Objective

Ankylosing spondylitis (AS) is diagnosed late, because radiographs of the sacroiliac joints often do not show definite sacroiliitis at the time of disease onset. The aim of this study was to investigate whether patients without definite radiographically defined sacroiliitis, referred to as nonradiographic axial spondylarthritis (SpA), are different from patients with AS with regard to clinical manifestations and disease activity measures. Moreover, we sought to identify determinants of the development of radiographic sacroiliitis.



Methods

In a cross-sectional analysis of 462 patients, we compared 226 patients with nonradiographic axial SpA (symptom duration ≤5 years) and 236 patients with AS (symptom duration ≤10 years) who are participants in the German Spondyloarthritis Inception Cohort. Radiographs of the sacroiliac joints and the spine were assessed by 2 readers in a blinded manner. Logistic regression analysis was applied to identify parameters associated with structural damage.



Results

The 2 groups did not differ in the frequency of HLA–B27 positivity, inflammatory back pain, arthritis, enthesitis, and uveitis and had similar levels of disease activity, using measures such as the Bath Ankylosing Spondylitis Disease Activity Index. In both groups, HLA–B27 positivity determined the age at disease onset. Male sex (adjusted odds ratio [OR] 2.38, 95% confidence interval [95% CI] 1.19–4.73 [P = 0.014]) and an elevated C-reactive protein (CRP) level (adjusted OR 1.85, 95% CI 0.96–3.56 [P = 0.066]) were associated with radiographic sacroiliitis. In patients with AS, male sex and an elevated CRP level were also associated with the presence of syndesmophytes.



Conclusion

Clinical manifestations and disease activity measures are highly comparable between patients with early nonradiographic axial SpA and those with early AS, suggesting that these 2 entities are part of the same disease. Male sex and an elevated CRP level are associated with structural damage on radiographs, whereas HLA–B27 positivity determines the age at disease onset.

https://www.onlinelibrary.wiley.com/doi/pdf/10.1002/art.24483

The early disease stage in axial spondylarthritis: results from the German Spondyloarthritis Inception Cohort.

Ankylosing spondylitis (AS) is a complex, potentially debilitating disease that is insidious in onset, progressing to radiological sacroiliitis over several years. Patients with symptomatic AS lose productivity owing to work disability and unemployment, have a substantial use of healthcare resources, and reduced quality of life. The pathogenesis of AS is poorly understood. However, immune mediated mechanisms involving human leucocyte antigen (HLA)-B27, inflammatory cellular infiltrates, cytokines (for example, tumour necrosis factor α and interleukin 10), and genetic and environmental factors are thought to have key roles. The detection of sacroiliitis by radiography, magnetic resonance imaging, or computed tomography in the presence of clinical manifestations is diagnostic for AS, although the presence of inflammatory back pain plus at least two other typical features of spondyloarthropathy (for example, enthesitis and uveitis) is highly predictive of early AS. Non-steroidal anti-inflammatory drugs (NSAIDs) effectively relieve inflammatory symptoms and are presently first line drug treatment. However, NSAID treatment has only a symptomatic effect and probably does not alter the disease course. For symptoms refractory to NSAIDs, second line treatments, including corticosteroids and various disease modifying antirheumatic drugs, are employed but are of limited benefit. Emerging biological therapies target the inflammatory processes underlying AS, and thus, may favourably alter the disease process, in addition to providing symptom relief.

https://ard.bmj.com/content/annrheumdis/61/suppl_3/iii8.full.pdf

Ankylosing spondylitis: an overview.

Objective

Tumor necrosis factor α (TNFα) has been detected in sacroiliac joint biopsy specimens from patients with spondylarthropathy. The present open pilot study was undertaken to test the efficacy of the anti-TNFα monoclonal antibody infliximab in the treatment of active ankylosing spondylitis (AS).



Methods

Eleven patients with AS of short duration (median 5 years, range 0.5–13 years) that had been active for at least 3 months (range 3–72 months) were treated with 3 infusions of infliximab (at weeks 0, 2, and 6), in a dosage of 5 mg/kg. Ten of the 11 patients had elevated C-reactive protein (CRP) levels (>6 mg/liter) before treatment; these elevations were known to have had persisted >1 year in at least 3 patients. The Bath AS Disease Activity Index (BASDAI), the Bath AS Functional Index (BASFI), pain as measured on a visual analog scale, and the Bath AS Metrology Index (BASMI) were assessed. Quality of life was assessed using the Short Form 36 instrument. Laboratory markers of disease activity, including interleukin-6 (IL-6) levels, were determined. Dynamic magnetic resonance imaging (MRI) of the spine was performed in 5 patients.



Results

One patient withdrew from the study due to the occurrence of urticarial xanthoma 8 days after the first infusion. At study enrollment, 3 of 5 patients had evidence of spinal inflammation (spondylitis and spondylodiscitis) as detected by MRI; followup MRI 2–6 weeks after the third infusion revealed improvement in 2. Improvement of ≥50% in activity, function, and pain scores was documented in 9 of 10 patients; the median improvement in the BASDAI after 4 weeks was 70% (range 41–94%). This clear-cut benefit lasted for 6 weeks after the third infusion in 8 of 10 patients. The median CRP level decreased from 15.5 mg/liter (range <6–90.8) to normal, and the median IL-6 level from 12.4 mg/liter (range 0–28.4) to normal (<5). There was improvement in all 9 SF-36 concepts; the improvement was significant for 6 concepts.



Conclusion

These data suggest that anti-TNFα therapy is very effective for several weeks in AS. Whether this therapy, in addition to its antiinflammatory effect, prevents ankylosis remains to be determined.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/1529-0131%28200006%2943%3A6%3C1346%3A%3AAID-ANR18%3E3.0.CO%3B2-E

Successful treatment of active ankylosing spondylitis with the anti–tumor necrosis factor α monoclonal antibody infliximab

Objective: Inflammatory back pain (IBP) is an important clinical symptom in patients with axial spondyloarthritis (SpA), and relevant for classification and diagnosis. In the present report, a new approach for the development of IBP classification criteria is discussed. Methods: Rheumatologists (n = 13) who are experts in SpA took part in a 2-day international workshop to investigate 20 patients with back pain and possible SpA. Each expert documented the presence/absence of clinical parameters typical for IBP, and judged whether IBP was considered present or absent based on the received information. This expert judgement was used as the dependent variable in a logistic regression analysis in order to identify those individual IBP parameters that contributed best to a diagnosis of IBP. The new set of IBP criteria was validated in a separate cohort of patients (n = 648). Results: Five parameters best explained IBP according to the experts. These were: (1) improvement with exercise (odds ratio (OR) 23.1); (2) pain at night (OR 20.4); (3) insidious onset (OR 12.7); (4) age at onset Conclusion: This new approach with real patients defines a set of IBP definition criteria using overall expert judgement on IBP as the gold standard. The IBP experts’ criteria are robust, easy to apply and have good face validity.

/pdf/new-criteria-for-inflammatory-back-pain-in-patients-with-60iz788e6g.pdf

New criteria for inflammatory back pain in patients with chronic back pain: a real patient exercise by experts from the Assessment of SpondyloArthritis international Society (ASAS)

Purpose To evaluate the efficacy and safety of adalimumab in patients with non-radiographic axial spondyloarthritis (nr-axSpA).

Methods Patients fulfilled Assessment of Spondyloarthritis international Society (ASAS) criteria for axial spondyloarthritis, had a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score of ≥ 4, total back pain score of ≥ 4 (10 cm visual analogue scale) and inadequate response, intolerance or contraindication to non-steroidal anti-inflammatory drugs (NSAIDs); patients fulfilling modified New York criteria for ankylosing spondylitis were excluded. Patients were randomised to adalimumab (N=91) or placebo (N=94). The primary endpoint was the percentage of patients achieving ASAS40 at week 12. Efficacy assessments included BASDAI and Ankylosing Spondylitis Disease Activity Score (ASDAS). MRI was performed at baseline and week 12 and scored using the Spondyloarthritis Research Consortium of Canada (SPARCC) index.

Results Significantly more patients in the adalimumab group achieved ASAS40 at week 12 compared with patients in the placebo group (36% vs 15%, p<0.001). Significant clinical improvements based on other ASAS responses, ASDAS and BASDAI were also detected at week 12 with adalimumab treatment, as were improvements in quality of life measures. Inflammation in the spine and sacroiliac joints on MRI significantly decreased after 12 weeks of adalimumab treatment. Shorter disease duration, younger age, elevated baseline C-reactive protein or higher SPARCC MRI sacroiliac joint scores were associated with better week 12 responses to adalimumab. The safety profile was consistent with what is known for adalimumab in ankylosing spondylitis and other diseases.

Conclusions In patients with nr-axSpA, adalimumab treatment resulted in effective control of disease activity, decreased inflammation and improved quality of life compared with placebo. Results from ABILITY-1 suggest that adalimumab has a positive benefit–risk profile in active nr-axSpA patients with inadequate response to NSAIDs.

https://ard.bmj.com/content/annrheumdis/72/6/815.full.pdf

Efficacy and safety of adalimumab in patients with non-radiographic axial spondyloarthritis : results of a randomised placebo-controlled trial (ABILITY-1)

Background: Ankylosing spondylitis (AS) and its early form account for up to 5% of all patients with chronic back pain. Interest has recently focused on shortening the delay of 5–10 years between the appearance of first symptoms and the diagnosis of AS, particularly because effective treatments have now become available. Referral parameters that are easy for doctors in primary care to apply to patients presenting with possible AS could contribute to earlier diagnosis. Methods: Orthopaedists and primary-care doctors were requested to refer patients with (1) chronic low back pain (duration >3 months) and (2) onset of back pain before Results: In total, 350 referred cases were analysed. A diagnosis of definite axial spondyloarthritis (axial SpA), comprising established AS and pre-radiographic axial SpA, could be made in 45.4% of all referred patients (of which 50.3% were classified as AS and 49.7% as preradiographic axial SpA), whereas 45.4% were classified as non-SpA and 9.1% as possible SpA. A diagnosis of definite axial SpA could be made in 34.2% if only one referral parameter was positive, and in 62.6% if there was >1 positive referral parameter. Conclusions: The proposed referral parameters have proven useful when applied in primary care in identifying patients with AS/pre-radiographic axial SpA among young to middle-aged patients with chronic low back pain.

/pdf/performance-of-referral-recommendations-in-patients-with-33i0o70mzd.pdf

Performance of referral recommendations in patients with chronic back pain and suspected axial spondyloarthritis

Objective

To determine Th1 and Th2 cytokine production in patients with reactive arthritis (ReA) in relation to disease outcome and in comparison with rheumatoid arthritis (RA).



Methods

Secretion of tumor necrosis factor α (TNFα), interferon-γ, interleukin-10 (IL-10), and IL-4 by peripheral blood mononuclear cells (PBMC) from 53 patients with early ReA (disease duration <8 weeks, 64% HLA–B27 positive) and 30 patients with early, untreated RA (disease duration <6 months) was determined by enzyme-linked immunosorbent assay (ELISA) after ex vivo stimulation. Intracellular cytokine staining with quantification of positive T cells by fluorescence-activated cell sorting (FACS) was performed in 12 ReA patients and 12 RA patients. In 27 ReA patients, cytokine secretion was measured again after 3 months. Patients were followed up for 1 year, and cytokine patterns were correlated with disease duration.



Results

TNFα secreted by whole PBMC and by T cells was significantly lower, by ELISA and by FACS, in ReA patients than in RA patients, while no significant differences were detected for the other cytokines. ReA patients with a disease duration of ≥6 months showed significantly lower TNFα secretion than patients with a disease duration of <6 months (mean ± SD 385 ± 207 pg/ml versus 684 ± 277 pg/ml; P = 0.003). Furthermore, low TNFα secretion after 3 months also correlated significantly with a more chronic course of disease. HLA–B27 positive patients secreted less TNFα than did those who were B27 negative (338 ± 214 pg/ml versus 512 ± 207 pg/ml; P = 0.05), and patients with a more chronic course had a higher frequency of B27 positivity (47% versus 80%; P = 0.01). Among the 27 HLA–B27 positive patients, TNFα secretion in those with a disease duration of ≥6 months was lower than that in the 7 with a disease duration of <6 months (308 ± 167 pg/ml versus 562 ± 308 pg/ml; P = 0.04).



Conclusion

Low TNFα secretion and HLA–B27 status correlate with longer disease duration in ReA patients, possibly with an additive effect. The diminished TNFα production might reflect a state of relative immunodeficiency contributing to bacterial persistence in ReA.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/1529-0131%28199910%2942%3A10%3C2039%3A%3AAID-ANR3%3E3.0.CO%3B2-6

Low secretion of tumor necrosis factor α, but no other Th1 or Th2 cytokines, by peripheral blood mononuclear cells correlates with chronicity in reactive arthritis

Objective. To evaluate 2 referral strategies for axial spondyloarthritis (SpA) in patients with chronic low back pain at the primary care level. Methods. Referral physicians (n = 259) were randomly assigned to either Strategy 1 or Strategy 2 in order to refer patients with chronic back pain (duration > 3 months), age at onset of back pain Results. In total, 560 consecutively referred patients were included in the analysis. Among 318 patients referred by Strategy 1, 41.8% (95% CI 36.5%–47.3%) were diagnosed with definite axial SpA. Among 242 patients referred by the second strategy, definite axial SpA was diagnosed in 36.8% (95% CI 31.0%–43.0%) of the cases. Conclusion. Both referral strategies demonstrated comparable performance in identification of patients with axial SpA. Strategy 1 might be preferred as an easy and reliable screening method for axial SpA at the primary care level.

https://www.jrheum.org/content/jrheum/38/11/2452.full.pdf

Evaluation of 2 Screening Strategies for Early Identification of Patients with Axial Spondyloarthritis in Primary Care

Objective This study was aimed at investigating the frequencies of non-radiographic axial spondyloarthritis (nr-axSpA) and ankylosing spondylitis (AS) diagnoses and their ratios in relation to symptom duration in patients referred because of chronic back pain and suspicion of axial SpA Methods In this monocentre study, orthopaedists and primary care physicians were requested to refer patients with chronic low back pain (duration >3 months) and onset of back pain before 45 years of age to a SpA-specialised rheumatology outpatient clinic for further diagnostic investigation, if proposed screening parameters were present The ratio of nr-axSpA to AS was analysed in relation to the duration of symptoms Results A diagnosis of definite axial SpA was made in 437% of the referred patients (n=522) Axial SpA was diagnosed in a similar percentage of about 50% if back pain duration was 9 years Nr-axSpA represented the majority of patients (673%) only if duration of back pain was 1 year and less at the time of referral Between 1 and 6 years of back pain duration the probability of nr-axSpA and AS was nearly equal (1–3 years: 525% and 475%, respectively; 3–6 years: 537% and 463%, respectively) In patients with back pain duration of 6–9 years, AS was more likely (611%) to be diagnosed than nr-axSpA (389%), and this increased further over time Conclusions Non-radiographic axial SpA represents an important differential diagnosis of back pain, especially in patients with recent symptom onset

https://ard.bmj.com/content/annrheumdis/71/12/1998.full.pdf

The frequency of non-radiographic axial spondyloarthritis in relation to symptom duration in patients referred because of chronic back pain: results from the Berlin early spondyloarthritis clinic

Objective﻿ Inflammatory back pain (IBP), the key symptom of axial spondyloarthritis (axSpA), including ankylosing spondylitis, has been proposed as a screening test for patients presenting with chronic back pain in primary care. The diagnostic accuracy of IBP in the rheumatology setting is unknown. Methods Six rheumatology centres, representing secondary and tertiary rheumatology care, included routinely referred patients with consecutive chronic back pain with suspicion of axSpA. IBP (diagnostic test) was assessed in each centre by an independent (blinded) rheumatologist; a second (unblinded) rheumatologist made the diagnosis (axSpA or no-axSpA), which served as reference standard. Results Of 461 routinely referred patients, 403 received a final diagnosis. IBP was present in 67.3%, and 44.6% (180/403) were diagnosed as axSpA. The sensitivity of IBP according to various definitions (global judgement, Calin, Berlin, Assessment of SpondyloArthritis international Society criteria for IBP) was 74.4%–81.1 % and comparable to published figures, whereas the specificity was unexpectedly low (25.1%–43.9%). The resulting positive likelihood ratios (LR+) were 1.1–1.4 and without major differences between sets of IBP criteria. The presence of IBP according to various definitions increased the probability of axSpA by 2.5%–8.4% only (from 44.6% to 47.1%–53.0%). Conclusions The diagnostic utility of IBP in the rheumatology setting was smaller than expected. However, this was counterbalanced by a high prevalence of IBP among referred patients, demonstrating the effective usage of IBP in primary care as selection parameter for referral to rheumatology. Notably, this study illustrates potential shifts in specificity and LR+ of diagnostic tests if these tests are used to select patients for referral.

https://rmdopen.bmj.com/content/rmdopen/4/2/e000825.full.pdf

Inge Spiller

Papers

Performance of referral recommendations in patients with chronic back pain and suspected axial spondyloarthritis

Low secretion of tumor necrosis factor α, but no other Th1 or Th2 cytokines, by peripheral blood mononuclear cells correlates with chronicity in reactive arthritis

Evaluation of 2 Screening Strategies for Early Identification of Patients with Axial Spondyloarthritis in Primary Care

The frequency of non-radiographic axial spondyloarthritis in relation to symptom duration in patients referred because of chronic back pain: results from the Berlin early spondyloarthritis clinic

Diagnostic accuracy of inflammatory back pain for axial spondyloarthritis in rheumatological care.