Musculoskeletal Tuberculosis The Great Mimic

Musculoskeletal Tuberculosis: The Great Mimic Dr. Jonathan Stein, PGY3 Rheumatology Rounds August 23, 2005 Outline    TB Background & Epidemiology Pathophysiology of Infection MSK Tuberculosis Use of TNF Inhibitors Summary   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/ Mycobacteria Tuberculosis  Aerobic slow growing bacteria acquired by inhalation of aerosolized droplets Approximately 80% of non-HIV–related 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.    http://www.lung.ca/tb/tbhistory/ Epidemiology  Incidence: 8 million new cases per year  Prevalence: population 1/3 of the world's  Untreated, 1/3 of patients who have active TB die within 1 year and half die within 5 years remains a leading infectious killer and causes 2 million deaths annually  TB Epidemiology  Canada  U.S.A. 3 cases/100,000 population 6 cases/100,000 population  Spain 25 cases/100,000 population Africa 300 cases/100,000  Sub-Saharan population TB in Canada 1952 - INH developed http://www.lung.ca/tb/tbtoday 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/tbtoday/ TB in Canada Distribution of reported TB cases among population groups in Canada, in 1996. www.lung.ca/tb/tbtoday/ 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/ Immune Defense Against Tuberculosis  Ingestion of organisms by pulmonary macrophages   Cell-mediated immunity (CD4+T cells) Cytokine-mediated activation of macrophages (TNF-α, IFNγ, IL-12  Granulomas: contain organisms preventing their spread Latent Tuberculosis  95% of adults control the initial infection   TB is not eradicated 10% of patients with latent TB infection reactivate and become symptomatic Tuberculous Seeding Pulmonary (75%)  Extra-pulmonary (25%)        MSK Lymph nodes Reproductive / urinary CNS Peritoneum Liver/spleen Clinical Symptoms   Fatigue Weakness Weight loss Anorexia Low grade fever Night sweats Productive cough Hemoptysis       http://www.lung.ca/tb/tbtoday Musculoskeletal TB Musculoskeletal TB  1% to 5% of all patients with TB Men > women Hematogenous seeding most likely through arteries    Disease starts in bone or synovial membrane Articular cartilage destruction begins peripherally, weight bearing surfaces initially preserved  Tuberculous Spondylitis “Pott’s Disease”  Most common site of MSK involvement (50%)   Thoracic spine > Lumbar > Cervical Hematogenous spread Vertebral bodies have both anterior and posterior arterial supply  Musculoskeletal TB Pathophysiology Of Tuberculous Spondylitis Vuyst, D. et al. 2003. Imaging features of musculoskeletal tuberculosis. 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   Tuberculous Spondylitis – Radiological Findings Griffith, J. Imaging of Musculoskeletal Tuberculosis: A new look at an old disease. 2002. Clinical orthopedics and related research. 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. 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   Tuberculous spondylitis http://www.lung.ca/tb/tbhistory/ 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    TB vs. Pyogenic Vuyst, D. et al. 2003. Imaging features of musculoskeletal tuberculosis. 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 Tuberculous Arthritis  Reactive hyperemia results in osteoporosis Leads to erosions, bone destruction Phemister’s triad: i. ii. iii.   juxta-articular osteoporosis peripherally located erosions, gradual joint space narrowing Tuberculosis of the Hip  15% of all cases of osteoarticular Tb Age of presentation ~ 20’s and 30’s Presents with limping, night pain Painful, inflammatory trochanteric bursitis that may proceed to erosion of the bone    Tuberculosis of the Hip Babhulkar, S. 2002. Osteoarticular Tuberculosis: Extraspinal Tuberculosis. Clinical orthopedics and related research. Babhulkar, S. 2002. Osteoarticular Tuberculosis: Extraspinal Tuberculosis. Clinical orthopedics and related research. Babhulkar, S. 2002. Osteoarticular Tuberculosis: extra-spinal Tuberculosis Clinical orthopedics and related research. 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   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   Tuberculous Dactylitis Vuyst, D. et al. 2003. Imaging features of musculoskeletal tuberculosis. Cervical Tuberculosis Griffith, J. Imaging of Musculoskeletal Tuberculosis: A new look at an old disease. 2002. Clinical orthopedics and related research. http://www.lung.ca/tb/tbhistory/ http://www.lung.ca/tb/tbhistory/ Latent TB & TNF Inhibitors  Cytokine-mediated activation of macrophages and TNF-α production leads to granuloma contain organisms and prevent their spread  Granulomas  TNF inhibitors – increased incidence of TB reactivation 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 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)   Recommendations:  Treat for 9 months with 5mg/kg body weight of INH if: 1) History of untreated TB, or exposure to active case of TB 2) CXR indicative of prior TB infection 3) Reaction >5mm on PPD skin test Study Limitations   Authors did not report capture rate What is the completeness of the database? What proportion of patients receiving TNF inhibitors registered?  Elizabeth Olds (1896-1991)Tuberculosis Tests for Children, 1934, Lithograph http://www.lung.ca/tb/tbhistory/ 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   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. 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    Hochberg. M. 2005. The Benefit/Risk Profile of TNF-Blocking Agents: Findings of a Consensus Panel. Semin Arthritis Rheum. 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 Hochberg. M. 2005. The Benefit/Risk Profile of TNF-Blocking Agents: Findings of a Consensus Panel. Semin Arthritis Rheum. 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  http://www.lung.ca/tb/tbhistory/ Thank You !