An induction or flare of arthritis and/or sacroiliitis by vedolizumab in inflammatory bowel disease: a case series.

BACKGROUND: In inflammatory bowel disease (IBD), a new biological therapy has recently been approved. Vedolizumab is a humanised IgG1 monoclonal antibody to α4ß7 integrin that modulates gut lymphocyte trafficking. Although an exclusively local effect of vedolizumab could be expected based on the restricted presence of the α4ß7-mucosal vascular addressin cell adhesion molecule 1 complex in the gut, past combined success with anti-tumour necrosis factor, and previous demonstration of α4ß7 integrin in the joint, led to the expectation of a therapeutic efficacy in spondyloarthritis. Nonetheless, the effect of vedolizumab on extraintestinal manifestations-and especially the joint-has not been reported so far. CASE REPORT: A series of five patients with IBD who were treated with vedolizumab and promptly developed new onset or exacerbation of sacroiliitis or arthritis are reported. CONCLUSIONS: Vedolizumab therapy does not seem to show any efficacy in and might even induce arthritis and/or sacroiliitis. However, larger cohort studies are needed to provide information on the prevalence, the evolution and underlying mechanism.

MR signal in the sacroiliac joint space in spondyloarthritis: a new sign.

OBJECTIVES: To determine the diagnostic value of MR signal within the sacroiliac (SI) joint space in spondyloarthritis (SpA). METHODS: A retrospective analysis of MRIs of SI joints was performed in 363 patients, aged 16-45 years, clinically suspected of sacroiliitis. Intra-articular SI joint MR signals were categorized as normal, high T1 signal, fluid signal, ankylosis or vacuum phenomenon (VP). These MRI findings were correlated with the final diagnosis, according to the ASAS criteria. Sensitivity, specificity, and positive and negative likelihood ratios (LR) and predictive values were calculated. RESULTS: Presence of intra-articular high T1 signal, fluid signal and ankylosis had a specificity of 95.8 %, 95.3 % and 99.5 % for SpA. High T1 signal, fluid signal and ankylosis were present in 38.4 %, 19.2 % and 17.9 % of SpA patients and in 4.2 %, 4.7 % and 0.5 % of patients without SpA, resulting in LR+ of 9.0, 4.1 and 37.9, respectively. VP was present in 13.2 % of SpA patients and in 20.8 % of patients without SpA, resulting in an LR+ of 0.6. CONCLUSIONS: Presence of high T1 signal, fluid signal and ankylosis within the SI joint on MRI have high specificity for SpA. High T1 signal is the most sensitive MRI feature within the SI joint for SpA. KEY POINTS: • MRI of the SI joints is typically obtained for diagnosis of spondyloarthritis. • The MR signal within the SI joint itself reflects features of spondyloarthritis. • Intra-articular high T1 signal, fluid signal and ankylosis are seen in spondyloarthritis. • The vacuum phenomenon makes spondyloarthritis less likely.

Elevated calprotectin levels reveal bowel inflammation in spondyloarthritis.

INTRODUCTION: Microscopic bowel inflammation is present in up to 50% of patients with spondyloarthritis (SpA) and is associated with more severe disease. Currently no reliable biomarkers exist to identify patients at risk. Calprotectin is a sensitive marker of neutrophilic inflammation, measurable in serum and stool. OBJECTIVES: To assess whether serum and faecal calprotectin in addition to C-reactive protein (CRP) can be used to identify patients with SpA at risk of microscopic bowel inflammation. METHODS: Serum calprotectin and CRP were measured in 125 patients with SpA. In 44 of these patients, faecal samples were available for calprotectin measurement. All 125 patients underwent an ileocolonoscopy to assess the presence of microscopic bowel inflammation. RESULTS: Microscopic bowel inflammation was present in 53 (42.4%) patients with SpA. Elevated serum calprotectin and CRP were independently associated with microscopic bowel inflammation. Faecal calprotectin was also significantly higher in patients with microscopic bowel inflammation. Patients with CRP and serum calprotectin elevated had a frequency of bowel inflammation of 64% vs 25% in patients with low levels of both. When either CRP or serum calprotectin was elevated, the risk was intermediate (40%) and measuring faecal calprotectin provided further differentiation. Hence we suggest a screening approach where initially serum calprotectin and CRP are assessed and, if necessary, faecal calprotectin. The model using this scenario provided an area under the ROC curve of 74.4% for detection of bowel inflammation. CONCLUSIONS: Calprotectin measurements in stool and serum, in addition to CRP, may provide a promising strategy to identify patients with SpA at risk of bowel inflammation and could play a role in overall patient stratification.

Clinical and radiological factors associated with erosive radiographic progression in hand osteoarthritis.

OBJECTIVE: To identify prognostic factors of erosive progression in hand osteoarthritis (OA). METHOD: One hundred and fifty-four patients with hand OA were selected from an earlier cohort. X-rays, clinical and demographic data at baseline were present. All patients were seen for a follow-up between January and March 2014. Interphalangeal (IP) finger joints were scored on both radiographs using the anatomical scoring system. Radiographic progression was defined as a joint progressing from at least one anatomical phase, excluding the progression from a 'Normal' to 'Stationary' phase. Odds ratios (OR) and 95% confidence intervals (95% CI) of potential clinical and radiographic prognostic factors were calculated on joint, hand and patient level with a generalized estimating equation (GEE) model. RESULTS: Radiographic progression, including progression from 'N' to 'S' phase, was present in 1014 of 2750 joints (36.9%) after a mean follow-up of 5.8 years. On joint level, the following clinical factors were associated with radiographic progression (OR [95% CI]): presence of pain (1.48 [1.01-2.15]), tenderness (2.18 [1.56-3.05]), and soft tissue swelling (2.56 [1.54-4.24]). The following radiographic variables were significantly associated with erosive progression: presence of 'J' (16.74 [9.09-30.83]) and 'E' phase (76.34 [42.17-138.23]). On hand and patient level, soft tissue swelling, 'J' and 'E' phase were retained as prognostic factors. CONCLUSION: Pain, tenderness, soft tissue swelling, 'J' and 'E' phase were significantly associated with erosive progression in hand OA. These prognostic factors should be confirmed in further studies and considered when selecting patients for therapeutic trials with potential disease-modifying osteoarthritis drugs (DMODs).

Diagnostic value of pelvic enthesitis on MRI of the sacroiliac joints in spondyloarthritis.

OBJECTIVE: To determine the prevalence and diagnostic value of pelvic enthesitis on MRI of the sacroiliac (SI) joints in spondyloarthritis (SpA). MATERIALS AND METHODS: A retrospective study in 444 patients aged 17-45 years old with MRI of the SI joints and with clinically suspected sacroiliitis was performed. Patients were classified as having SpA if they fulfilled the Assessment of Spondyloarthritis International Society (ASAS) criteria. Pelvic enthesitis on MRI was correlated with the final diagnosis. Sensitivity, specificity, positive and negative likelihood ratio (LR) and predictive values (PV) of pelvic enthesitis for the diagnosis of SpA were calculated. RESULTS: MRI showed pelvic enthesitis in 24.4 % of patients with SpA and in 7.1 % of patients without SpA. Presence of any enthesitis had sensitivity, specificity, LR+, LR-, PPV and NPV of 24.4 %, 92.9 %, 3.45, 0.81, 69.4 % and 65.2 % for the diagnosis of SpA, respectively. The most commonly affected entheses were the longitudinal ligament insertion (4.5 %), the retroarticular ligaments (4.1 %) and the pubic symphysis (4.1 %). The sites of enthesitis with the highest PPV for SpA were the iliac crest/wing (85.7 %) and the retroarticular ligaments (81.3 %). CONCLUSION: Nearly one fourth of SpA patients with suspected sacroiliitis showed pelvic enthesitis on MRI. Such pelvic enthesitis has a high specificity for the diagnosis of spondyloarthritis. KEY POINTS: • Enthesitis is the primary clinical feature of spondyloarthritis. • Magnetic resonance imaging of the sacroiliac joints can demonstrate pelvic enthesitis. • Pelvic enthesitis has a high specificity for the diagnosis of spondyloarthritis.

Osteoarticular manifestations: specific treatments and/or treating intestinal disease?

Osteoarticular manifestations in inflammatory bowel diseases (IBD) belong to the concept of spondyloarthritis (SpA) including an axial and peripheral SpA according to predominant symptoms (inflammatory back pain vs. peripheral arthritis and enthesopathy). Careful examination of sacroiliac joints on MRI plays a crucial role in the recognition of an early axial SpA in young patients with inflammatory back pain and spinal inflammation on MRI but without structural changes on radiography (non-rx SpA). In this early form of SpA, chronic gut inflammation was already found in about 30% of patients. Moreover, more pronounced bone marrow edema was found in patients with axial SpA and chronic gut inflammation. Identification of a therapeutic window in patients with early gut and spine inflammation is important since anti-TNF suppresses inflammation and seems to prevent evolution to structural changes. Shared genetic factors probably predispose to both diseases. Careful analysis of the effect of medication on gut and spine inflammation in SpA and IBD patients is recommended in order to find new therapeutic agents.

Spondyloarthritis and inflammatory bowel disease. Comorbidity and treatment implications.

Spondyloarthritides (SpA) and inflammatory bowel disease (IBD) are chronic, idiopathic inflammatory disorders of the axial and peripheral joints and the intestinal tract, respectively, affecting up to 1 % of the population. There is clinical and genetic evidence supporting some degree of overlap between the pathogenesis of these two entities. Nevertheless, their treatment is at times conflicting. NSAIDs, although useful in SpA, are considered to be possible risk factors for flares in IBD. Moreover, etanercept, a soluble TNF receptor blocker used in SpA, is ineffective in IBD. As patients with SpA often develop microscopic gut inflammation, it is important to understand the impact on disease progression or even therapeutic response. Further research is mandatory in this regard.

First insights into human acetabular labrum cell metabolism.

OBJECTIVE: Hip labrum pathology has only begun to emerge as a significant source of groin pain in the last decade since the development of hip arthroscopy. Few data are available on the anatomy, histology and function of this structure. Moreover, no metabolic data exist at cellular level. The aim of this study was to characterize extracellular matrix (ECM) genes and pro-inflammatory mediators expressed by these cells. METHODS: Isolated human acetabular labrum cells were cultured in alginate beads for 10 days and additionally stimulated with interleukin (IL)-1 for 24 h. Gene expression levels and secretion of different ECM genes, enzymes and cytokines were examined by quantitative polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assay (ELISA) to assess the metabolic characteristics of labrum cells. Articular chondrocytes and meniscus cells served as controls. RESULTS: Labrum cells expressed high levels of COL1A1 and low levels of COL2A1, aggrecan and SOX-9 compared to chondrocytes. However, COL2A1 was more expressed by labrum cells than by meniscus cells. The expression of matrix metalloproteinase (MMP)-1/-2/-9, ADAMTS-4 and IL-6 was significantly higher in labrum cells than in chondrocytes. IL-1 suppressed the ECM gene expression levels of labrum cells, but increased the expression levels and release of MMP-1/-3/-9/-13 and ADAMTS-4 and IL-6 by these cells. Remarkably, MMP-9 was only significantly upregulated in acetabular labrum cells. CONCLUSIONS: The findings in this study demonstrated that the acetabular labrum is populated with unique highly active fibrochondrocyte-like cells. These cells are capable of expressing and releasing pro-inflammatory enzymes and cytokines and react to a pro-inflammatory stimulus. In this way, they contribute obviously to disturbed tissue function in hip labrum pathology.

The combination of microfracture and a cell-free polymer-based implant immersed with autologous serum for cartilage defect coverage.

PURPOSE: The purpose of this short-term pilot study was to determine the clinical and MRI outcome of a combination of microfracture with a cell-free polymer-based matrix for the treatment of cartilage defects in the knee. METHODS: The technique was used for treatment of symptomatic cartilage defects in the knee. Five patients were prospectively evaluated during 2 years with use of the Knee injury and Osteoarthritis Outcome Score (KOOS), the Tegner activity scale and the visual analog scale (VAS). MRI data were analyzed based on the original and modified MOCART (Magnetic Resonance Observation of Cartilage Repair Tissue) scoring system at 6, 12 and 24 months of follow-up. RESULTS: A gradual clinical improvement was observed during the follow-up. Adverse reactions to the matrix were not observed. The scaffold was firmly fixed with the use of bioresorbable pins. Both MOCART scoring systems revealed no significant deterioration or improvement in the repair tissue during the follow-up period. However, the majority of the patients exhibited subchondral lamina and bone changes. The formation of an intralesional osteophyte was observed in one case. CONCLUSIONS: The key finding in this study was that this procedure is safe for the treatment of cartilage defects in the knee. The patients showed a gradual clinical improvement postoperatively. Sixty percent (3/5) of the defects were adequately (complete or hypertrophic) filled with repair tissue at 2 years of follow-up. LEVEL OF EVIDENCE: IV.

Short-term outcome of the second generation characterized chondrocyte implantation for the treatment of cartilage lesions in the knee.

PURPOSE: To evaluate short-term clinical and MRI outcome of the second generation characterized chondrocyte implantation (CCI) for the treatment of cartilage defects in the knee. METHODS: Thirty-two patients aged 15-51 years with single International Cartilage Repair Society (ICRS) grade III/IV symptomatic cartilage defects of different locations in the knee were treated with CCI using a synthetic collagen I/III membrane to cover the defect. Clinical outcome was measured over 36 months by the Knee injury and Osteoarthritis Outcome Score (KOOS) and Visual Analogue Scale (VAS) for pain. Serial magnetic resonance imaging (MRI) scans of 22 patients were scored using the original and modified Magnetic resonance Observation of Cartilage Repair Tissue (MOCART) system. RESULTS: The patients included in this study showed a significant gradual clinical improvement after CCI. The MRI findings of this pilot study were considered to be promising. No signs of deterioration were observed. A complete or hypertrophic filling was observed in 76.5% of the cases at 24 months of follow-up. No preventive effect of an avital membrane on the occurrence of hypertrophic repair tissue was observed on MRI. Three failures were observed among the 32 patients until now (9.4%). CONCLUSIONS: This investigation provided useful information on the efficacy of this treatment. The short-term clinical and MRI outcome are promising. Large-scale and long-term trials are mandatory to confirm the results and the reliability of this procedure. LEVEL OF EVIDENCE: IV.

Subclinical gut inflammation in spondyloarthritis is associated with a pro-angiogenic intestinal mucosal phenotype.

BACKGROUND: Vascular endothelial growth factor (VEGF-A) and placental growth factor (PlGF) are major regulators of pathological angiogenesis, which is a prominent feature of both Crohn's disease (CD) and peripheral synovitis in spondyloarthritis. OBJECTIVE: To investigate the presence of VEGF-A and PlGF in the gut of spondyloarthritis patients and to link this finding with subclinical gut inflammation in these patients. METHODS: Intestinal biopsies from healthy controls, CD patients, spondyloarthritis patients with or without subclinical gut inflammation and rheumatoid arthritis (RA) patients were stained for VEGF-A, PlGF, CD31 and vascular cell adhesion molecule 1 (VCAM-1) and digitally analysed. RESULTS: Spondyloarthritis patients with subclinical gut inflammation had markedly increased intestinal VEGF-A expression (p<0.001), mucosal vascularisation (p<0.001) and VCAM-1 expression (p<0.01) compared with healthy controls and RA patients, which, unlike in CD patients, was also seen when the gut inflammation was in a quiescent state. PlGF expression was highly increased in the subclinically inflamed gut of spondyloarthritis (p<0.01 compared with healthy controls), but not at all in CD. CONCLUSION: A pro-angiogenic intestinal phenotype is observed in spondyloarthritis patients with quiescent chronic gut inflammation. This favours an environment for enhanced trafficking of immune cells in this subpopulation.

Autologous matrix-induced chondrogenesis combined with platelet-rich plasma gel: technical description and a five pilot patients report.

PURPOSE: This pilot study was designed to describe the technical details and to present the preliminary outcome of autologous matrix-induced chondrogenesis (AMIC) combined with platelet-rich plasma gel, the so called AMIC plus technique, for the treatment of patellar cartilage defects in the knee. METHODS: The AMIC plus technique was used for the treatment of (osteo) chondral patellar lesions in the knee. The surgical technique is extensively described. Five patients were clinically prospectively evaluated during 2 years. MRI data were analysed based on the original MOCART (Magnetic Resonance Observation of Cartilage Repair Tissue) and modified MOCART scoring system. RESULTS: A clinical improvement became apparent after 24 months of follow-up. Both MOCART scoring systems revealed no significant deterioration or improvement of the repair tissue between one and 2 years of follow-up. However, all cases showed subchondral lamina and bone changes. The formation of intralesional osteophytes was observed in 3 of the 5 patients during the 2 years of follow-up. CONCLUSIONS: AMIC plus is feasible for the treatment of symptomatic patellar cartilage defects and resulted in a clinical improvement in all patients. The favourable clinical outcome of the AMIC plus technique was not confirmed by the MRI findings. LEVEL OF EVIDENCE: IV.

A plant-derived glucocorticoid receptor modulator attenuates inflammation without provoking ligand-induced resistance.

BACKGROUND: Acquired resistance to glucocorticoids constitutes a major clinical challenge, often overlooked in the search for improved alternatives to classic steroids. We sought to unravel how two glucocorticoid receptor-activating compounds, dexamethasone and Compound A, influence glucocorticoid receptor levels and how this can be correlated to their gene regulatory potential. METHODS: Compound A and dexamethasone were applied in a short-term and long-term treatment protocol. By quantitative PCR analysis in fibroblast-like synoviocytes (FLS) the gene regulatory potential of both compounds in the two experimental conditions was analysed. A parallel Western blot assay revealed the glucocorticoid receptor protein levels in both conditions (ex vivo). In addition, this study examined the effect of systemic administration of dexamethasone and Compound A, in concentrations effective to inhibit collagen-induced arthritis, in DBA/1 mice on glucocorticoid receptor levels (in vivo). RESULTS: Compound A does not induce a homologous downregulation of glucocorticoid receptor in vivo and ex vivo, thereby retaining its anti-inflammatory effects after prolonged treatment in FLS. This is in sharp contrast to dexamethasone, showing a direct link between prolonged dexamethasone treatment, decreasing glucocorticoid receptor levels, and the abolishment of inflammatory gene repression in FLS. It was also observed that the acquired low receptor levels after prolonged dexamethasone treatment are still sufficient to sustain the transactivation of endogenous glucocorticoid-responsive element-driven genes in FLS, a mechanism partly held accountable for the metabolic side-effects. CONCLUSION: Compound A is less likely to evoke therapy resistance, as it does not lead to homologous glucocorticoid receptor downregulation, which is in contrast to classic glucocorticoids.

Rituximab in diffuse cutaneous systemic sclerosis: an open-label clinical and histopathological study.

OBJECTIVES: The safety and potential efficacy of rituximab was examined in diffuse cutaneous systemic sclerosis (dc-SSc). METHODS: A 24 week open-label study in which eight patients with dc-SSc received an infusion of 1000 mg rituximab administered at baseline and day 15, together with 100 mg methylprednisolone at each infusion. Assessment included CD19+ peripheral blood lymphocyte number, skin sclerosis score, indices of internal organ functioning, the health assessment questionnaire disability index, the 36-item Short Form health survey and histopathological evaluation of the skin. RESULTS: Ritixumab induced effective B-cell depletion in all patients (<5 CD19+ cells/microl blood). There was a significant change in skin score at week 24 (p<0.001). Also, significant improvements were measured in the dermal hyalinised collagen content (p = 0.014) and dermal myofibroblast numbers (p = 0.011). Two serious adverse events occurred, which were thought to be unrelated to the rituximab treatment. CONCLUSIONS: Rituximab appears to be well tolerated and may have potential efficacy for skin disease in dc-SSc.

Proteome characterization of human articular chondrocytes leads to novel insights in the function of small heat-shock proteins in chondrocyte homeostasis.

OBJECTIVE: In recent years, studies have been initiated to disclose the proteome of human chondrocytes and cartilage. Despite these studies, comprehensive information of the chondrocyte proteome remains limited. This study aimed to further explore the proteome expressed by human knee chondrocytes, and to study the functional aspects of heat-shock protein 27 (HSP27), a protein related to the previously described alphaBcrystallin, in chondrocyte biology. METHODS: Chondrocytes isolated from human knee articular cartilage were cultured in a three-dimensional alginate culture system. To simplify the protein mixtures, proteins extracted from chondrocyte cell lysates were fractionated based on hydrophobicity and molecular weight. Proteins were digested and the resulting peptides were separated and identified by an on-line two-dimensional (2-D) nanoliquid chromatography (nanoLC)-system coupled to a quadrupole time-of-flight (Qq-TOF) mass spectrometer. Differential expression analysis of HSP27 was performed by Western Blotting and quantitative polymerase chain reaction (QPCR). The effects of HSP27 on chondrocyte biology were explored by suppression of HSP27 expression induced by RNA interference (RNAi). RESULTS: In this study, we identified proteins with unknown functions together with membrane proteins, transcription factors and other low abundant proteins, which have not yet been described in chondrocytes. Based on previous knowledge on the related protein alphaBcrystallin, we selected HSP27 from the chondrocyte proteome database. Differential expression analysis revealed a decreased expression of HSP27 in Osteoarthritic (OA) chondrocytes. RNAi experiments revealed that HSP27 is involved in interleukin-1beta (IL-1beta) induced IL-6 secretion. CONCLUSION: These findings highlight that small HSPs, especially HSP27, play a prominent role in the maintenance of human articular chondrocyte homeostasis.

Role of lymphotoxin-alpha in cigarette smoke-induced inflammation and lymphoid neogenesis.

In chronic obstructive pulmonary disease (COPD), chronic inflammation is accompanied by peribronchial lymphoid aggregates. Lymphotoxin (LT)-alpha, crucial in secondary lymphoid organogenesis, may be involved in lymphoid neogenesis. We examined cigarette smoke (CS)-induced pulmonary lymphoid neogenesis and inflammation in vivo in LTalpha knockout (LTalpha(-/-)) and wild-type (WT) mice and studied the expression of lymphoid chemokines by lung fibroblasts in vitro. T-cell numbers (in bronchoalveolar lavage fluid (BALF) and lungs) and lymphoid aggregate numbers were significantly higher in air-exposed LTalpha(-/-) mice than in WT animals, and increased upon chronic CS exposure in both genotypes. In contrast, local immunoglobulin A responses upon chronic CS exposure were attenuated in LTalpha(-/-) mice. CXC chemokine ligand (CXCL) 13 and CC chemokine ligand (CCL) 19 mRNA in total lung and CXCL13 protein level in BALF increased upon CS exposure in WT, but not in LTalpha(-/-) mice. In vitro lymphotoxin-beta receptor (LTbetaR) stimulation induced CXCL13 and CCL19 mRNA in WT lung fibroblasts. Furthermore, in vitro exposure to CS extract upregulated CXCL13 mRNA expression in WT, but not in LTbetaR(-/-), lung fibroblasts. In this murine model of COPD, CS induces pulmonary expression of lymphoid chemokines CXCL13 and CCL19 in a LTalphabeta-LTbetaR-dependent fashion. However, LTalpha is not required for CS-induced pulmonary lymphocyte accumulation and neogenesis of lymphoid aggregates.

Juvenile-onset systemic lupus erythematosus: different clinical and serological pattern than adult-onset systemic lupus erythematosus.

OBJECTIVE: To investigate differences in clinical signs and symptoms, and in antinuclear antibodies (ANA), between patients with juvenile-onset and adult-onset systemic lupus erythematosus (SLE). METHODS: Clinical and serological data of 56 patients with juvenile-onset SLE were compared with data of 194 patients with adult-onset SLE. ANA were determined by line immunoassay and by indirect immunofluorescence on Crithidia luciliae. RESULTS: Renal involvement, encephalopathy and haemolytic anaemia were seen, and anti-dsDNA, anti-ribosomal P and antihistone antibodies found, significantly more often in juvenile-onset SLE. Anti-dsDNA antibodies were directly associated, and anti-ribosomal P antibodies inversely associated, with renal involvement in juvenile-onset SLE. In juvenile patients with SLE and anti-dsDNA and without anti-ribosomal P antibodies the odds ratio for glomerulonephritis was 9.00; no patients with anti-ribosomal P but without anti-dsDNA had renal involvement. CONCLUSION: Patients with juvenile-onset SLE more often have renal involvement and encephalopathy than patients with adult-onset SLE. Anti-ribosomal P, anti-dsDNA and antihistone antibodies are more often found in patients with juvenile-onset SLE.

Reversible changes in serum immunoglobulin galactosylation during the immune response and treatment of inflammatory autoimmune arthritis.

OBJECTIVES: Improved DNA sequencer-aided fluorophore-assisted carbohydrate electrophoresis (DSA-FACE) technology was used to monitor the changes in the galactosylation status of serum immunoglobulins during the immune response and therapy of autoimmune arthritis. METHODS: Collagen-induced arthritis (CIA) was induced in susceptible DBA/1 mice and the undergalactosylation status (UGS) of serum immunoglobulins was determined using the improved DSA-FACE technology. Prophylactic intravenous tolerisation with type II collagen as well as semitherapeutic treatment with dexamethasone (DEX) were performed and UGS was analysed. Next, the serum immunoglobulin glycosylation profiles of patients with rheumatoid arthritis (RA) and spondyloarthropathy (SpA) were studied and changes in the UGS scores during anti-tumour necrosis factor (TNF)alpha therapy followed. RESULTS: In the longitudinal CIA study, the undergalactosylation state of immunoglobulins was found to be significantly correlated with the clinical arthritis scores. Upon collagen-specific tolerisation as well as glucocorticoid semitherapeutic treatment, improvement of the clinical arthritis scores correlated with decreased levels of UGS. It was also demonstrated that withdrawal of DEX was associated with an increased UGS score. Interestingly, reversibility in the UGS was also shown during treatment of patients with RA and SpA with anti-TNFalpha. CONCLUSIONS: These findings demonstrate that the UGS of serum immunoglobulins changes during the disease course of CIA and that this UGS is inhibited by antigen-specific and antigen-independent treatment procedures. The observation that Ig galactosylation is a reversible process is also documented during treatment of patients with RA and SpA with anti-TNFalpha.

Glycolipid antigen processing for presentation by CD1d molecules.

The requirement for processing glycolipid antigens in T cell recognition was examined with mouse CD1d-mediated responses to glycosphingolipids (GSLs). Although some disaccharide GSL antigens can be recognized without processing, the responses to three other antigens, including the disaccharide GSL Gal(alpha1-->2)GalCer (Gal, galactose; GalCer, galactosylceramide), required removal of the terminal sugars to permit interaction with the T cell receptor. A lysosomal enzyme, alpha-galactosidase A, was responsible for the processing of Gal(alpha1-->2)GalCer to generate the antigenic monosaccharide epitope. These data demonstrate a carbohydrate antigen processing system analogous to that used for peptides and an ability of T cells to recognize processed fragments of complex glycolipids.