ARTHRITIS & RHEUMATISM
Vol. 52, No. 4, April 2005, pp 1000–1008
© 2005, American College of Rheumatology
The Challenge of Diagnosis and Classification in
Early Ankylosing Spondylitis
Do We Need New Criteria?
Martin Rudwaleit,1Muhammad A. Khan,2and Joachim Sieper1
Ankylosing spondylitis (AS) is a common chronic
inflammatory disease with an estimated prevalence of
0.2–1.2% (1–4). The disease typically starts during the
third decade of life and has a substantial socioeconomic
impact on the patient and society (5–7). Until recently,
the treatment options for AS were limited. The main-
stays of treatment were regular physical therapy and
nonsteroidal antiinflammatory drugs (NSAIDs) (8). In
contrast, disease-modifying antirheumatic drugs
(DMARDs) as well as corticosteroids, which are quite
effective in some of the other chronic inflammatory
diseases such as rheumatoid arthritis (RA), show only
very limited or no efficacy in AS (9–11). Thus, in the
past, a delayed diagnosis did not have much of an
adverse consequence because of the lack of highly
effective therapeutic choices.
Most recently, it has been convincingly demon-
strated that the tumor necrosis factor ? (TNF?)–
blocking agents infliximab and etanercept have a strong
and prompt effect on almost all features of AS, such as
clinical disease activity, physical function, spinal mobil-
ity, peripheral arthritis, enthesitis, and levels of acute-
phase reactants (12–19). In several studies of AS pa-
tients whose disease was refractory to NSAIDs and
physical therapy, ?50% of the patients have demon-
strated at least a 50% improvement when treated with
either of the two TNF?-blocking compounds. It has also
been shown that active juxtaarticular bony inflammation
(“bone edema”), as detected by magnetic resonance
imaging (MRI), can be suppressed (20,21), and it is
hoped that this kind of treatment will also favorably
influence long-term outcome, including reduction or
prevention of radiologic progression. Recent data also
show that AS patients with a short disease duration and
good functional status are more likely to respond to
TNF?-blocking agents than patients with longstanding
disease and impaired function (22). Thus, an early and
reliable diagnosis of AS has now become an important
and very relevant issue.
Evolution of criteria for AS
The Rome criteria (23) from 1961 were the first
set of criteria developed for the classification of AS, and
on their subsequent evaluation (24), 2 items from these
criteria were deleted: thoracic pain (because of its low
specificity) and uveitis (because of its low sensitivity).
This resulted in the New York classification criteria (25)
in 1966. In 1977, Calin et al had suggested criteria for
chronic inflammatory back pain (IBP) to help differen-
tiate IBP from other causes of chronic back pain (26).
This led in 1984 to the modified New York criteria for
the classification of AS (27). The modified New York
criteria incorporate the IBP components in place of the
rather nonspecific clinical symptom of chronic low back
pain that was used in both the Rome and the New York
criteria. A patient can be classified as having definite AS
if at least 1 clinical criterion (inflammatory back pain,
limitation of mobility of the lumbar spine, or limitation
of chest expansion) plus the radiologic criterion (radio-
graphic sacroiliitis of grade 2 bilaterally or grade 3–4
unilaterally) are fulfilled. These modified criteria are cur-
Supported by grant FKZ 01 GI 9946 from the BMBF
1Martin Rudwaleit, MD, Joachim Sieper, MD: Charite ´, Cam-
pus Benjamin Franklin, Berlin, Germany;2Muhammad A. Khan, MD:
MetroHealth Medical Center, Case Western Reserve University,
Address correspondence and reprint requests to Martin Rud-
waleit, MD, Rheumatologie, Medizinische Klinik I, Charite ´, Campus
Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany.
Submitted for publication September 16, 2004; accepted in
revised form January 5, 2005.
rently the most widely used classification criteria, and
clinicians are also using it for the clinical diagnosis of AS.
The early disease stage of AS
Over the last decades, it has become increasingly
evident that in many patients with AS, it takes years
from the onset of IBP until the appearance of radio-
graphic sacroiliitis. For example, in a study of 88 patients
with clinical features compatible with early AS (IBP plus
additional features such as peripheral arthritis, heel
pain, acute uveitis, or elevated levels of acute-phase
reactants) but with radiographically normal sacroiliac
joints, 36% had developed radiographic evidence of
sacroiliitis after 5 years and 59% had done so after 10
Thus, time (duration of symptoms/disease dura-
tion) is an important factor in determining the presence
or absence of radiographic sacroiliitis in predisposed
individuals. This was also shown in a study of HLA–B27–
positive relatives of patients with AS (1), where radio-
graphic sacroiliitis was noted in 16% of patients younger
than 45 years and increased to 38% of patients older
than 45 years. In another family study, radiographic
evidence of sacroiliitis was found in 40% of patients with
a symptom duration of ?10 years, 70% with symptoms
for 10–19 years, and 86% with symptoms for ?20 years
The absence of radiographic sacroiliitis during
the early stage of disease must certainly not imply that
there is no inflammation in the sacroiliac joints and/or
other parts of the axial skeleton. Recent application of
MRI techniques has demonstrated (and confirmed) that
ongoing active (“acute”) inflammation in fact does occur
in the sacroiliac joints and/or spine prior to the appear-
ance of changes detectable radiographically. In a pro-
spective study of 9 patients with normal or equivocal
findings on radiographs in the presence of active inflam-
mation on MRI at baseline, 6 developed definite radio-
graphic sacroiliitis (at least grade 2 bilaterally) after 3
years of followup (30). MRI seems to represent the most
recent milestone in diagnostic imaging of the preradio-
graphic phase of AS (30–32) (Figure 1), although a clear
definition of positive and negative findings on MRI is
needed, along additional data on the sensitivity and
specificity of MRI findings in patients with early disease.
An international effort to address these questions is
Burden of disease in early AS
Remarkably, the presence or absence of radio-
graphic sacroiliitis does not determine the burden of
disease during the early stage of AS. A study of the
German Spondyloarthropathy Inception Cohort
(GESPIC) has recently shown that patients with early
disease without radiographic sacroiliitis (undifferentiated
spondylarthritis [SpA] with axial involvement) do not
differ in this regard from patients with definite AS (with
radiographic sacroiliitis) of short duration (?10 years)
with respect to disease activity (as evaluated by the Bath
Ankylosing Spondylitis Disease Activity Index), level of
global pain, level of pain at night, patient’s global
assessment of disease activity, need for treatment, re-
sponse to treatment, and quality of life (33). In other
words, the presence or absence of changes detected by
conventional radiography does not primarily determine
the impact of the disease on daily life.
Radiographic and preradiographic AS, a single
Given the compelling amount of data suggesting
that the occurrence of radiographic sacroiliitis in pa-
tients with axial SpA is mainly a function of time, with
some influence of severity factors, the presence and
absence of radiographic sacroiliitis in patients with SpA
represent different stages of a single disease continuum
and, therefore, the same disease entity. Radiographic
sacroiliitis is often followed at a later stage by the
formation of syndesmophytes (Figure 1). Thus, the
presence of radiographic changes should be seen as a
Figure 1. Unifying concept of axial spondylarthritis (SpA), showing
schematically the transition from early to late axial SpA. Axial SpA
usually starts without sacroiliitis detectable by conventional radiogra-
phy, but with time (over years), sacroiliitis and possibly syndesmo-
phytes will become detectable by conventional radiography. Back pain
as the leading symptom may be present throughout the disease course.
During the early disease stage, magnetic resonance imaging (MRI)
may detect acute inflammatory lesions in the absence of radiographic
sacroiliitis. The vertical dotted line indicates the borderline that is
used, according to established criteria, to separate axial undifferenti-
ated SpA without radiographic changes from ankylosing spondylitis.
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APPENDIX A: DISEASE PROBABILITY CALCULATIONS
The likelihood ratio (LR) combines both the sensitivity and
the specificity of a given parameter in a single value and is defined as
Positive LR ? sensitivity/1 – specificity
if the parameter is present (52). The disease probability (posttest
probability) can be calculated by using the LR, as follows:
Posttest probability ? posttest odds/1 ? posttest odds
The posttest odds is derived from the product of the pretest odds and
the LR product of the various test parameters that are present or
positive, using the following formula:
Pretest odds ? LR1? LR2? LR3?. . . ? posttest odds
where LR1, LR2, LR3. . . represent the LR of the various diagnostic
parameters (tests) applied. The pretest odds can be calculated from
the pretest probability (disease prevalence) by the formula:
Pretest odds ? pretest probability/1 – pretest probability
In the calculations, we assume a pretest probability (preva-
lence of axial SpA among patients with chronic back pain) of 5% (44).
Thus, a pretest probability of 5% corresponds to a pretest odds of 0.05,
and a posttest probability of ?90% corresponds to a posttest odds of
?10. Using this approach and the LRs shown in Figure 3, one can
understand how many and which parameters need to be present in
order to reach a predefined level of disease probability (i.e., level of
diagnostic certainty). As shown in Figure 3, different combinations of
parameters can be chosen to reach an LR product of 200, which is
needed in order to reach a level of diagnostic certainty of at least 90%
(0.05 ? 200 ? 10).
1008 RUDWALEIT ET AL