Extra-pulmonary Tuberculosis (EPTB) Treatment
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There has been a surge in the number of EPTB cases in recent times (2). Share of EPTB as a proportion of total number tuberculosis [TB] cases in USA has increased from 7.6 in 1962 to 15.7% in 1993, and to 21.0% in 2006 (3-5). Bone and joint tuberculosis accounted for 5337 (11%) cases out of a total of 47,293 cases of EPTB reported in USA from 1993-2006 (6). In the absence of a reliable epidemiological data and very sparse published literature, it is not possible to give an exact figure on the relative contribution of EPTB to the total number of TB cases in India (1, 7). Bone and joint tuberculosis constitutes 10-11% of total EPTB cases which would be approximately 1-3% of all TB cases (8, 9).
MSK-TB is usually classified into Spinal TB and TB of peripheral joints (10). Spinal TB constitutes nearly 50% of all MSK-TB (11). The other relatively uncommon forms of MSK-TB are Poncet’s disease (para infectious TB arthritis), TB soft tissue rheumatism, and iatrogenic rheumatism and TB osteomyelitis (10). TB of the spine and peripheral joints has been covered in the chapter “Skeletal tuberculosis”. The main focus of present chapter will be on an overview of TB arthritis, Poncet’s disease [para infectious TB arthritis] and TB soft tissue rheumatism.
AETIOPATHOGENESIS AND PATHOLOGY
Though there are various species of Mycobacterium tuberculosis complex like M.tuberculosis, M.bovis, M.africanum and M.microti, the causative agent of MSK TB almost always is M.tuberculosis (11). The causation due to the other species is very rare. Infection with M.tuberculosis occurs through inhalational route, ingestion or direct inoculation (12). Particles less than 5 μm can pass through the natural protective mechanisms in the airways and carry 1-5 mycobacteria (12). These numbers can result in infection in an immunocompromised host like infant, elderly, and comorbidities like diabetes, hematological malignancies, immunosuppressive therapy and HIV etc (12). De novo infection depends upon the ability of the mycobacterium to escape the host defenses like alveolar macrophages [pneumocytes] and delayed hypersensitivity (12). There is an intracellular multiplication of mycobacteria with the help of toll like receptor-2 and complement binding receptors, mannose, cholesterol related receptors, and CD14, leading to burst of pneumocytes (12). The released mycobacteria are phagocytosed by other macrophages triggering a chain reaction resulting in cytokine production, inflammatory response and eventual hematological spread (12). There is development of protective immunity mediated by CD4+ lymphocytes with the help of CD8+ cytotoxic lymphocytes and B cells (12). Several virulence factors of the mycobacterial cell wall like cord factor, lipoarabinomannam (LAM), and 65-kDa heat shock protein [hsp65] also play a role in the pathogenesis. Various cytokines such as interleukins, interferon gamma and tumour necrosis factor α [TNF α] play a protective role against TB infection (12). These are responsible for formation and maintenance of granuloma. This is important for containing and killing mycobacterium. TNF α are being increasingly used in various rheumatic diseases like rheumatoid arthritis, spondyloarthropathies etc. There is a risk of reactivation of tuberculosis in these individuals and it might be due to disruption of TNF dependent cellular migration necessary for maintaining the integrity of the granuloma (12).
The MSK TB infection is mostly secondary to hematogenous spread from a primary focus, which may be in the lungs, lymph nodes or other organs and that source can be demonstrated in up to 40% of these patients with the help of sensitive imaging modalities like MRI (13). The joint infection is usually a result of either spread from a TB osteomyelitis or seeding of the synovium from due to the hematogenous spread. There is synovitis in the initial stage of infection, followed by formation of granulation tissue and pannus in the later stages, which eventually results in cartilage destruction (13). This is followed by demineralization and necrosis resulting in severe bone damage. There may be formation of para articular cold abscess [without signs of inflammation] and external fistulae (11).
Host genetic factors do play a role in susceptibility to TB (14). Various studies have shown associations of different genetic polymorphisms with either increased or less risk of development of tuberculosis (15-16). EPTB like MSK TB is predominantly a disease of the children and young adults in endemic areas. In the non endemic areas, it affects people with older age or some form of immunocompromised state (17-18). People with HIV infection, diabetes mellitus, and on immunosuppressive and cytotoxic therapies are at increased risk of TB (19-23). Patients on treatment for underlying rheumatologic diseases like SLE, RA or gout may also develop MSK TB (24-27). There may be TB involvement of the prosthetic joint also (28).
The clinical manifestations of MSK TB can be divided into four major categories (29): [i] Direct MSK involvement; [ii] Development of TB during treatment of rheumatic disease; [iii] Effects of antituberculosis drugs; and [iv] Reactive phenomenon
Direct MSK Involvement
Typical TB infection presents as a slow, smoldering localized infection of the bones [osteomyelitis], spine, peripheral joints and soft tissue. Since the spinal and peripheral joint involvement has been discussed in other chapter, only a brief overview of the tuberculosis arthritis is being provided in this chapter. TB osteomyelitis seen both in children and adults, but is more common in children, and may involve any bone. Femur and tibia are the most commonly involved bones, though ribs skull, phalanx and other bones may also be involved (12). In children, TB involvement of the phalanx may cause dactylitis and present as a diffuse ‘spindle like swelling of the finger’ (11).The overlying skin is shiny and stretched. Radioisotope bone scan may show ‘hot spots’ in the metaphysis of a short bone of the hands and feet (11).
Joint involvement is usually in the form of chronic monoarthritis of the large and medium weight bearing joints like hip and knee (30). Clinical manifestations are in the form of pain and swelling of the involved joint along with restriction of movement. Constitutional symptoms in form of fever and weight loss may also be present. Other joints like sacroiliac, shoulder, elbow, ankle, carpel and tarsal joints are less commonly involved. Polyarticular or oligoarticular involvement is uncommon. There may be a polyarticular involvement in a debilitated child or adult with a past history of TB or TB contact (11).The presentation mimicking juvenile idiopathic arthritis has also been reported rarely (31).
The soft tissue TB infection can present as tenosynovitis, bursitis, myositis or fasciitis. There may be a delay in diagnosis of these conditions when there is a resemblance to focal soft tissue inflammatory conditions (32).
Myositis is uncommon condition and the usual causative organism is Staph aureus (33). TB myositis is even rarer. Most of these patients have predisposing conditions for TB (34). The proposed mechanism of involvement is thought to be due to either a ‘hematogenous’ spread, ‘contiguous’ spread from the adjoining bone and soft tissue or ‘iatrogenic’ due to direct inoculation through contaminated instruments (34). Abnormalities on chest radiographs have been noted in up to half of these patients. Though rare, this has been reported to have significant mortality rate of around 14 per cent with even higher mortality [30%] in patients with possible hematogenous route of infection (34). The clinical presentation is in the form of local signs and symptoms of inflammation.
Development of TB During Treatment of Rheumatic Disease
Many patients with active inflammatory rheumatologically disorders receive various immunosuppressive drugs, making them susceptible to reactivation of tuberculosis. Though anti TNF therapy and corticosteroids are most commonly incriminated agents, all patients who receive any immunosuppressive therapy affecting the cellular immunity should be considered at risk of reactivation of tuberculosis (37). Data from a large patient registry reported a TB incidence of more than 1000 per 100,000 patient years of exposure to TNF blockers (38). This rate was reported to be 6 cases per 100,000 in patients with rheumatoid arthritis before the starting of widespread use of TNF blockers (38). Etanercept may be associated with relatively lower risk (39). This reactivation is mostly 6-12 months after initiating the TNF blockers, and is usually in form of EPTB. Proper screening for latent TB in these patients results in decrease in active TB (40). Glucocorticoids also increase the risk of reactivation in patients with latent TB infection. Though the risk appears to be dose related, it is the even in patients on low physiological dose of prednisolone 7.5 mg/day.
Effects of Antitubeculosis Drugs
Drugs used in TB treatment can produce various clinical conditions. Isoniazid and Rifampicin may produce drug induced lupus. These patients have ANA and anti Histone positivity. The disease is generally mild and reverses on stoppage of these drugs. Fluoroquinolones especially ciprofloxacin and levofloxacin have been associated with tendon rupture (37). This risk is higher in older individuals, and those on corticosteroids. Pyrazinamide can cause hyperuricemia due to interference with renal tubular excretion but this rarely results in gout (37).
Reactive Phenomenon (Poncet’s Disease)
This is a form of inflammatory arthritis without any evidence of direct TB involvement of the joint in the presence of TB elsewhere in the body. This was described by Poncet in 1887 in patients with current or past history of EPTB (38). In the absence of any diagnostic criteria, other disease conditions have been included in this diagnosis, and this has led to controversy over this terminology. The definite pathogenesis of Poncet’s is uncertain but is similar to ‘reactive arthritis’ as a result of molecular mimicry between Mycobacterium tuberculosis and articular cartilage. Mycobacteria are arthretogenic. A CD4+ T cell response to mycobacterial antigens is has been shown to play a role (39). Chronic synovitis resembling rheumatoid arthritis can be produced by injection of complete Freund’s adjuvant [heat killed and desiccated M. tuberculosis in oil]. Arthritis has also been reported as a side effect of the BCG immunotherapy in patients with bladder carcinoma. The description of clinical presentations of Poncet’s in the literature is derived from small case series and case reports (41-48). Poncet’s is more common in juveniles and young adults, with some female predilection. There may be fever and constitutional symptoms in some patients. The pattern of joint involvement commonly described is acute or sub acute symmetrical polyarthritis predominantly involving the large joints like knees and ankles. Symmetrical small joint involvement resembling rheumatoid arthritis has also been reported occasionally. The most common site of TB is pulmonary (49). Most common site of EPTB is lymph nodes (11). TB may sometimes develop during the course of Poncet’s (47). Manteaux test is usually strongly positive except in disseminated TB. Poncet’s is a diagnosis of exclusion and there is no evidence of active TB of the joint; and it resolves completely with anti tubercular therapy.
Panniculitis Associated with TB
Erythema nodosum [EN], the septal panniculitis, is the most common form of panniculitis seen in TB. Panniculitis is a non-suppurative inflammation of the subcutaneous fat without vasculitis. EN is due to delayed type of hypersensitivity reaction to variety of antigens. There may be various causes of EN like infections [bacterial, mycobacterial and fungal], drugs [especially sulphonamides and oral contraceptive pills], inflammatory bowel disease and various rheumatologically conditions like behcet’s disease and sarcoidosis. This may be associated with fever and constitutional symptoms in the eruptive stage. Arthralgia’s or arthritis may be seen in up to half of these patients. The characteristic presentation is in the form of erythematous tender nodules over the shins, which are palpable and often tender. There is induration of the overlying skin. Occasionally, it may be in the form of a sheet like indurated, hyper-pigmented swelling over the ankles and shin. Though any joint may be involved, but ankle, knee and wrist are the most commonly involved joints.
Erythema induratum [EI] of basin type is a lobular panniculitis and has a similar presentation in the form of tender erythematous nodules. These are more commonly seen on the calves but shin can also be involved occasionally. The other sites of involvement are trunk, buttocks, thighs and arms. Unlike EN, which heals without scarring, EI heals with ulceration or depressed scars. This can also be associated with ankle arthritis. EI is one of the three types of tuberculides, the other two being lichen scrofulosorum, and papulonecrotic tuberculide. Tuberculides are result of immunologic reactions to antigenic components of MTB. Histopathology and PCR may confirm TB in some of these patients and these respond to antituberculosis treatment.
UNUSUAL MANIFESTATIONS OF MSK TB
Various types of very unusual manifestations of MSK TB have been reported. Some of these are [a] non healing ulcerated mass resembling a synovial sarcoma due to TB synovitis, [b] hip pain due to trochanteric bursitis due to TB, [c] sternoclavicular mass, [d] bilateral steroclavicular involvement,[e] involvement of great toe,[f] lower end of fibula,[g] midtarsel joints, [h] sternum after sternotomy following bypass surgery (50-55). Bakers cyst has also been reported due to TB (56).
MUSCULOSKELETAL DISEASES ASSOCIATED WITH NON-TUBERCULOUS MYCOBACTERIA
MSK involvement due to non-tuberculous mycobacteria [NTM] are uncommon. Mycobacterium kansasii is the most common NTM species to cause MSK involvement, though involvement due to other species like M.xenopi, M.avium intracellulare, M.chelonei, M.fortuitum has also been reported (57-61). Synovial sheath infection is more common than infection of the osseous tissue (62). Most of these patients have some predisposing conditions though it has been reported in a patient without any apparent immunocompromise (63). These infections have also been reported in a patient with a rheumatic disease like SLE or Still’s disease (64). Arthritis due to NTM has also been reported after exposure to contaminated marine life (65, 66).
DIAGNOSIS OF MSK TB
A high index of suspicion is required for making the diagnosis of MSK TB. Common MSK manifestations are spondylitis or chronic monoarthritis. The cornerstone of diagnosis is the microbiological or histopathological evidence of MTB infection. Patients with risk factors for tuberculosis such as immunocompromised individuals, elderly, and children, those on immunosuppressive drugs must undergo these investigations in an appropriate clinical setting.
Laboratory investigations like elevated erythrocyte sedimentation rate [ESR], C-reactive protein level, are nonspecific. Positive culture is the gold standard. Conventional culture on Lowenstein-Jensen medium takes a longer time [3-6 weeks]. Newer techniques like BACTEC have reduced the isolation time to 2 weeks. Molecular diagnostic techniques like polymerase chain reaction [PCR] or Gen probe are even faster. PCR has been shown to be a good sensitive and specific technique for diagnosis of various extra pulmonary TB conditions including osteoarticular TB; and even for diagnosis of NTM infections like M.avium (67-73). Cepheid GeneXpert MTB/RIF assay is an automated cartridge based molecular diagnostic method which can diagnose MTB infection and rifampicin resistance in one and half hours. It has been not been extensively evaluated in EPTB conditions.
Skin testing, like tuberculin skin test [TST] indicates exposure to the MTB organism, and is a marker of latent TB infection; and may not mean active disease especially in high prevalence countries. Since the purified protein derivative [PPD] used for tuberculin test contains various MTB antigens which are almost identical to Bacille-Calmette-Guerin [BCG] antigens or NTM antigens, TST may also be positive in BCG vaccinated individuals or NTM infected individuals.
Interferon gamma release assays [IGRAs] like QuantiFERON TB gold and T-SPOT.TB have recently been developed to diagnose latent TB infection. These tests use two MTB specific antigens, ESAT-6 and CFP-10 and hence are not affected by BCG vaccination and NTM infections. Synovial fluid aspiration and synovial biopsy are very important for establishing diagnosis of TB arthritis.
Indications of Synovial Biopsy
The issues concerning procurement of adequate tissue for histopathological diagnosis of skeletal TB are discussed in the chapter “Skeletal tuberculosis [Chapter?]. The indications for a synovial biopsy in patients with MSK-TB from a rheumatologist’s perspective are discussed below.
When clinical evaluation and routine investigations fail to provide a diagnosis synovial biopsy is the logical next step. It is usually the only definitive method of diagnosing infection with fastidious organisms including TB. An absolute indication for synovial biopsy is a chronic inflammatory monoarthritis where synovial fluid examination including microbiological studies may have failed to give a definitive diagnosis. Another strong indication for synovial biopsy would be a patient with persistent disease activity in a single joint.
Imaging of MSK TB
Imaging in patients with skeletal TB is covered in detail in the chapter “Skeletal tuberculosis” [Chapter?]. Certain key issues related to imaging in MSK-TB are described here under to supplement the content covered in the chapter “Skeletal tuberculosis” [Chapter?]. Among the various available imaging techniques, computed tomographic scan [CT scan] is superior in depicting the degree of bony destruction and facilitating image-guided biopsy for spinal TB. On the other hand, for detailed anatomical evaluation and for distinguishing different densities of tissues [fibrous tissue, abscess, meninges, spinal cord etc.,] magnetic resonance imaging [MRI] with contrast is considered superior (74). The characteristic ‘Phemister’s triad’ is considered rather typical of TB. Three components of the triad are [i] juxta- articular osteoporosis, [ii] peripherally located osseous erosions, [iii] gradual narrowing of the joint space (75-77). On the other hand, in the course of RA and pyogenic arthritis, the joint space narrowing occurs early. For soft tissue TB, the ultrasonography is the method of choice as it shows the extent and degree of involvement. On the other hand, the MRI shows the extent of soft tissue, osseous and joint involvement (75). One of the other typical features of TB aetiology of the bones that have a relatively superficial cortical surface [e.g., metacarpals, metatarsals, phalanges, tibia and ulna] is the presence of lytic lesions surrounded by reactive subperiosteal new bone formation (13). It needs to be emphasized that despite these advances, the ‘gold standard’ for the diagnosis of TB of the MSK system still remains histo- pathological and/or microbiological confirmation; definitive treatment cannot be instituted before confirming the diagnosis (75).
Treatment consists of administration of standard antituberculosis drugs. Many workers suggest nine months of treatment for extrapulmonary TB including MSK-TB (78). The reader is referred to the chapters “Treatment of tuberculosis [Chapter?] For details.
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