Axial Spondyloarthritis

Philip Mease, Muhammad Asim Khan

• Publisher: Elsevier
• Year: 2019
• ISBN:
  9780323568012
• Topic: Medicina
• Subtopic: Reumatologia, ortopedia e protesiologia

Focusing on the key essentials you need to know, Axial Spondyloarthritis provides a quick, expert overview of axSpA from a clinical perspective. This concise resource by Drs. Philip Mease and Muhammad Khan presents practical recommendations and guidelines for the diagnosis, management, and treatment of spondyloarthritis impacting the axial skeleton alongside an overview of epidemiology, special populations, and patient education.

• Discusses key information on genetic factors and disease biomarkers.
• Presents an overview of clinical features, classification criteria, and imaging to aid in diagnosis.
• Covers management and treatment guidelines, including non-pharmacologic management and the use of biologics.
• Consolidates essential information on this timely topic into a single, convenient resource.

Chapter 1

Introduction

Philip Mease, MD, MACR, and Muhammad Asim Khan, MD, FRCP, MACP, MACR

Abstract

This textbook is a comprehensive review of axial spondyloarthritis (AxSpA). AxSpA is a chronic immunologic disease, which affects the axial spine and potentially peripheral joints and entheses, leading to significant pain, fatigue, disability, and potentially early mortality. This book addresses all aspects of the disease, including clinical manifestations, epidemiology, classification, pathogenesis, assessment, and management. The last two decades have seen an explosion of investigation in all of these aspects of the disease as we recognize that the full spectrum of the disease is much more common than had been thought, for example, up to 1.4% of the US population, as our understanding of cellular and molecular pathogenesis deepens, and the therapeutic armamentarium increases based on better understanding of the potential immunologic targets of therapy. This book is a compendium of 18 chapters authored by key experts in AxSpA, including high level discussion of pathogenesis that is suitable for basic researchers seeking a current grounding in topics such as genetics, microbiome influences, cellular biology of bone and enthesial pathology to practical discussion of clinical examination, classification criteria and diagnosis, imaging, and treatment for the practicing clinician. This book also covers all aspects of pharmacotherapy, including evidence for conventional systemic as well as more recent biologic immunomodulatory drugs, which have revolutionized our ability to achieve targets of remission or low disease activity. Nonpharmacologic treatment modalities are also reviewed. This book serves the need for an authoritative summary of our current knowledge about AxSpA.

Keywords

Ankylosing spondylitis; Axial spondyloarthritis; Back pain; Biologics; Diagnosis; Etiopathogenesis; Immunologic disease; Management; Spondyloarthritis

This textbook is a comprehensive review of axial spondyloarthritis (axSpA). Due to advances in our understanding of the genetics, pathogenesis, clinical features, assessment and therapeutics of axSpA, there has been an explosion of interest in this rheumatologic condition and related disorders. It is timely to have an updated textbook on axSpA highlighting our expanding knowledge as outlined below.

What is spondyloarthritis? Spondyloarthritis (SpA) is a group of inflammatory diseases which share a number of features including inflammation of the axial skeleton and occasionally peripheral joints, enthesial (tendon, ligament and joint capsule) insertion sites throughout the body, frequent association with the gene marker HLA-B27, and associated conditions including uveitis, inflammatory bowel disease (IBD), and psoriasis. Incidentally, in this book, HLA-B27 gene is also shown as HLA-B∗27 gene to conform with the most current nomenclature. Historically, the SpA conditions have been subdivided into five subtypes: ankylosing spondylitis (AS), psoriatic arthritis (PsA), reactive arthritis (ReA), IBD-related arthritis, and undifferentiated spondyloarthritis (uSpA). AS, a male-predominant disease, presents in individuals in their 20 and 30s as back pain with characteristic inflammatory features such as worsening with rest, improvement with activity, and stiffness. With time, syndesmophytes bridge vertebral bodies and cause ankylosing of the spine in the most severely affected individuals. This may be accompanied by occasional inflammatory arthritis symptoms in peripheral joints and entheses, particularly in the lower extremity. As outlined by Navarro and Deodhar in Chapter 4, classification of SpA has evolved and the most recent classification criteria divide the condition into predominantly axial or peripheral manifestations. Although this division may seem to be somewhat arbitrary, since there can be overlap in many individuals, it is a simple categorization that may aid recognition of SpA, especially by non-rheumatologists. Ultimately, we may enter an era in which phenotypes and subphenotypes of patients are characterized by genetic profiling, which will allow for more precise classification and treatment channeling - but for now this is only a future prospect.

What are the key clinical features of axSpA? How do we distinguish axSpA from other more common causes of back pain? As outlined by Khan in Chapter 2, disease manifestations can be quite diverse and no patient may exactly resemble another. A common denominator for the majority of patients is inflammatory back pain. As distinguished from more common forms of mechanical or degenerative back pain or fibromyalgia, inflammatory pain symptoms include a tendency to improve with activity, worsen with being still, e.g., while asleep, resulting in wakening with nocturnal and/or morning pain and stiffness, as well as having onset at a younger age. Typically the pain responds to non-steroidal anti-inflammatory drugs and effective immunomodulatory agents. Peripheral manifestations may include asymmetric joint inflammation, especially in the lower extremities. Enthesitis, wherein inflammation at tendon, ligament, or joint capsule fiber insertion sites, especially in lower extremities but also around the pelvic girdle and thorax causes persistent pain is an important feature which may be especially hard to diagnose correctly and may need advanced imaging approaches such as ultrasound and MRI to confirm. Dactylitis, swelling of a whole digit, can be an important extra-axial musculoskeletal clue to the diagnosis of axSpA. Non-musculoskeletal conditions which frequently are associated with axSpA include uveitis, IBD, and psoriasis. A few serum biomarkers may aid with diagnosis, including the presence of the genetic marker HLA-B27 and elevation of inflammation blood tests such as C reactive protein. However, these are not absolutely diagnostic, may be absent, and need to be interpreted in the context of clinical symptoms and signs. With time, and especially in male patients, progressive osteoproliferation of syndesmophytes can lead to bridging calcification of vertebral bodies, resulting in severe spinal pain, deformity and difficulty with stance and gait. In addition to limitation of function, impairment of quality of life, adverse impact on work and family life, a patient’s life may be foreshortened due to a variety of factors such as spinal fracture due to ankylosis and associated osteoporosis, cardiovascular comorbidity leading to premature myocardial infarction and stroke, infection due to immunosuppressive therapy and impaired chest expansion, and so forth. Disease manifestations such as spinal ankylosis may be milder in females, leading to frequent delayed or lack of recognition of the condition, even though symptom burden may be as severe as in males. Variants of the condition may occur in children and adolescents.

How common is axSpA? As reviewed by Akkoc and Khan in Chapter 3, historically, we have considered ankylosing spondylitis (AS) to occur in 0.5% of the population of Western countries, less in Africa and some parts of Asia. Further, it has historically been considered a male-predominant disease, manifest in a 2:1 male:female ratio. With the advent of more frequent use of magnetic resonance imaging (MRI) technology to assess for inflammation rather than just damage as evidenced by X-rays, and the routine availability of the HLA-B27 gene marker, we can now more sensitively diagnose a wider spectrum of patients with the newer category, axSpA. Using these more sensitive diagnostic approaches in patients presenting below the age of 45 with features of inflammatory back pain, axSpA may be seen in up to 1.4% of the population of the United States and in a similar frequency in Europe. Furthermore, many of these additional patients who do not display radiographic damage on X-ray of the sacroiliac joints and spine are female, making the male female ratio 1:1. Even though the prevalence of rheumatoid arthritis (RA) is 0.6%–1.0% of the North American and European population, i.e., less than axSpA, more RA is seen by rheumatologists. Indeed, many axSpA patients remain undiagnosed or misdiagnosed, presumably not seeking medical care because of the perception that back pain is common and not much can be done for it, or seeking medical care from primary care, orthopedic and chiropractic practitioners–never recognizing that this is a immunologic-inflammatory condition ideally managed with immunomodulatory therapy. There is a large unmet need to better educate non-rheumatologists about axSpA and increase public awareness about the disease in order to improve case finding.

How has axSpA been historically classified and how has this changed with increased understanding about the disease as well as increased recognition of it using advanced imaging and other approaches? Classification criteria are different than diagnostic criteria. The former are developed to try to identify a disease with a high degree of specificity so that when conducting a study of the disease (natural history, treatment, etc.), we are confident that the correct disease is being investigated. On the other hand, diagnostic criteria are used for the purpose of identifying any individual who may have a disease in order not to miss the opportunity to treat them effectively, thus high sensitivity for identification purposes is the goal. In Chapter 4, Navarro and Deodhar trace the history of classification criteria for axSpA, beginning with the original New York Modified criteria for AS published in 1984 and taking us through the most recent classification criteria for axSpA developed by the Assessment of SpondyloArthritis international Society (ASAS) published in 2009. The 1984 criteria, utilizing objective imaging technology available at the time, required plain X-ray evidence of sacroiliitis for reliable classification of AS. We now know that symptoms of the disease may occur long before this finding is present, and that this requirement skews the classification toward males who tend to show more prominent radiologic changes than females. As the field has advanced, including the wider availability MRI and use of HLA-B27 typing, we can now recognize the broader spectrum of disease not restricted to those solely with radiographic changes with minimal loss of specificity.

What causes axSpA? The pathogenesis of axSpA is a complex interplay of genetic factors, environmental and immunologic elements. AxSpA is one of the most heritable rheumatic diseases, as evidenced by the frequency of familial history of the disease or related diseases. The most prominent item in the genetic profile of axSpA is the HLA-B27 gene, but increasingly we are recognizing other key genes, such as ERAP1, that play an important role. Indeed, the presence of both HLA-B27 and ERAP1 appears to have a synergistic effect in disease proclivity. Brown, Xu, and Reveille provide detail in Chapter 5 about our current understanding of the genetics of axSpA, including an explication of the geographic distribution of HLA-B27 via historical pathways of population migration. These and other genes such as IL-23R, TYK2, and TNFR1, also give a hint about potential therapeutic pathways to target. The role of epigenetic alterations is also discussed.

Do alterations in the gut microbiome contribute to the pathophysiology of axSpA? Sternes and Brown in Chapter 6 contemplate the possible role of dysbiosis in the promulgation of axSpA, focusing on the gut microbiome. There has been a significant increase in study of the role of commensal bacteria and other organisms at interfaces such as the gut, skin and lung in the regulation or dysregulation of human physiology. There is clear evidence that both increase of pro-inflammatory and decrease of pro-anti-inflammatory bacteria occur in patients with axSpA. This appears to be influenced by the HLA-B27 gene. A hypothesis is that local gut inflammation and alterations in gut permeability resultant from dysbiosis lead to immunologic stimulation that can become systemic. For example, increased cytokine production in the gut may lead to stimulation of resident immune cells at sites of bone, joint, eye and cardiac tissues, resulting in chronic inflammation at those sites. A significant amount of research is underway to further investigate these processes and determine if there is the possibility of modulation of the microbiome as a new therapeutic pathway.

Ciccia, Srinath, Zeng, and Haroon in Chapter 7 link our traditional understanding of the pathogenesis of AxSpA/AS to evolving concepts that are emerging as new scientific findings come to light. The chapter starts with the role of HLA-B27 in AS followed by an introduction to aminopeptidases and other players in antigen processing and presentation. The gut-joint axis is discussed in some detail and finally bone-formation pathways in AS are explored. The hypotheses for the role of HLA-B27 include an arthritogenic peptide mechanism, a potential role for natural killer cell and their receptors activation, unfolded protein response, and autophagy. The co-association of HLA-B27 and endoplasmic reticulum aminopeptidases, ERAP1 and ERAP2, which have a role in peptide clipping in preparation for antigen presentation may have a role in pathogenesis. The possibility that a newly discovered gene Sec16a, variants of which may lead to differences in HLA-B27 trafficking to the cell surface may also have a role. It appears likely that intestinal lining pathology/inflammation contributes to axSpA pathophysiology, both due to gut dysbiosis as reviewed in this chapter and Chapter 6 on the gut microbiome, as well as activation of innate and adaptive immune mechanisms, especially involving the TH17 cell pathway and the IL23-IL17 axis. It is unknown at this time if manipulation of the microbiome or these immunologic pathways at the gut level could lead to improvement of axSpA, but these considerations are being researched. Complementing the chapter on bone pathophysiology, Lories’ Chapter 8, this chapter provides additional perspective on the roles of bone morphogenetic proteins, the Wnt signaling, Hedgehog, macrophage migratory inhibitory pathways, as well as the role of IL23, IL17, and prostaglandin E2 and E4 in bone remodeling as a pathological process in axSpA.

Why and how does bone ankylosis occur in axSpA? In Chapter 8, Lories details our current understanding about bone pathophysiology. Key pathways for excessive bone formation are the Wnt signaling pathway, bone morphogenetic proteins (BMPs), and the Hedgehog signaling pathway. The balance of Wnt signaling proteins and antagonists such as sclerostin is important in normal bone remodeling; imbalance may contribute to excessive bone formation. BMPs are growth factors that are essential in the pathogenesis of enthesophytes in animal models. In axSpA, their excessive activity may have partly to do with autoantibodies directed against their natural antagonist, noggin. The Hedgehog pathway involves differentiation of chondrocytes into hypertrophic cells, essential for replacement of cartilage by bone. Lories proceeds to explicate the findings and controversies around the role of TNF and IL17 inhibition in controlling pathologic bone formation and ankyloses as well as recent observations about the crucial role that mechanical loading and microtrauma may play in pathologic bone formation.

How do we clinically assess patients with axSpA rigorously in clinical trials? Magrey and Kiltz address our assessment techniques in Chapter 9, starting with the ASAS-OMERACT core set summarization of the clinical domains of axSpA, published in 1999. These include the domains of physical function, pain, spinal mobility, patient global assessment, morning stiffness, fatigue, peripheral joints and entheses, and acute phase reactants. They then proceed to detail the specific measures, many of them patient reported questionnaires such as the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and Bath Ankylosing Spondylitis Functional Index (BASFI), and the more recently developed Ankylosing Spondylitis Disease Activity Index (ASDAS), which includes an objective item, either a C-reactive protein (CRP) or Erythrocyte Sedimentation Rate (ESR) value. The patient questions in these composite measures ask about severity of the disease in relation to many of the items in the ASAS-OMERACT core set, including physical function and pain, both in the axial spine and periphery. Quantitative thresholds of disease severity have been defined, e.g., inactive or mild disease activity utilizing the ASDAS, which allows it to be used as a “treat-to-target” measure in clinical trials or clinical practice. Because axSpA can cause impaired mobility, e.g., when spinal ankyloses advances, specific measures of spine and hip mobility are utilized in clinical trials and to a certain extent in clinical practice to document progressive mobility impairment or (hopefully) lack thereof when patients are treated effectively. Specific measures for clinical domains such as enthesitis have been developed and are utilized in clinical trials to document changes in this domain. Newer measures which assess both quality of life and function, such as the ASAS Health Index, have been rigorously developed based on input from patient focus groups, guidance from psychometricians, and testing in patient populations for validation. As assessment tools become more reliable and validated, we can better rely on them to assess outcomes of interest in therapeutic clinical trials, long term observational registries, and to a certain extent, in clinical practice.

Maksymowych and Lambert provide in Chapter 10 an encyclopedic review of imaging modalities for and findings in axSpA, including plain radiography, computerized tomography (CT), and MRI. They also address the differential diagnosis from other mimicking conditions, including degenerative arthritis, infection, neoplasm, diffuse idiopathic skeletal hyperostosis, and osteitis condensans ilii. Whereas clearcut radiographic change of sacroiliac joints, including periarticular sclerosis and erosions can be virtually pathognomonic for AS, these findings are often absent or indistinct in early AS and in patients with axSpA who may never develop such changes, and so lack sensitivity for detecting the full spectrum of axSpA. CT scan provides more detailed features of bone anatomy, including cortical changes and erosive change, but is hampered by the problem of radiation exposure in its routine application. Newer CT applications with less radiation exposure hold promise. Advances in MRI scanning, along with generally greater access to this imaging modality have more significantly advanced our ability to diagnose and...