Novel approaches in the treatment of ankylosing spondylitis and other spondyloarthritides.

The therapeutic options for patients suffering from severe forms of spondyloarthritis (SpA) have been rather limited in recent decades. There is now accumulating evidence that anti-TNF therapy is highly effective in SpA, especially in ankylosing spondylitis (AS) and psoriatic arthritis (PsA). Based on the data recently published on what is now several hundred AS and PsA patients, this treatment seems to be even more effective than the same therapy in rheumatoid arthritis (RA). The anti-TNF-alpha agents currently available, infliximab (Remicade); Centocor), etanercept (Enbrel); Amgen) and adalimumab (Humira; Abbott), are approved for the treatment of RA in the US; infliximab and etanercept are approved in Europe. The situation in SpA is different to RA because there is an unmet medical need, especially in AS, since no therapies with disease-controlling antirheumatic drugs are available for severely affected patients, especially with spinal disease. Thus, TNF blockers might even be considered as first-line immunosuppressive agents in patients with active AS and PsA who are not sufficiently treated by non-steroidal anti-inflammatory drugs and sulfasalazine, if peripheral arthritis is present. For infliximab, a dosage of 5 mg/kg at intervals between 6 and 12 weeks was necessary to constantly suppress disease activity; this is also a major aim of long-term treatment. No dose-finding studies have yet been performed. The standard dose of etanercept is 25 mg s.c. twice-weekly. No studies on adalimumab (standard RA dose 20 - 40 mg s.c. every 2 weeks) have yet been conducted in SpA. The efficacy of etanercept was first demonstrated in PsA and etanercept is now approved for this indication. A double-blind study has also been performed in AS, with similarly clearcut efficacy. There is preliminary evidence that both agents do also work in other SpA such as undifferentiated SpA. Infliximab has recently been approved for short-term treatment of severe uncontrolled AS; the approval for etanercept is pending. Studies should be performed to document the long-term efficacy of this treatment. There is hope that ankylosis might be preventable but it remains to be shown whether patients benefit from long-term anti-TNF therapy and whether radiological progression and ankylosis can be stopped. Severe adverse events have remained rare. Complicated infections including tuberculosis have been reported. Tuberculosis can be mostly prevented if patients are checked for previous contact with tuberculosis. Currently, the benefits of anti-TNF therapy in AS seem to outweigh these shortcomings.

Effects of a loading dose regimen of three infusions of chimeric monoclonal antibody to tumour necrosis factor alpha (infliximab) in spondyloarthropathy: an open pilot study.

OBJECTIVE: To evaluate the efficacy and safety of a loading dose regimen of three intravenous infusions with infliximab in patients with active spondyloarthropathy. METHODS: A monocentre, open-label pilot study of 21 patients with different subtypes of spondyloarthropathy was conducted. Treatment resistant patients with active disease (fulfilling inclusion criteria) received three infusions of 5 mg/kg infliximab (at weeks 0, 2, and 6). Standard clinical assessments were performed at baseline, and on days 3, 7, and 14, and from then on every two weeks. In patients who fulfilled criteria for ankylosing spondylitis, axial assessment was performed at baseline and on days 14, 42, and 84. RESULTS: In all global assessments (visual analogue scale of patient global assessment, patient pain assessment, doctor global assessment), erythrocyte sedimentation rate, and C reactive protein, a highly significant decrease could be seen already at day 3 (compared with baseline), which was maintained up to day 84. In patients with peripheral disease (n=18), tender and swollen joint count significantly decreased. In patients with axial disease (n=11), functional and disease activity indices significantly improved. Moreover in eight patients with psoriatic arthritis a significant decrease of the psoriasis area and severity index was observed. The treatment was well tolerated in all patients; no significant adverse events were seen. CONCLUSION: In this open-label pilot study of a loading dose regimen of three infusions of chimeric monoclonal antibody to tumour necrosis factor alpha in patients with active spondyloarthropathy, there was a fast and significant improvement of axial and peripheral articular manifestations, without major adverse experiences.

Differential Th1/Th2 cytokine patterns in chronic arthritis: interferon gamma is highly expressed in synovium of rheumatoid arthritis compared with seronegative spondyloarthropathies.

OBJECTIVE: To investigate possible differences in Th1 and Th2 cytokine mRNA expression in the synovial tissue (ST) of patients with rheumatoid arthritis (RA) and seronegative spondyloarthropathies (SpA) with diagnostic and/or pathogenic interest. METHODS: Eleven RA patients and 14 SpA patients (10 with undifferentiated spondyloarthropathy (USpA), two with ankylosing spondylitis (AS) and two with psoriatic arthritis (PsA)) were included. Th1 (interferon gamma, interleukin 2) and Th2 (interleukin 4, interleukin 5 and interleukin 10) cytokine mRNA levels from arthritic knee ST were quantified by using an optimised polymerase chain reaction method with a computerised analysis system. Protein levels of proinflammatory cytokines (interleukin 1, tumour necrosis factor alpha and interleukin 6) in synovial fluid were quantified with a specific ELISA test. RESULTS: Th1 cytokines were detected in all of RA ST samples in contrast with 58% (interferon gamma) and 71% (interleukin 2) of SpA samples. Th2 cytokines were expressed in 90% of RA ST samples, but the findings in SpA were interleukin 10 in 90%, interleukin 4 in 60% and interleukin 5 in 40% of ST samples. However, when the mRNA levels of each cytokine were quantified and corrected for T cell mRNA levels, only interferon gamma levels were significantly higher in RA than in SpA (p<0.003). Thus, the Th1/Th2 cytokine ratio in RA was fivefold that of SpA. Synovial fluid interleukin 1beta concentrations were higher in RA than in SpA (p<0. 05); there were also higher synovial fluid levels of tumour necrosis factor alpha in RA than in SpA, but without statistical significance. CONCLUSION: This study has detected both Th1 and Th2 cytokine gene expression in ST from RA and SpA patients. Synovium interferon gamma mRNA levels and SF interleukin 1beta protein levels were significantly higher in RA than in SpA, so reflecting the known proinflammatory activity of interferon gamma through macrophage activation. Thus, the Th1 (interferon gamma)/Th2 (interleukin 4) ratio is significantly higher in RA than in SpA ST. These data confirm previous studies on ST Th1/Th2 balance in RA and extend previous work in comparing ST RA with subgroups of SpA distinct of ReA.

Quantitative analyses of sacroiliac biopsies in spondyloarthropathies: T cells and macrophages predominate in early and active sacroiliitis- cellularity correlates with the degree of enhancement detected by magnetic resonance imaging.

OBJECTIVE: Sacroiliitis is a hallmark of the spondyloarthropathies (SpA). The degree of inflammation can be quantified by magnetic resonance imaging (MRI). The aim of this study was to further elucidate the pathogenesis of SpA by quantitative cellular analysis of immunostained sacroiliac biopsy specimens and to compare these findings with the degree of enhancement in the sacroiliac joints (SJ) as detected by dynamic MRI. METHODS: The degree of acute sacroiliitis detected by MRI after intravenous administration of gadolinium-DTPA was quantitatively assessed by calculating the enhancement observed in the SJ and chronic changes were graded as described in 32 patients with ankylosing spondylitis (n=18), undifferentiated SpA (n=12) and psoriatic arthritis (n=2). Back pain was graded on a visual analogue scale (VAS, 0-10) and disease duration (DD) was assessed. Shortly after MRI, SJ of patients with VAS > 5 were biopsied guided by computed tomography. Immunohistological examination was performed using the APAAP technique; only whole sections > 3 mm were counted. RESULTS: By MRI, chronic changes II in 13 patients (group II, DD 7.3 (SD 4.8) years), while enhancement < 70% was found in eight (group A, DD 5.6 (SD 3.3) years) and > 70% in 12 patients (group B, DD 4.7 (SD 5.8) years). The relative percentage of cartilage (78-93%), bone (7-18%) and proliferating connective tissue (1-4%) was comparable between the groups (range). There were more inflammatory cells in group I compared with group II (mean (SD) 26.7(20.1) versus 5.3 (5. 2), p=0.04) and group A compared with B (21.8 (17.3) versus 6.0 (5. 6), p=0.05) cells/10 mm(2)), T cells (10.9 (8.5)) being slightly more frequent than macrophages (9.6 (16.8/10 mm(2))). Clusters of proliferating fibroblasts were seen in three and new vessel formation in seven cases. CONCLUSION: This study shows that T cells and macrophages are the most frequent cells in early and active sacroiliitis in SpA. The correlation of cellularity and MRI enhancement provides further evidence for the role of dynamic MRI to detect early sacroiliitis.

Cytokines and the immunopathology of the spondyloarthropathies.

In contrast to rheumatoid arthritis (RA), the triggering antigens are known in reactive arthritis (ReA) and Lyme arthritis. Thus, in these arthritides the antigen-specific T-cell response can be investigated in much detail and lessons possibly learned for other spondyloarthropathies (SpA) such as ankylosing spondylitis (AS) where T cells may well also play an important role in the pathogenesis. This article focusses on the immunopathology of the SpA, ReA, and AS with special reference to T cells and cytokines.

HLA-B27 and the seronegative spondyloarthropathies.

In the 25 years since the initial reports of the association of HLA-B27 with ankylosing spondylitis (AS) and subsequently with Reiter's syndrome, psoriatic spondylitis, and the spondylitis of inflammatory bowel disease, the association of HLA-B27 with the seronegative spondyloarthropathies has remained one of the best examples of a disease association with a hereditary marker. HLA-B27 has been recognized as representative of a spectrum of diseases, ranging from the majority of HLA-B27-positive individuals who have no disease at all, through those with isolated eye or skin involvement, to those with critical eye, heart, and peripheral joint compromise of full-blown AS. Yet HLA polymorphism has evolved in response to environmental stresses, and even the presence of HLA-B27 itself appears to confer advantages in certain infectious diseases, such as acquired immune deficiency syndrome (AIDS). This article will review what is currently known about HLA-B27 and disease, especially in the seronegative spondyloarthropathies. The structure-function relationship of HLA-B27 will be presented, including differences between the B27 subtypes both in their ethnic variation and possible disease implications. The disease spectrum conferred by the presence of HLA-B27 will also be discussed, and the theories of how HLA-B27 contributes to the pathogenesis of the spondyloarthropathies will be considered.

The seronegative spondyloarthropathies.

The four seronegative spondyloarthropathies can be divided into two main groups by their pattern of sacroiliitis and spondylitis (Table 1). The axial skeletal changes of ankylosing spondylitis and enteropathic arthropathy are often indistinguishable, as are those of psoriatic arthritis and Reiter's syndrome. Early proximal appendicular joint involvement in ankylosing spondylitis is a poor prognostic sign except in women where peripheral arthritis is more common, but has a more benign course. Peripheral joint destruction in enteropathic arthropathy is rare because treatment of the bowel disease also treats the arthritis. Distal appendicular involvement is characteristic of psoriatic arthritis and Reiter's syndrome. Proliferative erosions and enthesitis, periostitis, and normal mineralization aid in differentiating psoriatic arthritis and Reiter's syndrome from rheumatoid arthritis. The distribution of arthritis also differs from that seen in classic rheumatoid arthritis, with asymmetry and involvement of the distal interphalangeal joints more common in psoriatic disease and Reiter's syndrome.

Seronegative spondyloarthropathies and HLA-B27 subtyes: a study in Asian Indians.

In this study, 60 HLA-B27+ve SSA patients and 17 healthy controls belonging to North India were analyzed to ascertain heterogeneity of the B27 molecule in this population. ID-IEF and PCR-SSOP technologies were used to analyze polymorphism in exon 2 and 3 of the HLA-B27 gene. Four different subtypes were encountered: B*2702,04,05 and 07. Other subtypes of B27 viz B*2701,03,06 and 08 were not encountered. B*2704 (common oriental subtype) and B*2705 (common Caucasian subtype) were the most common subtypes in the control and patient groups. B*2707 was less frequently encountered in both groups and B*2702 was found in only one AAU patient. B*2704 was the predominant subtype in the AS group (70.8%) compared to its frequency of 47% in healthy controls (RR = 2.73) while in the undiff SpA group, B*2705 occurred most frequently (73.1%, RR = 3.05). B27 subtypes segregated differently in males and females. 12 of the 17 male AS patients carried B*2704 as compared to 1 of 8 healthy males (X2 = 3.9, P < 0.05). On the other hand, in the undiff SpA, B*2705 was significantly raised in female patients (100%) as compared to healthy females (22.2%, X2 = 4.9, P < 0.05). Subtype distribution is indicative of racial admixture in the Asian Indian population.

Spondyloarthropathies and psoriatic arthritis in children.

Data that are relevant to the general understanding of the juvenile-onset spondyloarthropathies are reviewed here. Seronegative enthesopathy and arthropathy syndrome is considered the earliest recognizable form of juvenile-onset spondyloarthropathy, from which other syndromes and diseases emerge. The group also includes juvenile-onset ankylosing spondylitis, a disease defined in adult-based terms when definite changes have occurred in the axial joints; ankylosing tarsitis, a complex disorder in which foot problems resemble those of the spine in ankylosing spondylitis; Crohn's disease and ulcerative colitis-related peripheral and, especially, HLA-B27 axial disease; reactive arthritis and Reiter's syndrome, which might be further classified according to its cause; and juvenile psoriatic arthritis, a disease that resembles juvenile rheumatoid arthritis more than does juvenile-onset spondyloarthropathy.

The arthritis of ulcerative colitis: clinical and genetic aspects.

Seventy-nine consecutive patients with active ulcerative colitis were studied to establish the prevalence and clinical features of articular involvement. HLA typing for A and B loci was performed. Forty-nine patients showed an articular involvement (62%). Three different clinical patterns were identified: ankylosing spondylitis occurring in 20 subjects; peripheral arthritis in 15; unclassifiable spondylitis in 14. When compared to the general population in our area, patients with colitis showed a significantly higher prevalence of the HLA-A1 (p less than 0.005), B21 (p less than 0.001) and B27 (p less than 0.05); among patients with colitis, those with arthritis revealed higher frequency of HLA-B27 (p less than 0.05). Our study reveals a high prevalence of unclassifiable spondylitis during ulcerative colitis, and suggests a new approach to the classification of seronegative spondarthritis.

Heart conduction disturbance: an HLA-B27 associated disease.

In recent studies from Sweden an increased prevalence of HLA-B27 associated diseases and of HLA-B27 was found in an unselected group of men with permanently implanted pacemakers and with a heart block. Furthermore, a significantly increased prevalence of HLA-B27 was found in men with a pacemaker who had no clinical or radiological signs of HLA-B27 associated disease. To obtain more insight into the association between HLA-B27 and heart block, and the possible role of HLA-B27 in causing this block, a study was made of 35 patients with a pacemaker and heart block of unknown cause, selected from a total group of 350 men with pacemakers who were still alive at the time of the study. One of these 35 men had ankylosing spondylitis and two patients had an asymptomatic sacroiliitis, but all three were HLA-B27 negative. HLA-B27 was present in five (14%) patients, which is a significantly higher prevalence than in healthy controls (17/292, 6%). This percentage is equal to the percentage of HLA-B27 positivity found in the Swedish study on unselected men with an implanted pacemaker, in whom the presence of an HLA-B27 associated disease had been excluded. It suggests that factors other than HLA-B27 are important in the pathogenesis of heart block in most patients.

Platelet aggregating activity in serum from patients with HLA-B27 associated rheumatic and cardiac disorders: a possible link to the proliferative vascular changes.

OBJECTIVE: To search for possible serum factors (immunochemical abnormalities) that reflect HLA-B27 associated inflammatory process with the proliferative endarteritis, which is an important cause of severe bradycardia and aortic valve regurgitation. PATIENTS AND METHODS: Seventy four men with pacemakers were studied: 24 were HLA-B27 positive and had associated rheumatic and cardiac disorders, 13 were B27 positive but had no clinical or radiographic signs of a related rheumatic condition, and 37 were B27 negative controls. Randomly obtained serum samples were examined for a series of serum factors. RESULTS: Thirteen (57%) of the 23 patients with HLA-B27 and associated rheumatic and cardiac conditions had platelet aggregating activity in their serum. No such activity was found in sera from patients in the other groups. None the less, immunochemical abnormalities were common among patients of all groups; 30 (41%) had antinuclear antibodies or rheumatoid factor or both. CONCLUSION: The platelet aggregating activity found in patients with HLA-B27 and associated rheumatic and cardiac conditions may reflect serum factors that increase the stickiness of platelets and increase their adhesion to the vessel wall. This suggests a link via release of platelet derived growth factor(s) with the characteristic histopathological feature of proliferative endarteritis. Immunochemical abnormalities were common in serum from all men with pacemakers.

Subclinical involvement of the gut in undifferentiated spondylarthropathies.

In order to evaluate the frequency of subclinical gut involvement in the seronegative spondylarthropathies, ileocolonoscopy with biopsies of the colon, ileocecal valve and ileum were performed on 211 patients with ankylosing spondylitis (AS), reactive arthritis (ReA) and undifferentiated spondylarthropathies. Inflammatory gut lesions were detected in a large number of these patients. It was concluded that the group of undifferentiated spondylarthropathies could be split into fairly equal subgroups: one subgroup suffering from subclinical inflammatory bowel disease associated with peripheral joint symptoms, a second subgroup presenting a form of enterogenic ReA, and a third subgroup in which no relation with the gut could be demonstrated. Ankylosing spondylitis, which has to be considered as a form of undifferentiated seronegative spondylarthropathy, could be subdivided into the same subgroups. These findings confirm the existence of subclinical gut involvement in patients with seronegative spondylarthropathies.

Macroscopic and histological changes of the ileum HLA-B27 related diseases: therapeutic consequences.

Ileocolonoscopy and microscopic examination of ileum biopsies have been performed on patients with reactive synovitis, ankylosing spondylitis (AS) and on a control group. Histological signs of gut inflammation were present in practically all patients with reactive synovitis, with the exception of the patients with sexually-acquired disease. In the AS group, inflammation of the ileum was observed in the HLA-B27 negative patients and in AS B27 positive patients with peripheral joint involvement. Occasionally, changes of the ileum were seen in the B27 positive AS patients without peripheral joint involvement. Signs of gut inflammation were absent in all controls. These data suggest that chronic inflammation of the ileum could be implicated in the pathogenesis of some cases of reactive synovitis and even in the peripheral joint involvement frequently seen in ankylosing spondylitis. In the second part of the study, sulfasalazine (Salazopyrin) was administered to 15 HLA-B27 positive patients with reactive synovitis, who had failed to respond to non-steroidal anti-inflammatory drugs. In 11 of the 15 patients, a clinical and biological remission occurred 3 to 11 months after the start of sulfasalazine treatment. The frequency of spontaneous remissions in reactive synovitis calls for confirmation of these encouraging results in double-blind controlled studies.