Low levels of apoptosis and high FLIP expression in early rheumatoid arthritis synovium

OBJECTIVES: To define synovial apoptosis with respect to disease duration, inflammatory cell type, FLIP (FLICE-like inhibitory protein), and cytokines expression in patients with rheumatoid arthritis (RA). METHODS: Synovial biopsy specimens from 11 patients with longstanding RA (median disease duration 21 years) and eight with early RA (median disease duration five months) were investigated. Apoptosis (TUNEL method combined with morphological analysis), cell surface markers (CD3, CD68), cytokines (interleukin (IL) 1alpha, IL1beta, tumour necrosis factor alpha, and IL6), and FLIP expression were evaluated. Computer assisted image analysis was used for quantification. RESULTS: The apoptosis level in RA synovium was significantly higher in the group of patients with longstanding RA than in the patients with early RA (8.8% v 0.6%, p=0.001), while the number of macrophages and FLIP expression were higher in the group with early disease than in the group with longstanding RA (16.2% v 8.3%, p=0.02 and 31.1% v 0.2%, p=0.001 respectively). All three markers correlated significantly with disease duration (R=-0.7, p<0.001 for FLIP, R=0.6, p=0.001 for apoptosis, and R=-0.5, p<0.05 for CD68). Cytokine expression and T cell score were not significantly different in early RA from longstanding RA. No differences were seen between patients treated or not treated with corticosteroids or between patients treated or not treated with disease modifying antirheumatic drugs. CONCLUSIONS: The findings suggest that RA synovial macrophages are resistant to apoptosis in early RA and express high levels of FLIP. During natural or drug modified disease progression the apoptotic mechanism may be restored with a specific increase of synovial apoptosis in patients with longstanding arthritis.     

Magnetic resonance imaging-determined synovial membrane and joint effusion volumes in rheumatoid arthritis and osteoarthritis. Comparison with the macroscopic and microscopic appearance of the synovium

Objective. To evaluate the relationship between synovial membrane and joint effusion volumes determined by magnetic resonance imaging (MRI) and macroscopic and microscopic synovial pathologic findings in patients with rheumatoid arthritis (RA) and osteoarthritis (OA). Methods. Synovial biopsies were performed, and macroscopic grades of synovitis assigned, at preselected knee sites during arthroscopy or arthrotomy in 17 knees with RA and 25 with OA. Synovial inflammation and 9 separate tissue characteristics were graded histologically. Synovial membrane and joint effusion volumes were determined by preoperative MRI, enhanced with intravenous gadopentetate dimeglumine. Results. MRI-determined synovial membrane volumes were correlated with the overall histologic assessment of synovial inflammation (Spearman's σ = 0.55, P < 0.001), with fibrin deposition, with subsynovial mononuclear and polymorphonuclear leukocyte infiltration (σ = 0.51-0.59), and less significantly with macroscopic synovitis, vessel proliferation, and granulation tissue formation (σ = 0.40-0.42). No correlation with synovial lining multiplication, perivascular edema, villous formation, or fibrosis was found (σ < 0.30). Conclusion. MRI-determined synovial volumes are correlated with synovial inflammatory activity. Synovial volumes probably mainly reflect the mass of cell-infiltrated, vascularized subsynovial tissue, but may also be influenced by the cumulative synovial proliferative activity. MRI-determined synovial membrane and effusion volumes may be sensitive markers and/or predictors of disease activity and treatment outcome in RA.     

Distinct synovial immunopathologic characteristics of juvenile-onset spondylarthritis and other forms of juvenile idiopathic arthritis

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.     

A comparison of clinical vs ultrasound determined synovitis in rheumatoid arthritis utilizing gray-scale, power Doppler and the intravenous microbubble contrast agent 'Sono-Vue'

OBJECTIVES: Synovitis in rheumatoid arthritis (RA) is assessed clinically by the presence of joint tenderness and swelling. Synovial thickening and increased vascularity may also be detected by high-resolution ultrasonography (US) and power Doppler (PD). This study investigated the relationship between clinical and sonographic features of synovial disease utilizing US, PD and the contrast agent Sono-Vue. METHODS: Forty RA patients were recruited. One proximal inter-phalangeal or metacarpophalangeal joint was selected per patient, as being unambiguously either: swollen and tender, just swollen, just tender or neither swollen nor tender (Nil). Ten joints were selected per clinical group. On US, the mean synovial thickness was measured and synovial hypertrophy and erosions were graded subjectively. Synovial vascularity demonstrated by PD was scored subjectively pre- and post-contrast. RESULTS: All grades of synovial vascularity were found in each clinical group including the Nil group. There were significant differences between the four clinical groups for both synovial hypertrophy (P = 0.024) and PD scores pre- (P = 0.022) and post- (P = 0.039) contrast. Tender-only joints showed significantly less vascularity than other groups. Post-contrast, the median PD scores increased in all but the Nil group, in some cases from the normal to abnormal range. CONCLUSION: Synovitis demonstrated by US and PD is not predicted by patterns of disease as described by joint swelling and tenderness despite unambiguous selection of joints. Synovial vascularity was the least in tender-only joints and was heterogeneous in all other groups, including Nil joints. These findings question the reliability of traditional clinical signs in RA synovitis assessment.     

Interleukin‐17–positive mast cells contribute to synovial inflammation in spondylarthritis

Objective

Studies comparing spondylarthritis (SpA) to rheumatoid arthritis (RA) synovitis suggest that innate immune cells may play a predominant role in the pathogenesis of SpA. Recent observations have indicated a marked synovial mast cell infiltration in psoriatic SpA. We therefore undertook the present study to investigate the potential contribution of mast cells to synovial inflammation in SpA.

Methods

Synovial tissue and fluid were obtained from patients with either nonpsoriatic or psoriatic SpA (n = 82) and patients with RA (n = 50). Synovial biopsy tissue was analyzed by immunostaining and used in ex vivo cultures. Synovial fluid was analyzed by enzyme‐linked immunosorbent assay.

Results

We observed a strong and specific increase of c‐Kit–positive mast cells in the synovium from patients with SpA compared to the synovium from patients with RA synovitis, which was independent of disease subtype (nonpsoriatic versus psoriatic), disease duration, and treatment. Staining of mast cell granules, analysis of synovial fluid, and results in ex vivo tissue culture did not indicate increased degranulation in SpA synovitis. However, mast cells expressed significantly more interleukin‐17 (IL‐17) in SpA than in RA synovitis, and mast cells constituted the major IL‐17–expressing cell population in the SpA synovium. Ex vivo targeting of synovial mast cells with the c‐Kit inhibitor imatinib mesylate significantly decreased the production of IL‐17 as well as other proinflammatory cytokines in synovial tissue cultures. Analysis of paired pre‐ and posttreatment synovial tissue samples indicated that the mast cell/IL‐17 axis in SpA was not modulated by effective tumor necrosis factor (TNF) blockade.

Conclusion

The specific and TNF‐independent increase in IL‐17–expressing mast cells may contribute to the progression of synovial inflammation in peripheral SpA.

     

Synovial fluid and serum concentrations of aminoterminal propeptide of type III procollagen in healthy volunteers and patients with joint disease.

OBJECTIVES--To analyse synovial fluid and serum concentrations of the amino-propeptide of the type III procollagen (PIIINP) in normal individuals and patients with joint disease, and to explore the relationship between synovial fluid PIIINP concentrations and the rheumatological diagnosis, local inflammation, and joint disease. METHODS--A radioimmunoassay was used to measure the PIIINP concentrations in serum and knee joint synovial fluid from 16 healthy volunteers and patients with osteoarthritis (OA) (n = 40), rheumatoid arthritis (RA) (n = 30), and psoriatic arthritis (PsA) (n = 12). The PIIINP measurements were related to demographic data, synovial fluid leucocyte counts, and radiographic changes at the knee. RESULTS--Serum PIIINP concentrations were greater in each of the disease groups than in control subjects, but there were no differences between the disease groups. Synovial fluid concentrations of PIIINP were much greater than those in serum, indicating local production, and were significantly greater in RA than in other disease groups (p < 0.001). There was only a weak positive correlation between synovial fluid leucocyte counts, some radiographic changes, and synovial fluid PIIINP concentrations. CONCLUSIONS--These data suggest that synovial fluid PIIINP concentrations may reflect local synovial proliferative processes in joint disease, and that they could be of diagnostic and prognostic value in inflammatory arthropathies.     

Analyse der Immunglobuline und Komplementfaktoren in Synovialflüssigkeit und Serum bei rheumatoider Arthritis, seronegativen Spondylarthropathien und Osteoarthritis: Pathophysiologie und retrospektive Analyse der klinischen Wertigkeit

Synovial fluid (SF) analysis was a mandatory investigation in rheumatological practice. In recent time, synovial fluid analysis lost importance predominantly due to unclear defined guidelines for the practical use. OBJECTIVE: To evaluate the clinical value of the determination of the complement components C'3c and C'4 and immunoglobulines IgG, IgA and IgM synovial fluid concentrations with regard to pathophysiology and currently used RA and SpA classification criteria. METHODS: Synovial fluid samples were obtained from 22 patients fulfilling ACR criteria for rheumatoid arthritis (RA), and 18 patients suffering from seronegative spondyloarthropathy (SpA) according to the ESSG criteria. Sixteen osteoarthritis (OA) SF samples were used as controls. IgG, IgA, IgM, C'3c and C'4 in SF and sera were determined by nephelometry. Comparison of the diseases, and linear as well as stepwise logistic regression analyses were performed in order to determine the interrelation of the determined parameters and a ranking of their diagnostic value for the identification of RA or SpA synovial fluids. RESULTS: SF-IgA, SF-IgG and SF-IgM concentrations were closely correlated with their corresponding serum levels (p < 0.01), while SF-C'3c and SF-C'4 depended on articular factors (p < 0.01). Determination of SF-C'3c (accuracy = 80.4%, improved chi 2 = 22.02, p < 0.001) and SF-C'4 (accuracy = 75.0%, improved chi 2 = 21.81, p < 0.001) both provided a good predictive value for the diagnosis of SpA when exceeding the cut off level of about 40 mg/dl (C'3c) or 15 mg/dl (C'4), respectively. Calculation of the C'-SF/S ratios did not provide an additional diagnostic benefit. SF-IgG, IgA and IgM as well as the calculated SF/S ratios were within the same range in RA and SpA fluids. CONCLUSIONS: SF concentration of complement components primarily depends on local articular factors. Significant differences of SF complement concentrations in established RA and SpA give reason for prospective analysis of these parameters in early undifferentiated oligoarthritis and evaluation in large studies, e.g. when re-evaluating the preliminary criteria for spondyloarthropathy.     

Synovial inflammation does not change in the absence of effective treatment: implications for the use of synovial histopathology as biomarker in early phase clinical trials in rheumatoid arthritis

OBJECTIVES: To determine the impact on synovial histopathology of changes in clinical disease activity in the absence of effective treatment. METHODS: Twelve patients with active RA not receiving effective treatment were studied over a 14 week period. Synovial biopsy specimens obtained at baseline and week 14 were analysed by histology and immunohistochemistry. RESULTS: Over the course of 14 weeks, there was a trend towards a decrease of the DAS28, with 7/12 patients being good or moderate DAS28 responders despite the absence of effective treatment. Patients' assessment of global disease activity and swollen joint count both decreased significantly. Histologically, there was a decrease of lining layer hyperplasia and lymphoid aggregates, a similar trend for vascularity, but there was no effect on global synovial infiltration. Accordingly, there was no decrease of the cellular infiltration with T lymphocytes (CD3, CD4, CD8), B lymphocytes (CD20), plasma cells (CD38), dendritic cells (CD1a, CD83), and even an increase of CD163+ sublining macrophages, with a similar trend for CD68+ sublining macrophages. The changes in DAS28 scores in these patients did not correlate with changes in histological variables, with the exception of an inverse correlation with plasma cells. Remarkably, even in the DAS28 responders, no significant changes in synovial inflammatory infiltration were noted. CONCLUSIONS: Despite variations in global disease activity, synovial inflammatory infiltration did not change significantly in the absence of effective treatment. The lack of a placebo effect on synovial markers of treatment response such as sublining macrophages can facilitate conclusive early phase trials with small numbers of patients with RA.     

Distinct synovial immunopathologic characteristics of juvenile‐onset spondylarthritis and other forms of juvenile idiopathic arthritis

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.

     

Quantitation of human synovial mast cells in rheumatoid arthritis and other rheumatic diseases

We examined sections of synovial membranes from 14 patients with rheumatoid arthritis (RA), 7 with other rheumatic diseases, and 10 with no apparent joint disease. Patients with RA and other rheumatic diseases had significantly more synovial mast cells/vessel than patients with no joint disease (0.49 and 0.20, respectively, versus 0.03). They also had significantly more total mast cells/10 fields than patients with no joint disease (9.9 and 5.0, respectively, versus 0.4). Within the rheumatoid group, patients with active disease had more total mast cells/10 fields than patients clinically considered to have end-stage disease (P < 0.05). Synovial basophils were not identified in any patient. Synovial vascularity was similar for all groups (2.3 vessels/field). The role of the synovial mast cell in RA and other rheumatic diseases remains to be determined.     

p53 expression in rheumatoid and psoriatic arthritis synovial tissue and association with joint damage

BACKGROUND: Overexpression and functional mutations of p53 have been found in the synovial tissue (ST) of patients with rheumatoid arthritis (RA), but their clinical significance remains unclear. OBJECTIVE: To analyse p53 expression in the ST of patients with RA and psoriatic arthritis (PsA) and its association with joint damage. METHODS: Synovial biopsy specimens were obtained by arthroscopy in 45 patients (27 RA, 18 PsA). Radiographs of hands, feet, and the joint undergoing arthroscopy were obtained to evaluate the presence of erosive disease. Synovial cell populations were analysed using CD4, CD8, CD138, CD20, and CD68 monoclonal antibodies (mAbs). The p53 protein was determined by immunohistology using DO7 mAb in 34 patients (18 RA, 16 PsA). In 11 patients with early RA, the association between p53 and 1 year progression of radiographic damage was analysed using the Larsen-Scott method. RESULTS: The p53 protein was detected in 16/18 (89%) patients with RA and in 9/16 (56%) patients with PsA, but its expression in RA was significantly higher than in PsA. In RA, p53 expression was significantly associated with erosive disease, and its scores were higher in patients with radiological progression. CD68 expression was also associated with erosions and radiological progression in RA. No association was found between either p53 or CD68 and erosive disease in PsA. CONCLUSIONS: These results suggest that p53 ST overexpression and association with joint damage is characteristic of RA rather than PsA, and that p53 ST expression might be a prognostic marker of joint damage in RA.     

Association of CD163+ macrophages and local production of soluble CD163 with decreased lymphocyte activation in spondylarthropathy synovitis

OBJECTIVE: Since CD163+ macrophages are selectively increased in spondylarthropathy (SpA) synovitis, we investigated the role of CD163+ macrophages in synovial inflammation. METHODS: Synovial biopsy samples from 26 SpA and 23 rheumatoid arthritis (RA) patients were analyzed for macrophage and lymphocyte subsets. Synovial fluid (SF) samples were analyzed by Western blotting and enzyme-linked immunosorbent assay for soluble CD163 (sCD163) and by flow cytometry for lymphocyte activation. We also analyzed sCD163 in sera from 100 SpA patients, 23 RA patients, 20 healthy controls, and 20 SpA patients treated with infliximab. Polymorphism of haptoglobin (Hp), the CD163 ligand, was determined in 130 SpA and 23 RA patients. RESULTS: CD163+ macrophages, but not CD68+ macrophages, were significantly increased in SpA versus RA synovium and in HLA-B27+ versus HLA-B27- SpA. Despite similar lymphocyte numbers, activated lymphocytes (CD69+) were significantly decreased in SpA versus RA patients, with an inverse correlation between CD163 and CD69 levels. Local production of sCD163 was evidenced by a 5-7-fold higher level of sCD163 in SF than in serum and by the correlation with synovial lining CD163+ macrophages in SpA. SF sCD163 levels correlated directly with global inflammation but correlated inversely with CD69+ SF T lymphocytes in the synovium. In contrast, serum sCD163 levels were only moderately increased, did not correlate with SF sCD163 levels or parameters of inflammation, and were unaffected by infliximab therapy. The distribution of Hp polymorphism was not altered in SpA and was not related to CD163 expression. CONCLUSION: Increased numbers of CD163+ macrophages in SpA synovium and local production of sCD163 are associated with global inflammation as well as impairment of T cell activation, suggesting a dual role for CD163+ macrophages in SpA synovitis.     

Sensitivity and significance of nuclear magnetic tomography findings of finger joints in rheumatoid arthritis

Evaluation of the sensitivity and value of magnetic resonance imaging (MRI) findings and miniarthroscopic investigations (mini-/needle-arthroscopy = MA) of metacarpophalangeal (MCP) joints in patients with rheumatoid arthritis (RA). 30 patients with RA (21 female, 9 male), disease duration 2 months to 22 years and mean disease activity score (DAS) of 3.90 (range: 2.00-7.67) were examined by MRI of the hand (MCP region) and following MA of the MCP-II joints. MRI parameters for arthritis (synovial enhancement, synovial extension, cortical alterations, joint gap width) and corresponding macroscopic items (synovial extension, synovial hyperemia and vascularity, cortical alterations) by MA, scored semiquantitatively for synovitis (graduated from 0-III degree), were correlated. Additionally, normal radiographs of the hands were performed and compared with MRI findings concerning the detection of bony lesions. Evaluation of the 30 MRI and MA examination revealed highly significant correlations (p < 0.0001) for the parameters of synovial extension (MRI/MA), cortical alterations (MRI/MA) and synovial enhancement (MRI) compared to synovial hyperemia and vascularity (MA). We found significant correlations for parameters of activity and chronicity of RA pathology as assessed by MRI and MA. The detection rate of cortical lesions by MRI was two and a half times higher than by X-ray. MRI findings of MCP-II joints compared to those of MCP III-V showed that the MCP-II joint was more strongly involved.     

Resistin in rheumatoid arthritis synovial tissue, synovial fluid and serum

BACKGROUND: Resistin is a newly identified adipocytokine which has demonstrated links between obesity and insulin resistance in rodents. In humans, proinflammatory properties of resistin are superior to its insulin resistance-inducing effects. OBJECTIVES: To assess resistin expression in synovial tissues, serum and synovial fluid from patients with rheumatoid arthritis, osteoarthritis and spondylarthropathies (SpA), and to study its relationship with inflammatory status and rheumatoid arthritis disease activity. METHODS: Resistin expression and localisation in synovial tissue was determined by immunohistochemistry and confocal microscopy. Serum and synovial fluid resistin, leptin, interleukin (IL)1beta, IL6, IL8, tumour necrosis factor alpha, and monocyte chemoattractant protein-1 levels were measured. The clinical activity of patients with rheumatoid arthritis was assessed according to the 28 joint count Disease Activity Score (DAS28). RESULTS: Resistin was detected in the synovium in both rheumatoid arthritis and osteoarthritis. Staining in the sublining layer was more intensive in patients with rheumatoid arthritis compared with those with osteoarthritis. In rheumatoid arthritis, macrophages (CD68), B lymphocytes (CD20) and plasma cells (CD138) but not T lymphocytes (CD3) showed colocalisation with resistin. Synovial fluid resistin was higher in patients with rheumatoid arthritis than in those with SpA or osteoarthritis (both p<0.001). In patients with rheumatoid arthritis and SpA, serum resistin levels were higher than those with osteoarthritis (p<0.01). Increased serum resistin in patients with rheumatoid arthritis correlated with both CRP (r=0.53, p<0.02), and DAS28 (r=0.44, p<0.05), but not with selected (adipo) cytokines. CONCLUSION: The upregulated resistin at local sites of inflammation and the link between serum resistin, inflammation and disease activity suggest a role for resistin in the pathogenesis of rheumatoid arthritis.     

Comparison of ultrasonographic assessment of synovitis and joint vascularity with radiographic evaluation in a randomized, placebo-controlled study of infliximab therapy in early rheumatoid arthritis

OBJECTIVE: To investigate sensitive ultrasonographic imaging methods for detection of synovial thickness and vascularity to discriminate between patients with early rheumatoid arthritis (RA) receiving infliximab + methotrexate (MTX) versus placebo + MTX over 18 weeks, and to compare the relationship between synovial thickening and vascularity at baseline and radiologic damage to joints of the hands and feet at 54 weeks. METHODS: Patients with early RA (duration <3 years) receiving stable dosages of MTX were randomly assigned to receive blinded infusions of 5 mg/kg infliximab (n = 12) or placebo (n = 12) at weeks 0, 2, 6, and then every 8 weeks until week 46. At baseline and week 18, clinical assessments were performed, and metacarpophalangeal joints were assessed by high-frequency ultrasonography and power Doppler ultrasonography measurements. Radiographs of the hands and feet taken at baseline and at 54 weeks were evaluated using the van der Heijde modification of the Sharp method (vdH-Sharp score). RESULTS: Using changes in the total vdH-Sharp score over 54 weeks and changes in synovial thickening and joint vascularity at 18 weeks, we were able to distinguish those patients receiving infusions of infliximab + MTX from those receiving placebo + MTX. Sonographic measurements of synovial thickening and vascularity at baseline in the placebo + MTX group demonstrated clear relationships with the magnitude of radiologic joint damage at week 54. Infliximab + MTX treatment abolished these relationships. CONCLUSION: The delay or reversal of inflammatory and joint-destructive mechanisms in patients with early RA was already apparent following 18 weeks of treatment with infliximab + MTX and was reflected in radiologic changes at 54 weeks.     

Why is biologic therapy useful in spondyloarthritis? Knowledge from synovial immunopathologic studies of spondyloarthritis

The pathogenesis of most rheumatic diseases remains unknown. It is believed that both genetic and environmental factors play a pivotal role in the development of synovial inflammation in rheumatoid arthritis (RA), spondyloarthritis (SpA) and osteoarthritis (OA). In the last two decades, there have been many immunopathologic studies on RA, SpA and OA, and the findings revealed different types of arthritis may also present different pathologic patterns. These included higher vascularity and increased infiltration with CD163 macrophages and neutrophils, but relatively low values for lining cell (LL) hyperplasia in SpA synovium. However, the increased LL hyperplasia, as well as CD1a+ cells and the presence of intracellular citrullinated protein were more prominent in RA than in SpA synovitis. Anti‐tumor necrosis factor alpha (anti‐TNFα) therapy can significantly reduce synovial LL hyperplasia, vascularity and mononuclear cells infiltration in the majority of RA or SpA patients. This may explain why clinically, arthritis patients can get significant improvement after TNFα blocker treatment.     

Identification of synovial biomarkers of response to experimental treatment in early-phase clinical trials in spondylarthritis

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.     

Miniarthroscopy of metacarpophalangeal joints in rheumatoid arthritis. Rating of diagnostic value in synovitis staging and efficiency of synovial biopsy.

OBJECTIVE: To evaluate miniarthroscopy (MA) (needle arthroscopy) of involved joints in rheumatoid arthritis (RA) in the early detection and staging of synovitis and its application in visual guided synovial biopsies. METHODS: 1.0 and 1.9 mm (0 degree/30 degrees) arthroscopes were used in a 2 portal technique. MA performance was developed and evaluated first on hand cadavers (n = 20) and then transferred to metacarpophalangeal (MCP) joints under local anesthesia conditions. Joints of 20 patients with RA with different disease activity and duration were scoped and rated according to scores adapted from arthroscopy of other joints. RESULTS: In 20/20 cases MA provided visualizing and magnification of intraarticular features of MCP joints in RA and allowed grading of synovial alterations, chondromalacia, and bony alterations. Synovial surface changes, thickness, and fibrosis were related to disease duration, as was damage to cartilage and bone. The degree of acute inflammatory reactions like vascularity and hyperemia varied independently of chronic changes; synovial proliferation was reflected to some extent by C-reactive protein. In 2 patients with early RA, synovitis criteria were found macroscopically and histologically. In 18/20 joints, biopsies were taken under visual control; in the other 2, progression of disease (Larsen score >3) limited arthroscopy to 1.0 scope imaging only. Sampling sizes were sufficient for histologic and molecular analysis. CONCLUSION: The developed standardized procedure of MCP arthroscopy is minimally invasive, practicable, and well tolerated by patients, and may allow synovitis monitoring, staging, and biopsy in patients with early as well as chronic arthritis.     

Diagnostic usefulness of synovial vascular morphology in chronic arthritis. A systematic survey of 100 cases

OBJECTIVES: To assess the diagnostic usefulness of the systematic analysis of synovial vascular morphology in various inflammatory, early, and longstanding arthropathies, and to examine the validity of the vascular patterns in predicting the evolution of a group of patients with undifferentiated arthritis (UA). METHODS: One hundred patients who underwent rheumatologic arthroscopy of a symptomatic joint (85 knees, 11 wrists, 3 elbows, 1 metacarpophalangeal joint) were evaluated. The same observer, blinded to patient diagnosis, analyzed the video recordings of the arthroscopies. Vascular morphology was classified into 3 patterns: straight, tortuous, and mixed. RESULTS: Eighty-one patients had inflammatory arthritis: 35 rheumatoid arthritis (RA), 16 psoriatic arthritis (PsA), 13 spondyloarthropathies (SpA), and 17 UA. Forty-nine percent of patients with RA had a straight pattern, 28% a mixed, and 23% a tortuous one. The sensitivity rate of the straight pattern for RA was 77% and the specificity rate was 70%. Seventy-six percent of RA patients with a straight pattern were rheumatoid factor positive (RF+) against 25% of RA patients with a tortuous pattern. The odds ratio for RA associated to straight compared with tortuous pattern was 57.3 (95% confidence interval, 6.6 to 499.5; P <.001). Patients with PsA and SpA shared the same pattern and were analyzed as 1 group. Ninety-three percent of patients with PsA/SpA had a tortuous pattern, 4% a straight pattern, and 3% a mixed pattern. The sensitivity rate of the tortuous pattern for PsA/SpA was 61% and the specificity rate was 95%. During 2 years of follow-up, 6 of 17 patients with UA were definitely diagnosed: 4 RA (2 RF+ and straight pattern; 2 with a tortuous pattern, 1 with RF+ and HLA-B27+); 1 SpA and 1 PsA, both with a tortuous pattern. No differences in vascular patterns were observed according to disease duration. Our results indicate that vascular patterns are not modified by disease modifying antirheumatic drug (DMARD) treatment. The other 19 patients had osteoarthritis (n = 8) and calcium pyrophosphate dihydrate crystal deposition disease (n = 11) and their predominant vascular pattern was tortuous-like. CONCLUSIONS: Arthroscopic assessment of synovial vascular changes in chronic arthritis may be of diagnostic and pathogenetic interest, although differences between published studies suggest a need for consensus in evaluating vascular patterns. A straight pattern is strongly associated with RF + RA whereas a tortuous pattern is generally associated with PsA or SpA; these associations are independent of disease duration. The vascular pattern likely does not change qualitatively with DMARD therapy. The application of this technique to the diagnosis or prognosis of patients with UA may be a complementary tool for the treatment of these patients, but larger, prospective studies are necessary to confirm this hypothesis.