Musculoskeletal Tuberculosis:

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Musculoskeletal Tuberculosis The Great Mimic
Dr. Jonathan Stein, PGY3 Rheumatology
Rounds August 23, 2005
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Outline

• TB Background Epidemiology
• Pathophysiology of Infection
• MSK Tuberculosis
• Use of TNF Inhibitors
• Summary

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In 1882, German microbiologist Robert Koch
isolated a rod-shaped bacterium now called
Mycobacterium tuberculosis, or simply, the
tubercle bacillus. www.lung.ca/tb/tbtoday/
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Mycobacteria Tuberculosis

• Aerobic slow growing bacteria acquired by
  inhalation of aerosolized droplets
• Approximately 80 of non-HIVrelated TB cases
  present with pneumonitis
• TB may spread to regional lymph nodes and then
  throughout the body
• Among patients who have HIV, two thirds present
  with extra-pulmonary involvement.

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http//www.lung.ca/tb/tbhistory/
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Epidemiology

• Incidence 8 million new cases per year
• Prevalence 1/3 of the world's population
• Untreated, 1/3 of patients who have active TB die
  within 1 year and half die within 5 years
• TB remains a leading infectious killer and causes
  2 million deaths annually

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Epidemiology

• Canada 3 cases/100,000 population
• U.S.A. 6 cases/100,000 population
• Spain 25 cases/100,000 population
• Sub-Saharan Africa 300 cases/100,000 population

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TB in Canada
1952 - INH developed
http//www.lung.ca/tb/tbtoday
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TB in Canada
Major causes of death in Canada in 1926, and in
1990. Tuberculosis accounts for 7 of deaths in
1926, and less than 1 in 1990--included under
"infectious diseases. http//www.lung.ca/tb/tbtoda
y/
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TB in Canada
Distribution of reported TB cases among
population groups in Canada, in 1996.
www.lung.ca/tb/tbtoday/
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Public education and awareness campaigns played a
large part in convincing the general public to
show up at TB clinics. By surveying the entire
population for tuberculosis, it was caught before
it spread. http//www.lung.ca/tb/tbhistory/
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Immune Defense Against Tuberculosis

• Ingestion of organisms by pulmonary macrophages
• Cell-mediated immunity (CD4T cells)
• Cytokine-mediated activation of macrophages
  (TNF-a, IFN?, IL-12
• Granulomas contain organisms preventing their
  spread

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Latent Tuberculosis

• 95 of adults control the initial infection
• TB is not eradicated
• 10 of patients with latent TB infection
  reactivate and become symptomatic

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Tuberculous Seeding

• Pulmonary (75)
• Extra-pulmonary (25)
• MSK
• Lymph nodes
• Reproductive / urinary
• CNS
• Peritoneum
• Liver/spleen

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Clinical Symptoms

• Fatigue
• Weakness
• Weight loss
• Anorexia
• Low grade fever
• Night sweats
• Productive cough
• Hemoptysis

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http//www.lung.ca/tb/tbtoday
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Musculoskeletal TB
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Musculoskeletal TB

• 1 to 5 of all patients with TB
• Men gt women
• Hematogenous seeding most likely through arteries
• Disease starts in bone or synovial membrane
• Articular cartilage destruction begins
  peripherally, weight bearing surfaces initially
  preserved

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Tuberculous Spondylitis Potts Disease

• Most common site of MSK involvement (50)
• Thoracic spine gt Lumbar gt Cervical
• Hematogenous spread
• Vertebral bodies have both anterior and posterior
  arterial supply

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Musculoskeletal TB
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Pathophysiology Of Tuberculous Spondylitis
Vuyst, D. et al. 2003. Imaging features of
musculoskeletal tuberculosis.
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Tuberculous spondylitis

• Clinical Symptoms
• Low grade evening fever
• Loss of appetite with weight loss
• Progressive local pain
• Difficulty in daily functioning due to painful
  and restricted spinal mobility
• Affection of the nervous system's function

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Tuberculous Spondylitis Radiological Findings
Griffith, J. Imaging of Musculoskeletal
Tuberculosis A new look at an old disease.
2002. Clinical orthopedics and related research.
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Imaging Features that Favor Spinal TB Rather than
Neoplastic Disease
Griffith, J. Imaging of Musculoskeletal
Tuberculosis A new look at an old disease.
2002. Clinical orthopedics and related research.
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Tuberculous spondylitis

• Cold Abscesses
• Not as hot, warm or painful as other abscesses
• Hidden deep inside the body
• May burst out leaving behind a track, or sinus,
  which discharges pus

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Tuberculous spondylitis
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http//www.lung.ca/tb/tbhistory/
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Paraspinal Infection

• Abscess occurs in 70 of patients with spinal TB
  (epidural extension)
• Lumbar region psoas abscess are large, extend
  to proximal thigh
• Present with groin mass
• In thoracic region posterior mediastinal mass

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TB vs. Pyogenic
Vuyst, D. et al. 2003. Imaging features of
musculoskeletal tuberculosis.
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Tuberculous Arthritis

• Monoarticular
• Most common hip and knee
• Less common elbow, wrist, SIJ, glenohumeral,
  sternoclavicular
• Primary TB metaphyseal focus crosses the
  epiphyseal plate.
• Transphyseal spread not found in pyogenic
  arthritis

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Tuberculous Arthritis

• Reactive hyperemia results in osteoporosis
• Leads to erosions, bone destruction
• Phemisters triad
• juxta-articular osteoporosis
• peripherally located erosions,
• gradual joint space narrowing

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Tuberculosis of the Hip

• 15 of all cases of osteoarticular Tb
• Age of presentation 20s and 30s
• Presents with limping, night pain
• Painful, inflammatory trochanteric bursitis that
  may proceed to erosion of the bone

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Tuberculosis of the Hip
Babhulkar, S. 2002. Osteoarticular Tuberculosis
Extraspinal Tuberculosis. Clinical orthopedics
and related research.
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Babhulkar, S. 2002. Osteoarticular Tuberculosis
Extraspinal Tuberculosis. Clinical orthopedics
and related research.
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Babhulkar, S. 2002. Osteoarticular Tuberculosis
extra-spinal Tuberculosis Clinical orthopedics
and related research.
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Tuberculosis of the Hip

• DDx transient synovitis, rheumatoid arthritis,
  osteoarthritis, and osteonecrosis.
• If not treated, progressive pattern of
  destruction
• Treatment drug therapy, traction, and supervised
  mobilization produces good results in patients
  with early stages of the disease

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Tb Tenosynovitis

• Synovial membrane of tendon sheaths
• Flexor or extensor tendons of hands most common
• Tendon, synovium or both may be thickened and
  hyperemic
• Spread to soft tissues, bones and joints
• Biopsy or synovectomy may be required

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Tuberculous Dactylitis
Vuyst, D. et al. 2003. Imaging features of
musculoskeletal tuberculosis.
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Cervical Tuberculosis
Griffith, J. Imaging of Musculoskeletal
Tuberculosis A new look at an old disease.
2002. Clinical orthopedics and related research.
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http//www.lung.ca/tb/tbhistory/
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http//www.lung.ca/tb/tbhistory/
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Latent TB TNF Inhibitors

• Cytokine-mediated activation of macrophages and
  TNF-a production leads to granuloma
• Granulomas contain organisms and prevent their
  spread
• TNF inhibitors increased incidence of TB
  reactivation

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Multicentre Active-Surveillance

• Observational study 1540 patients
• 71 participating centres in Spain
• 85 infliximab, 14 etanercept
• Infections in 118 patients, respiratory tract
  21, skin 13, urinary 11.

Gomez-reino, J. Treatment of Rheumatoid
Arthritis with Tumor Necrosis Factor. Inhibitors
May Predisopose to Significant Increase in
Tuberculosis Risk. Arthritis Rheumatism.
2003. 48(8) 2122-2127
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Multicentre Active-Surveillance

• 17 cases of TB in patients with infliximab, 15 of
  these were RA patients.
• 65 had extrapulmonary sites (LN, Liver-spleen,
  disseminated)
• Estimated incidence of TB with infliximab in RA
  patients 1893 per 100,000 (year 2000)

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Recommendations

• Treat for 9 months with 5mg/kg body weight of INH
  if
• History of untreated TB, or exposure to active
  case of TB
• CXR indicative of prior TB infection
• Reaction gt5mm on PPD skin test

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Study Limitations

• Authors did not report capture rate
• What is the completeness of the database?
• What proportion of patients receiving TNF
  inhibitors registered?

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Elizabeth Olds (1896-1991)Tuberculosis Tests for
Children, 1934, Lithograph
http//www.lung.ca/tb/tbhistory/
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Infliximab

• Monoclonal antibody with high affinity and
  specificity for its target cytokine
• Binds to soluble TNF monomers and trimers, as
  well as membrane-bound TNF-alpha, forming a
  stable complex
• Prevents TNF-alpha from binding to its receptor
  and triggering a biological response

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Infliximab vs. Etanercept

• Mice with only transmembrane TNF are relatively
  resistent against mycobacteria
• Transmembrane signalling is preserved with use of
  etanercept and may provide sufficient residual
  protective immunity against TB to prevent
  reactivation.

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Adalimumab (Humira)

• Adalimumab is a recombinant IgG antibody
• Binds to TNF-alpha, not to lymphotoxin (TNF-beta)
• Blocks its interaction with the p55 and p75 cell
  surface TNF receptors
• Modulates responses that are regulated by TNF,
  i.e., levels of adhesion molecules responsible
  for leukocyte migration

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Hochberg. M. 2005. The Benefit/Risk Profile of
TNF-Blocking Agents Findings of a Consensus
Panel. Semin Arthritis Rheum.
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TNF inhibitors Increase Risk of TB Reactivation

• TB skin test
• Must rule out active disease CXR, sputum
• If latent TB, INH for 9 months
• Start TNF-I after 1 month of INH
• If active disease, 4 medications
• Start TNF inhibitor after completion
• High index of suspicion for reactivation

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Hochberg. M. 2005. The Benefit/Risk Profile of
TNF-Blocking Agents Findings of a Consensus
Panel. Semin Arthritis Rheum.
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Summary

• Tuberculosis causes significant morbidity and
  mortality worldwide
• MSK TB affects spine and hip mimics other
  pyogenic infections
• TNF inhibitors take abrogate the main defense
  mechanism keeping latent TB at bay
• High index of suspicion needed

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http//www.lung.ca/tb/tbhistory/
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Thank You !