Efficacy of High‐Throughput Leukocytapheresis for Rheumatoid Arthritis With a Reduced Response to Infliximab

Infliximab (INF), a tumor necrosis factor‐alpha (TNF‐α) inhibitor, is an effective drug for patients with rheumatoid arthritis (RA). However, some patients receive no clinical benefit, or the agents gradually lose their effect. Five sessions of high‐throughput leukocytapheresis (LCAP) were given at a frequency of once a week using a Cellsorba CS‐180S to four patients with a reduced response to INF. The clinical response to LCAP was evaluated using the 28‐joint disease activity score with C‐reactive protein (DAS28‐CRP) and with the erythrocyte sedimentation rate (DAS28‐ESR). DAS28‐CRP decreased significantly from 5.8 ± 0.6 before LCAP to 3.9 ± 0.7 (P = 0.0182) at 1–2 weeks after completion of five sessions of LCAP, and DAS28‐ESR decreased significantly from 6.4 ± 0.6 to 4.6 ± 0.5 (P = 0.0267). Moreover, all patients had a moderate response according to the European League Against Rheumatism (EULAR) response criteria. The effect of LCAP continued for at least 6 months after its completion in all patients, with no changes in any of their concomitant drugs, and the effect was maintained for at least 1 year in three of the four patients. These results indicate that LCAP is a useful treatment for RA patients with a reduced response to INF.     

Ultrasound Evaluation of the Effects of Leukocytapheresis on Rheumatoid Arthritis

Leukocytapheresis (LCAP) is effective in treating rheumatoid arthritis (RA). Ultrasound (US) examination of joints is useful for evaluating disease activity and therapeutic effects in RA, but the clinical assessment of LCAP therapy with US has been little reported. We investigated the usefulness of US for evaluating the effects of LCAP in patients with RA. US examination was performed in six patients (total of seven cases) who underwent LCAP. Twenty‐eight joints (bilateral shoulders, elbows, wrists, 1st to 5th metacarpophalangeal joints, 1st to 5th proximal interphalangeal joints, and knee joints) were evaluated by a systematic multiplanar grey‐scale and power Doppler (PD) examination. Disease activity of RA was evaluated using the 28‐joint Disease Activity Score with erythrocyte sedimentation rate (DAS28‐ESR). Moderate or good responses to LCAP based on the DAS28‐ESR were observed in four of the seven cases although C‐reactive protein (CRP) and ESR did not decrease. LCAP significantly reduced the mean total PD score 17.3 ± 11.6 to 13.0 ± 10.5 (P = 0.0469). The total PD score decreased in six of the seven cases, and the number of joints with PD score ≥2 decreased in five of the seven cases. The rate of decrease in the number of joints with PD score ≥2 correlated strongly with the DAS28‐ESR and its components, especially swollen joint counts and evaluator's global assessment, but not with the rate of decrease in CRP and ESR. US imaging of joints may be useful for evaluating the therapeutic effects of LCAP on RA compared to other inflammatory parameters.     

Enhanced effect of high-dose leukocytapheresis using a large filter in rheumatoid arthritis

Abstract

To evaluate the efficacy of high-dose leukocytapheresis (LCAP) using a large filter in patients with refractory rheumatoid arthritis (RA), we conducted a multicenter, nonrandomized, open-label clinical study. Thirty patients with highly active RA were treated with high-dose LCAP performed 3–5 sessions at 1-week intervals using a CS-180S filter (CS-180S group); the treatment involves the removal of leukocytes from a higher blood volume per body weight (100^Sml/kg). The clinical response was evaluated at 4 and 8 weeks after a series of LCAP using the 28-joint disease activity score (DAS28). Similar data of 53 patients treated with conventional LCAP (60^Sml/kg) using a standard filter, CS-100, were compared as a control (CS-100 group). The CS-180S filter demonstrated a higher adsorption capacity for leukocytes, particularly lymphocytes. The CS-180S group exhibited significant improvements in each item of DAS28 after treatment although the CS-100 group did not demonstrate such improvements in the CRP level and the ESR. Compared to the CS-100 group, the patients of the CS-180S group exhibited a tendency toward improvement with respect to the CRP level and ESR (P = 0.057 and 0.041, respectively). According to the EULAR improvement criteria based on DAS28, 60% and 45% of the patients from CS-180S and CS-100 groups achieved moderate or more responses, respectively, at 4 weeks after treatment. These results suggest that compared to conventional LCAP, high-dose LCAP may enhance the suppression of RA disease activity.     

Successful leukocytapheresis therapy in a patient with rheumatoid arthritis on maintenance hemodialysis

Abstract

We report the case of a 44-year-old female undergoing maintenance hemodialysis in whom early-phase rheumatoid arthritis (RA) was successfully treated by leukocytapheresis (LCAP). The effects of prednisone, tacrolimus, and etanercept were limited, but LCAP was highly effective and its efficacy continued even after cessation of LCAP. Moreover, remission was maintained for 2 years after discontinuation of medication. LCAP may be an important treatment option for RA patients with end-stage renal failure who are on hemodialysis.     

Activated platelets as a possible early marker to predict clinical efficacy of leukocytapheresis in severe ulcerative colitis patients

Background Leukocytapheresis (LCAP) is an effective adjunct for patients with active ulcerative colitis (UC). Because LCAP may have the potential to remove and modulate not only leukocytes but also platelets, we evaluated the correlation between activated platelets and the therapeutic response to LCAP. Methods Fourteen patients with severe UC received weekly LCAP for 5 consecutive weeks. Their average clinical activity index (CAI) and endoscopic index (EI) were 9.6 ± 3.4 and 10.9 ± 1.0, respectively. Their peripheral blood was sampled before and after every LCAP and stained with fluorescent antibodies to the activation-dependent surface antigens of platelets (CD63, CD62-P) prior to flow cytometry. Endoscopic evaluations were performed after the last LCAP. Results Clinical remission (CAI < 4) was induced in 50% of the patients (7/14) after 5 weeks, and there were no significant differences observed in clinical background between the responder group (RG) and the nonresponder group (NG). In the RG, the populations of CD63⁺ (P < 0.03) and CD62-P⁺ (P < 0.05) platelets were significantly decreased after the first LCAP, and their reduction ratio decreased gradually with repeated LCAP. A significant improvement of the EI score, especially mucosal damage, was achieved in RG (P < 0.04) but not in NG. Conclusions These results indicate that the therapeutic responses to LCAP were reflected in modulations of population and/or platelet functions, especially after the first session. The decrease of such activated platelets immediately after the first LCAP may be an early marker for predicting the response in patients with severe UC.     

Enhanced effect of high-dose leukocytapheresis using a large filter in rheumatoid arthritis

To evaluate the efficacy of high-dose leukocytapheresis (LCAP) using a large filter in patients with refractory rheumatoid arthritis (RA), we conducted a multicenter, nonrandomized, open-label clinical study. Thirty patients with highly active RA were treated with high-dose LCAP performed 3–5 sessions at 1-week intervals using a CS-180S filter (CS-180S group); the treatment involves the removal of leukocytes from a higher blood volume per body weight (100^Sml/kg). The clinical response was evaluated at 4 and 8 weeks after a series of LCAP using the 28-joint disease activity score (DAS28). Similar data of 53 patients treated with conventional LCAP (60^Sml/kg) using a standard filter, CS-100, were compared as a control (CS-100 group). The CS-180S filter demonstrated a higher adsorption capacity for leukocytes, particularly lymphocytes. The CS-180S group exhibited significant improvements in each item of DAS28 after treatment although the CS-100 group did not demonstrate such improvements in the CRP level and the ESR. Compared to the CS-100 group, the patients of the CS-180S group exhibited a tendency toward improvement with respect to the CRP level and ESR (P = 0.057 and 0.041, respectively). According to the EULAR improvement criteria based on DAS28, 60% and 45% of the patients from CS-180S and CS-100 groups achieved moderate or more responses, respectively, at 4 weeks after treatment. These results suggest that compared to conventional LCAP, high-dose LCAP may enhance the suppression of RA disease activity.     

Twenty-four-week follow-up examination of a leukocytapheresis therapy in rheumatoid arthritis

Abstract

Several clinical trials have demonstrated that leukocytapheresis (LCAP) is a safe and effective therapy for patients with refractory rheumatoid arthritis (RA). However, most of those reports were limited to short-term clinical observation. We have treated 11 RA patients with LCAP and observed them for 24 weeks after the final administration. The 11 cases included 3 diabetes patients, 2 patients with interstitial pneumonia, 1 patient with diffuse panbronchiolitis, and 1 patient with old pulmonary tuberculosis. Alternative therapies for all of these patients were considered difficult. Once-a-week LCAP administration was added for 5 weeks to the previous therapeutic regime in all patients, and the treatment efficacy was prospectively qualified. At 4 weeks after the final LCAP therapy, 8 of the 11 patients (73%) had achieved an American College of Rheumatology (ACR) 20% response, and 3 of the 11 (27%) had achieved both ACR 50% and ACR 70% responses. Although the efficacy decreased after the observation periods, an ACR 20% response was maintained in 5 patients (45%) at 24 weeks. Although only a limited number of patients were examined in this study, the results suggested that LCAP therapy will be beneficial to RA patients, including patients who cannot be treated with tumor necrosis factor inhibitors or conventional disease-modifying antirheumatic drugs.     

Multivariate Analysis for Factors Predicting Rapid Response of Leukocytapheresis in Patients With Steroid‐resistant Ulcerative Colitis: A Multicenter Prospective Open‐label Study

Leukocytapheresis (LCAP) has been advocated as a treatment for moderate to severe active ulcerative colitis (UC) in Japan. To clarify the predictive factors for a rapid response to LCAP treatment, we conducted a multicenter prospective open‐label study. A total of 105 patients with UC were analyzed. LCAP was performed using a Cellsorba EX column once a week for 5–10 sessions. The response was evaluated by the clinical activity index (CAI). When the CAI score decreased to less than half the pretreatment value or to less than 5 points within 3 weeks, the patient was considered to be a rapid responder. The average CAI significantly decreased from 11.7 to 4.2 (P < 0.01). Seventy‐four percent of the patients responded to the therapy, and 53% of these patients were rapid responders. The following significant factors correlated with the rapid LCAP response: (i) steroid resistance (P < 0.05), (ii) severe disease indicated by a CAI score greater than 11 (P = 0.05), (iii) disease duration of less than 1 year (P < 0.05), and (iv) C‐reactive protein levels before treatment (P < 0.01). These results suggest that the early initiation of LCAP is beneficial in patients with steroid‐resistant UC.     

Association of arthritis with a gene complex encoding C‐type lectin–like receptors

Objective

To identify susceptibility genes in a rat model of rheumatoid arthritis (RA) and to determine whether the corresponding human genes are associated with RA.

Methods

Genes influencing oil‐induced arthritis (OIA) were position mapped by comparing the susceptibility of inbred DA rats with that of DA rats carrying alleles derived from the arthritis‐resistant PVG strain in chromosomal fragments overlapping the quantitative trait locus Oia2. Sequencing of gene complementary DNA (cDNA) and analysis of gene messenger RNA (mRNA) expression were performed to attempt to clone a causal gene. Associations with human RA were evaluated by genotyping single‐nucleotide polymorphisms (SNPs) in the corresponding human genes and by analyzing frequencies of alleles and haplotypes in RA patients and age‐, sex‐, and area‐matched healthy control subjects.

Results

Congenic DA rats were resistant to OIA when they carried PVG alleles for the antigen‐presenting lectin‐like receptor gene complex (APLEC), which encodes immunoregulatory C‐type lectin–like receptors. Multiple differences in cDNA sequence and mRNA expression precluded cloning of a single causal gene. Five corresponding human APLEC genes were identified and targeted. The SNP rs1133104 in the dendritic cell immunoreceptor gene (DCIR), and a haplotype including that marker and 4 other SNPs in DCIR and its vicinity showed an indication of allelic association with susceptibility to RA in patients who were negative for antibodies to cyclic citrullinated peptide (anti‐CCP), with respective odds ratios of 1.27 (95% confidence interval [95% CI] 1.06–1.52; uncorrected P = 0.0073) and 1.37 (95% CI 1.12–1.67; uncorrected P = 0.0019). Results of permutation testing supported this association of the haplotype with RA.

Conclusion

Rat APLEC is associated with susceptibility to polyarthritis, and human APLEC and DCIR may be associated with susceptibility to anti‐CCP–negative RA.

     

Interferon and alternative activation of monocyte/macrophages in systemic sclerosis–associated pulmonary arterial hypertension

Objective

To explore the relationship between biomarkers of pulmonary arterial hypertension (PAH), interferon (IFN)–regulated gene expression, and the alternative activation pathway in systemic sclerosis (SSc).

Methods

Peripheral blood mononuclear cells (PBMCs) were purified from healthy controls, patients with idiopathic PAH, and SSc patients (classified as having diffuse cutaneous SSc, limited cutaneous SSc [lcSSc] without PAH, and lcSSc with PAH). IFN‐regulated and “PAH biomarker” genes were compared after supervised hierarchical clustering. Messenger RNA levels of selected IFN‐regulated genes (Siglec1 and MX1), biomarker genes (IL13RA1, CCR1, and JAK2), and the alternative activation marker gene (MRC1) were analyzed on PBMCs and on CD14− and CD14+ cell populations. Interleukin‐13 (IL‐13) and IL‐4 concentrations were measured in plasma by immunoassay. CD14, MRC1, and IL13RA1 surface expression was analyzed by flow cytometry.

Results

Increased PBMC expression of both IFN‐regulated and biomarker genes distinguished SSc patients from healthy controls. Expression of genes in the biomarker cluster, but not in the IFN‐regulated cluster, distinguished lcSSc with PAH from lcSSc without PAH. The genes CCR1 (P < 0.001) and JAK2 (P < 0.001) were expressed more highly in lcSSc patients with PAH compared with controls and mainly by CD14+ cells. MRC1 expression was increased exclusively in lcSSc patients with PAH (P < 0.001) and correlated strongly with pulmonary artery pressure (r = 0.52, P = 0.03) and higher mortality (P = 0.02). MRC1 expression was higher in CD14+ cells and was greatly increased by stimulation with IL‐13. IL‐13 concentrations in plasma were most highly increased in lcSSc patients with PAH (P < 0.001).

Conclusion

IFN‐regulated and biomarker genes represent distinct, although related, clusters in lcSSc patients with PAH. MRC1, a marker for the effect of IL‐13 on alternative monocyte/macrophage activation, is associated with this severe complication and is related to mortality.

     

Gene expression profiling in autoantibody‐positive patients with arthralgia predicts development of arthritis

Objective

To identify molecular features associated with the development of rheumatoid arthritis (RA), to understand the pathophysiology of preclinical development of RA, and to assign predictive biomarkers.

Methods

The study group comprised 109 anti–citrullinated protein antibody (ACPA)– and/or rheumatoid factor–positive patients with arthralgia who did not have arthritis but were at risk of RA, and 25 patients with RA. The gene expression profiles of blood samples obtained from these patients were determined by DNA microarray analysis and quantitative polymerase chain reaction.

Results

In 20 of the 109 patients with arthralgia who were at risk of RA, arthritis developed after a median of 7 months. Gene expression profiling of blood cells revealed heterogeneity among the at‐risk patients, based on differential expression of immune‐related genes. This report is the first to describe gene signatures relevant to the development of arthritis. Signatures significantly associated with arthritis development were involved in interferon (IFN)–mediated immunity, hematopoiesis, and chemokine/cytokine activity. Logistic regression analysis revealed that the odds ratio (OR) for developing arthritis within 12 months was 21.0 (95% confidence interval [95% CI] 2.8–156.1 [P = 0.003]) for the subgroup characterized by increased expression of genes involved in IFN‐mediated immunity and/or cytokine/chemokine‐activity. Genes involved in B cell immunology were associated with protection against progression to arthritis (OR 0.38, 95% CI 0.21–0.70 [P = 0.002]). These processes were reminiscent of those in patients with RA, implying that the preclinical phase of disease is associated with features of established disease.

Conclusion

The results of this study indicate that IFN‐mediated immunity, hematopoiesis, and cell trafficking specify processes relevant to the progression of arthritis independent of ACPA positivity. These findings strongly suggest that certain gene signatures have value for predicting the progression to arthritis, which will pave the way to preventive medicine.

     

Effect of interactions of glutathione S‐transferase T1, M1, and P1 and HMOX1 gene promoter polymorphisms with heavy smoking on the risk of rheumatoid arthritis

Objective

Glutathione S‐transferase (GST) genes as well as heme oxygenase 1 gene (HMOX1) encode enzymes that detoxify carcinogens and protect against oxidative stress. This study was undertaken to examine the impact of gene–smoking interactions on susceptibility to rheumatoid arthritis (RA).

Methods

Caucasian patients with RA and matched control subjects (n = 549 each) were selected from the Nurses' Health Study. Genotyping of the patients' blood by TaqMan and BioTrove assays identified homozygous deletions at the M1 and T1 loci of GST (GSTM1‐null and GSTT1‐null, respectively) as well as alleles for GSTP1 (rs1695) and HMOX1 (rs2071746). In addition, the effect of gene–smoking interactions on the risk of all RA and RA serologic phenotypes was studied in separate logistic models that were adjusted for covariates. Multiplicative interactions were assessed by including a product term in a logistic model, and additive interactions were assessed using the attributable proportion (AP) due to interaction. For replication of the results, analyses revealing significant interactions were repeated in an independent case–control cohort from the Epidemiological Investigation of Rheumatoid Arthritis study.

Results

For the risk of all RA, multiplicative (P = 0.05) and additive (AP = 0.53, P = 0.0005) interactions between the GSTT1‐null polymorphism and smoking and multiplicative interactions (P = 0.05) between HMOX1 and smoking were observed. For the risk of seropositive RA, multiplicative (P = 0.01) and additive (AP = 0.62, P < 0.0001) interactions between GSTT1‐null and smoking and additive interactions (AP = 0.41, P = 0.03) between HMOX1 and smoking were observed. After correction for multiple comparisons, the additive interactions between GSTT1‐null and smoking remained significant. The M1‐null and P1 variants of GST did not show significant interactions, and no associations with seronegative RA were observed. In replication analyses, significant multiplicative interactions (P = 0.04) and additive interactions (AP = 0.32, P = 0.02) were observed between GSTT1‐null and smoking in the risk of anti–citrullinated protein antibody–positive RA.

Conclusion

Significant gene–environment interactions between the GSTT1‐null polymorphism and heavy smoking were observed when assessing the risk of RA. Future studies are needed to assess the impact of these interactions on RA prediction.

     

Leukocytapheresis therapy for steroid-naïve patients with active ulcerative colitis: its clinical efficacy and adverse effects compared with those of conventional steroid therapy

Background: Steroid administration currently plays a central role in the medical management of ulcerative colitis (UC); however, long‐term steroid usage causes adverse effects, which necessitates stoppage of drug intake, leading to worsening of the disease. A steroid‐sparing, well‐tolerated treatment is therefore required. As several investigators have reported the efficacy of leukocytapheresis (LCAP) combined with steroid therapy, we investigated the clinical usefulness and safety of LCAP for steroid‐naïve patients with active UC for comparison with those of conventional steroid therapy. Methods: Twenty‐nine Japanese patients with active UC without a history of steroid usage were selected to be treated with LCAP (n = 9) or prednisolone (PSL) (n = 20). LCAP administration continued for 10 weekly cycles. In the PSL group, patients with moderately severe disease received 0.5 mg/kg per day of PSL and those with severe disease 1.0 mg/kg per day. The PSL dosage was gradually tapered in accordance with improvement. Results: Eight (88.9%) of the LCAP group and 16 (80.0%) of the PSL group showed clinical improvement and three (33.3%) of the LCAP group and seven (35.0%) of the PSL group achieved remission. As for the treatment complications, three major adverse effects were observed in the PSL group, but none were observed in the LCAP group. Conclusion: The results of this study suggest that the efficacy and safety of LCAP are equivalent, and in terms of severe adverse effects, superior to those of steroid therapy. LCAP therapy may thus be a promising candidate therapy for steroid‐naïve patients with active UC. © 2005 Blackwell Publishing Asia Pty Ltd     

Analysis of pigmented villonodular synovitis with genome‐wide complementary DNA microarray and tissue array technology reveals insight into potential novel therapeutic approaches

Objective

To characterize the gene expression profile and determine potential diagnostic markers and therapeutic targets in pigmented villonodular synovitis (PVNS).

Methods

Gene expression patterns in 11 patients with PVNS, 18 patients with rheumatoid arthritis (RA), and 19 patients with osteoarthritis (OA) were investigated using genome‐wide complementary DNA microarrays. Validation of differentially expressed genes was performed by real‐time quantitative polymerase chain reaction and immunohistochemical analysis on tissue arrays (80 patients with PVNS, 51 patients with RA, and 20 patients with OA).

Results

The gene expression profile in PVNS was clearly distinct from those in RA and OA. One hundred forty‐one up‐regulated genes and 47 down‐regulated genes were found in PVNS compared with RA, and 153 up‐regulated genes and 89 down‐regulated genes were found in PVNS compared with OA (fold change ≥1.5; Q ≤ 0.001). Genes differentially expressed in PVNS were involved in apoptosis regulation, matrix degradation, and inflammation (ALOX5AP, ATP6V1B2, CD53, CHI3L1, CTSL, CXCR4, HSPA8, HSPCA, LAPTM5, MMP9, MOAP1, and SPP1).

Conclusion

The gene expression signature in PVNS is similar to that of activated macrophages and is consistent with the local destructive course of the disease. The gene and protein expression patterns suggest that the ongoing proliferation in PVNS is sustained by apoptosis resistance. This result suggests the possibility of a potential novel therapeutic intervention against PVNS.

     

Safety and efficacy of single‐needle leukocyte apheresis for treatment of ulcerative colitis

Leukocyte apheresis (LCAP) is a safe and effective treatment for active ulcerative colitis (UC) in Japan. Nevertheless, a limitation of LCAP is its requirement for two puncture sites (double‐needle [DN] apheresis), sometimes leading to problems with needle puncture. Single‐needle (SN) apheresis is useful in hemodialysis and reduces needle puncture pain. If SN apheresis were found to be useful in LCAP for UC, it may reduce patient burden. The aim of this study was to compare the safety and efficacy of SN apheresis with that of DN apheresis. Twenty‐four patients with active UC were retrospectively enrolled. They underwent either SN apheresis (n = 12) or conventional double‐needle (DN) apheresis (n = 12) at the Kurume University Hospital from February 2014 to March 2018. At each session, we recorded access problems defined by the time required to initiate apheresis and the frequency of puncture‐related problems, as well as blood circuit clotting, defined as clotting necessitating interruption of apheresis and changing of the circuit. Efficacy was assessed using partial Mayo scores. The number of apheresis sessions was comparable between SN and DN apheresis (9.0 ± 2.0 times vs 9.6 ± 1.4 times, mean ± SEM). SN significantly reduced the time required to start apheresis (10.0 ± 5.4 minutes vs 19.4 ± 11.9 minutes, P < .05) as well as needle puncture troubles (0.9% vs 11.5%, P < .05). SN had comparable frequency of blood clotting episodes (5.6% vs 8.7%). SN apheresis had similar clinical efficacy (P < .001 in SN and P < .01 in DN). The improvement and remission rates were comparable between groups. SN apheresis may be safe and effective and may reduce patient burden during UC treatment. Nevertheless, further comparative studies are needed.     

The Mechanism of the Efficiency of Leukocytapheresis on Rheumatoid Arthritis

Abstract: This study was designed to determine the efficacy of filtration leukocytapheresis (LCAP) in the treatment of rheumatoid arthritis (RA) and the mechanism of its efficacy. Three filtration LCAP procedures in 22 RA patients were performed. Heparinized samples were collected from peripheral blood and synovial fluid. The surface markers of T cells were measured by flow cytometry before the first and third procedures. Proportions of activated and memory T cells in the peripheral blood were paradoxically higher after the third procedure than they were prior to the first treatment. Inversely, the activated T-cell counts in the synovial fluid decreased after the third procedure. In RA patients, higher proportions of activated T lymphocytes are present in RA affected joints than in the peripheral blood. If LCAP induced the redistribution of activated T cells from the affected joints into the circulating blood, the effectiveness of LCAP in the treatment of RA might be explained by the mechanism.     

Association between single‐nucleotide polymorphisms in the SEC8L1 gene,which encodes a subunit of the exocyst complex,and rheumatoid arthritis in a Japanese population

Objective

To identify rheumatoid arthritis (RA) susceptibility genes in a Japanese population by conducting a large‐scale case–control association analysis and linkage disequilibrium (LD) mapping on chromosome 7q31–34, a candidate susceptibility locus identified in a preliminary genome‐wide scan in 53 Japanese families, using single‐nucleotide polymorphisms (SNPs).

Methods

We prepared 728 dense, evenly spaced SNPs with a minor allele frequency >0.15 in each gene locus on chromosome 7q31–34. Using these SNPs, a 2‐stage case–control analysis was performed on 760 RA patients (157 men and 603 women) and 806 non‐RA controls (189 men and 617 women). Haplotypes and LD mapping results were assessed based on SNP genotypes in 380 controls.

Results

Forty‐eight SNPs showed allele associations (P < 0.05) in the first set of DNA samples (380 RA cases and 380 non‐RA controls; first‐stage analysis). For 4 of the SNPs in the SEC8L1 gene, the association was replicated (P < 0.05) in the second, independent set of DNA samples (an additional 380 RA cases and 380 non‐RA controls; second‐stage analysis). When data from the 2 groups were combined, the most significant allele association was observed with SNP 441, an intronic SNP of the SEC8L1 gene (P = 0.000059). The SEC8L1 SNPs with significant allele associations were all located in a single conserved LD block (block 4). Haplotype analysis revealed the disease‐risk (P = 0.0015) and disease‐protective (P = 0.0000062) haplotypes. Resequencing of coding exons within block 4 did not identify any nonsynonymous SNPs. Real‐time quantitative polymerase chain reaction revealed that SEC8L1 was expressed ubiquitously in human tissues, including fibroblast‐like synoviocytes from RA patients.

Conclusion

Our locus‐wide association and LD analyses identified intronic SNPs and haplotypes in the SEC8L1 gene that are strongly associated with RA. We propose that SEC8L1, which encodes a component of the exocyst complex, is a candidate susceptibility gene for RA in the Japanese population.

     

Disease severity and domain‐specific arthritis self‐efficacy: Relationships to pain and functioning in patients with rheumatoid arthritis

Objective

To examine the degree to which disease severity and domains of self‐efficacy (pain, function, and other symptoms) explain pain and functioning in rheumatoid arthritis (RA) patients.

Methods

Patients (n = 263) completed the Arthritis Impact Measurement Scales 2 to assess pain and functioning (physical, affective, and social), the Arthritis Self‐Efficacy Scale to assess 3 self‐efficacy domains (pain, physical function, and other). Disease severity was assessed with C‐reactive protein level, physician's rating, and abnormal joint count. Structural equation modeling was used to examine 3 hypotheses: does disease severity have a direct relationship with pain and each area of functioning, does disease severity have a direct relationship with each arthritis self‐efficacy domain, and do the self‐efficacy domains mediate the relationship between disease severity and RA pain and each area of functioning.

Results

Disease severity was related to pain, physical functioning, and each self‐efficacy domain (β = 0.28–0.56, P < 0.001). Each self‐efficacy domain was related to its respective domain of functioning (e.g., self‐efficacy for pain was related to pain; β = 0.36–0.54, P < 0.001). Self‐efficacy mediated the relationship between disease severity and pain and functioning (β = 0.12–0.19, P < 0.001). Self‐efficacy for pain control and to perform functional tasks accounted for 32–42% of disease severity's total effect on their respective outcomes (e.g., self‐efficacy for pain control accounted for 32% of disease severity's total effect on pain). Variance accounted for by the total model was 52% for pain, 53% for physical functioning, and 44% for affective and social functioning.

Conclusion

Disease severity and self‐efficacy both impact RA functioning, and intervening in these areas may lead to better outcomes.