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case records of the massachusetts general hospital

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med 371;15 nejm.org october 9, 2014 1447

Founded by Richard C. CabotEric S. Rosenberg, M.D., Editor Nancy Lee Harris, M.D., EditorJo-Anne O. Shepard, M.D., Associate Editor Alice M. Cort, M.D., Associate EditorSally H. Ebeling, Assistant Editor Emily K. McDonald, Assistant Editor

From the Departments of Medicine (M.C.F., J.H.S.) and Radiology (W.E.P.), Massachusetts General Hospital, and the Departments of Medicine (M.C.F., J.H.S.) and Radiology (W.E.P.), Harvard Medical School — both in Boston.

N Engl J Med 2014;371:1447-55.DOI: 10.1056/NEJMcpc1404517Copyright © 2014 Massachusetts Medical Society.

Pr esen tation of C a se

Dr. Henry R. Kramer (Medicine): A 50-year-old man with back pain, fatigue, weight loss, and knee swelling was admitted to this hospital because of abnormal findings on magnetic resonance imaging (MRI) of the spine performed at another hospital.

The patient had been generally well until approximately 2 years before the cur-rent admission, when persistent pain of the thoracic and lumbosacral spine devel-oped. Approximately 11 months before admission, he fell and had increasing back spasms thereafter, with partial improvement after chiropractic treatment. During the 2 months before admission, he lost approximately 10 lb (4.5 kg) and his back pain became more severe; he rated it at 5 on a scale of 0 to 10, with 10 indicating the most severe pain. The pain was chronic with exacerbations, was localized in the thoracic and lumbar regions without radiation, worsened when he lay flat (despite the administration of narcotic agents for pain control), and diminished with am-bulation.

Dr. William E. Palmer: On the morning of admission, MRI was performed (without the administration of gadolinium) at another hospital to evaluate the patient’s increasing symptoms (Fig. 1). Fluid-sensitive images showed that the disk space between the 10th and 11th thoracic vertebral bodies (T10 and T11) was filled with fluid, and there was prominent bone marrow edema involving T10 and T11. These findings raised diagnostic concern about the possibility of diskitis–osteomyelitis or fracture with pseudoarthrosis.

Dr. Kramer: The patient was advised to go to the emergency department at this hospital for evaluation. On arrival, he reported intermittent numbness in both feet (greater in the left toes than in the right toes), but he had no shortness of breath, chest pain, leg weakness, or urinary or bowel incontinence. He had hypertension, nonischemic idiopathic cardiomyopathy with global hypokinesis, mild concentric left ventricular hypertrophy, and fatigue with exertion. He had a history of obesity, depression, gout, nephrolithiasis, an adrenal nodule, and elevated results of liver-function tests, as well as one episode of iritis of the left eye 15 years before admis-sion. He had also undergone numerous orthopedic procedures after traumatic injuries, including arthroplasty of the right knee and arthroscopy of the right

Case 31-2014: A 50-Year-Old Man with Back Pain, Fatigue, Weight Loss, and Knee SwellingMark C. Fisher, M.D., John H. Stone, M.D., M.P.H., and William E. Palmer, M.D.

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n engl j med 371;15 nejm.org october 9, 20141448

ankle. The ankle symptoms, which included chronic discomfort requiring prolonged use of crutches, were thought to have exacerbated his back pain. Medications included lisinopril, furo-semide, atenolol, allopurinol, fluoxetine, acetyl-salicylic acid, and thiamine hydrochloride, with hydrocodone and diazepam as needed for back pain and spasms. He had no known allergies, drank alcohol in moderation, and did not smoke or use illicit drugs. He was married, had adult children, and had worked in a service industry

until he became disabled by his back and ankle pain. He walked with the use of a cane or crutch-es. His father had had coronary artery disease.

On examination, the blood pressure was 152/82 mm Hg; the other vital signs and the oxy-gen saturation were normal. There was tenderness on palpation over the paraspinal regions of the lower thoracic and upper lumbar regions, without pain over the spinal processes. The left knee was warm to the touch, and a small effusion was pres-ent. There was trace pitting edema bilaterally.

A B

Figure 1. MRI Scan of the Spine.

On the day of admission, MRI of the spine was performed. A fluid-sensitive sagittal image of the thoracic spine shows that the disk space between the 10th and 11th thoracic vertebral bodies is filled with fluid (Panel A, arrow). There is also prominent bone marrow edema involving the adjacent vertebral bodies. A fat-sensitive sagittal image of the lumbar spine shows bridging ossifications at the levels of the T12–L1 disk space and the L1–L2 disk space (Panel B, arrows).



case records of the massachusetts gener al hospital


Strength was normal in both legs, but there was mild loss of sensation of light touch in the toes. The remainder of the examination was normal.

The level of C-reactive protein was 8.5 mg per liter (reference value, <8.0), and the erythrocyte sedimentation rate was 17 mm per hour (refer-ence range, 0 to 13). A complete blood count, a white-cell differential count, and results of tests of coagulation and liver and renal function were normal, as were blood levels of electrolytes, glu-cose, calcium, phosphorus, magnesium, total pro-tein, albumin, and globulin. Oxycodone was ad-ministered for pain.

The patient was admitted to this hospital, and diagnostic tests were performed.

Differ en ti a l Di agnosis

Dr. Mark C. Fisher: This 50-year-old man had a 2-year history of progressive back pain that di-minished with activity. MRI of the thoracic spine revealed findings at several contiguous spinal levels that were suggestive of diskitis. To con-struct an appropriate differential diagnosis, I will consider the most common categories of disease that cause diskitis: infection, cancer, and inflam-matory back pain (Table 1).1-4

Infection

Infection, the most common cause of diskitis, is more common in immunodeficient persons, such as those with human immunodeficiency vi-rus infection, cancer, diabetes, or chronic kidney disease or those who are taking glucocorticoids; this patient was not known to have any of these conditions. In patients with infectious diskitis, blood cultures may be negative and leukocytosis may be absent; therefore, infection should not be ruled out in this patient on the basis of these fac-tors alone.5,6 However, markers of inflammation such as the C-reactive protein level and the eryth-rocyte sedimentation rate are usually markedly abnormal, and in this patient, they were only minimally elevated, thus pointing away from the diagnosis of infectious diskitis. Several disorders, including polycythemia vera, sickle cell anemia, and congestive heart failure, can lead to spuri-ously low levels of acute-phase reactants (i.e., the erythrocyte sedimentation rate and, to a lesser extent, the C-reactive protein level). To my knowledge, this patient had none of these con-founding conditions, and we can therefore take

the results at face value, suggesting that infec-tion is unlikely.

Moreover, infectious diskitis is usually associ-ated with either direct inoculation or hematog-enous seeding from a primary source. The most common cause of infectious diskitis is Staphylo-coccus aureus, although in persons with seeding from a urinary tract infection, Escherichia coli or proteus species can lead to diskitis, and in per-sons with intravenous drug abuse, gram-negative rods, such as Pseudomonas aeruginosa, are possible causes. Rarer causes of infectious diskitis include tuberculosis (Pott’s disease) and invasive fungal

Table 1. Differential Diagnosis of Diskitis.

Infection

Staphylococcus aureus infection

Infections with gram-negative rods (e.g., Escherichia coli and proteus species)

Pott’s disease

Infections with fungal organisms

Brucellosis

Cancer

Metastatic

Lung cancer

Breast cancer

Colorectal cancer

Prostate cancer

Lymphoma

Melanoma

Renal-cell carcinoma

Primary

Myeloma

Plasmacytoma

Histiocytosis

Chordoma

Hemangioma

Osteosarcoma

Chondrosarcoma

Giant-cell tumor

Inflammatory back pain

Sarcoidosis

Psoriatic arthritis

Inflammatory bowel disease–associated arthritis

Reactive arthritis

Ankylosing spondylitis





infection.7 Brucella is associated with a character-istic lesion on imaging, but no such lesion was described on this patient’s MRI study.8 This pa-tient does not have identifiable risk factors for any of these infections.

Did this patient have infectious diskitis? Al-though infection is the most common cause of diskitis, the involvement of multiple spinal levels that was seen on imaging is highly unusual for infection, as is the 2-year duration, unless this patient has Pott’s disease. He did not have the clas-sic risk factors for infectious diskitis, and infection alone would not explain his peripheral arthritis.

Cancer

Cancer, the second most common cause of diski-tis, is also a consideration in this patient. Although often asymptomatic, metastatic disease is the most common presentation of cancer of the spine.9,10 Ap-proximately 70% of lesions involve the thoracic spine and can involve multiple levels; this patient had abnormal findings involving the thoracic spine. Furthermore, approximately 10% of can-cers are initially manifested as metastatic spinal disease, so the absence of a history of cancer in this patient does not rule out metastatic dis-ease.11 However, when cancer causes back pain, the pain typically occurs at night and is unaffected by activity. In contrast, this patient’s pain appears to be relieved with walking.

Lung cancer, the most common cause of spinal metastases, would explain the patient’s ankle pain if hypertrophic pulmonary osteoarthropathy were present.12 However, there is no evidence of lung cancer: he had no history of tobacco use or pul-monary symptoms. Breast cancer can metasta-size to the spine, but it is uncommon in men, and no abnormalities suggestive of breast cancer were noted in the patient’s history or on examination. Colorectal cancer can metastasize to the spine, but the patient had no family history of predis-posing conditions and no abdominal pain, ane-mia, or change in stool caliber to suggest this diagnosis. Prostate cancer can metastasize to the spine, but the patient is relatively young for metastatic prostate cancer, and his history and physical examination lack features suggesting this diagnosis. Other types of cancer to consider include lymphoma, melanoma, and renal-cell car-cinoma, but he has no history of constitutional symptoms other than weight loss, no abnormal skin lesions, and no history of hematuria.

Vertebral-body tumors include multiple my-eloma, which causes lytic lesions in multiple loca-tions.13,14 Myeloma is an unlikely diagnosis in this case, given the modestly elevated erythrocyte sedimentation rate and C-reactive protein level and the normal complete blood count. A plas-macytoma is more plausible because it does not have systemic effects, its peak onset is in the fifth decade of life, and laboratory test results in affected patients are essentially normal, but in-volvement of multiple spinal levels by a plasma-cytoma is unlikely. Langerhans’-cell histiocyto-sis, which is usually a systemic condition, can cause isolated skeletal lesions (often termed eo-sinophilic granulomas); however, it is usually manifested in the first two decades of life and would not explain the patient’s other symptoms.

Other primary tumors, all of which are rare, are also in the differential diagnosis. Chordo-mas, rare tumors from remnants of the noto-chord, are typically cranial or caudal in location and would not explain the peripheral-joint symptoms in this patient. Hemangioma is an intriguing diagnosis; the peak onset is in the fifth decade of life (which is consistent with the age of this patient), and when it affects the spine, the most common site of involvement is the thoracolumbar region. However, hemangioma would not cause the other symptoms in this patient. Osteosarcoma, which often affects the lumbosacral spine, is a possibility, although it usually occurs in childhood. This diagnosis would be more likely if the patient had a history of Paget’s disease affecting his spine. Chondro-sarcoma is an indolent tumor that has a peak onset in the sixth decade of life and is the only skeletal tumor that is more common in the axial skeleton than in other skeletal sites and that develops more often in adults than in children. All these tumors would have a characteristic ap-pearance on MRI that would be hard to confuse with diskitis. Giant-cell tumors are rare in the mobile spine, and they cause pain that dimin-ishes with rest, in contrast to the pain in this patient.

It is unlikely that this patient has cancer. His presentation lacks many features of the primary cancers that metastasize to the spine. His age at presentation would make a primary spinal tumor unlikely, and there are no primary tumors that would account for his peripheral-joint symptoms or the pattern of his pain.





Inflammatory Back Pain

A systemic inflammatory process could explain this patient’s back pain and account for many of the other features of his presentation. Inflamma-tory back pain typically diminishes with activity, which is consistent with this patient’s history.

Sarcoidosis is a rare disease that can cause rash, peripheral arthritis, iritis, and in rare cases, spondylodiskitis.15 Patients with sarcoidosis may have normal levels of inflammatory markers and white-cell counts. However, this patient had no pulmonary findings, the hallmark of sarcoidosis. Moreover, sarcoidosis typically is manifested by a mass lesion when it affects the spine, and this feature was not seen on the patient’s MRI study.

Spondyloarthropathies, including psoriatic ar-thritis, reactive arthritis, ankylosing spondylitis, and inflammatory bowel disease–associated ar-thritis, are a heterogeneous group of disorders that are defined as much by their extraarticular manifestations as they are by their articular fea-tures. All members of this family of diseases can affect the spine. A diagnosis of one of these disorders would explain the spinal involvement, peripheral-joint involvement, and history of iritis in this patient.

Psoriatic arthritis occurs in approximately 30% of patients with psoriasis and may precede the development of a rash. Psoriatic arthritis can affect the sacroiliac joints, but the pattern of sac-roiliitis is usually asymmetric. It can also affect the spine, with bridging between the vertebrae that is typically asymmetric and bulky.16 Although pso-riatic arthritis is a plausible diagnosis in this patient, the spinal involvement in psoriatic ar-thritis is unlikely to be confused with multilevel diskitis.

Reactive arthritis is an inflammatory arthri-tis that occurs after specific bacterial infections and viral syndromes. Postinfectious reactive ar-thritis typically is manifested by asymmetric oli-goarthritis of the legs and may involve the spine in a manner similar to that of psoriatic arthri-tis.17 However, this patient does not have a his-tory of antecedent infection.

Ankylosing spondylitis is a spondyloarthrop-athy defined by spinal involvement that can also involve peripheral joints and have extraarticular manifestations.1,18 The extraspinal joints involved in ankylosing spondylitis are usually large joints of the legs, such as the knee. In rare cases, anky-losing spondylitis is associated with Andersson

lesions (also known as chronic noninfectious spondylodiskitis or rheumatic spondylodiskitis), erosive changes in the vertebral end plate that mimic diskitis.19 Ankylosing spondylitis is also known to be associated with nephrolithiasis, which this patient had had.

Inflammatory bowel disease–associated ar-thritis occurs in up to 25% of patients with Crohn’s disease or ulcerative colitis.20 Spinal in-volvement is seen in 3 to 6% of cases of inflam-matory bowel disease and is typically symmetric and marginal, as it is in ankylosing spondylitis. There is a genetic association between inflam-matory bowel disease and ankylosing spondyli-tis. However, this patient had no history of in-flammatory bowel disease, no anemia, and no symptoms or signs on examination to suggest occult inflammatory bowel disease.

Does this patient have a spondyloarthropa-thy? The history of iritis and the current periph-eral- and axial-joint involvement are consistent with this diagnosis, but it is a rare cause of diski-tis. Levels of inflammatory markers are normal or mildly elevated in up to 40% of patients with active disease.21 Among the seronegative spondy-loarthropathies, ankylosing spondylitis is most consistent with this patient’s presentation.

Dr. Eric S. Rosenberg (Pathology): Dr. Stone, what was your impression when you first evaluated this patient?

Dr. John H. Stone: I was the patient’s inpatient at-tending physician, and as a rheumatologist, I took note at the mention of his remote history of iri-tis, a synonym for anterior uveitis. Although the episode of iritis had been isolated and had oc-curred 15 years earlier, its characteristics — uni-lateral, painful, and associated with photosensi-tivity and ocular erythema — were consistent with the type of inflammatory eye disease associ-ated with spondyloarthropathies.22 I therefore strongly suspected that a disease such as anky-losing spondylitis was causing the patient’s back pain. I asked my colleagues in the radiology de-partment to review the imaging studies with me.

Clinic a l Di agnosis

Ankylosing spondylitis.

DR . M A R K C . FISHER’S DI AGNOSIS

Ankylosing spondylitis.





DI AGNOS TIC IM AGING

Dr. Palmer: To characterize the spinal abnormali-ties seen on MRI, computed tomography (CT) was performed (Fig. 2). At the level of the T10–T11 disk space, there were chronic changes, in-cluding erosive destruction of the anterior end plate; disk-space widening and dense reactive sclerosis were noted. Sclerotic fracture lines ex-tended posteriorly from the disk space to the left and right pedicles and the articulating masses. These findings indicated pseudoarthrosis due to segmental instability and chronic mechanical hinging of the thoracic spine at this level. All other spinal levels that were visualized on CT had intervertebral syndesmophytes, intervertebral disk ossification with trabecular bone formation between vertebral bodies, ankylosis of facet-joint articulations, and bridging ossification between spinous processes.

Radiographic examination of the pelvis re-vealed symmetric ankylosis of the sacroiliac joints and confirmed the presence of syndesmophytes (Fig. 3). There were no notable findings at the hips.

These features observed on imaging are pathog-nomonic for spondyloarthropathy and are typical of ankylosing spondylitis. The sacroiliac joints, thoracic spine, and lumbar spine were solidly fused anteriorly and posteriorly at all levels except at the level of the T10–T11 disk space. At the level of the T10–T11 disk space, the MRI and CT findings indicated pseudoarthrosis and mechan-ical bone marrow edema that were most consis-tent with Andersson lesion.

Management

Dr. Stone: After reviewing the MRI study with Dr. Palmer, I was confident that the images did not show findings suggestive of infection or cancer but rather showed pseudoarthrosis resulting from

A B

Figure 2. CT Scan of the Spine.

To characterize the spinal abnormalities seen on MRI, CT was performed. A midline sagittal scan of the thoracic spine shows erosive destruction of the anterior end plate and disk-space widening at the level of the T10–T11 disk space (Panel A, white arrow), as well as syndesmophytes (black arrows) at other spinal levels. There are bridging os-sifications at the levels of the T12–L1 disk space and the L1–L2 disk space. On a paracentral sagittal CT scan, dense reactive sclerosis (Panel B, white arrows) bounds the abnormal disk space; a sclerotic fracture line extends posteri-orly from the disk space to the pedicle and articulating mass (black arrow).





an unstable spinal fracture. I surmised that this fracture had occurred at the time of the patient’s fall 11 months earlier, after which he had noticed increased back pain. In addition, a review of the spinal MRI study showed that the patient’s sacro-iliac joints were fused bilaterally. This finding is diagnostic of a spondyloarthropathy, and anky-losing spondylitis is the most common spondylo-arthropathy when both sacroiliac joints are fused. The characteristic Andersson lesions are indicative of inflammatory involvement of the interverte-bral disks by a seronegative spondyloarthropa-thy.19 These lesions develop late in the course of ankylosing spondylitis.

Ankylosing spondylitis affects 0.5% of the popu-lation and is strongly associated with the pres-ence of the HLA-B27 allele; 90% of patients with ankylosing spondylitis are positive for HLA-B27. The presence of HLA-B27 is neither necessary nor sufficient for the diagnosis of ankylosing spon-dylitis, because 10% of patients with ankylosing spondylitis are negative for HLA-B27 and be-cause the disease does not develop in all persons who are positive for HLA-B27.23 Therefore, the presence or absence of HLA-B27 should not be used as a diagnostic test for ankylosing spondyli-tis. In fact, this patient was negative for HLA-B27.

Furthermore, most patients with ankylosing spondylitis are younger than this patient when they receive the diagnosis, because the diagnosis is made when they initially present with symp-toms of inflammatory back pain. This patient did not receive the diagnosis until he was 50 years of age. It is possible that the absence of HLA-B27 in this patient led physicians away from this di-agnosis.

In ankylosing spondylitis, the entire spine can undergo fusion over time, typically beginning in the lower spinal segments and proceeding ceph-alad. Spinal fusion is associated with all the ra-diographic features seen in this case: interverte-bral syndesmophytes, disk ossification, ankyloses between joint articulations, and bridging ossifi-cation. The new bone formed in ankylosing spondylitis is unfortunately brittle. The trabecu-lar bone becomes osteoporotic over time, as well, with a high risk of spinal fractures.

The risk of fracture in ankylosing spondylitis stems from two main pathways (Fig. 4). One path-way causes bone resorption and erosion, while the other pathway leads to new bone formation at entheses and joint margins and to the formation

of syndesmophytes.24,25 Treatment strategies for ankylosing spondylitis must therefore target not only the inflammatory pathway that mediates symptoms of joint stiffness and bone erosions but also the pathway that leads to mechanical weakness of existing bone. Cytokine inhibitors, such as inhibitors of tumor necrosis factor (TNF), have led to profound symptomatic improvement in patients with ankylosing spondylitis, even those with advanced joint fusion. It is unclear whether TNF inhibition also slows the formation of frag-ile new bone associated with ankylosing spondy-litis.

This patient underwent surgical stabilization of the thoracic spine and had no direct complica-tions. However, several days after the procedure, bradycardia and hypotension developed, indicating third-degree heart block. Heart block is a rare complication of ankylosing spondylitis and is caused by the effects of obliterative endarteritis and fibrosis on the small arteries that nourish the cardiac conduction system.26 The patient un-derwent successful placement of a dual-chamber

Figure 3. Radiograph of the Pelvis.

An anteroposterior radiograph of the pelvis shows symmetric ankylosis of the left and right sacroiliac joints. Syndesmophytes bridge lower lumbar disks (ar-rows). These findings are diagnostic of a seronegative spondyloarthropathy and are typical of ankylosing spondylitis.





pacemaker and was discharged to a rehabilitation hospital.

A Physician: Do most patients with ankylosing spondylitis have a response to therapy with TNF inhibitors?

Dr. Fisher: Approximately 70% of patients have substantial improvement after treatment with TNF inhibitors.27,28

A Physician: Do persons who are negative for HLA-B27 have late-onset or less severe disease?

Dr. Fisher: Patients who are negative for HLA-B27 typically have less severe disease.29 The sever-

ity of disease in this patient is unusual because of the absence of HLA-B27. However, the association between HLA-B27 status and disease severity is extrapolated from population-based statistics and is not directly applicable to individual patients.

Fina l Di agnosis

Ankylosing spondylitis (HLA-B27–negative).

This case was discussed at the Medical Case Conference.Disclosure forms provided by the authors are available with

the full text of this article at NEJM.org.

TNF

WNT

Dickkopf-1

Interleukin-6

Up-regulation of osteoclast activity

Osteoblast activation

Vertebrae

Syndesmophytes

Intervertebraldisk

Osteoclast

New

bon

e fo

rmat

ion

Osteoblast

Osteocytes

Activation

Osteocytes

Bone

res

orpt

ion

Osteoclastprecursor

Osteoblast

RANKL

RANK

AUTHOR:

FIGURE:

ARTIST:

OLF:Issue date:

AUTHOR, PLEASE NOTE: Figure has been redrawn and type has been reset.

Please check carefully.

Fisher

4 of 4

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10-09-14 XX-XX-XX

Figure 4. Pathways of Bone Resorption and New Bone Formation in Patients with Ankylosing Spondylitis.

In one pathway, tumor necrosis factor (TNF), interleukin-6, and other cytokines stimulate osteoblasts to up-regulate receptor activator of nuclear factor κB ligand (RANKL), which promotes osteoclast maturation. TNF also directly stimulates osteoclast precursors and osteo-clasts, leading to osteoporosis in patients with ankylosing spondylitis. In a separate pathway, decreased levels of dickkopf-1, an inhibitor of Wnt, lead to increased Wnt signaling and osteoblast activation and ultimately lead to new bone formation.

References1. Mau G, Helbig B, Mann M. Discitis — a rare early symptom of ankylosing spondylitis. Eur J Pediatr 1981;137:85-8.2. Gabe MJ, Allmendinger AM, Krau-thamer A, Spektor V, Destian S, Zablow B. Imaging manifestations of malignant neo-plasia mimicking pyogenic osteodiscitis. Clin Imaging 2010;34:309-15.

3. Sasiadek M, Bladowska J. Hyperintense vertebral lesions. Neuroradiology 2011;53:Suppl 1:S169-S174.4. Fantoni M, Trecarichi EM, Rossi B, et al. Epidemiological and clinical features of pyogenic spondylodiscitis. Eur Rev Med Pharmacol Sci 2012;16:Suppl 2:2-7.5. Patzakis MJ, Rao S, Wilkins J, Moore

TM, Harvey PJ. Analysis of 61 cases of ver-tebral osteomyelitis. Clin Orthop Relat Res 1991;264:178-83.6. Unkila-Kallio L, Kallio MJ, Eskola J, Pel-tola H. Serum C-reactive protein, erythro-cyte sedimentation rate, and white blood cell count in acute hematogenous osteomy-elitis of children. Pediatrics 1994;93:59-62.





7. Cottle L, Riordan T. Infectious spon-dylodiscitis. J Infect 2008;56:401-12.8. Oztekin O, Calli C, Adibelli Z, Kitis O, Eren C, Altinok T. Brucellar spondylodis-citis: magnetic resonance imaging fea-tures with conventional sequences and diffusion-weighted imaging. Radiol Med 2010;115:794-803.9. Coleman RE. Clinical features of meta-static bone disease and risk of skeletal morbidity. Clin Cancer Res 2006;12: 6243s-9s.10. Fornasier VL, Horne JG. Metastases to the vertebral column. Cancer 1975; 36:590-4.11. Schiff D, O’Neill BP, Suman VJ. Spinal epidural metastasis as the initial manifes-tation of malignancy: clinical features and diagnostic approach. Neurology 1997;49:452-6.12. Armstrong DJ, McCausland EM, Wright GD. Hypertrophic pulmonary os-teoarthropathy (HPOA) (Pierre Marie-Bamberger syndrome): two cases present-ing as acute inflammatory arthritis: description and review of the literature. Rheumatol Int 2007;27:399-402.13. Kelley SP, Ashford RU, Rao AS, Dick-son RA. Primary bone tumours of the spine: a 42-year survey from the Leeds Regional Bone Tumour Registry. Eur Spine J 2007;16:405-9.14. Murphey MD, Andrews CL, Flemming DJ, Temple HT, Smith WS, Smirniotopou-los JG. From the archives of the AFIP: pri-mary tumors of the spine: radiologic

pathologic correlation. Radiographics 1996; 16:1131-58.15. Hasni SA, Kunz D, Finzel K, Gruber BL. Osseous sarcoidosis treated with tu-mor necrosis factor-inhibitors: case re-port and review of the literature. Spine (Phila Pa 1976) 2010;35:E904-E907.16. Lubrano E, Spadaro A. Axial psoriatic arthritis: an intriguing clinical entity or a subset of an intriguing disease? Clin Rheumatol 2012;31:1027-32.17. Cliff JM. Spinal bony bridging and carditis in Reiter’s disease. Ann Rheum Dis 1971;30:171-9.18. Tsuchiya K, Nagamine R, Iwamoto Y. Discovertebral lesion in ankylosing spon-dylitis: differential diagnosis with discitis by magnetic resonance imaging. Mod Rheumatol 2002;12:113-7.19. Park YS, Kim JH, Ryu JA, Kim TH. The Andersson lesion in ankylosing spondyli-tis: distinguishing between the inflam-matory and traumatic subtypes. J Bone Joint Surg Br 2011;93:961-6.20. Arvikar SL, Fisher MC. Inflammatory bowel disease associated arthropathy. Curr Rev Musculoskelet Med 2011;4:123-31.21. Sieper J, Braun J, Rudwaleit M, Boonen A, Zink A. Ankylosing spondylitis: an overview. Ann Rheum Dis 2002;61:Suppl 3:iii8-iii18.22. Pato E, Bañares A, Jover JA, et al. Un-diagnosed spondyloarthropathy in pa-tients presenting with anterior uveitis. J Rheumatol 2000;27:2198-202.23. Schlosstein L, Terasaki PI, Bluestone

R, Pearson CM. High association of an HL-A antigen, W27, with ankylosing spondylitis. N Engl J Med 1973;288:704-6.24. Gratacós J, Collado A, Filella X, et al. Serum cytokines (IL-6, TNF-alpha, IL-1 beta and IFN-gamma) in ankylosing spondylitis: a close correlation between serum IL-6 and disease activity and sever-ity. Br J Rheumatol 1994;33:927-31.25. Uderhardt S, Diarra D, Katzenbeisser J, et al. Blockade of Dickkopf (DKK)-1 in-duces fusion of sacroiliac joints. Ann Rheum Dis 2010;69:592-7.26. Dik VK, Peters MJ, Dijkmans PA, et al. The relationship between disease-related characteristics and conduction distur-bances in ankylosing spondylitis. Scand J Rheumatol 2010;39:38-41.27. Braun J, Brandt J, Listing J, et al. Treatment of active ankylosing spondyli-tis with infliximab: a randomised con-trolled multicentre trial. Lancet 2002; 359:1187-93.28. Callhoff J, Sieper J, Weiß A, Zink A, Listing J. Efficacy of TNFα blockers in pa-tients with ankylosing spondylitis and non-radiographic axial spondyloarthritis: a meta-analysis. Ann Rheum Dis 2014 April 9 (Epub ahead of print).29. Awada H, Abi-Karam G, Baddoura R, Okais J, Attoui S. Clinical, radiological, and laboratory findings in Lebanese spondylarthropathy patients according to HLA-B27 status. Joint Bone Spine 2000;67: 194-8.Copyright © 2014 Massachusetts Medical Society.

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