Early Diagnosis and Treatment with TNF Inhibitors for Improved Outcomes in Ankylosing Spondylitis

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MEDICAL FRONTIERS - 72nd Annual Scientific Meeting of the American College of Rheumatology

San Francisco, California / October 24-29, 2008

Ankylosing spondylitis (AS) is a progressive disease that ultimately leads to destruction of vertebral joints, with consequent deleterious effects on the quality of life (QoL) and productivity of patients with this disease. Therapy with tumour necrosis factor (TNF) inhibitors has proven to be highly effective in both reducing the symptoms of the disease and altering its natural history, to the point of reversing some aspects of the damage it causes. Researchers now believe that there is a strong rationale for investigating the use of TNF inhibitors as early as possible in the course of AS. Earlier diagnosis and treatment has the potential to reduce symptoms in the years before radiologically-diagnosed AS develops, slow the course of the disease and prevent at least some of the damage it causes.

The Benefits of Anti-TNF Therapy

Long-term efficacy and safety data for the treatment of AS patients with infliximab for seven years was presented by Dr. Xenophon Baraliakos, Rheumazentrum Ruhrgebiet, Herne, Germany (ACR 2008, abstract 1116). Of 37 patients, 38% achieved partial remission. More than 80% of patients reached an ASAS 20 response at least once during the seven years, and 82% of them achieved this at more than 75% of visits. Slightly more than half (54%) the patients rapidly maintained either remission (Figure 1) or low disease activity (BASDAI <3) for the majority of the study period. “Those patients who respond very well at the beginning also do well in the long term. Those patients who are not responding very well at the beginning are not going to respond also in the long term of five or seven years,” noted Dr. Baraliakos. Long-term therapy proved to be safe in this patient population.

One feature of the study design was a treatment break at three years, at which point the investigators waited for signs of renewed disease activity. All patients required resumption of therapy within 18 weeks. Response to the drug rapidly achieved the same levels as prior to discontinuation. “This means that in terms of, for example, elective surgery, you can stop the drug and restart without having concerns about how they will respond thereafter,” noted Dr. Baraliakos.

Figure 1.

Of people who attend hospital due to AS, one-third give up work prior to their normal retirement age. Others reduce their working hours or change the type of work they do as a result of the disease. To investigate the effectiveness of anti-TNF therapy in improving work status, Dr. Andrew Keat, Northwick Park Hospital, London, UK, undertook a prospective study of 72 patients with AS attending two UK hospital clinics for anti-TNF therapy. At baseline, patients had a mean disease duration of 22.5 years, a mean age of onset of disease of 24.2 years, and mean age at treatment of 44.1 years. Mean treatment duration was 21 months. Prior to treatment, 40 patients were working full-time, 10 part-time and 22 were not working. Following therapy, 47 were working full-time, eight part-time and 17 were not working. Therefore eight patients experienced an improvement in work status. In the year prior to treatment, those at work lost a mean 11.2 days due to sick leave, while following treatment, this figure dropped to 1.6 days (P=0.0001). Sleep quality, as measured by the Medical Outcomes Study sleep scale, also improved, with a mean score change from 39/60 to 44/60.

The Need for Earlier AS Diagnosis and Treatment

“Patients with significant symptoms should be treated with anti-TNF for all stages of disease, if they’re not responsive to standard therapies, such as anti-inflammatories,” stated Dr. Walter P. Maksymowych, Professor of Medicine, Division of Rheumatology, University of Alberta, Calgary. “I think a much more important question relates to the possibility that there is a window of opportunity to influence disease progression. We don’t actually have any information at all that addresses that, so I think the next high priority for a clinical trial would be a study of an anti-TNF agent in patients with very early disease and minimal radiographic findings in the spine. What we think is happening is that once a lesion has reached a certain threshold, there are bone growth factors present in the lesion, and the only thing that’s stopping that new bone from forming is the presence of TNF, which is acting though DKK1, the critical regulator of new bone formation. As soon as you give a person an anti-TNF, you neutralize the TNF and also downregulate DKK1, the bone growth factors basically take over and stimulate new bone formation. So our hypothesis is that for TNFs to have a major impact on disease progression, they should be used early on in disease, and if we wait until the lesion is too advanced and the disease is too advanced, then we may not have an ability to influence disease progression. I think there’s an urgent prerogative, an imperative now, to study anti-TNFs very early in the disease course.”

Dr. Robert Inman, Director Arthritis Centre of Excellence, UHN-Toronto Western Hospital, Ontario, agreed: “It’s a big issue, because we’re looking at seven or eight years of symptoms before the diagnosis is finally made, so many of our patients have been suffering with chronic low back pain for a long time, and have usually been inadequately or inappropriately managed, since they’re treated with all kinds of unusual alternative and complementary medicine, until somebody finally did an X-ray or made a diagnosis… When you have a young patient with chronic low back pain, AS should be [listed] higher in the diagnostic possibilities than it is. The second thing for us is that some of those patients are not going to meet New York criteria because they don’t have the X-ray changes yet because they take a while to develop. That’s an appropriate use for MRI, because MRI could actually put the diagnosis on a more objective footing than just symptoms alone. I think if we intervene earlier in the disease, there’s a good chance that we can actually affect outcomes. We know that in terms of symptoms, work productivity, even spinal mobility measures can be influenced with earlier intervention, and this presumes that you’re going to change the natural history radiographically. That’s still under study, but in terms of QoL, we can make a big difference for our patients with earlier diagnosis and earlier, more aggressive treatment for sure… That’s where anti-TNFs have revolutionized the care of AS: if you’ve failed your NSAIDs and your exercises, in the past there wasn’t much left except narcotics and prednisone, and that’s not acceptable, so (the anti-TNFs have) really opened the door to changing people’s lives dramatically.”

Because AS is a progressive disease that causes irreversible damage to the vertebral joints, it is important to diagnose the disease as early as possible in order to initiate early therapy. The importance of early therapy was underscored by a study of bone mineral density (BMD) changes in the lumbar spine and hips of 131 consecutive patients diagnosed with early spondyloarthritis (SpA) (ACR 2008, abstract 524). The duration of disease in these patients was very short (median 6.6 months). Nevertheless, osteopenia and low BMD were already present in some patients at this stage. The patients were followed prospectively. At three years, 47% of patients had low BMD (T-score <-1.0), including 8% with osteoporosis (T-score <u><</u>2.5). Univariate analysis identified male sex, AS diagnosis, elevated CRP, and high BASFI and BASMI scores (decreased functional capacity) as risk factors. Senior investigator Dr. Irene E. van der Horst-Bruinsma, VU University Medical Center, Amsterdam, The Netherlands, suggested that earlier treatment than is currently used should be considered. “I think it is very important to develop strategies to prevent further osteopenia and osteoporosis, and we know that TNF-blocking agents can inhibit the onset of osteopenia and osteoporosis.”

The use of infliximab in juvenile patients with a diagnosis of SpA (stratified into undifferentiated SpA and AS) was investigated in a 12-week randomized, controlled trial with an open 52-week extension (ACR 2008, abstract 1103). In this small study (26 patients), the number of active joints (primary end point) was significantly reduced at 12 weeks from 4.6 to 0.7, compared to a reduction from 6.1 to 4.1 for placebo (P=0.007). There were several objective and QoL secondary end points, which demonstrated further positive outcomes for this therapy.

The extension study indicated sustained benefits from continued treatment. Safety was good, and infliximab was well-tolerated, with no treatment-related serious adverse events. “If there is one molecule [for the treatment of juvenile SpA], this is it,” according to investigator Dr. Raúl Gutiérrez-Suárez, Hospital General de México, Mexico. “The impact is very big; for example, in the open phase, many patients had zero active joints, zero tender entheses, zero C-HAQ, and for these children, there are no other useful treatments.”

Improving Early Diagnosis

Early diagnosis of AS is notoriously difficult. Recent research has examined the possibility of using certain conditions that commonly exist as extra-articular manifestations of AS as early predictors of the disease. The most common of these conditions is acute anterior uveitis (AAU). A review of 276 AS patients revealed that 20% of them had experienced at least one episode of AAU (Podbielski et al., ACR 2008, abstract 528). Patients in this group had a mean disease duration of 20.6 ± 12.5 years. Of these patients, 82.4% had contracted AAU before the appearance of AS symptoms, while a further 14.7% experienced AAU and AS symptoms simultaneously (Figure 2). The investigators concluded that early referral of patients with AAU to a rheumatologist by the ophthalmologist might facilitate earlier diagnosis

Figure 2.


Another condition frequently associated with AS is hip arthritis. This condition has been identified as predictive of a poorer prognosis in AS, along with male sex, early age of onset and peripheral oligoarthritis (J Rheumatol 2003;30(2):316-20). Results of a study of 220 patients attending the spondylitis clinic at Toronto Western Hospital showed that 21.4% of patients had radiographic evidence of hip disease. Within this group, scores for the modified SASSS, BASFI and BASMI scales were significantly worse than for those patients without evidence of hip disease. Values were 32.4 vs. 16.1 (P<0.001), 5.1 vs. 3.6 (P<0.002) and 4.9 vs. 2.7 (P<0.001), respectively. Based on these findings, Dr. Finbar O’Shea, UHN-Toronto Western Hospital, concluded, “It may be possible to improve long-term functional outcome in AS by targeting high-risk individuals early in the disease course with more aggressive management strategies.”

Guidelines for the treatment of patients with AS (for example, the updated international ASAS consensus statement) specify that the modified New York criteria should be met before the commencement of treatment with TNF antagonists. However, as many as 10 years may elapse between the onset of back pain and meeting modified New York radiographic criteria. During this period, the patient suffers the same amount of pain and similar QoL reductions as does someone diagnosed with AS. However, MRI studies can help predict which of those patients with early inflammatory back pain are at high risk of progressing to meet the modified New York criteria for AS, according to Dr. Alexander Bennett, Leeds Institute of Molecular Medicine, University of Leeds, UK (ACR 2008, abstract 1185). Patients with inflammatory back pain of less than two years’ duration were assessed by MRI at baseline. They were also assessed for the presence of the HLA-B27 mutation, which occurs in 95% of patients with AS. At baseline, 83% of patients were diagnosed by MRI with acute inflammatory sacroiliitis, and 58% were positive for HLA-B27. Follow-up of 40 patients at eight years demonstrated that baseline severe, acute inflammatory sacroiliitis as determined by MRI, combined with positive HLA-B27 status, was highly predictive of AS by measures of specificity (92%), positive predictive value (80%) and positive likelihood ratio of 8.0 (Figure 3). “This has potential implications for diagnosing early AS and for the selection of appropr
y intervention with anti-TNF,” concluded Dr. Bennett.

Figure 3.


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