Increased risk of developing ankylosing spondylitis among first-born children.

OBJECTIVE: Studies in mice have demonstrated an increased risk of ankylosing enthesopathy in earlier litters compared with later-born offspring. In humans, birth order and maternal age as risk factors for ankylosing spondylitis (AS) have not been investigated previously. This study was undertaken to investigate whether first-born children have a higher risk of AS than later-born children and whether maternal age at delivery is another risk factor. METHODS: The birth order of 162 AS patients was compared with that of their healthy siblings, both for the total group and with stratification for maternal age at first delivery. Maternal age at the time of delivery of AS patients who were first-born children was compared with the mean maternal age at first delivery in the Dutch population. RESULTS: The number of first-born children with AS was significantly higher than would be expected in case of an equal risk between first-born and later-born children (26 versus 20 for families with 2 children [P = 0.029] and 63 versus 47.6 for all families [P = 0.004]). Also, the mean maternal age at first delivery was lower in mothers of AS patients (24.8 years) compared with mothers of healthy controls (26.1 years). CONCLUSION: Low birth order is a risk factor for AS in humans.

Evidence that HLA-B*2706 is not protective against spondyloarthropathy.

OBJECTIVE: Studies in Southeast Asia showed that HLA-B*2704 is positively associated with spondyloarthropathy (SpA), while B*2706 does not occur in such patients. In view of the absence of an association between B*2706 and SpA it was suggested that B*2706 protects against the disease, while it is supposed that B*2704 presents pathogenetic peptides. We studied families in which both B*2704 and B*2706 occurred to see whether in B*2704/B*2706 heterozygotes the effect of one of the subtypes shows a preponderance over the other. METHODS: Two families of mixed Chinese/Indonesian origin were studied. HLA-B27 subtyping was performed by polymerase chain reaction in combination with sequence specific oligonucleotide probes. RESULTS: In one family, members with B*2704, B*2706, or both occurred. In the other family B*2704, B*2706, and B*2708 were present. In both families SpA was seen only in B*2704 positive members, while the B*2706 and B*2708 positive members were healthy, except some B*2704/B*2706 or B*2704/B2708 heterozygotes. CONCLUSION: The pathogenic influence of B*2704 is thus dominant over the supposed protective influence of B*2706. It is probable that B*2704 can present pathogenetic peptides, while a protective influence of B*2706 does not exist. B*2708, which was until now described in only a few cases, behaved in this study as B*2706 and is probably not associated with SpA.

Spondyloarthropathy and idiopathic inflammatory bowel diseases.

: Spondyloarthropathy (SpA) as observed in patients with idiopathic inflammatory bowel diseases is categorized according to the recently developed criteria of the European Spondylarthropathy Group, and belongs to a large complex of rheumatic disorders, encompassing ankylosing spondylitis, Reiter's disease, psoriatic arthritis, and reactive arthritis. It has been recognized for many years that patients with ulcerative colitis or Crohn's disease frequently have arthritic complications. The gastroenterologist should therefore carefully evaluate any symptom of peripheral or axial arthritis, in an attempt to provide an accurate diagnosis, to define a realistic prognosis, and to establish adequate therapy at an early stage. In this review, clinical and etiopathogenic aspects are analyzed, not only of patients with inflammatory bowel diseases and SpA, but also of patients developing arthritic symptoms after gastrointestinal bacterial infections (reactive arthritis). The significance of ileal mucosal inflammation as observed frequently in patients with SpA is discussed; the contribution of immunogenetic factors in the development of SpA, such as HLA-B27, is briefly reviewed. Finally, analysis is made of the different therapeutic options that are available at present.

Absence of autoantibodies to peptides shared by HLA-B27.5 and Klebsiella pneumoniae nitrogenase in serum samples from HLA-B27 positive patients with ankylosing spondylitis and Reiter's syndrome.

Some microorganisms which are pathogenic in humans share amino acid sequences with human proteins (molecular mimicry). It has been suggested that molecular mimicry might be a reason for autoimmunity as a result of immunological cross reactivity. A homologous sequence of six amino acids has been found in both Klebsiella pneumoniae nitrogenase and the HLA-B27.5 molecule. In addition, (auto)antibodies to a synthetic peptide that contained the HLA-B27.5/klebsiella mimicking epitope have been detected in serum samples from HLA-B27 positive patients with ankylosing spondylitis and Reiter's syndrome. Confirmation of these data is important, because ankylosing spondylitis and Reiter's syndrome have so far been assumed to be 'seronegative' rheumatic diseases. It was, however, not possible to confirm the presence of autoantibodies against the mimicking peptide in serum samples from patients with ankylosing spondylitis and Reiter's syndrome. Serum samples from 81 patients with ankylosing spondylitis, 38 patients with Reiter's syndrome, and 81 healthy blood donors were tested against the 'mimicking peptide' in an enzyme linked immunosorbent assay (ELISA). Some of the serum samples from patients showed high but non-specific binding to the mimicking peptide. A highly significant correlation between binding to plastic coated with the mimicking peptide, to plastic coated with an irrelevant peptide, and even to non-coated plastic was observed. The nature of the serum component(s) in these patient serum samples (and some control serum samples) responsible for the high non-specific binding to plastic remains unclear. It was also shown that antibodies to the HLA-B27 peptide (containing the mimicking epitope) induced in rabbits do not cross react with the klebsiella peptide and vice versa.

The lifetime cumulative incidence of acute anterior uveitis in a normal population and its relation to ankylosing spondylitis and histocompatibility antigen HLA-B27.

The lifetime cumulative incidence of acute anterior uveitis (AAU) was determined in a sample of a large population (n = 10,500). Nine hundred seventeen subjects, who answered the question "Have you ever had a red eye" in the affirmative in 1977, were asked to participate in a follow-up study 10 years later. From the 917 respondents, 539 were studied completely. A questionnaire was used to collect historic data, and confirmation of these data was obtained from the treating ophthalmologists and physicians. From these data, subjects were selected for an ophthalmologic examination. The respondents also underwent a rheumatologic examination. The results revealed that the lifetime cumulative incidence of definite AAU is approximately 0.2% in the general population and 1% in the histocompatibility antigen HLA-B27-positive population. In one third of the definite AAU patients, the cause of the disease was known. The lifetime cumulative incidence of definite AAU of unknown cause was 0.15% in the general population. When possible and probable AAU are included, the lifetime cumulative incidence of AAU in the general population is about 0.4%. The observed frequency of the concurrence of AAU and ankylosing spondylitis (AS) was 0.4% in the HLA-B27-positive population and 0.02% in the HLA-B27-negative population. Comparison with the expected frequency of the concurrence of AAU and AS revealed that AAU and AS probably are related diseases irrespective of the association of both diseases with HLA-B27.

Follow-up study of ankylosing spondylitis over a period of 12 years (1977-1989).

A follow-up study was performed on 256 patients with ankylosing spondylitis. HLA-B27-negative Dutch patients very rarely had classical idiopathic ankylosing spondylitis. Most of these patients had psoriasis or inflammatory bowel disease or they were foreigners living in The Netherlands. Many of the B27-negative patients only have sacroiliitis. Psoriasis or inflammatory bowel disease among the HLA-B27-positive with a classical ankylosing spondylitis is rare.

Distribution of HLA-B27 subtypes in patients with ankylosing spondylitis: the disease is associated with a common determinant of the various B27 molecules.

HLA-B27 subtypes can be defined by cellular, serological, and biochemical techniques. The seven subtypes so far identified represent structural variants of B27 with limited variations in the amino acid sequence of the B27 molecule. The routinely typed B27 'antigen' remains a common (shared, public) determinant present on various B27 molecules. The distribution of the subtypes varies strongly among different ethnic groups and they occur in different linkage disequilibria. In the healthy Dutch population only two subtypes were found: B27W (B27 X 1, B27M2+) (90%) and B27K (B27 X 2, B27M2-) (10%). A similar distribution of B27 subtypes was observed in 91 unrelated Dutch patients with ankylosing spondylitis (AS)--namely, 92% B27W and 8% B27K. In Oriental populations the subtype distribution is quite different: B27W occurs in less than 50%, whereas more than 50% individuals are of the B27C and B27D subtypes. Preliminary data indicate that the distribution of subtypes in healthy and diseased Oriental individuals is similar. These results suggest that the B27 and disease (AS) association is not correlated with the structural variations of one of the B27 subtypes, but with a common B27 determinant shared by various B27 subtypes. Consequently, the disease is older than the B27 variants. Further studies on disease and subtype distribution in various ethnic groups might contribute to a better understanding of the origin of both.

Antibodies to Enterobacteriaceae in ankylosing spondylitis.

Serological studies on ankylosing spondylitis (AS; N = 82) show that although statistically more AS patients than controls (N = 24) may possess elevated serum titres to enterobacteria such as Salmonella, Shigella and Yersinia, this does not necessarily imply enterobacterial involvement in AS, as other groups without enteritis or arthropathies that frequent health care facilities (N = 72) may also display this phenomenon, presumably due to increased exposure. Moreover, an inventory of all detectable antibody reactivities to the separated cell envelope antigens of five enterobacterial species suspected of involvement in AS (notably Enterobacter, Klebsiella, Salmonella, Shigella and Yersinia) failed to reveal statistical associations with AS. This might be explained, assuming that the aetiology of AS entails a set of enterobacteria rather than a few individual species. It is proposed that serological studies on AS should be supported by additional information, e.g. that of the faecal carriage, and that these combined studies encompassing other enterobacteria, in addition to Klebsiella, might be fruitful.

The use of HLA-B27 as a diagnostic and prognostic aid in acute anterior uveitis (AAU) in The Netherlands.

Acute anterior uveitis (AAU) may be considered to be one manifestation of the seronegative spondylarthropathies of which ankylosing spondylitis (AS) is the prototype, especially when the patient is HLA-B27 positive. However, it is not yet clear under which circumstances a patient with AAU should be referred to the rheumatologist. In a retrospective study we evaluated the management of 68 consecutive HLA-B27+ AAU patients from a rheumatologic point of view. Although the majority (73%) showed rheumatic problems, only half (52%) of the patients was referred to a rheumatologist, due to problems in evaluation of clinical history and of x-ray reading of the sacroiliac (SI) joints. Because HLA-B27 typing will determine whether the AAU patients "at risk" have AS or a related arthropathy, we suggest using HLA-B27 typing in AAU patients as a diagnostic and prognostic aid. When the AAU patient is found to be HLA-B27 positive, the rheumatologist will be able to "split" these patients into those with AS and those without. Early diagnosis of AS in AAU patients is important as an early start of drug therapy and physiotherapy may prevent deformities and improve final rheumatologic outcome.

Possible ankylosing spondylitis in acute anterior uveitis.

HLA-B27 typing of 103 acute anterior uveitis (AAU) patients showed that 49 (48%) were positive for this antigen. Of these HLA-B27 positive AAU patients, 27 (55%) had ankylosing spondylitis (AS) according to the New York criteria. The 22 HLA-B27 positive AAU patients without AS, however, also showed symptoms and signs of AS. Seventeen (77%) of these 22 HLA-B27 positive AS negative AAU patients fulfilled a set of criteria for classification as possible AS. In the group of 54 HLA-B27 negative AAU patients, only two patients (4%) had AS. Of the remaining 52 patients only seven (13%) had possible AS. Of the 21 patients having posterior uveitis (PU) none was HLA-B27 positive nor met the criteria for AS or possible AS. These findings indicate a strong relationship between AAU, AS or possible AS and HLA-B27 and suggest that HLA-B27 typing in AAU patients is important for early diagnosis of AS.

Antibodies against cell envelope antigens of Yersinia enterocolitica in reactive arthritis and ankylosing spondylitis.

Yersinia enterocolitica is suspected of involvement in the aetiology of reactive arthritis and ankylosing spondylitis. Its two major outer membrane proteins are important targets for IgA and other protein A reactive immunoglobulins in the sera of some patients with these diseases.

Sthenia, ambition and educational level in patients suffering from ankylosing spondylitis: a controlled study of personality features as compared to rheumatoid arthritis and unspecified low back pain.

As compared to control-groups of rheumatoid arthritis and chronic non-inflammatory low back pain, over a hundred polyclinical patients suffering from ankylosing spondylitis were assessed with respect to several personality characteristics by psychological testing and proved to be relatively sthenic and educated. In trying to explain these personality features some disease-related factors seem to be relevant in ankylosing spondylitis: a relatively mild course of disease, the relief of complaints by exercise and a long pre-diagnostic period.

Histocompatibility antigens and other markers in ankylosing spondylitis and inflammatory bowel diseases.

An increased frequency of HLA B27 was confirmed in a series of 118 patients with ankylosing spondylitis. This was significantly higher in patients who acquired the disease at an early age. Other deviating antigen frequencies were found to be due to linkage disequilibrium. An increased frequency of antigen BW16 was noted in B27 negative patients. In ulcerative colitis, a significantly raised incidence of A11 was found, as well as an increased frequency of B18 in Crohn's disease. The only deviating frequency from controls for blood and serum groups was in blood group Kell, which was increased in Crohn's disease.