J. Braun

Radiologic diagnosis and pathology of the spondyloarthropathies.

Five different subtypes of spondyloarthropathy (SpA) are now recognized. Clinical and radiologic involvement of the sacroiliac joint is an outstanding feature of the SpA, especially ankylosing spondylitis (AS). In this partly debilitating form of SpA a unique type of inflammatory axial involvement is observed which is characterized by inflammation and new bone formation at different spinal sites. In longstanding disease sacroiliitis, spondylitis and spondylodiscitis are easily recognized by conventional radiography and even better by computed tomography--especially when bony changes have already taken place. The advantage of dynamic magnetic resonance imaging (MRI) is to visualize morphologic changes and inflammation at the same time. This facilitates detection of sacroiliitis and spondylitis/spondylodiscitis at early time points. Hopefully, this will lead to other forms of therapy to prevent ankylosis of the spine. The origin of the granulation tissue infiltrating cartilage and bone in AS might be the synovium, the subchondrium or the bone marrow itself. T cells and macrophages seem to play an important role in this inflammatory process in which TNF-alpha is present in severe cases. The mechanisms responsible for the increased bone formation observed in the course of AS are unknown.

Low T cell production of TNFα and IFNγ in ankylosing spondylitis: its relation to HLA-B27 and influence of the TNF-308 gene polymorphism

OBJECTIVE To test the hypothesis that ankylosing spondylitis (AS) is a T helper cell type 2 polarised disease by quantifying the T cell cytokines interferon γ (IFNγ), interleukin 4 (IL4), tumour necrosis factor α (TNFα), and IL10 at the single cell level in patients with AS in comparison with healthy HLA-B27 negative and HLA-B27 positive controls. METHODS Peripheral blood mononuclear cells from 65 subjects (25 HLA-B27 positive patients with active AS, 18 healthy HLA-B27 positive controls, and 22 healthy HLA-B27 negative controls) were stimulated with phorbol myristate acetate/ionomycin for six hours, surface stained for CD3 and CD8, intracellularly stained for the cytokines IFNγ, TNFα, IL4, and IL10, and analysed by flow cytometry. TNFα production was related to the genotype of the TNFα promoter at the -308 and -238 polymorphisms. RESULTS In peripheral blood the percentage of TNFα+ T cells was significantly lower in HLA-B27 positive patients with AS (median 5.1% for CD4+ T cells) than in healthy HLA-B27 negative controls (median 9.5%; p=0.008). Surprisingly, the percentage of TNFα+ T cells was also significantly lower in healthy HLA-B27 positive controls (median 7.48%) than in healthy HLA-B27 negative controls (p=0.034). Furthermore, the percentage of IFNγ+ T cells was lower in patients with AS and in healthy HLA-B27 positive controls than in healthy HLA-B27 negative controls (p=0.005 and p=0.003, respectively). The percentage of IL10+/CD8+ T cells was higher in patients with AS than in both control groups. In HLA-B27 positive subjects, TNF1/2 heterozygosity at -308 (n=6) was associated with a higher percentage of TNFα+ T cells than TNF1/1 homozygosity (n=25; median 9.97%v 5.11% for CD4+ T cells; p=0.017). In contrast, in HLA-B27 negative controls (n=18) there was no such genotype/phenotype correlation (median 9.4%v 10.6%). CONCLUSIONS The lower T cell production of TNFα and IFNγ shown at the single cell level in HLA-B27 positive patients with AS and healthy HLA-B27 positive controls may contribute to the increased susceptibility of HLA-B27 positive subjects to develop AS. Preliminary genotype-phenotype correlations suggest that in HLA-B27 positive subjects TNF2 at -308 or a linked gene results in higher TNFα production and, therefore, might be a marker for a protective haplotype.

Imaging of sacroiliitis.

Abstract: Inflammation of one or both sacroiliac joints is a characteristic feature of patients with spondyloarthropathies (SpA). Sacroiliitis often leads to inflammatory back pain (IBP). IBP and asymmetric peripheral arthritis of the lower limbs are the main clinical symptoms and criteria for classification and diagnosis of SpA in which sacroiliac joints are uni- or bilaterally affected with an intensity ranging from mild to very severe inflammation resulting in partial or complete ankylosis Sacroiliitis is a very frequent feature of undifferntiated SpA. In ankylosing spondylitis (AS) inflammation in the axial skeleton occurs rarely in the absence of sacroiliitis. Objective evidence of sacroiliitis obtained by imaging procedures, especially x-rays, has always been part of diagnostic and classification criteria for AS. This is in contrast to spinal radiography which, however, has been recently included in a core set of outcome items to be assessed in clinical studies. In early and acute stages of sacroiliitis the diagnosis can be difficult because conventional radiographs - which are known to have considerable intra- and interobserver variability - may be normal. Since IBP is not a specific indicator of sacroiliitis there is need for valuable imaging techniques. Scintigraphy lacks specificity. Computed tomography (CT) is a very good method to demonstrate already established bony changes and magnetic resonance imaging (MRI) has the advantage of combining a good visualisation of the complicated anatomy of the sacroiliac joint with the ability to localise different degrees of inflammation and oedema and prove a possible spread to muscles as it occurs in septic sacroiliitis, an important differential diagnosis.

T cells are responsible for the enhanced synovial cellular immune response to triggering antigen in reactive arthritis

In reactive arthritis (ReA) there is specific proliferation of synovial fluid (SF) mononuclear cells (MNC) to the triggering bacterial antigen; comparatively little or no response is seen in peripheral blood (PB). To investigate the mechanism of this elevated local immune response, we examined patients with typical ReA who showed an enhanced antigen‐specific synovial immune response in bulk culture. Using separated fractions of T cells and antigen‐presenting cells (APC) from PB and SF we showed that the synovial T cells rather than SF APC are responsible for the specific proliferation. By limiting dilution analysis, the frequency of T cells responding to the specific antigen was found to be significantly increased compared with the frequency of irrelevant antigen‐specific T cells. Furthermore, the frequency of T cells responding to the specific antigen was higher in SF (between 1/619 and 1/4846, mean 1/2389) than in PB (between 1/1286 and 1/16279, mean 1/7350). We conclude that the specific synovial cellular immune response in ReA is mainly due to an expansion of antigen‐specific T cells within the joint. However, the non‐specific hyper‐reactivity of SF T cells and differences between SF and PB APC may make a more minor contribution.

Treatment of spondyloarthropathies with antibodies against tumour necrosis factor α: first clinical and laboratory experiences

Drug treatment of patients with spondyloarthropathies (SpA), especially ankylosing spondylitis (AS) has limited capacity.1 Pain but not disease activity can be reduced by non-steroidal anti-inflammatory drugs (NSAIDs), in severe cases very high doses are needed.2 By examination of sacroiliac biopsy specimens we have shown that, in correlation to disease activity assessed by magnetic resonance imaging (MRI), T cells and macrophages3 and tumour necrosis factor α (TNFα) mRNA4 and protein (fig 1) but no bacterial DNA5 is present in these joints that are pathognomonically involved in AS.6 Furthermore, anti-TNFα monoclonal antibodies (mAb) have recently been shown to be efficacious in Crohns disease7—a disease that is strongly linked to AS because more than 60% of AS patients have clinically often silent gut lesions resembling Crohns colitis.8 Furthermore, in another chronic inflammatory rheumatic disease, rheumatoid arthritis (RA), anti-TNF treatment has proved efficacious and even seems to prevent joint damage.9nnnnFigure 1 nImmunohistological examination of a sacroiliac biopsy specimen obtained by computed tomography guided biopsy of a 23 year old patient with ankylosing spondylitis, four years disease duration, with inflammatory back pain grade 6 on a visual analogue scale (0–10). The red staining indicates a mononuclear cell positive for TNFα (APAAP staining technique).nnnnTNFα is a cytokine that is mainly produced by monocytes and macrophages and to a lesser degree by T cells. There are two specific receptors, a 55 kDa and a 75 kDa present on many cell types. TNFα mediates inflammatory and immunoregulatory activities. Effects on cells such as lymphocyte activation and fibroblast proliferation, on mediators such as other cytokines like interleukin 1(IL1), IL6 and IL8, chemokines, prostaglandins, metalloproteinases, on the vasculature by promoting angiogenesis and on upregulation of adhesion molecules and transendothelial migration of leucocytes are well described. In in vitro and in …

Aetiological role of bacteria associated with reactive arthritis in pauciarticular juvenile chronic arthritis.

BACKGROUND: The cause of juvenile chronic arthritis (JCA) is unknown. Pauciarticular JCA is the most common subtype and can be subdivided into early (type I) and late onset (type II) forms, the latter clinically resembling reactive arthritis. METHODS: The cellular immune responses to bacteria associated with reactive arthritis in blood and synovial fluid from 39 children with pauciarticular JCA, three children with classical reactive arthritis, and two children with psoriatic arthritis were examined. Specific titres of antibodies to bacteria in serum samples were measured in all patients. RESULTS: A bacteria specific synovial cellular immune response was found in two of three (67%) patients with reactive arthritis and 14 of 28 (50%) patients with pauciarticular JCA type II but only in one of 11 (9%) patients with pauciarticular JCA type I and none in patients with psoriatic arthritis. Six patients responded specifically to Chlamydia trachomatis and 11 to Yersinia enterocolitica. Antigen specific lymphocyte proliferation correlated poorly with the specific antibody response. CONCLUSIONS: These findings suggest that bacteria with associated reactive arthritis may have a causative role in pauciarticular JCA type II but not in JCA type I.

Staging of patients with ankylosing spondylitis: a preliminary proposal

Patients with ankylosing spondylitis (AS) are characterised by a wide range of clinical presentations, radiographic profiles, and outcomes, which are not well differentiated by current diagnostic and classification systems for the disorder. Inadequacies in these systems may limit clinicians’ ability to manage their patients with AS appropriately and act as an obstacle to reasonable comparison of therapeutic trial results. A standardised staging system for AS is therefore proposed that would provide a more detailed categorisation of patients based on assessment of structural damage, peripheral joint and organ involvement, presence of concomitant diseases, and the severity and extent of disease activity and functional impairment. The proposed system needs to be evaluated closely and amended as needed to assure its usefulness in clinical and research settings.

Epidemiologie und Versorgung im Bereich der Spondylarthropathien

Zusammenfassung Zu den bedeutendsten entzündlich rheumatischen Erkrankungen werden die Spondylarthropathien neben der rheumatoiden Arthritis gezählt. Ihre Prävalenz wurde lange unterschätzt. Heute ist bekannt, dass sie als Gesamtgruppe nahezu ebenso häufig wie die rheumatoide Arthritis vorkommen. Hauptvertreter der Spondylarthropathien in der westlichen Welt sind die ankylosierende Spondylitis (AS) und die undifferenzierte Spondylarthropathie (uSpA). Die Diagnose insbesondere der frühen Formen ist schwierig. Bislang ist die Datenlage zur sozioökonomischen Situation jedoch spärlich, und die Therapiemöglichkeiten limitiert. In den letzten Jahren sind Fortschritte auf diesem Gebiet gemacht worden, erste sozioökonomische Untersuchungen und Daten über die Krankeitsbelastung, aber auch bessere diagnostische Möglichkeiten stehen für die Frühdiagnose zur Verfügung. In jüngster Zeit gibt es vielversprechende Therapieansätze u.a. seit die gute Wirksamkeit von TNF-alpha-Blockern nachgewiesen werden konnte. Weitere Untersuchungen zu dieser unterschätzten Erkrankungsgruppe sind notwendig und erfolgen innerhalb des Kompetenznetzes Rheumatologie.Summary Within the group of inflammatory rheumatic diseases, spondyloarthropathy is the most common diagnosis after rheumatoid arthritis. Its prevalence was long underestimated. Ankylosing spondylitis (AS) and undifferentiated spondyloathropathy (uSpA) are the most common subgroups in western countries. There are still difficulties in diagnosis especially of the early forms of the spondyloarthropathies. Data of socioeconomics and therapeutic options are limited. In more recent times, researchers have started to investigate the burden of disease and the socioeconomic aspects. Better diagnostic options are available and promising new therapeutic agents, especially TNF-alpha blocking agents, have been investigated. However, further studies are urgently needed for this underestimated group of diseases and are currently being performed inside the German rheumatology network.

Die Therapie der ankylosierenden Spondylitis und der undifferenzierten Spondyloarthritis mit TNFα-Antagonisten

Zusammenfassung. Die Gruppe der Spondyloarthritiden (SpA) gehören mit einer Prävalenz von 0,6–1,9% zu den häufigsten entzündlich rheumatischen Erkrankungen. Die ankylosierende Spondylitis (AS) und die undifferenzierte Spondyloarthritis (uSpA) sind die häufigsten Erkrankungen innerhalb der Gruppe der SpA. Frauen erkranken etwa gleichhäufig wie Männer, deren Erkrankungsverlauf ist aber meist leichter. Schwere Verlaufsformen der AS treten bei etwa einem Drittel der Patienten auf und haben ähnlich deutliche Auswirkungen auf die körperliche Funktionsfähigkeit und Lebensqualität der betroffenen Patienten wie bei Patienten mit rheumatoider Arthritis. Die AS beginnt durchschnittlich aber 20–30 Jahre früher. Damit wird klar, dass die AS nicht nur zu erheblichen gesundheitlichen, sondern auch zu relevanten sozioökonomischen Belastungen führt.Nach Jahrzehnten des Stillstands in der Entwicklung innovativer therapeutischer Möglichkeiten zur Behandlung der SpA, gibt es jetzt erstmals Grund zur Hoffnung, durch die Anti-TNFα-Therapie nicht nur die Entzündung und die daraus resultierende klinische Symptomatik zu verbessern, sondern möglicherweise auch das Fortschreiten der Erkrankung zu verhindern und die Krankheitslast wirksam zu reduzieren. Hierfür sprechen nicht zuletzt auch die Ergebnisse jüngster kernspintomographischer Verlaufsuntersuchungen.Der nachfolgende Artikel gibt einen Überblick über den aktuellen Stand der Studienergebnisse. Der gegenwärtige Kenntnisstand hinsichtlich der Wirkungen und der Nebenwirkungen wird dargestellt und es wird über die bisherigen Erfahrungen mit unterschiedlichen Dosierungen berichtet. Vor dem Hintergrund der in diesem Jahr zu erwartenden Zulassung von Infliximab und Etanercept für die Indikation AS wurden internationale Richtlinien zur Indikationsstellung, Durchführung und Beendigung einer Anti-TNFα-Therapie vorgeschlagen, die hier erstmals vorgestellt werden.Summary. The spondyloarthritides (SpA) are common inflammatory rheumatic diseases with an overall prevalence of 0.6–1.9%. Ankylosing spondylitis (AS) and undifferentiated spondyloarthritis (uSpA) are the most common subsets of SpA. Women are almost as frequently affected as men, but the total burden of disease may be similar. At least one third of AS patients are severely affected with impaired function and a poor quality of life similar to patients with rheumatoid arthritis. However, AS starts 20–30 years earlier in life. Thus, AS has a relevant socioeconomic impact on society.After decades of no progress concerning treatment options in SpA, there is now accumulating evidence that the new anti-TNFα agents do not only reduce signs and symptoms of AS caused by inflammation but they may also diminish structural damage. Very recent magnetic resonance imaging (MRI) data of a follow-up study support this assumption.The following paper reviews the currently available literature on anti-TNFα therapy in AS and uSpA. Efficacy, side effects and experiences with different doses are discussed. In expectation of the approval of infliximab and etanercept for the treatment of active AS international guidelines for initiation, monitoring and discontinuation of these agents have been recently proposed.

T cell response to human HSP60 and yersinia 19 kDa in ankylosing spondylitis and rheumatoid arthritis: no evidence for a causal role of these antigens in the pathogenesis

The pathogenesis of two important inflammatory rheumatic diseases, rheumatoid arthritis (RA) and ankylosing spondylitis (AS), is not clear. In both diseases an immune response against an unknown autoantigen may have a crucial role.1,2 It has been repeatedly suggested that heat shock proteins (HSP) play a part in various autoimmune diseases such as RA, diabetes, and multiple sclerosis,3 based on high interspecies sequence homologies, inducible tissue expression, and a strong immunogenicity. On the other hand, some studies indicate that HSP may even be protective in arthritis.4nnThe 19 kDa urease β subunit of yersinia is regarded as a major immunodominant protein for both T cell and antibody responses in patients with yersinia induced reactive arthritis.5 Because 20–30% of HLA-B27+ patients with yersinia induced reactive arthritis develop the full picture of AS after 10–20 years,6 it is an obvious question to ask whether a T cell response against the yersinia-specific 19 kDa protein is also detectable in patients with AS. …