Continuing Education Activity

Seronegative spondyloarthropathies are a family of joint disorders that classically include ankylosing spondylitis (AS), psoriatic arthritis (PsA), inflammatory bowel disease (IBD) associated arthritis, reactive arthritis (formerly Reiter syndrome; ReA), and undifferentiated SpA. Patients with seronegative spondyloarthropathy often present with inflammatory joint pain characterized by morning stiffness lasting more than one hour and improving with activity. NSAIDs may improve symptoms. This activity illustrates the evaluation and treatment of seronegative spondyloarthropathies and reviews the role of the interprofessional team in managing patients with this condition.

Objectives:

• Describe the pathophysiology of seronegative spondyloarthropathy.
• Review the presentation of a patient with seronegative spondyloarthropathy.
• Summarize the treatment options for seronegative spondyloarthropathy.
• Outline the importance of collaboration and communication among the interprofessional team members in reducing functional limitations, reducing symptoms, and decreasing complication which will improve outcomes for those with this disease.

Introduction

Seronegative spondyloarthropathies (SpA) are a family of rheumatologic disorders that classically include[1]:

1. Ankylosing spondylitis (AS)
2. Psoriatic arthritis (PsA)
3. Inflammatory bowel disease (IBD) associated arthritis
4. Reactive arthritis (formerly Reiter syndrome; ReA)
5. Undifferentiated SpA. 

Recently, these disorders have been differentiated further into three additional categories including non-radiographic axial SpA (nr-axSpA), peripheral SpA, and lastly, juvenile-onset SpA. This family of disorders shares several clinical features and has common genetic associations.

Etiology

There is a classic correlation between the prevalence of SpA and the prevalence of HLA-B27 gene in a given population. The strongest relationship is in AS. In the United States, the prevalence of HLA-B27 is 7% of the general population, but it is present in 90% of those diagnosed with AS[2][3]. PsA is associated with multiple HLA molecules including HLA-B27, HLA-DR7, and HLA-DQ3. In IBD associated arthritis (Crohn disease and ulcerative colitis), the HLA association is weaker compared to the other SpAs. ReA (which follows enteric or urogenital infection) has a variable relationship with HLA-B27 with studies reporting anywhere from below 50% to 60% to 85% association[4][5]. HLA-B27 is positive in about 50% of those with undifferentiated SpA and 60% to 80% of those with juvenile-onset SpA.

Epidemiology

The worldwide prevalence of SpA is estimated to be between 0.5% to 1.9%[3]. In the United States, AS and non-radiographic axial SpA are the most common types of SpA and have a combined prevalence of 0.7% to 1.4%[2]. PsA is thought to affect men and women equally with a prevalence of 0.1% to 0.2% and incidence of 0.006%[6]. PsA is thought to be present in 4% to 30% of individuals with psoriasis. IBD-associated arthritis (both axial and peripheral) is present in 3% to 13% of patients with either ulcerative colitis or Crohn disease[7]. ReA is thought to be quite rare. The typical organisms causing ReA are Chlamydia, Campylobacter, Salmonella, Shigella, Clostridium difficile. Globally, the prevalence is estimated to be 0.03% to 0.04%[8].

Pathophysiology

Enthesitis, or inflammation of the sites where the tendons or ligaments insert into the bone, is a key pathological finding in SpA[9]. This finding differentiates it from rheumatoid arthritis and other inflammatory polyarthritides. As mentioned above, the major gene involved in several key pathogenic steps is HLA-B27. Several non-HLA genes have also been identified in disease pathogenesis. Environmental exposure of the immune system to microorganisms is also important. Several cytokines have been shown to participate in the inflammatory process. One of these cytokines is tumor necrosis factor (TNF) which is a target for a class of drugs used to treat the SpA[9]. It is thought that microtrauma from stress also triggers inflammation at the enthesis[10]. These inflammatory processes lead to change in bone and pathologic new bone formation, which is seen in AS but not in rheumatoid arthritis.

Histopathology

Histologic studies on synovial fluid show hypervascularity and the presence of macrophages and CD4+ and CD8+ T-cells. Interestingly, some of these same subsets of immune cells are also found in the gut mucosa. Macrophages and macrophage-driven cytokines such as TNF-alpha and IL10 are mediators of disease inflammation[11].

History and Physical

History should be taken to evaluate for inflammatory back and/or peripheral joint pain. Inflammatory joint pain is associated with morning stiffness lasting more than one hour, improving with activity, and worsening with rest or inactivity. NSAIDs may markedly improve symptoms. Patients with axial SpA typically have chronic low back pain for more than three months with insidious onset before the age of 45. In these patients, the Schober’s test (for assessment of lumbar flexion) and occiput to wall test (for assessment of upper thoracic/cervical spine mobility) should be a routine part of the physical exam[12]. Those with peripheral SpA have peripheral arthritis (acute onset, usually knees and ankles), enthesitis, and dactylitis. It is important to note that the peripheral arthritis is usually asymmetric. Enthesitis is relatively specific to SpA and is usually seen at the insertion of the calcaneal tendon. This typically leads to difficulty walking and to tenderness upon palpation. Dactylitis is a non-specific finding but is often seen in PsA and ReA. Non-musculoskeletal features that are important to ascertain in the history include ocular inflammation (uveitis, iritis, conjunctivitis), preceding/current gastrointestinal or genitourinary (GI/GU) infection, or diagnosis of or signs of psoriasis or IBD. Lastly, family history of SpA and other autoimmune disorders should be assessed.

Evaluation

Evaluation of SpA involves both laboratory and radiographic testing. The approach differs depending on whether a patient presents with inflammatory back pain vs. inflammatory arthritis, enthesitis, or dactylitis.

In a patient who presents with inflammatory back pain, the initial step is to obtain plain films of the sacroiliac joints and spine as well as inflammatory markers. Inflammatory markers should be elevated in the presence of a SpA. In AS, plain films typically detect late structural changes and may not be useful early in the disease. Classic findings on plain film are 1) “shiny corner (sclerosis at the attachment of annulus fibrosis to the anterior corner of vertebral endplate), 2) “bamboo spine” (calcification of fibrous ring of the intervertebral discs forming marginal syndesmophytes), and 3) “squaring” of vertebral bodies[12]. Typically, if a patient does not have strong plain film evidence of AS, HLA-B27 is obtained; at that time, MRI can also be considered as it is useful for early detection of signs of inflammation. Patients with nr-axSpA do not have definitive radiographic findings of sacroiliitis but have serological and clinical evidence of a SpA[13].

In a patient who presents with signs of inflammatory arthritis, enthesitis, or dactylitis, the presence of psoriasis, IBD, or preceding infection should be evaluated. In the presence of a predisposing condition, a diagnosis of PsA, IBD-related SpA, or ReA can be made. In the absence of a predisposing condition, autoimmune (including HLA-B27) and inflammatory markers should be obtained, and patients should have radiographs of their affected joint(s) and be evaluated for uveitis.

Treatment / Management

Treatment goals for SpA are reducing symptoms, reducing functional limitations, and decreasing complications associated with the disease. A mainstay of therapy is an exercise to preserve spine and peripheral joint strength and range of motion. Often, formal physical therapy is beneficial[14]. The main pharmacologic therapy is a NSAID, usually in maximal doses (except in IBD associated arthritis), and at least two NSAIDs must be tried before advancing to the next class of pharmacologic agents[15]. In the event NSAIDs fail to control symptoms, are intolerable due to side effects, or are contraindicated due to other co-morbid conditions, the next step in treatment depends on whether the disease is axial disease or peripheral disease.

In axial disease (AS), biologics (TNF inhibitors) are the next line of therapy. Five TNF inhibitors, infliximab, etanercept, adalimumab, golimumab, and certolizumab, are shown to achieve partial or full remission of symptoms. Of note, active infection (including latent or active tuberculosis which should be treated before starting treatment), advanced heart failure, lupus, multiple sclerosis, and cancer are contraindications for treatment with TNF inhibitors. Secukinumab, a monoclonal antibody to interleukin 17A, has been recently approved to treat AS and has been shown to be quite effective in those who cannot tolerate TNF inhibitors[16]. Non-biologic DMARDS (disease modifying anti-rheumatic drugs) such as methotrexate and sulfasalazine are not effective in axial disease but are a second-line treatment for the peripheral disease[15]. In the event, the non-biologics do not control disease, TNF-inhibitors are the third line, and at times, combination therapy with both biologic and non-biologic DMARDs is required. Systemic glucocorticoids have a limited role in SpA. For IBD associated arthritis and patients with severe uveitis, they may be unavoidable. Localized glucocorticoid injections should be used very sparingly due to the risk of tendon rupture. It is important to note that although ReA is usually a self-limited disease, it can be treated similarly to any other disease in the SpA family. Surgery is the very last resort management strategy. Disease progression is measured by history, physical exam, inflammatory markers, and serial imaging[15].

Differential Diagnosis

• Congenital Spinal Deformity

• Degenerative Disk Disease

• Diabetic Foot Ulcers

• Herniated Nucleus Pulposus

• Heterotopic Ossification Imaging

• Kyphosis

• Lumbar Disc Disease

• Lumbar Spondylosis

• Osteoarthritis

• Osteofibrous Dysplasia

Enhancing Healthcare Team Outcomes

Seronegative spondyloarthropathy is difficult to diagnose and treat. An interprofessional approach of specialty trained rehabilitation nurses, physical therapists, and rehabilitation and rheumatology clinicians will provide the most successful management of this condition. A pharmacist should assist in monitor phramacotherapy. [Level V]