Pathogenesis and Differential diagnostic of Axial Spondyloarthritis. “Treatment to Target”.

By Dr. Maria Benito

Axial spondylitis (AxSpA) is an umbrella term for non-radiographic AxSpA (Nr-AxSpA) –the earlier form of the disease–, and Ankylosing Spondylitis (AS) –the advanced stage. AxSpA has been described as “a form of spondyloarthritis in which the predominant symptom is back pain, and where radiographic sacroiliitis might or might not be present. If definite radiographic sacroiliitis on plain X-rays is present, the disease can be classified as ankylosing spondylitis.”

AS is a chronic inflammatory disease that affects the axial skeleton –sacroiliac joints and spine–, and part of the spine including bones, muscles and ligaments, with distinct swelling between the vertebrae and in the joints between the spine and pelvis, which causes back pain, stiffness and sometimes disability.

Back pain –mainly due to inflammatory, osteodestructive and osteoproliferative changes in the sacroiliac joints and the spine, in addition to osteoporotic changes in the vertebral column– is the principal symptom in patients with AxSpA, a chronic inflammatory rheumatic disease that mainly affects the axial skeleton. The increased risk of fractures in vertebrae and degenerative changes in the spine may be an additional source of pain. Additional changes specific of the disease include periarticular bone marrow edema, erosions, sclerosis, fat metaplasia and ankylosis in the sacroiliac joints or spondylitis, spondylodiscitis, facet joint involvement, or syndesmophytes in the spine of patients with AxSpA. Uveitis occurs in approximately 20% of AxSpA patients, and concomitant disorders such as psoriasis or inflammatory bowel disease are not uncommon.

Sacroiliitis, spondylitis, spondylodiscitis, and spondylarthritis are the main inflammatory manifestations in the axial skeleton, which may lead to new bone formation as syndesmophytes –calcifications or ossifications inside a spinal ligament or of the annulus fibrosus pathologically similar to osteophytes– and ankylosis in the vertebral column.

Pre-radiographic AxSpA axial spondyloarthritis may take up to 10 years before and the X-rays turn positive for sacroiliitis, the hallmark of AS. However, many patients never develop radiographic sacroiliitis, but display other spondyloarthropaties (SpA) features such as inflammatory back pain, positive HLA-B27 –with 90% heritabilty–, enthesitis, or uveitis. Remarkably, women suffering AxSpA but with normal inflammatory markers are less likely to progress to AS.

Diagnosis

The correct diagnosis of AxSpA is crucial in order to use the right treatment. The Assessment of Spondyloarthritis international Society (ASAS) and the European League Against Rheumatism (EULAR) recommend treat-to-target therapy to improve symptoms, considering important targets in AxSpA a reduction of pain and abrogation of inflammation, which can be achieved by pharmacological and non-pharmacological treatments, and in some cases by surgical procedures.

Although conventional radiographs are still considered the gold standard for assessment of structural changes in the axial skeleton of AxSpA patients, and computed tomography (CT) is useful to detect structural changes in the sacroiliac joints, in the absence of structural changes magnetic resonance imaging (MRI) is the most important imaging method to detect and visualize inflammatory changes, especially bone marrow edema in the axial skeleton. MRI is also able to visualize the anatomy of the region of the sacroiliac joints, including characteristic abnormalities of the periarticular soft tissue, and structural changes in patients including periarticular fat deposition, subchondral erosions, sclerosis and ankylosis.

The scale of the pathologic changes in the axial skeleton of AxSpA patients is useful in clinical trials to assess inflammatory and structural changes and outcomes using different scoring systems such as the presence of syndesmophytes detected by X-ray, or the degree of inflammatory changes in the sacroiliac joints –detected by MRI in combination with HLA B27. Syndesmophyte progression –a major contributor to the structural damage, as a result of the osteoproliferation– is highly variable in patients with AxSpA, and can lead to the complete fusion of the axial skeleton or peripheral joints in some cases. Typical findings also include sclerosis, erosions, pseudodilatation, and/or bony bridges.

It is important to consider the age of the patients when doing the diagnosis. Thus, younger patients with back pain of inflammatory characteristics and suspicion of AxSpA may develop structural changes in sacroiliac joints rather quickly, whereas the bone changes in sacroiliac joints in older patients may be due to osteoarthritis. Likewise, subchondral sclerosis of the sacroiliac joints –a phenomenon associated with age–, narrowing of the joint space, erosions, and ankylosis may be misleading in elderly patients.

Scintigraphy –a nuclear medical method that uses radionuclide technetium99 that enriches in areas of increased metabolism or inflammation– is not useful to make a diagnosis of AxSpA, and exposes the patients to radiation.

It has been shown the correlation between conventional histology and immunohistology in the sacroiliac inflammation and clinical symptoms of AxSpA.

Inflammatory markers and Scores

Although the trigger for inflammation and the mechanisms of interaction between inflammation and replacement of subchondral bone marrow by repair tissue –key for the stimulation of new bone formation– is not fully known, studies suggests that tumour necrosis factor (TNF)-α, interleukin-17 (IL-17) and IL-23 have a relevant role in the pathogenic inflammation of AxSpA.

Acute phase reactants (APR) levels have been shown to be significantly associated with progression of damage in AxSpA –associated with active joint or spinal disease, even progressing in low disease activity–, and are the only objective measure of articular or spinal disease activity. However, C reactive protein (CRP) or erythrocyte sedimentation rate (ESR) were not included in the Minimal Disease Activity (MDA) –or in the clinical Disease Activity in Psoriatic Arthritis (DAPSA)–, despite these markers are still associated with good outcomes.

In 2009, the Assessment of SpondyloArthritis international Society (ASAS) established the classification criteria for AxSpA based on imaging, clinical, and laboratory criteria, considering as AxPsA these two types of features: patients younger than 45 years old with back pain for 3 or more months, sacroiliitis confirmed on MRI or X-ray, and at least one clinical or laboratory finding characteristic of SpA; or people with a positive test result for HLA-B27 plus two features of AS detected on clinical examination or laboratory analysis. According to the ASAS criteria, only in a minority of patients who suffer Nr-AxSpA for over a decade, the disease progress to AS. Most of Nr-AxSpA patients are females, with shorter disease duration, lower level of inflammatory markers, and lower prevalence of HLA-27 –a class I surface antigen encoded by the B locus in the major histocompatibility complex (MHC)– in comparison to AS patients.

Guidelines from 2012 suggest adjusting therapy according to disease activity –including musculoskeletal measures and extra-articular manifestations–, targeting optimisation to minimize or eradicate inflammation achieving disease remission –defined as the absence of clinical and laboratory evidence of significant disease activity–, and considering clinical signs and symptoms as well as acute phase reactants. These recommendations include taking into consideration comorbidities and risks of therapy, using imaging tools as addition to clinical and laboratory assessments –and not instead of–, as well as the importance of sustaining a good outcome, once achieved.

Treatments

The existing recommendations for SpA in its different versions do not address any specific type of treatment but rather deal with a general approach to treating these types of arthropaties in the so called “treatment to target” by measuring and adjusting the therapy according to the disease activity, which improves outcomes.
In the case of AxSpA, the goals of treatment are to improve the long-term patient’s quality of life through controlling the symptoms aiming for clinical remission or inactive disease of musculoskeletal –such as arthritis, dactylitis, enthesitis, axial disease– and extra-articular manifestations –defined as the absence of clinical and laboratory evidence of significant disease activity–, as well as preventing structural damage. It is crucial for the treatment target to use individualised therapies based on the clinical manifestations of the disease in each patient. A key factor in the treatment is to avoid toxicity and minimize possible comorbidities.
Non-steroidal anti-inflammatory drugs (NSAIDs) are the first-line drug treatment for pain and stiffness –including selective inhibitors of cyclooxygenase 2–, which can be continued adjusting the dose in accordance with the severity of symptoms in case of persistently active, symptomatic disease.
Other treatments include disease-modifying anti-rheumatic drugs (DMARDs) –methotrexate– or biologic DMARDs (bDMARDs), which should significantly improve symptoms within 3 months and accomplish the target within 6 months, while sulfasalazine is useful in patients with peripheral arthritis.

For patients whose symptoms are not controlled with NSAIDs or have negative side effects, the next line of treatments include TNF inhibitors –infliximab, etanercept, adalimumab, golimumab, certolizumab–, which achieve partial or full remission in 60% of patients.

Although the long-term use of glucocorticoids is contraindicated, –due to the increased risk of vertebral osteoporosis–, they can be used to treat isolated local inflammation of sacroiliac joints, one or two peripheral joints, or enthuses.

Abatacept –inhibitor of T-cells–, anakinra –IL-1 blocker–, and anti–IL-6 agents have shown no efficacy, while it is not clear the benefit of methotrexate –alone or in combination with TNF inhibitors– and rituximab –anti-CD20 monoclonal antibody– in spondyloarthropaties. However, therapies targeting the IL-23 or blockade of IL-17 pathway seem promising treatment options, but its role in spondyloarthritis still has to be evaluated.