplinary job‐retention VR program (n = 74) or usual outpatient care (UC) (n = 66). Patients in the VR group were assessed and guided by a multidisciplinary team, whereas patients in the UC group received care as initiated by their rheumatologist, supplemented with written information. The main outcome measure was the occurrence of job loss (complete work disability or unemployment); additional outcome measures included job satisfaction, pain, functional status, emotional status, and quality of life.

Results

There was no difference between the 2 groups regarding the proportion of patients having lost their job at any time point, with 24% and 23% of the patients in the VR and UC groups, respectively, having lost their job after 24 months. Over the total period of 24 months, patients in the VR group had a significantly greater improvement of the fatigue visual analog scale and of emotional status (all P values < 0.05).

Conclusion

A job‐retention VR program did not reduce the risk of job loss but improved fatigue and mental health in patients with chronic rheumatic diseases at risk for job loss.

     

Atacicept in patients with rheumatoid arthritis: Results of a multicenter,phase ib,double‐blind,placebo‐controlled,dose‐escalating,single‐ and repeated‐dose study

Objective

Atacicept is a recombinant fusion protein that binds and neutralizes B lymphocyte stimulator and a proliferation‐inducing ligand. The purpose of this study was to investigate the tolerability, pharmacokinetics, and pharmacodynamics of atacicept treatment in patients with rheumatoid arthritis (RA) and to collect exploratory data on clinical outcomes.

Methods

In this multicenter, phase Ib, randomized, placebo‐controlled, dose‐escalating trial, 73 patients were enrolled into 6 escalating‐dose cohorts. Patients received atacicept or placebo as single doses (70, 210, or 630 mg) or as repeated doses given at 2‐week intervals (3 doses of 70 mg, 3 doses of 210 mg, or 7 doses of 420 mg), followed by 10 weeks of trial assessments, with a followup assessment at 3 months after the final dose.

Results

Atacicept was well tolerated, with few differences between treatment groups and no obvious safety concerns. The pharmacokinetics profile was nonlinear, but was consistent and predictable across all doses and regimens. Treatment‐related decreases in immunoglobulin (particularly IgM) and rheumatoid factor levels were evident, and a clear decrease in anti–citrullinated protein antibodies was observed in the cohort that received 7 doses of 420 mg. The B cell response was biphasic, with an initial transient increase (dominated by memory B cells) followed by a dose‐related decrease (dominated by mature B cells). Clinical assessments showed trends toward improvement with the 3‐month treatment. Little effect on the erythrocyte sedimentation rate or C‐reactive protein levels was seen.

Conclusion

Atacicept was well tolerated both systemically and locally. The results demonstrated that the biologic activity of atacicept was consistent with its mechanism of action.

     

Benefit of an extract of Tripterygium Wilfordii Hook F in patients with rheumatoid arthritis: A double‐blind,placebo‐controlled study

Objective

To examine the safety and efficacy of an extract of Tripterygium wilfordii Hook F (TWHF) in the treatment of patients with rheumatoid arthritis (RA).

Methods

An ethanol/ethyl acetate extract from the roots of TWHF was prepared and used in a prospective, double‐blind, placebo‐controlled study in patients with longstanding RA in whom conventional therapy had failed. Patients were randomly assigned to receive either placebo or low‐dose (180 mg/day) or high‐dose (360 mg/day) extract for 20 weeks, followed by an open‐label extension period. Clinical responses were defined as 20% improvement in disease activity according to the American College of Rheumatology criteria. Side effects were actively queried and recorded at each visit.

Results

A total of 35 patients were enrolled in the trial; 21 patients completed the 20‐week study. One patient from each group withdrew because of side effects. Twelve, 10, and 10 patients in the placebo, low‐dose, and high‐dose groups, respectively, completed at least 4 weeks of treatment. Of these patients, 8 and 4 in the high‐dose and low‐dose groups, but none in the placebo group, met criteria for clinical response. Four, 4, and 7 patients in the placebo, low‐dose, and high‐dose groups, respectively, were enrolled in the open‐label extension; of these, 2, 4, and 5 patients, respectively, met criteria for clinical response. The most common side effect was diarrhea, which caused 1 patient in the high‐dose group to withdraw from the trial. No patients withdrew because of adverse events during the open‐label extension.

Conclusion

The ethanol/ethyl acetate extract of TWHF shows therapeutic benefit in patients with treatment‐refractory RA. At therapeutic dosages, the TWHF extract was well tolerated by most patients in this study.

     

Risks of rheumatic diseases in first‐ and second‐generation immigrants in Sweden: A nationwide followup study

Objective

To examine whether there is an association between country of birth in first‐generation immigrants and first hospitalization for a rheumatic disease, and to study whether any such association remains in second‐generation immigrants.

Methods

In this followup study, the Swedish MigMed database at the Karolinska Institute in Stockholm was used to identify all primary hospital diagnoses of rheumatic diseases in first‐ and second‐generation immigrants in Sweden between January 1, 1964 and December 31, 2004. Incidence ratios, standardized with regard to age, geographic region, and socioeconomic status, were estimated by sex in first‐ and second‐generation immigrants.

Results

First‐generation immigrants from Iraq had a higher risk of rheumatoid arthritis than did subjects in the native‐born Swede reference group, and the risk of systemic lupus erythematosus was increased in immigrants from Iraq and Africa; these raised risks persisted in the second generation. The lower risk of rheumatoid arthritis in some first‐generation immigrants disappeared in the second generation. In groups of second‐generation immigrants, the risk of ankylosing spondylitis was similar to the risk in the corresponding parental groups. Polish‐born immigrants and second‐generation Yugoslavs and Russians showed a significantly increased risk of systemic sclerosis. The raised risk of systemic sclerosis did not persist in the second generation, but was clustered in groups involved in certain blue collar occupations.

Conclusion

Country of birth affected the risk of rheumatic disease. These findings indicate that both genetic and environmental factors are involved in the etiology of specific rheumatic diseases.

     

Epitope‐specific recognition of type II collagen by rheumatoid arthritis antibodies is shared with recognition by antibodies that are arthritogenic in collagen‐induced arthritis in the mouse

Objective

To analyze the fine specificity of IgG autoantibodies in sera from rheumatoid arthritis (RA) patients for type II collagen (CII) epitopes that are arthritogenic in collagen‐induced arthritis (CIA), a relevant murine model of RA.

Methods

For enzyme‐linked immunosorbent assay (ELISA) analysis of conformation‐dependent autoantibody binding, recombinant chimeric collagens that harbor the respective CII epitopes as an insertion within the frame of a constant type X collagen triple helix were constructed. In addition, synthetic peptides mimicking the native collagen structures were applied for the first time in the ELISA assessment of humoral CII autoimmunity.

Results

The pathogenicity of IgG responses to certain CII determinants in CIA was demonstrated by arthritis development in BALB/c mice upon the combined transfer of 2 mouse monoclonal antibodies specific for precisely mapped conformational CII epitopes (amino acid residues 359–369 [C1^III] and 551–564 [J1]), whereas antibodies to another epitope (F4) were not arthritogenic. To test whether human autoimmune responses are similarly directed to these conserved CII determinants, serum IgG was analyzed. The prevalence of sera with increased IgG binding to the C1^III epitope was significantly higher in RA compared with sera from healthy donors or from patients with other rheumatic conditions, e.g., osteoarthritis (OA), systemic lupus erythematosus (SLE), or relapsing polychondritis (RP), whereas levels of antibodies specific for the nonarthritogenic F4 epitope were associated with OA rather than RA.

Conclusion

Autoimmunity to CII, although detectable in different rheumatic conditions, differs in fine specificity between distinct disease entities. In RA, in contrast to degenerative joint disease, RP, and SLE, autoantibody responses are directed to an evolutionary conserved CII structure that is also targeted by pathogenic autoimmune responses in murine models of arthritis.

     

Antibody response is reduced following vaccination with 7‐valent conjugate pneumococcal vaccine in adult methotrexate‐treated patients with established arthritis,but not those treated with tumor necrosis factor inhibitors

Objective

To study the influence of antiinflammatory treatments, including methotrexate (MTX) and tumor necrosis factor (TNF) inhibitors, on antibody response following vaccination using a 7‐valent conjugate pneumococcal vaccine in adult patients with established arthritis.

Methods

Patients with rheumatoid arthritis (RA) or spondylarthropathy (SpA) (including psoriatic arthritis) were vaccinated (n = 505). All patients were stratified into 6 prespecified groups based on diagnosis and treatment (RA patients receiving MTX, RA patients receiving anti‐TNF agents and MTX, RA patients receiving TNF inhibitors as monotherapy, SpA patients receiving anti‐TNF agents and MTX, SpA patients receiving TNF inhibitors as monotherapy, and SpA patients receiving nonsteroidal antiinflammatory drugs [NSAIDs] and/or analgesics). SpA patients receiving only NSAIDs/analgesics served as a control group. All patients received 1 dose (0.5 ml) of vaccine intramuscularly. Levels of IgG antibodies against 23F and 6B serotypes were measured at vaccination and at 4–6 weeks following vaccination, using standardized enzyme‐linked immunosorbent assays.

Results

Positive antibody response was defined as an antibody response ratio (ARR) (i.e., ratio of post‐ to prevaccination antibody levels) of ≥2. The ARR differed significantly between the groups. A better ARR was seen among patients in the control group compared to those in groups treated with MTX or MTX in combination with TNF inhibitors. Among patients treated with TNF inhibitors as monotherapy, ARRs for both serotypes were lower numerically, but were not significantly different, compared to those in controls. Ongoing MTX treatment was predictive of reduced response (odds ratio 0.41 [95% confidence interval 0.24–0.68], P = 0.001). Higher age was associated with impaired positive antibody response. Concomitant prednisolone treatment elicited better positive antibody response in patients with RA.

Conclusion

Treatment with MTX and higher age were predictive of an impaired antibody response to the 7‐valent conjugate pneumococcal vaccine in this cohort of patients with chronic arthritis. TNF inhibitors did not significantly affect antibody responses.

     

Development and validation of Cedars‐Sinai Health‐Related Quality of Life in Rheumatoid Arthritis (CSHQ‐RA) short form instrument

Objective

To develop an abridged version of the 33‐item Cedars‐Sinai Health‐Related Quality of Life in Rheumatoid Arthritis instrument (CSHQ‐RA) and test the validity and reliability of the abridged instrument.

Methods

Items from the original 33‐item, 5‐domain CSHQ‐RA were assessed using psychometric and regression analyses of survey responses from 274 patients with rheumatoid arthritis. Items were retained in the final instrument based on statistical analysis and evaluation by an expert panel. Test‐retest reliability, internal consistency, convergent and discriminant validity, and ceiling and floor effects were examined for the shortened CSHQ‐RA.

Results

Statistical analysis and expert assessment yielded an 11‐item instrument including questions in 4 domains. Test‐retest reliability and internal consistency were high and the instrument showed good convergent and discriminant validity.

Conclusion

The abridged CSHQ‐RA short form is a valid and reliable instrument that can be used to examine the impact of RA on patients' health‐related quality of life. Prospective validation in clinical trial settings is warranted.

     

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.

     

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.

     

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.