Delayed Diagnosis of Ankylosing Spondylitis: A Missed Opportunity?

Ankylosing spondylitis is an inflammatory condition involving the axial spine, often associated with the human leukocyte antigen (HLA)-B27 genotype and supporting radiographic imaging findings. Patients develop symptomatic low back and/or hip pain beginning in late adolescence or early adulthood. Diagnosis of ankylosing spondylitis is based primarily on clinical presentation and imaging studies. In this article, we are presenting a case of a 40-year-old male patient who presented to the office with chief concerns of chronic mid-thoracic back pain and restricted range of motion of his neck. The imaging study obtained was suggestive of fusion of the sacroiliac joints. This article also highlights the presence of elevated inflammatory markers in the setting of the patients chronic symptomatic complaints which could have guided in early diagnosis.


Introduction
Ankylosing spondylitis is a chronic inflammatory disease, affecting the axial skeleton, entheses, and peripheral joints. Ankylosing spondylitis (AS) is categorized under axial spondyloarthropathy and is differentiated from non-axial spondyloarthropathy due to the significant involvement of the sacroiliac joints observed in AS. The age of onset of AS is typically in late teens and early 20's. The incidence rate of AS is more common among men [1]. The estimated prevalence of AS in various countries ranges from 0.7 to 49 per 10,000 [2]. Hereditary prevalence of AS is high especially amongst siblings with positive human leukocyte antigen (HLA)-B27 [3].

Case Presentation
A 40-years-old male patient with past medical history consistent of congenital left leg-length discrepancy of about three-fourth inches, status postoperative multiple corrective surgeries for the same, severe bilateral hip osteoarthritis with status postoperative right hip resurfacing surgery, presents to the office with chief concerns of chronic thoracic back pain, and restricted range of motion of his neck. The patient reports intermittent back pain since he was in his 20's. His neck pain started approximately five to seven years ago. The patient rates his pain an average of three on a pain scale of 10; ranging between one to eight out of 10. He is unable to bend down to pick up objects. His neck pain and stiffness are markedly limiting his activities. He feels his pain is muscular in nature, especially in his neck. The patient conveys his inability of touching his toes during his high school. The patient's stiffness lasts all day; hot shower in the morning helps decrease it minimally. He reports progressively worsening difficulty sleeping. Until four years ago, he was able to practice yoga which significantly helped his pain. The patient tried various nonsteroidal anti-inflammatory agents (NSAID's) without significant improvement. Muscle relaxers caused increased drowsiness and weakness. Massage therapy to his neck markedly alleviates his neck pain. Physical therapy and chiropractic services were unimpressive in the past. The patient denies any bowel/bladder incontinence, saddle anesthesia, fever, shortness of breath, bleeding per rectum, tingling or numbness. He denies any recent trauma or injury. The patient denies any gastrointestinal symptoms (irritable bowel syndrome, Crohn's disease or ulcerative colitis), psoriasis or inflammation of his eyes (iritis, scleritis or episcleritis.) The patient has not had his human leukocyte antigen (HLA)-B27 marker checked. Otherwise, the patient reports to be in good health. The patient states people have told him that he walks like his father. His father had difficulty walking with his head up due to neck stiffness and used a back brace for support. The patient's brother has Crohn's disease. He is unaware of his brother's HLA-B27 marker status. The patient has two healthy children: a son and a daughter. The patient reports drinking about one alcoholic beverage a day ranging from beer, rum and coke or a martini. He smokes a cigar once a month.
Upon examination, his vitals are within normal limits. The patient is conscious, cooperative, well-oriented in time, place and person. The patient has diaphragmatic respiration with lungs clear on auscultation. Cardiovascular examination is normal. The abdomen is soft, nontender without organomegaly. His extremity examination is consistent with left leg-length discrepancy of about three-fourth inches, left leg shorter than the right. The left leg is markedly atrophic and weaker compared to the right leg. No range of motion of his left ankle joint. Left foot deformity present. The patient has only five percent range of motion of his neck. On neurological examination, he walks with a stiff posture, limping gait without touching his left heel to the floor. On noticing his left foot while walking, he first walks on his toes and then supports himself on his left heel. He cannot bend down to touch his toes.
The patient's previous and recent laboratory test results and imaging results were reviewed with him. His complete blood count, comprehensive metabolic panel and thyroid-stimulating hormone levels were normal (   Findings: There appears to be a fusion of the sacroiliac (SI) joints (yellow circles). There is a marked narrowing of the left hip joint (red circle). There is a hip resurfacing prosthesis on the right.
Impression: There is a fusion of the SI joints. Prominent degenerative change and narrowing of the left hip joint. Resurfacing prosthesis on the right hip. Impression: Degenerative changes as described above. Findings are most marked in the facets at L4 and L5. There is no evidence of vertebral fracture.

FIGURE 3: X-ray of the cervical spine
Findings: The heights of the cervical vertebral bodies are normal. There is the mild narrowing of the cervical C2-C3 disc space. There is a mild anterior spurring at the cervical C3-C4 disc levels. There does not appear to be significant narrowing. Remaining cervical disc spaces are fairly wellpreserved. There are mild degenerative facet changes in the mid and upper cervical spine. The odontoid appears intact.
Impression: Mild degenerative disc changes. Degenerative facet changes. There is no evidence of cervical spine fracture.
On assessment, the patient's symptoms are suggestive of ankylosing spondylitis (AS). The constellation of the limited range of motion of his neck, lumbar spine stiffness, elevated inflammatory markers, and fused sacroiliac joints (SI joints) confirmed on an imaging study, are supportive of ankylosing spondylitis as the diagnosis. Furthermore, his family history consistent with his father having similar symptoms and posture, and his brother with Crohn's disease, increases the patient's probability of spondyloarthropathy. We discussed ankylosing spondylitis in detail with the patient, including the extra-articular symptoms associated with AS. Due to the SI joint, and the absence of confluent ossification of at least four continuous vertebral levels makes diffuse idiopathic skeletal hyperostosis (DISH) unlikely. The patient did not present with active inflammation or synovitis of his peripheral joints (hands, knees or wrists), along with negative rheumatoid factor and cyclic citrulline peptide antibody levels, making inflammatory arthropathy like rheumatoid arthritis less likely. After discussing the high pretest probability of AS with a positive human leukocyte antigen (HLA)-B27 marker, and its hereditary nature, a laboratory test checking for HLA-B27 marker was ordered.
For the patient's management, the importance of good posture, ergonomics, and corestrengthening exercises was reiterated. The patient was encouraged to lose weight, quit smoking and limit his alcohol consumption. He was recommended undergoing physical therapy to help with his neck pain. Unfortunately, due to the progression of his medical condition, the patient was made aware of the irreversible complications. To avoid further progression, we recommended initiating subcutaneous citrate-free adalimumab injection 40 milligrams per 0.4 milliliters once every 14 days. We prescribed him a muscle relaxer, tizanidine 2-milligram tablet, to take at bedtime to help his muscle spasm. It was recommended taking occasional oral NSAID's as needed for pain.
The patient's HLA-B27 marker, QuantiFERON® tuberculosis test, and hepatitis B surface antigen were negative. The patient followed-up at the office about three months later, reporting a gradual improvement in his neck pain. The patient did develop an episode of iritis in the interim; he was prescribed prednisolone topical eye drops by his ophthalmologist. The patient is currently in stable condition and continues to follow-up with his team of providers.

Discussion
Ankylosing spondylitis (AS), an axial spondyloarthropathy is often characterized by a fusion of the spine. It is a form of arthritis which mostly affects the spine but can also involve other joints. Inflammation of the spinal joints leads to severe, chronic pain. As the inflammation progresses, it can lead to ankylosis which is new bone formation in the spine. This causes sections of the spine to become fused. There is a strong association with HLA-B27. This is a normal gene found in eight percent of the Caucasian population. Testing for this gene is not diagnostic for AS due to the variations seen amongst different ethnicities. However, in the Caucasian race, it is a strong predictor [4].
Patients complain of developing symptoms before the age of 40 years. Patients will usually present with fatigue, low-grade fever, weight loss, lower back pain and stiffness along with limitations in movement. They may also present with enthesitis which is inflammation at the site where tendons insert into bone [1]. The healing that occurs following entheses may eventually lead to scarring of the tissue. This may result in the formation of more bone. This will lead to an increase in spinal fractures due to the restricted range of movement. Affected individuals may develop a forward curvature of the spine, also known as kyphosis, due to the way the spine is fusing. Lower back pain and stiffness are worse with rest and improve with physical activities [5]. As more of the spine is affected, it becomes brittle and more prone to fractures. Patients may also present with chest pain that may feel like a heart attack or will complain of pain while taking deep breaths. This is due to long term inflammation of the joints between the ribs and the spine along with the joints between the ribs and sternum. The inflammation will eventually end up with long term scarring resulting in decreased chest expansion. The extra-articular manifestations of AS are summarized in (

2: Extra-articular manifestations of ankylosing spondylitis
Ankylosing spondylitis can be diagnosed via a thorough physical exam, imaging studies of the lumbar and pelvis, family history of AS, along with laboratory tests inclusive of inflammatory markers (elevated C-reactive protein and erythrocyte sedimentation rate) and to evaluate for HLA-B27 marker. If the radiographic imaging studies are inconclusive, computer tomographic study of the sacroiliac joints or magnetic resonance imaging of the sacroiliac joints should be obtained. The differential diagnosis is summarized in (   Some complications of ankylosing spondylitis include restrictive lung disease due to thoracic spine involvement, eye involvement, cauda equina syndrome, spine fractures with spinal cord injury, osteoporosis and spondylodiscitis [10][11][12][13]. Majority of patients with ankylosing spondylitis have persistent symptoms for decades varying from unremitting spinal pain, hip destruction, and spinal fusion. Depending on the disease severity, about 10-30 percent of patients develop working disability after 10 years. A number of prognostic indicators have been identified ( Table 5) [14].

Prognostic indicators in patients with ankylosing spondylitis:
Hip arthritis

Conclusions
Ankylosing spondylitis is an inflammatory axial spondyloarthropathy consistent with chronic symptomatic complaints. The incidence rate of the disease is common amongst younger individuals, complaining of intermittent chronic arthralgia. A thorough history of presenting illness including a family history of any back pathologies or any associated-symptoms of spondyloarthropathy should be enquired. The presence of elevated inflammatory markers and imaging studies evaluating for sacroiliitis should be obtained in patients suspected to have AS. Physical therapy and exercise should be encouraged in patients with ankylosing spondylitis to maintain a good range of motion. Pertinent to our patient, literature review on ankylosing spondylitis suggests that early diagnosis and appropriate therapy is known to slow the progression of the disease.