It has recently been demonstrated in a variety of autoimmune diseases that the appearance of specific serum antibodies may precede the onset of clinical disease by many years.4
These antibodies may not be directly responsible for many of the manifestations of the disease, but are markers of future disease in presently healthy individuals. A partial list includes rheumatoid arthritis,5
systemic lupus erythematosus (SLE),6
and type I diabetes mellitus.7
In the case of SLE, a concept of a crescendo of autoimmunity culminating in clinical illness was formed.6
This concept is supported by data showing increasing concentrations of autoantibodies before diagnosis.6,8
The prospectively assembled IDF serum repository has provided an opportunity to examine the development of ASCA and pANCA before the onset of clinical illness in patients with IBD. ASCA were present in a subgroup of CD patients, years before the clinical onset of disease: 31.3% of patients were ASCA positive before clinical diagnosis and 54.5% after diagnosis versus none in controls. Overall, the mean interval between ASCA detection and diagnosis was 38 months (range 20–77). As in the majority of these subjects the first serum sample was ASCA positive, this means that the time interval was actually underestimated. In six patients who were ASCA positive after clinical onset, serum samples were also available before diagnosis. In all of these cases ASCA were present in prediagnostic serum samples.
Our findings correlate with the previously observed frequency of these antibodies in CD patients (40–70%).9–11
Despite modest sensitivity, several studies have found ASCA expression (either IgA or IgG) to be nearly 95% specific for CD.9,11,12
The reason for generation of ASCA remains unclear. ASCA are detected through their reactivity with sequences of mannose residues expressed in the cell wall mannan of S cerevisiae
It was hypothesised that increased permeability in the small bowel of CD patients might lead to increased exposure of yeast antigens (which are a resident part of the normal intestinal flora) to immune reactive cells. Increased permeability of the small bowel as an early event in the pathogenesis of CD (before gross inflammatory damage to the bowel wall is apparent) may also explain our findings of the early appearance of ASCA. However, no association was found between ASCA titres and permeability of the small intestine, as measured by the cellobiose/mannitol test,14
Thus ASCA and increased permeability of the small bowel are most likely independent phenomena in CD.16
ASCA have also been described as a genetic (or a familial) marker in IBD. This is based on studies demonstrating ASCA positivity in 20–25% of unaffected first degree relatives of patients with CD.16–18
It was argued that whether the presence of ASCA in these healthy relatives is genetically determined or attributed to an environmental factor, it does not have any clinical implication.1
As none of the studies provided long term follow up on these subjects, no conclusion can be made as to whether they actually remain unaffected in years to come. We found that ASCA levels increased in asymptomatic subjects as the time to diagnosis of CD approached (fig 2). Therefore, the question relating to the clinical importance of the presence of ASCA in an asymptomatic family member may only be resolved by prospective studies with follow up of ASCA titres, as well as clinical symptoms in these individuals.
Recent evidence suggests that ASCA serology may correlate with particular clinical features, including young age at onset of disease,16
and development of strictures and fistulae.20
Furthermore, ASCA have also been associated with increased risk for early surgery (defined as occurring within three years of diagnosis).21,22
Early identification of a rising titre of ASCA may help to identify a subgroup of patients that might benefit from a more aggressive approach with preventive medical therapy or immunomodulation. This may alter the course of disease and decrease the necessity for surgery.22
Should asymptomatic persons incidentally discovered to be ASCA positive be monitored? Based on our findings it can be argued that the presence of ASCA in asymptomatic subjects may be in itself a predictor for future development of CD, with the distinct pattern of clinical features, as described above. This would be especially relevant for high risk individuals, such as asymptomatic first degree family members of CD patients. None the less, it is too early to recommend a specific course of action until further data are obtained through prospective clinical trials.
We were able to identify a relatively small number of UC patients with available serum samples before diagnosis of disease. pANCA were present in 25% of UC patients before clinical diagnosis compared with none of the controls. In our small cohort, only 1/6 patients (16.7%) were pANCA positive after diagnosis. The accuracy of pANCA as a diagnostic tool largely depends on the technique employed.3,23
A wide range of sensitivities (from 0% to 63%) has been reported24
although, as in the case of ASCA for CD patients, the specificity of pANCA for diagnosis of UC is high.
ANCA constitute a heterogenous group of antibodies which are mainly directed against constituents of neutrophil granules in patients with primary vascultides. The neutrophil specific pANCA-like antibodies found in the sera of patients with UC however seem to target many different neutrophil antigens located in nuclei, granules, and cytosol.3
In UC, serum pANCA are thought to reflect mucosal pANCA production,25
thus implying that recognition of mucosal antigen(s) is involved. Most studies do not support a relationship between the presence or level of pANCA and UC activity,26
and pANCA persist after total colectomy.27
Although our study reports only a small number of UC patients, it clearly demonstrates that pANCA is present in a subgroup of patients before clinical diagnosis.
In summary, our results demonstrate that clinical IBD is preceded by the presence of specific antibodies for many years before diagnosis. In the case of CD, we found a steady increase in the percentage of ASCA positive cases as well as a significant rise in levels of ASCA as time progresses, until symptoms of clinical illness appear. This distinct pattern, which is a common feature of autoimmune disease, undermines the current belief that ASCA are simply a genetic marker of CD.
Thus the presence of ASCA in a high risk healthy individual might be a marker for future development of CD and may even predict the clinical course. A similar association may exist for pANCA and UC.