Exposure to nuclear antigens contributes to the induction of humoral autoimmunity during tumour necrosis factor alpha blockade.

OBJECTIVE: Type I interferons and apoptotic particles contribute to antinuclear autoimmunity in experimental models. This study assessed whether similar mechanisms contribute to break peripheral B-cell tolerance in humans by studying the induction of antinuclear antibodies by tumour necrosis factor blockade in spondyloarthritis. METHODS: 40 spondyloarthritis patients treated with infliximab or etanercept and 20 renal cell carcinoma patients treated with sorafenib were studied. Serum antinucleosome IgM and nucleosomes were measured by ELISA. Type I interferon serum activity was measured using a functional reporter cell assay. Synovial apoptosis was assessed by terminal transferase nick end-labelling (TUNEL) assay and anti-active caspase-3 immunostaining. Complement was measured by nephelometry. RESULTS: Despite a similar clinical improvement and reduction of synovial inflammation, antinucleosome IgM were induced by infliximab but not etanercept. This induction did not correlate with type I interferon activity, which was transiently downmodulated by infliximab but persistently upregulated by etanercept. In contrast, antinucleosome IgM levels did correlate with serum nucleosome levels, which were significantly upregulated by infliximab but not by etanercept treatment. This increase in serum nucleosome levels was not directly related to massive cell death, but rather to a decrease of complement 3 and 4 serum levels during infliximab treatment. CONCLUSION: Infliximab and etanercept have a differential effect on both type I interferon activity and nucleosome levels. Only elevated serum nucleosomes relate to the induction of antinucleosome antibodies after infliximab treatment.

Melanoma inhibitory activity, a biomarker related to chondrocyte anabolism, is reversibly suppressed by proinflammatory cytokines in rheumatoid arthritis.

OBJECTIVE: In mice, melanoma inhibitory activity (MIA) is a chondrocyte-specific molecule with similar regulation to collagen type II. As MIA is a small secreted protein, its value as cartilage biomarker in human inflammatory arthritis was assessed. METHODS: MIA tissue distribution was studied by quantitative PCR and immunohistochemistry. The regulation of MIA production was studied in vivo in rheumatoid arthritis (RA) (n = 37) and spondyloarthritis (SpA) (n = 30) synovial fluid (SF), and in vitro in alginate embedded human chondrocytes. Therapeutic modulation of serum MIA was evaluated during tumour necrosis factor (TNF)alpha and interleukin (IL)1 blockade in RA. RESULTS: MIA was primarily expressed by chondrocytes in the human joint. SF MIA levels were lower in RA than in SpA despite similar levels of overall synovial inflammation. Further analysis indicated that these levels were inversely correlated with the degree of joint inflammation in RA, but not in SpA, and that the levels of TNFalpha and IL1beta were significantly increased in RA versus SpA. Accordingly, these proinflammatory cytokines suppressed MIA mRNA and protein in cultured chondrocytes. This suppression was paralleled by suppression of cartilage anabolism as assessed by collagen type 2 and aggrecan mRNA. Treatment of patients with RA with TNF blockade or IL1 blockade induced an increase of serum MIA levels. CONCLUSION: The decreased levels of MIA in the inflamed RA joint and the coregulation of MIA and cartilage matrix molecules by proinflammatory cytokines indicate that joint inflammation in RA not only drives accelerated cartilage degradation but also suppresses cartilage anabolism. This inflammation-driven suppression is reversible in vivo.

Altered gut transcriptome in spondyloarthropathy.

BACKGROUND: Intestinal inflammation is a common feature of spondyloarthropathy (SpA) and Crohn's disease. Inflammation is manifested clinically in Crohn's disease and subclinically in SpA. However, a fraction of patients with SpA develops overt Crohn's disease. AIMS: To investigate whether subclinical gut lesions in patients with SpA are associated with transcriptome changes comparable to those seen in Crohn's disease and to examine global gene expression in non-inflamed colon biopsy specimens and screen patients for differentially expressed genes. METHODS: Macroarray analysis was used as an initial genomewide screen for selecting a comprehensive set of genes relevant to Crohn's disease and SpA. This led to the identification of 2625 expressed sequence tags that are differentially expressed in the colon of patients with Crohn's disease or SpA. These clones, with appropriate controls (6779 in total), were used to construct a glass-based microarray, which was then used to analyse colon biopsy specimens from 15 patients with SpA, 11 patients with Crohn's disease and 10 controls. RESULTS: 95 genes were identified as differentially expressed in patients with SpA having a history of subclinical chronic gut inflammation and also in patients with Crohn's disease. Principal component analysis of this filtered set of genes successfully distinguished colon biopsy specimens from the three groups studied. Patients with SpA having subclinical chronic gut inflammation cluster together and are more related to those with Crohn's disease. CONCLUSION: The transcriptome in the intestine of patients with SpA differs from that of controls. Moreover, these gene changes are comparable to those seen in patients with Crohn's disease, confirming initial clinical observations. On the basis of these findings, new (genetic) markers for detection of early Crohn's disease in patients with SpA can be considered.

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.

Effect of age on prevalence of anticitrullinated protein/peptide antibodies in polyarticular juvenile idiopathic arthritis.

OBJECTIVES: Anticitrullinated protein/peptide antibodies (ACPA) have an excellent diagnostic performance for rheumatoid arthritis (RA). Despite similarities between RA and polyarticular juvenile idiopathic arthritis (JIA), the prevalence of ACPA in polyarticular JIA is low. We wanted to evaluate the influence of age, disease duration and total immunoglobulin G (IgG) concentration on ACPA positivity in this cohort. METHODS: Patients with JIA were classified according to age and International League of Associations for Rheumatology classification. Sixty-one JIA patients aged less than 16 yr were included and classified as polyarticular JIA (poly JIA <16; n=23) or non-polyarticular JIA (n=38). In addition, a group of 21 polyarticular JIA patients, aged more than 16 yr (poly JIA >16) and a group of 51 RA patients were included. Antibodies to the synthetic citrullinated peptides pepA and pepB were detected by line immunoassay and antibodies to cyclic citrullinated peptides (CCP2) by enzyme-linked immunosorbent assay. Serum IgG was measured by fixed-time immunonephelometry. RESULTS: No ACPA reactivity was observed in the non-polyarticular group. In poly JIA <16, only 1/23 had anti-CCP2 antibody, whereas in poly JIA >16 patients a significantly higher fraction was detected (6/21). All but one of the anti-CCP2 reactive patients were rheumatoid factor (RF) positive. Assessing anti-CCP2 antibody concentration as a continuous variable, significantly higher titres were found in poly JIA >16 compared with poly JIA <16. No correlation between anti-CCP2 concentration and total IgG was detected. Four patients demonstrated immunoreactivity against pepA and pepB; all of them were anti-CCP2 reactive, poly JIA >16 patients. CONCLUSIONS: ACPA are present in low prevalence in polyarticular JIA and are particularly found in the RF-positive subset. With age, a significant increase in anti-CCP2 positivity is observed in polyarticular JIA patients.

Cyclodextrin polysulphates repress IL-1 and promote the accumulation of chondrocyte extracellular matrix.

OBJECTIVE: To evaluate the influence of cyclodextrin polysulphate (CDPS) on the extracellular matrix (ECM) metabolism of human articular cartilage chondrocytes. METHODS: Isolated chondrocytes from femoral condyle cartilage of human knee joints were cultured in gelled alginate to maintain their differentiated phenotype. During 1 week of culture, the cells were exposed to different concentrations of CDPS. Synthesis of aggrecans was investigated in these cultures after using Na(2)(35)SO(4) as a radioactive precursor during the last 24h of culture. The artificial matrix was then solubilised with Na-citrate and newly synthesised aggrecan aggregates, accumulated during culture, were liberated and assayed. The isolated chondrocytes were labelled with antibodies against aggrecan and type II collagen to analyse the ECM molecules in the cell-associated matrix (CAM). Plasma membrane levels of receptors for insulin-like growth factor-1 (IGF-1RI) and for interleukin-1 (IL-1RI and IL-1RII), as well as levels of IGF-1, IL-1alpha and -beta were determined after the cells had been permeabilized and stained with the appropriate antibodies. The release of IL-6 in the culture media was used as a variable reflecting auto/paracrine IL-1 activity of the cells in different experimental conditions. RESULTS: CDPS significantly increased total (35)S-incorporation rates in ECM aggrecan. When compared with controls, CDPS-treated chondrocytes expressed significantly higher CAM aggrecan and type II collagen levels. As plasma membrane-bound IGFR1 and intracellular IGF-1 levels remained unchanged, this increase in accumulated CAM compounds may have resulted from suppressed catabolic activities by the chondrocytes in culture. CDPS-treated cells expressed significantly lower amounts of intracellular IL-1alpha and -beta levels. Plasma membrane-bound IL-1RI and decoy IL-1RII remained unchanged. beta-cyclodextrin-treated chondrocytes released significantly less IL-6 in the supernatant culture media. CONCLUSION: CDPS is a novel polysulfated polysaccharide showing cartilage structure modifying effects in vitro as it improves the synthesis of aggrecan and the accumulation of CAM macromolecules. This effect probably resulted in part from the downregulation of IL-1.

Anti-citrullinated protein/peptide antibodies (ACPA) in rheumatoid arthritis: specificity and relation with rheumatoid factor.

Anti-citrullinated protein/peptide antibodies (ACPA) are highly specific and sensitive markers for rheumatoid arthritis (RA). For instance, for the anti-CCP2 assay, sensitivities ranging from 55% to 80% and specificities ranging from 90% to 98% have been reported. Despite their high specificity, recent reports have suggested that ACPA may be found in some patients with other rheumatic autoimmune diseases, including psoriatic arthritis, systemic lupus erythematosus and Sjögren's syndrome. Also, the differences between the classical rheumatoid factor (RF) and ACPA, as well as the complementarity between both tests have recently been demonstrated more clearly. Indeed, both antibody systems have a different association with specific RA features like extra-articular manifestations, a different association with the HLA shared epitope and, behave differently following anti-TNF therapy.

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 alpha 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.

CARD15 polymorphisms are associated with anti-Saccharomyces cerevisiae antibodies in caucasian Crohn's disease patients.

Carriage of CARD15 gene polymorphisms and the serological marker anti-Saccharomyces cerevisiae antibodies (ASCA) are two markers for Crohn's disease (CD). Similar phenotypes have been associated with both markers. In the present study we analysed whether both markers were associated with each other and, if so, whether this association could be explained by a direct link or by an indirect association with those phenotypes. Therefore, we included 156 consecutive Caucasian CD patients and assessed the prevalence of the three common single nucleotide polymorphisms in the CARD15 gene. Serum samples were analysed for IgA and IgG ASCA by ELISA. CD patients with CARD15 polymorphisms were more frequently ASCA positive (OR 2.7 (1.4-5.2); P = 0.002) and had higher titres for ASCA IgA (P = 0.005) and ASCA IgG (P < 0.001) compared to patients carrying the wild type polymorphisms. Multivariate analysis demonstrated that this association was independent from ileal disease, penetrating disease and stricturing disease, the need for resective bowel surgery, familial cases, smoking habits and early age at onset. Homozygotes or compound heterozygotes for CARD15 polymorphisms had significantly more frequent ASCA positivity compared to single heterozygotes (OR 9.1 (1.1-74.2), P(c) (corrected P-value) = 0.030). These data indicate that there is a significant association between the carriage of CARD15 polymorphisms and ASCA, independent of the described phenotypes. Moreover, ASCA positivity is more frequent in CD patients carrying 2 CARD15 polymorphisms compared to single heterozygotes.

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 TNF alpha blockade not only downregulates inflammation but also leads to tissue remodelling.

Colon mucosa of patients both with spondyloarthritis and Crohn's disease is enriched with macrophages expressing the scavenger receptor CD163.

BACKGROUND: Crohn's disease is associated with an increased number of macrophages in ileal and colonic mucosa. Data on macrophages in gut mucosa of patients with spondyloarthritis (SpA) are scarce. OBJECTIVE: To investigate macrophages and other antigen presenting cells in gut mucosa from patients with SpA and Crohn's disease, given the relationship between both entities. METHODS: Biopsy specimens from patients with SpA, Crohn's disease, ulcerative colitis, and from controls were immunohistochemically stained with different markers for macrophages and dendritic cells. Slides were scored semiquantitatively on a four point scale. RESULTS: SpA and Crohn's disease were associated with large numbers of CD68+ macrophages. Colon mucosa of both patients with SpA and Crohn's disease, but not ulcerative colitis, showed increased numbers of macrophages expressing the scavenger receptor CD163. CONCLUSIONS: Macrophages expressing the scavenger receptor CD163 are increased in colonic mucosa in SpA and in Crohn's disease, highlighting the relationship between these entities. The increased number of CD163+ macrophages in colon mucosa of patients with SpA suggests this is another argument for a role of macrophage scavenger receptors in this group of diseases.

Rheumatoid factor, but not anti-cyclic citrullinated peptide antibodies, is modulated by infliximab treatment in rheumatoid arthritis.

OBJECTIVES: To analyse the effect of infliximab on IgM rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP) antibodies, and determine whether baseline autoantibody titres (IgM RF and anti-CCP antibodies) are associated with changes in acute phase reactants. PATIENTS AND METHODS: 62 patients with refractory RA were treated with infliximab combined with methotrexate. At baseline and week 30, serum samples were tested for IgM RF by two agglutination assays, and for anti-CCP antibodies by an ELISA. Percentage change in C reactive protein (CRP) and erythrocyte sedimentation rate (ESR) was calculated. RESULTS: At baseline and week 30 RF titres were reduced significantly during infliximab treatment (p<0.001 and p = 0.038, respectively), whereas anti-CCP antibodies were unchanged (p = 0.240). Baseline IgM RF titres, but not anti-CCP antibodies, correlated inversely with changes in CRP and ESR during treatment. Patients with a marked decrease in acute phase reactants had lower IgM RF titres than those with a smaller decrease in CRP and ESR; no significant differences were found for anti-CCP antibodies. CONCLUSION: The differential effect of infliximab treatment on IgM RF and anti-CCP antibodies, and the different predictive value on changes in acute phase reactants during infliximab treatment support the existing evidence that RF and anti-CCP antibodies are independent autoantibody systems in RA.

CARD15 gene polymorphisms in patients with spondyloarthropathies identify a specific phenotype previously related to Crohn's disease.

BACKGROUND: The association between spondyloarthropathy and Crohn's disease is well known. A risk for evolution to Crohn's disease has already been shown in the subgroup of patients with spondyloarthropathy associated with chronic gut inflammation. OBJECTIVE: To investigate whether the reported polymorphisms in the CARD15 gene, a susceptibility gene for Crohn's disease, are associated with the presence of preclinical intestinal inflammation observed in spondyloarthropathies. METHODS: 104 patients with spondyloarthropathies were studied. All underwent ileocolonoscopy with biopsies between 1983 and 2004. The prevalence of three single nucleotide polymorphisms in the CARD15 gene (R702W, G908R, and 1007fs) was assessed using restriction fragment length polymorphism-polymerase chain reaction (RFLP-PCR); the patients were compared with an ethnically matched Crohn's disease population and a control population. RESULTS: The carrier frequency of R702W, G908R, or 1007fs variants in the spondyloarthropathy populations (20%) was similar to the control population (17%), but increased to 38% in the spondyloarthropathy subgroup with chronic gut inflammation. This frequency was significantly higher than in the other spondyloarthropathy subgroups (p = 0.001) or the control group (p = 0.006), but not different from the Crohn's disease group (49%) (NS). This indicates that CARD15 polymorphisms are associated with a higher risk for development of chronic gut inflammation. CONCLUSIONS: CARD15 gene polymorphisms clearly identify a subgroup of patients with spondyloarthropathies associated with chronic intestinal inflammation.

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.

Tumour necrosis factor alpha independent disease mechanisms in rheumatoid arthritis: a histopathological study on the effect of infliximab on rheumatoid nodules.

BACKGROUND: It has been suggested that the immunopathology of rheumatoid nodules parallels that of inflamed synovium in rheumatoid arthritis (RA). OBJECTIVE: To analyse the effect of infliximab on the immunopathology of rheumatoid nodules in order to provide new insights into the relationship between synovial inflammation and rheumatoid nodules. MATERIALS AND METHODS: Nodules were present at baseline in six patients with RA and after infliximab treatment in five patients, including paired nodules before and after treatment in three patients. In one patient, the nodule appeared during treatment. Paraffin sections were used for histological analysis. Frozen sections were stained by immunohistochemistry for cellular markers (CD3, CD4, CD8, CD16, CD20, CD68), blood vessels (CD146, vWF, alphavbeta3), and adhesion molecules (E-selectin, VCAM-1, ICAM-1). RESULTS: No manifest immunopathological differences were found between the nodules before and after infliximab treatment. All nodules depicted the classical structure with a central necrotic zone, surrounding the palisade layer, and an outer connective tissue zone. Immunohistochemistry showed the presence of CD68+ and CD16+ macrophages in the palisade and the connective tissue zone, as well as a small number of CD3+, CD4+ T lymphocytes in the perivascular areas. Small vessels were seen in the connective tissue and were sometimes positive for the neovascularisation marker alphavbeta3. They expressed no VCAM-1, E-selectin weakly, but ICAM-1 strongly. ICAM-1 was also strongly expressed on palisade cells. CONCLUSIONS: Despite an improvement of articular symptoms, infliximab treatment had no distinct effect on the histopathology of rheumatoid nodules, suggesting that different pathogenetic mechanisms mediate the two disease manifestations in RA.

Technical validation of cDNA based microarray as screening technique to identify candidate genes in synovial tissue biopsy specimens from patients with spondyloarthropathy.

OBJECTIVES: To validate the use of cDNA based microarray on synovial biopsies by analysing the experimental variability due to amplification of RNA, reproducibility of the assay, heterogeneity of the tissue, and statistical analysis. METHODS: Total RNA was extracted from three spondyloarthropathy (SpA) and three osteoarthritis (OA) synovial tissue biopsy specimens and from the peripheral blood mononuclear cells (PBMC) of four healthy donors. Exponential RNA amplification by SMART-PCR was compared with linear amplification. Reproducibility was tested by comparing different microarray systems and by performing duplicate experiments. Sample heterogeneity was assessed by comparing overall gene expression profiles, histopathology, and analysis of genes expressed in the synovium and normal PBMC. Statistical analysis using t test and Bonferroni adjustment was verified by permutation of class labels. RESULTS: Gene expression was concordant in 12/14 (86%) cytokine/chemokine genes between both microarrays and different RNA amplification systems. When one microarray system was used, expressed genes were 78-95% concordant in duplicate experiments. Gene expression profiles had a higher degree of similarity between SpA synovium than between PBMC or OA synovium despite clear histopathological differences between synovial samples. Comparison of SpA synovium with OA synovium and with PBMC yielded 11 and 18 expressed transcripts, respectively; six were shared in both comparisons. Permutations of SpA and OA samples yielded only one expressed gene in 19 comparisons. CONCLUSIONS: These data provide evidence that microarrays can be used for analysis of synovial tissue biopsies with high reproducibility and low variability of the generated gene expression profiles.

Systematic safety follow up in a cohort of 107 patients with spondyloarthropathy treated with infliximab: a new perspective on the role of host defence in the pathogenesis of the disease?

BACKGROUND: Recent studies with infliximab indicate the therapeutic potential of tumour necrosis factor alpha blockade in spondyloarthropathy (SpA). Because defective host defence is implicated in the pathogenesis of SpA, the potential side effects of this treatment due to impact on the antimicrobial defence are a major concern. OBJECTIVE: To report systematically the adverse events seen in a large cohort of patients with SpA treated with infliximab, with special attention to bacterial infections. PATIENTS AND METHODS: 107 patients with SpA were treated with infliximab for a total of 191.5 patient years. All serious and/or treatment related adverse events were reported. RESULTS: Eight severe infections occurred, including two reactivations of tuberculosis and three retropharyngeal abscesses, and six minor infections with clear bacterial focus. One patient developed a spinocellular carcinoma of the skin. No cases of demyelinating disease or lupus-like syndrome were seen. Two patients had an infusion reaction, which, however, did not relapse during the next infusion. Finally, three patients with ankylosing spondylitis developed palmoplantar pustulosis. All patients recovered completely with adequate treatment, and infliximab treatment had to be stopped in only five patients with severe infections. CONCLUSIONS: Although the global safety of infliximab in SpA is good compared with previous reports in rheumatoid arthritis and Crohn's disease, the occurrence of infections such as tuberculosis and retropharyngeal abscesses highlights the importance of careful screening and follow up. Focal nasopharyngeal infections and infection related symptoms, possibly induced by streptococci, occurred frequently, suggesting an impairment of specific host defence mechanisms in SpA.

Anti-saccharomyces cerevisiae IgA antibodies are raised in ankylosing spondylitis and undifferentiated spondyloarthropathy.

OBJECTIVES: To investigate whether anti-Saccharomyces cerevisiae antibodies (ASCA), a marker for Crohn's disease (CD), are present in spondyloarthropathies (SpA) and in the subgroups ankylosing spondylitis (AS), undifferentiated SpA (uSpA), and psoriatic arthritis (PsA), in comparison with healthy and inflammatory controls (patients with rheumatoid arthritis (RA)). METHODS: ASCA IgA and IgG levels were measured with an enzyme linked immunosorbent assay (ELISA) kit (Medipan, Germany) in 26 patients with CD, 108 patients with SpA (43 patients with AS, 20 patients with uSpA, 45 patients with PsA), 56 patients with RA and 45 healthy controls. Gut biopsy samples were available in 18 AS and 10 patients with uSpA, these samples were screened for the presence of inflammation. RESULTS: Both ASCA IgG and IgA levels were raised in CD compared with healthy controls and patients with RA. ASCA IgA, but not IgG levels, were higher in SpA than in both healthy and RA controls. ASCA IgA levels were raised in AS and uSpA, but not in PsA. No significant differences in ASCA IgA levels were noted between patients with SpA with and without histological gut inflammation. CONCLUSION: ASCA IgA levels are significantly higher in SpA, and more specifically in AS, than in healthy controls and patients with RA. This is the first serum marker associated with SpA. No correlation between the presence of subclinical bowel inflammation and ASCA IgA levels was noted. However, it remains to be evaluated whether patients with SpA with ASCA have an increased risk of developing CD.

Influence of the gut and cytokine patterns in spondyloarthropathy.

Clinical and histological studies have previously shown that spondyloarthropathy (SpA) patients can have subclinical gut inflammation. This gut inflammation is related to enterocolitis in Crohn's disease (CD) and may evolve to overt inflammatory bowel disease in a subset of these patients. Moreover, there is an intriguing clinical link between gut inflammation and peripheral joint inflammation. In order to explore immunologically these concepts, recent studies have characterized phenotypically and functionally the inflammatory cells in both the gut and the synovium of SpA patients and have provided a number of new insights. Firstly, they confirm histological and pre-histological alterations of the gut immune system in SpA, which are redundant of CD and which are linked to alterations of the peripheral joints. Secondly, both the acquired and the innate immune system contribute to these alterations, with an important role for both T cells and macrophages and their cytokines. Thirdly, interpretation of these data support the hypothesis that gut and joint inflammation in SpA are induced by the combination of an impaired anti-bacterial host defence and an uncontrolled pro-inflammatory response of the innate immune system. The insights provided by the study of the gut immunology in SpA have contributed to develop new therapeutic strategies, with TNFalpha blockade as prototype.