Eric Veys

Transplantation of viable meniscal allograft. Survivorship analysis and clinical outcome of one hundred cases.

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.

Synovial histopathology of psoriatic arthritis, both oligo- and polyarticular, resembles spondyloarthropathy more than it does rheumatoid arthritis

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, αVβ3, 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.

Transplantation of Viable Meniscal Allograft

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.

Infiltration of the synovial membrane with macrophage subsets and polymorphonuclear cells reflects global disease activity in spondyloarthropathy

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.

Anti-citrullinated peptide antibodies may occur in patients with psoriatic arthritis

Background: Anti-cyclic citrullinated peptide (anti-CCP) antibodies are considered highly specific markers of rheumatoid arthritis. Despite the high specificity of the test, anti-CCP antibodies have also been observed in psoriatic arthritis. Objective: To determine the frequency of anti-CCP antibodies in psoriatic arthritis and to describe the clinical characteristics of such patients. Methods: Serum samples from 192 patients with psoriatic arthritis were analysed for anti-CCP antibodies. A previously defined cut off point was applied at a specificity level of ⩾98.5% (42 U/ml). Antibodies against pepA and pepB (two synthetic citrullinated peptides) were determined on samples containing anti-CCP antibodies by line immune assay. The swollen joint count and the numbers of affected joints (present or past) were recorded. Clinical features were noted and if available radiographs of hands and feet were scored for erosions. Rheumatoid factor was determined in all samples. Results: Anti-CCP antibodies were found in 15 patients (7.8%); 13 of 15 anti-CCP2 positive samples were also positive for anti-pepA or pepB antibodies. The prevalence of anti-CCP antibodies was higher than expected in view of the highly specific cut off applied in the test. Detailed analysis of the clinical and radiological features makes it improbable that the high prevalence of anti-CCP antibodies resulted solely from concomitant psoriasis and rheumatoid arthritis or from misclassification. Conclusions: Anti-CCP antibodies may be present in patients with psoriatic arthritis. Although some of the present cohort could have had psoriasis with concomitant rheumatoid arthritis, a proportion at least had the typical characteristics of psoriatic arthritis as the primary diagnosis.

The effect of TNFalpha blockade on the antinuclear antibody profile in patients with chronic arthritis: biological and clinical implications

Since the first proof of efficacy of TNFalpha blockade, both the number of patients treated worldwide and the number of indications for treatment with TNFalpha blockers have grown steadily. Surprisingly, the profound immunomodulation induced by anti-TNFalpha therapy is associated with a relatively low incidence of immune-related complications such as lupus-like syndromes and demyelinating disease. This contrasts sharply with the prominent induction of autoantibodies such as antinuclear antibodies (ANA) and anti-dsDNA antibodies during TNFalpha blockade. Although this phenomenon has been recognized for several years, the clinical and biological implications are not yet fully understood. In this review, recent studies analysing the effect of TNFalpha blockade (infliximab and etanercept) on the ANA profile in autoimmune arthritis will be discussed. Taken together, these reports indicate that the prominent ANA and anti-dsDNA autoantibody response is 1) not a pure class effect of TNFalpha blockers, 2) independent of the disease background, 3) largely restricted to the induction of short-term IgM anti-dsDNA antibodies, and 4) not associated with other serological or clinically relevant signs of lupus. Nevertheless, a careful follow-up of patients treated with TNFalpha blockers remains mandatory, including monitoring for lupus-like characteristics.

Histological evidence that infliximab treatment leads to downregulation of inflammation and tissue remodelling of the synovial membrane in spondyloarthropathy

Objective: To confirm and extend the immunopathological evidence of effects of infliximab on the synovium in active spondyloarthropathy. Methods: Synovial biopsies obtained in patients with spondyloarthropathy at baseline and week 12 were stained and scored by two independent observers. Two study populations were evaluated: I, a cohort of 10 patients treated with 5 mg/kg infliximab at week 0, 2, and 6, plus three placebo treated patients; and II, a pooled cohort of 20 patients fulfilling identical inclusion and exclusion criteria and treated with the same loading dose regimen. Results: In study population I, treatment with infliximab induced reduction in synovial lining layer thickness (p = 0.015), endothelial activation (E-selectin, p = 0.034), and inflammatory cell infiltration with neutrophils (p = 0.041), macrophages (p = 0.034), and T cells (p = 0.026), but not with B cells and plasma cells; no such trends were observed in the placebo treated patients. Besides confirming the highly significant downregulation of inflammation, analysis of cohort II showed structural changes such as normalisation of lining layer thickness (p = 0.030), reduction in the number of blood vessels (p = 0.039), and downregulation of follicular organisation (p = 0.050). No differences in histopathological response were observed between spondyloarthropathy subtypes. Conclusions: Profound immunomodulatory changes in the synovium parallel the clinical benefit in patients with spondyloarthropathy treated with infliximab, independently of the subtype. The study provides histological evidence that TNFα blockade not only downregulates inflammation but also leads to tissue remodelling.

Involvement of neurotrophins and their receptors in spondyloarthritis synovitis: relation to inflammation and response to treatment

Objective: To investigate whether expression of the four members of the neurotrophin (NT) family and their four corresponding receptors is related to synovial inflammation in patients with spondyloarthritis (SpA). Material and Methods: Synovial fluid (SF) and serum NTs and their receptors were measured by ELISA. Immunohistochemistry was used for synovial tissue biopsy specimens from patients with SpA, rheumatoid arthritis, and osteoarthritis (OA). In SpA synovium, immunoreactivity of the receptors trkA and NGFRp75 was also assessed before and after 12 weeks of treatment with the monoclonal anti-tumour necrosis factor α antibody, infliximab. Results: mRNA transcripts of all NTs and receptors were expressed in the inflamed synovium. At the protein level, brain derived neurotrophic factor and NT-3 were significantly higher in the SF of patients with SpA than in those with OA. In contrast, ELISA of serum samples showed that the highest member in SpA was NT-4. Immunohistochemistry demonstrated that the NT receptors trkA and NGFRp75 were highly expressed in the inflamed synovium of patients with SpA, correlating with vascularity and lymphoid aggregates, respectively. Additionally, immunoreactivity of both receptors was significantly decreased after infliximab treatment. Conclusions: NTs and their receptors are expressed in inflamed peripheral joints of patients with SpA. Their expression is not constitutive but related to inflammation and they may be involved in the local disease processes.

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.

Expression of host defense scavenger receptors in spondylarthropathy.

OBJECTIVE Reactive arthritis (ReA) is postulated to be caused by a defective host defense against gram-negative bacteria. HLA-B27 could play a role in this process, but does not account for the many HLA-B27 negative patients. The objective of this study was to test the expression of 3 macrophage scavenger receptors (SRs) that are responsible for innate immunity against gram-negative bacteria: SR class A type I (SR-AI), SR-AII, and the macrophage receptor with collagenous structure (MARCO). We postulate that defects in such receptors might also contribute to the host risk factors that increase the predisposition to ReA and perhaps other subtypes of spondylarthropathy (SpA). METHODS Peripheral blood, synovial fluid, and synovial tissue samples were obtained from patients with recent Salmonella infection, ReA, other SpA, and rheumatoid arthritis (RA). The expression of SRs receptors was assessed by semiquantitative reverse transcriptase-polymerase chain reaction. RESULTS Evaluation of the peripheral blood mononuclear cells (PBMC) from 4 patients who were recently infected with Salmonella, showed that PBMC from 2 patients who developed ReA expressed positive levels of MARCO, while PBMC from 2 patients who recovered from infection without sequelae did not. The synovial fluid mononuclear cells (SFMC) from some ReA patients expressed MARCO, but the levels were only moderate. The level of MARCO in the SFMC from the SpA patient group was low. In marked contrast, MARCO expression was high in almost all samples of RA SFMC. These findings also extended to synovial tissues. CONCLUSION Expression of the host defense gene MARCO was susceptible to modulation, not only during infections, but also in the inflammatory arthritis conditions RA and SpA. MARCO is a variable to be considered as a candidate factor that might contribute to ReA.