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.

     

Major reduction in spinal inflammation in patients with ankylosing spondylitis after treatment with infliximab: Results of a multicenter,randomized, double‐blind,placebo‐controlled magnetic resonance imaging study

Objective

To determine whether the effects of anti–tumor necrosis factor α (TNFα) in reducing the signs and symptoms of ankylosing spondylitis (AS) coincide with a reduction in spinal inflammation as detected by magnetic resonance imaging (MRI).

Methods

Pre‐ and postgadolinium T1 and STIR MR images of the spine were acquired at baseline and at week 24 in patients with AS who participated in a multicenter, randomized, double‐blind, placebo‐controlled study. Patients were randomly assigned at an 8:3 ratio to receive infusions of infliximab (5 mg/kg) or placebo at weeks 0, 2, and 6 and then every 6 weeks thereafter. MR images were obtained and evaluated independently by 2 readers who were blinded to the treatment allocation and time sequence of the images.

Results

A total of 194 patients in the infliximab group and 72 patients in the placebo group had evaluable images at baseline and week 24. About 80% of the patients had at least 1 active spinal lesion at baseline, as assessed by MRI. The improvement in the MRI Activity Score after 6 months was significantly greater in the patients who received infliximab (mean 5.02, median 2.72) than in those who received placebo (mean 0.60, median 0.0) (P < 0.001). Almost complete resolution of spinal inflammation was seen in most patients who received infliximab, irrespective of baseline activity.

Conclusion

Patients with AS who received infliximab therapy showed a decrease in spinal inflammation as detected by MRI, whereas those who received placebo showed persistent inflammatory spondylitis.

     

Juvenile‐onset ankylosing spondylitis is associated with worse functional outcomes than adult‐onset ankylosing spondylitis

Objective

To compare functional outcome of patients with juvenile‐onset ankylosing spondylitis (JoAS; defined as AS with symptom onset before 16 years of age) with that of patients with adult‐onset AS (AoAS) and to identify variables associated with a poor functional outcome of JoAS.

Methods

A cross‐sectional study was performed of 326 JoAS patients who participated in a postal survey conducted by the Spondylitis Association of America. This cohort was compared with 2,021 AoAS patients who participated in the same survey. Simple and multiple logistic regression analyses were performed to identify differences with respect to clinical features, demographic features, and functional outcome (defined by the Bath Ankylosing Spondylitis Functional Index [BASFI]) between the 2 groups. A validation cohort of 255 AS patients was also surveyed.

Results

The mean ± SD BASFI score (controlled for disease duration) for JoAS was 51.3 ± 1.5 compared with 46.4 ± 0.6 for AoAS (P < 0.0001). Multiple logistic regression identified only age (P < 0.0001) and income status (P < 0.0001) as factors associated with functional impairment.

Conclusion

It appears that JoAS is a progressive disease and is associated with significant delay in diagnosis and worse functional outcome compared with AoAS. Furthermore, women do worse than men with JoAS. This would argue for the importance of early diagnosis and treatment of AS, particularly in the subgroup of patients with JoAS.

     

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.

     

Persistence of CCR5 usage among primary human immunodeficiency virus isolates of individuals receiving intermittent interleukin‐2

Objective

To investigate the impact of intermittent interleukin‐2 (IL‐2) plus combination antiretroviral therapy (cART) on HIV‐1 entry co‐receptor use.

Methods

Primary HIV‐1 isolates were obtained from 54 HIV‐1‐positive individuals at baseline and after 12 months using co‐cultivation of peripheral blood mononuclear cells (PBMC) with activated PBMC of HIV‐negative healthy donors. HIV‐1 co‐receptor use was determined on U87‐CD4 cells.

Results

Fourteen out of the 21 (67%) IL‐2‐treated individuals harbouring a primary CCR5‐dependent (R5) HIV‐1 isolate at baseline confirmed an R5 virus isolation after 12 months in contrast to 3 out of 7 (43%) of those receiving cART only. After 12 months, only 1 R5X4 HIV‐1 isolate was obtained from 21 cART+IL‐2‐treated individuals infected with an R5 virus at entry (5%) vs. 2/7 (29%) patients receiving cART alone, as confirmed by a 5‐year follow‐up on some individuals.

Conclusions

Intermittent IL‐2 administration plus cART may prevent evolution towards CXCR4 usage in individuals infected with R5 HIV‐1.

     

The comparative effectiveness of tumor necrosis factor–blocking agents in patients with rheumatoid arthritis and patients with ankylosing spondylitis: A six‐month,longitudinal, observational,multicenter study

Objective

To compare the effectiveness of tumor necrosis factor (TNF)–blocking agents (etanercept and infliximab) in patients with rheumatoid arthritis (RA) and patients with ankylosing spondylitis (AS).

Methods

Data from an ongoing longitudinal, observational study in Norway were used to assess changes in health‐related quality of life (HRQOL) in patients with RA (n = 291) and AS (n = 62). Patients received anti‐TNF therapy, and changes in scores on the Short Form 36 (SF‐36), SF‐6D, modified Health Assessment Questionnaire, and visual analog scales for patients' assessments of pain, fatigue, and global status from baseline to followup examinations at 3 and 6 months were compared. Data were adjusted for age, sex, and baseline values and are presented as crude estimates as well as standardized response means.

Results

Both groups had improvements in all measures at 3 and 6 months. At 3 months, the changes were significantly better in the AS group compared with the RA group for all measures except the SF‐36 social functioning scores. At 6 months, all changes were numerically greater in the AS group. Differences were significant for the SF‐36 role emotional scores and were borderline significant for the SF‐36 physical functioning, role physical, and vitality scores and for the SF‐6D scores.

Conclusion

In this real‐life setting, patients with AS experienced improvement in HRQOL that was comparable to, and sometimes greater than, that observed in RA patients. These results support the idea that patients with AS should have the same access to TNF‐blocking agents as patients with RA.

     

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.

     

Spondylarthritis‐associated and non–spondylarthritis‐associated B27 subtypes differ in their dependence upon tapasin for surface expression and their incorporation into the peptide loading complex

Objective

B27 subtypes associated with susceptibility to ankylosing spondylitis (AS), and those reported not to be associated with AS, are found to differ in the amino acids that are known in other HLA class I molecules to alter the requirements for tapasin and incorporation into the peptide loading complex. The purpose of this study was to examine the behavior of B*2704 and B*2705 in comparison with B*2706 and B*2709 during early events in HLA class I antigen expression, and determine if their behavior correlates with disease association.

Methods

Cell lines with nonfunctional tapasin were transiently transfected with different B27 subtypes and their site‐directed mutants, and surface expression analyzed by flow cytometry. The association with the peptide loading complex was determined by immunoprecipitation of heterodimeric transporter‐associated peptide and analysis of coprecipitated B27.

Results

Amino acids at positions 114, 116, and 152 in the different B27 subtypes were shown to perform key roles in defining a requirement for interaction with tapasin. Not all disease‐associated alleles were expressed optimally in the absence of tapasin; furthermore, dependence on tapasin for cell surface expression did not correlate with disease association. Although B*2706, which is not associated with disease, exhibited a number of properties different from those of the disease‐associated subtypes, these properties were not displayed by the non–disease‐associated allele B*2709.

Conclusion

These results indicate that the ability to exhibit optimal cell surface expression in the absence of tapasin is not a prerequisite for susceptibility to AS.

     

Association of ankylosing spondylitis with HLA–B*1403 in a West African population

Objective

To investigate the contribution of HLA class I alleles in the susceptibility to primary ankylosing spondylitis (AS) in West African patients living in Togo.

Methods

A large epidemiologic analysis of 9,065 West African rheumatology patients living in Togo was performed in order to identify those who had AS. Eight Togolese patients with AS were identified. HLA was typed by polymerase chain reaction using sequence‐specific oligonucleotide probes. DNA typing was also performed on a control population of 85 healthy subjects matched for ethnic background.

Results

A significant association between AS and B*14 was identified. This allele was found in 62.5% of the AS patients (odds ratio 69), but was carried by only 2% of the healthy controls. Analysis for B14 subtypes showed that B*1403 was the predominant allele in AS patients (odds ratio 171), and that this allele was absent in healthy controls. B27 was virtually absent, being observed in only 1 AS patient (B*2705).

Conclusion

HLA–B*1403 shows the B27 “supertype” motif and may exert an effect on AS susceptibility according to the arthritogenic peptide model. The association of B*1403 with AS has not previously been reported in either population.

     

Dysregulation of interleukin‐10–dependent gene expression in rheumatoid arthritis synovial macrophages

Objective

The inflammatory cytokines tumor necrosis factor α (TNFα) and interleukin‐1 (IL‐1) are produced by activated macrophages, are key mediators of pathogenesis, and are validated therapeutic targets in rheumatoid arthritis (RA) and seronegative spondylarthritis (SpA). IL‐10 is a potent antiinflammatory cytokine that suppresses macrophage TNFα and IL‐1 production, yet is not effective in suppressing inflammatory arthritis. To gain insight into IL‐10 responses in inflammatory arthritis, we used microarray analysis to determine the patterns of IL‐10–inducible gene expression in freshly isolated RA and seronegative SpA synovial macrophages.

Methods

Macrophages from the synovial fluid of 5 patients with RA and 3 with seronegative SpA (2 with psoriatic arthritis and 1 with ankylosing spondylitis) were isolated by positive selection and stimulated ex vivo with IL‐10 or interferon‐γ (IFNγ). Gene expression was analyzed using Affymetrix microarrays and protocols. Real‐time polymerase chain reaction was used to confirm changes in gene expression.

Results

The number of genes induced by IL‐10 in arthritic macrophages was markedly smaller than that induced in control macrophages, and the strength of induction was lower in arthritic macrophages for most genes. The residual response of arthritic macrophages to IL‐10 stimulation was qualitatively altered, such that IL‐10 preferentially increased expression of IFNγ‐inducible genes. In contrast, arthritic macrophages expressed many IFNγ‐inducible genes prior to stimulation, and their response to IFNγ remained mostly intact.

Conclusion

These results demonstrate that IL‐10 responses are dysregulated in RA synovial macrophages. An altered biologic response to IL‐10, with attenuation of its antiinflammatory function and a concomitant retention of IFNγ‐like activating functions, provides a basis for the lack of efficacy of IL‐10 in suppressing inflammatory arthritis.

     

Adalimumab significantly reduces both spinal and sacroiliac joint inflammation in patients with ankylosing spondylitis: A multicenter,randomized, double‐blind,placebo‐controlled study

Objective

To compare the efficacy of adalimumab versus placebo in reducing spinal and sacroiliac (SI) joint inflammation, by magnetic resonance imaging (MRI) in patients with active ankylosing spondylitis (AS).

Methods

This was a randomized, multicenter, double‐blind, placebo‐controlled study. Patients (n = 82) received 40 mg adalimumab or placebo every other week during an initial 24‐week double‐blind period. MRIs of both the spine and SI joints were obtained at baseline, week 12, and week 52. Spinal and SI joint inflammation were measured using the Spondyloarthritis Research Consortium of Canada (SPARCC) MRI index.

Results

The spine SPARCC score in placebo‐treated patients increased by a mean of 9.4% from baseline, compared with a mean decrease of 53.6% in adalimumab‐treated patients (P < 0.001); the SI joint SPARCC score decreased by a mean of 12.7% from baseline in placebo‐treated patients and by 52.9% in adalimumab‐treated patients (P = 0.017). The response in adalimumab‐treated patients was maintained at week 52. Placebo‐treated patients were switched to open‐label adalimumab treatment at week 24 and experienced similar reductions in spinal and SI joint inflammation by week 52. Similar large reductions in the spine and SI joint SPARCC scores were noted, even in patients who failed to meet the ASsessment in Ankylosing Spondylitis (International Working Group) criteria (nonresponders) at 12 weeks. In adalimumab‐treated patients, a reduced C‐reactive protein concentration at week 12 was significantly associated with improvement in the spine SPARCC score (P = 0.018).

Conclusion

Adalimumab significantly reduced both spinal and SI joint inflammation in patients with active AS after 12 weeks of treatment, and these improvements were maintained for up to 52 weeks.

     

Validation of single‐factor structure and scoring protocol for the health assessment questionnaire‐disability index

Objective

The extensively used Health Assessment Questionnaire Disability Index (HAQ‐DI) has been well received by the research and clinical community, notably because of its measurement strengths including reliability and stability of scores over time, utility in observational studies and clinical trials, predictive relationship with morbidity and mortality in rheumatoid arthritis (RA), and its translation for use in different countries. However, HAQ‐DI scoring has not been validated. The purpose of this study was to examine the structural validity of the HAQ‐DI and evaluate the latent factors underlying HAQ‐DI scoring.

Methods

This study used a cross‐validation approach on a total of 278 patients with RA. Exploratory and confirmatory factor analyses were performed.

Results

Results yielded a single‐factor HAQ‐DI score, which favored the current scoring system of the HAQ‐DI. Additionally, modification indices suggested improved model fit with the secondary inclusion of correlated residual scores from a motor skills subdomain.

Conclusion

The current study provides the first validation of the HAQ‐DI scoring system as determined by its latent factor structure. In addition, the findings suggest some benefit from a secondary interpretation of the scores based on domains that measure motor skills.

     

Responsiveness and discriminative capacity of the assessments in ankylosing spondylitis disease‐controlling antirheumatic therapy core set and other outcome measures in a trial of etanercept in ankylosing spondylitis

Objective

To investigate the responsiveness and discriminative capacity, and the relationship between both, of instruments selected for the disease‐controlling antirheumatic therapy (DC‐ART) core set by the Assessments in Ankylosing Spondylitis Working Group (ASAS).

Methods

Responsiveness and discriminative capacity of different measures reflecting disease activity and function, either included in the ASAS DC‐ART core set or not, were evaluated in a randomized controlled clinical trial comparing etanercept with placebo in patients with ankylosing spondylitis. Guyatt's method was used as the primary analysis for responsiveness, and Student's t‐test for discriminative capacity.

Results

At day 28 of therapy, almost all measures indicated moderate to large responsiveness in the etanercept group (Guyatt 0.60–3.11). Some scales of the Short Form 36 (general health, mental component summary, and role emotional), the modified Schober's test, and the Fatigue Severity Scale were not responsive. The results were similar if analyzed at day 112 of therapy. Peripheral joint counts, joint scores, and occiput‐to‐wall distance could not be evaluated due to a floor effect. In general, the relation between responsiveness and discriminative capacity was strong: Measures that demonstrated high responsiveness also showed high between‐group t values.

Conclusion

Measures included in the ASAS DC‐ART core set, except modified Schober's test, have good responsiveness and good discriminatory capacity. Some measures could not be evaluated due to a floor effect.

     

NF‐κB protects Behçet's disease T cells against CD95‐induced apoptosis up‐regulating antiapoptotic proteins

Objective

To determine whether prolongation of the inflammatory reaction in patients with Behçet's disease (BD) is related to apoptosis resistance and is associated with the up‐regulation of antiapoptotic factors.

Methods

The percentage of cell death was evaluated by flow cytometry in peripheral blood mononuclear cells from 35 patients with BD and 30 healthy volunteers. The expression levels of antiapoptotic factors and NF‐κB regulatory proteins were measured using Western blotting and immunohistochemical analyses. To down‐regulate NF‐κB nuclear translocation, BD T lymphocytes were exposed in vitro to thalidomide and subjected to transfection with NF‐κB small interfering RNA.

Results

Although CD95 is highly expressed in BD T cells, the absence of sensitivity to CD95‐induced apoptosis observed may be attributable to the inhibitory action of antiapoptotic genes. Immunoblot analysis for major antiapoptotic proteins showed considerable up‐regulation of the short form of cellular FLIP (cFLIP) and Bcl‐x_L in BD activated T cells, while levels of Bcl‐2, caspase 3, and caspase 8 in activated T cells from patients with BD were comparable with those in activated T cells from normal donors. Moreover, expression of IKK and IκB was up‐regulated, whereas NF‐κB translocated to the nucleus in BD T cells, suggesting that NF‐κB activation may modulate the expression of antiapoptotic genes. Interestingly, thalidomide and NF‐κB small interfering RNA down‐regulated cFLIP and Bcl‐x_L expression levels and sensitized BD activated T cells to CD95‐induced apoptosis.

Conclusion

Taken together, these results indicate that NF‐κB contributes to the regulation of the apoptosis‐related factors and death receptors leading to apoptosis resistance in BD T cell subsets. Our results suggest that NF‐κB plays a crucial role in the pathogenesis of BD, and that its pharmacologic control could represent a key strategy in modulating specific immune‐mediated disease.

     

Maintenance of infliximab treatment in ankylosing spondylitis: Results of a one‐year randomized controlled trial comparing systematic versus on‐demand treatment

Objective

Continuous treatment with the anti–tumor necrosis factor α (anti‐TNFα) antibody infliximab is efficacious in ankylosing spondylitis (AS), whereas treatment discontinuation results in disease relapse, with variable delay. This study was undertaken to compare the efficacy of continuous treatment with infliximab with that of a treatment regimen adapted to symptom recurrence. Methotrexate (MTX) in combination with infliximab was also tested.

Methods

Patients with active AS were randomly assigned at week 0 to receive infliximab every 6 weeks (continuous treatment) or upon symptom recurrence (on‐demand treatment), following infusions at weeks 4, 6, and 10. Patients in the on‐demand group were randomly assigned to receive either MTX in combination with infliximab or infliximab alone. Patients were monitored for 1 year. The primary end point was the proportion of patients who met the ASsessment in AS International Working Group criteria for 20% improvement (ASAS20) at week 58.

Results

Of 247 patients, 124 were assigned to receive infliximab every 6 weeks and 123 to receive on‐demand treatment. Among the latter, 62 received MTX, and 61 received infliximab alone. A greater proportion of patients receiving infliximab every 6 weeks fulfilled ASAS20 response criteria at week 58 than did patients receiving on‐demand treatment (75% versus 46%; P < 0.0001). Patients in the continuous treatment group received more infliximab infusions after week 10 than did those in the on‐demand group (mean ± SD 5.8 ± 2.2 versus 3.5 ± 2; P < 0.0001). Addition of MTX did not significantly affect the proportion of patients with an ASAS20 response at week 58, nor the number of infliximab infusions administered.

Conclusion

These findings indicate that continuous treatment of AS with infliximab is more efficacious than on‐demand treatment, and that the addition of MTX to infliximab provides no significant benefit.

     

Decreased incidence of anterior uveitis in patients with ankylosing spondylitis treated with the anti–tumor necrosis factor agents infliximab and etanercept

Objective

To estimate the incidence of anterior uveitis in patients with ankylosing spondylitis (AS) who underwent anti–tumor necrosis factor (anti‐TNF) therapy, using data from recently performed trials.

Methods

Data from 4 placebo‐controlled studies with anti‐TNF agents in AS (2 with etanercept and 2 with infliximab) and 3 open‐label studies were analyzed for the prestudy prevalence and the incidence of reported flares of anterior uveitis.

Results

A total of 717 patients who received treatment for anterior uveitis during the course of published clinical studies were identified by a systematic literature search using Medline. Followup information on the course of anterior uveitis was available for 397 patients. Of these, 297 were exposed to etanercept and 90 were exposed to infliximab for a total of 430 and 146.4 years, respectively. Among 190 patients who received placebo, the overall exposure was 70.5 years. The frequency of flares of anterior uveitis in the placebo group was 15.6 per 100 patient‐years (95% confidence interval 7.8–27.9), while the patients treated with anti‐TNF agents had a mean of only 6.8 anterior uveitis flares per 100 patient‐years (P = 0.01). Flares of anterior uveitis occurred less frequently (although not significantly) in patients treated with infliximab than in patients treated with etanercept (3.4 per 100 patient‐years and 7.9 per 100 patient‐years, respectively).

Conclusion

Treatment of AS patients with biologic agents directed against TNFα is associated with a significant decrease in the number of anterior uveitis flares. This reduction was slightly more marked among patients treated with infliximab, but the difference was not significant.

     

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.

     

Thalidomide dramatically improves the symptoms of early‐onset Sarcoidosis/Blau syndrome: Its possible action and mechanism

Objective

Early‐onset sarcoidosis (EOS), which occurs in children younger than 5 years of age, is associated with granulomatous lesions and a sporadic genetic mutation of the nucleotide‐binding oligomerization domain 2 that causes constitutive NF‐κB activation. The symptoms of EOS can be uncontrollable, progressive, and associated with profound complications. However, appropriate therapy is still under investigation. The aim of this study was to assess the efficacy of thalidomide in patients with severe EOS, based on etiology supporting an initial role of NF‐κB in activation of this disease.

Methods

Thalidomide was given to 2 patients with EOS (a 16‐year‐old girl and an 8‐year‐old boy) at an initial dosage of 2 mg/kg/day, and the dosage was increased if necessary. To elucidate the mechanism of the drug, peripheral blood monocytes were isolated from the patients and stimulated with cytokines (macrophage colony‐stimulating factor, tumor necrosis factor α, and interleukin‐4), and their ability to form multinucleated giant cells (MGCs) and osteoclasts was measured.

Results

Both patients showed dramatic improvement of their clinical symptoms (alleviation of fever and optic nerve papillitis, achievement of a response according to the American College of Rheumatology Pediatric 50 and Pediatric 70 criteria) and laboratory findings. Monocytes from patients with EOS had a greater ability to survive and induce MGCs and osteoclasts than those from healthy control subjects. The formation of MGCs and osteoclasts was inhibited by the presence of thalidomide.

Conclusion

The ability of thalidomide to improve clinical symptoms and laboratory findings in patients with EOS indicates a central role for NF‐κB activity in this disorder. Inhibition of IKK might be a pharmacologic action by which thalidomide down‐regulates NF‐κB signaling. Thalidomide may be an effective medication in patients with severe complications of EOS, including ocular involvement.

     

Gap between short‐ and long‐term effects of patient education in rheumatoid arthritis patients: A systematic review

Objective

To systematically review educational or psychoeducational interventions for patients with rheumatoid arthritis focusing on long‐term effects, especially health status.

Methods

Two independent reviewers appraised the methodologic quality of the included randomized controlled trials, published between 1980 and July 2002.

Results

Validity scores of studies ranged from 3 to 9 (of 11). The 7 educational programs mainly improved knowledge and compliance in the short and long term, but there was no improvement in health status. All 4 psychoeducational programs improved coping behavior in the short term, 2 of them showing a positive long‐term effect on physical or psychological health variables.

Conclusion

Methodologically better‐designed studies had more difficulties demonstrating positive outcome results. Short‐term effects in program targets are generally observed, whereas long‐term changes in health status are not convincingly demonstrated. There is a need to find better strategies to enhance the transfer of short‐term effects into gains in health status.