ABSTRACT
OBJECTIVE: In vitro spontaneous osteoclastogenesis from peripheral blood mononuclear cells (PBMCs) is increased in diseases with excessive bone loss. The purpose of this study was to reassess the role of T lymphocytes in this process. METHODS: Fresh or cryopreserved PBMCs obtained from healthy subjects and from patients with rheumatoid arthritis, psoriatic arthritis, and non-psoriatic spondylarthritis were cultured at high density and stained for tartrate-resistant acid phosphatase (TRAP). Resorption of mineralized matrix was assessed by a dentin disc assay. CD14+ monocytes and CD3+ T cells were selected using magnetically labeled antibodies. RESULTS: Numerous multinucleated, TRAP+, dentin-resorbing osteoclasts developed spontaneously from fresh PBMCs from healthy individuals. This process was abrogated by T cell depletion and was restored by exogenous macrophage colony-stimulating factor (M-CSF) and RANKL, indicating the important role of T cells in spontaneous osteoclastogenesis in vitro. Using physiologic freezing and thawing as a model for the activation of PBMCs, spontaneous osteoclastogenesis was significantly increased in cryopreserved versus fresh cells. Under these conditions, spontaneous osteoclastogenesis was not dependent on T lymphocytes, since it was not influenced by T cell depletion and persisted in purified CD14+ cell cultures supplemented with M-CSF and RANKL. In contrast to studies with fresh PBMCs, spontaneous osteoclastogenesis under these conditions did not appear to be clearly different between healthy subjects and patients with arthritis. CONCLUSION: Spontaneous osteoclastogenesis in vitro is dependent on T lymphocytes or on the direct activation of monocytic cells, depending on the test conditions. This variability warrants better validation of the relevance of this functional test for in vivo osteoclastogenesis.
Subject(s)
Bone Resorption/immunology , Cell Communication/immunology , Osteoclasts/cytology , Rheumatic Diseases/immunology , T-Lymphocytes/cytology , Adolescent , Adult , Aged , Arthritis, Psoriatic/immunology , Arthritis, Psoriatic/pathology , Arthritis, Rheumatoid/immunology , Arthritis, Rheumatoid/pathology , Bone Resorption/pathology , CD3 Complex/metabolism , Cell Differentiation/immunology , Female , Humans , In Vitro Techniques , Lipopolysaccharide Receptors/metabolism , Male , Middle Aged , Monocytes/cytology , Monocytes/immunology , Monocytes/metabolism , Osteoclasts/immunology , Rheumatic Diseases/pathology , Spondylarthritis/immunology , Spondylarthritis/pathology , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Young AdultABSTRACT
This case report describes a 50-year-old woman with rheumatoid arthritis (RA) in whom nodular opacities were found on chest X-ray. She developed a bilateral spontaneous pneumothorax treated with surgical pleurodesis. Cultures remained negative. Histological examination of specimens confirmed the clinical diagnosis of rheumatoid granulomata. Therefore, corticosteroid therapy was started, after which the nodules decreased slightly in size and inflammatory parameters normalized. Three months later, she presented with respiratory insufficiency based on pulmonary fungus infection. Differential diagnosis between rheumatoid nodules and granulomas caused by Aspergillus is difficult in RA patients with pulmonary nodular lesions; in this case, both complications appeared subsequently.
Subject(s)
Aspergillosis/pathology , Aspergillus fumigatus/isolation & purification , Lung Diseases, Fungal/pathology , Pneumothorax/pathology , Rheumatoid Nodule/pathology , Amphotericin B/therapeutic use , Antifungal Agents/therapeutic use , Antirheumatic Agents/therapeutic use , Aspergillosis/complications , Aspergillosis/drug therapy , Aspergillosis/microbiology , Drug Therapy, Combination , Fatal Outcome , Female , Humans , Immunocompromised Host , Lung Diseases, Fungal/complications , Lung Diseases, Fungal/microbiology , Middle Aged , Pneumothorax/etiology , Pneumothorax/microbiology , Radiography, Thoracic , Rheumatoid Nodule/drug therapy , Rheumatoid Nodule/microbiologyABSTRACT
OBJECTIVE: To characterize the synovial immunopathologic features of juvenile-onset spondylarthritis (SpA) in relation to adult SpA and other forms of juvenile idiopathic arthritis (JIA). METHODS: Synovial biopsy samples were obtained from 10 patients with juvenile-onset SpA, 23 with adult SpA, 19 with rheumatoid arthritis (RA), 8 with juvenile polyarthritis, and 12 with juvenile oligoarthritis. Synovial immunopathologic features were studied by extensive histologic and immunohistochemical analyses. RESULTS: Synovitis in juvenile SpA was characterized by marked lining layer hyperplasia, clear hypervascularity, and pronounced inflammatory cell infiltration with lymphocytes and macrophages, independent of disease duration or time of sampling. The immunopathologic features of juvenile SpA resembled those of adult SpA in terms of hypervascularity and absence of RA-specific intracellular citrullinated proteins and HLA-DR4/human cartilage glycoprotein 39(263-275) complexes, but differed markedly by a stronger lining layer hyperplasia and lower numbers of CD163+ macrophages. Accordingly, class prediction analysis failed to classify juvenile SpA synovitis in the SpA group. Comparison of juvenile SpA with other JIA subtypes showed a broad overlap, with the exception of slightly lower vascularity in juvenile polyarthritis and higher inflammatory cell infiltration in juvenile oligoarthritis. Unsupervised clustering analysis identified a subgroup of samples characterized by high plasma cell infiltration, which corresponded with active, longstanding JIA, mostly of the oligoarthritis subtype. CONCLUSION: Despite some similarities with adult SpA, the findings with regard to lining layer hyperplasia and CD163+ macrophage infiltration are indicative of important differences in the synovial immunopathologic features of juvenile-onset SpA. The partial overlap with other JIA subtypes emphasizes the need for further biologic characterization of JIA in order to define pathophysiologic, rather than phenotypic, subgroups.
Subject(s)
Arthritis, Juvenile/pathology , Spondylitis, Ankylosing/pathology , Synovial Membrane/pathology , Adolescent , Adult , Aged , Antigens, CD/immunology , Antigens, CD/metabolism , Antigens, Differentiation, Myelomonocytic/immunology , Antigens, Differentiation, Myelomonocytic/metabolism , Arthritis, Juvenile/immunology , Arthritis, Juvenile/metabolism , Biomarkers/metabolism , Biopsy, Needle , Child , Female , Fluorescent Antibody Technique, Indirect , Humans , Knee Joint/pathology , Macrophages/metabolism , Macrophages/pathology , Male , Middle Aged , Receptors, Cell Surface/immunology , Receptors, Cell Surface/metabolism , Spondylitis, Ankylosing/immunology , Spondylitis, Ankylosing/metabolism , Synovial Membrane/immunology , Synovial Membrane/metabolismABSTRACT
OBJECTIVE: To identify biomarkers for effective treatment in early-phase clinical trials of spondylarthritis (SpA), by analyzing which synovial features can be reliably identified in patients with SpA. METHODS: Synovial biopsies were performed at weeks 0 and 12 in 20 SpA patients treated with infliximab, 20 treated with etanercept, and 12 who were not treated. Primary clinical outcome measures were patient and physician global assessment of disease activity. Extensive histologic evaluation included assessment of lining layer hyperplasia, vascularity, markers of cellular infiltration, and metalloproteinases (MMPs) in the lining and sublining layers. RESULTS: Changes in levels of CD163 (resident tissue macrophages) in the lining, and CD163, MMP-3, and myeloid-related protein 14 (MRP-14; infiltrating myeloid cells) in the sublining correlated significantly with changes in the primary clinical outcomes. Comparison between responders (n = 35) and nonresponders (n = 17) showed differences in the degree of change in the levels of CD163 in the lining and CD163, MMP-3, and CD3 in the sublining, whereas trends in change in the levels of MRP-8 and MRP-14 in the lining and sublining were similar in the 2 groups. Accordingly, the highest differences in standardized response means (SRMs) between the 2 groups were found for CD163 in the lining, MMP-3, CD163, CD3, and MRP-8 in the sublining, and the level of polymorphonuclear cells (PMNs). When comparing treated and untreated patients, high differences in SRMs were again found for CD163 in the lining, MMP-3, CD163, and MRP-8 in the sublining, and PMNs. These parameters performed prognostically as well as the erythrocyte sedimentation rate and better than the C-reactive protein level. Class prediction analysis yielded a 90% correct prediction using 8 synovial parameters, as follows: lining and sublining CD163, MRP-8, and MRP-14, sublining MMP-3, and PMNs. In validation analyses with independent samples, effective treatment was correctly predicted in 24 of 30 SpA patients and in 2 of 2 placebo-treated patients. CONCLUSION: Changes in synovial macrophage subsets, PMN levels, and MMP-3 expression reflect response to treatment in SpA. The ability of these parameters to correctly identify effective therapy makes them interesting biomarkers for use in early-phase clinical trials in SpA.
Subject(s)
Biomarkers/analysis , Spondylarthritis/drug therapy , Synovial Membrane/chemistry , Adult , Aged , Antibodies, Monoclonal/therapeutic use , Antigens, CD/analysis , Antigens, Differentiation, Myelomonocytic/analysis , Antirheumatic Agents/therapeutic use , CD3 Complex/analysis , Calgranulin A/analysis , Calgranulin B/analysis , Etanercept , Female , Humans , Immunoglobulin G/therapeutic use , Infliximab , Male , Matrix Metalloproteinase 3/analysis , Metalloproteases/analysis , Middle Aged , Neutrophils/cytology , Prognosis , Receptors, Cell Surface/analysis , Receptors, Tumor Necrosis Factor/therapeutic use , Spondylarthritis/diagnosis , Synovial Membrane/pathologyABSTRACT
BACKGROUND: Few medium-term or long-term reports on meniscal allograft transplantations are available. In this study, we present the results of a survival analysis of the clinical outcomes of our first 100 procedures involving transplantation of viable medial and lateral meniscal allografts performed in ninety-six patients. METHODS: Thirty-nine medial and sixty-one lateral meniscal allografts were evaluated after a mean of 7.2 years. Survival analysis was based on specific clinical end points, with failure of the allograft defined as moderate occasional or persistent pain or as poor function. An additional survival analysis was performed to assess the results of the sixty-nine procedures that involved isolated use of a viable allograft (twenty of the thirty-nine medial allograft procedures and forty-nine of the sixty-one lateral allograft procedures) and of the thirteen viable medial meniscal allografts that were implanted in combination with a high tibial osteotomy in patients with initial varus malalignment of the lower limb. RESULTS: Overall, eleven (28%) of the thirty-nine medial allografts and ten (16%) of the sixty-one lateral allografts failed. The mean cumulative survival time (11.6 years) was identical for the medial and lateral allografts. The cumulative survival rates for the medial and lateral allografts at ten years were 74.2% and 69.8%, respectively. The mean cumulative survival time and the cumulative survival rate for the medial allografts used in combination with a high tibial osteotomy were 13.0 years and 83.3% at ten years, respectively. CONCLUSIONS: Transplantation of a viable meniscal allograft can significantly relieve pain and improve function of the knee joint. Survival analysis showed that this beneficial effect remained in approximately 70% of the patients at ten years. This study identified the need for a prospective study comparing patients with similar symptoms and clinical findings treated with and without a meniscal allograft and followed for a longer period with use of clinical evaluation as well as more objective documentation tools regarding the actual fate of the allograft itself and the articular cartilage.
Subject(s)
Arthroplasty/methods , Knee Joint/surgery , Menisci, Tibial/transplantation , Anterior Cruciate Ligament/surgery , Humans , Joint Deformities, Acquired/surgery , Osteotomy/methods , Tibia/surgery , Transplantation, HomologousABSTRACT
Long-term data on the clinical outcome and the fate of the meniscus allograft after transplantation are scarce. In this study we present the clinical, radiological and MRI outcome of the meniscus graft and the articular cartilage after 42 meniscus allograft transplantations in 41 patients with a minimum follow-up of 10 years. A total of 27 medial and 15 lateral meniscal allografts were transplanted. Eleven of the medial allograft procedures were associated with a high tibial osteotomy. The patients were evaluated clinically at the time of transplantation and at the final follow-up using the modified HSS scoring system. The knee injury and osteoarthritis outcome score (KOOS) was used as an evaluation tool for patient-related outcome at the final follow-up. Joint space width narrowing and Fairbank changes were radiological outcome parameters, which were available for 32 patients. Femoral and tibial cartilage degeneration, graft extrusion and signal intensity were scored on MRI scans obtained in 17 patients approximately 1 year after transplantation and at the final follow-up (>10 years). For statistical analysis the patients were divided into three groups: lateral meniscal allograft (LMT), medial meniscal allograft transplantation with a high tibial osteotomy (MMT+HTO) and without (MMT). The modified HSS score revealed a significant improvement in pain and function at the final follow-up for all groups. Further analysis also revealed that an MMT+HTO procedure resulted in a greater improvement at the final follow-up when compared to MMT. Nonetheless, the KOOS scores obtained at the final follow-up revealed the presence of substantial disability and symptoms, in addition to a reduced quality of life. Radiographical analysis revealed no further joint space narrowing in 13/32 knees (41%). Fairbank changes remained stable in 9/32 knees (28%). MRI analysis showed no progression of cartilage degeneration in 6/17 knees (35%). An increased signal intensity of the allograft was present, as was partial graft extrusion in the majority of patients at the final follow-up. Seven cases had to be converted to a total knee arthroplasty during the follow-up; the overall failure rate was 18%. Long-term results after viable meniscus allograft transplantation are encouraging in terms of pain relief and improvement of function. Despite this significant improvement, substantial disability and symptoms were present in all investigated subgroups. Progression of further cartilage degeneration or joint space narrowing was absent in a considerable number of cases, indicating a potential chondroprotective effect. Level of evidence is therapeutic study, Level IV and retrospective analysis of prospectively collected data.
Subject(s)
Knee Joint/pathology , Menisci, Tibial/transplantation , Adult , Arthroplasty, Replacement, Knee/statistics & numerical data , Cartilage Diseases/pathology , Cartilage, Articular/pathology , Disability Evaluation , Female , Follow-Up Studies , Humans , Joint Instability/surgery , Magnetic Resonance Imaging , Male , Middle Aged , Osteotomy , Pain Measurement , Patient Satisfaction , Quality of Life , Retrospective Studies , Tibia/surgery , Transplantation, Homologous , Treatment OutcomeABSTRACT
OBJECTIVE: Because different tumor necrosis factor alpha (TNFalpha) blockers may have distinct immunomodulatory effects on specific disease manifestations, the present study was carried out to investigate the immunomodulating effects of etanercept on peripheral synovitis in the spondylarthropathies (SpA). METHODS: Peripheral joint disease was assessed clinically, histologically, and radiologically in a prospective 2-year study of 20 patients with SpA treated with etanercept. Synovial tissue biopsy samples obtained at weeks 0, 12, and 52 were analyzed by histology and immunohistochemistry for the extent of inflammation, changes to tissue architecture, and matrix degradation. Serum levels of myeloid-related protein 8 (MRP-8)/MRP-14, matrix metalloproteinase 3 (MMP-3), and cartilage oligomeric matrix protein (COMP) were determined by enzyme-linked immunosorbent assay. RESULTS: Etanercept induced a rapid and sustained clinical improvement of peripheral joint disease. Histologic synovitis was down-regulated, with a profound reduction in global cellular infiltration and T lymphocytes, but not B lymphocytes. The most prominent change in markers of inflammation was a reduction in the different macrophage subsets (CD68, CD163, MRP-8, and MRP-14), but this was not paralleled by a decrease in serum MRP-8/MRP-14. Structural changes included normalization of lining layer hyperplasia and a moderate reduction in vascularity. However, no effect on the microarchitecture of lymphoid aggregates was observed. In terms of an effect on matrix degradation, the synovial expression of MMP-3 and MMP-9 was down-modulated in correlation with a rapid and profound decrease in serum MMP-3. At week 52, serum COMP levels were also reduced. No significant radiologic disease progression was observed in these patients over a 2-year period. CONCLUSION: Use of etanercept effectively down-modulated the immunopathologic processes of SpA synovitis, both in the short term and in the long term.
Subject(s)
Antirheumatic Agents/administration & dosage , Immunoglobulin G/administration & dosage , Receptors, Tumor Necrosis Factor/administration & dosage , Spondylarthropathies/drug therapy , Synovitis/drug therapy , Adult , Aged , Antirheumatic Agents/adverse effects , Bone and Bones/immunology , Bone and Bones/pathology , Cartilage/immunology , Cartilage/pathology , Down-Regulation/drug effects , Down-Regulation/immunology , Etanercept , Extracellular Matrix/immunology , Extracellular Matrix/pathology , Female , Humans , Immunoglobulin G/adverse effects , Immunologic Factors/administration & dosage , Immunologic Factors/adverse effects , Knee Joint/immunology , Knee Joint/pathology , Male , Middle Aged , Spondylarthropathies/immunology , Spondylarthropathies/pathology , Synovial Membrane/immunology , Synovial Membrane/pathology , Synovitis/immunology , Synovitis/pathology , Treatment OutcomeABSTRACT
This study is based on an expanded access program in which 511 patients suffering from active refractory rheumatoid arthritis (RA) were treated with intravenous infusions of infliximab (3 mg/kg+methotrexate (MTX)) at weeks 0, 2, 6 and every 8 weeks thereafter. At week 22, 474 patients were still in follow-up, of whom 102 (21.5%), who were not optimally responding to treatment, received a dose increase from week 30 onward. We aimed to build a model to discriminate the decision to give a dose increase. This decision was based on the treating rheumatologist's clinical judgment and therefore can be considered as a clinical measure of insufficient response. Different single and composite measures at weeks 0, 6, 14 and 22, and their differences over time were taken into account for the model building. Ranking of the continuous variables based on areas under the curve of receiver-operating characteristic (ROC) curve analysis, displayed the momentary DAS28 (Disease Activity Score including a 28-joint count) as the most important discriminating variable. Subsequently, we proved that the response scores and the changes over time were less important than the momentary evaluations to discriminate the physician's decision. The final model we thus obtained was a model with only slightly better discriminative characteristics than the DAS28. Finally, we fitted a discriminant function using the single variables of the DAS28. This displayed similar scores and coefficients as the DAS28. In conclusion, we evaluated different variables and models to discriminate the treating rheumatologist's decision to increase the dose of infliximab (+MTX), which indicates an insufficient response to infliximab at 3 mg/kg in patients with RA. We proved that the momentary DAS28 score correlates best with this decision and demonstrated the robustness of the score and the coefficients of the DAS28 in a cohort of RA patients under infliximab therapy.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Antirheumatic Agents/therapeutic use , Arthritis, Rheumatoid/drug therapy , Autoimmune Diseases/drug therapy , Physicians/psychology , Severity of Illness Index , Antibodies, Monoclonal/administration & dosage , Antirheumatic Agents/administration & dosage , Area Under Curve , Cohort Studies , Drug Therapy, Combination , Humans , Infliximab , Judgment , Methotrexate/administration & dosage , Methotrexate/therapeutic use , ROC Curve , Surveys and QuestionnairesABSTRACT
OBJECTIVE: To address the ongoing debate concerning the specificity of synovial citrullinated proteins for rheumatoid arthritis (RA) and to analyze their pathophysiologic relevance to the induction or perpetuation of the RA-specific anti-citrullinated protein antibodies (ACPAs). METHODS: Synovium of 19 RA patients and 19 non-RA controls was immunostained for the presence of citrullinated proteins with a mouse monoclonal antibody (F95), for the citrullinating enzyme peptidyl arginine deiminase type 2 (PAD-2), and for the free citrulline-producing enzyme inducible nitric oxide synthase (iNOS). Extending the RA cohort to 61 patients, the findings of anticitrulline staining in synovium were related to serum and synovial fluid ACPA levels, as measured by enzyme-linked immunosorbent assay. RESULTS: F95 staining indicated the presence of synovial intracellular citrullinated proteins in 53% of RA samples versus 5% of control samples, whereas extracellular staining was not RA specific. Immunoblotting and inhibition experiments confirmed that the antibody recognized citrullinated proteins but not free citrulline. Accordingly, iNOS was equally found in RA and control synovium and in intracellular citrullinated protein-positive and intracellular citrullinated protein-negative samples. In contrast, intracellular citrullinated proteins colocalized with PAD-2, which was found in 59% of RA samples versus 17% of control samples. Independent of local disease activity, the presence of the RA-specific synovial intracellular citrullinated proteins was associated with significantly higher systemic and local ACPA levels and with local ACPA production in the joint. CONCLUSION: These data confirm the presence of RA-specific intracellular citrullinated proteins in synovium. The link with PAD-2 and local and systemic ACPA levels emphasizes their pathophysiologic relevance for RA-specific humoral autoimmunity.
Subject(s)
Arthritis, Rheumatoid/immunology , Autoimmunity , Citrulline/immunology , Intracellular Membranes/metabolism , Proteins/immunology , Synovial Membrane/metabolism , Antibody Formation , Case-Control Studies , Citrulline/metabolism , Epitopes , Humans , Hydrolases/metabolism , Protein-Arginine Deiminases , Proteins/metabolism , Tissue DistributionABSTRACT
OBJECTIVE: Abnormal host defense against pathogens has been implicated in the pathogenesis of spondylarthropathy (SpA), a disease characterized by abundant synovial infiltration with innate immune cells. Given the role of Toll-like receptors (TLRs) in activation of innate inflammation and the occurrence of TLR-dependent infections after tumor necrosis factor alpha (TNFalpha) blockade treatment, the present study was undertaken to analyze TLRs and their modulation by TNFalpha blockade in SpA. METHODS: Peripheral blood mononuclear cells (PBMCs) were obtained from SpA and rheumatoid arthritis (RA) patients during infliximab therapy, and from healthy controls. TLR-2 and TLR-4 expression and TNFalpha production upon lipopolysaccharide (LPS) stimulation were analyzed by flow cytometry on different monocyte subsets. Synovial biopsy specimens from 23 SpA patients before and after infliximab or etanercept treatment, from 15 RA patients, and from 18 osteoarthritis (OA) patients were analyzed by immunohistochemistry. RESULTS: Expression of TLR-4, but not TLR-2, was increased on PBMCs from patients with SpA, whereas both TLRs were increased in RA patients. TLR expression was particularly increased on the CD163+ macrophage subset. Infliximab reduced TLR-2 and TLR-4 expression on monocytes of SpA and RA patients, leading to lower levels than in controls and to impaired TNFalpha production upon LPS stimulation. In inflamed synovium, the expression of both TLRs and of CD163 was significantly higher in patients with SpA than in those with RA or OA. Paralleling the systemic effect, TLRs in synovium were down-regulated following treatment with infliximab as well as etanercept, indicating a class effect of TNFalpha blockers. CONCLUSION: Inflammation in SpA is characterized by increased TLR-2 and TLR-4 expression, which is sharply reduced by TNFalpha blockade. These findings suggest a potential role of innate immunity-mediated inflammation in SpA and provide an additional clue regarding the mechanism of action as well as the potential side effects of TNFalpha blockade.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Antirheumatic Agents/therapeutic use , Immunoglobulin G/therapeutic use , Membrane Glycoproteins/metabolism , Receptors, Cell Surface/metabolism , Receptors, Tumor Necrosis Factor/therapeutic use , Spondylarthropathies/drug therapy , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Adult , Aged , Aged, 80 and over , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/immunology , Arthritis, Rheumatoid/metabolism , Down-Regulation , Etanercept , Female , Flow Cytometry , Humans , Immunoenzyme Techniques , Infliximab , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/immunology , Leukocytes, Mononuclear/metabolism , Lipopolysaccharides/pharmacology , Macrophages/drug effects , Macrophages/immunology , Macrophages/metabolism , Male , Middle Aged , Osteoarthritis, Knee/drug therapy , Osteoarthritis, Knee/immunology , Osteoarthritis, Knee/metabolism , Spondylarthropathies/immunology , Spondylarthropathies/metabolism , Synovial Membrane/metabolism , Synovial Membrane/pathology , Toll-Like Receptor 2 , Toll-Like Receptor 4 , Toll-Like Receptors , Treatment OutcomeABSTRACT
OBJECTIVE: To analyze the clinical and biologic correlates of autoantibody induction during longer-term tumor necrosis factor alpha (TNFalpha) blockade with either the monoclonal antibody infliximab or the soluble receptor etanercept. METHODS: Thirty-four patients with spondylarthropathy (SpA) and 59 patients with rheumatoid arthritis (RA) were treated with infliximab for 2 years. Additionally, 20 patients with SpA were treated with etanercept for 1 year. Sera were blindly analyzed for antinuclear antibodies (ANAs), anti-double-stranded DNA (anti-dsDNA) antibodies, anti-extractable nuclear antigen (anti-ENA) antibodies, and antihistone, anti-nucleosome, and anticardiolipin antibodies (aCL). The anti-dsDNA antibodies were isotyped. RESULTS: High numbers of infliximab-treated patients with SpA or RA had newly induced ANAs (61.8% and 40.7%, respectively) and anti-dsDNA antibodies (70.6% and 49.2%, respectively) after 1 year, but no further increase between year 1 and year 2 was observed. In contrast, induction of ANAs and anti-dsDNA antibodies was observed only occasionally in the etanercept-treated patients with SpA (10% of patients each). Isotyping revealed almost exclusively IgM or IgM/IgA anti-dsDNA antibodies, which disappeared upon interruption of treatment. Neither infliximab nor etanercept induced other lupus-related reactivities such as anti-ENA antibodies, antihistone antibodies, or anti-nucleosome antibodies, and no clinically relevant lupus-like symptoms were observed. Similarly, infliximab but not etanercept selectively increased IgM but not IgG aCL titers. CONCLUSION: The prominent ANA and anti-dsDNA autoantibody response is not a pure class effect of TNFalpha blockers, is largely restricted to short-term IgM responses, and is not associated with other serologic or clinical signs of lupus. Similar findings with aCL suggest that modulation of humoral immunity may be a more general feature of infliximab treatment.
Subject(s)
Antibodies, Antinuclear/immunology , Antibodies, Monoclonal/therapeutic use , Antirheumatic Agents/therapeutic use , DNA/immunology , Immunoglobulin G/therapeutic use , Receptors, Tumor Necrosis Factor/therapeutic use , Spondylitis, Ankylosing/drug therapy , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Adult , Aged , Drug Therapy, Combination , Etanercept , Female , Humans , Immunoglobulin M/blood , Infliximab , Male , Middle Aged , Spondylitis, Ankylosing/immunologyABSTRACT
At present only few biological data are available to indicate whether psoriatic arthritis (PsA) is part of the spondyloarthropathy (SpA) concept, whether it is a separate disease entity or a heterogeneous disease group with oligoarticular/axial forms belonging to SpA and polyarticular forms resembling rheumatoid arthritis (RA). To address this issue with regard to peripheral synovitis, we compared the synovial characteristics of PsA with those of ankylosing spondylitis (AS)/undifferentiated SpA (USpA) and RA, and compared the synovium of oligoarticular versus polyarticular PsA. Synovial biopsies were obtained from patients with RA, nonpsoriatic SpA (AS + USpA), and oligoarticular and polyarticular PsA. The histological analysis included examination(s) of the lining layer thickness, vascularity, cellular infiltration, lymphoid aggregates, plasma cells and neutrophils. Also, we performed immunohistochemical assessments of CD3, CD4, CD8, CD20, CD38, CD138, CD68, CD163, CD83, CD1a, CD146, alphaVbeta3, E-selectin, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, S100A12, intracellular citrullinated proteins and major histocompatibility complex (MHC)-human cartilage (HC) gp39 peptide complexes. Comparing SpA (PsA + AS + USpA) with RA, vascularity, and neutrophil and CD163+ macrophage counts were greater in SpA (P < 0.05), whereas lining layer thickness and the number of CD83+ dendritic cells were greater in RA (P < 0.05). In RA, 44% of samples exhibited positive staining for intracellular citrullinated proteins and 46% for MHC-HC gp39 peptide complexes, whereas no staining for these markers was observed in SpA samples. We excluded influences of disease-modifying antirheumatic drug and/or corticosteroid treatment by conducting systematic analyses of treated and untreated subgroups. Focusing on PsA, no significant differences were observed between PsA and nonpsoriatic SpA. In contrast, vascularity (P < 0.001) and neutrophils were increased in PsA as compared with RA (P = 0.010), whereas staining for intracellular citrullinated proteins and MHC-HC gp39 peptide complexes was exclusively observed in RA (both P = 0.001), indicating that the same discriminating features are found in PsA and other SpA subtypes compared with RA. Exploring synovial histopathology between oligoarticular and polyarticular PsA, no significant differences were noted. Moreover, intracellular citrullinated proteins and MHC-HC gp39 peptide complexes, which are specific markers for RA, were observed in neither oligoarticular nor polyarticular PsA. Taken together, these data indicate that the synovial histopathology of PsA, either oligoarticular or polyarticular, resembles that of other SpA subtypes, whereas both groups can be differentiated from RA on the basis of these same synovial features, suggesting that peripheral synovitis in PsA belongs to the SpA concept.
Subject(s)
Arthritis, Psoriatic/pathology , Arthritis, Rheumatoid/pathology , Spondylarthropathies/pathology , Synovial Membrane/pathology , Adult , Aged , Antirheumatic Agents/therapeutic use , Arthritis, Psoriatic/drug therapy , Arthritis, Psoriatic/metabolism , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/metabolism , Cohort Studies , Female , Humans , Male , Middle Aged , S100 Proteins/biosynthesis , S100A12 Protein , Spondylarthropathies/drug therapy , Spondylarthropathies/metabolism , Synovial Membrane/metabolism , Synovitis/drug therapy , Synovitis/metabolism , Synovitis/pathologyABSTRACT
Blocking tumor necrosis factor-alpha either with monoclonal antibodies or with soluble receptor constructs has been proven to be effective with an acceptable safety profile in patients with rheumatoid arthritis, and more recently also in the diseases belonging to the spondyloarthropathy concept. Nevertheless multiple questions still remain unresolved especially concerning longer-term treatment. Data from a recent manuscript by Baraliakos and colleagues seem to indicate that at least for the vast majority of ankylosing spondylitis patients treatment with infliximab can not be withdrawn, if one wants to control disease activity in a continuous way. Although still unproven, this might be of crucial importance with regard to structure modification and prevention of ankylosis in this chronic inflammatory disorder.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Antirheumatic Agents/therapeutic use , Spondylitis, Ankylosing/drug therapy , Spondylitis, Ankylosing/prevention & control , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Anti-Inflammatory Agents, Non-Steroidal/economics , Antirheumatic Agents/economics , Humans , Spondylitis, Ankylosing/economics , Spondylitis, Ankylosing/pathology , Tumor Necrosis Factor-alpha/economicsABSTRACT
BACKGROUND: Few medium-term or long-term reports on meniscal allograft transplantations are available. In this study, we present the results of a survival analysis of the clinical outcomes of our first 100 procedures involving transplantation of viable medial and lateral meniscal allografts performed in ninety-six patients. METHODS: Thirty-nine medial and sixty-one lateral meniscal allografts were evaluated after a mean of 7.2 years. Survival analysis was based on specific clinical end points, with failure of the allograft defined as moderate occasional or persistent pain or as poor function. An additional survival analysis was performed to assess the results of the sixty-nine procedures that involved isolated use of a viable allograft (twenty of the thirty-nine medial allograft procedures and forty-nine of the sixty-one lateral allograft procedures) and of the thirteen viable medial meniscal allografts that were implanted in combination with a high tibial osteotomy in patients with initial varus malalignment of the lower limb. RESULTS: Overall, eleven (28%) of the thirty-nine medial allografts and ten (16%) of the sixty-one lateral allografts failed. The mean cumulative survival time (11.6 years) was identical for the medial and lateral allografts. The cumulative survival rates for the medial and lateral allografts at ten years were 74.2% and 69.8%, respectively. The mean cumulative survival time and the cumulative survival rate for the medial allografts used in combination with a high tibial osteotomy were 13.0 years and 83.3% at ten years, respectively. CONCLUSIONS: Transplantation of a viable meniscal allograft can significantly relieve pain and improve function of the knee joint. Survival analysis showed that this beneficial effect remained in approximately 70% of the patients at ten years. This study identified the need for a prospective study comparing patients with similar symptoms and clinical findings treated with and without a meniscal allograft and followed for a longer period with use of clinical evaluation as well as more objective documentation tools regarding the actual fate of the allograft itself and the articular cartilage.
Subject(s)
Menisci, Tibial/transplantation , Adolescent , Adult , Female , Graft Survival , Humans , Male , Middle Aged , Osteotomy , Tibia/surgery , Tissue Transplantation/methods , Transplantation, Homologous , Treatment OutcomeABSTRACT
Synovial macrophages play a pivotal role in the pathogenesis of chronic autoimmune arthritis by contributing to local inflammation and tissue damage and are therefore a primary target for therapeutic intervention. The aim of the present study was to investigate in more detail the relative contribution of different synovial macrophage subsets with potentially different inflammatory or anti-inflammatory functions by analysing the two most frequent forms of human autoimmune arthritis, spondyloarthropathy (SpA) and rheumatoid arthritis (RA). Both infiltrating macrophages from peripheral blood expressing myeloid-related proteins (MRP) 8 and 14, and resident tissue macrophages expressing CD163 were abundant in inflamed synovium. Whereas the global number of synovial macrophages was similar in both diseases, infiltrating macrophages were increased in the RA lining layer in contrast with resident tissue macrophages, which were more frequently observed in SpA. Soluble MRP8/MRP14 complexes, which were secreted locally in the joint during the infiltration process, were increased in the serum of arthritis patients and, in contrast with soluble CD163 shed from resident tissue macrophages, correlated well with global inflammatory parameters. Treatment in vivo with anti-TNFalpha had a rapid and pronounced effect on the infiltration of MRP-positive macrophages into tissues, as evidenced by histopathological analysis and serum MRP8/MRP14 levels. Taken together, these data support an important role for infiltrating versus resident tissue macrophages in human autoimmune synovitis and indicate that macrophage products such as soluble MRP8/MRP14 complexes are valuable biomarkers for the experimental and clinical monitoring of specific disease mechanisms in vivo.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Arthritis, Rheumatoid/drug therapy , Macrophage Activation , Spondylarthritis/drug therapy , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Adult , Aged , Arthritis, Rheumatoid/immunology , Calgranulin A/blood , Calgranulin B/blood , Female , Humans , Immunohistochemistry/methods , Infliximab , Macrophages/immunology , Male , Middle Aged , Spondylarthritis/immunology , Statistics, Nonparametric , Synovial Fluid/immunology , Synovial Membrane/immunology , Tumor Necrosis Factor-alpha/immunologyABSTRACT
We investigated the cytosolic proteome of inflamed synovial tissue by hierarchical clustering analysis and validated the feasibility of this proteome analysis by identifying proteins that were differentially expressed between rheumatoid arthritis (RA), spondyloarthropathy (SpA), and osteoarthritis (OA). Synovial biopsy samples were obtained from 18 patients undergoing needle arthroscopy for knee synovitis associated with RA (n = 6) and SpA (n = 6), and for joint effusion of the knee associated with OA (n = 6). Cytosolic proteins were extracted from the tissue and subjected to two-dimensional gel electrophoresis. Protein expression patterns were statistically analyzed and used for hierarchical cluster analysis. Proteins of interest were independently identified by matrix-assisted laser desorption/ionization- and electrospray ionization-mass spectrometry. Hierarchical cluster analysis of the complete match set, containing 640 spots, remarkably segregated SpA from RA and OA. Next, we used a subset of spots that was statistically, differentially expressed (P < 0.01), between RA and SpA, SpA and OA, or RA and OA, in both Student's t-test and Mann-Whitney U-test. The dendrograms revealed distinct clustering of RA versus SpA and RA versus OA. Spots that were differentially expressed between the groups were identified by tandem mass spectrometry. Fructose bisphosphate aldolase A and alpha-enolase showed higher expression levels in SpA than in OA (P < 0.01). Calgranulin A myeloid related protein-8 (MRP-8) was markedly up-regulated in RA and SpA patients in comparison to OA patients where this spot was below detection limit. The analysis of the cytosolic proteome of synovial tissue is a useful approach to identify disease-associated proteins in chronic inflammatory arthritis.
Subject(s)
Arthritis, Rheumatoid/pathology , Gene Expression Profiling , Mass Spectrometry , Proteins/metabolism , Spondylarthropathies/pathology , Synovial Membrane/chemistry , Synovitis/pathology , Adult , Aged , Aged, 80 and over , Arthritis, Rheumatoid/genetics , Biomarkers, Tumor , Biopsy, Needle , Calgranulin A/metabolism , Cytosol/chemistry , DNA-Binding Proteins/metabolism , Electrophoresis, Gel, Two-Dimensional , Feasibility Studies , Female , Fructose-Bisphosphate Aldolase/metabolism , Humans , Male , Middle Aged , Osteoarthritis/genetics , Osteoarthritis/pathology , Phosphopyruvate Hydratase/metabolism , Proteins/chemistry , Proteins/isolation & purification , Proteomics , Reverse Transcriptase Polymerase Chain Reaction , Spectrometry, Mass, Electrospray Ionization , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization , Spondylarthropathies/genetics , Synovectomy , Synovial Membrane/pathology , Tumor Suppressor Proteins/metabolism , Up-RegulationABSTRACT
Considering the relation between synovial inflammation and global disease activity in rheumatoid arthritis (RA) and the distinct but heterogeneous histology of spondyloarthropathy (SpA) synovitis, the present study analyzed whether histopathological features of synovium reflect specific phenotypes and/or global disease activity in SpA. Synovial biopsies obtained from 99 SpA and 86 RA patients with active knee synovitis were analyzed for 15 histological and immunohistochemical markers. Correlations with swollen joint count, serum C-reactive protein concentrations, and erythrocyte sedimentation rate were analyzed using classical and multiparameter statistics. SpA synovitis was characterized by higher vascularity and infiltration with CD163+ macrophages and polymorphonuclear leukocytes (PMNs) and by lower values for lining-layer hyperplasia, lymphoid aggregates, CD1a+ cells, intracellular citrullinated proteins, and MHC-HC gp39 complexes than RA synovitis. Unsupervised clustering of the SpA samples based on synovial features identified two separate clusters that both contained different SpA subtypes but were significantly differentiated by concentration of C-reactive protein and erythrocyte sedimentation rate. Global disease activity in SpA correlated significantly with lining-layer hyperplasia as well as with inflammatory infiltration with macrophages, especially the CD163+ subset, and with PMNs. Accordingly, supervised clustering using these synovial parameters identified a cluster of 20 SpA patients with significantly higher disease activity, and this finding was confirmed in an independent SpA cohort. However, multiparameter models based on synovial histopathology were relatively poor predictors of disease activity in individual patients. In conclusion, these data indicate that inflammatory infiltration of the synovium with CD163+ macrophages and PMNs as well as lining-layer hyperplasia reflect global disease activity in SpA, independently of the SpA subtype. These data support a prominent role for innate immune cells in SpA synovitis and warrant further evaluation of synovial histopathology as a surrogate marker in early-phase therapeutic trials in SpA.
Subject(s)
Knee Joint/pathology , Macrophages/pathology , Neutrophils/pathology , Spondylarthropathies/pathology , Synovial Membrane/pathology , Synovitis/pathology , Adult , Aged , Antigens, CD/analysis , Antigens, Differentiation/analysis , Antigens, Differentiation, Myelomonocytic/analysis , Arthritis, Psoriatic/blood , Arthritis, Psoriatic/pathology , Arthritis, Rheumatoid/blood , Arthritis, Rheumatoid/pathology , Autoimmune Diseases/blood , Autoimmune Diseases/pathology , Biopsy, Needle , Blood Sedimentation , C-Reactive Protein/analysis , Citrulline/immunology , Cluster Analysis , Cohort Studies , Female , Humans , Hyperplasia , Inflammatory Bowel Diseases/blood , Inflammatory Bowel Diseases/complications , Macrophages/classification , Male , Middle Aged , Phenotype , Receptors, Cell Surface/analysis , Severity of Illness Index , Spondylarthropathies/blood , Spondylarthropathies/complications , Spondylitis, Ankylosing/blood , Spondylitis, Ankylosing/pathology , Synovitis/bloodABSTRACT
Lymphotoxin (LT) alpha 1 beta 2, a tumour necrosis factor (TNF) cytokine critically involved in lymphoid organogenesis, is indispensable for the differentiation of V alpha 14i natural killer T (NKT) cells, a lymphocyte subset with important immunoregulatory properties. However, it is not required for the development of conventional T-cells. LT alpha 1 beta 2 signals through the LT beta receptor, which is expressed on non-lymphoid cells. Triggering of this receptor induces a unique signalling cascade leading to the activation of the transcription factor RelB through activation of NF-kappa B inducing kinase. This pathway is required for V alpha 14i NKT cell differentiation as appears from studies in gene-deficient animals. By reciprocal bone marrow chimeras, it was shown that RelB is required in a radiation-resistant host cell or stromal cell for normal V alpha 14i NKT cell development, presumably in the thymic stroma. These stromal cells are not required for the positive selection of these cells but rather play a prominent role in their terminal differentiation. Altogether, these observations underscore the unique developmental requirements of this particular lymphocyte subset.