Clinical and ultrasound features of difficult-to-treat rheumatoid arthritis: A multicenter RA ultrasound cohort study.

OBJECTIVE: The optimal strategy for difficult-to-treat (D2T) rheumatoid arthritis (RA) has not been identified, and the ultrasound characteristics of D2T RA have not been reported. We investigated the clinical characteristics and factors contributing to the outcome in D2T RA in a multicentre RA ultrasound observational cohort. METHOD: We reviewed 307 Japanese patients diagnosed with RA who underwent treatment with biological and targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs). We compared the differences in patient characteristics between the D2T RA and non-D2T RA groups. We examined the factors contributing to a good response [defined as b/tsDMARD continuation and Clinical Disease Activity Index (CDAI) ≤ 10 at 12 months] in the D2T RA patient group. RESULTS: Forty-three patients (14%) were categorized as D2T RA and the remaining 264 (86%) as non-D2T RA at baseline. The grey-scale (GS) score, disease duration, and CDAI at the initiation of treatment were significantly higher in the D2T RA group than in the non-D2T RA group. In contrast, the power Doppler (PD) score was not significantly different between the two groups. Of the 43 D2T RA patients, 20 achieved a good response. The introduction of CTLA4-Ig (n = 5) was significantly associated with a good response in analysis based on inverse probability weighting with propensity score. GS and PD scores at baseline were not significantly associated with therapeutic response at 12 months in D2T RA patients. CONCLUSIONS: Patients with D2T RA had high clinical and ultrasound activity and poor responses to treatment with b/tsDMARDs. CTLA4-Ig was associated with a good response at 12 months in D2T RA patients.

Ultrasound efficacy of targeted-synthetic disease-modifying anti-rheumatic drug treatment in rheumatoid arthritis: a multicenter prospective cohort study in Japan.

OBJECTIVE: This study investigated the effectiveness of treatment with Janus kinase (JAK) inhibitors in rheumatoid arthritis (RA) assessed by ultrasonography (US) activity, and the influence of patient characteristics and previous treatments. METHOD: This prospective study assessed 60 treatment initiations among 53 Japanese patients diagnosed with RA who underwent treatment with JAK inhibitors during June 2013 to February 2020. Of the 53 patients, seven patients were enrolled in duplicate because they were treated with two different JAK inhibitors at different periods. For each case, the improvement rate on the power Doppler (PD) score was assessed at 6 month follow-up. Median improvement rate of PD score was used to classify cases as either US responders or non-responders, and patient characteristics were compared between the two groups. RESULTS: All indicators of clinical disease activity and US activity showed a significant improvement at 3 months compared with baseline. Although the JAK inhibitor-cycler group and the interleukin-6 (IL-6) inhibitor inadequate response (IR) group tended to show a later improvement for US activity, all indicators of clinical disease activity and US activity showed a significant improvement at 6 months compared with baseline for both groups. Multivariate analysis showed that concomitant methotrexate use and an IR to the previous biologic or targeted-synthetic disease-modifying anti-rheumatic drug (b/tsDMARD) treatment were independently and significantly associated with US responders. CONCLUSION: Use of a JAK inhibitor in combination with methotrexate and an absence of IR to any previous b/tsDMARDs demonstrated superior effectiveness for patients with RA.

Discontinuation of infliximab after attaining low disease activity in patients with rheumatoid arthritis: RRR (remission induction by Remicade in RA) study.

BACKGROUND: Tumour necrosis factor (TNF) inhibitors enable tight control of disease activity in patients with rheumatoid arthritis (RA). Discontinuation of TNF inhibitors after acquisition of low disease activity (LDA) is important for safety and economic reasons. OBJECTIVE: To determine whether infliximab might be discontinued after achievement of LDA in patients with RA and to evaluate progression of articular destruction during the discontinuation. METHODS: 114 patients with RA who had received infliximab treatment, and whose Disease Activity Score, including a 28-joint count (DAS28) was <3.2 (LDA) for 24 weeks, were studied. RESULTS: The mean disease duration of the 114 patients was 5.9 years, mean DAS28 5.5 and mean modified total Sharp score (mTSS) 63.3. After maintaining LDA for >24 weeks by infliximab treatment, the drug was discontinued and DAS28 in 102 patients was evaluated at year 1. Fifty-six patients (55%) continued to have DAS28<3.2 and 43% reached DAS<2.6 at 1 year after discontinuing infliximab. For 46 patients remission induction by Remicade in RA (RRR) failed: disease in 29 patients flared within 1 year and DAS28 was >3.2 at year 1 in 17 patients. Yearly progression of mTSS (DeltaTSS) remained <0.5 in 67% and 44% of the RRR-achieved and RRR-failed groups, respectively. The estimated DeltamTSS was 0.3 and 1.6 and Health Assessment Questionnaire-Disability Index was 0.174 and 0.614 in the RRR-achieved and RRR-failed groups, respectively, 1 year after the discontinuation. CONCLUSION: After attaining LDA by infliximab, 56 (55%) of the 102 patients with RA were able to discontinue infliximab for >1 year without progression of radiological articular destruction.

Overcoming drug resistance induced by P-glycoprotein on lymphocytes in patients with refractory rheumatoid arthritis.

OBJECTIVE: P-glycoprotein (P-gp), a member of the ATP-binding cassette transporter family, causes drug resistance by exclusion of intracellular drugs. Here, we elucidate the clinical relevance of P-gp expression on lymphocytes to drug resistance in patients with rheumatoid arthritis (RA). METHODS: P-gp expression on lymphocytes from 20 normal volunteers and 100 RA patients was analysed by flow cytometry. Drug exclusion analysis of lymphocytes was conducted by radioisotope-labelled dexamethasone. RESULTS: P-gp was overexpressed on RA lymphocytes compared with normal lymphocytes. P-gp expression levels were higher in partial responders with a Disease Activity Score (DAS) 28-3 of >5.1 despite taking at least two disease-modifying antirheumatic drugs (DMARDs) or one DMARD and corticosteroids for at least 2 years. P-gp expression levels correlated with DAS28-3. Intracellular dexamethasone levels (IDLs) in RA lymphocytes decreased according to P-gp expression. Tacrolimus, a P-gp inhibitor, restored IDLs in RA lymphocytes. P-gp overexpression in patients with highly active RA was suppressed by methotrexate but enhanced by corticosteroids. Furthermore, infliximab (3 mg/kg) resulted in improvement of RA disease activity, reduction of P-gp and recovery of IDLs. CONCLUSIONS: P-gp overexpression on lymphocytes might cause efflux of corticosteroids and DMARDs, P-gp substrates, from lymphocytes, resulting in drug resistance in patients with highly active RA. P-gp inhibition/reduction could overcome such drug resistance. Measurement of P-gp expression on lymphocytes could be a potentially useful marker for assessing drug resistance in RA, and may be suitable for selecting infliximab or DMARDs including tacrolimus for RA treatment.

Serum keratan sulfate is a promising marker of early articular cartilage breakdown.

OBJECTIVES: To find serum markers that may serve as indices for an early diagnosis of degeneration or damage of the articular cartilage. METHODS: Twenty-four healthy volunteers, 19 individuals with knee trauma (KT) and 31 with knee osteoarthritis (OA) were evaluated. KT patients were divided into a group (n = 5) with an injury <2 months old (recent KT) and a group (n = 14) with that >2 months old (old KT). Articular cartilage damage was assessed using either arthroscopy or direct observation. Serum concentrations of hyaluronic acid (HA), cartilage proteoglycan aggrecan turnover epitope (CS846) and cartilage oligomeric protein (COMP) were measured using enzyme-linked immunosorbent assay kits and those of keratan sulfate (KS) and chondroitin-6-sulfate (C6S) using high-performance liquid chromatography. RESULTS: Serum KS in the recent KT group (2095 +/- 594 ng/ml) was significantly higher than that in the old KT group (1373 +/- 418 ng/ml; P = 0.021), and serum COMP in the recent KT group (1572 +/- 182 ng/ml) showed a tendency that was higher than that in the old KT group (1350 +/- 250 ng/ml; P = 0.079). Serum KS in OA patients with Kellgren and Lawrence (KL) grades 0 and I (1456 +/- 334 ng/ml) showed a tendency that was higher than that in OA patients with KL grades II, III and IV (1248 +/- 220 ng/ml; P = 0.084). CONCLUSIONS: The serum concentration of KS correlated with the damage of the articular cartilage and it was significantly increased even at an early stage after the injury.

Down-regulation of CD40 and CD80 on B cells in patients with life-threatening systemic lupus erythematosus after successful treatment with rituximab.

OBJECTIVES: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoreactive T cells and polyclonally activated B cells that produce autoantibodies. Five SLE patients who failed to respond to conventional immunosuppressants were treated with anti-CD20 antibody (rituximab) and their clinical manifestations and laboratory data were evaluated, including phenotypic analysis of B cells. METHODS: Rituximab (375 mg/m(2)) was administered weekly for 2 weeks in five SLE patients who developed severe manifestations despite intensive treatment. RESULTS: Rituximab resulted in rapid improvement (within several days) in clinical manifestations such as consciousness disorder, seizures, progressive sensory disorder, haemolytic crisis, cardiac function and laboratory data. The effects lasted 20 months in one patient; other patients were in remission for more than 6 months. Flow cytometric analysis revealed down-regulation of CD40 and CD80 expression on CD19-positive B cells 1 week after infusion of rituximab, and such down-regulation was seen for more than 7 months in two patients. CONCLUSIONS: Our pilot study provides sufficient evidence of excellent tolerability and high efficacy of rituximab therapy in refractory SLE. Rituximab not only reduced B-cell number and IgG levels but down-regulated CD40 and CD80 on B cells, suggesting possible disturbance of T-cell activation through these costimulatory molecules. Reduction of both quantity and quality of B cells suggests that rituximab could improve the disease course in patients with refractory SLE.

Local bone formation by injection of recombinant human bone morphogenetic protein-2 contained in polymer carriers.

The regenerating potential of human bone is limited. The repair of large bone defects often associated with bone tumor resections is not observed, and nonunion or delayed union of bone is a serious problem for fracture treatment. In these cases, autogeneic or allogeneic bone grafting has been routinely indicated, but these approaches require invasive surgical procedures. An alternative approach described in this paper involves the injection of bone morphogenetic proteins (BMPs) in a polymeric delivery system. We demonstrate that synthetic biodegradable polymers, poly-D,L-lactic acid-polyethylene glycol (PLA-PEG) block copolymers, which exhibit an exquisite temperature-dependent liquid-semisolid transition, work well as an injectable delivery system for recombinant human (rh) BMP-2. The thermosensitive property of the PLA-PEG/rhBMP-2 composite is permissive to percutaneous injection when heated. The fluidity of this composite decreases as it cools down to body temperature and the resultant semisolid form provides a scaffold for bone formation through the gradual local release of the rhBMP-2. This new type of injectable osteoinductive material will enable a less invasive approach to surgeries involving the restoration or repair of bone tissues.

Trabecular minimodeling in human iliac bone.

In adult human beings, remodeling creates nearly all of new bone tissue. However, Frost hypothesized that modeling can go on in trabeculae throughout life. As this hypothesis has not been verified, we looked for histologic evidence of trabecular modeling (minimodeling) during bone histomorphometry of transiliac bone biopsy specimens obtained from 34 patients (age range, 38-81 years; mean age, 58.4 years; female, 31/34) at the time of total hip arthroplasty. Before the bone biopsy study, we performed quantitative bone scintigraphy of bilateral hip joints and bilateral iliac crests in 10 other patients with unilateral hip disease and confirmed that the bone biopsy site was not affected by ipsilateral hip joint disease. Patients who had metabolic bone diseases or who had taken medications known to affect bone metabolism were excluded from the study. During modeling where bone formation and bone resorption are not coupled, bone formation can occur on quiescent bone surfaces without preceding bone resorption and create smooth cement lines. Therefore, the combination of fluorochrome labeling and a smooth cement line without interruption of surrounding collagen fibers was regarded as evidence of minimodeling. Histologic evidence of minimodeling was detected in 21 of the entire 34 specimens (62%) and 17 of 27 specimens obtained from postmenopausal patients (63%). Bone volume of minimodeling sites was less than 1% of the trabecular bone volume, and these sites accounted for less than 2% of the entire bone surface on average. However, osteoid volume of minimodeling sites comprised approximately one-tenth of the entire osteoid volume, and their labeled surface constituted one-fourth to half of the entire labeled surface on average. Therefore, when performing bone histomorphometry of adult cancellous bone, minimodeling should be taken into account when dealing with parameters related to osteoid volume and mineralization. A comparison of specimens with and without minimodeling demonstrated that the presence of minimodeling was correlated with smaller physique of patients, accelerated mineralization (as indicated by the higher mean MS/BS and MAR values and the shorter mean Omt), and higher metabolic turn-over of bone (as indicated by the higher mean BFR/BV value). Although the findings still need to be verified in a larger number of normal subjects without hip joint disease, they support Frost's hypothesis that minimodeling can continue throughout human life.

Cytomegalovirus infection in patients with systemic lupus erythematosus.

Cytomegalovirus (CMV) infection is known to induce several autoimmune abnormalities in mice that resemble those found in systemic lupus erythematosus (SLE). In addition, a potential role for CMV in the development and/or progression of SLE has been suggested. In order to further clarify this issue, we reviewed the relationship between SLE and CMV infection on the basis of the clinical and immunological features of cases reported in the literature and our own patients.

Activated peripheral blood mononuclear cells detected in lupus patients using cDNA coding for proliferating cell nuclear antigen.

Abstract The expression of proliferating cell nuclear antigen (PCNA) mRNA in peripheral blood mononuclear cells (PBMCs) from patients with systemic lupus erythematosus (SLE) was measured by dot blot hybridization using a PCNA cDNA, and correlated with the percentage of PCNA-positive cells detected immunohistochemically using a monoclonal anti-PCNA antibody. PCNA-positive PBMCs were detected in 72.2% of SLE patients (n = 36), which is significantly more than among healthy controls. In addition, among those in whom PCNA expression was detected, the percentage of PBMCs expressing PCNA was significantly higher in SLE patients (mean 2.5% vs. 0.15%). The level of PCNA mRNA was increased in PBMCs from 83.3% of SLE patients, and was significantly correlated with the percentage of PCNA-positive cells (r = 0.54, P < 0.01) and with the disease activity score (r = 0.56, P < 0.01). A longitudinal study of two SLE patients confirmed that PCNA mRNA expression and the percentages of PCNA-positive cells varied in parallel with disease activity. Thus, an analysis of activated PBMCs from SLE patients using PCNA cDNA may be a useful method by which to estimate SLE disease activity.

Morphological characteristics of the bony birth canal in patients with developmental dysplasia of the hip (DDH): investigation by three-dimensional CT.

We investigated the three-dimensional morphological characteristics of the pelvis in adult female patients with developmental dysplasia of the hip (DDH), using computerized tomography (CT) images. Forty-two subjects with normal hips and 40 DDH patients were recruited for the study. In the DDH group, the average transverse diameter of the pelvic inlet was significantly less and the average transverse diameter of the pelvic outlet was significantly greater than the measurements in the normal group. Further, the bony birth canal in DDH patients exhibited a higher incidence of anthropoid-type geometry, as defined by a longer sagittal diameter relative to the transverse diameter of the pelvic inlet. These findings indicate a characteristic pelvic geometry and suggest different development of the pelvis in the transverse direction in DDH patients. In addition, the obstetric conjugate length/transverse diameter of the pelvic inlet ratio was correlated to the degree of severity of acetabular dysplasia. This finding suggests that DDH is a manifestation of a developmental characteristic of the pelvis.

Hemophagocytosis in autoimmune disease.

Reactive hemophagocytic syndrome (HPS) is known to be associated with various autoimmune diseases, as well as infection and/or malignancy. Here we review the features of autoimmune-associated HPS and describe the possible role of autoantibodies, especially antiphospholipid antibodies (aPL), in HPS based on data obtained from our own patients.

Biodegradable poly-D,L-lactic acid-polyethylene glycol block copolymers as a BMP delivery system for inducing bone.

BACKGROUND: Bone morphogenetic proteins (BMPs) are biologically active molecules capable of eliciting new bone formation. In combination with biomaterials, these proteins can be used in a clinical setting as bone-graft substitutes to promote bone repair. Collagen from animal sources has previously been the preferred carrier material in animal experiments. More recently, synthetic biodegradable polymers have been tested as a delivery vehicle for osteoinductive agents. In earlier studies performed in our laboratory, it was found that the polylactic acid homopolymers (PLA650) and poly-D,L-lactic acid-polyethylene glycol block copolymers (PLA650-PEG200) are viscous liquids that can be used as BMP delivery systems. METHODS: To obtain new PLA-PEG polymers that exhibit greater plasticity, the molecular sizes of PLA and PEG segments in the copolymer chains were increased. Plastic PLA-PEG polymers with various molecular sizes and PLA/PEG ratios were synthesized, mixed with recombinant human (rh) BMP-2, and implanted into the dorsal muscles of mice for 3 weeks to evaluate their capacity to elicit new bone formation. To compare the plastic PLA-PEG polymer with the liquid PLA650-PEG200 polymer, these two polymers were combined with rhBMP-2, implanted, and harvested after 3 weeks. Bone mineral content (BMC), bone area, and bone mineral density (BMD) of the ectopic new bone were measured by means of single energy X-ray absorptiometry (SXA). RESULTS: All of the PLA6,500-PEG3,000 implants with 10 or 20 microg of rhBMP-2 showed new bone formation. In contrast, little or no bone formation was seen in other plastic PLA-PEG implants with rhBMP-2. Control implants that lacked rhBMP-2 did not show new bone formation. Radiographic and histologic examinations showed that the PLA6,500-PEG3,000 implants with rhBMP-2 harvested 3 weeks after implantation had normal bone characteristics with hematopoietic marrow and osseous trabeculae. SXA analysis showed that the values for bone mineral content (BMC), bone area, and bone mineral density (BMD) of new bone resulting from the use of plastic PLA6,500-PEG3,000 polymers with rhBMP-2 were significantly higher than those obtained with the liquid PLA650-PEG200 polymers (p < 0.001 for each of the three values). CONCLUSIONS: These results indicate that the PLA6,500-PEG3000 block copolymer with plastic properties works effectively as a BMP delivery system. These data suggest that the total molecular size and ratio of PLA size to PEG size is an essential factor in determining the efficacy of a BMP delivery system. After implantation, it is possible that the PLA6,500-PEG3,000 pellets might have absorbed tissue fluids and become swollen, resulting in bone formation that exceeded the size of the original implants. This expansion characteristic is a potentially beneficial property, given the intended practical application of the polymer in the repair of bone defects. CLINICAL RELEVANCE: New synthetic biodegradable delivery systems will play an important role in the clinical applications of rhBMPs in which local formation of bone via an osteoinductive graft material is needed. Further pre-clinical and clinical work is necessary to establish the safety of these implants before they are adopted for widespread clinical use.

A biodegradable polymer as a cytokine delivery system for inducing bone formation.

Bone morphogenetic proteins (BMPs) that have the potential to elicit new bone in vivo have been used in a tissue-engineering approach for the repair of bone injuries and bone defects. Although it is now possible to generate large amounts of recombinant human (rh) BMPs for medical use, the major challenge remains in the development of optimal local delivery systems for these proteins. Here we describe the development of a synthetic biodegradable polymer, poly-d,l-lactic acid-p-dioxanone-polyethylene glycol block copolymer (PLA-DX-PEG). This polymer exhibits promising degradation characteristics for BMP delivery systems and good biocompatibility under test conditions. PLA-DX-PEG/rhBMP-2 composite implants induced ectopic new bone formation effectively when tested in vivo, and can repair large bone defects orthotopically. This polymeric delivery system represents an advance in the technology for the enhancement of bone repair.

Possible triggering effect of cytomegalovirus infection on systemic lupus erythematosus.

We report on a patient with systemic lupus erythematosus (SLE) who showed elevated titers of IgM antibodies to cytomegalovirus (CMV), suggesting CMV infection at the onset of SLE. Serum CMV antigens were also detected in the patient. These findings raise the possibility that CMV infection may be related to the onset of SLE in certain patients.

Two cases of reactive hemophagocytic syndrome: a patient with adult-onset Still's disease and a patient with herpes zoster and autoimmune abnormalities.

Abstract We report two cases of bone marrow hemophagocytosis. One patient had adult-onset Still's disease, and the other had herpes zoster associated with potential autoimmune abnormalities. Our findings suggested a pos-sible role of cytokines and/or antibodies in the induction of hemophagocytosis in patients with connective tissue diseases and/or immune abnormalities.